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Sample records for hypothalamus-pituitary-adrenal axis activity

  1. Estrogen receptors ERα and ERβ participation in hypothalamus-pituitary-adrenal axis activation by hemorrhagic stress.

    PubMed

    Silva-Alves, Luana Maria; Barcelos Filho, Procópio Cleber Gama de; Franci, Celso Rodrigues

    2017-05-04

    The sympato-adrenal-system and hypothalamus-pituitary-adrenal (HPA) axis are anatomically and functionally connected with participation of several brain areas that express estrogen receptors (ERα and ERβ). We assessed the neuronal activity of these areas for FOS expression and the action of PPT (ERα agonist) or DPN (ERβ agonist) in HPA axis activity during hemorrhagic stress. Ovariectomized Wistar rats treated with vehicle (DMSO) or ER agonists were catheterized for blood collection. Animals received (control) or not (hemorrhagic) immediate reposition with the same volume of saline. Immunohistochemistry was performed for FOS, tyrosine hydroxylase (TH) and corticotropin releasing hormone (CRH) in the brain areas. In vehicle-treated animals, hemorrhage enhanced: plasma corticosterone (CORT), oxytocin (OT) and vasopressin (AVP) measured by radioimmunoassay; the expression of TH-FOS co-localized neurons in ventrolateral medulla (A1C1) and FOS expression in medial parvocellular paraventricular nucleus (mpPVN). In controls, PPT decreased: plasma CORT; FOS expression at locus coeruleus (LC); FOS and CRH-FOS at mpPVN, compared to vehicle. After hemorrhage, PPT decreased: plasma CORT; FOS expression at LC and mpPVN; TH-FOS at LC, solitary tract nucleus (NTS), A1C1; CRH-FOS at mpPVN, compared to vehicle. After hemorrhage DPN decreased: plasma CORT; FOS expression at LC and mpPVN; TH-FOS at LC, A1C1; CRH-FOS at mpPVN, compared to vehicle. PPT blocked the increase of OT secretion and increased AVP secretion, after hemorrhage. DPN reduced OT and increased AVP levels, regardless hemorrhage. In hemorrhagic stress, ERα and ERβ reduced the HPA axis activation and neuronal activity in brain areas involved in the HPA axis control.

  2. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

  3. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; Ramírez-Expósito, María Jesús

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

  4. Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis: a study in healthy volunteers.

    PubMed

    Jacobs, G E; Hulskotte, E G J; de Kam, M L; Zha, G; Jiang, J; Hu, P; Zhao, Q; van Pelt, J; Goekoop, J G; Zitman, F G; van Gerven, J M A

    2010-12-01

    The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

  5. Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment.

    PubMed

    Ronzoni, Giacomo; Antón, Maria; Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto

    2016-01-15

    The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

  6. The critical importance of the fetal hypothalamus-pituitary-adrenal axis

    PubMed Central

    Wood, Charles E.; Keller-Wood, Maureen

    2016-01-01

    The fetal hypothalamus-pituitary-adrenal (HPA) axis is at the center of mechanisms controlling fetal readiness for birth, survival after birth and, in several species, determination of the timing of birth. Stereotypical increases in fetal HPA axis activity at the end of gestation are critical for preparing the fetus for successful transition to postnatal life. The fundamental importance in fetal development of the endogenous activation of this endocrine axis at the end of gestation has led to the use of glucocorticoids for reducing neonatal morbidity in premature infants. However, the choice of dose and repetition of treatments has been controversial, raising the possibility that excess glucocorticoid might program an increased incidence of adult disease (e.g., coronary artery disease and diabetes). We make the argument that because of the critical importance of the fetal HPA axis and its interaction with the maternal HPA axis, dysregulation of cortisol plasma concentrations or inappropriate manipulation pharmacologically can have negative consequences at the beginning of extrauterine life and for decades thereafter. PMID:26918188

  7. Modeling the hypothalamus-pituitary-adrenal axis: A review and extension

    PubMed Central

    Rahmandad, Hazhir; Wittenborn, Andrea K.

    2015-01-01

    Multiple models of the hypothalamus-pituitary-adrenal (HPA) axis have been developed to characterize the oscillations seen in the hormone concentrations and to examine HPA axis dysfunction. We reviewed the existing models, then replicated and compared five of them by finding their correspondence to a dataset consisting of ACTH and cortisol concentrations of 17 healthy individuals. We found that existing models use different feedback mechanisms, vary in the level of details and complexities, and offer inconsistent conclusions. None of the models fit the validation dataset well. Therefore, we re-calibrated the best performing model using partial calibration and extended the model by adding individual fixed effects and an exogenous circadian function. Our estimated parameters reduced the mean absolute percent error significantly and offer a validated reference model that can be used in diverse applications. Our analysis suggests that the circadian and ultradian cycles are not created endogenously by the HPA axis feedbacks, which is consistent with the recent literature on the circadian clock and HPA axis. PMID:26277048

  8. The role of the hypothalamus-pituitary-adrenal/interrenal axis in mediating predator-avoidance trade-offs.

    PubMed

    Harris, Breanna N; Carr, James A

    2016-05-01

    Maintaining energy balance and reproducing are important for fitness, yet animals have evolved mechanisms by which the hypothalamus-pituitary-adrenal/interrenal (HPA/HPI) axis can shut these activities off. While HPA/HPI axis inhibition of feeding and reproduction may have evolved as a predator defense, to date there has been no review across taxa of the causal evidence for such a relationship. Here we review the literature on this topic by addressing evidence for three predictions: that exposure to predators decreases reproduction and feeding, that exposure to predators activates the HPA/HPI axis, and that predator-induced activation of the HPA/HPI axis inhibits foraging and reproduction. Weight of evidence indicates that exposure to predator cues inhibits several aspects of foraging and reproduction. While the evidence from fish and mammals supports the hypothesis that predator cues activate the HPA/HPI axis, the existing data in other vertebrate taxa are equivocal. A causal role for the HPA axis in predator-induced suppression of feeding and reproduction has not been demonstrated to date, although many studies report correlative relationships between HPA activity and reproduction and/or feeding. Manipulation of HPA/HPI axis signaling will be required in future studies to demonstrate direct mediation of predator-induced inhibition of feeding and reproduction. Understanding the circuitry linking sensory pathways to their control of the HPA/HPI axis also is needed. Finally, the role that fear and anxiety pathways play in the response of the HPA axis to predator cues is needed to better understand the role that predators have played in shaping anxiety related behaviors in all species, including humans.

  9. Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat.

    PubMed

    Steiner, Michel A; Sciarretta, Carla; Brisbare-Roch, Catherine; Strasser, Daniel S; Studer, Rolf; Jenck, Francois

    2013-04-01

    The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.

  10. Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

    PubMed

    Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui

    2014-11-05

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

  11. Childhood adversity and DNA methylation of genes involved in the hypothalamus-pituitary-adrenal axis and immune system: whole-genome and candidate-gene associations.

    PubMed

    Bick, Johanna; Naumova, Oksana; Hunter, Scott; Barbot, Baptiste; Lee, Maria; Luthar, Suniya S; Raefski, Adam; Grigorenko, Elena L

    2012-11-01

    In recent years, translational research involving humans and animals has uncovered biological and physiological pathways that explain associations between early adverse circumstances and long-term mental and physical health outcomes. In this article, we summarize the human and animal literature demonstrating that epigenetic alterations in key biological systems, the hypothalamus-pituitary-adrenal axis and immune system, may underlie such disparities. We review evidence suggesting that changes in DNA methylation profiles of the genome may be responsible for the alterations in hypothalamus-pituitary-adrenal axis and immune system trajectories. Using some preliminary data, we demonstrate how explorations of genome-wide and candidate-gene DNA methylation profiles may inform hypotheses and guide future research efforts in these areas. We conclude our article by discussing the many important future directions, merging perspectives from developmental psychology, molecular genetics, neuroendocrinology, and immunology, that are essential for furthering our understanding of how early adverse circumstances may shape developmental trajectories, particularly in the areas of stress reactivity and physical or mental health.

  12. Antidepressant and anxiolytic-like behavioral effects of erucamide, a bioactive fatty acid amide, involving the hypothalamus-pituitary-adrenal axis in mice.

    PubMed

    Li, Miao-Miao; Jiang, Zheng-Er; Song, Ling-Yun; Quan, Zhe-Shan; Yu, Hai-Ling

    2017-02-15

    (including open arms and closed arms) compared to the control group. Biochemical tests found that after 7days of drug treatment, compared with the control group, ACTH and CORT serum levels in mice were significantly decreased, although T-AOC levels did not significantly change. In conclusion, Era (dose range of 5-20mg/kg) administered orally may alleviate depression- and anxiety-like behaviors in mice, and the antidepressant and anti-anxiety effects of Era may be related to the regulation of the hypothalamus-pituitary-adrenal axis (HPA).

  13. Changes of adrenomedullin and its receptor components mRNAs expression in the brain stem and hypothalamus-pituitary-adrenal axis of stress-induced hypertensive rats.

    PubMed

    Li, Xia; Li, Liang; Shen, Lin-Lin; Qian, Yuan; Cao, Yin-Xiang; Zhu, Da-Nian

    2004-12-25

    In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the changes in mRNAs levels of preproadrenomedullin (ppADM) gene encoding adrenomedullin (ADM) and the essential receptor components of ADM, calcitonin receptor-like receptor (CRLR), and the receptor activity modifying protein 2 and 3 (RAMP2 and RAMP3) in the medulla oblongata, hypothalamus, midbrain, pituitary gland and adrenal gland of the stress-induced hypertensive rats. It was shown that chronic foot-shock and noise stress for 15 consecutive days induced a significant increase in systolic blood pressure (SBP) and unique changes in ppADM and its receptor components mRNAs in all areas studied. As compared with the control group, the level of ppADM mRNA, normalized against a glyceraldehydes-3-phosphate dehydrogenase (GAPDH) control, was up-regulated in the hypothalamus-pituitary-adrenal (HPA) axis, but down-regulated in the medulla oblongata and midbrain (P<0.01 and P<0.05, respectively). The relative amount of CRLR mRNA was higher in the hypothalamus than that in other areas. The level of CRLR mRNA expression was significantly increased in the medulla oblongata of the stress group (P<0.01), but decreased in the midbrain (P<0.01) as well as hypothalamus(P<0.05), as compared with that of the control group. Chronic stress for 15 consecutive days produced an increase in the level of RAMP2 mRNA expression in the medulla oblongata (P<0.01) and a decrease in the adrenal gland (P<0.01), as compared with the control. No significant stress-related changes in RAMP2 mRNA were observed in the midbrain, hypothalamus and pituitary gland. The amount of RAMP3 mRNA was relatively higher in the midbrain and hypothalamus than that in the medulla oblongata, adrenal gland and adrenal gland. Stress-induced hypertensive rats exhibited an increased RAMP3 mRNA expression in the hypothalamus and pituitary gland (P<0.01 and P<0.05, respectively) and a decrease in the adrenal gland and midbrain (P<0

  14. Effects of prenatal restraint stress on the hypothalamus-pituitary-adrenal axis and related behavioural and neurobiological alterations.

    PubMed

    Maccari, Stefania; Morley-Fletcher, Sara

    2007-08-01

    Chronic hyper-activation of the hypothalamus-pituitary axis is associated with the suppression of reproductive, growth, thyroid and immune functions that may lead to various pathological states. Although many individuals experiencing stressful events do not develop pathologies, stress seems to be a provoking factor in those individuals with particular vulnerability, determined by genetic factors or earlier experience. Exposure of the developing brain to severe and/or prolonged stress may result in hyper-activity of the stress system, defective glucocorticoids-negative feedback, altered cognition, novelty seeking, increased vulnerability to addictive behaviour, and mood-related disorders. Therefore, stress-related events that occur in the perinatal period can permanently change brain and behaviour of the developing individual. Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioural alterations including impaired feedback mechanisms of the HPA axis, disruption of circadian rhythms and altered neuroplasticity. Chronic treatments with antidepressants at adulthood have proven high predictive validity of the PRS rat as animal model of depression and, reinforce the idea of the usefulness of the PRS rat as an interesting animal model for the design and testing of new pharmacologic strategies in the treatment of stress-related disorders.

  15. Emotional exhaustion and overcommitment to work are differentially associated with hypothalamus-pituitary-adrenal (HPA) axis responses to a low-dose ACTH1-24 (Synacthen) and dexamethasone-CRH test in healthy school teachers.

    PubMed

    Wolfram, Maren; Bellingrath, Silja; Feuerhahn, Nicolas; Kudielka, Brigitte M

    2013-01-01

    Evidence for a detrimental impact of chronic work stress on health has accumulated in epidemiological research. Recent studies indicate altered hypothalamus-pituitary-adrenal (HPA) axis regulation as a possible biological pathway underlying the link between stress and disease. However, the direction of dysregulation remains unclear, with reported HPA hyper- or hyporeactivity. To disentangle potential effects on different functional levels in the HPA axis, we examined responses using two pharmacological stimulation tests in 53 healthy teachers (31 females, 22 males; mean age: 49.3 years; age range: 30-64 years): a low-dose adrenocorticotrophic hormone (ACTH(1-24), Synacthen) test was used to assess adrenal cortex sensitivity and the combined dexamethasone-corticotropin releasing hormone (DEX-CRH) test to examine pituitary and adrenal cortex reactivity. Blood and saliva samples were collected at - 1,+15,+30,+45,+60,+90,+120 min. Emotional exhaustion (EE), the core dimension of burnout, was measured with the Maslach Burnout Inventory. Overcommitment (OC) was assessed according to Siegrist's effort-reward-imbalance model. We found a significant association between EE and higher plasma cortisol profiles after Synacthen (p = 0.045). By contrast, OC was significantly associated with attenuated ACTH (p = 0.045), plasma cortisol (p = 0.005), and salivary cortisol (p = 0.023) concentrations following DEX-CRH. Results support the notion of altered HPA axis regulation in chronically work-stressed teachers, with differential patterns of hyper- and hyporeactivity depending on individual stress condition and the tested functional level of the HPA axis.

  16. Effort-reward-imbalance and overcommitment are associated with hypothalamus-pituitary-adrenal (HPA) axis responses to acute psychosocial stress in healthy working schoolteachers.

    PubMed

    Bellingrath, Silja; Kudielka, Brigitte M

    2008-11-01

    In this study, we examined HPA axis responses to acute psychosocial stress in relation to effort-reward-imbalance (ERI) and overcommitment (OC) to test whether chronic stress at work is accompanied by altered HPA axis stress responses in teachers. According to Siegrist's work stress model, ERI reflects stress due to a lack of reciprocity between personal costs and gains at work, whereas OC is conceptualized as a personality trait mainly characterized by the inability to withdraw from work obligations. Fifty-three medication-free, non-smoking, healthy teachers (33 women, 20 men, 29-63 years, mean age 49.9+/-8.58 years) were confronted with the Trier Social Stress Test (TSST), a widely used standardized stress protocol to induce acute psychosocial stress in the laboratory. ACTH (five samples), total plasma (six samples) and free salivary cortisol (eight samples) were repeatedly measured before and after challenge. In the total group, ERI and OC were only marginally associated with HPA axis responses to acute stress. However, in the subgroup of responders (N=30) high levels of OC were significantly associated with lower ACTH (p=0.03) as well as plasma (p=0.02) and salivary cortisol (p<0.001) responses and results remained significant controlling for depressive symptoms. When additionally controlling for acute perceived stressfulness of the TSST, significant associations between OC and HPA axis responses emerged in responders as well as the total study sample. In respect to ERI, higher stress levels were solely related to significantly stronger plasma cortisol increases after TSST exposure, but this effect became non-significant controlling for depressive symptomatology. In sum, our findings support the notion of HPA axis hyporeactivity in highly overcommitted schoolteachers.

  17. Effects of orchidectomy and testosterone replacement on mouse pyrrolidone carboxypeptidase activity in the HPA axis.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2004-03-01

    Pyrrolidone carboxypeptidase, also known as pyroglutamyl aminopeptidase, removes pyroglutamyl terminal residues from biologically active peptides such as thyrotropin-releasing hormone. The aim of the present work was to study the influence of orchidectomy and testosterone replacement on soluble (pyrrolidone carboxypeptidase type I) and membrane-bound (pyrrolidone carboxypeptidase type II) activities in the hypothalamus-pituitary-adrenal axis. Forty male mice (Balb/C) were distributed into five groups: sham-operated controls, orchidectomized, and orchidectomized treated with increasing doses of testosterone in each group (3, 6 and 12 mg/kg). In the hypothalamus, orchidectomy increased pyrrolidone carboxypeptidase type I, whereas the highest dose of testosterone returned this activity to control levels. In the pituitary, neither pyrrolidone carboxypeptidase type I nor type II activities changed after orchidectomy, although both activities increased after administration of testosterone in both cases. On the other hand, orchidectomy increased pyrrolidone carboxypeptidase type I and type II activities in adrenal glands, while testosterone replacement returned it to control levels. These results suggest that testosterone differentially modulates pyrrolidone carboxypeptidase type I and type II activities, and therefore also their endogenous substrate regulation. Thus, the influence of sex hormones in the physiology of the HPA axis through the modulation of the Pyrrolidone carboxypeptidase type I and type II activities is of great importance on stress and neuropathology associated with HPA dysfunction

  18. Effects of orchidectomy and testosterone replacement on mouse enkephalin-degrading aminopeptidase activity in the HPA axis.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2003-12-01

    Opiates are involved in the regulation of several functions in the hypothalamus-pituitary-adrenal (HPA) axis under physiological conditions. The aim of the present work is to study the influence of orchidectomy and testosterone (T) replacement on soluble (S) and membrane bound (MB) enkephalin-degrading aminopeptidase (EDA) activities in the HPA axis. Forty male mice (Balb/C) were distributed in five groups: sham-operated control (C), orchidectomized (OR-C), and orchidectomized treated with increasing doses of T (3, 6 or 12 mg/kg). In hypothalamus, orchidectomy did not modify either S or MB EDA, although T replacement increased S but not MB EDA. In pituitary, neither S nor MB EDA activities changed with orchidectomy, although both activities changed after T replacement. On the other hand, in adrenal glands, orchidectomy increased S and MB EDA activities, whereas T replacement returned both activities to control levels. These results suggest a direct effect of T in S and MB EDA activities and therefore, an influence on their endogenous substrates regulation.

  19. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats

    PubMed Central

    Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

    2016-01-01

    Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that

  20. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats.

    PubMed

    Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

    2016-01-01

    Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that

  1. Activation of PPAR-γ reduces HPA axis activity in diabetic rats by up-regulating PI3K expression.

    PubMed

    Torres, Rafael Carvalho; Magalhães, Nathalia Santos; E Silva, Patrícia M R; Martins, Marco A; Carvalho, Vinicius F

    2016-10-01

    Increased hypothalamus-pituitary-adrenal axis (HPA) activity in diabetes is strongly associated with several morbidities noted in patients with the disease. We previously demonstrated that hyperactivity of HPA axis under diabetic conditions is associated with up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal and down-regulation of glucocorticoid receptors (GR and MR) in pituitary. This study investigates the role of peroxisome proliferator-activated receptor (PPAR)-γ in HPA axis hyperactivity in diabetic rats. Diabetes was induced by intravenous injection of alloxan into fasted rats. The PPAR-γ agonist rosiglitazone and/or PI3K inhibitor wortmannin were administered daily for 18 consecutive days, starting 3days after diabetes induction. Plasma ACTH and corticosterone were evaluated by radioimmunoassay, while intensities of MC2R, proopiomelanocortin (POMC), GR, MR, PI3K p110α and PPAR-γ were assessed using immunohistochemistry. Rosiglitazone treatment inhibited adrenal hypertrophy and hypercorticoidism observed in diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced increase in the MC2R expression in adrenal cortex. We noted that rosiglitazone reduced the number of corticotroph cells and inhibited both anterior pituitary POMC expression and plasma ACTH levels. Furthermore, rosiglitazone treatment was unable to restore the reduced expression of GR and MR in the anterior pituitary of diabetic rats. Rosiglitazone increased the number of PPAR-γ(+) cells and expression of PI3K p110α in both anterior pituitary and adrenal cortex of diabetic rats. In addition, wortmannin blocked the ability of rosiglitazone to restore corticotroph cell numbers, adrenal hypertrophy and plasma corticosterone levels in diabetic rats. In conclusion, our findings revealed that rosiglitazone down-regulates HPA axis hyperactivity in diabetic rats via a mechanism dependent on PI3K activation in pituitary and adrenal glands.

  2. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    PubMed

    Zhu, Li-Juan; Liu, Meng-Ying; Li, Huan; Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang

    2014-01-01

    Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  3. Time-of-day-dependent adaptation of the HPA axis to predictable social defeat stress.

    PubMed

    Koch, C E; Bartlang, M S; Kiehn, J T; Lucke, L; Naujokat, N; Helfrich-Förster, C; Reber, S O; Oster, H

    2016-12-01

    In modern societies, the risk of developing a whole array of affective and somatic disorders is associated with the prevalence of frequent psychosocial stress. Therefore, a better understanding of adaptive stress responses and their underlying molecular mechanisms is of high clinical interest. In response to an acute stressor, each organism can either show passive freezing or active fight-or-flight behaviour, with activation of sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis providing the necessary energy for the latter by releasing catecholamines and glucocorticoids (GC). Recent data suggest that stress responses are also regulated by the endogenous circadian clock. In consequence, the timing of stress may critically affect adaptive responses to and/or pathological effects of repetitive stressor exposure. In this article, we characterize the impact of predictable social defeat stress during daytime versus nighttime on bodyweight development and HPA axis activity in mice. While 19 days of social daytime stress led to a transient reduction in bodyweight without altering HPA axis activity at the predicted time of stressor exposure, more detrimental effects were seen in anticipation of nighttime stress. Repeated nighttime stressor exposure led to alterations in food metabolization and reduced HPA axis activity with lower circulating adrenocorticotropic hormone (ACTH) and GC concentrations at the time of predicted stressor exposure. Our data reveal a circadian gating of stress adaptation to predictable social defeat stress at the level of the HPA axis with impact on metabolic homeostasis underpinning the importance of timing for the body's adaptability to repetitive stress.

  4. Role of Paraventricular Nucleus Glutamate Signaling in Regulation of HPA Axis Stress Responses.

    PubMed

    Evanson, Nathan K; Herman, James P

    The hypothalamus-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response, activation of which leads to the production of glucocorticoid hormones. Glucocorticoids are steroid hormones that are secreted from the adrenal cortex, and have a variety of effects on the body, including modulation of the immune system, suppression of reproductive hormones maintenance of blood glucose levels, and maintenance of blood pressure. Glutamate plays an important role in coordination of HPA axis output. There is strong evidence that glutamate drives HPA axis stress responses through excitatory signaling via ionotropic glutamate receptor signaling. However, glutamate signaling via kainate receptors and group I metabotropic receptors inhibit HPA drive, probably via presynaptic inhibitory mechanisms. Notably, kainate receptors are also localized in the median eminence, and appear to play an excitatory role in control of CRH release at the nerve terminals. Finally, glutamate innervation of the PVN undergoes neuroplastic changes under conditions of chronic stress, and may be involved in sensitization of HPA axis responses. Altogether, the data suggest that glutamate plays a complex role in excitation of CRH neurons, acting at multiple levels to both drive HPA axis responses and limit over-activation.

  5. Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress.

    PubMed

    Evanson, Nathan K; Herman, James P

    2015-10-15

    Glutamate is an important neurotransmitter in the regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in the regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling.

  6. Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development.

    PubMed

    Rao, Raghavendra

    2015-08-28

    Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA) axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.

  7. Fetal and Neonatal HPA Axis.

    PubMed

    Wood, Charles E; Walker, Claire-Dominique

    2015-12-15

    Stress is an integral part of life. Activation of the hypothalamus-pituitary-adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied-sheep and rodents-because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress-related or stress-induced pathologies and forge a better future for upcoming generations.

  8. The Environmental Pollutant Tributyltin Chloride Disrupts the Hypothalamic-Pituitary-Adrenal Axis at Different Levels in Female Rats.

    PubMed

    Merlo, Eduardo; Podratz, Priscila L; Sena, Gabriela C; de Araújo, Julia F P; Lima, Leandro C F; Alves, Izabela S S; Gama-de-Souza, Letícia N; Pelição, Renan; Rodrigues, Lívia C M; Brandão, Poliane A A; Carneiro, Maria T W D; Pires, Rita G W; Martins-Silva, Cristina; Alarcon, Tamara A; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B

    2016-08-01

    Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.

  9. The immune-pineal axis: stress as a modulator of pineal gland function.

    PubMed

    Couto-Moraes, Renato; Palermo-Neto, João; Markus, Regina Pekelmann

    2009-02-01

    The temporal organization of mammals presents a daily adjustment to the environmental light/dark cycle. The environmental light detected by the retina adjusts the central clock in the suprachiasmatic nuclei, which innervate the pineal gland through a polysynaptic pathway. During the night, this gland produces and releases the nocturnal hormone melatonin, which circulates throughout the whole body and adjusts several bodily functions according to the existence and duration of darkness. We have previously shown that during the time frame of an inflammatory response, pro-inflammatory cytokines, such as tumor necrosis factor-alpha, inhibit while anti-inflammatory mediators, such as glucocorticoids, enhance the synthesis of melatonin, interfering in the daily adjustment of the light/dark cycle. Therefore, injury disconnects the organism from environmental cycling, while recovery restores the light/dark information to the whole organism. Here, we extend these observations by evaluating the effect of a mild restraint stress, which did not induce macroscopic gastric lesions. After 2 h of restraint, there was an increase in circulating corticosterone, indicating activation of the hypothalamus-pituitary-adrenal (HPA) axis. In parallel, an increase in melatonin production was observed. Taking into account the data obtained with models of inflammation and stress, we reinforce the hypothesis that the activity of the pineal gland is modulated by the state of the immune system and the HPA axis, implicating the darkness hormone melatonin as a modulator of defense responses.

  10. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling

    PubMed Central

    Shimizu, Noriaki; Maruyama, Takako; Yoshikawa, Noritada; Matsumiya, Ryo; Ma, Yanxia; Ito, Naoki; Tasaka, Yuki; Kuribara-Souta, Akiko; Miyata, Keishi; Oike, Yuichi; Berger, Stefan; Schütz, Günther; Takeda, Shin’ichi; Tanaka, Hirotoshi

    2015-01-01

    Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity. PMID:25827749

  11. Prenatal Stress Induces Long-Term Effects in Cell Turnover in the Hippocampus-Hypothalamus-Pituitary Axis in Adult Male Rats

    PubMed Central

    Baquedano, Eva; García-Cáceres, Cristina; Diz-Chaves, Yolanda; Lagunas, Natalia; Calmarza-Font, Isabel; Azcoitia, Iñigo; Garcia-Segura, Luis M.; Argente, Jesús; Chowen, Julie A.; Frago, Laura M.

    2011-01-01

    Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations. PMID:22096592

  12. Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis.

    PubMed

    Hall, Jessica M F; Cruser, Desanges; Podawiltz, Alan; Mummert, Diana I; Jones, Harlan; Mummert, Mark E

    2012-01-01

    Psychological stress, an evolutionary adaptation to the fight-or-flight response, triggers a number of physiological responses that can be deleterious under some circumstances. Stress signals activate the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Elements derived from those systems (e.g., cortisol, catecholamines and neuropeptides) can impact the immune system and possible disease states. Skin provides a first line of defense against many environmental insults. A number of investigations have indicated that the skin is especially sensitive to psychological stress, and experimental evidence shows that the cutaneous innate and adaptive immune systems are affected by stressors. For example, psychological stress has been shown to reduce recovery time of the stratum corneum barrier after its removal (innate immunity) and alters antigen presentation by epidermal Langerhans cells (adaptive immunity). Moreover, psychological stress may trigger or exacerbate immune mediated dermatological disorders. Understanding how the activity of the psyche-nervous -immune system axis impinges on skin diseases may facilitate coordinated treatment strategies between dermatologists and psychiatrists. Herein, we will review the roles of the HPA axis and the sympathetic nervous system on the cutaneous immune response. We will selectively highlight how the interplay between psychological stress and the immune system affects atopic dermatitis and psoriasis.

  13. Influence of hormonal status on enkephalin-degrading aminopeptidase activity in the HPA axis of female mice.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2005-04-01

    Opioids are involved in the regulation of hypothalamus-pituitary-adrenal (HPA) axis activity under physiological conditions. In the present work, we analyzed the influence of ovariectomy and estradiol (E), progesterone (P) or estradiol plus progesterone (E+P) replacement on soluble (S) and membrane-bound (MB) enkephalin-degrading aminopeptidase activity (EDA) in the HPA axis. Female mice (Balb/C) were distributed in 15 groups of 10 animals each: sham-operated controls (C), ovariectomized controls (OV-C), and ovariectomized mice treated with increasing doses of E (10, 20 or 40 mg/kg), P (100, 200 or 400 mg/kg) or E+P (10+100, 20+200 or 40+400 mg/kg). In hypothalamus, ovariectomy increased both S and MB EDA activities, whereas E replacement returned them to control levels, although MB EDA activity increased again after the replacement with 40 mg/kg E. P replacement increased S EDA activity, but returned MB EDA activity to control levels. The replacement of E+P returned both S and MB EDA activities to control levels, although MB EDA activity was lower than control values after the replacement with 10+100 mg/kg E+P. In pituitary, neither ovariectomy nor the replacement of E or E+P changed S EDA, although the highest concentrations of P increased S EDA activity. However, ovariectomy increased MB EDA and E replacement returned the activity to control or below control levels, depending on the concentration used. However, P administration returned the activity to control or below control levels depending on the concentration used, although 200 mg/kg P had no effects on MB EDA. E+P replacement returned pituitary MB EDA activity to control levels. In adrenal glands, ovariectomy did change either S or MB EDA. However, E, P or E+P replacement decreased S EDA activity in different degrees, depending of the dose administrated. No changes were detected in MB EDA after hormone replacement. These results indicate that female steroid hormones influence EDA activity at different

  14. Metabolic response in liver and Brockmann bodies of rainbow trout to inhibition of lipolysis; possible involvement of the hypothalamus-pituitary-interrenal (HPI) axis.

    PubMed

    Librán-Pérez, Marta; Velasco, Cristina; Otero-Rodiño, Cristina; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

    2015-05-01

    We previously demonstrated in rainbow trout that the decrease in circulating levels of fatty acid (FA) induced by treating fish with SDZ WAG 994 (SDZ) induced a counter-regulatory response in which the activation of the hypothalamus-pituitary-interrenal (HPI, equivalent to mammalian hypothalamus-pituitary-adrenal) axis was likely involved. This activation, probably not related to the control of food intake through FA sensor systems but to the modulation of lipolysis in peripheral tissues, liver and Brockmann bodies (BB, the main site of pancreatic endocrine cells in fish), would target the restoration of FA levels in plasma. To assess this hypothesis, we lowered circulating FA levels by treating fish with SDZ alone, or SDZ in the presence of metyrapone (an inhibitor of cortisol synthesis). In liver, the changes observed were not compatible with a direct FA-sensing response but with a stress response, which allows us to suggest that the detection of a FA decrease in the hypothalamus elicits a counter-regulatory response in liver, resulting in an activation of lipolysis to restore FA levels in plasma. The activation of these metabolic changes in liver could be attributable to the activation of the HPI axis and/or to the action of sympathetic pathways. In contrast, in BB, changes in circulating FA levels induce changes in several parameters compatible with the function of FA-sensing systems informing about the decrease in circulating FA levels.

  15. Impaired release of corticosterone from adrenals contributes to impairment of circadian rhythms of activity in hyperammonemic rats.

    PubMed

    Llansola, Marta; Ahabrach, Hanan; Errami, Mohammed; Cabrera-Pastor, Andrea; Addaoudi, Kaoutar; Felipo, Vicente

    2013-08-15

    Patients with liver cirrhosis may present impaired sleep-wake and circadian rhythms, relative adrenal insufficiency and altered hypothalamus-pituitary-adrenal gland (HPA) axis. The underlying mechanisms remain unclear. Circadian rhythms are modulated by corticosteroids which secretion is regulated by HPA axis. Hyperammonemia alters circadian rhythms of activity and corticosterone in rats. The aims were: (1) assessing whether corticosterone alterations are responsible for altered circadian rhythm in hyperammonemia: (2) to shed light on the mechanism by which corticosterone circadian rhythm is altered in hyperammonemia. The effects of daily corticosterone injection at ZT10 on circadian rhythms of activity, plasma corticosterone, adreno-corticotropic hormone (ACTH) and hypothalamic corticotropic releasing hormone (CRH) were assessed in control and hyperammonemic rats. ACTH-induced corticosterone release was analyzed in cultured adrenal cells. Corticosterone injection restores the corticosterone peak in hyperammonemic rats and their activity and circadian rhythm. Plasma ACTH and CRH in hypothalamus are increased in hyperammonemic rats. Corticosterone injection normalizes ACTH. Chronic hyperammonemia impairs adrenal function, reduces corticosterone content and ACTH-induced corticosterone release in adrenals, leading to reduced feedback modulation of HPA axis by corticosterone which contributes to impair circadian rhythms of activity. Impaired circadian rhythms and motor activity may be corrected in hyperammonemia and hepatic encephalopathy by corticosterone treatment.

  16. CRH stimulates POMC activity and corticosterone production in dermal fibroblasts.

    PubMed

    Slominski, Andrzej; Zbytek, Blazej; Semak, Igor; Sweatman, Trevor; Wortsman, Jacobo

    2005-05-01

    It has been previously documented that human skin cells including epidermal keratinocytes and dermal fibroblasts produce and process proopiomelanocortin (POMC), corticotropin releasing hormone (CRH), and express functional CRH receptors type-1 (CRH-R1). The skin also has corticosteroidogenic activity, suggesting a functional connection between these elements. In the current study, we found that human dermal fibroblasts (but not normal epidermal keratinocytes) respond to CRH with stimulation of cAMP, with POMC gene and protein expression, and ACTH production and release. Furthermore, CRH and ACTH stimulate production of corticosterone in fibroblasts, with ACTH being more potent. Although cortisol-immunoreactivity accumulation/production in fibroblasts has been detected by ELISA, it appears to be constitutive (not affected by CRH or ACTH). These effects are absent in keratinocytes. Therefore, we propose that fibroblasts but not keratinocytes display a functional CRH-POMC-corticosteroid axis organized similarly to the hypothalamus-pituitary-adrenal (HPA) axis. However, it diverges from the HPA organization in its distal step, where CRH and ACTH stimulate production of corticosterone, instead of cortisol.

  17. The appetite suppressant d-fenfluramine reduces water intake, but not food intake, in activity-based anorexia.

    PubMed

    Hillebrand, J J G; Heinsbroek, A C M; Kas, M J H; Adan, R A H

    2006-02-01

    Biochemical, genetic and imaging studies support the involvement of the serotonin (5-HT) system in anorexia nervosa. Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa, and combines scheduled feeding with voluntary running wheel activity (RWA). We investigated the effect of d-fenfluramine (d-FEN) treatment on development and propagation of ABA. d-FEN is an appetite suppressant and acts on 5-HT(2C) receptors that are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Since stimulation activation of the melanocortin system stimulates ABA, we hypothesized that d-FEN treatment enhances the development and propagation of ABA. Rats were exposed to the ABA model and chronically infused with d-FEN. Unexpectedly, d-FEN-treated ABA rats did not reduce food intake or increase wheel running as compared with vehicle-treated ABA rats. Furthermore d-FEN treatment did not affect body weight loss, hypothalamus-pituitary-adrenal axis activation, or starvation-induced hypothermia in ABA rats. POMC mRNA levels in d-FEN-treated rats were not different from vehicle-treated rats after one week of exposure to the ABA paradigm. However, d-FEN-treated ABA rats showed hypodypsia and increased plasma osmolality and arginine-vasopressin expression levels in the hypothalamus. We conclude that d-FEN treatment does not enhance ABA under the experimental conditions of this study, but strongly reduces water intake in ABA rats.

  18. Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats.

    PubMed

    Mairesse, Jérôme; Gatta, Eleonora; Reynaert, Marie-Line; Marrocco, Jordan; Morley-Fletcher, Sara; Soichot, Marion; Deruyter, Lucie; Camp, Gilles Van; Bouwalerh, Hammou; Fagioli, Francesca; Pittaluga, Anna; Allorge, Delphine; Nicoletti, Ferdinando; Maccari, Stefania

    2015-12-01

    Oxytocin receptors are known to modulate synaptic transmission and network activity in the hippocampus, but their precise function has been only partially elucidated. Here, we have found that activation of presynaptic oxytocin receptor with the potent agonist, carbetocin, enhanced depolarization-evoked glutamate release in the ventral hippocampus with no effect on GABA release. This evidence paved the way for examining the effect of carbetocin treatment in "prenatally restraint stressed" (PRS) rats, i.e., the offspring of dams exposed to repeated episodes of restraint stress during pregnancy. Adult PRS rats exhibit an anxious/depressive-like phenotype associated with an abnormal glucocorticoid feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and, remarkably, with a reduced depolarization-evoked glutamate release in the ventral hippocampus. Chronic systemic treatment with carbetocin (1mg/kg, i.p., once a day for 2-3 weeks) in PRS rats corrected the defect in glutamate release, anxiety- and depressive-like behavior, and abnormalities in social behavior, in the HPA response to stress, and in the expression of stress-related genes in the hippocampus and amygdala. Of note, carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala. These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.

  19. The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback.

    PubMed

    Zschucke, Elisabeth; Renneberg, Babette; Dimeo, Fernando; Wüstenberg, Torsten; Ströhle, Andreas

    2015-01-01

    According to the cross-stressor adaptation hypothesis, physically trained individuals show lower physiological and psychological responses to stressors other than exercise, e.g. psychosocial stress. Reduced stress reactivity may constitute a mechanism of action for the beneficial effects of exercise in maintaining mental health. With regard to neural and psychoneuroendocrine stress responses, the acute stress-buffering effects of exercise have not been investigated yet. A sample of highly trained (HT) and sedentary (SED) young men was randomized to either exercise on a treadmill at moderate intensity (60-70% VO2max; AER) for 30 min, or to perform 30 min of "placebo" exercise (PLAC). 90 min later, an fMRI experiment was conducted using an adapted version of the Montreal Imaging Stress Task (MIST). The subjective and psychoneuroendocrine (cortisol and α-amylase) changes induced by the exercise intervention and the MIST were assessed, as well as neural activations during the MIST. Finally, associations between the different stress responses were analysed. Participants of the AER group showed a significantly reduced cortisol response to the MIST, which was inversely related to the previous exercise-induced α-amylase and cortisol fluctuations. With regard to the sustained BOLD signal, we found higher bilateral hippocampus (Hipp) activity and lower prefrontal cortex (PFC) activity in the AER group. Participants with a higher aerobic fitness showed lower cortisol responses to the MIST. As the Hipp and PFC are brain structures prominently involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, these findings indicate that the acute stress-buffering effect of exercise relies on negative feedback mechanisms. Positive affective changes after exercise appear as important moderators largely accounting for the effects related to physical fitness.

  20. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes.

    PubMed

    Clark, Allison; Mach, Núria

    2016-01-01

    Fatigue, mood disturbances, under performance and gastrointestinal distress are common among athletes during training and competition. The psychosocial and physical demands during intense exercise can initiate a stress response activating the sympathetic-adrenomedullary and hypothalamus-pituitary-adrenal (HPA) axes, resulting in the release of stress and catabolic hormones, inflammatory cytokines and microbial molecules. The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including metabolism, endocrine, neuronal and immune function. The gut microbiome and its influence on host behavior, intestinal barrier and immune function are believed to be a critical aspect of the brain-gut axis. Recent evidence in murine models shows that there is a high correlation between physical and emotional stress during exercise and changes in gastrointestinal microbiota composition. For instance, induced exercise-stress decreased cecal levels of Turicibacter spp and increased Ruminococcus gnavus, which have well defined roles in intestinal mucus degradation and immune function. Diet is known to dramatically modulate the composition of the gut microbiota. Due to the considerable complexity of stress responses in elite athletes (from leaky gut to increased catabolism and depression), defining standard diet regimes is difficult. However, some preliminary experimental data obtained from studies using probiotics and prebiotics studies show some interesting results, indicating that the microbiota acts like an endocrine organ (e.g. secreting serotonin, dopamine or other neurotransmitters) and may control the HPA axis in athletes. What is troubling is that dietary recommendations for elite athletes are primarily based on a low consumption of plant polysaccharides, which is associated with reduced microbiota diversity and functionality (e.g. less synthesis of byproducts such as short chain fatty acids and neurotransmitters). As more

  1. The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis.

    PubMed

    Navarria, Andrea; Tamburella, Alessandra; Iannotti, Fabio A; Micale, Vincenzo; Camillieri, Giovanni; Gozzo, Lucia; Verde, Roberta; Imperatore, Roberta; Leggio, Gian Marco; Drago, Filippo; Di Marzo, Vincenzo

    2014-09-01

    In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-Arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal and stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rat behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.

  2. Consumption of green tea epigallocatechin-3-gallate enhances systemic immune response, antioxidative capacity and HPA axis functions in aged male swiss albino mice.

    PubMed

    Sharma, Rohit; Sharma, Anamika; Kumari, Amita; Kulurkar, Pankaj Markand; Raj, Rajneesh; Gulati, Ashu; Padwad, Yogendra S

    2017-03-24

    The present investigation assessed the potential of green tea phytochemical epigallocatechin-3-gallate (EGCG) in alleviating age-associated aberrations in immunity, hypothalamus-pituitary-adrenal (HPA) axis and redox homeostasis using 16 months old male Swiss albino mice. Four groups of animals (n = 6 per group) were supplemented with either aqueous EGCG at 25, 50 and 100 mg/kg/animal or vehicle control for 6 weeks. A concurrent analysis of CD4(+) and CD8(+) lymphocytes in splenocytes, differential leucocyte population, T cell differentiation markers in peripheral blood mononuclear cells (PBMCs), neutrophil functions, immunoglobulins profile in intestine, circulatory HPA axis hormonal levels as well as inflammatory and oxidative stress in the liver was performed. We observed a remarkable increase in plasma dehydroepiandrosterone (DHEA) levels of 100 mg EGCG fed animals while eosinophils and monocytes counts in blood increased. EGCG consumption increased the fraction of CD3(+)CD8(+) cells in splenocytes and CD28 expression on PBMCs. The immunoglobulins profile revealed decreased production of secretory IgA, IgE and IgG1/IgG2a ratio. Liver extracts showed increase in superoxide dismutase activity and total antioxidant capacity while lipid peroxidation along with inflammatory markers (IL-6 and TNF-α) decreased. Our results collectively show that EGCG consumption during aging strengthens systemic immunity by enhancing cellular immune response and simultaneously attenuating antibody response aided by an increase in adrenal DHEA production. Thus, consumption of green tea may be beneficial in alleviating some of the deleterious aspects of aging and immunosenescence in elderly.

  3. Ozone-Induced Pulmonary Injury and Vascular Contractility are Differentially Impacted by Coconut, Fish, and Olive Oil-Rich Diets

    EPA Science Inventory

    Pulmonary and systemic effects of ozone (O3) are mediated by hypothalamus pituitary adrenal (HPA)-axis activation. Fish oil (FO) and olive oil (OO) dietary supplementation have several cardioprotective benefits, but it is not established if these supplements can protect against t...

  4. A Laboratory Exercise to Illustrate Increased Salivary Cortisol in Response to Three Stressful Conditions Using Competitive ELISA

    ERIC Educational Resources Information Center

    Haussmann, Mark F.; Vleck, Carol M; Farrar, Eugenia S.

    2007-01-01

    Perceived stress activates the hypothalamus-pituitary-adrenal axis, resulting in the release of glucocorticoids into the systemic circulation. Glucocorticoids cause the elevation of blood glucose, providing the necessary energy for the organism to cope with stress. Here, we outline a laboratory exercise that uses a competitive ELISA kit to…

  5. Systemic Metabolic Impairment and Lung Injury Following Acrolein Inhalation

    EPA Science Inventory

    A single ozone exposure causes pulmonary injury and systemic metabolic alterations through neuronal and hypothalamus pituitary adrenal axis activation. Metabolically impaired Goto Kakizaki (GK) rats with non-obese type-2 diabetes are more sensitive to ozone induced changes than h...

  6. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress.

    PubMed

    Xia, Nan; Li, Jie; Wang, Hongwei; Wang, Jian; Wang, Yangtian

    2016-01-01

    The aim of the present study was to investigate the effects of Schisandra chinensis (S. chinensis) and Rhodiola rosea (R. rosea) on rats subjected to 5 h of stress, induced by water-floating followed by treadmill exercise. Hypothalamus-pituitary-adrenal (HPA) activity and c-Fos and Fos-related antigen 2 (Fra-2) mRNA expression levels in the hypothalamus of the rats were evaluated. Rats were distributed into four groups: S. chinensis (n=12), R. rosea (n=10), stress control (n=10) and quiet control (n=8). Following a training period of 6 consecutive days, the S. chinensis, R. rosea and stress control groups underwent a 3-h water-floating session in the presence of feline predators immediately followed by 2 h treadmill running to induce psychological and physical stress. Following compound stress induction, the serum levels of corticosterone (CORT), adrenocorticotropic hormone and interleukin-1β and the mRNA expression levels of hypothalamic corticotropin-releasing hormone (CRH), neuropeptide-Y, c-Fos and Fra-2 were evaluated using enzyme-linked immunosorbent assay, radioimmunoassay and quantitative polymerase chain reaction, respectively. The results indicated that S. chinensis and R. rosea markedly decreased the stress-induced elevation of CRH and peripheral CORT levels. The mRNA expression levels of c-Fos and Fra-2 in the hypothalamus were significantly increased after 5 h compound stress, and reduced levels of c-Fos expression were detected in rats treated with R. rosea. Thus, S. chinensis and R. rosea exert an anti-stress effect in rats subjected to stress by balancing the HPA axis, and possibly by reducing the expression of c-Fos in the hypothalamus.

  7. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress

    PubMed Central

    XIA, NAN; LI, JIE; WANG, HONGWEI; WANG, JIAN; WANG, YANGTIAN

    2016-01-01

    The aim of the present study was to investigate the effects of Schisandra chinensis (S. chinensis) and Rhodiola rosea (R. rosea) on rats subjected to 5 h of stress, induced by water-floating followed by treadmill exercise. Hypothalamus-pituitary-adrenal (HPA) activity and c-Fos and Fos-related antigen 2 (Fra-2) mRNA expression levels in the hypothalamus of the rats were evaluated. Rats were distributed into four groups: S. chinensis (n=12), R. rosea (n=10), stress control (n=10) and quiet control (n=8). Following a training period of 6 consecutive days, the S. chinensis, R. rosea and stress control groups underwent a 3-h water-floating session in the presence of feline predators immediately followed by 2 h treadmill running to induce psychological and physical stress. Following compound stress induction, the serum levels of corticosterone (CORT), adrenocorticotropic hormone and interleukin-1β and the mRNA expression levels of hypothalamic corticotropin-releasing hormone (CRH), neuropeptide-Y, c-Fos and Fra-2 were evaluated using enzyme-linked immunosorbent assay, radioimmunoassay and quantitative polymerase chain reaction, respectively. The results indicated that S. chinensis and R. rosea markedly decreased the stress-induced elevation of CRH and peripheral CORT levels. The mRNA expression levels of c-Fos and Fra-2 in the hypothalamus were significantly increased after 5 h compound stress, and reduced levels of c-Fos expression were detected in rats treated with R. rosea. Thus, S. chinensis and R. rosea exert an anti-stress effect in rats subjected to stress by balancing the HPA axis, and possibly by reducing the expression of c-Fos in the hypothalamus. PMID:26889268

  8. Neurohormonal activation in ischemic stroke: effects of acute phase disturbances on long-term mortality.

    PubMed

    Anne, Mäkikallio; Juha, Korpelainen; Timo, Mäkikallio; Mikko, Tulppo; Olli, Vuolteenaho; Kyösti, Sotaniemi; Heikki, Huikuri; Vilho, Myllylä

    2007-08-01

    A stress response consisting of elevated levels of cortisol and catecholamines is common after acute stroke. The plasma levels of natriuretic peptides are known to be elevated after ischemic stroke, but the relations of these neurohormonal systems in the acute phase of stroke and their impact on long-term prognosis have not been studied previously. A series of 51 consecutive patients (mean age 68+/-11 years) with an ischemic first-ever stroke underwent a comprehensive clinical investigation, scoring of their neurologic deficit by Scandinavian Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking Scale (MRS) as well as measurements of plasma cortisol, norepinephrine, epinephrine, ACTH and atrial (N-ANP) and brain (N-BNP) natriuretic peptides on the 2nd and 7th days after ischemic stroke. The patients were followed up for 44+/-21 months. Higher levels of cortisol, ACTH and natriuretic peptides were observed in the stroke patients who died (n=22) during the follow-up than in the stroke survivors. Cortisol levels associated significantly with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine levels (r= 0.55 - 0.94, p<0.01 for all) and measures of neurologic deficit (r= 0.36 - -0.44, p<0.05). High acute phase cortisol levels assessed either in the morning (RR=5.4, p<0.05) or in the evening (RR=5.8, p<0.05) predicted long-term mortality after stroke in multivariate analysis. Activation of the hypothalamus-pituitary-adrenal axis in ischemic stroke is associated with elevated levels of natriuretic peptides. High cortisol and natriuretic peptide values predict long-term mortality after ischemic stroke, suggesting that this profound neurohumoral disturbance is prognostically unfavourable.

  9. Hypothalamus-Pituitary-Adrenal cell-mediated immunity regulation in the Immune Restoration Inflammatory Syndrome

    PubMed Central

    Khakshooy, Allen; Chiappelli, Francesco

    2016-01-01

    Over one third of the patients sero-positive for the human immunodeficiency virus (HIV) with signs of the acquired immune deficiency syndrome (AIDS), and under treatment with anti-retroviral therapy (ART), develop the immune reconstitution inflammatory syndrome (IRIS). It is not clear what variables are that determine whether a patient with HIV/AIDS will develop ART-related IRIS, but the best evidence base thus far indicates that HIV/AIDS patients with low CD4 cell count, and HIV/AIDS patients whose CD4 count recovery shows a sharp slope, suggesting a particularly fast "immune reconstitution", are at greater risk of developing IRIS. Here, we propose the hypothesis that one important variable that can contribute to low CD4 cell count number and function in ART-treated HIV/AIDS patients is altered hypothalamic-pituitary-adrenal (HPA) cell-mediated immune (CMI) regulation. We discuss HPA-CMI deregulation in IRIS as the new frontier in comparative effectiveness research (CRE) for obtaining and utilizing the best evidence base for treatment of patients with HIV/AIDS in specific clinical settings. We propose that our hypothesis about altered HPA-CMI may extend to the pathologies observed in related viral infection, including Zika PMID:27212842

  10. HPA- and HPT-axis alterations in chronic posttraumatic stress disorder.

    PubMed

    Olff, Miranda; Güzelcan, Yener; de Vries, Giel-Jan; Assies, Johanna; Gersons, Berthold P R

    2006-11-01

    Posttraumatic stress disorder (PTSD) has been associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis as well as of the hypothalamus-pituitary-thyroid (HPT) axis. Findings have not been consistent and may depend on methodological issues like controlling for relevant variables. This study examines the levels of six HPA and HPT-axis related hormones in civilian PTSD patients without psychotropic medication. In a cross sectional study, 39 chronic PTSD patients and 44 healthy volunteers were included. Psychometric instruments included SCID, SI-PTSD, IES-R and BDI. The plasma hormones levels assessed were cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), prolactin, thyrotropin (TSH), and free thyroxin (fT4). Results showed that patients had significantly lower plasma cortisol, prolactin and TSH levels compared to the comparison group. The difference between TSH levels in patients and comparison subjects only emerged after controlling for relevant background variables. Furthermore, the severity of PTSD symptoms was negatively related to cortisol levels. Secondary analyses revealed no statistically significant effect of comorbid depression (26% of patients) on any of the hormone levels. Complex feedback mechanisms are likely to result in altered levels of stress related hormones in PTSD, and results depend on controlling for relevant variables. Further research with longitudinal designs is needed to find out whether these lower hormone levels are preexisting risk factors or consequence of trauma and whether these alterations are deleterious or adaptive.

  11. Stress-induced sensitization: the hypothalamic-pituitary-adrenal axis and beyond.

    PubMed

    Belda, Xavier; Fuentes, Silvia; Daviu, Nuria; Nadal, Roser; Armario, Antonio

    2015-01-01

    Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.

  12. HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

    PubMed

    Valli, I; Crossley, N A; Day, F; Stone, J; Tognin, S; Mondelli, V; Howes, O; Valmaggia, L; Pariante, C; McGuire, P

    2016-05-03

    The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

  13. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear

    PubMed Central

    Meyer, Retsina M.; Burgos-Robles, Anthony; Liu, Elizabeth; Correia, Susana S.; Goosens, Ki A.

    2014-01-01

    Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is not a clear relationship between the levels of these hormones and stress-associated mental illnesses such as post-traumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin releasing factor (CRF) or corticosterone. Repeated intra-amygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was increased by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin

  14. Combined pre- and postnatal environmental enrichment programs the HPA axis differentially in male and female rats.

    PubMed

    Welberg, L; Thrivikraman, K V; Plotsky, P M

    2006-06-01

    Experimental environmental enrichment (EE) is usually applied in adulthood or immediately after weaning, with robust effects on physiology and behaviour. To investigate the effects of EE earlier in life, female rats were maintained under moderate enrichment during pregnancy and, together with their pups, during lactation until weaning. A separate group of dams housed under standard conditions during pregnancy and lactation served as controls. Dams housed under EE exhibited fewer nursing episodes and were off the nest more often, but the frequency of pup licking was not affected on postnatal days 3-5. EE effects on hypothalamus-pituitary-adrenal (HPA) axis responses to an acute stressor were determined in adult male and female offspring with and without previous exposure to the chronic stressor of constant light. In female offspring, chronic stress significantly increased basal corticosterone (CORT) levels, but not if rats had been exposed to early EE. Furthermore, while control females exposed to chronic stress showed a greatly reduced adrenocorticotropin (ACTH) response to an acute stressor, EE females did not display this desensitization. There was no significant effect of EE on basal ACTH and CORT levels in adult male offspring, nor did it alter their response to acute stress. Maternal licking frequency was moderately but significantly correlated with net corticosterone increases in response to acute stress, the direction of the correlation crucially depending on the offspring's sex and stress conditions. This study shows that EE during pregnancy and lactation has long-lasting effects on reactivity to acute and chronic stress in offspring and that these effects are dependent on the offspring's sex but not greatly on early postpartum maternal behaviour.

  15. Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post-traumatic stress disorder (PTSD) in humans.

    PubMed

    Sriram, K; Rodriguez-Fernandez, Maria; Doyle, Francis J

    2012-01-01

    Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (n = 3) in each category and created a model subject (n = 1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative

  16. Evaluation of immune system function in neonatal pigs born vaginally or by Cesarean section

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Eight full term crossbred sows were selected for study of the interaction of the immune system, hypothalamus-pituitary-adrenal axis, and growth in pigs born by Cesarean section (C-section) or vaginal-birth (n=4 each for vaginal-birth and C-section). Gestation length and birth weight did not differ b...

  17. Comparison of miRNA expression profiles in pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

    PubMed

    Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Fu, Jiangnan; Nie, Qinghua

    2016-01-01

    MicoRNAs (miRNAs), usually as gene regulators, participate in various biological processes, including stress responses. The hypothalamus-pituitary-adrenal axis (HPA axis) is an important pathway in regulating stress response. Although the mechanism that HPA axis regulates stress response has been basically revealed, the knowledge that miRNAs regulate stress response within HPA axis, still remains poor. The object of this study was to investigate the miRNAs in the pituitary and adrenal cortex that regulate chronic stress response with high-throughput sequencing. The pituitary and adrenal cortex of beagles and Chinese Field dogs (CFD) from a stress exposure group (including beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)) and a control group (including beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)), were selected for miRNA-seq comparisons. Comparisons, that were made in pituitary (including BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1 and BP2 vs. CFDP2) and adrenal cortex (including BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2), showed that a total of 39 and 18 common differentially expressed miRNAs (DE-miRNAs) (Total read counts > 1,000, Fold change > 2 & p-value < 0.001), that shared in at least two pituitary comparisons and at least two adrenal cortex comparisons, were detected separately. These identified DE-miRNAs were predicted for target genes, thus resulting in 3,959 and 4,010 target genes in pituitary and adrenal cortex, respectively. Further, 105 and 10 differentially expressed genes (DEGs) (Fold change > 2 & p-value < 0.05) from those target genes in pituitary and adrenal cortex were obtained separately, in combination with our previous corresponding transcriptome study. Meanwhile, in line with that miRNAs usually negatively regulated their target genes and the dual luciferase reporter assay, we finally

  18. Treatment of post-myocardial infarction depressive disorder.

    PubMed

    Kuyper, Astrid M G; Honig, Adriaan

    2008-07-01

    Both major and minor depressive disorder post-myocardial infarction (MI) are associated with an increased risk of all-cause mortality, cardiac mortality and new cardiovascular events. Post-MI depressive disorder predicts slow recovery and poor quality of life. This review attends to post-MI depressive disorder, its underlying mechanisms and options for and effects of treatment. Evidence has been found for several mechanisms to be involved in the pathophysiology, including hypothalamus-pituitary-adrenal axis activity, immune activity, polyunsaturated fatty acids, serotonin, platelet activation, type D personality and negative health behavior. Five leading randomized controlled trials are discussed, showing safety and efficacy of antidepressive treatment in post-MI patients. Effects on cardiac outcome remain unclear.

  19. Extra-adrenal glucocorticoid synthesis: immune regulation and aspects on local organ homeostasis.

    PubMed

    Talabér, Gergely; Jondal, Mikael; Okret, Sam

    2013-11-05

    Systemic glucocorticoids (GCs) mainly originate from de novo synthesis in the adrenal cortex under the control of the hypothalamus-pituitary-adrenal (HPA)-axis. However, research during the last 1-2 decades has revealed that additional organs express the necessary enzymes and have the capacity for de novo synthesis of biologically active GCs. This includes the thymus, intestine, skin and the brain. Recent research has also revealed that locally synthesized GCs most likely act in a paracrine or autocrine manner and have significant physiological roles in local homeostasis, cell development and immune cell activation. In this review, we summarize the nature, regulation and known physiological roles of extra-adrenal GC synthesis. We specifically focus on the thymus in which GC production (by both developing thymocytes and epithelial cells) has a role in the maintenance of proper immunological function.

  20. Biobehavioral indices of emotion regulation relate to school attitudes, motivation, and behavior problems in a low-income preschool sample.

    PubMed

    Miller, Alison L; Seifer, Ronald; Stroud, Laura; Sheinkopf, Stephen J; Dickstein, Susan

    2006-12-01

    Effective emotion regulation may promote resilience and preschool classroom adjustment by supporting adaptive peer interactions and engagement in learning activities. We investigated how hypothalamus-pituitary-adrenal axis (HPA) regulation, cardiac reactivity, and classroom emotion displays related to adjustment among low-income preschoolers attending Head Start. A total of 62 four-year-olds completed a laboratory session including a baseline soothing video; emotion-eliciting slides/video clips, and recovery. Salivary cortisol, heart rate, and vagal tone were measured throughout. Independent coders used handheld computers to observe classroom emotion expression/regulation. Teachers rated child motivation, persistence/attention, learning attitudes, and internalizing/externalizing symptoms. Results reveal associations between biobehavioral markers of regulatory capacity and early school adjustment.

  1. The neuroimmune connection interferes with tissue regeneration and chronic inflammatory disease in the skin.

    PubMed

    Peters, Eva M J; Liezmann, Christiane; Klapp, Burghard F; Kruse, Johannes

    2012-07-01

    Research over the past decades has revealed close interactions between the nervous and immune systems that regulate peripheral inflammation and link psychosocial stress with chronic somatic disease. Besides activation of the sympathetic and the hypothalamus-pituitary-adrenal axis, stress leads to increased neurotrophin and neuropeptide production in organs at the self-environment interface. The scope of this short review is to discuss key functions of these stress mediators in the skin, an exemplary stress-targeted and stress-sensitive organ. We will focus on the skin's response to acute and chronic stress in tissue regeneration and pathogenesis of allergic inflammation, psoriasis, and skin cancer to illustrate the impact of local stress-induced neuroimmune interaction on chronic inflammation.

  2. "Down will come baby": prenatal stress, primitive defenses and gestational dysregulation.

    PubMed

    Thomson, Paula

    2007-01-01

    Knowledge of maternal stress and its direct influence on the developing embryo and fetus (prenate) can influence psychotherapeutic treatment decisions, especially when treating patients who are severely traumatized and dissociative. Not only may maternal stress alter prenate neurobiological attachment and stress systems in the limbic-hypothalamus-pituitary-adrenal axis (LHPA) and limbic-autonomic nervous system (L-ANS), but it may also shape the development of prenate 'fixed action patterns' built from primitive defensive reflex activation. As a result, the offspring's defensive, mating and caregiving behavior may all be biased towards survival in a threatening world and may be more readily transmitted to subsequent generations. This theoretical article provides a prenatal relational model that outlines experience- dependent prenate development that is contingent on and concordant with maternal regulation and dysregulation. Not only anxiety, depression and anger, but also posttraumatic stress and dissociation in the mother, may affect the neurobiology of the prenate.

  3. Endomorphins and activation of the hypothalamo-pituitary-adrenal axis.

    PubMed

    Coventry, T L; Jessop, D S; Finn, D P; Crabb, M D; Kinoshita, H; Harbuz, M S

    2001-04-01

    Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in the central nervous system and immune tissues with high selectivity and affinity for the mu-opioid receptor. Intracerebroventricular (i.c.v.) administration of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 and EM-2 on HPA axis activation. Rats received a single i.c.v. injection of either EM-1 (0.1, 1.0, 10 microg), EM-2 (10 microg), morphine (10 microg), or vehicle (0.9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time points up to 4 h post-injection. Trunk blood, brains and pituitaries were collected at 4 h. Intracerebroventricular morphine increased plasma corticosterone levels within 30 min, whereas EM-1 and EM-2 were without effect. In addition, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophin-releasing factor (CRF) mRNA and arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in the anterior pituitary were found to be unaffected by either morphine or endomorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasma EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticosterone, ACTH and beta-endorphin were elevated following acute restraint stress, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and beta-endorphin were further elevated in adjuvant-induced arthritis (AA) rats by a single injection of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. These data suggest that endomorphins may be acting on a different subset of the mu-opioid receptor than morphine. The

  4. Transcriptome comparison in the pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

    PubMed

    Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Nie, Qinghua

    2015-10-01

    Chronic stress can induce a series of maladjustments, and the response to stress is partly regulated by the hypothalamus-pituitary-adrenal axis. The aim of this study was to investigate the genetic mechanisms of this axis regulating stress responsiveness. The pituitary and adrenal cortex of Beagle and Chinese Field Dog (CFD) from a stress exposure group [including Beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), Beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)] and a control group [including Beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), Beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)], selected to perform RNA-seq transcriptome comparisons, showed that 40, 346, 376, 69, 70, 38, 57 and 71 differentially expressed genes were detected in BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1, BP2 vs. CFDP2, BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2 respectively. NPB was a gene common to BAC1 vs. BAC2 and CFDAC1 vs. CFDAC2, indicating it was a potential gene affecting response to chronic stress, regardless of the extent of chronic stress induced. PLP1 was a gene common to BP1 vs. CFDP1 and BP2 vs. CFDP2, suggesting its important roles in affecting the stress-tolerance difference between the two breeds, regardless of whether there was stress exposure or not. Pathway analysis found 12, 4, 11 and 1 enriched pathway in the comparisons of BP1 vs. CFDP1, BP2 vs. CFDP2, CFDP1 vs. CFDP2 and BAC1 vs. BAC2 respectively. Glutamatergic synapse, neuroactive ligand-receptor interaction, retrograde endocannabinoid signaling, GABAergic synapse, calcium signaling pathway and dopaminergic synapse were the most significantly enriched pathways in both CFDP1 vs. CFDP2 and BP1 vs. CFDP1. GO, KEGG pathway and gene network analysis demonstrated that GRIA3, GRIN2A, GRIN2B and NPY were important in regulating the stress response in CFD. Nevertheless, ADORA1, CAMK2A, GRM1, GRM7 and NR4A1 might be critical genes contributing to the stress

  5. Pilot study of adrenal steroid hormones in hair as an indicator of chronic mental and physical stress

    PubMed Central

    Ullmann, E.; Barthel, A; Petrowski, K.; Stalder, T.; Kirschbaum, C.; Bornstein, S. R.

    2016-01-01

    Currently, the quantitative analysis of moderators affecting the function of the hypothalamus-pituitary-adrenal (HPA)-axis in health and sickness is still unreliable. This is, in particular, due to physiological factors such as pulsatile ultradian and circadian glucocorticoid secretion as well as to methodological limitations of the current techniques for steroid hormone determination. Based on this background, the determination of long-term hair steroid concentrations is an important methodological improvement allowing for the quantitative analysis of chronic HPA axis-activation. In order to determine the relationship between chronic mental and physical stress and a chronic activation of the HPA axis, we performed a cross-sectional pilot-study with 40 healthy students and examined the relationships between physical activity, mental burden(s), subjective stress perceptions, depressiveness, anxiety, physical complaints, sense of coherence, resilience, and the long-term integrated steroid hormone levels in hair. The results showed that the concentrations of cortisol, cortisone, and dehydroepiandrosterone in hair were significantly correlated to mental (p = 0.034) and physical stress (p = 0.001) as well as to subjective stress perception (p = 0.006). We conclude that steroid concentrations in hair are decisive predictors for an increase in the long-term-HPA axis activity. Moreover, this biomarker is suitable for capturing the stresslevel after burdening events and physical activity. PMID:27174654

  6. Stress, atopy and allergy

    PubMed Central

    Liezmann, Christiane; Klapp, Burghard

    2011-01-01

    Since the early days of psychosomatic thinking, atopic disease was considered exemplary. In the 70s and 80s numerous reports stated increased anxiety, depression or ill stresscoping in atopics in correlation with enhanced disease activity. Employed patient groups however were small and diverse and controls rare. Therefore, the question remained, whether psychopathological findings in atopics were of pathogenetic relevance or an epiphenomenon of chronic inflammatory disease. Recently, the discussion has been revived and refocused by psychoneuroimmunological findings. We now know that atopic disease is characterized by an imbalance of the classical stress-axis response along the hypothalamus-pituitary-adrenal axis (HPA) and the sympathetic axis (SA). This imbalance can be found shoulder-to-shoulder with enhanced expression of newly emerging neuroendocrine stress mediators such as substance P (SP) and nerve growth factor that form up to a third stress axis (neurotrophin neuropeptide axis: NNA). Together they can alter the inflammatory as well as the neuroendocrine stress-response on several levels. In skin, the immediate inflammatory response to stress involves neuropeptide release and mast cell degranulation, in short neurogenic inflammation. Systemically, antigen-presentation and TH2 cytokine bias are promoted under the influence of cortisol and neuropeptides. Imbalanced stress-responsiveness may therefore be at the core of exacerbated allergic disease and deserves re-evaluation of therapeutic options such as neutralization of SP-signaling by antagonists against its receptor NK1, cortisol treatment as supplementation and relaxation techniques to balance the stress-response. PMID:21519408

  7. Free cortisol and salivary alpha-amylase levels during a six-hour-water immersion in healthy young men

    NASA Astrophysics Data System (ADS)

    Rohleder, N.; Wirth, D.; Fraßl, W.; Kowoll, R.; Schlemmer, M.; Vogler, S.; Kirsch, K. A.; Kirschbaum, C.; Gunga, H.-C.

    2005-08-01

    Limited data are available on the response of stress systems to microgravity. Increased activity of stress systems is reported during space flight, but unchanged or decreased activity during simulated microgravity. We here investigated the impact of head-out water immersion on the activity of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) system.Eight healthy young men were exposed to a six-hour water immersion in a thermo neutral bath and a control condition. Saliva samples were taken before, during, and after interventions to assess cortisol as an index for HPA axis activity, and salivary α-amylase as an index for SAM system activity.Cortisol levels uniformly decreased during both conditions. Amylase levels increased during both conditions, but were significantly lower during the first half of water immersion compared to the control condition.In conclusion, the HPA axis is not influenced by simulated microgravity, while SAM system activity shows initial decreases during water immersion.

  8. Multi-sensor control for 6-axis active vibration isolation

    NASA Astrophysics Data System (ADS)

    Thayer, Douglas Gary

    The goal of this research is to look at the two different parts of the challenge of active vibration isolation. First is the hardware that will be used to accomplish the task and improve performance. The cubic hexapod, or Stewart platform, has become a popular solution to the problem because of its ability to provide 6-axis vibration isolation with a relatively simple configuration. A number of these hexapods have been constructed at different research facilities around the country to address different missions, each with their own approach. Hood Technology Corporation and the University of Washington took the lessons learned from these designs and developed a new hexapod that addresses the requirements of the Jet Propulsion Laboratory's planned space borne interferometry missions. This system has unique mechanical design details and is built with 4 sensors in each strut. This, along with a real time computer to implement controllers, allows for a great deal of flexibility in controller design and research into sensor selection. Other unique design features include a very soft axial stiffness, a custom designed voice coil actuator with a large displacement capability and elastomeric flexures both for guiding the actuator and providing pivot points on each strut. The second part, and the primary area of this research, is to examine multi-sensor control strategies in an effort to improve the performance of the controllers, their stability and/or how implementable they are. Up to this point, the primary method of control for systems of this type has been classical, designing single-input, single output controller loops to be closed around each strut. But because of the geometry of the hexapod and the different problems that can occur with some sensors, the classical approach is limited in what it can accomplish. This research shows the benefits to be gained by going to a multiple sensor controller and implementing controllers that are designed using a frequency

  9. Positive modulation of a neutral declarative memory by a threatening social event.

    PubMed

    Fernández, Rodrigo S; Bavassi, Luz; Campos, Jorge; Allegri, Ricardo F; Molina, Victor A; Forcato, Cecilia; Pedreira, María E

    2015-12-01

    Memories can be altered by negative or arousing experiences due to the activation of the stress-responsive sympatho-adrenal-medullary axis (SYM). Here, we used a neutral declarative memory that was acquired during multi-trial training to determine the effect of a threatening event on memory without emotional valence. To this end, participants received a new threatening social protocol before learning pairs of meaningless syllables and were tested either 15 min, 2 days or 8 days after acquisition. We first demonstrated that this threatening social situation activates not only the SYM axis (Experiment 1) and the hypothalamus-pituitary-adrenal axis (HPA; Experiment 2), but also, it improves the acquisition or early consolidation of the syllable pairs (Experiment 3). This improvement is not a transient effect; it can be observed after the memory is consolidated. Furthermore, this modulation increases the persistence of memory (Experiment 4). Thus, it is possible to affect memories with specific events that contain unrelated content and a different valence.

  10. Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression.

    PubMed

    Funke, R; Eichler, A; Distler, J; Golub, Y; Kratz, O; Moll, G H

    2016-12-16

    Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.

  11. Gene expression profiling in peripheral blood leukocytes as a new approach for assessment of human stress response.

    PubMed

    Rokutan, Kazuhito; Morita, Kyoko; Masuda, Kiyoshi; Tominaga, Kumiko; Shikishima, Michiyo; Teshima-Kondo, Shigetada; Omori, Tetsuro; Sekiyama, Atsuo

    2005-08-01

    Stress is the coordinated physiological processes to maintain a dynamic equilibrium under stressful conditions. The equilibrium is threatened by certain physiological and psychological stressors. Stressors trigger physiological, behavioural, and metabolic responses that are aimed at reinstating homeostasis. The hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system play an essential role in the stress response. Excessive,prolonged, or inadequate response that is termed as "allostasis" or "allostatic load" leads to pathological outcomes. Dysregulation of the HPA axis activity is involved in the pathogenesis of stress-related disorders including major depression. The complex brain-immune-endocrine network regulates the HPA axis, and hereditary predisposition as well as environmental factors such as traumatic experiences in early life also modifies the capacity of an individual to cope. Therefore, it is difficult to correctly assess the complex stress response. We have developed a microarray carrying 1,467 cDNAs that were selected to specifically measure stress response in peripheral blood leukocytes. Using this tool, we have succeeded to objectively assess individual response to acute psychological stress and to detect unique expression profiles in patients with depression. Gene expression profile in peripheral blood leukocytes may be a potentially useful for the detection of disease-associated, abnormal stress responses.

  12. CRF1 receptor-deficiency increases cocaine reward.

    PubMed

    Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo

    2017-01-27

    Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF1 receptor-deficient (CRF1-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF1-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF1-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF1-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF1-/- mice by exogenous corticosterone does not affect CRF1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF1 receptor in cocaine reward, independently of the closely related HPA axis activity.

  13. Active Circulation Control for Horizontal Axis Wind Turbine

    NASA Astrophysics Data System (ADS)

    Dumitrache, Alexandru; Dumitrescu, Horia; Preotu, Octavian

    2011-09-01

    A based method for modeling the aerodynamics of horizontal axis wind turbine has been developed. Circulation control is implemented by tangentially blowing a small high-velocity jet over a highly curved surface, such as a rounded trailing edge. This causes the boundary layer and the jet sheet to remain attached along the curved surface due to the Coanda effect and causing the jet to turn without separation. This analysis has been validated for the experimental data of a rotor tested at NASA Ames Research Center. Comparisons have been done against measurements for surface pressure distribution, force coefficients normal and tangential to the chord line, torque and root bending moments. This approach for enhancing the circulation around the airfoil sections (and hence L/D and power production) has been examined and found to produce useful increases in power at low wind speeds.

  14. Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning.

    PubMed

    Jahng, Jeong Won; Lee, Jong-Ho

    2015-12-05

    Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA.

  15. Interindividual differences in stress sensitivity: basal and stress-induced cortisol levels differentially predict neural vigilance processing under stress.

    PubMed

    Henckens, Marloes J A G; Klumpers, Floris; Everaerd, Daphne; Kooijman, Sabine C; van Wingen, Guido A; Fernández, Guillén

    2016-04-01

    Stress exposure is known to precipitate psychological disorders. However, large differences exist in how individuals respond to stressful situations. A major marker for stress sensitivity is hypothalamus-pituitary-adrenal (HPA)-axis function. Here, we studied how interindividual variance in both basal cortisol levels and stress-induced cortisol responses predicts differences in neural vigilance processing during stress exposure. Implementing a randomized, counterbalanced, crossover design, 120 healthy male participants were exposed to a stress-induction and control procedure, followed by an emotional perception task (viewing fearful and happy faces) during fMRI scanning. Stress sensitivity was assessed using physiological (salivary cortisol levels) and psychological measures (trait questionnaires). High stress-induced cortisol responses were associated with increased stress sensitivity as assessed by psychological questionnaires, a stronger stress-induced increase in medial temporal activity and greater differential amygdala responses to fearful as opposed to happy faces under control conditions. In contrast, high basal cortisol levels were related to relative stress resilience as reflected by higher extraversion scores, a lower stress-induced increase in amygdala activity and enhanced differential processing of fearful compared with happy faces under stress. These findings seem to reflect a critical role for HPA-axis signaling in stress coping; higher basal levels indicate stress resilience, whereas higher cortisol responsivity to stress might facilitate recovery in those individuals prone to react sensitively to stress.

  16. A Natural Mutation in Helix 5 of the Ligand Binding Domain of Glucocorticoid Receptor Enhances Receptor-Ligand Interaction

    PubMed Central

    Reyer, Henry; Ponsuksili, Siriluck; Kanitz, Ellen; Pöhland, Ralf; Wimmers, Klaus; Murani, Eduard

    2016-01-01

    The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40–50 percent. To unravel the molecular mechanisms behind this gain of function, receptor-ligand interactions were evaluated in silico, in vitro and in vivo. In accordance with previously observed phenotypic effects, the mutant Val610 GR showed significantly increased activation in response to glucocorticoid and non-glucocorticoid steroids, and, as revealed by GR-binding studies in vitro and in pituitary glands, enhanced ligand binding. Concordantly, the protein structure prediction depicted reduced binding distances between the receptor and ligand, and altered interactions in the ligand binding pocket. Consequently, the Ala610Val substitution opens up new structural information for the design of potent GR ligands and to examine effects of the enhanced GR responsiveness to glucocorticoids on the entire organism. PMID:27736993

  17. Psychosocial Stress-Induced Analgesia: An Examination of Effects on Heat Pain Threshold and Tolerance and of Neuroendocrine Mediation.

    PubMed

    Gaab, Jens; Jiménez, Julia; Voneschen, Livia; Oschwald, Daniel; Meyer, Andrea H; Nater, Urs M; Krummenacher, Peter

    2017-02-11

    Stress-induced analgesia (SIA) is an adaptive response of reduced nociception following demanding acute internal and external stressors. Although a psychobiological understanding of this phenomenon is of importance for stress-related psychiatric and pain conditions, comparably little is known about the psychobiological mechanisms of SIA in humans. The aim of this study was to investigate the effects of acute psychosocial stress on heat pain perception and its possible neuroendocrine mediation by salivary cortisol levels and α-amylase activity in healthy men. Employing an intra-individual assessment of heat pain parameters, acute psychosocial stress did not influence heat pain threshold but significantly, albeit slightly, increased heat pain tolerance. Using linear mixed-model analysis, this effect of psychosocial stress on heat pain tolerance was not mediated by increases of salivary cortisol and state anxiety levels or by the activity of α-amylase. These results show that while psychosocial stress is selectively analgesic for heat pain tolerance, this observed effect is not mediated by stress-induced increases of salivary cortisol and α-amylase activity, as proxies of both the hypothalamus-pituitary-adrenal axis and the autonomic nervous system activation.

  18. Role of multiligand/RAGE axis in platelet activation.

    PubMed

    Fuentes, Eduardo; Rojas, Armando; Palomo, Iván

    2014-03-01

    In the context of plaque progression, platelet hyperactivity associated with hyperlipidemia contributes to the development of a pro-thrombotic state. In this context, it has been demonstrated that advanced glycation end products (AGEs) significantly increases platelet activation and receptor for AGEs (RAGE) expression at the platelet surface membrane. In addition to AGEs, other ligands (S100, HMGB1 and amyloid β, among others) of RAGE have raised particular attention in platelet activation. Therefore, in this article we describe platelet hyperactivity by AGEs via RAGE-independent and RAGE-dependent pathways.

  19. Effect of handling on neurotransmitter profile in pig brain according to fear related behaviour.

    PubMed

    Arroyo, Laura; Carreras, Ricard; Valent, Daniel; Peña, Raquel; Mainau, Eva; Velarde, Antonio; Sabrià, Josefa; Bassols, Anna

    2016-12-01

    Chemical neurotransmitters (NT) are principal actors in all neuronal networks of animals. The central nervous system plays an important role in stress susceptibility and organizes the response to a stressful situation through the interaction of the dopaminergic and the serotonergic pathways, leading to the activation of the hypothalamus-pituitary-adrenal axis (HPA). This study was designed to investigate: a) the effects of stressful handling of pigs at the slaughterhouse on the neurotransmitter profile in four brain areas: amygdala, prefrontal cortex (PFC), hippocampus and hypothalamus, and b) whether the alterations in the brain NT profile after stressful handling were associated with fear, determined by the tonic immobility (TI) test. In the first place, the characterization of the NT profile allowed to distinguish the four brain areas in a principal component analysis. The most crucial pathway involved in the reaction of pigs to a stressful handling was the serotonergic system, and changes were observed in the amygdala with a decrease in serotonin (5-HT) and total indoleamines, and in the hippocampus, where this pathway was activated. Fearful and non-fearful pigs did not show significant differences in their NT profile in control conditions, but when subjected to a stressful handling in the slaughterhouse, fearful animals showed a significant variation in the serotonin pathway and, in a lesser extent, the dopamine (DA) pathway. In conclusion, the existence of an underlying biological trait - possibly fearfulness - may be involved in the pig's response toward stressful challenges, and the serotonergic system seems to play a central role in this response.

  20. Rapid Stress System Drives Chemical Transfer of Fear from Sender to Receiver

    PubMed Central

    de Groot, Jasper H. B.; Smeets, Monique A. M.; Semin, Gün R.

    2015-01-01

    Humans can register another person’s fear not only with their eyes and ears, but also with their nose. Previous research has demonstrated that exposure to body odors from fearful individuals elicited implicit fear in others. The odor of fearful individuals appears to have a distinctive signature that can be produced relatively rapidly, driven by a physiological mechanism that has remained unexplored in earlier research. The apocrine sweat glands in the armpit that are responsible for chemosignal production contain receptors for adrenalin. We therefore expected that the release of adrenalin through activation of the rapid stress response system (i.e., the sympathetic-adrenal medullary system) is what drives the release of fear sweat, as opposed to activation of the slower stress response system (i.e., hypothalamus-pituitary-adrenal axis). To test this assumption, sweat was sampled while eight participants prepared for a speech. Participants had higher heart rates and produced more armpit sweat in the fast stress condition, compared to baseline and the slow stress condition. Importantly, exposure to sweat from participants in the fast stress condition induced in receivers (N = 31) a simulacrum of the state of the sender, evidenced by the emergence of a fearful facial expression (facial electromyography) and vigilant behavior (i.e., faster classification of emotional facial expressions). PMID:25723720

  1. Agricultural land use and human presence around breeding sites increase stress-hormone levels and decrease body mass in barn owl nestlings.

    PubMed

    Almasi, Bettina; Béziers, Paul; Roulin, Alexandre; Jenni, Lukas

    2015-09-01

    Human activities can have a suite of positive and negative effects on animals and thus can affect various life history parameters. Human presence and agricultural practice can be perceived as stressors to which animals react with the secretion of glucocorticoids. The acute short-term secretion of glucocorticoids is considered beneficial and helps an animal to redirect energy and behaviour to cope with a critical situation. However, a long-term increase of glucocorticoids can impair e.g. growth and immune functions. We investigated how nestling barn owls (Tyto alba) are affected by the surrounding landscape and by human activities around their nest sites. We studied these effects on two response levels: (a) the physiological level of the hypothalamus-pituitary-adrenal axis, represented by baseline concentrations of corticosterone and the concentration attained by a standardized stressor; (b) fitness parameters: growth of the nestlings and breeding performance. Nestlings growing up in intensively cultivated areas showed increased baseline corticosterone levels late in the season and had an increased corticosterone release after a stressful event, while their body mass was decreased. Nestlings experiencing frequent anthropogenic disturbance had elevated baseline corticosterone levels, an increased corticosterone stress response and a lower body mass. Finally, breeding performance was better in structurally more diverse landscapes. In conclusion, anthropogenic disturbance affects offspring quality rather than quantity, whereas agricultural practices affect both life history traits.

  2. Rhythm and mood: relationships between the circadian clock and mood-related behavior.

    PubMed

    Schnell, Anna; Albrecht, Urs; Sandrelli, Federica

    2014-06-01

    Mood disorders are multifactorial and heterogeneous diseases caused by the interplay of several genetic and environmental factors. In humans, mood disorders are often accompanied by abnormalities in the organization of the circadian system, which normally synchronizes activities and functions of cells and tissues. Studies on animal models suggest that the basic circadian clock mechanism, which runs in essentially all cells, is implicated in the modulation of biological phenomena regulating affective behaviors. In particular, recent findings highlight the importance of the circadian clock mechanisms in neurological pathways involved in mood, such as monoaminergic neurotransmission, hypothalamus-pituitary-adrenal axis regulation, suprachiasmatic nucleus and olfactory bulb activities, and neurogenesis. Defects at the level of both, the circadian clock mechanism and system, may contribute to the etiology of mood disorders. Modification of the circadian system using chronotherapy appears to be an effective treatment for mood disorders. Additionally, understanding the role of circadian clock mechanisms, which affect the regulation of different mood pathways, will open up the possibility for targeted pharmacological treatments.

  3. Stress and memory in humans: twelve years of progress?

    PubMed

    Wolf, Oliver T

    2009-10-13

    Stress leads to an enhanced activity of the hypothalamus-pituitary adrenal (HPA) axis resulting in an increased release of glucocorticoids from the adrenal cortex. These hormones influence target systems in the periphery as well as in the brain. The present review paper describes the impact of the human stress hormone cortisol on episodic long-term memory. Starting out with our early observation that stress as well as cortisol treatment impaired declarative memory, experiments by the author are described, which result in an enhanced understanding of how cortisol influences memory. The main conclusions are that stress or cortisol treatment temporarily blocks memory retrieval. The effect is stronger for emotional arousing material independent of its valence. In addition cortisol only influences memory when a certain amount of testing induced arousal occurs. A functional magnetic resonance imaging (fMRI) study suggests that the neuronal correlate of the cortisol induced retrieval blockade is a reduced activity of the hippocampus. In contrast to the effects on retrieval cortisol enhances memory consolidation. Again this effect is often stronger for emotionally arousing material and sometimes occurs at the cost of memory for neutral material. A fMRI study revealed that higher cortisol levels were associated with a stronger amygdala response to emotional stimuli. Thus stimulatory effects of cortisol on this structure might underlie the cortisol induced enhancement of emotional memory consolidation. The findings presented are in line with models derived from experiments in rodents and are of relevance for our understanding of stress associated psychiatric disorders.

  4. Influence of mono-axis random vibration on reading activity.

    PubMed

    Bhiwapurkar, M K; Saran, V H; Harsha, S P; Goel, V K; Berg, Mats

    2010-01-01

    Recent studies on train passengers' activities found that many passengers were engaged in some form of work, e.g., reading and writing, while traveling by train. A majority of the passengers reported that their activities were disturbed by vibrations or motions during traveling. A laboratory study was therefore set up to study how low-frequency random vibrations influence the difficulty to read. The study involved 18 healthy male subjects of 23 to 32 yr of age group. Random vibrations were applied in the frequency range (1-10 Hz) at 0.5, 1.0 and 1.5 m/s(2) rms amplitude along three directions (longitudinal, lateral and vertical). The effect of vibration on reading activity was investigated by giving a word chain in two different font types (Times New Roman and Arial) and three different sizes (10, 12 and 14 points) of font for each type. Subjects performed reading tasks under two sitting positions (with backrest support and leaning over a table). The judgments of perceived difficulty to read were rated using 7-point discomfort judging scale. The result shows that reading difficulty increases with increasing vibration magnitudes and found to be maximum in longitudinal direction, but with leaning over a table position. In comparison with Times New Roman type and sizes of font, subjects perceived less difficulty with Arial type for all font sizes under all vibration magnitude.

  5. Paradoxical Sleep Deprivation Causes Cardiac Dysfunction and the Impairment Is Attenuated by Resistance Training

    PubMed Central

    Giampá, Sara Quaglia de Campos; Mônico-Neto, Marcos; de Mello, Marco Tulio; Souza, Helton de Sá; Tufik, Sergio; Lee, Kil Sun; Koike, Marcia Kiyomi; dos Santos, Alexandra Alberta; Antonio, Ednei Luiz; Serra, Andrey Jorge; Tucci, Paulo José Ferreira

    2016-01-01

    Background Paradoxical sleep deprivation activates the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, subsequently interfering with the cardiovascular system. The beneficial effects of resistance training are related to hemodynamic, metabolic and hormonal homeostasis. We hypothesized that resistance training can prevent the cardiac remodeling and dysfunction caused by paradoxical sleep deprivation. Methods Male Wistar rats were distributed into four groups: control (C), resistance training (RT), paradoxical sleep deprivation for 96 hours (PSD96) and both resistance training and sleep deprivation (RT/PSD96). Doppler echocardiograms, hemodynamics measurements, cardiac histomorphometry, hormonal profile and molecular analysis were evaluated. Results Compared to the C group, PSD96 group had a higher left ventricular systolic pressure, heart rate and left atrium index. In contrast, the left ventricle systolic area and the left ventricle cavity diameter were reduced in the PSD96 group. Hypertrophy and fibrosis were also observed. Along with these alterations, reduced levels of serum testosterone and insulin-like growth factor-1 (IGF-1), as well as increased corticosterone and angiotensin II, were observed in the PSD96 group. Prophylactic resistance training attenuated most of these changes, except angiotensin II, fibrosis, heart rate and concentric remodeling of left ventricle, confirmed by the increased of NFATc3 and GATA-4, proteins involved in the pathologic cardiac hypertrophy pathway. Conclusions Resistance training effectively attenuates cardiac dysfunction and hormonal imbalance induced by paradoxical sleep deprivation. PMID:27880816

  6. Selective enhancement of spatial learning under chronic psychosocial stress.

    PubMed

    Bartolomucci, Alessandro; de Biurrun, Gabriel; Czéh, Boldizsár; van Kampen, Marja; Fuchs, Eberhard

    2002-06-01

    The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.

  7. Neuroimmune mechanisms in health and disease: 2. Disease.

    PubMed Central

    Anisman, H; Baines, M G; Berczi, I; Bernstein, C N; Blennerhassett, M G; Gorczynski, R M; Greenberg, A H; Kisil, F T; Mathison, R D; Nagy, E; Nance, D M; Perdue, M H; Pomerantz, D K; Sabbadini, E R; Stanisz, A; Warrington, R J

    1996-01-01

    In the second part of their article on the emerging field of neuroimmunology, the authors present an overview of the role of neuroimmune mechanisms in defence against infectious diseases and in immune disorders. During acute febrile illness, immune-derived cytokines initiate an acute phase response, which is characterized by fever, inactivity, fatigue, anorexia and catabolism. Profound neuroendocrine and metabolic changes take place: acute phase proteins are produced in the liver, bone marrow function and the metabolic activity of leukocytes are greatly increased, and specific immune reactivity is suppressed. Defects in regulatory processes, which are fundamental to immune disorders and inflammatory diseases, may lie in the immune system, the neuro endocrine system or both. Defects in the hypothalamus-pituitary-adrenal axis have been observed in autoimmune and rheumatic diseases, chronic inflammatory disease, chronic fatigue syndrome and fibromyalgia. Prolactin levels are often elevated in patients with systemic lupus erythematosus and other autoimmune diseases, whereas the bioactivity of prolactin is decreased in patients with rheumatoid arthritis. Levels of sex hormones and thyroid hormone are decreased during severe inflammatory disease. Defective neural regulation of inflammation likely plays a pathogenic role in allergy and asthma, in the symmetrical form of rheumatoid arthritis and in gastrointestinal inflammatory disease. A better understanding of neuroimmunoregulation holds the promise of new approaches to the treatment of immune and inflammatory diseases with the use of hormones, neurotransmitters, neuropeptides and drugs that modulate these newly recognized immune regulators. PMID:8873636

  8. An aberrant parasympathetic response: a new perspective linking chronic stress and itch.

    PubMed

    Kim, Hei Sung; Yosipovitch, Gil

    2013-04-01

    Perceived stress has long been known to alter the dynamic equilibrium established between the nervous, endocrine and immune system and is widely recognised to trigger or enhance pruritus. However, the exact mechanism of how the major stress response systems, such as the hypothalamus-pituitary adrenal (HPA) axis and the autonomic nervous system induce or aggravate chronic itch, has not been elucidated. The limbic regions of the brain such as the prefrontal cortex and hippocampus are deeply involved in the regulation of the stress response and intersect with circuits that are responsible for memory and reward. According to the 'Polyvagal Theory', certain limbic structures that serve as a 'higher brain equivalent of the parasympathetic nervous system' play a foremost role in maintaining body homoeostasis by functioning as an active vagal brake. In addition, the limbic system has been postulated to regulate two distinct, yet related aspects of itch: (i) the sensory-discriminative aspect; and (ii) the affective-cognitive aspect. Chronic stress-induced itch is hypothesised to be caused by stress-related changes in limbic structure with subsequent rewiring of both the peripheral and central pruriceptive circuits. Herein, we review data suggesting that a dysfunctional parasympathetic nervous system associated with chronic stress may play a critical role in the regulatory control of key candidate molecules, receptors and brain structures involved in chronic itch.

  9. Adrenal gland volume, intra-abdominal and pericardial adipose tissue in major depressive disorder.

    PubMed

    Kahl, Kai G; Schweiger, Ulrich; Pars, Kaweh; Kunikowska, Alicja; Deuschle, Michael; Gutberlet, Marcel; Lichtinghagen, Ralf; Bleich, Stefan; Hüper, Katja; Hartung, Dagmar

    2015-08-01

    Major depressive disorder (MDD) is associated with an increased risk for the development of cardio-metabolic diseases. Increased intra-abdominal (IAT) and pericardial adipose tissue (PAT) have been found in depression, and are discussed as potential mediating factors. IAT and PAT are thought to be the result of a dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) with subsequent hypercortisolism. Therefore we examined adrenal gland volume as proxy marker for HPAA activation, and IAT and PAT in depressed patients. Twenty-seven depressed patients and 19 comparison subjects were included in this case-control study. Adrenal gland volume, pericardial, intraabdominal and subcutaneous adipose tissue were measured by magnetic resonance imaging. Further parameters included factors of the metabolic syndrome, fasting cortisol, fasting insulin, and proinflammatory cytokines. Adrenal gland and pericardial adipose tissue volumes, serum concentrations of cortisol and insulin, and serum concentrations tumor-necrosis factor-α were increased in depressed patients. Adrenal gland volume was positively correlated with intra-abdominal and pericardial adipose tissue, but not with subcutaneous adipose tissue. Our findings point to the role of HPAA dysregulation and hypercortisolism as potential mediators of IAT and PAT enlargement. Further studies are warranted to examine whether certain subtypes of depression are more prone to cardio-metabolic diseases.

  10. Expression of glucocorticoid receptors in the regenerating human skeletal muscle.

    PubMed

    Filipović, D; Pirkmajer, S; Mis, K; Mars, T; Grubic, Z

    2011-01-01

    Many stress conditions are accompanied by skeletal muscle dysfunction and regeneration, which is essentially a recapitulation of the embryonic development. However, regeneration usually occurs under conditions of hypothalamus-pituitary-adrenal gland axis activation and therefore increased glucocorticoid (GC) levels. Glucocorticoid receptor (GR), the main determinant of cellular responsiveness to GCs, exists in two isoforms (GRalpha and GRbeta) in humans. While the role of GRalpha is well characterized, GRbeta remains an elusive player in GC signalling. To elucidate basic characteristics of GC signalling in the regenerating human skeletal muscle we assessed GRalpha and GRbeta expression pattern in cultured human myoblasts and myotubes and their response to 24-hour dexamethasone (DEX) treatment. There was no difference in GRalpha mRNA and protein expression or DEX-mediated GRalpha down-regulation in myoblasts and myotubes. GRbeta mRNA level was very low in myoblasts and remained unaffected by differentiation and/or DEX. GRbeta protein could not be detected. These results indicate that response to GCs is established very early during human skeletal muscle regeneration and that it remains practically unchanged before innervation is established. Very low GRbeta mRNA expression and inability to detect GRbeta protein suggests that GRbeta is not a major player in the early stages of human skeletal muscle regeneration.

  11. The Anxiolytic Effects of Valtrate in Rats Involves Changes of Corticosterone Levels

    PubMed Central

    Shi, Shu-Ning; Shi, Jin-Li; Liu, Yong; Wang, Yan-Li; Wang, Chun-Guo; Hou, Wen-Hui; Guo, Jian-You

    2014-01-01

    Valtrate is a principle compound isolated from Valeriana jatamansi Jones, which is a Traditional Chinese Medicine used to treat various mood disorders. The aim of the present study was to investigate the anxiolytic effects of valtrate in rats. The animals were orally administered valtrate (5, 10, and 20 g/kg daily) for 10 days and exposed to open field test (OFT) and elevated plus-maze (EPM). Then the corticosterone levels in the rat serum were measured by enzyme-linked immunosorbent assay (ELISA). The valtrate (10 mg/kg, p.o.) exhibited the anxiolytic effect in rats by increasing the time and entry percentage into the open arms in the EPM and the number of central entries in the OFT. Valtrate (10 mg/kg, p.o.) significantly reduced the corticosterone level in the rat serum. Taken together, these results suggest that the valtrate has anxiolytic activity in behavioral models that might be mediated via the function of hypothalamus-pituitary-adrenal axis. PMID:24782906

  12. Neuroimmune mechanisms in health and disease: 2. Disease.

    PubMed

    Anisman, H; Baines, M G; Berczi, I; Bernstein, C N; Blennerhassett, M G; Gorczynski, R M; Greenberg, A H; Kisil, F T; Mathison, R D; Nagy, E; Nance, D M; Perdue, M H; Pomerantz, D K; Sabbadini, E R; Stanisz, A; Warrington, R J

    1996-10-15

    In the second part of their article on the emerging field of neuroimmunology, the authors present an overview of the role of neuroimmune mechanisms in defence against infectious diseases and in immune disorders. During acute febrile illness, immune-derived cytokines initiate an acute phase response, which is characterized by fever, inactivity, fatigue, anorexia and catabolism. Profound neuroendocrine and metabolic changes take place: acute phase proteins are produced in the liver, bone marrow function and the metabolic activity of leukocytes are greatly increased, and specific immune reactivity is suppressed. Defects in regulatory processes, which are fundamental to immune disorders and inflammatory diseases, may lie in the immune system, the neuro endocrine system or both. Defects in the hypothalamus-pituitary-adrenal axis have been observed in autoimmune and rheumatic diseases, chronic inflammatory disease, chronic fatigue syndrome and fibromyalgia. Prolactin levels are often elevated in patients with systemic lupus erythematosus and other autoimmune diseases, whereas the bioactivity of prolactin is decreased in patients with rheumatoid arthritis. Levels of sex hormones and thyroid hormone are decreased during severe inflammatory disease. Defective neural regulation of inflammation likely plays a pathogenic role in allergy and asthma, in the symmetrical form of rheumatoid arthritis and in gastrointestinal inflammatory disease. A better understanding of neuroimmunoregulation holds the promise of new approaches to the treatment of immune and inflammatory diseases with the use of hormones, neurotransmitters, neuropeptides and drugs that modulate these newly recognized immune regulators.

  13. Episodic stress associated with writing a graduation thesis and free cortisol secretion after awakening.

    PubMed

    Izawa, Shuhei; Sugaya, Nagisa; Ogawa, Namiko; Nagano, Yuichiro; Nakano, Masako; Nakase, Emiko; Shirotsuki, Kentaro; Yamada, Kosuke Chris; Machida, Kazuhiko; Kodama, Masahisa; Nomura, Shinobu

    2007-05-01

    Cortisol secretion after awakening, an index of hypothalamus-pituitary-adrenal axis activity, appears to be related to psychosocial stressors, or to symptoms caused by psychosocial stressors. The relationship between the quality, duration, and magnitude of psychosocial factors and cortisol secretion is however, unclear. Therefore, the effect of episodic stress associated with writing a graduation thesis on cortisol secretion after awakening was investigated. Saliva samples were collected from 10 undergraduate students at awakening, and 30, 45, and 60 min after awakening 1 month, 2 weeks, and a few days before the thesis submission and 1 week after the submission. They also completed the Short form of Profile of Moods Scale (POMS-S) on the night before each sampling. Results indicated that cortisol levels were higher a few days before the thesis submission compared to 1 month before submission. Scores of "Fatigue" and "Tension-Anxiety" in POMS-S were also higher a few days before submission. These results suggest that episodic stress associated with writing a graduation thesis caused an increase in cortisol levels after awakening.

  14. Immune Neuroendocrine Phenotypes in Coturnix coturnix: Do Avian Species Show LEWIS/FISCHER-Like Profiles?

    PubMed Central

    Nazar, F. Nicolas; Barrios, Bibiana E.; Kaiser, Pete; Marin, Raul H.; Correa, Silvia G.

    2015-01-01

    Immunoneuroendocrinology studies have identified conserved communicational paths in birds and mammals, e.g. the Hypothalamus-Pituitary-Adrenal axis with anti-inflammatory activity mediated by glucocorticoids. Immune neuroendocrine phenotypes (INPs) have been proposed for mammals implying the categorization of a population in subgroups underlying divergent immune-neuroendocrine interactions. These phenotypes were studied in the context of the LEWIS/FISCHER paradigm (rats expressing high or low pro-inflammatory profiles, respectively). Although avian species have some common immunological mechanisms with mammals, they have also evolved some distinct strategies and, until now, it has not been studied whether birds may also share with mammals similar INPs. Based on corticosterone levels we determined the existence of two divergent groups in Coturnix coturnix that also differed in other immune-neuroendocrine responses. Quail with lowest corticosterone showed higher lymphoproliferative and antibody responses, interferon-γ and interleukin-1β mRNA expression levels and lower frequencies of leukocyte subpopulations distribution and interleukin-13 levels, than their higher corticosterone counterparts. Results suggest the existence of INPs in birds, comparable to mammalian LEWIS/FISCHER profiles, where basal corticosterone also underlies responses of comparable variables associated to the phenotypes. Concluding, INP may not be a mammalian distinct feature, leading to discuss whether these profiles represent a parallel phenomenon evolved in birds and mammals, or a common feature inherited from a reptilian ancestor millions of years ago. PMID:25793369

  15. Longer-term increased cortisol levels in young people with mental health problems.

    PubMed

    Heinze, Kareen; Lin, Ashleigh; Reniers, Renate L E P; Wood, Stephen J

    2016-02-28

    Disturbance of hypothalamus-pituitary-adrenal axis activity is commonly reported in a range of mental disorders in blood, saliva and urine samples. This study aimed to look at longer-term cortisol levels and their association with clinical symptoms. Hair strands of 30 young people (16-25 years) presenting with mental health problems (Mage±SD=21±2.4, 26 females) and 28 healthy controls (HC, Mage±SD=20±2.9, 26 females) were analyzed for cortisol concentrations, representing the past 6 months prior to hair sampling. Clinical participants completed an assessment on psychiatric symptoms, functioning and lifestyle factors. All participants completed the Perceived Stress Scale. Hair cortisol concentrations representing the past 3 (but not 3-6) months were significantly increased in clinical participants compared to HC. Perceived stress in the past month was significantly higher in clinical participants compared to HC, but not significantly correlated with hair cortisol. Hair cortisol levels were not significantly associated with any other measures. Hair segment analyses revealed longer-term increased levels of cortisol in the past 3 months in early mental health problems. Further insight into the role of cortisol on the pathogenesis of mental illnesses requires longitudinal studies relating cortisol to psychopathology and progression of illness.

  16. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

    PubMed Central

    Viveros, María-Paz; Marco, Eva-María; Llorente, Ricardo; López-Gallardo, Meritxell

    2007-01-01

    The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long-term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms. PMID:17641734

  17. Enhancing effects of acute psychosocial stress on priming of non-declarative memory in healthy young adults.

    PubMed

    Hidalgo, Vanesa; Villada, Carolina; Almela, Mercedes; Espín, Laura; Gómez-Amor, Jesús; Salvador, Alicia

    2012-05-01

    Social stress affects cognitive processes in general, and memory performance in particular. However, the direction of these effects has not been clearly established, as it depends on several factors. Our aim was to determine the impact of the hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity to psychosocial stress on short-term non-declarative memory and declarative memory performance. Fifty-two young participants (18 men, 34 women) were subjected to the Trier Social Stress Task (TSST) and a control condition in a crossover design. Implicit memory was assessed by a priming test, and explicit memory was assessed by the Rey Auditory Verbal Learning Test (RAVLT). The TSST provoked greater salivary cortisol and salivary alpha-amylase (sAA) responses than the control task. Men had a higher cortisol response to stress than women, but no sex differences were found for sAA release. Stress was associated with an enhancement of priming but did not affect declarative memory. Additionally, the enhancement on the priming test was higher in those whose sAA levels increased more in response to stress (r(48) = 0.339, p = 0.018). Our results confirm an effect of acute stress on priming, and that this effect is related to SNS activity. In addition, they suggest a different relationship between stress biomarkers and the different memory systems.

  18. Stressed lungs: unveiling the role of circulating stress ...

    EPA Pesticide Factsheets

    Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction with lung lining components causing local oxidative changes, which then leads to cell damage and recruitment of inflammatory cells. It is postulated that the spillover of reactive intermediates and pro-inflammatory molecules from lung to systemic circulation mediates extra-pulmonary effects. However, recent work from our laboratory supports an alternative hypothesis that circulating stress hormones, such as epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects. We have shown in rats and humans that ozone increases the levels of circulating stress hormones through activation of the hypothalamus- pituitary-adrenal (HPA) axis before any measurable effects are observed in the lung. The surgical removal of adrenals diminishes circulating stress hormones and at the same time, the pulmonary effects of ozone suggesting a significant contribution of these hormones in ozone-induced lung injury and inflammation. While ozone effects in the lung have been extensively studied, the contribution of central nervous system -mediated hormonal stress response has not been examined. In order to understand the signaling pathways that might be involved in ozone-induced lun

  19. [Fetal pain - neurobiological causes and consequences].

    PubMed

    Gonçalves, Nuno; Rebelo, Sandra; Tavares, Isaura

    2010-01-01

    The existence of putatively painful situations to the fetus demands a careful evaluation of the issue of fetal pain. Several indirect approaches are used to evaluate the existence of fetal pain. Neurobiological studies showed that from the 30th week on, the anatomical and physiological system for pain transmission is already developed, with the connections from the periphery to the cortex being successively established. Stress responses to a painful stimulation are complex but they can be detected from the 16th week on. There is activation of the hypothalamus-pituitary-adrenal axis, autonomic nervous system and hemodynamic changes in response to nociceptive stimulation. In prematures exposed to pain there are significant increases of adrenaline, noradrenaline and cortisol, hemodynamic changes, motor reflexes and facial reactions. The changes induced by strong nociceptive stimulation of newborns have important postnatal consequences since they affect future reactions to noxious stimuli. Central sensitization and immaturity of the pain inhibitory system are the main neurobiological explanations for the increased pain. Detailed studies of the neurobiological mechanisms of the transmission of painful stimuli along with follow-up studies of the consequences of exposure to pain during the development of the fetus are necessary to fully understand fetal pain.

  20. Major off-axis hydrothermal activity on the northern Gorda Ridge

    USGS Publications Warehouse

    Rona, Peter A.; Denlinger, Roger P.; Fisk, M. R.; Howard, K. J.; Taghon, G. L.; Klitgord, Kim D.; McClain, James S.; McMurray, G. R.; Wiltshire, J. C.

    1990-01-01

    The first hydrothermal field on the northern Gorda Ridge, the Sea Cliff hydrothermal field, was discovered and geologic controls of hydrothermal activity in the rift valley were investigated on a dive series using the DSV Sea Cliff. The Sea Cliff hydrothermal field was discovered where predicted at the intersection of axis-oblique and axis-parallel faults at the south end of a linear ridge at mid-depth (2700 m) on the east wall. Preliminary mapping and smpling of the field reveal: a setting nested on nearly sediment-free fault blocks 300 m above the rift valley floor 2.6 km from the axis; a spectrum of venting types from seeps to black smokers; high conductive heat flow estimated to be equivalent to the convective flux of multiple black smokers through areas of the sea floor sealed by a caprock of elastic breccia primarily derived from basalt with siliceous cement and barite pore fillings; and a vent biota with Juan de Fuca Ridge affinites. These findings demonstrate the importance of off-axis hydrothermal activity and the role of the intersection of tectonic lineations in controlling hydrothermal sites at sea-floor spreading centers.

  1. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    PubMed

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.

  2. Recombinant human leptin attenuates stress axis activity in common carp (Cyprinus carpio L.).

    PubMed

    Gorissen, Marnix; Bernier, Nicholas J; Manuel, Remy; de Gelder, Stefan; Metz, Juriaan R; Huising, Mark O; Flik, Gert

    2012-08-01

    Proper functioning of the endocrine stress axis requires communication between the stress axis and other regulatory mechanisms. We here describe an intimate interplay between the stress axis and recombinant human leptin (rhLeptin) in a teleostean fish, the common carp Cyprinus carpio. Restraint stress (by netting up to 96h) increased plasma cortisol but did not affect hepatic leptin expression. Perifusion of pituitary glands or head kidneys with rhLeptin revealed direct effects of rhLeptin on both tissues. RhLeptin suppresses basal and CRF-induced ACTH-secretion in a rapid and concentration-dependent manner. The rhLeptin effect persisted for over an hour after administration had been terminated. RhLeptin decreases basal interrenal cortisol secretion in vitro, and by doing so attenuates ACTH-stimulated cortisol production; rhLeptin does not affect interrenal ACTH-sensitivity. Our findings show that the endocrine stress axis activity and leptin are inseparably linked in a teleostean fish, a notion relevant to further our insights in the evolution of leptin physiology in vertebrates.

  3. Immune Function and HPA Axis Activity in Free-Ranging Rhesus Macaques

    PubMed Central

    Hoffman, Christy L.; Higham, James P.; Heistermann, Michael; Coe, Christopher L.; Prendergast, Brian J.; Maestripieri, Dario

    2011-01-01

    In mammals, the hypothalamic-pituitary-adrenal (HPA) axis and immune system play an important role in the maintenance of homeostasis. Dysregulation of either system resulting, for example, from psychosocial or reproductive stress increases susceptibility to disease and mortality risk, especially in aging individuals. In a study of free-ranging rhesus macaques, we examined how female age, reproductive state, social rank, and body condition influence (i) aspects of cytokine biology (plasma concentrations of interleukin-1 receptor antagonist (IL-1ra), IL-6 and IL-8), and (ii) HPA axis activity (plasma and fecal glucocorticoid levels). We also assessed individual differences in cytokine and hormone concentrations over time to determine their consistency and to investigate relations between these two indicators of physiological regulation and demand. Female monkeys showed marked increases in HPA axis activity during pregnancy and lactation, and increased circulating levels of IL-1ra with advancing age. Inter-individual differences in IL-1ra and IL-8 were consistent over successive years, suggesting that both are stable, trait-like characteristics. Furthermore, the concentrations of fecal glucocorticoid hormones in non-pregnant, non-lactating females were correlated with their plasma cortisol and IL-8 concentrations. Some individuals showed permanently elevated cytokine levels or HPA axis activity, or a combination of the two, suggesting chronic stress or disease. Our results enhance our understanding of within- and between-individual variation in cytokine levels and their relationship with glucocorticoid hormones in free-ranging primates. These findings can provide the basis for future research on stress and allostatic load in primates. PMID:21635909

  4. The adrenocortical response of tufted puffin chicks to nutritional deficits

    USGS Publications Warehouse

    Kitaysky, A.S.; Romano, Marc D.; Piatt, J.F.; Wingfield, J.C.; Kikuchi, M.

    2005-01-01

    In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus-pituitary-adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation. 

  5. Associations between early life experience, chronic HPA axis activity, and adult social rank in rhesus monkeys.

    PubMed

    Dettmer, Amanda M; Wooddell, Lauren J; Rosenberg, Kendra L; Kaburu, Stefano S K; Novak, Melinda A; Meyer, Jerrold S; Suomi, Stephen J

    2017-02-01

    Early life experience and socioeconomic status (SES) are well-established predictors of health outcomes in people. Both factors likely influence health outcomes via hypothalamic-pituitary-adrenal (HPA) axis regulation. However, it is unclear how early experience and HPA axis activity influence adult social status. We studied differentially reared female rhesus monkeys (Macaca mulatta, N = 90) as models to test the hypothesis that chronic HPA axis activity assessed via hair cortisol concentrations (HCCs) mediated the relationship between early life experience and adult social rank. We found that mother-peer-reared (MPR) monkeys acquired higher social ranks than either of the two nursery-reared (NR) groups (peer-reared, PR, or surrogate-peer-reared, SPR monkeys) (β = -0.07, t(89) = -2.16, p = 0.034). We also found that MPR HCCs were lower during the juvenile period at 18 months (F(2,25) = 3.49, p = 0.047). Furthermore, for MPR but not NR monkeys, changes in HCCs from 18 to 24 months (r(s) = -0.627, p = 0.039) and adult HCCs (r(s) = -0.321, p = 0.03) were negatively correlated with adult social rank. These findings suggest that chronic HPA axis regulation in juvenility, and perhaps in adulthood, may influence adult social status for primates that experience typical early rearing. However, early life adversity may result in dissociation between neuroendocrine stress regulation and adult social competence, which may be risk factors for adverse health outcomes.

  6. HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression.

    PubMed

    Holsen, L M; Lancaster, K; Klibanski, A; Whitfield-Gabrieli, S; Cherkerzian, S; Buka, S; Goldstein, J M

    2013-10-10

    Decades of clinical and basic research indicate significant links between altered hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics and major depressive disorder (MDD). Recent neuroimaging studies of MDD highlight abnormalities in stress response circuitry regions which play a role in the regulation of the HPA-axes. However, there is a dearth of research examining these systems in parallel, especially as related to potential trait characteristics. The current study addresses this gap by investigating neural responses to a mild visual stress challenge with real-time assessment of adrenal hormones in women with MDD in remission and controls. Fifteen women with recurrent MDD in remission (rMDD) and 15 healthy control women were scanned on a 3T Siemens MR scanner while viewing neutral and negative (stress-evoking) stimuli. Blood samples were obtained before, during, and after scanning for the measurement of HPA-axis hormone levels. Compared to controls, rMDD women demonstrated higher anxiety ratings, increased cortisol levels, and hyperactivation in the amygdala and hippocampus, p<0.05, family-wise error (FWE)-corrected in response to the stress challenge. Among rMDD women, amygdala activation was negatively related to cortisol changes and positively associated with the duration of remission. Findings presented here provide evidence for differential effects of altered HPA-axis hormone dynamics on hyperactivity in stress response circuitry regions elicited by a well-validated stress paradigm in women with recurrent MDD in remission.

  7. Activity of the hypothalamus-pituitary-interrenal axis (HPI axis) and immune response in carp lines with different susceptibility to disease.

    PubMed

    Pijanowski, L; Jurecka, P; Irnazarow, I; Kepka, M; Szwejser, E; Verburg-van Kemenade, B M L; Chadzinska, M

    2015-10-01

    The stress response transmitted by the HPA axis is one of the best examples of neuroendocrine-immune interactions that are critical for survival. Analogous to the situation in mammals, the stress response in fish is characterized by the activation of the hypothalamo-pituitary-interrenal axis (HPI). Effects of cortisol on the fish immune system comply with findings in mammals and suggest that the differences in sensitivity to stress will influence the immune response and as a consequence of survival. Therefore, we studied the stress response and its immunity-related effects in four different carp lines (R3, R3xR8, K and R2) that display a differential pathogen susceptibility. Previous studies indicate that R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant to infection. Interestingly, the most striking effect of stress on leukocyte composition and activity was observed in the pathogen-resistant K carp, even though no robust changes in gene expression of stress-involved factors were observed. In contrast, R3 carp showed no spectacular stress-induced changes in their immunological parameters with concurrent significant activation of the HPI axis. Upon stress, the R3 carp showed up-regulation of crf, pomc and gr2 gene expression in the hypothalamus. Furthermore in R3 carp, at all levels of the HPI axis, stress induced the highest up-regulation of il-1β gene expression. Although we are aware of the complexity of the interactions between stress and pathogen susceptibility and of the risk of interpretation based on correlations, it is noteworthy that the fish more susceptible to infection also exhibited the highest response to stress.

  8. Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

    PubMed Central

    McIlwrick, Silja; Pohl, Tobias; Chen, Alon; Touma, Chadi

    2017-01-01

    Early-life stress (ELS) has been associated with lasting cognitive impairments and with an increased risk for affective disorders. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, the body’s main stress response system, is critically involved in mediating these long-term consequences of adverse early-life experience. It remains unclear to what extent an inherited predisposition for HPA axis sensitivity or resilience influences the relationship between ELS and cognitive impairments, and which neuroendocrine and molecular mechanisms may be involved. To investigate this, we exposed animals of the stress reactivity mouse model, consisting of three independent lines selectively bred for high (HR), intermediate (IR), or low (LR) HPA axis reactivity to a stressor, to ELS and assessed their cognitive performance, neuroendocrine function and hippocampal gene expression in early and in late adulthood. Our results show that HR animals that were exposed to ELS exhibited an HPA axis hyper-reactivity in early and late adulthood, associated with cognitive impairments in hippocampus-dependent tasks, as well as molecular changes in transcript levels involved in the regulation of HPA axis activity (Crh) and in neurotrophic action (Bdnf). In contrast, LR animals showed intact cognitive function across adulthood, with no change in stress reactivity. Intriguingly, LR animals that were exposed to ELS even showed significant signs of enhanced cognitive performance in late adulthood, which may be related to late-onset changes observed in the expression of Crh and Crhr1 in the dorsal hippocampus of these animals. Collectively, our findings demonstrate that the lasting consequences of ELS at the level of cognition differ as a function of inherited predispositions and suggest that an innate tendency for low stress reactivity may be protective against late-onset cognitive impairments after ELS. PMID:28261058

  9. Can parameters of the helical axis be measured reliably during active cervical movements?

    PubMed

    Barbero, Marco; Falla, Deborah; Clijsen, Ron; Ghirlanda, Filippo; Schneebeli, Alessandro; Ernst, Markus J; Cescon, Corrado

    2017-02-01

    Convex hull area (CHA) and mean angle (MA) have been proposed to describe the behaviour of the helical axis during joint kinematics. This study investigates the intra- and inter-session reliability of CHA and MA during active movements of the cervical spine. Twenty-seven healthy volunteers (19 women) aged 23 ± 2.8 years participated. Each volunteer was tested on two sessions. All participants were instructed to perform the following active movements of the cervical spine: rotation, flexion/extension and lateral bending, each performed to full range and repeated ten consecutive times. Cervical movements were registered with an electromagnetic tracking system. For each participant, each movement and each session, range of motion (ROM), CHA and MA were extracted. ROM showed high intra- and inter-session reliability during all cervical spine movements using this method. Overall, the intra- and inter-session reliability of the helical axis parameters varied depending on the movement direction and ranged from fair to almost perfect. The intra- and inter-session reliability of CHA and MA were almost perfect during rotation whereas the intra- and inter-session reliability of CHA was substantial during lateral bending and intra- and inter-session reliability of MA ranged from fair to substantial during flexion/extension and lateral bending. This is the first study to evaluate the reliability of helical axis measures during active movements of the cervical spine. The results show that CHA and MA are promising descriptors of cervical kinematics which could be applied in future studies to evaluate neck function in patients with cervical spine disorders.

  10. Stressor-specific effects of sex on HPA axis hormones and activation of stress-related neurocircuitry.

    PubMed

    Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge

    2013-11-01

    Experiencing stress can be physically and psychologically debilitating to an organism. Women have a higher prevalence of some stress-related mental illnesses, the reasons for which are unknown. These experiments explore differential HPA axis hormone release in male and female rats following acute stress. Female rats had a similar threshold of HPA axis hormone release following low intensity noise stress as male rats. Sex did not affect the acute release, or the return of HPA axis hormones to baseline following moderate intensity noise stress. Sensitive indices of auditory functioning obtained by modulation of the acoustic startle reflex by weak pre-pulses did not reveal any sexual dimorphism. Furthermore, male and female rats exhibited similar c-fos mRNA expression in the brain following noise stress, including several sex-influenced stress-related regions. The HPA axis response to noise stress was not affected by stage of estrous cycle, and ovariectomy significantly increased hormone release. Direct comparison of HPA axis hormone release to two different stressors in the same animals revealed that although female rats exhibit robustly higher HPA axis hormone release after restraint stress, the same effect was not observed following moderate and high intensity loud noise stress. Finally, the differential effect of sex on HPA axis responses to noise and restraint stress cannot readily be explained by differential social cues or general pain processing. These studies suggest the effect of sex on acute stress-induced HPA axis hormone activity is highly dependent on the type of stressor.

  11. The glucocorticoid receptor: pivot of depression and of antidepressant treatment?

    PubMed

    Anacker, Christoph; Zunszain, Patricia A; Carvalho, Livia A; Pariante, Carmine M

    2011-04-01

    Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and increased levels of glucocorticoid hormones in patients with depression have mostly been ascribed to impaired feedback regulation of the HPA axis, possibly caused by altered function of the receptor for glucocorticoid hormones, the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate many of the neurobiological disturbances in depression, including HPA axis hyperactivity, and thereby alleviate depressive symptoms. There is strong evidence for the notion that antidepressants exert these effects by modulating the GR. Such modulations, however, can be manifold and range from regulation of receptor expression to post-translational modifications, which may result in differences in GR nuclear translocation and GR-dependent gene transcription. The idea that the therapeutic action of antidepressants is mediated, at least in part, by restoring GR function, is consistent with studies showing that decreased GR function contributes to HPA axis hyperactivity and to the development of depressive symptoms. Conversely, excessive glucocorticoid signalling, which requires an active GR, is associated with functional impairments in the depressed brain, especially in the hippocampus, where it results in reduced neurogenesis and impaired neuroplasticity. In this review, we will focus on the GR as a key player in the precipitation, development and resolution of depression. We will discuss potential explanations for the apparent controversy between glucocorticoid resistance and the detrimental effects of excessive glucocorticoid signalling. We will review some of the evidence for modulation of the GR by antidepressants and we will provide further insight into how antidepressants may regulate the GR to overcome depressive symptoms.

  12. Active Design Method for the Static Characteristics of a Piezoelectric Six-Axis Force/Torque Sensor

    PubMed Central

    Liu, Jun; Li, Min; Qin, Lan; Liu, Jingcheng

    2014-01-01

    To address the bottleneck issues of an elastic-style six-axis force/torque sensor (six-axis force sensor), this work proposes a no-elastic piezoelectric six-axis force sensor. The operating principle of the piezoelectric six-axis force sensor is analyzed, and a structural model is constructed. The static-active design theory of the piezoelectric six-axis force sensor is established, including a static analytical/mathematical model and numerical simulation model (finite element model). A piezoelectric six-axis force sensor experimental prototype is developed according to the analytical mathematical model and numerical simulation model, and selected static characteristic parameters (including sensitivity, isotropic degree and cross-coupling) are tested using this model with three approaches. The measured results are in agreement with the analytical results from the static-active design method. Therefore, this study has successfully established a foundation for further research into the piezoelectric multi-axis force sensor and an overall design approach based on static characteristics. PMID:24451460

  13. Sound conditioning protects hearing by activating the hypothalamic-pituitary-adrenal axis.

    PubMed

    Tahera, Yeasmin; Meltser, Inna; Johansson, Peter; Salman, Hazim; Canlon, Barbara

    2007-01-01

    Sound conditioning primes the auditory system to low levels of acoustic stimuli and reduces damage caused by a subsequent acoustic trauma. This priming activates the HPA axis resulting in the elevation of plasma corticosterone with a consequent upregulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus in the mouse. This protective effect is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone. Sound conditioning prevents GR down-regulation induced by acoustic trauma and subsequently enhances GR activity in spiral ganglion neurons. Increased SRC-1 expression, triggered by sound conditioning, positively correlates with the upregulation of GR in the cochlea. These findings will help to define the cellular mechanisms responsible for protecting the auditory system from hearing loss by sound conditioning.

  14. Hypothalamic-pituitary-adrenal axis activity in patients with pathological gambling and internet use disorder.

    PubMed

    Geisel, Olga; Panneck, Patricia; Hellweg, Rainer; Wiedemann, Klaus; Müller, Christian A

    2015-03-30

    Alterations in secretion of stress hormones within the hypothalamic-pituitary-adrenal (HPA) axis have repeatedly been found in substance-related addictive disorders. It has been suggested that glucocorticoids might contribute to the development and maintenance of substance use disorders by facilitatory effects on behavioral responses to substances of abuse. The objective of this pilot study was to investigate HPA axis activity in patients with non-substance-related addictive disorders, i.e. pathological gambling and internet use disorder. We measured plasma levels of copeptin, a vasopressin surrogate marker, adrenocorticotropic hormone (ACTH) and cortisol in male patients with pathological gambling (n=14), internet use disorder (n=11) and matched healthy controls for pathological gambling (n=13) and internet use disorder (n=10). Plasma levels of copeptin, ACTH and cortisol in patients with pathological gambling or internet use disorder did not differ among groups. However, cortisol plasma levels correlated negatively with the severity of pathological gambling as measured by the PG-YBOCS. Together with our findings of increased serum levels of brain-derived neurotrophic factor (BDNF) in pathological gambling but not internet use disorder, these results suggest that the pathophysiology of pathological gambling shares some characteristics with substance-related addictive disorders on a neuroendocrinological level, whereas those similarities could not be observed in internet use disorder.

  15. Cranial irradiation modulates hypothalamic-pituitary-adrenal axis activity and corticosteroid receptor expression in the hippocampus of juvenile rat.

    PubMed

    Velickovic, Natasa; Djordjevic, Ana; Drakulic, Dunja; Stanojevic, Ivana; Secerov, Bojana; Horvat, Anica

    2009-01-01

    Glucocorticoids, essential for normal hypothalamic-pituitary-adrenal (HPA) axis activity, exert their action on the hippocampus through two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Recent studies report that exposure of juvenile rats to cranial irradiation adversely affects HPA axis stability leading to its activation along with radiation- induced inflammation. This study was aimed to examine the acute effects of radiation on HPA axis activity and hippocampal corticosteroid receptor expression in 18-day-old rats. Since immobilization was part of irradiation procedure, both irradiated and sham-irradiated animals were exposed to this unavoidable stress. Our results demonstrate that the irradiated rats exhibited different pattern of corticosteroid receptor expression and hormone levels compared to respective controls. These differences included upregulation of GR protein in the hippocampus with a concomitant elevation of GR mRNA and an increase in circulating level of corticosterone. In addition, the expression of MR, both at the level of protein and gene expression, was not altered. Taken together, this study demonstrates that cranial irradiation in juvenile rats leads to enhanced HPA axis activity and increased relative GR/MR ratio in hippocampus. The present paper intends to show that neuroendocrine response of normal brain tissue to localized irradiation comprise both activation of HPA axis and altered corticosteroid receptor balance, probably as consequence of innate immune activation.

  16. Sucralose activates an ERK1/2-ribosomal protein S6 signaling axis.

    PubMed

    Guerra, Marcy L; Kalwat, Michael A; McGlynn, Kathleen; Cobb, Melanie H

    2017-02-01

    The sweetener sucralose can signal through its GPCR receptor to induce insulin secretion from pancreatic β cells, but the downstream signaling pathways involved are not well-understood. Here we measure responses to sucralose, glucagon-like peptide 1, and amino acids in MIN6 β cells. Our data suggest a signaling axis, whereby sucralose induces calcium and cAMP, activation of ERK1/2, and site-specific phosphorylation of ribosomal protein S6. Interestingly, sucralose acted independently of mTORC1 or ribosomal S6 kinase (RSK). These results suggest that sweeteners like sucralose can influence β-cell responses to secretagogues like glucose through metabolic as well as GPCR-mediated pathways. Future investigation of novel sweet taste receptor signaling pathways in β cells will have implications for diabetes and other emergent fields involving these receptors.

  17. Basal activity of the HPA axis and cognitive function in anorexia nervosa.

    PubMed

    Seed, Julie A; McCue, Patricia M; Wesnes, Keith A; Dahabra, Sylvia; Young, Allan H

    2002-03-01

    Elevated cortisol and cognitive impairments have been described in anorexia nervosa, but the relationship between these two variables has not been adequately explored. We profiled the pattern and extent of the cognitive impairment in anorexia nervosa and determined how this related to cortisol secretion. Twenty patients with anorexia nervosa and a matched control group completed a computerized cognitive assessment battery. Diurnal cortisol secretion was measured by serial saliva sampling. Patients were significantly impaired on tasks of attention, long-term memory and working memory. Both groups showed the expected diurnal variation in cortisol production, but no evidence was found for patient cortisol hypersecretion. No correlation was found between cortisol secretion and any of the cognitive task measures. These data suggest that at least some of the cognitive impairments seen in anorexia nervosa are attributable to something other than a basal increase in cortisol secretion. The limitations of cortisol as an indicator of HPA axis activity are discussed.

  18. Kisspeptin activates the hypothalamic-adenohypophyseal-gonadal axis in prepubertal ewe lambs.

    PubMed

    Redmond, J S; Macedo, G G; Velez, I C; Caraty, A; Williams, G L; Amstalden, M

    2011-04-01

    The onset of puberty in mammals involves an increase in the pulsatile release of GNRH and LH. The KISS1 gene is essential for pubertal development, and its product, kisspeptin, stimulates the release of LH. The objective of this study was to determine the effects of kisspeptin in the hypothalamic-adenohypophyseal-gonadal axis of prepubertal ewe lambs. Ewe lambs (28 weeks of age) were treated intravenously with saline (control, n=6) or kisspeptin (20 μg kisspeptin; n=6) every hour for 24 h. Kisspeptin stimulated pulse-like release of LH within 15 min following injections, and increased the frequency and amplitude of LH pulses, and mean circulating concentrations of LH and estradiol. A surge-like release of LH was observed in four kisspeptin-treated lambs beginning 17 h after the onset of treatment, and all four lambs had elevated circulating concentrations of progesterone within 5 days post-treatment. However, circulating concentrations of progesterone decreased within 2 days after the initial rise in three of the four ewe lambs, indicating that induced luteal activity was of short duration. The proportion of lambs that were pubertal (defined by circulating concentrations of progesterone above 1 ng/ml for at least 7 days) by 35 weeks of age (8/11) and the mean age at puberty (32 ± 1 weeks) for those reaching puberty within the experimental period did not differ between treatments. Results support a role for kisspeptin in the activation of the hypothalamic-adenohypophyseal axis leading to the onset of puberty in ewe lambs.

  19. 3xTg-AD Mice Exhibit an Activated Central Stress Axis during Early-Stage Pathology

    PubMed Central

    Hebda-Bauer, Elaine K.; Simmons, Tracy A.; Sugg, Andrew; Ural, Eren; Stewart, James A.; Beals, James L.; Wei, Qiang; Watson, Stanley J.; Akil, Huda

    2012-01-01

    Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism’s innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer’s disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal glucocorticoid levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3–4-month-old 3xTg-AD mice. Despite normal glucocorticoid levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits. PMID:22976078

  20. Starring role of toll-like receptor-4 activation in the gut-liver axis

    PubMed Central

    Carotti, Simone; Guarino, Michele Pier Luca; Vespasiani-Gentilucci, Umberto; Morini, Sergio

    2015-01-01

    Since the introduction of the term “gut-liver axis”, many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types. PMID:26600967

  1. Microbial activity in surface sediments of Chacopata-Bocaripo lagoon axis, Sucre State, Venezuela.

    PubMed

    Segnini de B, Mary Isabel; Gómez, Irma; Brito, Leonor; Acosta, Vanessa; Troccoli, Luis

    2015-02-28

    The aim of this work was to evaluate the microbial activity of the surface sediments (0-10 cm) of the Chacopata-Bocaripo lagoon axis (Ch-BLA) through microbiological parameters: microbial biomass (Cmic) dehydrogenase activity (DHS), fluorescein diacetate hydrolysis (HFDA), arginine ammonification (AA) and biochemical parameters: phosphatase (PHa) and urease (URa) activity. They were determined during transition (July 2010) and upwelling (March 2011) periods. Total organic carbon (TOC) did not vary significantly (p⩾0.05) between climatic periods. All the parameters studied were higher in upwelling season: Cmic (191.79 mg Cmic kg(-1)), DHS (228.70 μg TFF g(-1) 24 h(-1)), HFDA (204.09 μg fluorescein g(-1) 24 h(-1)), AA (13.09 μg NH4-N g(-1) h(-1)), PHa (132.31 μg pNF g(-1) h(-1)), URa (12.90 μg NH4-N g(-1) h(-1)). They appear to be controlled by the availability and quality of nutrients in each climatic period, and were useful tools for evaluating changes in microbial activity in marine sediments.

  2. Stretching the stress boundary: Linking air pollution health effects to a neurohormonal stress response.

    PubMed

    Kodavanti, Urmila P

    2016-12-01

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer's and diabetes. A neurohormonal stress response (referred to here as a systemic response produced by activation of the sympathetic nervous system and hypothalamus-pituitary-adrenal (HPA)-axis) has been implicated in a variety of psychological and physical stresses, which involves immune and metabolic homeostatic mechanisms affecting all organs in the body. In this review, we provide new evidence for the involvement of this well-characterized neurohormonal stress response in mediating systemic and pulmonary effects of a prototypic air pollutant - ozone. A plethora of systemic metabolic and immune effects are induced in animals exposed to inhaled pollutants, which could result from increased circulating stress hormones. The release of adrenal-derived stress hormones in response to ozone exposure not only mediates systemic immune and metabolic responses, but by doing so, also modulates pulmonary injury and inflammation. With recurring pollutant exposures, these effects can contribute to multi-organ chronic conditions associated with air pollution. This review will cover, 1) the potential mechanisms by which air pollutants can initiate the relay of signals from respiratory tract to brain through trigeminal and vagus nerves, and activate stress responsive regions including hypothalamus; and 2) the contribution of sympathetic and HPA-axis activation in mediating systemic homeostatic metabolic and immune effects of ozone in various organs. The potential contribution of chronic environmental stress in cardiovascular, neurological, reproductive and metabolic diseases, and the knowledge gaps are also discussed. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

  3. Diazepam increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity by a cyclic AMP-dependent mechanism

    PubMed Central

    Vargas, M Luisa; Abella, Cristina; Hernandez, Jesus

    2001-01-01

    Previous studies in this laboratory have shown that diazepam behaves as a phosphodiesterase 4 (PDE 4) inhibitor. It has been reported that PDE-4 inhibitors activate the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat. In the present study we have examined whether activation of the cyclic AMP-dependent protein kinase (PKA) is involved in the effect of diazepam on basal HPA axis activity. Acute systemic administration of diazepam (10 mg kg−1 i.p.) was found to increase the basal HPA axis activity, increasing the plasma concentrations of corticotrophin (ACTH) and corticosterone 30 min post injection. Diazepam also elevated cyclic AMP content of the hypothalamus. Pretreatment of the animals with dexamethasone (1 mg kg−1 s.c.) for 3 days completely abolished the effect of diazepam on HPA axis activity. The antagonists of central and peripheral benzodiazepine receptors, flumazenil (10 mg kg−1 i.p.) and PK 11195 (5 mg kg−1 i.p.) did not affect the diazepam induced increase of HPA axis activity nor did they have an effect per se. The increase in ACTH and corticosterone levels was significantly reduced by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H-89, given either subcutaneously (5 mg kg−1 s.c.) or intracerebroventricularly (i.c.v.; 28 μg in 10 μl). The results indicate that diazepam can stimulate basal HPA axis activity in the rat by a cyclic AMP-dependent PKA mediated pathway. PMID:11498522

  4. Neuroendocrine-immune disorder in type 2 diabetic patients with retinopathy.

    PubMed

    Obulkasim, Mutallip; Turdi, Ablikim; Amat, Nurmuhammat; Haxim, Muhtar; Eziz, Rena; Haji, Hurxide; Li, Linlin; Chen, Xueyi; Upur, Halmurat; Ren, Jun

    2011-04-01

    1. Diabetes mellitus is usually accompanied by hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis. Diabetic retinopathy is one of the most devastating complications in diabetes although little is known with regards to the HPA activity in type 2 diabetic patients (T2DM) with diabetic retinopathy. The present study was designed to evaluate the HPA axis activity in type 2 diabetic patients with diabetic retinopathy. 2. Diabetic retinopathy was examined by fluorescein fundus angiography (FFA) in 174 consecutive type 2 diabetic patients. Levels of / were measured using flow cytometry. Serum concentrations of interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α), adrenocorticotrophic hormone (ACTH) and cortisone were measured by radioimmunoassay. Plasma levels of monoamines norepinephrine (NE) and dopamine (DA) were assessed using high performance liquid chromatograph equipped with a fluorescence detection. Patients were grouped into the non-diabetic retinopathy (NDR), non-proliferating diabetic retinopathy (NPR) and proliferating diabetic retinopathy (PDR) categories. 3. Patients with PDR showed significantly less than those with NDR and NPR (P<0.05). No significant correlation was found in / and NK or severity of retinopathy among the three patient groups. There was no significant difference in serum IL-1β, IL-6 and TNF-α levels among the different patient groups (P>0.05). The serum concentrations of ACTH and cortisone were lower in PDR patients than other groups. There was no significant difference in plasma concentrations of DA and NE among all three groups (P>0.05). 4. Our data suggest that HPA and immune dysfunction might play a role in the development and/or progression of PDR.

  5. Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder.

    PubMed

    Jazayeri, Shima; Keshavarz, Seyed A; Tehrani-Doost, Mehdi; Djalali, Mahmood; Hosseini, Mostafa; Amini, Homayoun; Chamari, Maryam; Djazayery, Abolghassem

    2010-06-30

    Treatment studies have suggested that omega-3 fatty acids (omega-3 FAs) as monotherapy or adjunctive treatment have therapeutic effects in depression. The authors recently reported a study in which fluoxetine and eicosapentaenoic acid (EPA), which is an omega-3 fatty acid, appeared to be equally effective in controlling depressive symptoms and their combination was superior to either of them alone. Regulation of hypothalamus-pituitary-adrenal (HPA) axis activity and reduction of inflammatory cytokines are among several biological mechanisms which potentially explain the impact of omega-3 FAs on depression. In the present study, plasma cortisol and serum interleukin-1beta (IL-1 beta) and interleukin-6 (Il-6) were measured in patients with a diagnosis of major depressive disorder (MDD) participating in aforementioned trial to determine the effects of 8 weeks of treatment of depression with 1000 mg EPA alone or in combination with 20 mg fluoxetine on HPA axis activity and inflammatory cytokine production and compare the changes in these variables with those of treating with 20 mg fluoxetine alone. Forty-two patients were included in analysis. Two-way repeated measures analysis of variance (ANOVA) showed that plasma cortisol decreased significantly after 8 weeks of intervention without significant difference among the groups. There was no interaction between group and response to treatment over time in the cortisol response based on three-way ANOVA. Serum concentrations of IL-1beta and IL-6 did not change significantly after intervention. In conclusion, EPA alone or in combination with fluoxetine, as well as fluoxetine alone decreased serum cortisol after 8 weeks of treatment in patients with major depression disorder (MDD) without any significant effect of response to treatment. Serum IL-1beta and IL-6 did not change significantly after intervention. These findings suggest that EPA may exert its therapeutic effects through reduction of cortisol.

  6. Garment-based detection of falls and activities of daily living using 3-axis MEMS accelerometer

    NASA Astrophysics Data System (ADS)

    Nyan, M. N.; Tay, Francis E. H.; Manimaran, M.; Seah, K. H. W.

    2006-04-01

    This paper studied the detection of falls and activities of daily living (ADL) with two objectives: (1) minimum number of sensors for a broad range of activities and (2) maximize the comfort of the wearer for long term use. We used a garment to provide long term comfort for the wearer, with a 3-axis MEMS accelerometer on the shoulder position, as a wearable platform. ADL were detected in time-frequency domain and summation of absolute peak values of 3-D acceleration signals was used as feature in fall detection. 6 male and female subjects performed approximately five-hour long experiment. Sensitivity of 94.98% and specificity of 98.83% for altogether 1495 activities were achieved. Our garment-based detection system fulfilled the objective of providing the comfort of the wearer in long term monitoring of falls and ADL with high sensitivity. In fall detection, our device can summon medical assistances via SMS (Short Message Service). This detection system can raise fall alarm (fall SMS) automatically to individuals to get a shortened interval of the arrival of assistance.

  7. Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women

    PubMed Central

    Ge, Fiona; Pietromonaco, Paula R.; DeBuse, Casey J.; Powers, Sally I.; Granger, Douglas A.

    2016-01-01

    We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only – not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu. PMID:27494071

  8. The CXCR4/SDF1 Axis Improves Muscle Regeneration Through MMP-10 Activity

    PubMed Central

    Bobadilla, Miriam; Sainz, Neira; Abizanda, Gloria; Orbe, Josune; Rodriguez, José Antonio; Páramo, José Antonio; Prósper, Felipe

    2014-01-01

    The CXCR4/SDF1 axis participates in various cellular processes, including cell migration, which is essential for skeletal muscle repair. Although increasing evidence has confirmed the role of CXCR4/SDF1 in embryonic muscle development, the function of this pathway during adult myogenesis remains to be fully elucidated. In addition, a role for CXCR4 signaling in muscle maintenance and repair has only recently emerged. Here, we have demonstrated that CXCR4 and stromal cell-derived factor-1 (SDF1) are up-regulated in injured muscle, suggesting their involvement in the repair process. In addition, we found that notexin-damaged muscles showed delayed muscle regeneration on treatment with CXCR4 agonist (AMD3100). Accordingly, small-interfering RNA-mediated silencing of SDF1 or CXCR4 in injured muscles impaired muscle regeneration, whereas the addition of SDF1 ligand accelerated repair. Furthermore, we identified that CXCR4/SDF1-regulated muscle repair was dependent on matrix metalloproteinase-10 (MMP-10) activity. Thus, our findings support a model in which MMP-10 activity modulates CXCR4/SDF1 signaling, which is essential for efficient skeletal muscle regeneration. PMID:24548137

  9. A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala.

    PubMed

    Streit, Fabian; Haddad, Leila; Paul, Torsten; Frank, Josef; Schäfer, Axel; Nikitopoulos, Jörg; Akdeniz, Ceren; Lederbogen, Florian; Treutlein, Jens; Witt, Stephanie; Meyer-Lindenberg, Andreas; Rietschel, Marcella; Kirsch, Peter; Wüst, Stefan

    2014-07-01

    We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

  10. Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress.

    PubMed

    Gastón, M S; Cid, M P; Salvatierra, N A

    2017-03-01

    Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor.

  11. Brain connectivity is altered by extreme physical exercise during non-REM sleep and wakefulness: indications from EEG and fMRI studies.

    PubMed

    Menicucci, D; Gentili, C; Piarulli, A; Laurino, M; Pellegrini, S; Mastorci, F; Bedini, R; Montanaro, D; Sebastiani, L; Gemignani, A

    2016-12-01

    Brain connectivity is associated to behavioral states (e.g. wake, sleep) and modified by physical activity although, to date, it is not clear which components (e.g. hypothalamus-pituitary-adrenal axis hormones, cytokines) associated to the exercise are involved. In this pilot study, we used extreme exercise (UltraTriathlon) as a model to investigate physical-activity-related changes of brain connectivity. We studied post-race brain synchronization during wakefulness and sleep as well as possible correlations between exercise-related cytokines/hormones and synchronization features. For wakefulness, global synchronization was evaluated by estimating from fMRI data (12 athletes) the brain global connectivity (GC). GC increased in several brain regions, mainly related to sensory-motor activity, emotional modulation and response to stress that may foster rapid exchange of information across regions, and reflect post-race internally-focused mental activity or disengagement from previous motor programs. No significant correlations between cytokines/hormones and GC were found. For sleep (8 athletes), synchronization was evaluated by estimating the local-(cortical) and global-related (thalamo- cortical) EEG features associated to the phenomenon of Sleep Slow Oscillations (SSO) of NREM sleep. Results showed that: power of fast rhythms in the baseline preceding the SSO increased in midline and parietal regions; amplitude and duration of SSOs increased, mainly in posterior areas; sigma modulation in the SSO up state decreased. In the post race, IL-10 positively correlated with fast rhythms baseline, SSO rate and positive slope; IL-1ra and cortisol inversely correlated with SSO duration; TNF-α and C-reactive protein positively correlated with fast rhythm modulation in the SSO up state. Sleep results suggest that: arousal during sleep, estimated by baseline fast rhythms, is increased; SSO may be sustained by cortical excitability, linked to anti-inflammatory markers (IL-10

  12. Antidepressant-like effects of Sanyuansan in the mouse forced swim test, tail suspension test, and chronic mild stress model.

    PubMed

    Yan, Shuo; You, Zi-Li; Zhao, Qiu-Ying; Peng, Cheng; He, Gang; Gou, Xiao-Jun; Lin, Bin

    2015-12-01

    Natural products have been widely reported as effective therapeutic alternatives for treatment of depression. Sanyuansan is a compound recipe composed of ginseng total saponins, fish oil, and valeriana. The aims of this study were to validate whether Sanyuansan has antidepressant-like effects through acute behavioral tests including the forced swimming test (FST), tail suspension test (TST), locomotor activity test, and chronic mild stress (CMS) mice model of depression. C57BL/6 mice were given oral administration of 30 mg/kg imipramine, Sanyuansan, and saline, respectively. The acute behavioral tests including the TST, FST, and locomotor activity test were done after the administration of drugs for consecutively three times (24 hours, 1 hour, and 0.5 hour prior to the tests). Furthermore, the sucrose preference and the serum corticosterone level of mice in the CMS model were examined. Sanyuansan only at 900 mg/kg markedly reduced immobility time in the TST compared with the saline-treated group of mice. Sanyuansan at doses of 225 mg/kg, 450 mg/kg, and 900 mg/kg significantly reduced immobility time of mice in the FST. Sanyuansan reversed the CMS-induced anhedonia and hyperactivation of the hypothalamus-pituitary-adrenal axis. In addition, our results showed that neither imipramine nor Sanyuansan at any dosage increased spontaneous motor activity. These results suggested that Sanyuansan induced significant antidepressant-like effects in mice in both acute and chronic animal models, which seemed unlikely to be attributed to an increase in locomotor activities of mice, and had no sedative-like effects.

  13. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.

    PubMed

    Hsu, Kai-Wen; Hsieh, Rong-Hong; Huang, Kuo-Hung; Fen-Yau Li, Anna; Chi, Chin-Wen; Wang, Tzu-Yin; Tseng, Min-Jen; Wu, Kou-Juey; Yeh, Tien-Shun

    2012-08-01

    Gastric carcinoma is one of the most common malignancies and a lethal cancer in the world. Notch signaling and transcription factors STAT3 (signal transducer and activator of transcription 3) and Twist regulate tumor development and are critical regulators of gastric cancer progression. Herein, the relationship among Notch, STAT3 and Twist pathways in the control of gastric cancer progression was studied. We found that Twist and phosphorylated STAT3 levels were promoted by the activated Notch1 receptor in human stomach adenocarcinoma SC-M1, embryonic kidney HEK293 and erythroleukemia K562 cells. Notch1 signaling dramatically induced Twist promoter activity through a C promoter binding factor-1-independent manner and STAT3 phosphorylation. Overexpression of Notch1 receptor intracellular domain (N1IC) enhanced the interaction between nuclear STAT3 and Twist promoter in cells. Gastric cancer progression of SC-M1 cells was promoted by N1IC through STAT3 phosphorylation and Twist expression including colony formation, migration and invasion. STAT3 regulated gastric cancer progression of SC-M1 cells via Twist. N1IC also elevated the progression of other gastric cancer cells such as AGS and KATO III cells through STAT3 and Twist. The N1IC-promoted tumor growth and lung metastasis of SC-M1 cells in mice were suppressed by the STAT3 inhibitor JSI-124 and Twist knockdown. Furthermore, Notch1 and Notch ligand Jagged1 expressions were significantly associated with phosphorylated STAT3 and Twist levels in gastric cancer tissues of patients. Taken together, these results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy.

  14. Active Control of a Moving Noise SOURCE—EFFECT of Off-Axis Source Position

    NASA Astrophysics Data System (ADS)

    GUO, J.; PAN, J.; HODGSON, M.

    2002-03-01

    An optimally arranged multiple-channel active-control system is known to be able to create a large quiet zone in free space for a stationary primary noise source. When the primary noise source moves, the active control of the noise becomes much more difficult, as the primary noise field changes with time in space. In this case, the controller of the control system must respond fast enough to compensate for the change; much research has been focused on this issue. In this paper, it is shown that a moving source also causes difficulties from an acoustical perspective. A moving source not only changes continuously the strengths and phases of the sound field in the space, but also changes the wavefront of the primary sound field continuously. It is known that the efficiency of active noise control is determined mainly by the wavefront matching between the primary and control fields. To keep the control system effective in the case of a moving source, the wavefront of the control field needs to change, in order to continuously match the primary-wavefront change. This paper shows that there are limitations to the control-wavefront change. An optimally pre-arranged, multiple-channel control system is not able to construct a matching wavefront when the primary source moves outside a certain range. In other words, the control system is still able to create a large quiet zone only when the primary source moves within a range around the central axis of the control system. Both the location and the size of the quiet zone change with the location of the primary source.

  15. SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

    PubMed Central

    Kim, Kwang-Youn; Jang, Hyun-Jun; Yang, Yong Ryul; Park, Kwang-Il; Seo, JeongKon; Shin, Il-Woo; Jeon, Tae-Il; Ahn, Soon-cheol; Suh, Pann-Ghill; Osborne, Timothy F.; Seo, Young-Kyo

    2016-01-01

    Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients. PMID:27767079

  16. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.

    PubMed

    Ablain, Julien; Rice, Kim; Soilihi, Hassane; de Reynies, Aurélien; Minucci, Saverio; de Thé, Hugues

    2014-02-01

    Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

  17. Exploring for Volcanic and Hydrothermal Activity Above Off-axis Melt Lenses near the East Pacific Rise

    NASA Astrophysics Data System (ADS)

    White, S. M.; Lee, A. J.; Rubin, K. H.

    2015-12-01

    Two Alvin dives (AL 4771 and 4774) transected the seafloor directly above the two largest Off-Axis Melt Lenses (O-AML) east of the East Pacific Rise (EPR) axis at 9 39'N and 9 54'N. In 2008, a 3D high-resolution seismic reflection survey (MGL-0812) discovered O-AMLs 3-7 km from the EPR at 2-3 km below the seafloor. Several other O-AML in the crust have been subsequently detected in several locations up to 20 km from the spreading axis at fast and intermediate spreading ridges; understanding their impacts is increasingly important. During the dives, no currently active hydrothermal venting or fresh lava was seen, suggesting that these features do not constantly power off-axis geological activity. However, the seafloor appears much younger at small volcanic seamounts in the 9 39'N than at the 9 54'N site. At 9 39'N, we used Alvin to explore the off-axis volcanic mound complex, reaching the summit of the three largest mounds. Although no evidence for on-going hydrothermal or volcanic activity was detected, the seafloor wore a thin sediment layer of ~10cm and thin Mn-coatings on 9 rock samples, suggesting volcanism more recently than would be expected based on the spreading-rate age of the crust. At 9 54'N, the Alvin trackline started south of a prominent abyssal hill, which has an unusual D-shape over 1 km wide in the center, crossed the abyssal hill, visited two local hummocks on top, and then attempted to find volcanic activity on the near slope of EPR axis by going as far west was possible during the dive. Heavy sediment everywhere on the abyssal hill, to the depth of push cores (~30 cm) and probably much deeper in many areas and 4 rock samples from the abyssal hill were quite weathered with little glass intact, suggest that this site is unaffected by the underlying O-AML. Upslope toward the EPR west of the abyssal hill, 4 rocks collected appear somewhat younger, and sediment became thinner. In addition, 3 CTD tow-yos over each O-AML found no evidence of active

  18. Exploring for Volcanic and Hydrothermal Activity Above Off-axis Melt Lenses near the East Pacific Rise

    NASA Astrophysics Data System (ADS)

    West, A. J.; Torres, M. A.; Nealson, K. H.

    2014-12-01

    Two Alvin dives (AL 4771 and 4774) transected the seafloor directly above the two largest Off-Axis Melt Lenses (O-AML) east of the East Pacific Rise (EPR) axis at 9 39'N and 9 54'N. In 2008, a 3D high-resolution seismic reflection survey (MGL-0812) discovered O-AMLs 3-7 km from the EPR at 2-3 km below the seafloor. Several other O-AML in the crust have been subsequently detected in several locations up to 20 km from the spreading axis at fast and intermediate spreading ridges; understanding their impacts is increasingly important. During the dives, no currently active hydrothermal venting or fresh lava was seen, suggesting that these features do not constantly power off-axis geological activity. However, the seafloor appears much younger at small volcanic seamounts in the 9 39'N than at the 9 54'N site. At 9 39'N, we used Alvin to explore the off-axis volcanic mound complex, reaching the summit of the three largest mounds. Although no evidence for on-going hydrothermal or volcanic activity was detected, the seafloor wore a thin sediment layer of ~10cm and thin Mn-coatings on 9 rock samples, suggesting volcanism more recently than would be expected based on the spreading-rate age of the crust. At 9 54'N, the Alvin trackline started south of a prominent abyssal hill, which has an unusual D-shape over 1 km wide in the center, crossed the abyssal hill, visited two local hummocks on top, and then attempted to find volcanic activity on the near slope of EPR axis by going as far west was possible during the dive. Heavy sediment everywhere on the abyssal hill, to the depth of push cores (~30 cm) and probably much deeper in many areas and 4 rock samples from the abyssal hill were quite weathered with little glass intact, suggest that this site is unaffected by the underlying O-AML. Upslope toward the EPR west of the abyssal hill, 4 rocks collected appear somewhat younger, and sediment became thinner. In addition, 3 CTD tow-yos over each O-AML found no evidence of active

  19. The psychology of HPA axis activation: Examining subjective emotional distress and control in a phobic fear exposure model.

    PubMed

    Mayer, Stefanie E; Snodgrass, Michael; Liberzon, Israel; Briggs, Hedieh; Curtis, George C; Abelson, James L

    2017-02-09

    The HPA axis plays a key role in mediating the effects of "stress" on health, but clarifying mechanisms requires an understanding of psycho-biological linkages. There has long been an implicit assumption that subjective emotional distress (e.g., fear) should activate the HPA axis. Although this assumption was challenged 25 years ago (Curtis, 1976), laboratory studies in humans are limited. In this study we sought to replicate Curtis' findings and extend it by investigating if presence or absence of stressor control shapes HPA axis reactivity in a phobic fear exposure model. We recruited 19-45-year-old specific phobia participants (n=32 spider/snake phobia; n=14 claustrophobia) and gradually exposed them to their feared object or situation while measuring hormonal (ACTH and cortisol) and subjective (emotional distress, perceived control) responses. Utilizing a dyadic yoked design, we compared HPA reactivity when the pace of exposure was controlled by participants to identical exposure given to matched participants in the absence of control. Results showed that phobic fear exposure generated intense emotional distress without a corresponding increase in HPA axis activity. Although our actual manipulation of control failed to impact HPA responses, perceived control during exposure was associated with lower cortisol, an effect that was moderated by actual availability of stressor control. Our findings replicate Curtis' findings and challenge the still common but unsupported assumption that HPA axis activity reflects subjective distress. These results also highlight the importance of both perceived and actual aspects of stressor control in understanding what is truly "stressful" to the HPA axis system.

  20. I'll take the low road: the evolutionary underpinnings of visually triggered fear

    PubMed Central

    Carr, James A.

    2015-01-01

    Although there is general agreement that the central nucleus of the amygdala (CeA) is critical for triggering the neuroendocrine response to visual threats, there is uncertainty about the role of subcortical visual pathways in this process. Primates in general appear to depend less on subcortical visual pathways than other mammals. Yet, imaging studies continue to indicate a role for the superior colliculus and pulvinar nucleus in fear activation, despite disconnects in how these brain structures communicate not only with each other but with the amygdala. Studies in fish and amphibians suggest that the neuroendocrine response to visual threats has remained relatively unchanged for hundreds of millions of years, yet there are still significant data gaps with respect to how visual information is relayed to telencephalic areas homologous to the CeA, particularly in fish. In fact ray finned fishes may have evolved an entirely different mechanism for relaying visual information to the telencephalon. In part because they lack a pathway homologous to the lateral geniculate-striate cortex pathway of mammals, amphibians continue to be an excellent model for studying how stress hormones in turn modulate fear activating visual pathways. Glucocorticoids, melanocortin peptides, and CRF all appear to play some role in modulating sensorimotor processing in the optic tectum. These observations, coupled with data showing control of the hypothalamus-pituitary-adrenal axis by the superior colliculus, suggest a fear/stress/anxiety neuroendocrine circuit that begins with first order synapses in subcortical visual pathways. Thus, comparative studies shed light not only on how fear triggering visual pathways came to be, but how hormones released as a result of this activation modulate these pathways. PMID:26578871

  1. Individual Variations in Maternal Care Early in Life Correlate with Later Life Decision-Making and c-Fos Expression in Prefrontal Subregions of Rats

    PubMed Central

    van Hasselt, Felisa N.; de Visser, Leonie; Tieskens, Jacintha M.; Cornelisse, Sandra; Baars, Annemarie M.; Lavrijsen, Marla; Krugers, Harm J.; van den Bos, Ruud; Joëls, Marian

    2012-01-01

    Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology–e.g. depression, anxiety and schizophrenia- later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-fos expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-fos expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-fos expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures. PMID:22693577

  2. Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis.

    PubMed

    de Andrade, J S; Céspedes, I C; Abrão, R O; Dos Santos, T B; Diniz, L; Britto, L R G; Spadari-Bratfisch, R C; Ortolani, D; Melo-Thomas, L; da Silva, R C B; Viana, M B

    2013-08-01

    Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

  3. Nasal temperature drop in response to a playback of conspecific fights in chimpanzees: A thermo-imaging study.

    PubMed

    Kano, Fumihiro; Hirata, Satoshi; Deschner, Tobias; Behringer, Verena; Call, Josep

    2016-03-01

    Emotion is one of the central topics in animal studies and is likely to attract attention substantially in the coming years. Recent studies have developed a thermo-imaging technique to measure the facial skin temperature in the studies of emotion in humans and macaques. Here we established the procedures and techniques needed to apply the same technique to great apes. We conducted two experiments respectively in the two established research facilities in Germany and Japan. Total twelve chimpanzees were tested in three conditions in which they were presented respectively with the playback sounds (Exp. 1) or the videos (Exp. 2) of fighting conspecifics, control sounds/videos (allospecific display call: Exp. 1; resting conspecifics: Exp. 2), and no sound/image. Behavioral, hormonal (salivary cortisol) and heart-rate responses were simultaneously recorded. The nasal temperature of chimpanzees linearly dropped up to 1.5 °C in 2 min, and recovered to the baseline in 2 min, in the experimental but not control conditions. We found the related changes in excitement behavior and heart-rate variability, but not in salivary cortisol, indicating that overall responses were involved with the activities of sympathetic nervous system but not with the measureable activities of the hypothalamus-pituitary-adrenal (HPA) axis. The influence of general activity (walking, eating) was not negligible but controllable in experiments. We propose several techniques to control those confounding factors. Overall, thermo-imaging is a promising technique that should be added to the traditional physiological and behavioral measures in primatology and comparative psychology.

  4. Dexamethasone inhibits corticosterone deposition in feathers of greenfinches.

    PubMed

    Hõrak, Peeter; Männiste, Marju; Meitern, Richard; Sild, Elin; Saks, Lauri; Sepp, Tuul

    2013-09-15

    Corticosterone (CORT) content of feathers is a potent source of information about activation of hypothalamus-pituitary-adrenal (HPA) axis during feather growth, which is used for assessment of well-being and stress history of individuals and populations in avian studies. However, little is known about factors affecting deposition of CORT into feathers and how feather CORT covaries with other markers of stress imposed upon individuals during feather growth. We addressed these questions by measuring CORT levels in feathers of wild-caught greenfinches (Carduelis chloris) brought into captivity. One tail feather was removed from all the birds upon arrival to the laboratory and the CORT levels of replacement feathers, grown in captivity were recorded. The birds were subjected to treatments of immune activation (by injection of phytohaemagglutinin) and synthetic glucocorticoid (dexamethasone, DEX) administration. Only DEX injection affected feather CORT levels. DEX-injected birds deposited on average 37% less of CORT in their feathers than saline-injected birds. Despite significant effects of DEX and immune activation treatments on differential leukocyte counts, we did not find any correlations between CORT and leukocyte hemoconcentrations or heterophil/lymphocyte ratios (a haematological index of stress), measured at three stages of feather growth. Our findings provide novel evidence that feather CORT levels are sensitive to manipulation of hormonal balance of birds, thereby supporting the diagnostic value of feather CORT measurements. However, we did not find any evidence about covariation between feather CORT and other markers of stress perceived during the period of feather growth. This calls for further research on information content of feather CORT, preferably in experiments manipulating more diverse array of psychological, immunological and abiotic stressors.

  5. Active optical alignment of off-axis telescopes based on nodal aberration theory.

    PubMed

    Zhang, Xiaobin; Zhang, Dong; Xu, Shuyan; Ma, Hongcai

    2016-11-14

    Our paper mainly separates the specific aberration contributions of third-order astigmatism and third-order coma from the total aberration fields, on the framework of the modified nodal aberration theory (NAT), for the perturbed off-axis telescope. Based on the derived aberration functions, two alignment models for the same off-axis two-mirror telescope are established and compared. Among them, one is based on third-order NAT, the other is based on fifth-order NAT. By comparison, it is found that the calculated perturbations based on fifth-order NAT are more accurate. It illustrates that third-order astigmatism and third-order coma contributed from fifth-order aberrations can't be neglected in the alignment process. Then the fifth-order NAT is used for the alignment of off-axis three-mirror telescopes. After simulation, it is found that the perturbed off-axis three-mirror telescope can be perfectly aligned as well. To further demonstrate the application of the alignment method based on fifth-order NAT (simplified as NAT method), Monte-Carlo simulations for both off-axis two-mirror telescope and off-axis three-mirror telescope are conducted in the end. Meantime, a comparison between NAT method and sensitivity table method is also conducted. It is proven that the computation accuracy of NAT method is much higher, especially in poor conditions.

  6. Periodicity Signatures of Lightcurves of Active Comets in Non-Principal-Axis Rotational States

    NASA Astrophysics Data System (ADS)

    Samarasinha, Nalin H.; Mueller, Beatrice E. A.; Barrera, Jose G.

    2016-10-01

    There are two comets (1P/Halley, 103P/Hartley 2) that are unambiguously in non-principal-axis (NPA) rotational states in addition to a few more comets that are candidates for NPA rotation. Considering this fact, and the ambiguities associated with how to accurately interpret the periodicity signatures seen in lightcurves of active comets, we have started an investigation to identify and characterize the periodicity signatures present in simulated lightcurves of active comets. We carried out aperture photometry of simulated cometary comae to generate model lightcurves and analyzed them with Fourier techniques to identify their periodicity signatures. These signatures were then compared with the input component periods of the respective NPA rotational states facilitating the identification of how these periodicity signatures are related to different component periods of the NPA rotation. Ultimately, we also expect this study to shed light on why only a small fraction of periodic comets is in NPA rotational states, whereas theory indicates a large fraction of them should be in NPA states (e.g., Jewitt 1999, EMP, 79, 35). We explore the parameter space with respect to different rotational states, different orientations for the total rotational angular momentum vector, and different locations on the nucleus for the source region(s). As for special cases, we also investigate potential NPA rotational states representative of comet 103P/Hartley2, the cometary target of the EPOXI mission. The initial results from our investigation will be presented at the meeting. The NASA DDAP Program supports this work through grant NNX15AL66G.

  7. Genetic factors, perceived chronic stress, and the free cortisol response to awakening.

    PubMed

    Wüst, S; Federenko, I; Hellhammer, D H; Kirschbaum, C

    2000-10-01

    Recent studies have demonstrated that the free cortisol response to awakening can serve as a useful index of hypothalamus-pituitary-adrenal axis (HPA) activity. This endocrine marker is rather consistent, shows good intraindividual stability across time and appears to be able to uncover subtle changes in HPA regulation. The present twin study investigated genetic factors as sources of the interindividual variation of the cortisol awakening response. Furthermore, the relationship between psychological variables and morning cortisol levels was studied. On two consecutive days saliva samples were collected 0, 30, 45 and 60 minutes after awakening in 52 monozygotic and 52 dizygotic twin pairs. Moreover, samples were obtained at 0800, 1100, 1500 and 2000 h. ('short day-time profile'). Additionally, the participants filled out questionnaires assessing chronic stress load, self-esteem and self-efficacy.Heritability estimates of h(2)=0.40 for the mean increase and of h(2)=0.48 for the area under the response curve indicate a significant impact of genetic factors on cortisol levels after awakening. However, no genetic influence on the short day-time profile could be observed. Furthermore, several aspects of perceived chronic stress, namely 'worries', 'social stress' and 'lack of social recognition' were significantly associated with the awakening cortisol response. The evidence for a medium-sized, yet distinct genetic influence on cortisol levels after awakening is discussed with regard to a potential clinical relevance of genetic determinants of HPA (re)activity. In line with several recent studies, the present findings further support the view that the cortisol awakening responses is consistently enhanced under chronic stress conditions.

  8. MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta.

    PubMed

    Ogimoto, Kayoko; Harris, Marvin K; Wisse, Brent E

    2006-09-01

    Systemic inflammatory signals can disrupt the physiological regulation of energy balance, causing anorexia and weight loss. In the current studies, we investigated whether MyD88, the primary, but not exclusive, intracellular signal transduction pathway for Toll-like receptor 4 and IL-1 receptor I, is necessary for anorexia and weight loss to occur in response to stimuli that activate these key innate immune receptors. Our findings demonstrate that the absence of MyD88 signaling confers complete protection against anorexia induced by either lipopolysaccharide (LPS) (20 h food intake in MyD88-/- mice 5.4 +/- 0.3 vs. 3.3 +/- 0.4 g in MyD88+/+ control mice, P < 0.001) or IL-1 beta (20 h food intake in MyD88-/- mice 4.9 +/- 0.5 vs. 4.0 +/- 0.3 g in MyD88+/+ control mice, P < 0.001). However, absent MyD88 signaling does not prevent these inflammatory mediators from causing weight loss (LPS, -0.4 +/- 0.1 g; IL1 beta, -0.1 +/- 0.1 g, both P < 0.01 vs. vehicle-injected MyD88-/- mice, +0.4 +/- 0.2 g). Furthermore, LPS-induced weight loss occurs in the absence of adipsia, fever, or hypothalamus-pituitary-adrenal axis activation in MyD88-deficient mice. In addition, the peripheral inflammatory response to LPS is surprisingly intact in mice lacking MyD88. Together, these observations indicate that LPS reduces food intake via a mechanism that is dissociated from its effect on peripheral cytokine production, and whereas the presence of circulating proinflammatory cytokines per se is insufficient to cause anorexia in the absence of MyD88 signaling, it may contribute to LPS-induced weight loss.

  9. Inhibition of brain prostaglandin endoperoxide synthase-2 prevents the preparturient increase in fetal adrenocorticotropin secretion in the sheep fetus.

    PubMed

    Gersting, Jason; Schaub, Christine E; Keller-Wood, Maureen; Wood, Charles E

    2008-08-01

    Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (i.c.v) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E(2) concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.

  10. A systematic review of non-invasive brain stimulation therapies and cardiovascular risk: implications for the treatment of major depressive disorder.

    PubMed

    Sampaio, Leonardo Augusto Negreiros Parente Capela; Fraguas, Renerio; Lotufo, Paulo Andrade; Benseñor, Isabela Martins; Brunoni, André Russowsky

    2012-01-01

    Major depressive disorder (MDD) and cardiovascular diseases are intimately associated. Depression is an independent risk factor for mortality in cardiovascular samples. Neuroendocrine dysfunctions in MDD are related to an overactive hypothalamus-pituitary-adrenal (HPA) axis and increased sympathetic activity. Novel intervention strategies for MDD include the non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In fact, although these techniques have being increasingly used as a treatment for MDD, their cardiovascular effects were not sufficiently investigated, which would be important considering the dyad MDD/cardiovascular disorders. We investigated this issue through a systematic review for published articles from the first date available to May 2012 in MEDLINE and other databases, looking for main risk factors and surrogate markers for cardiovascular disease such as: cortisol, heart rate variability (HRV), alcohol, smoking, obesity, hypertension, glucose. We identified 37 articles (981 subjects) according to our eligibility criteria. Our main findings were that NIBS techniques might be effective strategies for down-regulating HPA activity and regulating food, alcohol, and cigarette consumption. NIBS's effects on HRV and blood pressure presented mixed findings, with studies suggesting that HRV values can decrease or remain unchanged after NIBS, while one study found that rTMS increased blood pressure levels. Also, a single study showed that glucose levels decrease after tDCS. However, most studies tested the acute effects after one single session of rTMS/tDCS; therefore further studies are necessary to investigate whether NIBS modifies cardiovascular risk factors in the long-term. In fact, considering the burden of cardiac disease, further trials in cardiovascular, depressed, and non-depressed samples using NIBS should be performed.

  11. Phytochemical constituents as future antidepressants: a comprehensive review.

    PubMed

    Bahramsoltani, Roodabeh; Farzaei, Mohammad Hosein; Farahani, Marzieh Sarbandi; Rahimi, Roja

    2015-01-01

    Depression is a major mental disease that is ranked as the fourth leading cause of disability. In order to avoid unwanted adverse reactions, as well as improve efficacy, current researches are seeking alternatives to conventional antidepressants. Phytochemicals provide an extensive research area in antidepressant therapies. The aim of the present study is to comprehensively review neurological evidences demonstrating the efficacy of phytochemicals in depression. For this purpose, electronic databases were searched to collect all data on the antidepressant mechanisms of phytochemicals from 1966 up to 2015. Plant metabolites from different categories including polyphenols (flavonoids, phenolic acids, lignanes, coumarins), alkaloids, terpenes and terpenoids, saponins and sapogenins, amines, and carbohydrates were found to possess antidepressant activity. Naringenin, quercetin derivatives, eugenol, piperine, diterpene alkaloids, berberine, hyperforin, riparin derivatives, ginsenosides, as well as β-carboline alkaloids are among the most relevant ones. Naringenin has represented its antidepressant effect by elevation of serotonin (5-HT), norepinephrine, brain-derived neurotrophic factor (BDNF), and glucocorticoid receptors. Piperine demonstrated inhibition of monoamine oxidase enzymes, elevation of brain 5-HT and BDNF levels, and modulation of the hypothalamus-pituitary-adrenal axis. The serotonergic, noradrenergic, and dopaminergic effect of berberine has been proven in several studies. Quercetin derivatives have revealed antidepressant potential via elevating pro-opiomelanocortin and neuroprotective properties, as well as reduction of proinflammatory cytokines. Assessing the structure-activity relationship of highly potent antidepressant phytochemicals is suggested to find future natural, semisynthetic, or synthetic antidepressants. Further clinical studies are also necessary for confirmation of natural antidepressant efficacy and completion of their safety profile.

  12. Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis

    PubMed Central

    Jackson, Joseph W.; Singh, Meera V.; Singh, Vir B.; Jones, Letitia D.; Davidson, Gregory A.; Ture, Sara; Morrell, Craig N.; Schifitto, Giovanni; Maggirwar, Sanjay B.

    2016-01-01

    Platelets play an essential role in hemostasis and wound healing by facilitating thrombus formation at sites of injury. Platelets also mediate inflammation and contain several pro-inflammatory molecules including cytokines and chemokines that mediate leukocyte recruitment and activation. Not surprisingly, platelet dysfunction is known to contribute to several inflammatory disorders. Antiplatelet therapies, such as aspirin, adenosine diphosphate (ADP) antagonists, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, and anticoagulants such as warfarin, dampen platelet activity at the risk of unwarranted bleeding. Thus, the development of drugs that reduce platelet-mediated inflammation without interfering with thrombus formation is of importance to combat platelet-associated disorders. We have shown here for the first time that the tetracycline antibiotic, minocycline, administered to HIV-infected individuals reduces plasma levels of soluble CD40L and platelet factor 4 levels, host molecules predominately released by platelets. Minocycline reduced the activation of isolated platelets in the presence of the potent platelet activator, thrombin, as measured by ELISA and flow cytometry. Platelet degranulation was reduced upon exposure to minocycline as shown by mepacrine retention and flow cytometry. However, minocycline had no effect on spreading, aggregation, GPIIb/IIIa activation, or in vivo thrombus formation. Lastly, immunoblot analysis suggests that the antiplatelet activity of minocycline is likely mediated by inhibition of mixed lineage kinase 3 (MLK3)-p38 MAPK signaling axis and loss of p38 activity. Our findings provide a better understanding of platelet biology and a novel repurposing of an established antibiotic, minocycline, to specifically reduce platelet granule release without affecting thrombosis, which may yield insights in generating novel, specific antiplatelet therapies. PMID:27270236

  13. Stress-induced alterations in the programmed natural cycles of post-natal lymphoid organ development in C57BL/6 mice: Evidence for a regulatory feedback relationship between bone marrow and thymus.

    PubMed

    Domínguez-Gerpe, Lourdes

    2007-01-01

    This study investigated some effects of weaning and immobilization stress in C57BL/6 mice aged 22-68 days, i.e., over a period including activation of the hypothalamus-pituitary-adrenal (HPA) axis and puberty. Specifically, the study evaluated the evolution, over the referred age interval, of a set of variables (body, thymus, spleen and axillary lymph nodes weights, the proportion of lymphoid cells in the bone marrow, the relative chemoattraction capacity of thymic supernatants for lymphoid cells and the migratory capacity of bone marrow lymphoid cells) in either weaned mice or weaned mice subjected to immobilization stress, compared to "non-stressed" unweaned mice. Cyclic patterns, observed for most variables in unweaned mice, were especially pronounced in two cases: the relative migratory capacity of bone marrow lymphoid cells collected at different ages towards neonatal thymic supernatant, and the relative chemoattraction capacity of thymic supernatants of different ages as tested against a sample of bone marrow lymphoid cells from mice aged 35 days. Weaning stress tended to intensify the involution stages of the cycles in thymus, spleen and lymph node weight, but increased the relative proportion of lymphoid cells in the bone marrow cell population. Both types of exogenous stress tended to affect cycle phase, i.e., cycle peaks and troughs were shifted in time. Correlations were observed between patterns seen in the thymus and bone marrow, suggesting the existence of an autoregulatory feedback loop governing pre-T cell migration and bone marrow/thymus homeostasis. These results also suggest that exogenous stress acts as a non-programmed regulator, modulating the naturally programmed cyclic patterns.

  14. Blubber cortisol: a potential tool for assessing stress response in free-ranging dolphins without effects due to sampling.

    PubMed

    Kellar, Nicholas M; Catelani, Krista N; Robbins, Michelle N; Trego, Marisa L; Allen, Camryn D; Danil, Kerri; Chivers, Susan J

    2015-01-01

    When paired with dart biopsying, quantifying cortisol in blubber tissue may provide an index of relative stress levels (i.e., activation of the hypothalamus-pituitary-adrenal axis) in free-ranging cetacean populations while minimizing the effects of the act of sampling. To validate this approach, cortisol was extracted from blubber samples collected from beach-stranded and bycaught short-beaked common dolphins using a modified blubber steroid isolation technique and measured via commercially available enzyme immunoassays. The measurements exhibited appropriate quality characteristics when analyzed via a bootstraped stepwise parallelism analysis (observed/expected = 1.03, 95%CI: 99.6 - 1.08) and showed no evidence of matrix interference with increasing sample size across typical biopsy tissue masses (75-150 mg; r(2) = 0.012, p = 0.78, slope = 0.022 ng(cortisol deviation)/ul(tissue extract added)). The relationships between blubber cortisol and eight potential cofactors namely, 1) fatality type (e.g., stranded or bycaught), 2) specimen condition (state of decomposition), 3) total body length, 4) sex, 5) sexual maturity state, 6) pregnancy status, 7) lactation state, and 8) adrenal mass, were assessed using a Bayesian generalized linear model averaging technique. Fatality type was the only factor correlated with blubber cortisol, and the magnitude of the effect size was substantial: beach-stranded individuals had on average 6.1-fold higher cortisol levels than those of bycaught individuals. Because of the difference in conditions surrounding these two fatality types, we interpret this relationship as evidence that blubber cortisol is indicative of stress response. We found no evidence of seasonal variation or a relationship between cortisol and the remaining cofactors.

  15. Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.

    PubMed

    Peña-Philippides, Juan Carlos; Razani-Boroujerdi, Seddigheh; Singh, Shashi P; Langley, Raymond J; Mishra, Neerad C; Henderson, Rogene F; Sopori, Mohan L

    2007-05-01

    Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.

  16. Immediate recall influences the effects of pre-encoding stress on emotional episodic long-term memory consolidation in healthy young men.

    PubMed

    Wolf, Oliver T

    2012-05-01

    The stress-associated activation of the hypothalamus-pituitary-adrenal axis influences memory. Several studies have supported the notion that post-learning stress enhances memory consolidation, while pre-retrieval stress impairs retrieval. Findings regarding the effects of pre-encoding stress, in contrast, have been rather inconsistent. In the current two studies, the impact of an immediate retrieval task on these effects was explored. In the first study, 24 healthy young male participants were exposed to a psychosocial laboratory stressor (Trier Social Stress Test) or a control condition before viewing positive, negative, and neutral photographs, which were accompanied by a brief narrative. Immediate as well as delayed (24 h later) free recall was assessed. Stress was expected to enhance emotional long-term memory without affecting immediate recall performance. Stress caused a significant increase in salivary cortisol concentrations but had no significant effects on immediate or delayed retrieval performance, even though a trend toward poorer memory of the stress group was apparent. Based on these findings, the second experiment tested the hypothesis that the beneficial effects of stress on emotional long-term memory performance might be abolished by an immediate recall test. In the second study (n = 32), the same design was used, except for the omission of the immediate retrieval test. This time stressed participants recalled significantly more negative photographs compared to the control group. The present study indicates that an immediate retrieval attempt of material studied after stress exposure can prevent or even reverse the beneficial effects of pre-encoding stress on emotional long-term memory consolidation.

  17. Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women.

    PubMed

    Lupis, Sarah B; Lerman, Michelle; Wolf, Jutta M

    2014-11-01

    While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6±1.7 yr) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p>.23). Increases in self-reported fear predicted blunted cortisol responses in men (β=0.41, p=.04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β=0.67 p=.004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β=0.51, p=.033; β=0.46, p=.066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p>.23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health-promoting ways of

  18. [Behavior-immunity relationship: the role of cytokines].

    PubMed

    Espinosa, E; Bermúdez-Rattoni, F

    2001-01-01

    There are several phenomena in which the immune and the central nervous systems regulate each other. However, their mechanisms are poorly understood. Since cytokines have a central role in the regulation of the immune response, this review describes their participation in two forms of neuro-immune communication, immunomodulation by psychological stress and behavioral conditioning of immune response. The role of cytokines in the endocrine and behavioral effects of acute phase, where cytokines have an effect in functions of the central nervous system, is also reviewed. The effects of psychological stress are described as both immunosuppressing and immunoenhancing. Among them, a relevant immunosuppressing one is the reduction of IL-1, IL-2, and IFN-gamma levels. In contrast, some of the pro-inflammatory effects of stress are mediated by an increase in the levels of IL-6, IL-1, and TNF mediated by the neurotransmitter Substance P. A possible role for IL-1 and IFN-beta as possible messengers in immune regulation by behavioral conditioning is proposed. Pro-inflammatory cytokines in turn can activate the hypothalamus-pituitary-adrenal axis and induce sickness behavior during the acute phase response, during which the parasympathetic nervous system serves as pathway for their detection by the central nervous system. An account is given about recent findings on the regulation of cytokine expression by neurotransmitters from the sympathetic nervous system (epinephrine and norepinephrine), a key piece in all these mechanisms of brain-immune communication. Possible mechanisms and pathways of communication between the brain and the immune system, as well as the possible participation of other cytokines are discussed.

  19. Blubber Cortisol: A Potential Tool for Assessing Stress Response in Free-Ranging Dolphins without Effects due to Sampling

    PubMed Central

    Kellar, Nicholas M.; Catelani, Krista N.; Robbins, Michelle N.; Trego, Marisa L.; Allen, Camryn D.; Danil, Kerri; Chivers, Susan J.

    2015-01-01

    When paired with dart biopsying, quantifying cortisol in blubber tissue may provide an index of relative stress levels (i.e., activation of the hypothalamus-pituitary-adrenal axis) in free-ranging cetacean populations while minimizing the effects of the act of sampling. To validate this approach, cortisol was extracted from blubber samples collected from beach-stranded and bycaught short-beaked common dolphins using a modified blubber steroid isolation technique and measured via commercially available enzyme immunoassays. The measurements exhibited appropriate quality characteristics when analyzed via a bootstraped stepwise parallelism analysis (observed/expected = 1.03, 95%CI: 99.6 – 1.08) and showed no evidence of matrix interference with increasing sample size across typical biopsy tissue masses (75–150mg; r2 = 0.012, p = 0.78, slope = 0.022ngcortisol deviation/ultissue extract added). The relationships between blubber cortisol and eight potential cofactors namely, 1) fatality type (e.g., stranded or bycaught), 2) specimen condition (state of decomposition), 3) total body length, 4) sex, 5) sexual maturity state, 6) pregnancy status, 7) lactation state, and 8) adrenal mass, were assessed using a Bayesian generalized linear model averaging technique. Fatality type was the only factor correlated with blubber cortisol, and the magnitude of the effect size was substantial: beach-stranded individuals had on average 6.1-fold higher cortisol levels than those of bycaught individuals. Because of the difference in conditions surrounding these two fatality types, we interpret this relationship as evidence that blubber cortisol is indicative of stress response. We found no evidence of seasonal variation or a relationship between cortisol and the remaining cofactors. PMID:25643144

  20. Effects of cold stress and Salmonella Heidelberg infection on bacterial load and immunity of chickens.

    PubMed

    Borsoi, Anderlise; Quinteiro-Filho, Wanderley Moreno; Calefi, Atilio Sersun; Ferreira, Antonio José Piantino; Astolfi-Ferreira, Claudete Serrano; Florio, Jorge Camilo; Palermo-Neto, João

    2015-01-01

    We analysed the effects of cold stress (19 ± 1°C, 6 h /day, from the first to the seventh day of life) applied to specific pathogen free (SPF) chickens. On experimental Day 1 (ED1), chicks were divided into four groups: C (not infected and kept under thermoneutral condition); CS (not infected and cold stressed); PC (Salmonella Heidelberg (SH) infected and kept under thermoneutral condition) and PCS (SH infected and cold stressed). High concentrations of corticosterone were found in the cold stressed birds on ED7 and ED21, with a greater increase in birds of the PCS group. Stress or non-stressed SH-infected birds had high levels of norepinephrine on ED21. On ED21, an increased percentage and number of SH were found in birds of the PCS group. On ED7, a decrease in macrophages presenting MHCII, CD8(+) and CD8(+) γδ cells was observed in the chickens of the CS group. Decrease was observed in CD3(+) cells in the birds of the PCS group and increase in macrophages presenting MHCII cells and of the CD4(+)/CD8(+) ratio in chickens of the CS group on ED21. There was a decrease in CD8(+) γδ cells in birds of the CS group on ED21 and in the CD3(+) and CD8(+)cell numbers in chickens of the PCS group on ED21. Our results suggest that cold stress applied to chickens in the first 7 days of life increases both the hypothalamus pituitary adrenal axis and the sympathetic nervous system activities, leading to long-term immune cell dysfunction, thus allowing increased SH invasion and persistence within the birds' body.

  1. The cortisol awakening response (CAR) across the female menstrual cycle.

    PubMed

    Wolfram, Maren; Bellingrath, Silja; Kudielka, Brigitte M

    2011-07-01

    The cortisol awakening response (CAR) has been established as a useful marker of hypothalamus-pituitary-adrenal (HPA) axis activity and has become a standard tool for stress research in ambulatory settings. Although much knowledge has been accumulated on a variety of factors modulating the CAR, the impact of the female menstrual cycle, especially during ovulation, still remains unclear. To the best of our knowledge, this is the first study that measured the CAR during menses, the follicular phase, ovulation and the luteal phase in a repeated measurement design. For this purpose, a final sample of 29 naturally cycling, healthy, non-smoking, and medication-free women collected saliva samples directly after awakening as well as 30, 45, and 60 min later during each of the four different phases. To determine the timing of ovulation, an ambulatory chromatographic ovulation test kit was applied. A repeated measurements ANOVA resulted in a significant interaction effect sample × cycle phase (p=0.04), with the highest awakening response during ovulation. While awakening cortisol levels were comparable across the four cycle phases (p=n.s.), the net increase was significantly elevated during ovulation (p=0.05). Our data also confirmed earlier cross-sectional results reporting no differences in the CAR between the follicular and luteal phase. Finally, a concurrent assessment of mood applying the POMS (Profile of Mood States) yielded no differences across the four cycle phases (all p=n.s.). In sum, the present data points to the idea that the CAR is elevated during ovulation, an effect which is presumably mediated by elevated sex steroid levels during the ovulation period.

  2. Hypoxia activates the cyclooxygenase-2–prostaglandin E synthase axis

    PubMed Central

    Lee, James J.; Natsuizaka, Mitsuteru; Ohashi, Shinya; Wong, Gabrielle S.; Takaoka, Munenori; Michaylira, Carmen Z.; Budo, Daniela; Tobias, John W.; Kanai, Michiyuki; Shirakawa, Yasuhiro; Naomoto, Yoshio; Klein-Szanto, Andres J.P.; Haase, Volker H.; Nakagawa, Hiroshi

    2010-01-01

    Hypoxia-inducible factors (HIFs), in particular HIF-1α, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1α target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1α by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1α. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E2 (PGE2) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE2 production in a HIF-1α-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1α and IGFBP3. Activation of the COX-2–PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1β and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1α target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin. PMID:20042640

  3. [Gut microbiome and major depressive disorder : The other side of ourselves].

    PubMed

    Manook, A; Hiergeist, A; Rupprecht, R; Baghai, T C

    2016-11-01

    Microbiological ecology and its ambition to describe the complete genome of complex living communities as a whole, have given us powerful tools to characterize the human gut microbiome on a genetic and, hence, taxonomic and abundance level; for a decade now, they have become sufficiently inexpensive, fast and feasible. Thus, opportunities arose to have a fresh and closer look at the microbiota-gut-brain-axis and its impact on human health; this axis comprises a complex multisystemic network of multidirectional interactions between brain and gut including influences beyond one generation. Gnotobiotic animal models have become essential for specific research targets. Combining gut microbiome analysis with observations on the hypothalamus-pituitary-adrenal axis and various aspects of inflammation helped to gain first insights into the role of the microbiota-gut-brain-axis in depressive disorders. Therapeutic endeavors with psychobiotics have not yet shown their value in clinical studies.

  4. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral fimctions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  5. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)###

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral functions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  6. HPA-Axis Activation as a Key Moderator of Childhood Trauma Exposure and Adolescent Mental Health.

    PubMed

    Kuhlman, Kate R; Geiss, Elisa G; Vargas, Ivan; Lopez-Duran, Nestor

    2017-02-18

    Individual differences in a child's sensitivity to stress may influence whether youth exposed to trauma develop symptoms of psychopathology. We examined the interaction between HPA-axis reactivity to an acute stressor and exposure to different types of childhood trauma as predictors of mental health symptoms in a sample of youth. Youth (n = 121, ages 9-16; 47% female) completed a standardized stress task, including 5 post-stress salivary cortisol samples. Parents also completed the Child Behavior Checklist as a measure of child internalizing and externalizing symptoms in the past month, and completed the Early Trauma Inventory (ETI) as a measure of their child's trauma exposure. More emotional abuse and non-intentional trauma were associated with greater internalizing symptoms. Youth exposed to physical abuse who demonstrated slower HPA-axis reactivity had elevated internalizing and externalizing symptoms. Youth exposed to emotional abuse or non-intentional traumatic events who demonstrated faster HPA-axis reactivity had elevated internalizing and externalizing symptoms. Profiles of exaggerated or attenuated HPA-axis reactivity to acute stress may be risk factors for psychopathology in children facing different stressful social environments.

  7. Magnetic bearing momentum wheels with magnetic gimballing capability for 3-axis active attitude control and energy storage

    NASA Technical Reports Server (NTRS)

    Sindlinger, R. S.

    1977-01-01

    A 3-axis active attitude control system with only one rotating part was developed using a momentum wheel with magnetic gimballing capability as a torque actuator for all three body axes. A brief description of magnetic bearing technology is given. It is concluded that based on this technology an integrated energy storage/attitude control system with one air of counterrotating rings could reduce the complexity and weight of conventional systems.

  8. Active stall control for large offshore horizontal axis wind turbines; a conceptual study considering different actuation methods

    NASA Astrophysics Data System (ADS)

    Pereira, R.; van Bussel, G. J. W.; Timmer, W. A.

    2014-12-01

    The increasing size of Horizontal Axis Wind Turbines and the trend to install wind farms further offshore demand more robust design options. If the pitch system could be eliminated, the availability of Horizontal Axis Wind Turbines should increase. This research investigates the use of active stall control to regulate power production in replacement of the pitch system. A feasibility study is conducted using a blade element momentum code and taking the National Renewable Energy Laboratory 5 MW turbine as baseline case. Considering half of the blade span is equipped with actuators, the required change in the lift coefficient to regulate power was estimated in ΔCl = 0.7. Three actuation technologies are investigated, namely Boundary Layer Transpiration, Trailing Edge Jets and Dielectric Barrier Discharge actuators. Results indicate the authority of the actuators considered is not sufficient to regulate power, since the change in the lift coefficient is not large enough. Active stall control of Horizontal Axis Wind Turbines appears feasible only if the rotor is re-designed from the start to incorporate active-stall devices.

  9. Hypothalamic-pituitary-adrenal axis activity is not elevated in a songbird (Junco hyemalis) preparing for migration.

    PubMed

    Bauer, Carolyn M; Needham, Katie B; Le, Chuong N; Stewart, Emily C; Graham, Jessica L; Ketterson, Ellen D; Greives, Timothy J

    2016-06-01

    During spring, increasing daylengths stimulate gonadal development in migratory birds. However, late-stage reproductive development is typically postponed until migration has been completed. The hypothalamic-pituitary-adrenal (HPA) axis regulates the secretion of glucocorticoids, which have been associated with pre-migratory hyperphagia and fattening. The HPA-axis is also known to suppress the hypothalamic-pituitary-gonadal (HPG) axis, suggesting the possibility that final transition into the breeding life history stage may be slowed by glucocorticoids. We hypothesized that greater HPA-axis activity in individuals preparing for migration may foster preparation for migration while simultaneously acting as a "brake" on the development of the HPG-axis. To test this hypothesis, we sampled baseline corticosterone (CORT), stress-induced CORT, and negative feedback efficacy of Dark-eyed Juncos (Junco hyemalis) in an overwintering population that included both migratory (J.h. hyemalis) and resident (J.h. carolinensis) individuals. We predicted that compared to residents, migrants would have higher baseline CORT, higher stress-induced CORT, and weaker negative feedback. Juncos were sampled in western Virginia in early March, which was about 2-4wk before migratory departure for migrants and 4-5wk before first clutch initiation for residents. Contrary to our predictions, we found that migrants had lower baseline and stress-induced CORT and similar negative feedback efficacy compared with residents, which suggests that delayed breeding in migrants is influenced by other physiological mechanisms. Our findings also suggest that baseline CORT is not elevated during pre-migratory fattening, as migrants had lower baseline CORT and were fatter than residents.

  10. Three-axis active control system for gravity gradient stabilised microsatellite

    NASA Astrophysics Data System (ADS)

    Si Mohammed, A. M.; Benyettou, M.; Bentoutou, Y.; Boudjemai, A.; Hashida, Y.; Sweeting, M. N.

    2009-04-01

    In this paper, the control system of the first Algerian microsatellite in orbit Alsat-1 is presented. Alsat-1 is a 3-axis stabilised microsatellite, using a pitch momentum wheel and yaw reaction wheel, with dual redundant 3-axis magnetorquers. A gravity gradient boom is employed to provide a high degree of platform stability. Two vector magnetometers and four dual sun sensors are carried in order to determine the attitude. This paper examines the low Earth orbit (LEO) control system requirements and design in the context of a real system, the Surrey Satellite Technology Limited (SSTL) advanced microsatellite platform and puts forward designs for the control system to match the advanced capability of the enhanced microsatellite platform. Numerical results show the effectiveness of the implementation. Comparison with in orbit results is presented to evaluate the performance of the control system during accurate Nadir pointing control.

  11. Activity of the pituitary-gonadal axis is increased prior to the onset of spawning migration of chum salmon.

    PubMed

    Onuma, Takeshi A; Sato, Shunpei; Katsumata, Hiroshi; Makino, Keita; Hu, Weiwei; Jodo, Aya; Davis, Nancy D; Dickey, Jon T; Ban, Masatoshi; Ando, Hironori; Fukuwaka, Masa-Aki; Azumaya, Tomonori; Swanson, Penny; Urano, Akihisa

    2009-01-01

    The activity of the pituitary-gonadal axis (PG axis) in pre-migratory and homing chum salmon was examined because endocrine mechanisms underlying the onset of spawning migration remain unknown. Pre-migratory fish were caught in the central Bering Sea in June, July and September 2001, 2002 and 2003, and in the Gulf of Alaska in February 2006. They were classified into immature and maturing adults on the basis of gonadal development. The maturing adults commenced spawning migration to coastal areas by the end of summer, because almost all fish in the Bering Sea were immature in September. In the pituitaries of maturing adults, the copy numbers of FSHbeta mRNA and the FSH content were 2.5- to 100-fold those of the immature fish. Similarly, the amounts of LHbeta mRNA and LH content in the maturing adults were 100- to 1000-fold those of immature fish. The plasma levels of testosterone, 11-ketotestosterone and estradiol were higher than 10 nmol l(-1) in maturing adults, but lower than 1.0 nmol l(-1) in immature fish. The increase in the activity of the PG-axis components had already initiated in the maturing adults while they were still in the Gulf of Alaska in winter. In the homing adults, the pituitary contents and the plasma levels of gonadotropins and plasma sex steroid hormones peaked during upstream migration from the coast to the natal hatchery. The present results thus indicate that the seasonal increase in the activity of the PG axis is an important endocrine event that is inseparable from initiation of spawning migration of chum salmon.

  12. Preliminary Associations Between Childhood Neglect, MIF, and Cortisol: Potential Pathways to Long-Term Disease Risk

    PubMed Central

    Bick, Johanna; Nguyen, Victoria; Leng, Lin; Piecychna, Marta; Crowley, Michael J.; Bucala, Richard; Mayes, Linda C.; Grigorenko, Elena L.

    2015-01-01

    The study examined Hypothalamus Pituitary Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF. PMID:25380347

  13. Poverty and Awakening Cortisol in Adolescence: The Importance of Timing in Early Life.

    PubMed

    McFarland, Michael J; Hayward, Mark D

    2014-03-01

    The deleterious effects of poverty on mental and physical health are routinely argued to operate, at least in part, via dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, although empirical examinations connecting poverty with HPA axis functioning are rare. Research on the effects of timing of poverty is a particularly neglected aspect of this relationship. This study uses 15 years of prospective data from the Study of Early Child Care and Youth Development to assess how exposure to poverty during infancy, childhood, and adolescence is related to awakening cortisol (n = 826), a marker of HPA axis functioning. Among female participants, poverty exposure in infancy and adolescence, but not childhood, was negatively associated with awakening cortisol. Poverty exposure was unrelated to cortisol among male participants. The importance of timing and gender differences are discussed along with directions for future research.

  14. Associations between psychiatric symptoms and cortisol levels in Nicaraguan young school-age children.

    PubMed

    Isaksson, Johan; Högberg, Ulf; Valladares, Eliette; Lindblad, Frank

    2016-06-30

    The regulation of the Hypothalamus-Pituitary-Adrenal axis (HPA-axis) with its end product cortisol seems to be affected in several psychiatric disorders. Although findings are not conclusive, internalizing symptoms have primarily been associated with higher diurnal cortisol levels and externalizing symptoms with lower cortisol levels. In this study on nine-year-olds in Nicaragua (n=111), we investigated associations between child psychiatric symptoms, using the Child Behavior Check List (CBCL), and saliva cortisol levels collected in the morning and afternoon, also adjusting for potential confounders. In line with previous findings, internalizing symptoms were significantly associated with higher morning, but not afternoon cortisol levels. Surprisingly, externalizing symptoms were also significantly associated with higher morning cortisol levels. Possibly, this association between externalizing symptoms and cortisol levels may be characteristic of early ages, representing a higher exposure to external stressors. The study highlights the need for prospective studies, following the development of the HPA-axis and its association with psychiatric symptoms.

  15. Possible role of serotonin and neuropeptide Y on the disruption of the reproductive axis activity by perfluorooctane sulfonate.

    PubMed

    López-Doval, S; Salgado, R; Fernández-Pérez, B; Lafuente, A

    2015-03-04

    Perfluorooctane sulfonate (PFOS) is an endocrine disruptor, whose exposure can induce several alterations on the reproductive axis activity in males during adulthood. This study was undertaken to evaluate the possible role of serotonin and neuropeptide Y (NPY) on the disruption of the hypothalamic-pituitary-testicular (HPT) axis induced by PFOS in adult male rats. For that, adult male rats were orally treated with 0.5; 1.0; 3.0 and 6.0mg of PFOS/kg/day for 28 days. After PFOS exposure, serotonin concentration increased in the anterior and mediobasal hypothalamus as well as in the median eminence. The metabolism of this amine (expressed as the ratio 5-hydroxyindolacetic acid (5-HIAA)/serotonin) was diminished except in the anterior hypothalamus, with the doses of 3.0 and 6.0mg/kg/day, being this dose 0.5mg/kg/day in the median eminence. In general terms, PFOS-treated rats presented a decrease of the hypothalamic concentration of the gonadotropin releasing hormone (GnRH) and NPY. A diminution of the serum levels of the luteinizing hormone (LH), testosterone and estradiol were also shown. These results suggest that both serotonin and NPY could be involved in the inhibition induced by PFOS on the reproductive axis activity in adult male rats.

  16. The Effect of Nicotine on HPA Axis Activity in Females is Modulated by the FKBP5 Genotype.

    PubMed

    Koopmann, Anne; Bez, Jennifer; Lemenager, Tagrid; Hermann, Derik; Dinter, Christina; Reinhard, Iris; Schuster, Rilana; Wiedemann, Klaus; Winterer, Georg; Kiefer, Falk

    2016-05-01

    Tobacco smoking modulates activity in the hypothalamic-pituitary-adrenal (HPA) axis and is used to cope with stress, especially by females. The single nucleotide polymorphism (SNP) rs1360780, linked to FK506-binding protein 51 (FKBP5), has been shown to affect HPA axis functioning, and has thus been suggested as a promising candidate for indicating vulnerability to stress-related disorders. The aim of this study was to investigate the interaction between nicotine consumption and rs1360780 on cortisol plasma levels in females. A total of 296 female smokers (assessed by the Fagerström Test for Nicotine Dependence; FTND) were genotyped for the SNP rs1360780. We measured participants' cortisol plasma concentration in blood plasma collected 3 h after standardized tobacco smoking exposure. In the 36 TT-homozygotes, we found a significant negative correlation between the FTND sum score and cortisol plasma concentrations. Using linear regression analysis, we found that the FTND sum score accounted for 12.4% of the variance of cortisol plasma levels. This association was not detected in C-allele carriers. Our results suggest that nicotine is an important confounder in the modulation of HPA axis activity by FKBP5. In light of these findings, future studies on FKBP5 should seek to include data on nicotine consumption as a covariate.

  17. Prematurity, Birth Weight, and Socioeconomic Status Are Linked to Atypical Diurnal Hypothalamic-Pituitary-Adrenal Axis Activity in Young Adults.

    PubMed

    Winchester, Suzy Barcelos; Sullivan, Mary C; Roberts, Mary B; Granger, Douglas A

    2016-02-01

    In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life.

  18. Time-course of hypothalamic-pituitary-adrenal axis activity and inflammation in juvenile rat brain after cranial irradiation.

    PubMed

    Veličković, Nataša; Drakulić, Dunja; Petrović, Snježana; Grković, Ivana; Milošević, Maja; Stanojlović, Miloš; Horvat, Anica

    2012-10-01

    Recent studies reported that exposure of juvenile rats to cranial irradiation affects hypothalamic-pituitary-adrenal (HPA) axis stability, leading to its activation along with radiation-induced inflammation. In the present study, we hypothesized whether inflammatory reaction in the CNS could be a mediator of HPA axis response to cranial irradiation (CI). Therefore, we analyzed time-course changes of serum corticosterone level, as well IL-1β and TNF-α level in the serum and hypothalamus of juvenile rats after CI. Protein and gene expression of the glucocorticoid receptor (GR) and nuclear factor kappaB (NFκB) were examined in the hippocampus within 24 h postirradiation interval. Cranial irradiation led to rapid induction of both GR and NFκB mRNA and protein in the hippocampus at 1 h. The increment in NFκB protein persisted for 2 h, therefore NFκB/GR protein ratio was turned in favor of NFκB. Central inflammation was characterized by increased IL-1β in the hypothalamus, with maximum levels at 2 and 4 h after irradiation, while both IL-1β and TNF-α were undetectable in the serum. Enhanced hypothalamic IL-1β probably induced the relocation of hippocampal NFκB to the nucleus and decreased NFκB mRNA at 6 h, indicating promotion of inflammation in the key tissue for HPA axis regulation. Concomitant increase of corticosterone level and enhanced GR nuclear translocation in the hippocampus at 6 h might represent a compensatory mechanism for observed inflammation. Our results indicate that acute radiation response is characterized by increased central inflammation and concomitant HPA axis activation, most likely having a role in protection of the organism from overwhelming inflammatory reaction.

  19. Magnetic bearing momentum wheels with magnetic gimballing capability for 3-axis active attitude control and energy storage

    NASA Technical Reports Server (NTRS)

    Sindlinger, R. S.

    1977-01-01

    Magnetic bearings used for the suspension of momentum wheels provide conclusive advantages: the low friction torques and the absence of abrasion allow the realization of lightweight high speed wheels with high angular momentum and energy storage capacity and virtually unlimited lifetime. The use of actively controlled bearings provides a magnetic gimballing capability by applying the external signals to the two servo loops controlling the rotational degrees of freedom. Thus, an attitude control system can be realized by using only one rotating mass for 3-axis active satellite stabilization.

  20. Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder.

    PubMed

    Martinac, Marko; Pehar, Davor; Karlović, Dalibor; Babić, Dragan; Marcinko, Darko; Jakovljević, Miro

    2014-03-01

    Depression has been associated with various cardiovascular risk factors such as hypertension, obesity, atherogenic dyslipidemia and hyperglycemia. In depressive disorder, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and changes in the immune system have been observed. On the other hand, somatic diseases such as obesity, hyperlipidemia, hypertension and diabetes mellitus type 2 are now perceived as important comorbid conditions in patients with depression. The pathogenesis of the metabolic syndrome and depression is complex and poorly researched; however, it is considered that the interaction of chronic stress, psychotrauma, hypercotisolism and disturbed immune functions contribute to the development of these disorders. The aim of the study was to investigate the relationship between depression and metabolic syndrome regarding the HPA axis dysfunction and altered inflammatory processes. Literature search in Medline and other databases included articles written in English published between 1985 and 2012. Analysis of the literature was conducted using a systematic approach with the search terms such as depression, metabolic syndrome, inflammation, cytokines, glucocorticoids, cortisol, and HPA axis. In conclusion, the relationship between depression and metabolic syndrome is still a subject of controversy. Further prospective studies are required to clarify the possible causal relationship between depression and metabolic syndrome and its components. Furthermore, it is important to explore the possibility of a common biologic mechanism in the pathogenesis of these two disorders, in which special attention should be paid to the immune system function, especially the possible specific mechanisms by which cytokines can induce and maintain depressive symptoms and metabolic disorders. The data presented here emphasize the importance of recognition and treatment of depressive disorders with consequent reduction in the incidence of metabolic syndrome, but

  1. Characteristics of hydrothermal convection in inclined layers: implications for hydrothermal activity at slow-spreading axis.

    NASA Astrophysics Data System (ADS)

    Fontaine, F. J.; Cannat, M.; Escartin, J.; Dusunur, D.

    2006-12-01

    The thermal structure of segments along (slow-spreading) mid-ocean ridges is likely to be a key parameter controlling the distribution, dynamics and geometry of hydrothermal systems. It is usually considered that the depth of penetration of hydrothermal fluids at the ridge axis is a function of the depth to the brittle-ductile transition. At slow-spreading axis, it is likely that this depth varies both along- and across-axis, with a deepening of several kilometers from the segment center towards its ends [e.g., Hooft et al., 2000]. This geometry is a consequence of focused melt supply to the segment center, resulting in the episodic and localized injection of magma bodies in the crust, as observed at the Lucky Strike segment of the Mid-Atlantic ridge [Singh et al., 2005]. In order to study the effect of such slopes of the basal temperature on the dynamics of slow-spreading axis hydrothermal systems, we ran a series of two-dimensional numerical models of hydrothermal convection. As a first approximation and following previous studies [e.g., Rabinowicz et al., 1999], we assume that these systems can be represented as rectangular and inclined permeable layers. The models are single-phase and incorporate realistic fluid properties and permeabilities. We have explored the cases of slopes ranging from 0 to 15°, aspect ratios from 1 to 16, and permeabilities up to 10^{-14} m2. The basal slope controls the number of convective cells. As the slope increases, the ratio of the size of the downflow and upflow areas increases. Above a critical slope the circulation is uni-cellular and composed of a broad recharge zone and a focused discharge zone, and encompassing the whole length of the segment. We will present the implication of our models for the distribution of vent sites along slow-spreading ridge segments. The segment-scale circulation and focused outflow obtained could also explain the elevated heat flux at some of the main sites found along slow-spreading ridges like

  2. Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis

    PubMed Central

    Cao, Xi; Yang, Fangyuan; Shi, Tingting; Yuan, Mingxia; Xin, Zhong; Xie, Rongrong; Li, Sen; Li, Hongbing; Yang, Jin-Kui

    2016-01-01

    The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2−/y) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2−/y mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1–7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what’s more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1–7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1–7)/Mas axis in prevention and treatment of hepatic lipid metabolism. PMID:26883384

  3. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.

    PubMed

    Xu, Dan; Zhang, Benjian; Liang, Gai; Ping, Jie; Kou, Hao; Li, Xiaojun; Xiong, Jie; Hu, Dongcai; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in

  4. Activation of 5-HT1A receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Stamper, Christopher E; Hassell, James E; Kapitz, Adam J; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A

    2017-03-27

    Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well-being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress-induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 μL, 0.1 μL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress-induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT1A receptors in the dorsomedial

  5. Puberty and Perimenopause: Reproductive Transitions and their Implications for Women's Health

    PubMed Central

    Hoyt, Lindsay T.; Falconi, April

    2015-01-01

    This scoping review synthesizes existing research on two major transitions in females’ lives: puberty and perimenopause. These two periods of vast physiological change demarcate the beginning and the end of the reproductive life cycle and are associated with major neuroendocrine reorganization across two key systems, the hypothalamic-pituitary-gonadal (HPG) axis the hypothalamus-pituitary-adrenal (HPA) axis. Despite growing evidence suggesting that the timing and experience of puberty and perimenopause are related to various physical and mental health outcomes (e.g., mood disorders, metabolism, cardiovascular health, autoimmune conditions and cancer), these two processes are rarely examined together. In this paper, we bridge these disparate literatures to highlight similarities, isolate inconsistencies, and identify important areas for future research in women’s health. PMID:25797100

  6. [The behavioral-neuroendocrine mechanism of development of homosexuality].

    PubMed

    Xue, Hui; Tai, Fa-Dao

    2007-10-01

    In this review, we primarily focus on the behavioral-neuroendocrine mechanism of development of homosexuality from genetic, neuroendocrine neuroanatomical and behavioral studies. Besides the influence of genetics and environment, sexual orientation was determined by the early perinatal hormone exposure. Gonadal steroidal hormone interacted with many neurotransmitters in individual development by hypothalamus pituitary adrenal axis and hypothalamus pituitary gonadal axis, which regulated the individual's sexual orientation. It was summarized here about the future directions on sexual orientation and demonstrated problems which would have to investigate next step. All these may be beneficial for our understanding of the homosexuality and paying attention to psychological and physiological health of homosexuality, which is useful to prevent the development of teenage homosexuality.

  7. Puberty and perimenopause: reproductive transitions and their implications for women's health.

    PubMed

    Hoyt, Lindsay Till; Falconi, April M

    2015-05-01

    This scoping review synthesizes existing research on two major transitions in females' lives: puberty and perimenopause. These two periods of vast physiological change demarcate the beginning and the end of the reproductive life cycle and are associated with major neuroendocrine reorganization across two key systems, the hypothalamic-pituitary-gonadal (HPG) axis the hypothalamus-pituitary-adrenal (HPA) axis. Despite growing evidence suggesting that the timing and experience of puberty and perimenopause are related to various physical and mental health outcomes (e.g., mood disorders, metabolism, cardiovascular health, autoimmune conditions, and cancer), these two processes are rarely examined together. In this paper, we bridge these disparate literatures to highlight similarities, isolate inconsistencies, and identify important areas for future research in women's health.

  8. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling

    PubMed Central

    Rodríguez-Nieves, José A.; Patalano, Susan C.; Almanza, Diego; Gharaee-Kermani, Mehrnaz; Macoska, Jill A.

    2016-01-01

    Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis. PMID:27434301

  9. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling.

    PubMed

    Rodríguez-Nieves, José A; Patalano, Susan C; Almanza, Diego; Gharaee-Kermani, Mehrnaz; Macoska, Jill A

    2016-01-01

    Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.

  10. Combined effects of androgen anabolic steroids and physical activity on the hypothalamic-pituitary-gonadal axis.

    PubMed

    Hengevoss, Jonas; Piechotta, Marion; Müller, Dennis; Hanft, Fabian; Parr, Maria Kristina; Schänzer, Wilhelm; Diel, Patrick

    2015-06-01

    Analysing effects of pharmaceutical substances and training on feedback mechanisms of the hypothalamic-pituitary-gonadal axis may be helpful to quantify the benefit of strategies preventing loss of muscle mass, and in the fight against doping. In this study we analysed combined effects of anabolic steroids and training on the hypothalamic-pituitary-gonadal axis. Therefore intact male Wistar rats were dose-dependently treated with metandienone, estradienedione and the selective androgen receptor modulator (SARM) S-1. In serum cortisol, testosterone, 17β-estradiol (E2), prolactin, inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), Insulin-like growth factor 1 (IGF-1), and thyroxine (T4) concentrations were determined. Six human volunteers were single treated with 1-androstenedione. In addition abusing and clean body builders were analysed. Serum concentrations of inhibin B, IGF-1, cortisol, prolactin, T4, thyroid-stimulating hormone (TSH), testosterone and LH were determined. In rats, administration of metandienone, estradienedione and S-1 resulted in an increase of muscle fiber diameter. Metandienone and estradienedione but not S-1 administration significantly decreases LH and inhibin B serum concentration. Administration of estradienedione resulted in an increase of E2 and S-1 in an increase of cortisol. Single administration of 1-androstenedione in humans decreased cortisol and inhibin B serum concentrations. LH was not affected. In abusing body builders a significantly decrease of LH, TSH and inhibin B and an increase of prolactin, IGF-1 and T4 was detected. In clean body builders only T4 and TSH were affected.

  11. Activation of EphA1-Epha receptor axis attenuates diabetic nephropathy in mice.

    PubMed

    Li, Yihui; Yan, Hongdan; Wang, Feng; Huang, Shanying; Zhang, Yun; Wang, Zhihao; Zhong, Ming; Zhang, Wei

    2017-05-06

    The Eph family of receptor tyrosine kinases serves as key modulators of various cellular functions, including inflammation, hypertrophy and fibrosis. Recent analyses have revealed that a member of the Eph family, EphA1, plays a pivotal role in regulating insulin metabolism and kidney injury. However, the importance of EphA1 in diabetic nephropathy has not been recognized. We established a diabetic nephropathy mouse model using a high-fat diet and streptozotocin (STZ) injection. Then, the recombinant adeno-associated virus type 9 (AAV9) overexpressing EphA1 or a negative control was injected locally into the kidney. Metabolite testing and histopathological analyses of kidney fibrosis, pancreatic islet function and signaling pathways were evaluated. Our study showed that hyperglycemia, insulin resistance, and renal fibrosis accompanied the deterioration of kidney function in diabetic mice. The overexpression of EphA1 in the kidney attenuated renal fibrosis and improved kidney function but did not affect systemic glucose metabolism and pancreatic islet function. Furthermore, the overexpression of EphA1 decreased the phosphorylation of ERK1/2, JNK and MYPT1 (a substrate of Rho kinase). The overexpression of EphA1 can be therapeutically targeted to inhibit diabetic renal fibrosis, which suggests that the EphA1-Epha receptor axis may be a novel therapy target for diabetic nephropathy. Mechanistically, the overexpression of EphA1 could inhibit MAPK and the Rho pathway in diabetic kidneys.

  12. The PD-1/PD-L1 axis may be aberrantly activated in occupational cholangiocarcinoma.

    PubMed

    Sato, Yasunori; Kinoshita, Masahiko; Takemura, Shigekazu; Tanaka, Shogo; Hamano, Genya; Nakamori, Shoji; Fujikawa, Masahiro; Sugawara, Yasuhiko; Yamamoto, Takatsugu; Arimoto, Akira; Yamamura, Minako; Sasaki, Motoko; Harada, Kenichi; Nakanuma, Yasuni; Kubo, Shoji

    2017-03-01

    An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.

  13. Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

    PubMed

    Xiao, Hong-Li; Li, Chun-Sheng; Zhao, Lian-Xing; Yang, Jun; Tong, Nan; An, Le; Liu, Qi-Tong

    2016-11-01

    Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

  14. [The hypothalamic-pituitary-adrenal axis, and reproductive system activity changing of female rats with prenatal stress during aging].

    PubMed

    Shamolina, T S; Pivina, S G; Ordian, N E

    2009-09-01

    The effect of female rat daily 1-hour immobilization in the period from the 15th to the 18th gestation days on the sex steroid secretion subject to estrous cycle, hypothalamic-pituitary-adrenal axis (HPA) activity and its sensitivity to regulatory signals based on the mechanism of negative feedback in ternale offspring during different ontogenesis stages, was studied. It has been shown that prenatal stress causes significant reproductive system activity disturbances, leading to a significant decrease in the HPA sensitivity to feedback signal in aging female rats. The obtained data indicate a modifying influence of mothers' stress on changing of female rat reproductive functions during aging together with influence on significant decrease in efficiency of HPAs' feedback path.

  15. HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity

    PubMed Central

    Semba, Hiroaki; Takeda, Norihiko; Isagawa, Takayuki; Sugiura, Yuki; Honda, Kurara; Wake, Masaki; Miyazawa, Hidenobu; Yamaguchi, Yoshifumi; Miura, Masayuki; Jenkins, Dana M. R.; Choi, Hyunsung; Kim, Jung-whan; Asagiri, Masataka; Cowburn, Andrew S.; Abe, Hajime; Soma, Katsura; Koyama, Katsuhiro; Katoh, Manami; Sayama, Keimon; Goda, Nobuhito; Johnson, Randall S.; Manabe, Ichiro; Nagai, Ryozo; Komuro, Issei

    2016-01-01

    In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity. PMID:27189088

  16. Toxic stress, inflammation and symptomatology of chronic complications in diabetes

    PubMed Central

    Downs, Charles A; Faulkner, Melissa Spezia

    2015-01-01

    Diabetes affects at least 382 million people worldwide and the incidence is expected to reach 592 million by 2035. The incidence of diabetes in youth is skyrocketing as evidenced by a 21% increase in type 1 diabetes and a 30.5% increase in type 2 diabetes in the United States between 2001 and 2009. The effects of toxic stress, the culmination of biological and environmental interactions, on the development of diabetes complications is gaining attention. Stress impacts the hypothalamus-pituitary-adrenal axis and contributes to inflammation, a key biological contributor to the pathogenesis of diabetes and its associated complications. This review provides an overview of common diabetic complications such as neuropathy, cognitive decline, depression, nephropathy and cardiovascular disease. The review also provides a discussion of the role of inflammation and stress in the development and progression of chronic complications of diabetes, associated symptomatology and importance of early identification of symptoms of depression, fatigue, exercise intolerance and pain. PMID:25987953

  17. Does maternal prenatal stress adversely affect the child's learning and memory at age six?

    PubMed

    Gutteling, Barbara M; de Weerth, Carolina; Zandbelt, Noortje; Mulder, Eduard J H; Visser, Gerard H A; Buitelaar, Jan K

    2006-12-01

    Prenatal maternal stress has been shown to affect postnatal development in animals and humans. In animals, the morphology and function of the offspring's hippocampus is negatively affected by prenatal maternal stress. The present study prospectively investigated the influence of prenatal maternal stress on learning and memory of 112 children (50 boys, 62 girls, Age: M=6.7 years, SD=8.4 months), with the Test of Memory and Learning (TOMAL). Maternal stress levels were determined three times during pregnancy by self-report questionnaires. Furthermore, maternal saliva cortisol samples were used as a measure of hypothalamus-pituitary-adrenal axis functioning. Results of hierarchical multivariate regression analyses showed that maternal life events measured during the first part of pregnancy were negatively associated with the child's attention/concentration index, while controlling for overall IQ, gender, and postnatal stress. No associations were found between prenatal maternal cortisol and the offspring's learning and memory.

  18. Physiology of psychoneuroimmunology: a personal view.

    PubMed

    Besedovsky, Hugo O; Rey, Adriana Del

    2007-01-01

    This article offers a personal view on how the concept of the existence of a network of immune-neuro-endocrine interactions has evolved in the last 30 years. The main topic addressed is the relevance of the exchange of signals between the immune, endocrine and nervous systems for immunoregulation and brain functions. Particular emphasis is given to circuits involving immune cell products, the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. The operation of these circuits can affect immune functions and the course of inflammatory, autoimmune and infectious diseases. We also discuss increasing evidence that brain-born cytokines play an important role in brain physiology and in the integration of the immune-neuro-endocrine network.

  19. [LED LIGHTING AS A FACTOR FOR THE STIMULATION OF THE HORMONE SYSTEM].

    PubMed

    Deynego, V N; Kaptsov, V A

    2015-01-01

    There are considered questions of non-visual effects of blue LED light sources on hormonal systems (cortisol, glucose, insulin) providing the high human performance. In modern conditions hygiene strategy for child and adolescent health strategy was shown to be replaced by a strategy of light stimulation of the hormonal profile. There was performed a systematic analysis of the axis "light stimulus-hypothalamus-pituitary-adrenals-cortisol-glucose-insulin". The elevation of the content of cortisol leads to the increase of the glucose level in the blood and the stimulation of the production of insulin, which can, like excessive consumption of food, give rise to irreversible decline in the number of insulin receptors on the cell surface, and thus--to a steady reduction in the ability of cells to utilize glucose, i.e. to type 2 diabetes or its aggravation.

  20. Delta(9)-tetrahydrocannabinol enhances an increase of plasma corticosterone levels induced by forced swim-stress.

    PubMed

    Sano, Kazunori; Koushi, Emi; Irie, Keiichi; Higuchi, Sei; Tsuchihashi, Ryota; Kinjo, Junei; Egashira, Nobuaki; Oishi, Ryozo; Uchida, Naoki; Nagai, Hiroshi; Nishimura, Ryoji; Tanaka, Hiroyuki; Morimoto, Satoshi; Mishima, Kenichi; Iwasaki, Katsunori; Fujiwara, Michihiro

    2009-12-01

    The present study was designed to determine the effect of delta(9)-tetrahydrocannabinol (THC) on susceptibility to stress. We reported that THC significantly prolonged the immobility time during the forced swim-stress. The selective cannabinoid CB(1) receptor antagonist O-2050 significantly reduced the enhancement of immobility by THC. We investigated the effect of THC on levels of stress hormone corticosterone under non-stress and forced swim-stress conditions. THC did not affect plasma corticosterone levels under non-stress conditions. However, THC, together with forced swim-stress, significantly increased plasma corticosterone levels. This effect was inhibited by O-2050. This evidence suggests that THC, under stressful conditions, enhances the susceptibility of the hypothalamus-pituitary-adrenal-axis to stress via the CB(1) receptor, thereby increasing the risk of depression.

  1. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

    SciTech Connect

    Wang, Bing Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

    2013-07-19

    Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

  2. Aberrantly activated Gli2-KIF20A axis is crucial for growth of hepatocellular carcinoma and predicts poor prognosis

    PubMed Central

    Shi, Chao; Huang, Dengliang; Lu, Nonghua; Chen, Dan; Zhang, Minhong; Yan, Yehong; Deng, Libin; Lu, Quqin; Lu, Hua; Luo, Shiwen

    2016-01-01

    Glioma-associated oncogene 2 (Gli2), a primary transcriptional regulator of Hedgehog (Hh) signaling, is essential for hepatocellular carcinoma (HCC) growth and survival. However, the underlying molecular mechanism and crucial downstream targets of Gli2 in human HCC are not fully understood. Here, we report the identification of kinesin family member 20A (KIF20A) as a novel downstream target of Gli2, which is important for HCC proliferation and tumor growth. Inhibition of Hh signaling leads to a remarkable decrease of KIF20A expression in HCC cells, whereas overexpression of Gli2 elevates KIF20A expression by activating Forkhead Box M1 (FoxM1)-MMB complex-mediated transcription of this kinesin gene. Gli2-induced HCC cell growth requires enhanced expression of KIF20A, and knockdown of Gli2 or KIF20A represses the proliferation of HCC cells in vitro and in vivo. Correlated with these results, analyses of clinical HCC samples show that Gli2, FoxM1 and KIF20A are highly elevated in primary HCC samples and represent significant risk factors for HCC recurrence and survival. Conclusion: KIF20A is an important downstream target gene of Hh signaling. And, the Gli2-KIF20A axis is essential for the proliferation and growth of human HCC cells. Our study also suggests Gli2-KIF20A axis as a potential target for future therapeutic intervention and as an independent prognostic biomarker for HCC. PMID:27036048

  3. Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice.

    PubMed

    Majidi, Jafar; Kosari-Nasab, Morteza; Salari, Ali-Akbar

    2016-01-01

    Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early

  4. Development of a satellite flywheel family operating on one active axis magnetic bearings

    NASA Technical Reports Server (NTRS)

    Poubeau, P. C.

    1977-01-01

    Magnetic bearings with radial passive centering and axial active control of the rotor position are described in terms of optimization for satellite flywheel applications and kinetic storage of energy for satellites.

  5. Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells

    PubMed Central

    van Senten, Jeffrey R.; Fraile-Ramos, Alberto; Siderius, Marco; Smit, Martine J.

    2016-01-01

    The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells. The constitutive activity of US28 increases HIF-1 protein stability through a Gαq-, CaMKII- and Akt/mTOR-dependent mechanism. Furthermore, we found that VEGF and lactate secretion are increased and HIF-1 target genes, glucose transporter type 1 (GLUT1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), involved in glucose metabolism, are upregulated in US28 expressing cells. In addition, PKM2 is phosphorylated and found to be in a tumor-associated dimeric state upon US28 expression. Also in HCMV-infected cells HIF-1 activity is enhanced, which in part is US28-dependent. Finally, increased proliferation of cells expressing US28 is abolished upon inhibition of the HIF-1α/PKM2 cascade. These data highlight the importance of HIF-1α and PKM2 in US28-induced proliferation, angiogenesis and metabolic reprogramming. PMID:27602585

  6. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype

    PubMed Central

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M.; Dahiya, Rajvir; Lovett, David H.

    2011-01-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel–Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial–mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial–mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial–mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal

  7. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype.

    PubMed

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M; Dahiya, Rajvir; Lovett, David H

    2011-12-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel-Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial-mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial-mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial-mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal cell

  8. Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity.

    PubMed

    Shivers, Kai-Yvonne; Amador, Nicole; Abrams, Lisa; Hunter, Deirtra; Jenab, Shirzad; Quiñones-Jenab, Vanya

    2015-04-01

    Although estrogen reduces inflammatory-mediated pain responses, the mechanisms behind its effects are unclear. This study investigated if estrogen modulates inflammatory signaling by reducing baseline or inflammation-induced cytokine levels in the injury-site, serum, dorsal root ganglia (DRG) and/or spinal cord. We further tested whether estrogen effects on cytokine levels are in part mediated through hypothalamic-pituitary-adrenal (HPA) axis activation. Lumbar DRG, spinal cord, serum, and hind paw tissue were analyzed for cytokine levels in 17β-estradiol-(20%) or vehicle-(100% cholesterol) treated female rats following ovariectomy/sham adrenalectomy (OVX), adrenalectomy/sham ovariectomy (ADX) or ADX+OVX operation at baseline and post formalin injection. Formalin significantly increased pro-inflammatory interleukin (IL)-6 levels in the paw, as well as pro- and anti-inflammatory cytokine levels in the DRG, spinal cord and serum in comparison to naïve conditions. Estrogen replacement significantly increased anti-inflammatory IL-10 levels in the DRG. Centrally, estradiol significantly decreased pro-inflammatory tumor necrosis factor (TNF)-α and IL-1β levels, as well as IL-10 levels, in the spinal cord in comparison to cholesterol treatment. At both sites, most estradiol modulatory effects occurred irrespective of pain or surgical condition. Estradiol alone had no influence on cytokine release in the paw or serum, indicating that estrogen effects were site-specific. Although cytokine levels were altered between surgical conditions at baseline and following formalin administration, ADX operation did not significantly reverse estradiol's modulation of cytokine levels. These results suggest that estrogen directly regulates cytokines independent of HPA axis activity in vivo, in part by reducing cytokine levels in the spinal cord.

  9. Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes

    PubMed Central

    Hoencamp, Erik; Penninx, Brenda W. J. H.

    2015-01-01

    Introduction Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients. Methods Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers. Results In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women. Conclusion Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity

  10. CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma.

    PubMed

    Li, Fei; Zou, Zhigeng; Suo, Ning; Zhang, Zongpu; Wan, Fangzhu; Zhong, Guangxin; Qu, Yan; Ntaka, Kwanele Siphelele; Tian, Hua

    2014-09-01

    Secondary lymphoid tissue chemokine (SLC/CCL21) and its receptor CCR7 have been implicated in lymph node metastasis, whereas the mechanism of which remains unclear. Epithelial-mesenchymal transition (EMT) plays an important role in invasion and migration of cancer cells. We presumed that CCL21/CCR7 axis activates EMT process to induce cancer cell invasion and metastasis. Firstly, the expressions of CCR7 and EMT markers were examined by immunohistochemical staining in the primary breast carcinoma tissues from 60 patients who underwent radical mastectomy. Then, we investigated whether CCL21/CCR7 induces EMT process during mediating cancer cell invasion or migration in vitro. By immunohistolochemistry, high expressions of CCR7, Slug and N-cadherin were seen in 60, 65, and 76.67 % of tumors, respectively, and significantly associated with lymph node metastases as well as clinical pathological stage. Furthermore, the CCR7 expression was significantly correlated to Slug and N-cadherin. In vitro, stimulating breast cancer cell lines 1428, MCF-7 and MDA-MB-231 with CCL21, the invasion and migration of tumor cells were promoted, and simultaneously, EMT phenotype of tumor cells was enhanced, including down-regulation of E-cadherin, up-regulation of Slug, Vimentin and N-cadherin at both protein and mRNA levels. Inversely, knockdown of CCR7 by shRNA suppressed tumor cell invasion, migration and EMT phenotype induced by CCL21. These results indicated that CCL21/CCR7 axis could activate EMT process during chemotaxis of breast carcinoma cells.

  11. Hypothalamic-Ptuitary-Adrenal (HPA) Axis Activity in Adults with Intellectual Disabilities: A Preliminary Investigation

    ERIC Educational Resources Information Center

    Presland, A. D.; Clare, I. C. H.; Broughton, S.; Luke, L.; Wheeler, E.; Fairchild, G.; Watson, P. C.; Chan, W. Y. S.; Kearns, A.; Ring, H. A.

    2013-01-01

    Background: Cortisol is a marker of physiological arousal, exhibiting a characteristic pattern of diurnal activity. The daily cortisol profile has been examined extensively and is atypical in a number of clinical disorders. However, there are very few studies focussing on the cortisol profile in adults with intellectual disabilities (ID). This…

  12. Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

    PubMed Central

    Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

    2016-01-01

    Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

  13. A six-axis hybrid vibration isolation system using active zero-power control supported by passive weight support mechanism

    NASA Astrophysics Data System (ADS)

    Emdadul Hoque, Md.; Mizuno, Takeshi; Ishino, Yuji; Takasaki, Masaya

    2010-08-01

    This paper presents a six-degree-of-freedom hybrid vibration isolation system integrated with an active negative suspension, an active-passive positive suspension and a passive weight support mechanism. The aim of the research consists in maximizing the system and control performances, and minimizing the system development and maintenance costs. The vibration isolation system is, fundamentally, developed by connecting an active negative suspension realized by zero-power control in series with an active-passive positive suspension. The system could effectively isolate ground vibrations in addition to suppress the effect of on-board generated direct disturbances of the six-axis motions, associated with vertical and horizontal directions. The system is further reinforced by introducing a passive weight support mechanism in parallel with the basic system. The modified system with zero-power control allows simplified design of the isolation table without power consumption. It also offers enhanced performance on direct disturbance suppression and large payload supporting capabilities, without degrading transmissibility characteristics. A mathematical model of the system is presented and, therefore, analyzed to demonstrate that zero-compliance to direct disturbance could be generated by the developed system. Experimental demonstrations validate the proposed concept that exhibits high stiffness of the isolation table to static and dynamic direct disturbances, and good transmissibility characteristics against ground vibration. Further improvements of the vibration isolation system and the control system are discussed as well.

  14. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

    PubMed Central

    Carroll, Bernadette; Maetzel, Dorothea; Maddocks, Oliver DK; Otten, Gisela; Ratcliff, Matthew; Smith, Graham R; Dunlop, Elaine A; Passos, João F; Davies, Owen R; Jaenisch, Rudolf; Tee, Andrew R; Sarkar, Sovan; Korolchuk, Viktor I

    2016-01-01

    The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling. DOI: http://dx.doi.org/10.7554/eLife.11058.001 PMID:26742086

  15. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function.

    PubMed

    Lee, Guan-Lin; Wu, Jing-Yiing; Tsai, Chien-Sung; Lin, Chih-Yuan; Tsai, Yi-Ting; Lin, Chin-Sheng; Wang, Yi-Fu; Yet, Shaw-Fang; Hsu, Yu-Juei; Kuo, Cheng-Chin

    2016-08-24

    Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration.

  16. Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism.

    PubMed

    Menicucci, D; Sebastiani, L; Comparini, A; Pingitore, A; Ghelarducci, B; L'Abbate, A; Iervasi, G; Gemignani, A

    2013-03-01

    There is evidence of an association between thyroid hormones (TH) alterations and mental dysfunctions related to procedural and working memory functions, but the physiological link between these domains is still under debate, also for the presence of age as a confounding factor. Thus, we investigated the TH tuning of cerebral functions in young females affected by the borderline condition of subclinical hypothyroidism (SH) and in euthyroid females of the same age. The experiment consisted in the characterization of the affective state and cognitive abilities of the subjects by means of specific neuropsychological questionnaires, and of brain activity (EEG) in resting state and during the passive viewing of emotional video-clips. We found that SH had i) increased anxiety for Physical Danger; ii) better scores for both Mental Control and no-working-memory-related functions; iii) association between anxiety for Physical Danger and fT4 levels. Thus, in young adults, SH increases inward attention and paradoxically improves some cognitive functions. In addition, self-assessed questionnaires showed that SH had a greater susceptibility to unpleasant emotional stimulation. As for EEG data, SH compared to controls showed: i) reduction of alpha activity and of gamma left lateralization in resting state; ii) increased, and lateralized to the right, beta2 activity during stimulations. Both results indicated that SH have higher levels of arousal and greater susceptibility to negative emotion than controls. In conclusion, our study indicates that minimal changes in TH levels produce subtle but well-defined mental changes, thus encouraging further studies for the prediction of pathology evolution.

  17. Hair cortisol as a marker of hypothalamic-pituitary-adrenal Axis activity in female patients with major depressive disorder.

    PubMed

    Pochigaeva, Ksenia; Druzhkova, Tatiana; Yakovlev, Alexander; Onufriev, Mikhail; Grishkina, Maria; Chepelev, Aleksey; Guekht, Alla; Gulyaeva, Natalia

    2017-04-01

    Hair cortisol is regarded as a promising marker of hypothalamic-pituitary-adrenal axis (HPAA) activity alterations due to stress, somatic and mental health conditions. Hair cortisol was previously reported to be elevated in patients with depression, however the data related to remission and recurrent depressive episodes are different. In this study, levels of hair cortisol were assessed in female patients with major depressive disorder (MDD) and the validity of hair cortisol as a marker of HPAA activity in this condition was evaluated. Hair cortisol was measured in 1 cm hair segments of 21 female patients with MDD and 22 female age-matched controls using enzyme-immunoassay analysis. Concurrently, serum cortisol was assessed and psychological status was evaluated using 17-item Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory (BDI) and the Spielberger state trait anxiety inventory (STAI). The levels of hair cortisol were significantly lower in the MDD group, while serum cortisol levels were significantly higher in patients, as compared with controls. A significant negative correlation was found between HAMD-17 scores and hair cortisol. Decreased hair cortisol found in female patients with MDD as compared to controls suggests downregulation of HPAA activity during the preceding month. Further studies are needed to investigate the profiles of hair cortisol at different stages of depressive disorder to establish this parameter as a handy clinical tool.

  18. Cocaine-mediated microglial activation involves the ER stress-autophagy axis

    PubMed Central

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases. PMID:26043790

  19. Cocaine-mediated microglial activation involves the ER stress-autophagy axis.

    PubMed

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases.

  20. Overexpression of prohibitin-1 inhibits RANKL-induced activation of p38-Elk-1-SRE signaling axis blocking MKK6 activity.

    PubMed

    Lee, Chang Hoon; Choi, Sik-Won; Kim, Ju-Young; Kim, Seong Hwan; Yoon, Kwon-Ha; Oh, Jaemin; Lee, Myeung Su

    2015-08-07

    Prohibitin-1 (PHB) regulates diverse cellular processes by controlling several signaling pathways. In this study, we investigated the functional involvement of PHB in osteoclast differentiation. PHB expression was time-dependently increased by RANKL in BMMs. However, the retroviral over-expression of PHB strongly inhibited the expression of c-Fos and NFATc1, and activation of p38-Elk-1-SRE signaling pathway. Anti-osteoclastogenic action of PHB was significantly inhibited by constitutively active forms of MKK6, but not Elk-1. Collectively, PHB negatively regulates the formation of mature osteoclasts via inhibition of MKK6 activity that affects the activation of the p38-Elk-1 signaling axis required for the expression of c-Fos and NFATc1.

  1. A Spaceflight Magnetic Bearing Equipped Optical Chopper with Six-Axis Active Control

    NASA Technical Reports Server (NTRS)

    Blumenstock, K. A.; Lee, K. Y.; Schepis, J. P.

    1998-01-01

    This paper describes the development of an ETU (Engineering Test Unit) rotary optical chopper with magnetic bearings. An ETU is required to be both flight-like, nearly identical to a flight unit without the need for material certifications, and demonstrate structural and performance integrity. A prototype breadboard design previously demonstrated the feasibility of meeting flight performance requirements using magnetic bearings. The chopper mechanism is a critical component of the High Resolution Dynamics Limb Sounder (HIRDLS) which will be flown on EOS-CHEM (Earth Observing System-Chemistry). Particularly noteworthy are the science requirements which demand high precision positioning and minimal power consumption along with full redundancy of coils and sensors in a miniature, lightweight package. The magnetic bearings are unique in their pole design to minimize parasitic losses and utilize collocated optical sensing. The motor is of an unusual disk-type ironless stator design. The ETU design has evolved from the breadboard design. A number of improvements have been incorporated into the ETU design. Active thrust control has been added along with changes to improve sensor stability, motor efficiency, and touchdown and launch survivability. It was necessary to do all this while simultaneously reducing the mechanism volume. Flight-like electronics utilize a DSP (Digital Signal Processor) and contain all sensor electronics and drivers on a single five inch by nine inch circuit board. Performance test results are reported including magnetic bearing and motor rotational losses.

  2. Dysregulated responses to emotions among abstinent heroin users: correlation with childhood neglect and addiction severity.

    PubMed

    Gerra, G; Somaini, L; Manfredini, M; Raggi, M A; Saracino, M A; Amore, M; Leonardi, C; Cortese, E; Donnini, C

    2014-01-03

    The aim of this paper was to investigate the subjective responses of abstinent heroin users to both neutral and negative stimuli and the related hypothalamus-pituitary-adrenal reactions to emotional experience in relationship to their perception of childhood adverse experiences. Thirty male abstinent heroin dependents were included in the study. Emotional responses and childhood neglect perception were measured utilizing the State-Trait Anxiety Inventory Y-1 and the Child Experience of Care and Abuse Questionnaire. Neutral and unpleasant pictures selected from the International Affective Picture System and the Self-Assessment Manikin procedure have been used to determine ratings of pleasure and arousal. These ratings were compared with normative values obtained from healthy volunteers used as control. Blood samples were collected before and after the experimental sessions to determine both adrenocorticotropic hormone and cortisol plasma levels. Basal anxiety scores, cortisol and adrenocorticotropic hormone levels were higher in abstinent heroin users than in controls. Tests showed that anxiety scores did not change in controls after the vision of neutral slides, whilst they did in abstinent heroin addicts, increasing significantly; and increased less significantly after the unpleasant task, in comparison to controls. Abstinent heroin users showed significantly higher levels of parent antipathy and childhood emotional neglect perception than controls for both the father and the mother. Plasma adrenocorticotropic hormone and cortisol levels did not significantly increase after unpleasant slide set viewing among addicted individuals, because of the significantly higher basal levels characterizing the addicted subjects in comparison with controls. Multiple regression correlation showed a significant relationship between childhood neglect perception, arousal reaction, impaired hypothalamus-pituitary-adrenal axis response and addiction severity. Early adverse experiences

  3. Changes in α-glucosidase activities along the jejunal-ileal axis of normal rats by the α-glucosidase inhibitor miglitol.

    PubMed

    Mochizuki, Kazuki; Hanai, Emiko; Suruga, Kazuhito; Kuranuki, Sachi; Goda, Toshinao

    2010-10-01

    Miglitol, an α-glucosidase inhibitor that inhibits postprandial hyperglycemia by delaying carbohydrate digestion and absorption along the jejunal-ileal axis, has recently been approved for use in patients with type 2 diabetes mellitus. Miglitol treatment may lead to increased α-glucosidase activities toward the ileum because carbohydrate flow toward the ileum increases. However, it is not yet known if miglitol treatment alters the α-glucosidase activities along the jejunal-ileal axis. In this study, we examined the effects of miglitol supplementation for 3 or 7 days on α-glucosidase activities along the jejunal-ileal axis of Wistar rats. Supplementation with miglitol for 3 or 7 days in rats increased tissue weights of the lower jejunum and ileum, but did not alter tissue weights of the upper jejunum and cecum or the contents of the cecum. Furthermore, supplementation with miglitol for 7 days reduced the activities of isomaltase and maltase in the upper jejunum and increased the activities of sucrase, isomaltase, and maltase in the lower jejunum and ileum. These results suggest that the delay in carbohydrate digestion and absorption along the jejunal-ileal axis by miglitol supplementation in rats is associated with increased α-glucosidase activities toward the ileum.

  4. Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic–pituitary–adrenal axis: first evidence from two independent subsamples

    PubMed Central

    Ridder, S.; Treutlein, J.; Nees, F.; Lang, S.; Diener, S.; Wessa, M.; Kroll, A.; Pohlack, S.; Cacciaglia, R.; Gass, P.; Schütz, G.; Schumann, G.; Flor, H.

    2012-01-01

    Background Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis. Method In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. Results Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity. Conclusions This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning. PMID:22410078

  5. Helicobacter urease–induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma

    PubMed Central

    Koch, Katrin N.; Hartung, Mara L.; Urban, Sabine; Kyburz, Andreas; Bahlmann, Anna S.; Lind, Judith; Backert, Steffen; Taube, Christian; Müller, Anne

    2015-01-01

    Inflammasome activation and caspase-1–dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1β promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori–infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro–IL-1β expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow–derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1β and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori–specific immune regulation. PMID:26214524

  6. Elastic flexure explains the offset of primary volcanic activity upstream of the Réunion and Hawaii plume axis

    NASA Astrophysics Data System (ADS)

    Gerbault, Muriel; Fontaine, Fabrice; Rabinowicz, Michel; Bystricky, Micha

    2016-04-01

    Recent tomography reveals that surface volcanism at la Réunion and Hawaii develops offset by 150-180 km upstream to the plume axis with respect to plate motion. We use elasto-visco-plastic 2D numerical models to describe the development of compressional stresses at the base of the lithosphere, resulting from elastic plate bending above the upward load exerted by the plume head. This horizontal compression is ~20 km thick, has a ~ 150 km radius and lays around ~50-70 km depth where temperature varies from ~600°C to ~750°C. It is suggested that the buoyant melts percolating in the plume head pond below this zone of compression and eventually spread laterally to the extent where compression vanishes. There, melts resume their ascension and propagate through dikes up to ~35 km depth where the field stress rotates again due to plate curvature change. Flexural compression is a transient phenomenon that depends: (i) on the relaxation time of elasto-plastic stresses between ~600° and ~750°C, (ii) on the thermal erosion of the lithosphere induced by the plume, and (iii) on the ratio of the normal versus tangential stress exerted by the plume on the lithosphere. We find that for a plate 70 My old, this horizontal compression lasts for about 5 Myrs. This time span exceeds the time during which both the Indian and Pacific plates drift over the Reunion and Hawaii plumes, respectively. Accordingly, our model explains i) the ~150 km shift between the surface volcanism and the axis of the plume, ii) the ~5 Myrs synchronous activity of the volcanoes of la Réunion and Mauritius, and (iii) the present pounding of melts at 35 km depth detected below the Reunion and Mauritius Islands. Plume-lithosphere interaction is one of the numerous subjects that Genia Burov studied and modeled; the present study uses a similar code to the one he used, and is inspired by several of his assumptions. In support of his own goals and worries, we show here the importance of thermo

  7. NF-kappaB activity affects learning in aversive tasks: possible actions via modulation of the stress axis.

    PubMed

    Lehmann, Michael L; Brachman, Rebecca A; Listwak, Samuel J; Herkenham, Miles

    2010-08-01

    The role of altered activity of nuclear factor kappaB (NF-kappaB) in specific aspects of motivated behavior and learning and memory was examined in mice lacking the p50 subunit of the NF-kappaB/rel transcription factor family. Nfkb1-deficient mice are unable to produce p50 and show specific susceptibilities to infections and inflammatory challenges, but the behavioral phenotype of such mice has been largely unexamined, owing in large part to the lack of understanding of the role of NF-kappaB in nervous system function. Here we show that Nfkb1 (p50) knockout mice more rapidly learned to find the hidden platform in the Morris water maze than did wildtype mice. The rise in plasma corticosterone levels after the maze test was greater in p50 knockout than in wildtype mice. In the less stressful Barnes maze, which tests similar kinds of spatial learning, the p50 knockout mice performed similarly to control mice. Adrenalectomy with corticosterone replacement eliminated the differences between p50 knockout and wildtype mice in the water maze. Knockout mice showed increased levels of basal anxiety in the open-field and light/dark box tests, suggesting that their enhanced escape latency in the water maze was due to activation of the stress (hypothalamic-pituitary-adrenal) axis leading to elevated corticosterone production by strongly but not mildly anxiogenic stimuli. The results suggest that, as in the immune system, p50 in the nervous system normally serves to dampen NF-kappaB-mediated intracellular activities, which are manifested physiologically through elevated stress responses to aversive stimuli and behaviorally in the facilitated escape performance in learning tasks.

  8. Acute incremental exercise, performance of a central executive task, and sympathoadrenal system and hypothalamic-pituitary-adrenal axis activity.

    PubMed

    McMorris, Terry; Davranche, Karen; Jones, Glenys; Hall, Ben; Corbett, Jo; Minter, Charles

    2009-09-01

    The purposes of this study were to examine the effect of acute incremental exercise on the performance of a central executive task; the responses of the sympathoadrenal system (SAS) and hypothalamic-pituitary-adrenal axis (HPAA) during exercise, while simultaneously carrying out the central executive task; and the ability of Delta plasma concentrations of epinephrine, norepinephrine, adrenocorticotropin hormone (ACTH) and cortisol to predict Delta performance on the central executive task. Subjects undertook a flanker task at rest and during exercise at 50% and 80% maximum aerobic power (MAP). SAS and HPAA activity were measured pre- and post-treatment by plasma concentrations of catecholamines, and cortisol and ACTH, respectively. Reaction time (RT) and number of errors for congruent and incongruent trials on the flanker task showed significant main effects with performance at 80% MAP higher than in the other conditions. RT post-correct responses were significantly faster than RT post-error at rest and 50% MAP but not at 80%. Pre- and post-treatment catecholamines showed a main effect of exercise with a linear increase. Post-treatment ACTH concentrations at 80% MAP were significantly greater than in the other conditions. Delta epinephrine and ACTH combined were significant predictors of Delta RT and Delta norepinephrine was a significant predictor of Delta number of errors. It was concluded that exercise must be at a high intensity to affect performance on the flanker task. Both the SAS and HPAA appear to play a role in the exercise-cognition interaction.

  9. TSLP Is a Potential Initiator of Collagen Synthesis and an Activator of CXCR4/SDF-1 Axis in Keloid Pathogenesis.

    PubMed

    Shin, Jung U; Kim, Seo Hyeong; Kim, Hyeran; Noh, Ji Yeon; Jin, Shan; Park, Chang Ook; Lee, Won Jai; Lee, Dong Won; Lee, Ju Hee; Lee, Kwang Hoon

    2016-02-01

    Recently, thymic stromal lymphopoietin (TSLP), which is well studied in allergic diseases, has been reported in fibrotic diseases, including idiopathic pulmonary fibrosis and atopic dermatitis fibrosis. However, the role of TSLP in keloid is obscure. In this study, we assessed the expression of TSLP in keloid tissue and investigated the possible role of TSLP in keloid pathogenesis. We observed that TSLP expression was increased in keloid tissue compared to normal tissue. Furthermore, TSLP treatment induced increased collagen I and collagen III expression in fibroblasts via transforming growth factor-?; however, there was higher expression in keloid fibroblasts compared to normal fibroblasts. Stromal cell-derived factor-1?, which was recently reported to enhance wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area, increased after TSLP treatment in fibroblasts and was primarily expressed in ?-smooth muscle action-positive myofibroblasts in keloid tissue. Furthermore, fibrocytes expressing CXCR4, a stromal cell-derived factor-1? receptor, were significantly increased in keloid tissue compared to normal tissue. Finally, intradermal TSLP injection on BALB/c mice increased stromal cell-derived factor-1? expression and CXCR4(+) fibrocytes infiltration. Our data suggest that TSLP is a potent inducer of collagen and transforming growth factor-? production in keloid fibroblasts. In addition, it might activate the CXCR4/stromal cell-derived factor-1 axis to increase fibrocyte infiltration into the keloid tissue.

  10. Income, cumulative risk, and longitudinal profiles of hypothalamic-pituitary-adrenal axis activity in preschool-age children.

    PubMed

    Zalewski, Maureen; Lengua, Liliana J; Thompson, Stephanie F; Kiff, Cara J

    2016-05-01

    Environmental risk predicts disrupted basal cortisol levels in preschool children. However, little is known about the stability or variability of diurnal cortisol morning levels or slope patterns over time in young children. This study used latent profile analysis to identify patterns of the hypothalamic-pituitary-adrenal axis activity during the preschool period. Using a community sample (N = 306), this study measured income, cumulative risk, and children's diurnal cortisol (morning level and slope) four times across 2.5 years, starting when children were 36 months old. Latent profile analysis profiles indicated that there were predominantly stable patterns of diurnal cortisol level and slope over time and that these patterns were predicted by income and cumulative risk. In addition, there were curvilinear relations of income and cumulative risk to profiles of low morning cortisol level and flattened diurnal slope across time, suggesting that both lower and higher levels of income and cumulative risk were associated with a stress-sensitive physiological system. Overall, this study provides initial evidence for the role of environmental risk in predicting lower, flattened basal cortisol patterns that remain stable over time.

  11. Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease

    PubMed Central

    Min, Hae-Ki; Mirshahi, Faridoddin; Verdianelli, Aurora; Pacana, Tommy; Patel, Vaishali; Park, Chun-Geon; Choi, Aejin; Lee, Jeong-Hoon; Park, Chung-Berm; Ren, Shunlin

    2015-01-01

    The status of the GP130-STAT3 signaling pathway in humans with nonalcoholic fatty liver disease (NAFLD) and its relevance to disease pathogenesis are unknown. The expression of the gp130-STAT3 axis and gp130 cytokine receptors were studied in subjects with varying phenotypes of NAFLD including nonalcoholic steatohepatitis (NASH) and compared with lean and weight-matched controls without NAFLD. Gp130 and its downstream signaling element (Tyk2 and STAT3) expression were inhibited in obese controls whereas they were increased in NAFLD. IL-6 levels were increased in NASH and correlated with gp130 expression (P < 0.01). Palmitate inhibited gp130-STAT3 expression and signaling. IL-6 and palmitate inhibited hepatic insulin signaling via STAT3-dependent and independent mechanisms, respectively. STAT3 overexpression reversed palmitate-induced lipotoxicity by increasing autophagy (ATG7) and decreasing endoplasmic reticulum stress. These data demonstrate that the STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis. PMID:25747354

  12. Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis

    PubMed Central

    Huang, Chi-Ruei; Lee, Chung-Ta; Chang, Kwang-Yu; Chang, Wen-Chang; Liu, Yao-Wen; Lee, Jenq-Chang; Chen, Ben-Kuen

    2015-01-01

    The aryl hydrocarbon receptor nuclear translocator (ARNT) is broadly involved in regulating tumorigenesis by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrate that ARNT protein levels were decreased in late-stage human colorectal cancer using immunohistochemical analysis. Down-regulation of ARNT protein promoted cancer cell migration and invasion, which was mediated by activation of the fibronectin/integrin β1/FAK signaling axis. In addition, the enhancement of migration and invasion in ANRT knockdown cells was blocked when ARNT was restored in the cells. In xenografts in severe combined immunodeficiency mice, tumor growth was significantly inhibited in the ARNT-knockdown condition. However, the tail-vein injection animal model revealed that the depletion of ARNT-induced metastatic lung colonies was further enhanced when ARNT expression was recovered post-injection. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted the invasion of residual tumor cells. These results suggest that ARNT may play a positive role during tumor growth (either in early-stage tumor growth or in organ metastases), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy during different cancer stages should be carefully evaluated. PMID:25839165

  13. [Stress, mental disorders and coronary heart disease].

    PubMed

    Lederbogen, F; Ströhle, A

    2012-11-01

    There are numerous associations between stress, mental disorders and coronary heart disease (CHD). Exposure to an acute stressor leads to activation of the hypothalamus-pituitary-adrenal and sympathoadrenal systems and chronic stressors are associated with sustained functional changes of these systems. Experiencing acute and chronic stress is paralleled by an increased incidence of mental disorders with the most consistent evidence on the triggering of major depressive episodes. Various mental disorders, including depression, anxiety and schizophrenia, are associated with an increased risk of CHD. Furthermore, acute and chronic stressors have been identified as risk factors or triggers of acute coronary syndromes. Thus therapeutic strategies aim at reducing subjective stress experience, therapy of mental disorders and treatment of cardiac risk factors known to be more prevalent in increased stress states and mental disorders.

  14. Activation of the Tor/Myc signaling axis in intestinal stem and progenitor cells affects longevity, stress resistance and metabolism in drosophila.

    PubMed

    Strilbytska, Olha M; Semaniuk, Uliana V; Storey, Kenneth B; Edgar, Bruce A; Lushchak, Oleh V

    2017-01-01

    The TOR (target of rapamycin) signaling pathway and the transcriptional factor Myc play important roles in growth control. Myc acts, in part, as a downstream target of TOR to regulate the activity and functioning of stem cells. Here we explore the role of TOR-Myc axis in stem and progenitor cells in the regulation of lifespan, stress resistance and metabolism in Drosophila. We found that both overexpression of rheb and myc-rheb in midgut stem and progenitor cells decreased the lifespan and starvation resistance of flies. TOR activation caused higher survival under malnutrition conditions. Furthermore, we demonstrate gut-specific activation of JAK/STAT and insulin signaling pathways to control gut integrity. Both genetic manipulations had an impact on carbohydrate metabolism and transcriptional levels of metabolic genes. Our findings indicate that activation of the TOR-Myc axis in midgut stem and progenitor cells influences a variety of traits in Drosophila.

  15. Potent HGF/c-Met axis inhibitors from Eucalyptus globulus: the coupling of phloroglucinol and sesquiterpenoid is essential for the activity.

    PubMed

    Yang, Sheng-Ping; Zhang, Xiao-Wei; Ai, Jing; Gan, Li-She; Xu, Jin-Biao; Wang, Ying; Su, Zu-Shang; Wang, Lu; Ding, Jian; Geng, Mei-Yu; Yue, Jian-Min

    2012-09-27

    Eucalyptin A (1), together with two known compounds 2 and 3 exhibiting potent inhibition on HGF/c-Met axis, was discovered from the fruits of Eucalyptus globulus. 1 possessed an unprecedented carbon framework of phloroglucinol-coupled sesquiterpenoid, and its structure was elucidated by spectroscopic method and ECD calculation. A brief structure-activity relationship discussion indicated that the coupling of a phloroglucinol and a sesquiterpenoid is essential for the activity.

  16. Early life stress in depressive patients: role of glucocorticoid and mineralocorticoid receptors and of hypothalamic-pituitary-adrenal axis activity.

    PubMed

    Juruena, Mario Francisco; Werne Baes, Cristiane Von; Menezes, Itiana Castro; Graeff, Frederico Guilherme

    2015-01-01

    Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the pathogenesis of depression, being well established as acute triggers of psychiatric illness. The vulnerability for developing depression is associated to changes in neurobiological systems related to stress regulation. The hypothalamic-pituitaryadrenal (HPA) axis responds to external and internal stimuli. Reported results indicate that stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to depression. These abnormalities appear to be related to the HPA axis deregulation in depression, partially due to an imbalance between glucocorticoid receptors (GR) and mineral ocorticoid receptors (MR). While most studies have consistently demonstrated that GR function is impaired in major depression (reduced GR-mediated feedback in HPA axis), data about the MR role in depression are still limited and contr oversial. Thus, in this review article we summarize the main reported findings about the consequences of ELS in HPA axis functioning and in the responsivity of MR/GR receptors in depression.

  17. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis

    PubMed Central

    Kirkby, Nicholas S.; Tesfai, Abel; Ahmetaj-Shala, Blerina; Gashaw, Hime H.; Sampaio, Walkyria; Etelvino, Gisele; Leão, Nádia Miricéia; Santos, Robson A.; Mitchell, Jane A.

    2016-01-01

    Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and NG-nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.—Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis. PMID:27601438

  18. Activation of ATP-sensitive potassium channel by iptakalim normalizes stress-induced HPA axis disorder and depressive behaviour by alleviating inflammation and oxidative stress in mouse hypothalamus.

    PubMed

    Zhao, Xiao-Jie; Zhao, Zhan; Yang, Dan-Dan; Cao, Lu-Lu; Zhang, Ling; Ji, Juan; Gu, Jun; Huang, Ji-Ye; Sun, Xiu-Lan

    2017-02-01

    Stress-induced disturbance of the hypothalamic-pituitary-adrenal (HPA) axis is strongly implicated in incidence of mood disorders. A heightened neuroinflammatory response and oxidative stress play a fundamental role in the dysfunction of the HPA axis. We have previously demonstrated that iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could prevent oxidative injury and neuroinflammation against multiple stimuli-induced brain injury. The present study was to demonstrate the impacts of Ipt in stress-induced HPA axis disorder and depressive behavior. We employed 2 stress paradigms: 8 weeks of continuous restraint stress (chronic restraint stress, CRS) and 2h of restraint stress (acute restraint stress, ARS), to mimic both chronic stress and severe acute stress. Prolonged (4 weeks) and short-term (a single injection) Ipt treatment was administered 30min before each stress paradigm. We found that HPA axis was altered after stress, with different responses to CRS (lower ACTH and CORT, higher AVP, but normal CRH) and ARS (higher CRH, ACTH and CORT, but normal AVP). Both prolonged and short-term Ipt treatment normalized stress-induced HPA axis disorders and abnormal behaviors in mice. CRS and ARS up-regulated mRNA levels of inflammation-related molecules (TNFα, IL-1β, IL-6 and TLR4) and oxidative stress molecules (gp91phox, iNOS and Nrf2) in the mouse hypothalamus. Double immunofluorescence showed CRS and ARS increased microglia activation (CD11b and TNFα) and oxidative stress in neurons (NeuN and gp91phox), which were alleviated by Ipt. Therefore, the present study reveals that Ipt could prevent against stress-induced HPA axis disorders and depressive behavior by alleviating inflammation and oxidative stress in the hypothalamus.

  19. Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats.

    PubMed

    Allen, Camryn D; Lee, Soon; Koob, George F; Rivier, Catherine

    2011-06-01

    Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration.

  20. Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in male rats.

    PubMed

    Jensen, J B; Jessop, D S; Harbuz, M S; Mørk, A; Sánchez, C; Mikkelsen, J D

    1999-06-01

    It is well established that the maximal therapeutic effect of selective serotonin reuptake inhibitors (SSRI) are achieved in depressive patients after several weeks of treatment, but the adaptive processes leading to the therapeutic effects are unclear. It has been shown that hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis in depressive patients is affected by long-term antidepressant treatment. These changes occur in association with the mood normalising effect, suggesting that antidepressants affect the HPA axis and this effect is associated with the therapeutic effect. Male Wistar rats were treated with the SSRI, citalopram, to investigate time-related changes in components that may be involved in the desensitization of the HPA axis. A single injection of citalopram (10 mg/kg, s.c.), increased the plasma levels of ACTH and corticosterone in a dose-dependent manner and increased the number of c-Fos containing cells in the hypothalamic paraventricular nucleus. A daily treatment with the same compound (10 mg/kg, s.c.) for 14 days decreased the expression of POMC mRNA ( approximately 40%). In addition, a blunted response to citalopram was observed in animals long-term treated with citalopram. Also CRF-stimulated cAMP accumulation in the pituitary was altered. In conclusion, acute citalopram activated the HPA-axis at the hypothalamic level and long-term citalopram treatment desensitized the HPA-axis at the pituitary level. These results support the hypothesis that the therapeutic effects of long-term antidepressant treatments reduce HPA axis responsiveness.

  1. Systemic Administration of Oleoylethanolamide Protects from Neuroinflammation and Anhedonia Induced by LPS in Rats

    PubMed Central

    Sayd, Aline; Antón, María; Alén, Francisco; Caso, Javier Rubén; Pavón, Javier; Leza, Juan Carlos; Rodríguez de Fonseca, Fernando

    2015-01-01

    Background: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. Methods: We tested whether oleoylethanolamide/palmitoylethanolamide (10mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5mg/kg, i.p.) in rats. Results: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2 -) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both

  2. Transverse axis fluid turbine

    SciTech Connect

    Brenneman, B.

    1983-11-15

    A fluid turbine, the rotation axis of which is transverse to the direction of fluid flow, has at least two blade assemblies mounted for rotation about the rotation axis. Each blade assembly includes a streamlined elongated blade having a span parallel to the rotation axis. Each blade is pivotable about a pivot axis parallel to and spaced from the rotation axis. The pivot axis is located circumferentially ahead of the blade center of pressure with respect to the direction of turbine rotation. Each blade assembly is so constructed that its center of mass is located either at its pivot axis or circumferentially at its pivot axis and radially outboard of its pivot axis.

  3. Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation.

    PubMed

    Yang, Weiwei; Li, Qinghua; Pan, Zhifang

    2014-01-01

    Successful placentation depends on the proper invasion of extravillous trophoblast (EVT) cells into maternal tissues. Previous reports demonstrated that S1P receptors are expressed in the EVT cells and S1P could regulate migration and function of trophoblast cells via S1P receptors. However, little is known about roles of S1P in the invasion of EVT cells. Our study was performed to investigate S1P effect on the invasion of EVT cells. We used the extravillous trophoblast cell line HTR8/SVneo cells to evaluate the effect. In vitro invasion assay was employed to determine the invasion of HTR8/SVneo cells induced by S1P. MMP-2 enzyme activity and relative level in the supernatants of HTR8/SVneo was assessed by gelatin zymography and western blot. Based on the above, siRNA and specific inhibitors were used for the intervention and study of potential signal pathways, and Real-time qPCR and western blot were used to test the mRNA and protein level of potential signal targets. We found that S1P could promote HTR8/SVneo cell invasion and upregulates activity and level of MMP-2. The promotion requires activation of MEK-ERK and is dependent on the axis of S1P/S1PR1. Our investigation of S1P may provide new insights into the molecular mechanisms of EVT invasion.

  4. [Activity of the hypothalamo-pituitary-adrenals axis in the Siberian tiger (Panthera tigris altaica) in captivity and in the wild, and their dynamics throughout the year].

    PubMed

    Naidenko, S V; Ivanov, E A; Lukarevskiĭ, V S; Hernandez-Blanko, J A; Sorokin, P A; Litvinov, M N; Kotliar, A K; Rozhnov, V V

    2011-01-01

    A noninvasive evaluation method of hypothalamo-pituitary-adrenals axis (HPA) activity in the Siberian tiger was verified. Comparison of the activity level of HPA in Siberian tigers in the wild and in captivity, and their alterations over the year was carried out. Significant seasonal deviations between activity levels of HPA in tigers in captivity were not found. In the wild, this level was significantly higher, reaching the maximum from November to January, which can be related with an unfavorable influence on tigers in low temperatures and deep snow cover.

  5. Lack of specific association between panicogenic properties of caffeine and HPA-axis activation. A placebo-controlled study of caffeine challenge in patients with panic disorder.

    PubMed

    Masdrakis, Vasilios G; Markianos, Manolis; Oulis, Panagiotis

    2015-09-30

    A subgroup of patients with Panic Disorder (PD) exhibits increased sensitivity to caffeine administration. However, the association between caffeine-induced panic attacks and post-caffeine hypothalamic-pituitary-adrenal (HPA)-axis activation in PD patients remains unclear. In a randomized, double-blind, cross-over experiment, 19 PD patients underwent a 400-mg caffeine-challenge and a placebo-challenge, both administered in the form of instant coffee. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at both baseline and post-challenge. No patient panicked after placebo-challenge, while nine patients (47.3%) panicked after caffeine-challenge. Placebo administration did not result in any significant change in hormones' plasma levels. Overall, sample's patients demonstrated significant increases in ACTH, cortisol, and DHEAS plasma levels after caffeine administration. However, post-caffeine panickers and non-panickers did not differ with respect to the magnitude of the increases. Our results indicate that in PD patients, caffeine-induced panic attacks are not specifically associated with HPA-axis activation, as this is reflected in post-caffeine increases in ACTH, cortisol and DHEAS plasma levels, suggesting that caffeine-induced panic attacks in PD patients are not specifically mediated by the biological processes underlying fear or stress. More generally, our results add to the evidence that HPA-axis activation is not a specific characteristic of panic.

  6. Regulation of mitochondrial poly(ADP-Ribose) polymerase activation by the β-adrenoceptor/cAMP/protein kinase A axis during oxidative stress.

    PubMed

    Brunyanszki, Attila; Olah, Gabor; Coletta, Ciro; Szczesny, Bartosz; Szabo, Csaba

    2014-10-01

    We investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 minutes) mitochondrial DNA damage, and concomitant activation of PARP1 in the mitochondria. These early events were followed by a progressive mitochondrial oxidant production and nuclear PARP1 activation (by 6 hours). These processes led to a functional impairment of mitochondria, culminating in cell death of mixed (necrotic/apoptotic) type. β-Adrenoceptor blockade with propranolol or inhibition of its downstream cAMP/PKA signaling attenuated, while β-adrenoceptor agonists and cAMP/PKA activators enhanced, the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the β-adrenergic receptor/cAMP/PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes during bacterial lipopolysaccharide (LPS)-induced systemic inflammation in mice. We conclude that the activation of mitochondrial PARP1 is an early, active participant in oxidant-induced cell death, which is under the control of β-adrenoceptor/cAMP/PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.

  7. In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

    PubMed Central

    Tenk, Judit; Mátrai, Péter; Hegyi, Péter; Rostás, Ildikó; Garami, András; Szabó, Imre; Solymár, Margit; Pétervári, Erika; Czimmer, József; Márta, Katalin; Mikó, Alexandra; Füredi, Nóra; Párniczky, Andrea; Zsiborás, Csaba; Balaskó, Márta

    2016-01-01

    Background Obesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations. Objectives We aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies. Data Sources 3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses. Study Eligibility Criteria Empirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol). Statistical Methods We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger’s test was used. Results Obesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups. Conclusions Our analysis demonstrated that obesity or healthy aging does not

  8. Impaired hypothalamic-pituitary-testicular axis activity, spermatogenesis, and sperm function promote infertility in males with lead poisoning.

    PubMed

    Gandhi, Jason; Hernandez, Rafael J; Chen, Andrew; Smith, Noel L; Sheynkin, Yefim R; Joshi, Gargi; Khan, Sardar Ali

    2017-02-10

    Lead poisoning is a stealthy threat to human physiological systems as chronic exposure can remain asymptomatic for long periods of time before symptoms manifest. We presently review the biophysical mechanisms of lead poisoning that contribute to male infertility. Environmental and occupational exposure of lead may adversely affect the hypothalamic-pituitary-testicular axis, impairing the induction of spermatogenesis. Dysfunction at the reproductive axis, namely testosterone suppression, is most susceptible and irreversible during pubertal development. Lead poisoning also appears to directly impair the process of spermatogenesis itself as well as sperm function. Spermatogenesis issues may manifest as low sperm count and stem from reproductive axis dysfunction or testicular degeneration. Generation of excessive reactive oxygen species due to lead-associated oxidative stress can potentially affect sperm viability, motility, DNA fragmentation, membrane lipid peroxidation, capacitation, hyperactivation, acrosome reaction, and chemotaxis for sperm-oocyte fusion, all of which can contribute to deter fertilization. Reproductive toxicity has been tested through cross-sectional analysis studies in humans as well as in vivo and in vitro studies in animals.

  9. Palatable solutions during paradoxical sleep deprivation: reduction of hypothalamic-pituitary-adrenal axis activity and lack of effect on energy imbalance.

    PubMed

    Suchecki, D; Antunes, J; Tufik, S

    2003-09-01

    Paradoxical sleep deprivation (PSD) induces increased energy expenditure in rats, insofar as rats eat more but loose weight throughout the deprivation period. In the present study, rats were offered water, saccharin or sucrose to drink during the deprivation period, since it has been proposed that carbohydrates reduce the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Rats were submitted to the flower pot technique for 96 h. During the PSD period, they were weighed daily and food and fluid intake was assessed twice a day. At the end of the PSD period, rats were killed and plasma concentrations of glucose, adrenocorticotropic hormone (ACTH) and corticosterone were assayed. Compared to their control counterparts, all paradoxical sleep-deprived rats consumed more food, but lost weight. Paradoxical sleep-deprived rats given sucrose drank more than their control counterparts (especially in the light phase of the light/dark cycle). Paradoxical sleep-deprived rats showed increased food intake during all periods throughout the experiment, with peak intake during the dark phase and nadir during the light phase of the light/dark cycle. All paradoxical sleep-deprived rats showed lower glucose plasma levels than control rats and increased relative adrenal weight. However, when given saccharin or sucrose, paradoxical sleep-deprived rats showed lower concentrations of ACTH and corticosterone than their water-provided counterparts, indicating that palatable fluids were capable of lowering HPA axis activation produced by PSD. The fact that PSD induced energy imbalance regardless of the relative attenuation of the HPA axis activity produced by saccharin or sucrose suggests that the HPA axis may play only a secondary role in this phenomenon, and that other mechanisms may account for this effect. The data also suggest that supply of palatable fluids can be an additional modification to reduce the stress of the flower pot method.

  10. High levels of corticotropin-releasing factor (CRF) are inversely correlated with low levels of maternal CRF-binding protein in pregnant women with pregnancy-induced hypertension.

    PubMed

    Petraglia, F; Florio, P; Benedetto, C; Gallo, C; Woods, R J; Genazzani, A R; Lowry, P J

    1996-02-01

    Corticotropin-releasing factor-binding protein (CRF-BP) is suggested to play a role in modulating the activity of the hypothalamus-pituitary-adrenal axis during pregnancy, counteracting the actions of circulating or locally acting CRF. The aim of the present study was to evaluate whether maternal levels of CRF-BP and CRF are modified in pregnant women with a high risk of developing pregnancy-induced hypertension (n = 21). A group of nine patients developed the disease between 25-35 weeks gestation, and sequential blood samples were taken every 5 weeks throughout the pregnancy. As a control group, healthy pregnant women were studied (n = 9) using the same protocol; a group of women with pregnancy-induced hypertension (n = 5) was studied starting from the time of diagnosis. In a subgroup of patients (n = 10), CRF-BP and CRF levels were studied after 5 weeks of antihypertensive treatment. Levels of CRF-BP were determined using a specific RIA, whereas CRF was evaluated by a two-site immunoradiometric assay. In patients at risk, circulating levels of CRF-BP followed the same pattern as that in healthy controls, showing a significant decrease at term (36-40 weeks; P < 0.05). A significant and progressive increase in plasma CRF levels was observed in both groups of pregnant women; the highest values were found at term (P < 0.01). In the nine patients who developed pregnancy-induced hypertension, maternal levels of CRF-BP at the onset of signs and symptoms were lower than control values, and CRF levels were significantly higher at the onset of the disease (P < 0.01). Similarly, in these hypertensive patients studied at the time of hospitalization, CRF-BP levels were lower whereas those of CRF were higher than levels in healthy patients (P < 0.01). No effect of antihypertensive therapy on either CRF-BP or CRF levels was observed. The present study shows an inverse correlation between reduced plasma CRF-BP levels and increased CRF levels in the maternal circulation of

  11. Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women

    PubMed Central

    Lupis, Sarah B.; Lerman, Michelle; Wolf, Jutta M.

    2014-01-01

    While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6+/−1.7 yrs.) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p > .23). Increases in self-reported fear predicted blunted cortisol responses in men (β = 0.41, p = .04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β = 0.67 p = .004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β = 0.51, p = .033; β = 0.46, p = .066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p > .23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health

  12. SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system.

    PubMed

    Santarelli, S; Wagner, K V; Labermaier, C; Uribe, A; Dournes, C; Balsevich, G; Hartmann, J; Masana, M; Holsboer, F; Chen, A; Müller, M B; Schmidt, M V

    2016-01-01

    Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission.

  13. Adenomatous Polyposis Coli Tumor Suppressor Protein Has Signaling Activity in Xenopus laevis Embryos Resulting in the Induction of an Ectopic Dorsoanterior Axis

    PubMed Central

    Vleminckx, Kris; Wong, Ellen; Guger, Kathy; Rubinfeld, Bonnee; Polakis, Paul; Gumbiner, Barry M.

    1997-01-01

    Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are linked to both familial and sporadic human colon cancer. So far, a clear biological function for the APC gene product has not been determined. We assayed the activity of APC in the early Xenopus embryo, which has been established as a good model for the analysis of the signaling activity of the APC-associated protein β-catenin. When expressed in the future ventral side of a four-cell embryo, full-length APC induced a secondary dorsoanterior axis and the induction of the homeobox gene Siamois. This is similar to the phenotype previously observed for ectopic β-catenin expression. In fact, axis induction by APC required the availability of cytosolic β-catenin. These results indicate that APC has signaling activity in the early Xenopus embryo. Signaling activity resides in the central domain of the protein, a part of the molecule that is missing in most of the truncating APC mutations in colon cancer. Signaling by APC in Xenopus embryos is not accompanied by detectable changes in expression levels of β-catenin, indicating that it has direct positive signaling activity in addition to its role in β-catenin turnover. From these results we propose a model in which APC acts as part of the Wnt/β-catenin signaling pathway, either upstream of, or in conjunction with, β-catenin. PMID:9015311

  14. A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus–pituitary–adrenal axis activity early in ontogeny

    PubMed Central

    Muráni, Eduard; Ponsuksili, Siriluck; Jaeger, Alexandra; Görres, Andreas; Tuchscherer, Armin; Wimmers, Klaus

    2016-01-01

    We comprehensively characterized the effects of a unique natural gain-of-function mutation in the glucocorticoid receptor (GR), GRAla610Val, in domestic pigs to expand current knowledge of the phenotypic consequences of GR hypersensitivity. Cortisol levels were consistently reduced in one-week-old piglets, at weaning and in peripubertal age, probably due to a reduced adrenal capacity to produce glucocorticoids (GC), which was indicated by an adrenocortical thinning in GRAla610Val carriers. Adrenocorticotrophic hormone (ACTH) levels were significantly reduced in one-week-old piglets only. Expression analyses in peripubertal age revealed significant downregulation of hypothalamic expression of CRH and AVP, the latter only in females, and upregulation of hepatic expression of SERPINA6, by GRAla610Val. Transcriptional repression of proinflammatory genes in peripheral blood mononuclear cells (PBMCs) from GRAla610Val carriers was more sensitive to dexamethasone treatment ex vivo. However, no significant effects on growth, body composition, blood chemistry or cell counts were observed under baseline conditions. These results suggest that GRAla610Val-induced GR hypersensitivity elicits a compensatory reduction in endogenous, bioactive glucocorticoid levels via readjustment of the hypothalamus–pituitary–adrenal (HPA) axis early in ontogeny to maintain an adequate response, but carriers are more sensitive to exogenous GC. Therefore, GRAla610Val pigs represent a valuable animal model to explore GR-mediated mechanisms of HPA axis regulation and responses to glucocorticoid-based drugs. PMID:27440422

  15. Hypothalamic-pituitary-adrenal axis activity, dehydroepiandrosterone sulphate and their relationships with aggression in early and late alcohol withdrawal.

    PubMed

    Ozsoy, Saliha; Esel, Ertugrul

    2008-02-15

    The study aims at investigating the relationship between hypothalamic-pituitary-adrenal (HPA) axis alterations and aggression level in alcoholic patients during early and late alcohol withdrawal. Serum levels of basal cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured three times, and cortisol and DHEAS response to dexamethasone twice during the early and late withdrawal periods in alcohol dependent males (n=30) and once in healthy control males (n=20). Abnormal cortisol non-suppression response to dexamethasone in dexamethasone suppression test (DST) was observed in some proportion of the patients in early withdrawal, which normalized in late withdrawal. The study revealed reduced basal DHEAS levels and reduced DHEAS response to dexamethasone in late withdrawal. When the patients were assessed in two separate groups as high- and low-aggressives, in the high-aggression group abnormality in DST was observed during both early and late withdrawal periods, in the low-aggression group it was observed only in early withdrawal. While basal DHEAS levels were low in the high-aggression group only in early withdrawal, it was reduced in the low-aggression group during late withdrawal period. Some alterations of the HPA axis during alcohol withdrawal might be associated not only with alcohol use per se but also with aggressivity tendency of alcoholic patients.

  16. Human podoplanin-positive monocytes and platelets enhance lymphangiogenesis through the activation of the podoplanin/CLEC-2 axis.

    PubMed

    Hur, Jin; Jang, Jae Hee; Oh, Il-Young; Choi, Jae-Il; Yun, Ji-Yeon; Kim, Joonoh; Choi, Young-Eun; Ko, Seung-Bum; Kang, Jin-A; Kang, Jeehoon; Lee, Sang Eun; Lee, Hwan; Park, Young-Bae; Kim, Hyo-Soo

    2014-08-01

    Emerging studies suggested that murine podoplanin-positive monocytes (PPMs) are involved in lymphangiogenesis. The goal of this study was to demonstrate the therapeutic lymphangiogenesis of human PPMs by the interaction with platelets. Aggregation culture of human peripheral blood mononuclear cells (PBMCs) resulted in cellular aggregates termed hematospheres. During 5-day culture, PPMs expanded exponentially and expressed several lymphatic endothelial cell-specific markers including vascular endothelial growth factor receptor (VEGFR)-3 and well-established lymphangiogenic transcription factors. Next, we investigated the potential interaction of PPMs with platelets that had C-type lectin-like receptor-2 (CLEC-2), a receptor of podoplanin. In vitro coculture of PPMs and platelets stimulated PPMs to strongly express lymphatic endothelial markers and upregulate lymphangiogenic cytokines. Recombinant human CLEC-2 also stimulated PPMs through Akt and Erk signaling. Likewise, platelets in coculture with PPMs augmented secretion of a lymphangiogenic cytokine, interleukin (IL)-1-β, via podoplanin/CLEC-2 axis. The supernatant obtained from coculture was able to enhance the migration, viability, and proliferation of lymphatic endothelial cell. Local injection of hematospheres with platelets significantly increased lymphatic neovascularization and facilitated wound healing in the full-thickness skin wounds of nude mice. Cotreatment with PPMs and platelets augments lymphangiogenesis through podoplanin/CLEC-2 axis, which thus would be a promising novel strategy of cell therapy to treat human lymphatic vessel disease.

  17. In search of the HPA axis activity in unipolar depression patients with childhood trauma: Combined cortisol awakening response and dexamethasone suppression test.

    PubMed

    Lu, Shaojia; Gao, Weijia; Huang, Manli; Li, Lingjiang; Xu, Yi

    2016-07-01

    The aim of the present study was to examine the impact of childhood trauma on HPA axis activity both in depression patients and healthy controls in order to determine the role of HPA axis abnormalities in depression and to find the differences in HPA axis functioning that may lead certain individuals more susceptible to the depressogenic effects of childhood trauma. Eighty subjects aged 18-45 years were recruited into four study groups (n = 18, depression patients with childhood trauma exposures, CTE/MDD; n = 17, depression patients without childhood adversity, non-CTE/MDD; n = 23, healthy persons with childhood trauma, CTE/non-MDD; and n = 22, healthy persons without childhood adversity, non-CTE/non-MDD). Each participant collected salivary samples in the morning at four time points: immediately upon awakening, 30, 45, and 60 min after awakening for the assessment of CAR and underwent a 1 mg-dexamethasone suppression test (DST). Regardless of depression, subjects with CTE exhibited an enhanced CAR and the CAR areas under the curve to ground (AUCg) were associated with their childhood trauma questionnaire (CTQ) physical neglect scores and CTQ total scores. In addition, the CTE/MDD group also showed a highest post-DST cortisol concentration and a decreased glucocorticoid feedback inhibition among four groups of subjects. The present findings suggested that childhood trauma was associated with hyperactivity of HPA axis as measured with CAR, potentially reflecting the vulnerability for developing depression after early life stress exposures. Moreover, dysfunction of the GR-mediated negative feedback control might contribute to the development of depression after CTE.

  18. Activation of p53/miR-34a Tumor Suppressor Axis by Chinese Herbal Formula JP-1 in A549 Lung Adenocarcinoma Cells

    PubMed Central

    Chow, Jyh-Ming; Lin, Pei-Chun; Hu, Tsai-Shu; Kuo, Hui-Ching; Huang, Jhy-Shrian

    2016-01-01

    Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR-34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKα and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment. PMID:28074102

  19. Protocatechualdehyde prevents methylglyoxal-induced mitochondrial dysfunction and AGEs-RAGE axis activation in human lens epithelial cells.

    PubMed

    Wang, Yue-Hua; Han, Yu-Pei; Yu, Hai-Tao; Pu, Xiao-Ping; Du, Guan-Hua

    2014-09-05

    Methylglyoxal (MGO), a glucose derived dicarbonyl intermediate, is a major precursor of advanced glycation end products (AGEs) which have been linked to the development of diabetic cataract. Protocatechualdehyde (PCA), a phenolic acid compound, is found in the roots of Salvia miltiorrhiza. This study was to investigate the effect of PCA against MGO-induced cytotoxicity in human lens epithelial cells (SRA01/04 cells) and the possible involved molecular mechanism. The results showed that PCA alleviated MGO-induced mitochondrial dysfunction and apoptosis in SRA01/04 cells. Furthermore, PCA was capable of inhibiting MGO-mediated AGEs formation and blocking receptor of AGEs expression in SRA01/04 cells. It is concluded that PCA could be useful in attenuation of MGO-induced cell damage and the possible mechanism is involved in modulating AGEs-receptor of AGEs axis in human lens epithelial cells, which suggests that PCA has a potential protective effect on diabetic cataract.

  20. Blubber transcriptome response to acute stress axis activation involves transient changes in adipogenesis and lipolysis in a fasting-adapted marine mammal

    PubMed Central

    Khudyakov, J. I.; Champagne, C. D.; Meneghetti, L. M.; Crocker, D. E.

    2017-01-01

    Stress can compromise an animal’s ability to conserve metabolic stores and participate in energy-demanding activities that are critical for fitness. Understanding how wild animals, especially those already experiencing physiological extremes (e.g. fasting), regulate stress responses is critical for evaluating the impacts of anthropogenic disturbance on physiology and fitness, key challenges for conservation. However, studies of stress in wildlife are often limited to baseline endocrine measurements and few have investigated stress effects in fasting-adapted species. We examined downstream molecular consequences of hypothalamic-pituitary-adrenal (HPA) axis activation by exogenous adrenocorticotropic hormone (ACTH) in blubber of northern elephant seals due to the ease of blubber sampling and its key role in metabolic regulation in marine mammals. We report the first phocid blubber transcriptome produced by RNAseq, containing over 140,000 annotated transcripts, including metabolic and adipocytokine genes of interest. The acute response of blubber to stress axis activation, measured 2 hours after ACTH administration, involved highly specific, transient (lasting <24 hours) induction of gene networks that promote lipolysis and adipogenesis in mammalian adipocytes. Differentially expressed genes included key adipogenesis factors which can be used as blubber-specific markers of acute stress in marine mammals of concern for which sampling of other tissues is not possible. PMID:28186107

  1. Calorie restriction minimizes activation of insulin signaling in response to glucose: potential involvement of the growth hormone-insulin-like growth factor 1 axis.

    PubMed

    Hayashi, Hiroko; Yamaza, Haruyoshi; Komatsu, Toshimitsu; Park, Seongjoon; Chiba, Takuya; Higami, Yoshikazu; Nagayasu, Takeshi; Shimokawa, Isao

    2008-09-01

    Calorie restriction (CR) may modulate insulin signaling in response to energy intake through suppression of the growth hormone (GH)-IGF-1 axis. We investigated the glucose-stimulated serum insulin response and subsequent alterations in insulin receptor (IR), Akt, and FoxO1 in the rat liver and quadriceps femoris muscle (QFM). Nine-month-old wild-type (W) male Wistar rats fed ad libitum (AL) or a 30% CR diet initiated at 6 weeks of age and GH-suppressed transgenic (Tg) rats fed AL were killed 15 min after intraperitoneal injection of glucose or saline. In W-AL rats, the serum insulin concentration was elevated by glucose injection. Concomitantly, the phosphorylated (p)-IR and p-Akt levels were increased in both tissues. The active FoxO1 level was decreased in the liver, but not significantly in the QFM. In W-CR and Tg-AL rats, the serum insulin response was lower, and no significant changes were noted for the p-IR, p-Akt, or active FoxO1 levels in the liver. In the QFM, the p-Akt level was increased in W-CR and Tg-AL rats with an insignificant elevation of p-IR levels. The phenotypic similarity of W-CR and Tg-AL rats suggest that CR minimizes activation of insulin signaling in response to energy intake mostly through the GH-IGF-1 axis.

  2. Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions

    PubMed Central

    Johnson, Lance A.; Weber, Sydney; Raber, Jacob

    2016-01-01

    Rationale Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown. Objectives In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration. Methods (Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection. Results (Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3. Conclusions HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms. PMID:26525566

  3. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model.

    PubMed

    Takeda, Atsushi; Tamano, Haruna; Nishio, Ryusuke; Murakami, Taku

    2016-07-16

    Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer's disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.

  4. Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning.

    PubMed

    Guijarro, Jussara Z; Tiba, Paula A; Ferreira, Tatiana L; Kawakami, Suzi E; Oliveira, Maria Gabriela M; Suchecki, Deborah

    2007-12-03

    Previous studies show that early life events result in neurobehavioural alterations that may be either beneficial or detrimental to the stress response. Given the close relationship between corticosterone secretion and mnemonic processes, the purpose of the present study was to investigate the effects of brief (BMS, 15 min) and long maternal separations (LMS, 180 min) on memory tasks in adult rats, assessed by context and tone fear conditioning. At adulthood, males were evaluated for behavioural and hormonal reaction to the training environment, being tested for context fear conditioning; tone fear conditioning; and learning curve in the context fear conditioning, in which rats were daily re-exposed to the context, followed by a brief footshock and in the last day of the experiment (day 5) animals were exposed to the context. Corticosterone and ACTH plasma levels were determined in naïve rats (basal) or 5, 25 or 45 min after each test. Peak ACTH and corticosterone levels were similar among the groups after context fear conditioning; however, levels of CTL rats remained elevated for a longer time. In the learning curve of context fear conditioning, both BMS and LMS rats exhibited less freezing behaviour than CTL rats, without differences in hormone secretion. There was neither an association between activity of the HPA axis and performance on memory tasks nor different activational properties of the tasks on the HPA axis between BMS and LMS rats, i.e., both manipulations lead to similar performance in hippocampus-dependent and independent memory tasks.

  5. Effects of Acute Confinement Stress-induced Hypothalamic-Pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

    PubMed Central

    Coplan, Jeremy D.; Gopinath, Srinath; Abdallah, Chadi G.; Margolis, Jeffrey; Chen, Wei; Scharf, Bruce A.; Rosenblum, Leonard A.; Batuman, Olcay A.; Smith, Eric L. P.

    2017-01-01

    Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive and neuroprotective properties. The hypothalamic-pituitary-adrenal (HPA) axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg IM). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid (CSF) to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand (VFD) conditions. Since there were no rearing effects at baseline or for any of the conditions tested -- either for cortisol or TGF-β -- the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and CSF cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in CSF but not in serum. Together the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occurs in the face of HPA axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompts exploration of protective measures against glucocorticoid-induced neurotoxicity.

  6. Selective disruption of one Cartesian axis of cortical maps and receptive fields by deficiency in ephrin-As and structured activity.

    PubMed

    Cang, Jianhua; Niell, Cristopher M; Liu, Xiaorong; Pfeiffenberger, Cory; Feldheim, David A; Stryker, Michael P

    2008-02-28

    The topographic representation of visual space is preserved from retina to thalamus to cortex. We have previously shown that precise mapping of thalamocortical projections requires both molecular cues and structured retinal activity. To probe the interaction between these two mechanisms, we studied mice deficient in both ephrin-As and retinal waves. Functional and anatomical cortical maps in these mice were nearly abolished along the nasotemporal (azimuth) axis of the visual space. Both the structure of single-cell receptive fields and large-scale topography were severely distorted. These results demonstrate that ephrin-As and structured neuronal activity are two distinct pathways that mediate map formation in the visual cortex and together account almost completely for the formation of the azimuth map. Despite the dramatic disruption of azimuthal topography, the dorsoventral (elevation) map was relatively normal, indicating that the two axes of the cortical map are organized by separate mechanisms.

  7. Dopamine D2-like receptors modulate freezing response, but not the activation of HPA axis, during the expression of conditioned fear.

    PubMed

    de Oliveira, Amanda R; Reimer, Adriano E; Reis, Fernando M C V; Brandão, Marcus L

    2017-02-01

    Considering the complexity of aversive information processing and defensive response expression, a combined action of stress modulators may be required for an optimal performance during threatening situations. Dopamine is now recognized as one of the most active modulators underlying states of fear and anxiety. On the other hand, activation of hypothalamic-pituitary-adrenocortical (HPA) axis, which leads to the release of corticosterone in rodents, has been considered a key part of the stress response. The current study is an extension of prior work investigating modulatory effects of dopamine and corticosterone on conditioned fear expression. We have showed that corticosterone, acting through mineralocorticoid receptors in the ventral tegmental area (VTA), upregulates dopaminergic system in the basolateral amygdala (BLA), enabling the expression of conditioned freezing response. The novel question addressed here is whether VTA-BLA dopaminergic signaling is necessary for increases in corticosterone during conditioned fear expression. Using site-specific treatment with D2-like agonist quinpirole (VTA) and D2-like antagonist sulpiride (BLA), we evaluated freezing and plasma corticosterone in rats exposed to a light used as aversive conditioned stimulus (CS). Intra-VTA quinpirole and intra-BLA sulpiride significantly decreased freezing expression in the conditioned fear test, but this anxiolytic-like effect of the dopaminergic drugs was not associated with changes in plasma corticosterone concentrations. Altogether, data suggest that interferences with the ability of the CS to activate the dopaminergic VTA-BLA pathway reduce the expression of freezing, but activation of the HPA axis seems to occur upstream of the recruitment of dopaminergic mechanisms in conditioned fear states.

  8. The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats.

    PubMed

    Szymańska, Magdalena; Budziszewska, Bogusława; Jaworska-Feil, Lucylla; Basta-Kaim, Agnieszka; Kubera, Marta; Leśkiewicz, Monika; Regulska, Magdalena; Lasoń, Władysław

    2009-07-01

    Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity is thought to be an important factor in pathogenesis of depression. In animals, stress or glucocorticoids given in prenatal period lead to long-lasting behavioral and neuroendocrine changes similar to those observed in depressed patients. However, molecular basis for HPA disturbances in animals exposed to prenatal stress - a model of depression - have been only partially recognized. Therefore, in the present study we investigated the effect of prenatal stress on behavioral changes, blood corticosterone level, concentrations of glucocorticoid receptor (GR) and its cochaperone, FKBP51, in the hippocampus and frontal cortex in adult rats. It has been found that prenatally stressed rats display high level of immobility in the Porsolt test and anxiety-like behavior. The HPA axis hyperactivity in theses animals was evidenced by corticosterone hypersecretion at the end of the light phase and 1h following acute stress. Western blot study revealed that GR level was significantly elevated in the hippocampus but not in the frontal cortex of prenatally stressed rats, whereas concentration of FKBP51 was decreased only in the former brain structure. Chronic treatment with imipramine, fluoxetine, mirtazapine and tianeptine have diminished both behavioral and biochemical alterations observed in this animal model of depression. These data indicate that the increase in hippocampal GR level and low concentration of FKBP51 in the frontal cortex may be responsible for enhanced glucocorticoid action in depression.

  9. E6/E7-P53-POU2F1-CTHRC1 axis promotes cervical cancer metastasis and activates Wnt/PCP pathway

    PubMed Central

    Zhang, Rong; Lu, Huan; Lyu, Yuan-yuan; Yang, Xiao-mei; Zhu, Lin-yan; Yang, Guang-dong; Jiang, Peng-cheng; Re, Yuan; Song, Wei-wei; Wang, Jin-hao; Zhang, Can-can; Gu, Fei; Luo, Tian-jiao; Wu, Zhi-yong; Xu, Cong-jian

    2017-01-01

    Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis. PMID:28303973

  10. Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.

    PubMed

    Qu, Changju; Liu, Yadong; Kunkalla, Kranthi; Singh, Rajesh R; Blonska, Marzenna; Lin, Xin; Agarwal, Nitin Kumar; Vega, Francisco

    2013-06-06

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-κB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gαi and Gα12 to activate PKCβ/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.

  11. Hypothalamic-pituitary-adrenal (HPA) axis function in the California mouse (Peromyscus californicus): Changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle

    PubMed Central

    Harris, Breanna N.; Saltzman, Wendy; de Jong, Trynke R.; Milnes, Matthew R.

    2012-01-01

    The California mouse, Peromyscus californicus, is an increasingly popular animal model in behavioral, neural, and endocrine studies, but little is known about its baseline hypothalamicpituitary-adrenal (HPA) axis activity or HPA responses to stressors. We characterized plasma corticosterone (CORT) concentrations in P. californicus under baseline conditions across the diurnal cycle, in response to pharmacological manipulation of the HPA axis, and in response to a variety of stressors at different times of day. In addition, we explored the use of fecal samples to monitor adrenocortical activity non-invasively. California mice have very high baseline levels of circulating CORT that change markedly over 24 hours, but that do not differ between the sexes. This species may be somewhat glucocorticoid-resistant in comparison to other rodents as a relatively high dose of dexamethasone (5 mg/kg, s.c.) was required to suppress plasma CORT for 8 h post-injection. CORT responses to stressors and ACTH injection differed with time of day, as CORT concentrations were elevated more readily during the morning (inactive period) than in the evening (active period) when compared to time-matched control. Data from 3H-CORT injection studies show that the time course for excretion of fecal CORT, or glucocorticoid metabolites, differs with time of injection. Mice injected in the evening excreted the majority of fecal radioactivity 2–4 h post-injection whereas mice injected during the morning did so at 14–16 h post-injection. Unfortunately, the antibody we used does not adequately bind the most prevalent fecal glucocorticoid metabolites and therefore we could not validate its use for fecal assays. PMID:23026495

  12. Helicobacter pylori activates the TLR2/NLRP3/caspase-1/IL-18 axis to induce regulatory T-cells, establish persistent infection and promote tolerance to allergens.

    PubMed

    Koch, Katrin N; Müller, Anne

    2015-01-01

    The Gram-negative bacterium Helicobacter pylori is both a normal constituent of the human gastric microbiota as well as a pathogen tightly associated with severe gastric disorders. The ability of H. pylori to activate the inflammasome and caspase-1 in antigen-presenting and other cells, and the resulting processing and release of caspase-1-dependent cytokines, impacts both the immunomodulatory and pathogenic activities of H. pylori. This article summarizes recent insights by us and others on the bacterial and host prerequisites of inflammasome activation. H. pylori predominantly activates the NLRP3 inflammasome through a process that requires TLR2-dependent licensing. We identified the urease enzyme, a colonization determinant known to be required for acid adaptation, as critically required for activation of the TLR2/NLRP3/caspase-1 axis. The phenotypes of urease mutants, as well as mouse strains defective for TLR2 or NLRP3, are discussed with respect to their ability to support persistent colonization, immune tolerance and immunity to H. pylori.

  13. Helicobacter pylori activates the TLR2/NLRP3/caspase-1/IL-18 axis to induce regulatory T-cells, establish persistent infection and promote tolerance to allergens

    PubMed Central

    Koch, Katrin N; Müller, Anne

    2015-01-01

    The Gram-negative bacterium Helicobacter pylori is both a normal constituent of the human gastric microbiota as well as a pathogen tightly associated with severe gastric disorders. The ability of H. pylori to activate the inflammasome and caspase-1 in antigen-presenting and other cells, and the resulting processing and release of caspase-1-dependent cytokines, impacts both the immunomodulatory and pathogenic activities of H. pylori. This article summarizes recent insights by us and others on the bacterial and host prerequisites of inflammasome activation. H. pylori predominantly activates the NLRP3 inflammasome through a process that requires TLR2-dependent licensing. We identified the urease enzyme, a colonization determinant known to be required for acid adaptation, as critically required for activation of the TLR2/NLRP3/caspase-1 axis. The phenotypes of urease mutants, as well as mouse strains defective for TLR2 or NLRP3, are discussed with respect to their ability to support persistent colonization, immune tolerance and immunity to H. pylori. PMID:26727421

  14. Increasing sediment accumulation rates in La Fonera (Palamós) submarine canyon axis and their relationship with bottom trawling activities

    NASA Astrophysics Data System (ADS)

    Puig, P.; Martín, J.; Masqué, P.; Palanques, A.

    2015-10-01

    Previous studies conducted in La Fonera (Palamós) submarine canyon (NW Mediterranean) found that trawling activities along the canyon flanks cause resuspension and transport of sediments toward the canyon axis. 210Pb chronology supported by 137Cs dating applied to a sediment core collected at 1750 m in 2002 suggested a doubling of the sediment accumulation rate since the 1970s, coincident with the rapid industrialization of the local trawling fleet. The same canyon area has been revisited a decade later, and new data are consistent with a sedimentary regime shift during the 1970s and also suggest that the accumulation rate during the last decade could be greater than expected, approaching ~2.4 cm yr-1 (compared to ~0.25 cm yr-1 pre-1970s). These results support the hypothesis that commercial bottom trawling can substantially affect sediment dynamics and budgets on continental margins, eventually initiating the formation of anthropogenic depocenters in submarine canyon environments.

  15. Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2-β-catenin axis.

    PubMed

    Du, Qianming; Wang, Yajing; Liu, Chao; Wang, Hong; Fan, Huimin; Li, Yan; Wang, Jianing; Zhang, Xu; Lu, Jinrong; Ji, Hui; Hu, Rong

    2016-04-05

    Nonresolving inflammation in the intestine predisposes individuals to colitis-associated colorectal cancer (CAC), which leads to high morbidity and mortality. Here we show that genistein-27 (GEN-27), a derivative of genistein, inhibited proliferation of human colorectal cancer cells through inhibiting β-catenin activity. Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced β-catenin nuclear localization, which resulted from the inhibition of NF-κB/p65 nuclear localization and up-regulation of caudal-related homeobox transcription factor 2 (CDX2). Furthermore, GEN-27 decreased binding of p65 to the silencer region of CDX2 and increased binding of CDX2 to the promoter regions of APC and AXIN2, thus inhibiting the activation of β-catenin induced by TNF-α. Importantly, GEN-27 protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and tumor volume. Histopathology, immunohistochemistry and flow cytometry revealed that dietary GEN-27 significantly decreased secretion of proinflammatory cytokines and macrophage infiltration. Moreover, GEN-27 inhibited AOM/DSS-induced p65 and β-catenin nuclear translocation, while promoted the expression of CDX2, APC, and AXIN2. Taken together, our findings demonstrate that the anti-proliferation effect of GEN-27 in vitro and the prevention of CAC in vivo is mediated by p65-CDX2-β-catenin axis via inhibiting β-catenin target genes. Our results imply that GEN-27 could be a promising candidate for the chemoprevention of CAC.

  16. Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic- pituitary-adrenal axis activation

    PubMed Central

    Reynolds, Anna R.; Saunders, Meredith A.; Brewton, Honoree’ W.; Winchester, Sydney R.; Elgumati, Ibrahim S.; Prendergast, Mark A.

    2015-01-01

    Background The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Methods Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 1100 hrs on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60 mg/kg/i.g.) or a placebo and withdrawal was monitored. Results Peak BELs of 225.52 mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g. aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. Conclusions The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. PMID:26143299

  17. Transmyocardial drilling revascularization combined with heparinized bFGF-incorporating stent activates resident cardiac stem cells via SDF-1/CXCR4 axis

    SciTech Connect

    Zhang, Guang-Wei; Wen, Ti; Gu, Tian-Xiang; Li-Ling, Jesse; Wang, Chun; Zhao, Ye; Liu, Jing; Wang, Ying; Liu, Tian-Jun; Lue, Feng

    2012-02-15

    Objective: To investigate whether transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) can promote myocardial regeneration after acute myocardial infarction (AMI). Methods: A model of AMI was generated by ligating the mid-third of left anterior descending artery (LAD) of miniswine. After 6 h, the animals were divided into none-treatment (control) group (n = 6) and TMDRSI group (n = 6). For TMDRSI group, two channels with 3.5 mm in diameter were established by a self-made drill in the AMI region, into which a stent was implanted. Expression of stromal cell-derived factor-1{sub {alpha}} (SDF-1{sub {alpha}}) and CXC chemokine receptor 4 (CXCR4), cardiac stem cell (CSC)-mediated myocardial regeneration, myocardial apoptosis, myocardial viability, and cardiac function were assessed at various time-points. Results: Six weeks after the operation, CSCs were found to have differentiated into cardiomyocytes to repair the infarcted myocardium, and all above indices showed much improvement in the TMDRSI group compared with the control group (P < 0.001). Conclusions: The new method has shown to be capable of promoting CSCs proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following AMI and improving cardiac function. This may provide a new strategy for myocardial regeneration following AMI. -- Highlights: Black-Right-Pointing-Pointer The effects of TMDR and bFGF-stent on myocardial regeneration were studied in a pig model of AMI. Black-Right-Pointing-Pointer TMDR and bFGF-stent implantation activated CSCs via the SDF-1/CXCR4 axis. Black-Right-Pointing-Pointer CSC-mediated myocardial regeneration improved cardiac function. Black-Right-Pointing-Pointer It may be a new therapeutic strategy for AMI.

  18. Three axis attitude control system

    NASA Technical Reports Server (NTRS)

    Studer, Philip A. (Inventor)

    1988-01-01

    A three-axis attitude control system for an orbiting body comprised of a motor driven flywheel supported by a torque producing active magnetic bearing is described. Free rotation of the flywheel is provided about its central axis and together with limited angular torsional deflections of the flywheel about two orthogonal axes which are perpendicular to the central axis. The motor comprises an electronically commutated DC motor, while the magnetic bearing comprises a radially servoed permanent magnet biased magnetic bearing capable of producing cross-axis torques on the flywheel. Three body attitude sensors for pitch, yaw and roll generate respective command signals along three mutually orthogonal axes (x, y, z) which are coupled to circuit means for energizing a set of control coils for producing torques about two of the axes (x and y) and speed control of the flywheel about the third (z) axis. An energy recovery system, which is operative during motor deceleration, is also included which permits the use of a high-speed motor to perform effectively as a reactive wheel suspended in the magnetic bearing.

  19. Vertical Axis Wind Turbine

    SciTech Connect

    Homicz, Greg

    2002-04-01

    Blade fatigue life is an important element in determining the economic viability of the Vertical-Axis Wind Turbine (VAWT). VAWT-SAL Vertical Axis Wind Turbine- Stochastic Aerodynamic Loads Ver 3.2 numerically simulates the stochastic (random0 aerodynamic loads of the Vertical-Axis Wind Turbine (VAWT) created by the atomspheric turbulence. The program takes into account the rotor geometry, operating conditions, and assumed turbulence properties.

  20. The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation

    PubMed Central

    Yip, Kwok Ho; Kolesnikoff, Natasha; Hauschild, Nicholas; Biggs, Lisa; Lopez, Angel F.; Galli, Stephen J.; Kumar, Sharad; Grimbaldeston, Michele A.

    2016-01-01

    Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FcɛRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Restraint of intracellular signal transduction pathways that promote release of mast cell-derived pro-inflammatory mediators is necessary to dampen activation and restore homoeostasis. Here we show that the ligase Nedd4-2 and the adaptor Ndfip1 (Nedd4 family interacting protein 1) limit the intensity and duration of IgE-FcɛRI-induced positive signal transduction by ubiquitinating phosphorylated Syk, a tyrosine kinase that is indispensable for downstream FcɛRI signalosome activity. Importantly, loss of Nedd4-2 or Ndfip1 in mast cells results in exacerbated and prolonged IgE-mediated cutaneous anaphylaxis in vivo. Our findings reveal an important negative regulatory function for Nedd4-2 and Ndfip1 in IgE-dependent mast cell activity. PMID:27786273

  1. Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis

    PubMed Central

    Shen, Na; Yan, Fei; Wu, Lai-Chu; Al-Kali, Aref; Litzow, Mark R.; Peng, Yong; Lee, Robert J.; Liu, Shujun

    2016-01-01

    The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for BCR/ABL expression. Inactivation of Sp1 by genetic and pharmacological approaches abrogated BCR/ABL expression, leading to suppression of BCR/ABL kinase signaling and CML cell proliferation. Because of potential adverse side effects of bortezomib (BORT) in imatinib-refractory CML patients, we designed a transferrin (Tf)-targeted liposomal formulation (Tf-L-BORT) for BORT delivery. Cellular uptake assays showed that BORT was efficiently delivered into K562 cells, with the highest efficacy obtained in Tf-targeted group. After administered into mice, L-BORT exhibited slower clearance with less toxicity compared to free BORT. Furthermore, L-BORT exposure significantly blocked BCR/ABL kinase activities and sensitized CML cell lines, tumor cells and doxorubicin (DOX) resistant cells to DOX. This occurred through the more pronounced inhibition of BCR/ABL activity by L-BORT and DOX. Collectively, these findings highlight the therapeutic relevance of disrupting BCR/ABL protein expression and strongly support the utilization of L-BORT alone or in combination with DOX to treat CML patients with overexpressing BCR/ABL. PMID:27144331

  2. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

    PubMed Central

    Wang, Xiaowei; Shaw, Dana K.; Hammond, Holly L.; Sutterwala, Fayyaz S.; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J.; Bonventre, Joseph V.; Velayutham, Thangam S.; Evans, Sean M.; Rodino, Kyle G.; VieBrock, Lauren; Scanlon, Karen M.; Carbonetti, Nicholas H.; Carlyon, Jason A.; Miao, Edward A.; McBride, Jere W.; Kotsyfakis, Michail

    2016-01-01

    Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID:27482714

  3. The C-ETS2-TFEB Axis Promotes Neuron Survival under Oxidative Stress by Regulating Lysosome Activity

    PubMed Central

    Fang, Zijun; Luo, Wenwen; Yang, Yunzhi; Wang, Chenyao; Zhang, Qian; Wang, Huafei; Chen, Huaiyong; Chan, Chi bun; Liu, Zhixue

    2016-01-01

    Excessive reactive oxygen species/reactive nitrogen species (ROS/RNS) produced as a result of ageing causes damage to macromolecules and organelles or leads to interference of cell signalling pathways, which in turn results in oxidative stress. Oxidative stress occurs in many neurodegenerative diseases (e.g., Parkinson's disease) and contributes to progressive neuronal loss. In this study, we show that cell apoptosis is induced by oxidative stress and that lysosomes play an important role in cell survival under oxidative stress. As a compensatory response to this stress, lysosomal genes were upregulated via induction of transcription factor EB (TFEB). In addition, localization of TFEB to the nucleus was increased by oxidative stress. We also confirmed that TFEB protects cells from oxidative stress both in vitro and in vivo. Finally, we found that C-ETS2 senses oxidative stress, activates TFEB transcription, and mediates the upregulation of lysosomal genes. Our results demonstrate a mechanistic pathway for inducing lysosomal activity during ageing and neurodegeneration. PMID:27195074

  4. Hypothalamic-pituitary-adrenal axis activity, personality traits, and BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in metabolically obese normal-weight women.

    PubMed

    Porzezińska-Furtak, Joanna; Krzyżanowska-Świniarska, Barbara; Miazgowski, Tomasz; Safranow, Krzysztof; Kamiński, Ryszard

    2014-09-01

    We sought associations among metabolic profiles, copeptin levels, emotional control, personality traits, and hypothalamic-pituitary-adrenal axis activity in metabolically obese normal-weight young women (MONW). We assessed body composition, including fat-free mass; body fat (BF) and android and gynoid fat depots; fasting blood glucose, insulin, copeptin, cortisol (baseline and after dexamethasone), adrenocorticotropin (ACTH), triglycerides, total cholesterol, low- (LDL) and high-density (HDL) lipoproteins; and the BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in 59 MONW and 71 healthy women aged 20-40 years. We also evaluated personality traits using the NEO-Five Factor Inventory and the subjective extent of emotional suppression by the Courtauld Emotional Control Scale. Compared to the controls, MONW had significantly higher insulin, cholesterol, LDL, triglycerides, and waist circumference, but lower HDL. MONW also had increased BF (>30 % of weight) and unfavorable regional fat distribution with excess android fat. The android/BF ratio was 8.29 % (MONW) versus 7.89 % (controls) (p = 0.005), while the gynoid/BF ratio was 31.99 versus 34.1 %, respectively (p = 0.008). Despite similar ACTH levels in both groups, MONW had higher cortisol levels both at the baseline (p < 0.001) and in the dexamethasone suppression test (p = 0.003). Copeptin levels and the distribution of glucocorticoid receptor polymorphisms were similar in both groups. There were also no significant differences in psychological features between MONW and controls. In conclusion, the MONW phenotype was associated with hypothalamic-pituitary-adrenal axis dysregulation, unfavorable metabolic profiles, and fat accumulation, but normal distribution of glucocorticoid receptor gene polymorphisms and copeptin levels, and no significant differences in psychological features between MONW and controls.

  5. Roads Centre-Axis Extraction in Airborne SAR Images: AN Approach Based on Active Contour Model with the Use of Semi-Automatic Seeding

    NASA Astrophysics Data System (ADS)

    Lotte, R. G.; Sant'Anna, S. J. S.; Almeida, C. M.

    2013-05-01

    Research works dealing with computational methods for roads extraction have considerably increased in the latest two decades. This procedure is usually performed on optical or microwave sensors (radar) imagery. Radar images offer advantages when compared to optical ones, for they allow the acquisition of scenes regardless of atmospheric and illumination conditions, besides the possibility of surveying regions where the terrain is hidden by the vegetation canopy, among others. The cartographic mapping based on these images is often manually accomplished, requiring considerable time and effort from the human interpreter. Maps for detecting new roads or updating the existing roads network are among the most important cartographic products to date. There are currently many studies involving the extraction of roads by means of automatic or semi-automatic approaches. Each of them presents different solutions for different problems, making this task a scientific issue still open. One of the preliminary steps for roads extraction can be the seeding of points belonging to roads, what can be done using different methods with diverse levels of automation. The identified seed points are interpolated to form the initial road network, and are hence used as an input for an extraction method properly speaking. The present work introduces an innovative hybrid method for the extraction of roads centre-axis in a synthetic aperture radar (SAR) airborne image. Initially, candidate points are fully automatically seeded using Self-Organizing Maps (SOM), followed by a pruning process based on specific metrics. The centre-axis are then detected by an open-curve active contour model (snakes). The obtained results were evaluated as to their quality with respect to completeness, correctness and redundancy.

  6. Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse.

    PubMed

    Jiang, Sunny Zhihong; Eiden, Lee E

    2016-07-01

    We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2-3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP's actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress.

  7. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis

    PubMed Central

    Cao, Lei; Choi, Eugene Y.; Liu, Xianglan; Martin, Adam; Wang, Chuansong; Xu, Xiaohua; During, Matthew J.

    2011-01-01

    SUMMARY Living in an enriched environment with complex physical and social stimulation leads to improved cognitive and metabolic health. In white fat, enrichment induced the upregulation of the brown fat cell fate determining gene Prdm16, brown fat specific markers, and genes involved in thermogenesis and β-adrenergic signaling. Moreover, pockets of cells with prototypical brown fat morphology and high UCP1 levels were observed in the white fat of enriched mice associated with resistance to diet-induced obesity. Hypothalamic overexpression of BDNF reproduced the enrichment-associated activation of the brown fat gene program and lean phenotype. Inhibition of BDNF signaling by genetic knockout or dominant negative trkB reversed this phenotype. Our genetic and pharmacologic data suggest a mechanism whereby induction of hypothalamic BDNF expression in response to environmental stimuli leads to selective sympathoneural modulation of white fat to induce “browning” and increased energy dissipation. PMID:21907139

  8. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

    PubMed

    Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

    2016-07-01

    Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

  9. GABAergic activation inhibits the hypothalamic-pituitary-ovaric axis and sexual development in the immature female rat. Associated changes in hypothalamic glutamatergic and taurinergic systems.

    PubMed

    Feleder, C; Ginzburg, M; Wuttke, W; Moguilevsky, J A; Arias, P

    1999-09-06

    The aim of the present studies was to assess, in immature female rats, the effect of the GABAergic system on the reproductive axis and on pubertal development. With this purpose we initially evaluated, in 30-day-old female rats, the effect of persistently enhanced GABAergic activity (aminooxyacetic acid (AOAA) 10 mg/kg per day i.p., during postnatal days 23-29) on hypothalamic gonadotropin-releasing hormone (GnRH) and amino acid neurotransmitter (AANT; glutamate or GLU, and taurine or TAU) concentrations, on circulating luteinizing hormone (LH) and estradiol levels, and on ovaric weight. In a second group of similarly treated rats, the date of vaginal opening (VO) was recorded. Complementary in vitro experiments (superfusion of anterior/mediobasal hypothalamic fragments obtained from rats aged 30 days) were performed to evaluate the effect of the short-term activation of the GABAergic system (by means of AOAA, muscimol or baclofen) on hypothalamic GnRH and AANT release. Prolonged treatment with AOAA led to a marked increase in hypothalamic gamma-aminobutyric-acid (GABA) concentrations (p<0.002), and to a significant decrease in hypothalamic GnRH and GLU content (p<0.05 and <0.02, respectively). Furthermore, treated animals showed diminished serum LH (p<0.05) and estradiol (p<0.005) levels, and a clear reduction in ovaric weight (p<0.002). Mean age at VO was 30. 8+/-0.6 days in control animals (range: 29-34 days), and 36.7+/-0.98 days in AOAA-treated rats (range: 33-40 days; p<0.0001). Acute treatment with AOAA resulted in a decreased GnRH and GLU output, and in an increased TAU release from superfused hypothalamic fragments. This effect was mimicked by the GABA-A and GABA-B agonists. Our results show that the activation of the GABAergic system during postnatal days 23-29 significantly restrains the hypothalamic-pituitary-ovaric axis, resulting in a clear-cut delay in sexual development. This can be attributed to the inhibitory effect exerted by GABA (acting on both

  10. Interleukin (IL)-9/IL-9R axis drives γδ T cells activation in psoriatic arthritis patients.

    PubMed

    Guggino, G; Ciccia, F; Di Liberto, D; Lo Pizzo, M; Ruscitti, P; Cipriani, P; Ferrante, A; Sireci, G; Dieli, F; Fourniè, J J; Giacomelli, R; Triolo, G

    2016-12-01

    Cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, IL-23 and, more recently, IL-9, have been implicated in the initiation/maintenance of inflammation in psoriasis and psoriatic arthritis (PsA). In the present study we aimed to characterize the role of γδ T cells in peripheral blood and synovial fluid of PsA patients and to investigate their response to in-vitro stimulation with antigen or cytokines (IL-9 and IL-23). γδ T cells isolated from peripheral blood mononuclear cells and synovial fluid were analysed by flow cytometry to evaluate the phenotype and cytokine production. IL-23R and IL-9R gene expression were also evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells (PBMC), sorted γδ T cells and γδ cell lines were also stimulated in vitro with isopentenyl pyrophosphate (IPP), recombinant IL-9 or recombinant IL-23. Our results show an expansion of γδ T cells with a predominant effector memory phenotype in peripheral blood and synovium of untreated PsA patients, which reverses significantly after treatment with anti-TNF-α or anti-IL-12/IL-23R monoclonal antibodies (mAbs). Moreover, in PsA patients γδ T cells activation is driven prevalently by IL-9/IL-9R interaction, and not only by IL-23/IL-23R. Together these findings indicate γδ T cells and IL-9 as new players in the pathogenesis of PsA.

  11. Limitation of activities of daily living accompanying reduced neck mobility after laminoplasty preserving or reattaching the semispinalis cervicis into axis.

    PubMed

    Takeuchi, Kazunari; Yokoyama, Toru; Ono, Atsushi; Numasawa, Takuya; Wada, Kanichiro; Itabashi, Taito; Toh, Satoshi

    2008-03-01

    Although difficulties with neck mobility often interfere with patients' activities of daily living (ADL) after cervical laminoplasty, there was no detailed study on the relation between the limitations of ADL accompanying postoperative reduced neck mobility and the cervical posterior approach. The aim of this study was to compare retrospectively the frequency of limitations of ADL accompanying neck mobility after laminoplasty preserving the semispinalis cervicis inserted into the C2 spinous process with that after laminoplasty reattaching the muscle to C2. Forty-nine patients after C4-C7 laminoplasty with C3 laminectomy preserving the semispinalis cervicis inserted into C2 (Group A) and 24 patients after C3-C7 laminoplasty reattaching the muscle (Group B) were evaluated. The frequency of postoperative limitations of ADL accompanying each of three neck movements of extension, flexion and rotation were investigated. The postoperative O-C7 angles at extension and flexion was measured on lateral extension and flexion radiographs of the cervical spine, respectively. The postoperative cervical range of motion in rotation was measured in the cranial view using a digital camera. Frequency of limitations of ADL accompanying extension was lower (P = 0.037) in Group A (2%) than in Group B (17%). Frequency of limitations of ADL accompanying flexion was similar in Group A (8%) and Group B (4%). Frequency of limitations of ADL accompanying rotation was lower (P = 0.031) in Group A (12%) than in Group B (33%). Average O-C7 angle at extension was significantly larger (P = 0.002) in Group A (147 degrees ) than in Group B (136 degrees ). Average O-C7 angle at flexion was similar in Group A (93 degrees ) and Group B (91 degrees ). Average range of motion in rotation was significantly larger (P = 0.004) in Group A (110 degrees ) than in Group B (91 degrees ). This retrospective study suggested that the frequency of limitations of ADL accompanying neck extension or rotation was lower

  12. Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis.

    PubMed

    Zhang, Shuai; Bian, Huan; Li, Xiaoxu; Wu, Huanhuan; Bi, Qingwei; Yan, Yingbin; Wang, Yixiang

    2016-05-01

    Hydrogen sulfide, the third gaseous transmitter, is one of the main causes of halitosis in the oral cavity. It is generally considered as playing a deleterious role in many oral diseases including oral cancer. However, the regulatory mechanisms involved in the effects of hydrogen sulfide on oral cancer growth remain largely unknown. In the present study, we investigated the underlying mechanisms through CCK-8 assay, EdU incorporation, real-time PCR, western blot and pathway blockade assays. Our results showed that hydrogen sulfide promoted oral cancer cell proliferation through activation of the COX2, AKT and ERK1/2 pathways in a dose-dependent manner. Blocking any of the three above pathways inhibited hydrogen sulfide-induced oral cancer cell proliferation. Meanwhile, blockade of COX2 by niflumic acid downregulated NaHS-induced p-ERK and p-AKT expression. Inactivation of the AKT pathway by GSK690693 significantly decreased NaHS‑induced p-ERK1/2 expression, and inhibition of the ERK1/2 pathway by U0126 markedly increased NaHS-induced p-AKT expression. Either the AKT or ERK1/2 inhibitor did not significantly alter the COX2 expression level. Our data revealed, for the first time, that hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis, suggesting new potential targets to eliminate the effect of hydrogen sulfide on the development of oral cancer.

  13. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.

    PubMed

    Young, Christian D; Zimmerman, Lisa J; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B; Gatza, Michael L; Morrison, Meghan M; Moore, Preston D; Whitwell, Corbin A; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E; Silva, Grace O; Patel, Premal; Brantley-Sieders, Dana M; Levin, Maren; Horiates, Marina; Palma, Norma A; Wang, Kai; Stephens, Philip J; Perou, Charles M; Weaver, Alissa M; O'Shaughnessy, Joyce A; Chang, Jenny C; Park, Ben Ho; Liebler, Daniel C; Cook, Rebecca S; Arteaga, Carlos L

    2015-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.

  14. Growth arrest of lung carcinoma cells (A549) by polyacrylate-anchored peroxovanadate by activating Rac1-NADPH oxidase signalling axis.

    PubMed

    Chatterjee, Nirupama; Anwar, Tarique; Islam, Nashreen S; Ramasarma, T; Ramakrishna, Gayatri

    2016-09-01

    Hydrogen peroxide is often required in sublethal, millimolar concentrations to show its oxidant effects on cells in culture as it is easily destroyed by cellular catalase. Previously, we had shown that diperoxovanadate, a physiologically stable peroxovanadium compound, can substitute H2O2 effectively in peroxidation reactions. We report here that peroxovanadate when anchored to polyacrylic acid (PAPV) becomes a highly potent inhibitor of growth of lung carcinoma cells (A549). The early events associated with PAPV treatment included cytoskeletal modifications, increase in GTPase activity of Rac1, accumulation of the reactive oxygen species, and also increase in phosphorylation of H2AX (γH2AX), a marker of DNA damage. These effects persisted even at 24 h after removal of the compound and culminated in increased levels of p53 and p21 together with growth arrest. The PAPV-mediated growth arrest was significantly abrogated in cells pre-treated with the N-acetylcysteine, Rac1 knocked down by siRNA and DPI an inhibitor of NADPH oxidase. In conclusion, our results show that polyacrylate derivative of peroxovanadate efficiently arrests growth of A549 cancerous cells by activating the axis of Rac1-NADPH oxidase leading to oxidative stress and DNA damage.

  15. Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.

    PubMed

    Ghosh, Sayan; Shang, Peng; Yazdankhah, Meysam; Bhutto, Imran; Hose, Stacey; Montezuma, Sandra R; Luo, Tianqi; Chattopadhyay, Sreya; Qian, Jiang; Lutty, Gerard A; Ferrington, Deborah A; Zigler, J Samuel; Sinha, Debasish

    2017-04-01

    Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  16. Highly context-specific activation of the HPG axis in the dark-eyed junco and implications for the challenge hypothesis.

    PubMed

    Rosvall, Kimberly A; Peterson, Mark P; Reichard, Dustin G; Ketterson, Ellen D

    2014-05-15

    One of the best studied hormone-behavior interactions is the transient rise in testosterone (T) associated with male-male aggression. However, recent research on songbirds has demonstrated numerous exceptions to this pattern.One species previously thought to elevate T in response to a simulated territorial intrusion is the dark-eyed junco (Junco hyemalis). Here, we show that under most circumstances male juncos do not elevate circulating T or CORT levels in response to social stimuli, despite being physiologically capable of elevating T as indicated by their response to GnRH. The lack of hormonal response was found regardless of the sex of the social stimulus (singing male vs. soliciting female), its sensory modality (song only, song + live lure, song + taxidermic mount), or the timecourse of sampling. Notably, males did elevate T levels when exposed to a simulated territorial intrusion in the days following simulated predation of their chicks. Whether the high T seen in these narrow circumstances represents stage-dependent social modulation of T or re-activation of male reproductive physiology in preparation for re-nesting (i.e. socially independent T modulation) remains to be determined. It is clear, however, that activation of the HPG axis is highly context-specific for male juncos. These results highlight important and unresolved issues regarding the socially mediated component of the challenge hypothesis and how it relates to the evolution of hormone-mediated traits.

  17. Highly context-specific activation of the HPG axis in the dark-eyed junco and implications for the Challenge Hypothesis

    PubMed Central

    Rosvall, Kimberly A.; Peterson, Mark P.; Reichard, Dustin G.; Ketterson, Ellen D.

    2014-01-01

    One of the best studied hormone-behavior interactions is the transient rise in testosterone (T) associated with male-male aggression. However, recent research on songbirds has demonstrated numerous exceptions to this pattern. One species previously thought to elevate T in response to a simulated territorial intrusion is the dark-eyed junco (Junco hyemalis). Here, we show that under most circumstances male juncos do not elevate circulating T or CORT levels in response to social stimuli, despite being physiologically capable of elevating T as indicated by their response to GnRH. The lack of hormonal response was found regardless of the sex of the social stimulus (singing male vs. soliciting female), its sensory modality (song only, song + live lure, song + taxidermic mount), or the timecourse of sampling. Notably, males did elevate T levels when exposed to a simulated territorial intrusion in the days following simulated predation of their chicks. Whether the high T seen in these narrow circumstances represents stage-dependent social modulation of T or re-activation of male reproductive physiology in preparation for re-nesting (i.e. socially independent T modulation) remains to be determined. It is clear, however, that activation of the HPG axis is highly context-specific for male juncos. These results highlight important and unresolved issues regarding the socially mediated component of the challenge hypothesis and how it relates to the evolution of hormone-mediated traits. PMID:24698788

  18. Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: the HPA axis, BDNF expression and phosphorylation of ERK.

    PubMed

    Wang, Zhen; Gu, Jianhua; Wang, Xueer; Xie, Kai; Luan, Qinsong; Wan, Nianqing; Zhang, Qun; Jiang, Hong; Liu, Dexiang

    2013-11-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of resveratrol. The present study assessed whether resveratrol treatment (20, 40 and 80mg/kg, i.p., 21days) has an antidepressant-like effect on the forced swim test (FST) and tail suspension test (TST) in mice and examined what its molecular targets might be. The results showed that resveratrol administration produced antidepressant-like effects in mice, evidenced by the reduced immobility time in the FST and TST, while it had no effect on the locomotor activity in the open field test. Resveratrol treatment significantly reduced serum corticosterone levels, which had been elevated by the FST and TST. Moreover, resveratrol increased brain-derived neurotrophic factor (BDNF) protein and extracellular signal-regulated kinase (ERK) phosphorylation levels in the prefrontal cortex and hippocampus. All of these antidepressant-like effects of resveratrol were essentially similar to those observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of resveratrol in the FST and TST are mediated, at least in part, by modulating hypothalamic-pituitary-adrenal axis, BDNF and ERK phosphorylation expression in the brain region of mice.

  19. Inhibition of miR-222-3p activity promoted osteogenic differentiation of hBMSCs by regulating Smad5-RUNX2 signal axis.

    PubMed

    Yan, Jihong; Guo, Duo; Yang, Shu; Sun, Huaimei; Wu, Bo; Zhou, Deshan

    2016-02-12

    miRNAs are recently found playing important roles in osteogenesis. In this study, we identified that miR-222-3p decreased during osteogenic differentiation of human mesenchymal stem cells (hBMSCs) using Quantitative Real-Time Reverse Transcription PCR (qRT-PCR). Furthermore, we investigated the effect of miR-222-3p on osteogenic differentiation of hBMSCs. Inhibition of miR-222-3p function in hBMSCs using infection of lentiviruses carrying miR-222-3p specific inhibitor promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Whereas, overexpression of miR-222-3p inhibited osteoblast differentiation of hBMSCs in vitro. Moreover, Smad5 and RUNX2, which are the critical transcription factors in osteogenic differentiation, were predicted to be targets of miR-222-3p by bioinformatic analysis. Overexpression of miR-222-3p in hBMSCs significantly suppressed the protein levels of Smad5 and RUNX2, while inhibition of miR-222-3p increased their protein levels. Furthermore, inhibition of miR-222-3p increased phosphorylation of Smad1/5/8, which regulated the expression of osteogenic genes. Our findings suggest that suppression of miR-222-3p activity promoted osteogenic differentiation hBMSCs through regulating Smad5-RUNX2 signaling axis.

  20. Hypothalamic-pituitary GnRH/LH axis activity is affected by salsolinol in sheep during lactation: Effects of intracerebroventricular infusions of salsolinol and its antagonizing analogue.

    PubMed

    Marciniak, Elżbieta; Górski, Konrad; Hasiec, Małgorzata; Misztal, Tomasz

    2016-11-01

    The aim of the study was to test the hypothesis that salsolinol, a derivative of dopamine, is involved in the regulation of hypothalamic-pituitary gonadotropic (GnRH/LH) axis activity in lactating sheep. In the first experiment performed on sheep during the fifth week of lactation, a structural analogue of salsolinol (1-MeDIQ) was infused into the third brain ventricle (IIIv) to antagonize its action within the central nervous system (CNS). A push-pull perfusion of the infundibular nucleus/median eminence was performed simultaneously, and blood samples were collected from the jugular vein. In the second experiment, sheep received infusions of salsolinol into the IIIv, 48 hours after the weaning of their 8-week-old lambs. Blood samples were collected during the experimental periods, and the anterior pituitary (AP) tissue was dissected immediately after the end of the experiment. Perfusate GnRH concentration (experiment 1), plasma LH concentration (experiments 1 and 2), and relative LHβ mRNA levels in the AP tissue (experiment 2) were assayed. Blocking of salsolinol action in the CNS of lactating sheep caused a significant (P < 0.001) decrease in the perfusate GnRH concentrations in comparison with controls. Treatment with 1-MEDIQ also significantly decreased (P < 0.001) the LH concentration in the blood plasma. In turn, salsolinol infused 48 hours after lamb weaning significantly (P < 0.001) increased plasma LH concentration, reflected in the significant (P < 0.05) increase in the amplitude of LH pulses in the treated sheep as compared to the control animals. There was no significant difference in the relative levels of LHβ-subunit mRNA in the AP between control and salsolinol-infused sheep. The results lead to a conclusion that salsolinol affects the secretory activity of the GnRH/LH axis in sheep during lactation. Whether salsolinol infused into the IIIv evokes this stimulatory effect by itself or by modulation of other regulatory systems needs to be

  1. [Effect of ming-men mixture on corticosterone-rats' neuro-endocrino-immunological network].

    PubMed

    Cai, D F; Shen, Z Y; Zhang, L J

    1995-03-01

    The hypothalamus-pituitary adrenal-thymus(HPAT) axis is an important form of the neuroendocrino-immunological network (NEIN). To study the essential link between Ming-Men, Kidney and the NEIN, the corticosterone (CORT) injected rats was used. The CORT The CORT caused HPAT axis inhibiting model was established and then the regulation of Ming-Men mixture (MMM) was observed. The results showed that the number of corticotropin-releasing factor (CRF) positive neurones in hypothalamic paraventricular nucleus, CRF positive neurofibril in in median eminence, anterior pituitary ACTH positive secretory cells decreased markedly in the CORT inhibited rats and the immunohistochemical ABC staining became lighter than the control. We also observed that there was atrophy in adrenal, especially fasculate zone became thinner compared with the control. The thymus atrophied, the number of lymphocytes and thymic corpuscles decreased obviously. The content of ACTH and CORT in plasma decreased, the proliferative reaction of lymphocytes, interleukin-2 and the inductive ability of gamma-IFN reduced. After the MMM was instilled into stomach in experimental group, it was foiund that MMM could improve the inhibition on HPAT axis caused by CORT significantly, P < 0.01. It suggested that MMM possibly was an effective and ideal prescription which could regulate the HPAT axis.

  2. A low cortisol response to acute stress is related to worse basal memory performance in older people

    PubMed Central

    Almela, Mercedes; Hidalgo, Vanesa; van der Meij, Leander; Pulopulos, Matías M.; Villada, Carolina; Salvador, Alicia

    2014-01-01

    Age-related memory decline has been associated with a faulty regulation of the hypothalamus-pituitary-adrenal axis (HPA-axis). The aim of this study was to investigate whether the magnitude of the stress-induced cortisol increase is related to memory performance when memory is measured in non-stressful conditions. To do so, declarative and working memory performance were measured in 31 men and 35 women between 55 and 77 years of age. On a different day, the magnitude of their cortisol response to acute psychosocial stress was measured. The relationship between the cortisol response and memory performance was U shaped: a low cortisol response to stress was related to poorer declarative and working memory performance, whereas those who did not increase their cortisol levels and those who had the largest cortisol increase had better declarative and working memory capabilities. Sex did not moderate these relationships. These results suggest that a low cortisol response to stress could reflect a defective HPA-axis response to stressors that is accompanied by poorer memory performance. Conversely, a high cortisol response seems to reflect a correct functioning of the HPA-axis and may protect against memory deficits in the later stages of human life. PMID:25076903

  3. Stress and the Reproductive Axis

    PubMed Central

    Toufexis, Donna; Rivarola, Maria Angelica; Lara, Hernan; Viau, Victor

    2014-01-01

    There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes wherein the activation of one affects the function of the other and vice versa. For instance, both testosterone and oestrogen modulate the response of the HPA axis, while activation of the stress axis, especially activation that is repeating or chronic, has an inhibitory effect upon oestrogen and testosterone secretion. Alterations in maternal care can produce significant effects on both HPG and HPA physiology and behaviour in the offspring at adulthood. For example, changes in reproductive behaviour induced by altered maternal care may alter the expression of sex hormone receptors like ERα that govern sexual behaviour, and may be particularly important in determining the sexual strategies utilized by females. Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine (NE) into the ovary, which produces a non-cyclic anovulatory ovary that develops cysts. In the opposite direction, sex differences and sex steroid hormones regulate the HPA axis. For example, although serotonin (5-HT) has a stimulatory effect on the HPA axis in humans and rodents that is mediated by the 5-HT1A receptor, only male rodents respond to 5-HT1A antagonism to show increased corticosterone responses to stress. Furthermore, oestrogen appears to decrease 5-HT1A receptor function at presynaptic sites, yet increase 5-HT1A receptor expression at postsynaptic sites. These mechanisms could explain heightened stress HPA axis responses in females compared to males. Studies on female rhesus macaques show that chronic stress in socially subordinate female monkeys produces a distinct behavioral phenotype that is largely unaffected by oestrogen, a hypo-responsive HPA axis that is hypersensitive to the modulating effects of oestrogen, and changes in 5-HT

  4. Activation of NK cells and disruption of PD-L1/PD-1 axis: two different ways for lenalidomide to block myeloma progression.

    PubMed

    Giuliani, Massimo; Janji, Bassam; Berchem, Guy

    2017-02-09

    Natural Killer (NK) cells play a critical role against tumor cells in hematological malignancies. Their activating receptors are essential in tumor cell killing. In Multiple Myeloma (MM) patients, NK cell differentiation, activation and cytotoxic potential are strongly impaired leading to MM escape from immune surveillance in tissues and bone marrow. Mechanisms used by MM to affect NK cell functions are mediated by the release of soluble factors, the expression of activating and inhibitory NK cell ligands, and the expression of immune check-point inhibitors. Lenalidomide represents an efficient clinical approach in MM treatment to improve patients' survival. Lenalidomide does not only promotes tumor apoptosis, but also stimulates T and NK cells, thereby facilitating NK-mediated tumor recognition and killing. This occurs since Lenalidomide acts on several critical points: stimulates T cell proliferation and cytokine secretion; decreases the expression of the immune check-point inhibitor Programmed Death-1 (PD-1) on both T and NK cells in MM patients; decreases the expression of both PD-1 and PD-L1 on MM cells; promotes MM cell death and abrogates MM/stromal microenvironment cross-talk, a process known to promote the MM cell survival and proliferation. This leads to the inhibition of the negative signal induced by PD-1/PD-L1 axis on NK cells, restoring NK cell cytotoxic functions. Given the importance of an effective immune response to counteract the MM progression and the promising approaches using anti-PD-1/PD-L1 strategies, we will discuss in this review how Lenalidomide could represent an adequate approach to re-establish the recognition against MM by exhausted NK cell.

  5. Adolescence fluoxetine increases serotonergic activity in the raphe-hippocampus axis and improves depression-like behaviors in female rats that experienced neonatal maternal separation.

    PubMed

    Yoo, Sang Bae; Kim, Bom-Taeck; Kim, Jin Young; Ryu, Vitaly; Kang, Dong-Won; Lee, Jong-Ho; Jahng, Jeong Won

    2013-06-01

    This study was conducted to examine if fluoxetine, a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor, would reverse adverse behavioral effects of neonatal maternal separation in female rats. Sprague-Dawley pups were separated from dam daily for 3h during postnatal day (PND) 1-14 (maternal separation; MS) or left undisturbed (non-handled; NH). Female NH and MS pups received intraperitoneal injection of fluoxetine (10mg/kg) or vehicle daily from PND 35 until the end of the whole experimental period. Rats were either subjected to behavioral tests during PND 44-54, or sacrificed for neurochemical analyses during PND 43-45. Daily food intake and weight gain of both NH and MS pups were suppressed by fluoxetine, with greater effects in MS pups. MS experience increased immobility and decrease swimming in forced swim test. Swimming was increased, although immobility was not significantly decreased, in MS females by adolescence fluoxetine. However, adolescence fluoxetine increased immobility during forced swim test and decreased time spent in open arms during elevated plus maze test in NH females. Fluoxetine normalized MS-induced decrease of the raphe 5-HT levels and increased 5-HT metabolism in the hippocampus in MS females, and increased the hypothalamic 5-HT both in NH and MS. Fluoxetine decreased the raphe 5-HT and increased the plasma corticosterone in NH females. Results suggest that decreased 5-HTergic activity in the raphe nucleus is implicated in the pathophysiology of depression-like behaviors, and increased 5-HTergic activities in the raphe-hippocampus axis may be a part of anti-depressant efficacy of fluoxetine, in MS females. Also, an extra-hypothalamic 5-HTergic activity may contribute to the increased anorectic efficacy of fluoxetine in MS females. Additionally, decreased 5-HT in the raphe and elevated plasma corticosterone may be related with fluoxetine-induced depression- and/or anxiety-like behaviors in NH females.

  6. Single-Axis Accelerometer

    NASA Technical Reports Server (NTRS)

    Tucker, Dennis Stephen (Inventor); Capo-Lugo, Pedro A. (Inventor)

    2016-01-01

    A single-axis accelerometer includes a housing defining a sleeve. An object/mass is disposed in the sleeve for sliding movement therein in a direction aligned with the sleeve's longitudinal axis. A first piezoelectric strip, attached to a first side of the object and to the housing, is longitudinally aligned with the sleeve's longitudinal axis. The first piezoelectric strip includes a first strip of a piezoelectric material with carbon nanotubes substantially aligned along a length thereof. A second piezoelectric strip, attached to a second side of the object and to the housing, is longitudinally aligned with the sleeve's longitudinal axis. The second piezoelectric strip includes a second strip of the piezoelectric material with carbon nanotubes substantially aligned along a length thereof. A voltage sensor is electrically coupled to at least one of the first and second piezoelectric strips.

  7. Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

    PubMed Central

    Yoshida, Natsu; Maejima, Yuko; Sedbazar, Udval; Ando, Akihiko; Kurita, Hideharu; Damdindorj, Boldbaatar; Takano, Eisuke; Gantulga, Darambazar; Iwasaki, Yusaku; Kurashina, Tomoyuki; Onaka, Tatsushi; Dezaki, Katsuya; Nakata, Masanori; Mori, Masatomo; Yada, Toshihiko

    2010-01-01

    A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses. PMID:20966530

  8. Vertical-axis rotations and deformation along the active strike-slip El Tigre Fault (Precordillera of San Juan, Argentina) assessed through palaeomagnetism and anisotropy of magnetic susceptibility

    NASA Astrophysics Data System (ADS)

    Fazzito, Sabrina Y.; Rapalini, Augusto E.; Cortés, José M.; Terrizzano, Carla M.

    2017-03-01

    Palaeomagnetic data from poorly consolidated to non-consolidated late Cenozoic sediments along the central segment of the active El Tigre Fault (Central-Western Precordillera of the San Juan Province, Argentina) demonstrate broad cumulative deformation up to 450 m from the fault trace and reveal clockwise and anticlockwise vertical-axis rotations of variable magnitude. This deformation has affected in different amounts Miocene to late Pleistocene samples and indicates a complex kinematic pattern. Several inherited linear structures in the shear zone that are oblique to the El Tigre Fault may have acted as block boundary faults. Displacement along these faults may have resulted in a complex pattern of rotations. The maximum magnitude of rotation is a function of the age of the sediments sampled, with largest values corresponding to middle Miocene-lower Pliocene deposits and minimum values obtained from late Pleistocene deposits. The kinematic study is complemented by low-field anisotropy of magnetic susceptibility data to show that the local strain regime suggests a N-S stretching direction, subparallel to the strike of the main fault.

  9. Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors.

    PubMed

    Danilova, Ludmila; Wang, Hao; Sunshine, Joel; Kaunitz, Genevieve J; Cottrell, Tricia R; Xu, Haiying; Esandrio, Jessica; Anders, Robert A; Cope, Leslie; Pardoll, Drew M; Drake, Charles G; Taube, Janis M

    2016-11-29

    Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database. We found that in some tumor types, PD-L2 expression is more closely linked to Th1/IFNG expression and PD-1 and CD8 signaling than PD-L1 In contrast, mutational load was not correlated with a Th1/IFNG gene signature in any tumor type. PD-L1, PD-L2, PD-1, CYT expression, and mutational density are all positive prognostic features in melanoma, and conditional inference modeling revealed PD-1/CYT expression (i.e., an inflamed tumor microenvironment) as the most impactful feature, followed by mutational density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti-PD-1/PD-L1 will benefit from tumor-type-specific, integrated, mRNA, protein, and genomic approaches.

  10. Vertical-axis rotations and deformation along the active strike-slip El Tigre Fault (Precordillera of San Juan, Argentina) assessed through palaeomagnetism and anisotropy of magnetic susceptibility

    NASA Astrophysics Data System (ADS)

    Fazzito, Sabrina Y.; Rapalini, Augusto E.; Cortés, José M.; Terrizzano, Carla M.

    2016-05-01

    Palaeomagnetic data from poorly consolidated to non-consolidated late Cenozoic sediments along the central segment of the active El Tigre Fault (Central-Western Precordillera of the San Juan Province, Argentina) demonstrate broad cumulative deformation up to ~450 m from the fault trace and reveal clockwise and anticlockwise vertical-axis rotations of variable magnitude. This deformation has affected in different amounts Miocene to late Pleistocene samples and indicates a complex kinematic pattern. Several inherited linear structures in the shear zone that are oblique to the El Tigre Fault may have acted as block boundary faults. Displacement along these faults may have resulted in a complex pattern of rotations. The maximum magnitude of rotation is a function of the age of the sediments sampled, with largest values corresponding to middle Miocene-lower Pliocene deposits and minimum values obtained from late Pleistocene deposits. The kinematic study is complemented by low-field anisotropy of magnetic susceptibility data to show that the local strain regime suggests a N-S stretching direction, subparallel to the strike of the main fault.

  11. CXCR6-CXCL16 axis promotes prostate cancer by mediating cytoskeleton rearrangement via Ezrin activation and αvβ3 integrin clustering

    PubMed Central

    Singh, Rajesh; Kapur, Neeraj; Mir, Hina; Singh, Nalinaksha; Lillard, James W.; Singh, Shailesh

    2016-01-01

    Cytoskeletal rearrangement is required for migration and invasion, which are the key steps of cancer metastasis. Ezrin and integrin co-ordinate these processes by regulating cellular adhesion and cytoskeletal polymerization-depolymerization. It is also well established that chemokine-chemokine receptor axis plays a crucial role in regulating cancer cell migration and invasion. In this study, we show involvement of CXC chemokine receptor 6 (CXCR6) and its only natural ligand CXCL16 in pathobiology of prostate cancer (PCa). CXCR6 is highly expressed in PCa tissues and cell lines (LNCaP and PC3), relative to normal tissue and cells. CXCR6 expression in PCa tissues correlated with higher Gleason score. Similarly, aggressive PCa cells (PC3) show high CXCR6 compared to less aggressive LNCaP. Besides, PC3 cells show higher MMPs expression compared to LNCaP cells following CXCL16 stimulation. Intriguingly, CXCR6-CXCL16 interaction in PCa cells promotes Ezrin activation, αvβ3 integrin clustering and capping at the leading edge in FAK/PI3K/PKC dependent manner, thereby modifying cellular adhesion as well as motility. Together these results demonstrate that CXCL16 stimulation changes cytoskeletal dynamics resulting in enhanced migration, invasion and adhesion to endothelial cells, ultimately enabling PCa cells to achieve their metastatic goal. PMID:26799186

  12. Thermal History of an Oceanic Core Complex, Atlantis Bank, Southwest Indian Ridge: Evidence for Hydrothermal Activity 2.6 Myr Off-Axis

    NASA Astrophysics Data System (ADS)

    Schwartz, J. J.; John, B. E.; Cheadle, M. J.; Reiners, P. W.; Baines, G.

    2004-12-01

    We report 26 new (U-Th)/He zircon dates from the Atlantis Bank Oceanic Core Complex (OCC), Southwest Indian Ridge. The low (~200 °C) closure temperature of the (U-Th)/He isotopic system, together with higher temperature (850 °C) crystallization ages from U-Pb zircon dating, allow us to constrain the timescales and rates of lower crustal cooling in oceanic crust. Samples from the detachment fault surface exposed at the sea floor, indicate that the denuded crust cooled rapidly through 200 °C in <1 Myr, yielding mean cooling rates >1200 °C/Myr, consistent with existing models for cooling of oceanic crust. However, samples collected along post-detachment, N-S- and E-W-trending fault scarps record (U-Th)/He ages averaging 2.6 Myr younger than their corresponding igneous crystallization ages. These ages are inconsistent with steady-state conductive cooling models for lower oceanic crust and cannot be explained by simple monotonic cooling. Instead, they record cooling through 200 °C when the crust was well outside the rift valley, ~36 km off-axis assuming a half spreading rate of 14km/Myr. These samples display extensive post-crystallization greenschist-facies alteration and contain metamorphic mineral assemblages of chlorite + actinolite ± hornblende ± epidote ± serpentine ± clay, consistent with hydrothermal alteration. Therefore, we suggest that these anomalously young (U-Th)/He zircon ages record localized thermal heating events associated with high- temperature (>300 °C) hydrothermal fluid flow along transform-parallel and transform-normal faults that were active outside the rift valley during transtension along the bounding Atlantis II transform fault. A significant component of the heat driving hydrothermal fluid flow may have been derived from underplated mafic magmas emplaced during transtension. The young (U-Th)/He ages therefore delimit zones of hydrothermal upflow, and record evidence of protracted hydrothermal circulation up to ~3 Myr off-axis at

  13. Thermal History of an Oceanic Core Complex, Atlantis Bank, Southwest Indian Ridge: Evidence for Hydrothermal Activity 2.6 Myr Off-Axis

    NASA Astrophysics Data System (ADS)

    Schwartz, J. J.; John, B. E.; Cheadle, M. J.; Reiners, P. W.; Baines, G.

    2007-12-01

    We report 26 new (U-Th)/He zircon dates from the Atlantis Bank Oceanic Core Complex (OCC), Southwest Indian Ridge. The low (~200 °C) closure temperature of the (U-Th)/He isotopic system, together with higher temperature (850 °C) crystallization ages from U-Pb zircon dating, allow us to constrain the timescales and rates of lower crustal cooling in oceanic crust. Samples from the detachment fault surface exposed at the sea floor, indicate that the denuded crust cooled rapidly through 200 °C in <1 Myr, yielding mean cooling rates >1200 °C/Myr, consistent with existing models for cooling of oceanic crust. However, samples collected along post-detachment, N-S- and E-W-trending fault scarps record (U-Th)/He ages averaging 2.6 Myr younger than their corresponding igneous crystallization ages. These ages are inconsistent with steady-state conductive cooling models for lower oceanic crust and cannot be explained by simple monotonic cooling. Instead, they record cooling through 200 °C when the crust was well outside the rift valley, ~36 km off-axis assuming a half spreading rate of 14km/Myr. These samples display extensive post-crystallization greenschist-facies alteration and contain metamorphic mineral assemblages of chlorite + actinolite ± hornblende ± epidote ± serpentine ± clay, consistent with hydrothermal alteration. Therefore, we suggest that these anomalously young (U-Th)/He zircon ages record localized thermal heating events associated with high- temperature (>300 °C) hydrothermal fluid flow along transform-parallel and transform-normal faults that were active outside the rift valley during transtension along the bounding Atlantis II transform fault. A significant component of the heat driving hydrothermal fluid flow may have been derived from underplated mafic magmas emplaced during transtension. The young (U-Th)/He ages therefore delimit zones of hydrothermal upflow, and record evidence of protracted hydrothermal circulation up to ~3 Myr off-axis at

  14. Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.

    PubMed

    Hampl, V; Herget, J; Bíbová, J; Baňasová, A; Husková, Z; Vaňourková, Z; Jíchová, Š; Kujal, P; Vernerová, Z; Sadowski, J; Červenka, L

    2015-01-01

    The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT₁) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT₁receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT₁receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.

  15. HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing

    PubMed Central

    Todkar, Aniruddha; Granholm, Linnea; Aljumah, Mujtaba; Nilsson, Kent W.; Comasco, Erika; Nylander, Ingrid

    2016-01-01

    The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation

  16. Volcanic activities in the Southern part of East African rift initiation: Melilitites and nephelinites from the Manyara Basin (North Tanzania rift axis)

    NASA Astrophysics Data System (ADS)

    Baudouin, Celine; Parat, Fleurice; Tiberi, Christel; Gautier, Stéphanie; Peyrat, Sophie

    2016-04-01

    The East African Rift exposes different stages of plate boundary extension, from the initiation of the rift (North (N) Tanzania) to oceanic accretion (Afar). The N Tanzania rift-axis (north-south (S) trend) is divided into 2 different volcanic and seismic activities: (1) the Natron basin (N) with shallow seismicity and intense volcanism and (2) the Manyara basin (S) with deep crustal earthquakes and sparse volcanism. The Natron basin is characterized by extinct volcanoes (2 Ma-0.75 Ma) and active volcano (Oldoinyo Lengai) and a link between seismicity and volcanism has been observed during the Oldoinyo Lengai crisis in 2007. In the S part of the N Tanzanian rift, volcanoes erupted in the Manyara basin between 0.4 and 0.9 Ma. In this study, we used geochemical signature of magmas and deep fluids that percolate into the lithosphere beneath Manyara basin, to define the compositions of magmas and fluids at depth beneath the S part of the N Tanzania rift, compare to the Natron basin and place constrain on the volcanic and seismic activities. The Manyara basin has distinct volcanic activities with mafic magmas as melilitites (Labait) and Mg-nephelinites (carbonatite, Kwaraha), and more differentiated magmas as Mg-poor nephelinites (Hanang). Melilitites and Mg-nephelinites are primary magmas with olivine, clinopyroxene (cpx), and phlogopite recording high-pressure crystallization environment, (melilitites >4 GPa and Mg-nephelinites>1 GPa) with high volatile contents (whole rock: 0.7-4.6 wt% CO2, 0.1-0.3 wt% F and 0.1 wt% Cl). FTIR analyses of olivine constrained the water content of Labait and Kwaraha magmas at 0.1 and 0.4 wt% H2O, respectively. Geochemical modelling suggests that mafic magmas result from a low degree of partial melting (1-2%) of a peridotitic source with garnet and phlogopite (high Tb/Yb (>0.6) and Rb/Sr (0.03-0.12) ratio). Mg-poor nephelinites from Hanang volcano crystallized cpx, Ti-garnet, and nepheline as phenocrysts. Magmas result from fractional

  17. Genetic variants within the dopaminergic system interact to modulate endocrine stress reactivity and recovery.

    PubMed

    Alexander, Nina; Osinsky, Roman; Mueller, Eva; Schmitz, Anja; Guenthert, Sarah; Kuepper, Yvonne; Hennig, Juergen

    2011-01-01

    Catecholamines modulate endocrine stress reactivity by affecting regulatory influences of extra-hypothalamic brain structures on hypothalamus-pituitary-adrenal (HPA)-axis. Therefore, we aimed to investigate combined effects of functional allelic variations that affect dopamine availability in both cortical (COMT Val¹⁵⁸Met polymorphism) and subcortical (DAT1 VNTR) brain regions on HPA-axis reactivity to psychosocial stress. By using a standardized laboratory stress task (public speaking) we obtained saliva cortisol samples during stress exposure and an extended recovery period in 100 healthy male adults. We report for the first time significant epistasis between COMT Val¹⁵⁸Met and DAT1 VNTR on cortisol response patterns. Subjects homozygous for both the Met¹⁵⁸ and the 10-repeat allele of DAT1 VNTR were characterized by markedly elevated cortisol reactivity and impaired stress recovery compared to all other groups. Our results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes.

  18. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    PubMed Central

    Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  19. Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus).

    PubMed

    Harris, Breanna N; Saltzman, Wendy

    2013-06-01

    Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (∼18-20months) and young (∼4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and

  20. Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis.

    PubMed

    Davari, S; Talaei, S A; Alaei, H; Salami, M

    2013-06-14

    Diabetes mellitus-induced metabolic disturbances underlie the action of many systems including some higher functions of the brain such as learning and memory. Plenty of evidence supports the effects of probiotics on the function of many systems including the nervous system. Here we report the effect of probiotics treatment on the behavioral and electrophysiological aspects of learning and memory disorders. Diabetic rats were made through intraperitoneal injection of streptozocin. The control and diabetic rats were fed with either normal regimen (control rats recieving normal regimen (CO) and diabetics rats receiving normal regimen (DC), respectively) or normal regimen plus probiotic supplementation for 2months (control rats receiving probiotic supplementation (CP) and diabetics rats recieving probiotic supplementation (DP), respectively). The animals were first introduced to spatial learning task in the Morris water maze. Then, in electrophysiological experiments, stimulating the Schaffer collaterals the basic and potentiated excitatory postsynaptic potential (EPSPs) were recorded in the CA1 area of the hippocampus. Finally, the serum levels of glucose, insulin, superoxide dismutase and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. We found that probiotics administration considerably improved the impaired spatial memory in the diabetic animals. The probiotics supplementation in the diabetic rats recovered the declined basic synaptic transmission and further restored the hippocampal long-term potentiation (LTP). While the probiotics administration enhanced the activation of superoxide dismutase and increased the insulin level of serum it decreased both the glucose level of serum and the 8-OHdG factor. From the present results we concluded that probiotics efficiently reverse deteriorated brain functions in the levels of cognitive performances and their proposed synaptic mechanisms in diabetes mellitus. These considerations imply on the necessity of an optimal

  1. Activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis at midgestation by estrogen-induced changes in placental corticosteroid metabolism

    SciTech Connect

    Pepe, G.J.; Waddell, B.J.; Albrecht, E.D. )

    1990-12-01

    We have hypothesized that the change in placental cortisol (F)-cortisone (E) metabolism induced by estrogen late in gestation is important to activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis, culminating in the ontogenesis of de novo F secretion by the fetal adrenal. The present study tested this hypothesis in vivo by comparing the proportion of F in the fetus derived via maternal and fetal production on day 100 (n = 7; term = day 184) and day 165 (n = 4) in untreated baboons and on day 100 in baboons (n = 9) in which 50-mg pellets of androstenedione were implanted sc in the mother in increasing numbers (i.e. two on day 70, four on day 78, six on day 86, and eight on day 94) to increase placental estrogen production. Maternal, uterine, and umbilical venous samples were collected during constant maternal infusion (120 min) of (3H)F/(14C)E, endogenous and radiolabeled F/E content was determined, and corticosteroid dynamics were quantified. The MCR and peripheral interconversion of F and E as well as the production rate of F were unaltered in the mother. However, at midgestation, androstenedione increased (P less than 0.05) estrogen by 62% and altered transuterofeto placental F-E metabolism from preferential reduction of E to preferential oxidation of F, a pattern similar to that at term. In untreated baboons, on day 100 none of the F in the fetus was due to fetal production, whereas by day 165, 49 +/- 6% was of fetal origin. In animals treated with androstenedione at midgestation, 22 +/- 4% of fetal F was derived de novo within the fetus. Thus, production of F by the fetus was negligible on day 100, increased near term in association with an increase in transplacental oxidation of F to E, and was induced at midgestation in baboons in which placental F-E metabolism was altered by an increase in estrogen production.

  2. Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis.

    PubMed

    Nepal, Saroj; Park, Pil-Hoon

    2013-10-01

    Hepatocellular apoptosis is an important pathological entity of alcoholic liver disease. Previously, we have shown that globular adiponectin (gAcrp) protects liver cells from ethanol-induced apoptosis by modulating an array of signaling pathways. In the present study, we investigated the role of autophagy induction by gAcrp in the suppression of ethanol-induced apoptosis and its potential mechanism(s) in liver cells. Here, we demonstrated that gAcrp significantly restores ethanol-induced suppression of autophagy-related genes, including Beclin-1 and microtubule-associated protein light chain (LC3B) both in primary rat hepatocytes and human hepatoma cell line (HepG2). Globular adiponectin also restored autophagosome formation suppressed by ethanol treatment in HepG2. Furthermore, inhibition of gAcrp-induced autophagic process by knock-down of LC3B prevented protection from ethanol-induced apoptosis. In particular, the autophagic process induced by gAcrp was involved in the suppression of ethanol-induced activation of caspase-8 and expression of Bax. Moreover, knock-down of AMPK by small interfering RNA (siRNA) blocked gAcrp-induced expression of genes related to autophagy, which in turn prevented protection from ethanol-induced apoptosis, suggesting that AMPK plays an important role in the induction of autophagy and protection of liver cells by gAcrp. Finally, we also showed that gAcrp treatment induces translocation of the forkhead box O member protein, FoxO3A, into the nucleus, which may play a role in the induction of autophagy-related genes. Taken together, our data demonstrated that gAcrp protects liver cells from ethanol-induced apoptosis via induction of autophagy. Further, the AMPK-FoxO3A axis plays a cardinal role in gAcrp-induced autophagy and subsequent inhibition of ethanol-induced apoptosis.

  3. Protein kinase Cα suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGFβ signaling axis

    PubMed Central

    Hill, KS; Erdogan, E; Khoor, A; Walsh, MP; Leitges, M; Murray, NR; Fields, AP

    2014-01-01

    Protein kinase C alpha (PKCα) can activate both pro- and anti-tumorigenic signaling depending upon cellular context. Here, we investigated the role of PKCα in lung tumorigenesis in vivo. Gene expression data sets revealed that primary human non-small lung cancers (NSCLC) express significantly decreased PKCα levels, indicating that loss of PKCα expression is a recurrent event in NSCLC. We evaluated the functional relevance of PKCα loss during lung tumorigenesis in three murine lung adenocarcinoma models (LSL-Kras, LA2-Kras and urethane exposure). Genetic deletion of PKCα resulted in a significant increase in lung tumor number, size, burden and grade, bypass of oncogene-induced senescence, progression from adenoma to carcinoma and a significant decrease in survival in vivo. The tumor promoting effect of PKCα loss was reflected in enhanced Kras-mediated expansion of bronchio-alveolar stem cells (BASCs), putative tumor-initiating cells, both in vitro and in vivo. LSL-Kras/Prkca−/− mice exhibited a decrease in phospho-p38 MAPK in BASCs in vitro and in tumors in vivo, and treatment of LSL-Kras BASCs with a p38 inhibitor resulted in increased colony size indistinguishable from that observed in LSL-Kras/Prkca−/− BASCs. In addition, LSL-Kras/Prkca−/− BASCs exhibited a modest but reproducible increase in TGFβ1 mRNA, and addition of exogenous TGFβ1 to LSL-Kras BASCs results in enhanced growth similar to untreated BASCs from LSL-Kras/Prkca−/− mice. Conversely, a TGFβR1 inhibitor reversed the effects of PKCα loss in LSL-Kras/Prkca−/−BASCs. Finally, we identified the inhibitors of DNA binding (Id) Id1–3 and the Wilm’s Tumor 1 as potential downstream targets of PKCα-dependent tumor suppressor activity in vitro and in vivo. We conclude that PKCα suppresses tumor initiation and progression, at least in part, through a PKCα-p38MAPK-TGFβ signaling axis that regulates tumor cell proliferation and Kras-induced senescence. Our results provide the

  4. Sex differences in the HPA axis.

    PubMed

    Goel, Nirupa; Workman, Joanna L; Lee, Tiffany T; Innala, Leyla; Viau, Victor

    2014-07-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

  5. Depression during pregnancy and postpartum: contribution of stress and ovarian hormones.

    PubMed

    Brummelte, S; Galea, Liisa A M

    2010-06-30

    Depression is the most common psychiatric disease among women, exhibiting a prevalence which is 2-3x higher than in men. The postpartum period is considered the time of greatest risk for women to develop major depression and postpartum depression affects approximately 15% of women. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is the most prominent endocrine change seen in depression and normalization of the HPA axis is a major target of recent therapies. Females exhibit different stress sensitivities than males which might contribute to their increased vulnerability for depression. Maternal stress or depression during pregnancy and/or postpartum is particularly concerning as early developmental influences can affect the maturation of the offspring as well as the mental health of the mother. Despite the urgent need for more information on depression in females, especially during pregnancy and postpartum, most animal models of depression have utilized only males. Given the sex differences in incidence of depression and treatment, it is vitally important to create or validate animal models of depression in females. This review will focus on the association between stress, glucocorticoids and depression in humans, with a special focus on depression in women during pregnancy and postpartum and on animal models of postpartum depression and the consequences for the offspring.

  6. Circadian Rhythm Hypotheses of Mixed Features, Antidepressant Treatment Resistance, and Manic Switching in Bipolar Disorder

    PubMed Central

    Son, Gi-Hoon; Geum, Dongho

    2013-01-01

    Numerous hypotheses have been put forth over the years to explain the development of bipolar disorder. Of these, circadian rhythm hypotheses have gained much importance of late. While the hypothalamus-pituitary-adrenal (HPA) axis hyperactivation hypothesis and the monoamine hypothesis somewhat explain the pathogenic mechanism of depression, they do not provide an explanation for the development of mania/hypomania. Interestingly, all patients with bipolar disorder display significant disruption of circadian rhythms and sleep/wake cycles throughout their mood cycles. Indeed, mice carrying the Clock gene mutation exhibit an overall behavioral profile that is similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, and lower anxiety. It was recently reported that monoamine signaling is in fact regulated by the circadian system. Thus, circadian rhythm instability, imposed on the dysregulation of HPA axis and monoamine system, may in turn increase individual susceptibility for switching from depression to mania/hypomania. In addition to addressing the pathophysiologic mechanism underlying the manic switch, circadian rhythm hypotheses can explain other bipolar disorder-related phenomena such as treatment resistant depression and mixed features. PMID:24302944

  7. Acute stress impairs recall after interference in older people, but not in young people.

    PubMed

    Hidalgo, Vanesa; Almela, Mercedes; Villada, Carolina; Salvador, Alicia

    2014-03-01

    Stress has been associated with negative changes observed during the aging process. However, very little research has been carried out on the role of age in acute stress effects on memory. We aimed to explore the role of age and sex in the relationship between hypothalamus-pituitary-adrenal axis (HPA-axis) and sympathetic nervous system (SNS) reactivity to psychosocial stress and short-term declarative memory performance. To do so, sixty-seven participants divided into two age groups (each group with a similar number of men and women) were exposed to the Trier Social Stress Test (TSST) and a control condition in a crossover design. Memory performance was assessed by the Rey Auditory Verbal Learning Test (RAVLT). As expected, worse memory performance was associated with age; but more interestingly, the stressor impaired recall after interference only in the older group. In addition, this effect was negatively correlated with the alpha-amylase over cortisol ratio, which has recently been suggested as a good marker of stress system dysregulation. However, we failed to find sex differences in memory performance. These results show that age moderates stress-induced effects on declarative memory, and they point out the importance of studying both of the physiological systems involved in the stress response together.

  8. Why is the topic of the biological embedding of experiences important for translation?

    PubMed

    Rutter, Michael

    2016-11-01

    Translational research focuses on innovation in healthcare settings, but this is a two-way process that may have implications for either treatment or prevention. Smoking and lung cancer and the fetal alcohol syndrome are used as examples. Experimental medicine that budges basic and clinical science often constitutes a key way forward. Areas of scientific progress and challenge are discussed in relation to drug action, social cognition, cognitive neuroscience, molecular genetics, gene-environment interaction, and epigenetics. Key concepts and challenges in relation to stress include toxicity, allostatic load, the hypothalamus-pituitary-adrenal axis, and objectives versus subjective stress. The reasons for the need to test causal inferences are discussed. Various kinds of "natural experiments" are discussed in illustration using the assisted conception design, the discordant monozygotic twin design, and the study of universal exposure. Animal models are discussed in relation to enrichment and deprivation effects and the effects of infant separation experiences, epigenetic effects, and the biological embedding of experiences. Translational issues are discussed in relation to the hypothalamic-pituitary-adrenal axis, epigenetics, and inflammation. In conclusion, it is suggested that there are immediate possibilities for experimental medicine but caution is needed with respect to moving into translation too quickly.

  9. Clinical applications of cortisol measurements in hair.

    PubMed

    Wester, Vincent L; van Rossum, Elisabeth F C

    2015-10-01

    Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cyclic hypercortisolism. HCC have also been shown to increase with psychological stressors, including major life events, as well as physical stressors, such as endurance exercise and shift work. Initial studies show that HCC may be increased in depression, but decreased in general anxiety disorder. In posttraumatic stress disorder, changes in HCC seem to be dependent on the type of traumatic experience and the time since traumatization. Increased hair cortisol is consistently linked to obesity, metabolic syndrome and cardiovascular disease. Potentially, HCC could form a future marker for cardiovascular risk stratification, as well as serve as a treatment target.

  10. Reproductive aspects in female rats exposed prenatally to hydrocortisone.

    PubMed

    Piffer, R C; Pereira, O C M

    2004-10-01

    We investigated the effects of hydrocortisone during the prenatal period and its later repercussion on reproductive aspects of female rats. Pregnant rats were treated (s.c.) with hydrocortisone acetate, at 1.5 mg/day on the 17th, 18th, and 19th days of pregnancy. Although the present study was not intended to identify mechanisms of toxicity, the treatment with hydrocortisone in the last period of pregnancy presented no signs of toxicity. The efficacy of the hydrocortisone in reducing the adrenal wet mass and plasma corticosterone levels immediately after delivery in both the treated mothers and in respective pups at birth may indicate impairment of the hypothalamus-pituitary-adrenal axis. In addition, the treatment with hydrocortisone did not interfere in the development of the female descendants until puberty. However, it affected the estrous cycle and fertility. Probably, the prenatal exposure to corticosteroids had altered at least partially the hypothalamus-pituitary-gonadal axis, resulting in the damages observed in adult life. These results indicate that the use of the hydrocortisone at a dose that apparently does not endanger the neonate led to undesirable effects in the adult reproductive phase, resulting in later deleterious alteration of the reproductive physiology in female rats.

  11. Stress, memory, and the hippocampus.

    PubMed

    Wingenfeld, Katja; Wolf, Oliver T

    2014-01-01

    Stress hormones, i.e. cortisol in human and cortisone in rodents, influence a wide range of cognitive functions, including hippocampus-based declarative memory performance. Cortisol enhances memory consolidation, but impairs memory retrieval. In this context glucocorticoid receptor sensitivity and hippocampal integrity play an important role. This review integrates findings on the relationships between the hypothalamus-pituitary-adrenal (HPA) axis, one of the main coordinators of the stress response, hippocampus, and memory. Findings obtained in healthy participants will be compared with selected mental disorders, including major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and borderline personality disorder (BPD). These disorders are characterized by alterations of the HPA axis and hippocampal dysfunctions. Interestingly, the acute effects of stress hormones on memory in psychiatric patients are different from those found in healthy humans. While cortisol administration has failed to affect memory retrieval in patients with MDD, patients with PTSD and BPD have been found to show enhanced rather than impaired memory retrieval after hydrocortisone. This indicates an altered sensitivity to stress hormones in these mental disorders.

  12. The aging reproductive neuroendocrine axis.

    PubMed

    Brann, Darrell W; Mahesh, Virendra B

    2005-04-01

    It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.

  13. Vertical axis windmill

    SciTech Connect

    Campbell, J.S.

    1980-04-08

    A vertical axis windmill is described which involves a rotatable central vertical shaft having horizontal arms pivotally supporting three sails that are free to function in the wind like the main sail on a sail boat, and means for disabling the sails to allow the windmill to be stopped in a blowing wind.

  14. Reduced hypothalamic-pituitary-adrenal axis activity in chronic multi-site musculoskeletal pain: partly masked by depressive and anxiety disorders

    PubMed Central

    2014-01-01

    Background Studies on hypothalamic-pituitary-adrenal axis (HPA-axis) function amongst patients with chronic pain show equivocal results and well-controlled cohort studies are rare in this field. The goal of our study was to examine whether HPA-axis dysfunction is associated with the presence and the severity of chronic multi-site musculoskeletal pain. Methods Data are from the Netherlands Study of Depression and Anxiety including 1125 subjects with and without lifetime depressive and anxiety disorders. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multi-site musculoskeletal pain. Subjects were categorized into a chronic multi-site musculoskeletal pain group (n = 471) and a control group (n = 654). Salivary cortisol samples were collected to assess HPA-axis function (awakening level, 1-h awakening response, evening level, diurnal slope and post-dexamethasone level). Results In comparison with the control group, subjects with chronic multi-site musculoskeletal pain showed significantly lower cortisol level at awakening, lower evening level and a blunted diurnal slope. Lower cortisol level at awakening and a blunted diurnal slope appeared to be restricted to those without depressive and/or anxiety disorders, who also showed a lower 1-h awakening response. Conclusions Our results suggest hypocortisolemia in chronic multi-site musculoskeletal pain. However, if chronic pain is accompanied by a depressive or anxiety disorder, typically related to hypercortisolemia, the association between cortisol levels and chronic multi-site musculoskeletal pain appears to be partly masked. Future studies should take psychopathology into account when examining HPA-axis function in chronic pain. PMID:25007969

  15. 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling.

    PubMed

    Chen, Huang-Hui; Chen, Yu-Tsen; Huang, Yen-Wen; Tsai, Hui-Ju; Kuo, Ching-Chuan

    2012-03-15

    The Nrf2/ARE pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and has been considered a potential target for cancer chemoprevention because it eliminates harmful reactive oxygen species or reactive intermediates generated from carcinogens. The objectives of this study were to identify novel Nrf2/ARE activators and to investigate the mechanistic signaling pathway involved in the activation of Nrf2-mediated cytoprotective effects against oxidative-induced cell injury. A stable ARE-driven luciferase reporter cell line was established to screen a potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (α-γ) double-cyclized type of lignan obtained from adlay (Coix lachryma-jobi L. var. ma-yuen Stapf), activates ARE-driven luciferase activity more effectively than the classical ARE activator tert-butylhydroquinone. 4-KPR treatment resulted in a transient increase in AKT phosphorylation and subsequent phosphorylation and nuclear translocation of Nrf2, along with increased expression of ARE-dependent cytoprotective genes, such as heme oxygenase-1 (HO-1), aldo-keto reductases, and glutathione synthetic enzyme. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via upregulation of HO-1. Inhibition of PI3K/AKT signaling by chemical inhibitors or RNA interference not only suppressed 4-KPR-induced Nrf2/HO-1 activation, but also eliminated the cytoprotective effect against oxidative damage. These observations in an ARE-regulated gene system suggest that 4-KPR is a novel Nrf2/ARE-mediated transcription activator, activates the Nrf2/HO-1 axis, and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling.

  16. Multiple axis reticle

    NASA Technical Reports Server (NTRS)

    Barns, Chris E. (Inventor); Gunter, William D. (Inventor)

    1990-01-01

    A reticle permits the alignment of three orthogonal axes (X, Y and Z) that intersect at a common target point. Thin, straight filaments are supported on a frame. The filaments are each contained in a different orthogonal plane (S sub xy, S sub xz, and S sub yz) and each filament intersects two of the three orthogonal axes. The filaments, as viewed along the frame axis, give the appearance of a triangle with a V extending from each triangle vertex. When axial alignment is achieved, the filament portions adjacent to a triangle vertex are seen (along the axis of interest) as a right-angle cross, whereas these filament portions are seen to intersect at an oblique angle when axial misalignment occurs. The reticle is open in the region near the target point leaving ample space for alignment aids such as a pentaprism or a cube mirror.

  17. Epigenetic Alterations Associated with War Trauma and Childhood Maltreatment.

    PubMed

    Ramo-Fernández, Laura; Schneider, Anna; Wilker, Sarah; Kolassa, Iris-Tatjana

    2015-10-01

    Survivors of war trauma or childhood maltreatment are at increased risk for trauma-spectrum disorders such as post-traumatic stress disorder (PTSD). In addition, traumatic stress has been associated with alterations in the neuroendocrine and the immune system, enhancing the risk for physical diseases. Traumatic experiences might even affect psychological as well as biological parameters in the next generation, i.e. traumatic stress might have transgenerational effects. This article outlines how epigenetic processes, which represent a pivotal biological mechanism for dynamic adaptation to environmental challenges, might contribute to the explanation of the long-lasting and transgenerational effects of trauma. In particular, epigenetic alterations in genes regulating the hypothalamus-pituitary-adrenal axis as well as the immune system have been observed in survivors of childhood and adult trauma. These changes could result in enduring alterations of the stress response as well as the physical health risk. Furthermore, the effects of parental trauma could be transmitted to the next generation by parental distress and the pre- and postnatal environment, as well as by epigenetic marks transmitted via the germline. While epigenetic research has a high potential of advancing our understanding of the consequences of trauma, the findings have to be interpreted with caution, as epigenetics only represent one piece of a complex puzzle of interacting biological and environmental factors. Copyright © 2015 John Wiley & Sons, Ltd.

  18. Learning, memory and brain plasticity in posttraumatic stress disorder: context matters.

    PubMed

    Flor, Herta; Nees, Frauke

    2014-01-01

    We review evidence from our laboratory that suggests that in addition to enhanced cue conditioning and delayed cue extinction disturbed contextual learning may play an important role in the development and maintenance of posttraumatic stress disorder. Based on data from a longitudinal sample of rescue workers at high risk for posttraumatic stress disorder and data on single trauma exposed persons with and without posttraumatic stress disorder we show the crucial role of the hippocampus for contextual memory and impaired contextual learning along with enhanced cue conditioning and delayed extinction in PTSD. Using structural and functional magnetic resonance imaging we confirmed animal data on the role of the hippocampus in contextual and the importance of the amygdala in cue conditioning and the role of the frontal cortex in extinction. Genetic variants related to the modulation of the hypothalamus-pituitary-adrenal axis are associated with cue and genetic variants related to calcium signaling and memory processes and the regulation of the stress response are associated with context conditioning. These genes also play a role in PTSD. Further research needs to identify the predictive nature of these learning processes and plastic brain changes and their interaction with genetic characteristics changes for the transition into PTSD and its maintenance. A further focus needs to be on the identification of learning and memory mechanisms and the associated brain plasticity across disorders.

  19. The Anti-Inflammatory Effects of Acupuncture and Their Relevance to Allergic Rhinitis: A Narrative Review and Proposed Model

    PubMed Central

    McDonald, John L.; Cripps, Allan W.; Smith, Peter K.; Smith, Caroline A.; Xue, Charlie C.; Golianu, Brenda

    2013-01-01

    Classical literature indicates that acupuncture has been used for millennia to treat numerous inflammatory conditions, including allergic rhinitis. Recent research has examined some of the mechanisms underpinning acupuncture's anti-inflammatory effects which include mediation by sympathetic and parasympathetic pathways. The hypothalamus-pituitary-adrenal (HPA) axis has been reported to mediate the antioedema effects of acupuncture, but not antihyperalgesic actions during inflammation. Other reported anti-inflammatory effects of acupuncture include an antihistamine action and downregulation of proinflammatory cytokines (such as TNF-α, IL-1β, IL-6, and IL-10), proinflammatory neuropeptides (such as SP, CGRP, and VIP), and neurotrophins (such as NGF and BDNF) which can enhance and prolong inflammatory response. Acupuncture has been reported to suppress the expression of COX-1, COX-2, and iNOS during experimentally induced inflammation. Downregulation of the expression and sensitivity of the transient receptor potential vallinoid 1 (TRPV1) after acupuncture has been reported. In summary, acupuncture may exert anti-inflammatory effects through a complex neuro-endocrino-immunological network of actions. Many of these generic anti-inflammatory effects of acupuncture are of direct relevance to allergic rhinitis; however, more research is needed to elucidate specifically how immune mechanisms might be modulated by acupuncture in allergic rhinitis, and to this end a proposed model is offered to guide further research. PMID:23476696

  20. The anti-inflammatory effects of acupuncture and their relevance to allergic rhinitis: a narrative review and proposed model.

    PubMed

    McDonald, John L; Cripps, Allan W; Smith, Peter K; Smith, Caroline A; Xue, Charlie C; Golianu, Brenda

    2013-01-01

    Classical literature indicates that acupuncture has been used for millennia to treat numerous inflammatory conditions, including allergic rhinitis. Recent research has examined some of the mechanisms underpinning acupuncture's anti-inflammatory effects which include mediation by sympathetic and parasympathetic pathways. The hypothalamus-pituitary-adrenal (HPA) axis has been reported to mediate the antioedema effects of acupuncture, but not antihyperalgesic actions during inflammation. Other reported anti-inflammatory effects of acupuncture include an antihistamine action and downregulation of proinflammatory cytokines (such as TNF- α , IL-1 β , IL-6, and IL-10), proinflammatory neuropeptides (such as SP, CGRP, and VIP), and neurotrophins (such as NGF and BDNF) which can enhance and prolong inflammatory response. Acupuncture has been reported to suppress the expression of COX-1, COX-2, and iNOS during experimentally induced inflammation. Downregulation of the expression and sensitivity of the transient receptor potential vallinoid 1 (TRPV1) after acupuncture has been reported. In summary, acupuncture may exert anti-inflammatory effects through a complex neuro-endocrino-immunological network of actions. Many of these generic anti-inflammatory effects of acupuncture are of direct relevance to allergic rhinitis; however, more research is needed to elucidate specifically how immune mechanisms might be modulated by acupuncture in allergic rhinitis, and to this end a proposed model is offered to guide further research.

  1. Adverse childhood experiences (ACEs), genetic polymorphisms and neurochemical correlates in experimentation with psychotropic drugs among adolescents.

    PubMed

    Somaini, L; Donnini, C; Manfredini, M; Raggi, M A; Saracino, M A; Gerra, M L; Amore, M; Leonardi, C; Serpelloni, G; Gerra, G

    2011-08-01

    Epidemiological and clinical data show frequent associations between adverse childhood experiences (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences suggests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function induced by childhood traumatic experiences and emotional neglect could constitute one of the essential biological changes implementing substance abuse vulnerability. Moreover, genotype variables and its environment interactions have been associated with an increased risk for early onset substance abuse. In this paper we present several data that support the hypothesis of the involvement of hypothalamus-pituitary-adrenal (HPA) axis in mediating the combined effect of early adverse experiences and gene variants affecting neurotransmission. The presented data also confirm the relationship between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective measures of neglect during childhood on the other hand: the higher the mother and father neglect (CECA-Q) scores are, the higher the plasma levels of the two HPA hormones are. Furthermore, such positive relationship has been proved to be particularly effective and important when associated with the "S" promoter polymorphism of the gene encoding the 5-HTT transporter, both in homozygote and heterozygote individuals.

  2. Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder.

    PubMed

    Martín-Blanco, Ana; Ferrer, Marc; Soler, Joaquim; Salazar, Juliana; Vega, Daniel; Andión, Oscar; Sanchez-Mora, Cristina; Arranz, Maria Jesús; Ribases, Marta; Feliu-Soler, Albert; Pérez, Víctor; Pascual, Juan Carlos

    2014-10-01

    The hypothalamus-pituitary-adrenal axis (HPA) is essential in the regulation of stress responses. Increased methylation of the promoter region of the glucocorticoid receptor gene (NR3C1) has been described both in subjects with history of childhood trauma and in patients with Borderline Personality Disorder (BPD). However, no data on the possible association between a higher methylation of this gene and clinical severity is available. The aim of this study was to evaluate the association between NR3C1 methylation status, the history of childhood trauma, and current clinical severity in subjects with BPD. A sample of 281 subjects with BPD (diagnosed by SCID-II and DIB-R semi-structured diagnostic interviews) was recruited. Clinical variables included previous hospitalizations, self-injurious behavior, and self-reported history of childhood trauma. DNA was extracted from peripheral blood. The results indicated a significant positive correlation between NR3C1 methylation status and childhood maltreatment (specifically physical abuse). In addition, a positive correlation between methylation status and clinical severity (DIB-R total score and hospitalizations) was observed. These findings suggest that NR3C1 methylation in subjects with BPD may be associated not only with childhood trauma but also with clinical severity, adding new evidence to the involvement of gene-environment interactions in this disorder.

  3. Cortisol responses to naturalistic and laboratory stress in student teachers: comparison with a non-stress control day.

    PubMed

    Wolfram, Maren; Bellingrath, Silja; Feuerhahn, Nicolas; Kudielka, Brigitte M

    2013-04-01

    Ambulatory assessments of hypothalamus-pituitary-adrenal axis responses to acute natural stressors yield evidence on stress regulation with high ecological validity. Sampling of salivary cortisol is a standard technique in this field. In 21 healthy student teachers, we assessed cortisol responses to a demonstration lesson. On a control day, sampling was repeated at analogous times. Additionally, the cortisol awakening response (CAR) was assessed on both days. Participants were also exposed to a laboratory stressor, the Trier Social Stress Test, and rated their individual levels of chronic work stress. In pre-to-post-stress assessment, cortisol levels declined after the lesson. However, post-stress cortisol levels were significantly higher compared with those on the control day. Also, the Trier Social Stress Test yielded higher cortisol responses when using the control day as reference baseline. Associations between the CAR and chronic stress measures were observed solely on the control day. There were no significant associations between cortisol responses to the natural and laboratory stressors. Our results indicate that a control day might be an important complement in laboratory but especially in ambulatory stress research. Furthermore, associations between chronic stress measures and the CAR might be obscured by acute stress exposure. Finally, responses to the laboratory stressor do not seem to mirror natural stress responses.

  4. Glia in the cytokine-mediated onset of depression: fine tuning the immune response

    PubMed Central

    Jo, Wendy K.; Zhang, Yuanyuan; Emrich, Hinderk M.; Dietrich, Detlef E.

    2015-01-01

    Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system’s (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted. PMID:26217190

  5. Glucocorticoid Induces Incoordination between Glutamatergic and GABAergic Neurons in the Amygdala

    PubMed Central

    Cui, Shan; Wang, Jin-Hui

    2016-01-01

    Background Stressful life leads to mood disorders. Chronic mild stress is presumably major etiology for depression, and acute severe stress leads to anxiety. These stressful situations may impair hypothalamus-pituitary-adrenal axis and in turn induce synapse dysfunction. However, it remains elusive how the stress hormones mess up subcellular compartments and interactions between excitatory and inhibitory neurons, which we have investigated in mouse amygdala, a structure related to emotional states. Methods and Results Dexamethasone was chronically given by intraperitoneal injection once a day for one week or was acutely washed into the brain slices. The neuronal spikes and synaptic transmission were recorded by whole-cell patching in amygdala neurons of brain slices. The chronic or acute administration of dexamethasone downregulates glutamate release as well as upregulates GABA release and GABAergic neuron spiking. The chronic administration of dexamethasone also enhances the responsiveness of GABA receptors. Conclusion The upregulation of GABAergic neurons and the downregulation of glutamatergic neurons by glucocorticoid impair their balance in the amygdala, which leads to emotional disorders during stress. PMID:27861545

  6. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis.

    PubMed

    Li, Ping; Sun, Fei; Cao, Huang-Ming; Ma, Qin-Yun; Pan, Chun-Ming; Ma, Jun-Hua; Zhang, Xiao-Na; Jiang, He; Song, Huai-Dong; Chen, Ming-Dao

    2009-12-25

    Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.

  7. Cortisol response to acute stress in asthma: Moderation by depressive mood.

    PubMed

    Trueba, Ana F; Simon, Erica; Auchus, Richard J; Ritz, Thomas

    2016-05-15

    Both individuals with asthma and depression show signs of a dysregulated hypothalamus-pituitary-adrenal axis. However, little is known about the cortisol response to stress in the context of co-occurring asthma and depressive mood. Thirty-nine individuals with asthma and 41 healthy controls underwent a combined speech and mental arithmetic stressor. During the course of the laboratory session, salivary cortisol was collected 5 times, with 1 sample at 0min before the stressor and 4 samples at 0, 15, 30 and 45min after the stressor. Depressive mood in the past week was assessed with the Hospital Anxiety and Depression Scale at the beginning of the session. Depressive symptoms moderated cortisol response to the acute stressor, but only among asthmatic patients. Higher depressive mood was associated with a significant increase in cortisol, whereas low depressive mood was associated with no cortisol response. In healthy participants, depressive mood had no substantial effect on cortisol response to the stressor. These findings suggest that depressive mood and chronic inflammatory diseases such as asthma can interact to augment cortisol response to stress.

  8. Obesity and psychiatric disorders: commonalities in dysregulated biological pathways and their implications for treatment.

    PubMed

    Lopresti, Adrian L; Drummond, Peter D

    2013-08-01

    Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus-pituitary-adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined.

  9. Stress decreases the ability to resist smoking and potentiates smoking intensity and reward.

    PubMed

    McKee, Sherry A; Sinha, Rajita; Weinberger, Andrea H; Sofuoglu, Mehmet; Harrison, Emily L R; Lavery, Meaghan; Wanzer, Jesse

    2011-04-01

    We have developed a novel human laboratory model to examine two primary aspects of stress-precipitated tobacco relapse: (1) Does stress reduce the ability to resist the first cigarette? (2) Once the first cigarette is initiated, does stress facilitate subsequent smoking? Using a within-subject design, daily smokers (n = 37) who were nicotine deprived overnight received a personalized imagery induction (stress or neutral) on two separate days, and then had the option of initiating a tobacco self-administration session or delaying initiation for up to 50 min in exchange for three levels of monetary reinforcement. Subsequently, the tobacco self-administration session entailed a 1-hour period in which subjects could choose to smoke using a smoking topography system. Following the stress induction, subjects were less able to resist smoking, smoked more intensely (increased puffs, shorter inter-puff interval, and greater peak puff velocity), and perceived greater satisfaction and reward from smoking. Stress significantly increased hypothalamus-pituitary-adrenal (HPA) axis reactivity, tobacco craving, negative emotion, and physiologic reactivity relative to the neutral condition. In addition, increased cortisol, ACTH, and tobacco craving were associated with reduced ability to resist smoking following stress. These findings have implications for understanding the impact of stress on smoking relapse and model development to assess smoking lapse behavior.

  10. Gut vagal afferents differentially modulate innate anxiety and learned fear.

    PubMed

    Klarer, Melanie; Arnold, Myrtha; Günther, Lydia; Winter, Christine; Langhans, Wolfgang; Meyer, Urs

    2014-05-21

    Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior.

  11. Foetal programming and cortisol secretion in early childhood: A meta-analysis of different programming variables.

    PubMed

    Pearson, Jessica; Tarabulsy, George M; Bussières, Eve-Line

    2015-08-01

    It is widely recognized that different events may take place in the intrauterine environment that may influence later developmental outcome. Scholars have long postulated that maternal prenatal stress, alcohol or drug use, and cigarette smoking may impact foetal formation of the hypothalamus-pituitary-adrenal (HPA) axis, which may later influence different aspects of early childhood socioemotional and cognitive development. However, results linking each of these factors with child cortisol secretion have been mixed. The current meta-analysis examined the relation between each of these programming variables and child cortisol secretion in studies conducted up to December 31st, 2012. Studies were included if they were conducted prior to child age 60 months, and if they reported an index of effect size linking either maternal prenatal stress, alcohol or drug use, or cigarette smoking with an index of child cortisol secretion. In total, 19 studies (N=2260) revealed an average effect size of d=.36 (p<.001). Moderator analyses revealed that greater effect sizes could be traced to maternal alcohol use, to the use of retrospective research methodology, where mothers are questioned after childbirth regarding programming variables, and to the use of baseline measures of cortisol secretion, as opposed to recovery measures. Discussion focuses on processes that link the environment to foetal development and how both are linked to later adaptation.

  12. Glucocorticoid-Mediated Enhancement of Glutamatergic Transmission May Outweigh Anti-Inflammatory Effects under Conditions of Neuropathic Pain

    PubMed Central

    Le Coz, Glenn-Marie; Anton, Fernand; Hanesch, Ulrike

    2014-01-01

    At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic pain (chronic constriction injury, CCI) by studying the effects of glucocorticoid receptor agonist (dexamethasone) and antagonist (RU-486) administration on pain behavior and spinal biochemical mediators. Daily injections were performed in Sprague Dawley rats. Weight, plasma corticosterone levels and mechanical pain thresholds were assessed before and during 21 days post-CCI. At days four and 21 we investigated the mRNA expression of spinal mediators. In the dexamethasone-injected group, we observed a diminution of body weight and plasma corticosterone levels during the 21 days post surgery period and a more pronounced pain sensitivity until day 7 post-CCI. This enhanced pain sensitivity in the early period following nerve injury was accompanied by a transient increase of the glutamate receptors mGluR5 and NMDA at day 4. However, at this time point we did not observe any effect of the agonist/antagonist injections on the mRNA expression of pro-inflammatory cytokines. The RU-486-injected rats showed a slight mechanical hypoalgesia until 7 days post-CCI, but without any significant correlation with the expression of the measured markers. Our results indicate that glucocorticoid-related modulations of neuropathic pain processing may rather depend on a modification of glutamatergic transmission than on a change in pro-inflammatory cytokine expression. PMID:24618816

  13. Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders

    PubMed Central

    Gu, Simeng; Wang, Wei; Huang, Jason H.

    2016-01-01

    Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC)/norepinephrine (NE) system is regarded as a critical part of the central “stress circuitry,” whose major function is to induce “fight or flight” behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty). The reason for this discrepancy might be that NE is not only for flight (fear), but also for fight (anger). Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. “Adrenaline rush or norepinephrine rush” and fear and anger emotion might act as biomarkers for mental disorders. PMID:27051536

  14. Salivary cortisol and α-amylase: subclinical indicators of stress as cardiometabolic risk

    PubMed Central

    Cozma, S.; Dima-Cozma, L.C.; Ghiciuc, C.M.; Pasquali, V.; Saponaro, A.; Patacchioli, F.R.

    2017-01-01

    Currently, the potential for cardiovascular (CV) stress-induced risk is primarily based on the theoretical (obvious) side effects of stress on the CV system. Salivary cortisol and α-amylase, produced respectively by the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary (SAM) system during stress response, are still not included in the routine evaluation of CV risk and require additional and definitive validation. Therefore, this article overviews studies published between 2010 and 2015, in which salivary cortisol and α-amylase were measured as stress biomarkers to examine their associations with CV/CMR (cardiometabolic risk) clinical and subclinical indicators. A comprehensive search of PubMed, Web of Science and Scopus electronic databases was performed, and 54 key articles related to the use of salivary cortisol and α-amylase as subclinical indicators of stress and CV/CMR factors, including studies that emphasized methodological biases that could influence the accuracy of study outcomes, were ultimately identified. Overall, the biological impact of stress measured by salivary cortisol and α-amylase was associated with CV/CMR factors. Results supported the use of salivary cortisol and α-amylase as potential diagnostic tools for detecting stress-induced cardiac diseases and especially to describe the mechanisms by which stress potentially contributes to the pathogenesis and outcomes of CV diseases. PMID:28177057

  15. Investigating the stress attenuating potential of furosemide in immobilization and electric foot-shock stress models in mice.

    PubMed

    Kaur, Aalamjeet; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar Singh

    2015-05-01

    The present study was designed to investigate the antistress effect of furosemide (sodium potassium chloride co-transporter inhibitor) in immobilization and foot-shock stress-induced behavioral alterations in the mice. Acute stress was induced in Swiss albino mice either by applying electric foot shocks of 0.6-mA intensity of 1-s duration with 30-s inter-shock interval for 1 h or immobilizing for 150 min. The acute stress-induced behavioral changes were assessed by using actophotometer, hole board, open-field, and social interaction tests. Biochemically, the corticosterone levels were estimated in the serum as a biomarker of hypothalamus-pituitary-adrenal (HPA) axis. Acute stress resulted in the development of behavioral alterations and elevation of the corticosterone levels. Intraperitoneal administration of furosemide (25 and 50 mg/kg) significantly attenuated immobilization and foot-shock stress-induced behavioral changes along with normalization of the corticosterone levels. It may be concluded that furosemide produces beneficial effects in reestablishing the behavioral and biochemical alterations in immobilization and foot-shock-induced acute stress in mice.

  16. Jiaweisinisan facilitates neurogenesis in the hippocampus after stress damage☆

    PubMed Central

    Wu, Lili; Ran, Chuanlian; Liu, Shukao; Liao, Lizhen; Chen, Yanling; Guo, Hualei; Wu, Weikang; Yan, Can

    2013-01-01

    The traditional Chinese medicine Jiaweisinisan has antidepressant effects, and can inhibit hypothalamus-pituitary-adrenal gland axis hyperactivity in stress-induced depression. In this study, rat hippocampal neural precursor cells were cultured in serum-free medium in vitro and a stress damage model was established with 120 μM corticosterone. Cells were treated with 10% (v/v) Jiaweisinisan drug-containing serum and the corticosterone antagonist RU38486. Results of the 3-(4,5-dimethylthiazol-2-yl)-3,5-di-phenytetrazoliumromide assay showed that both Jiaweisinisan drug-containing serum and RU38486 promoted the proliferation of neural precursor cells after corticosterone exposure. Immunofluorescence detection showed that after Jiaweisinisan drug-containing serum and RU38486 treatment, the 5-bromo-2-deoxyuridine/terminal deoxynucleotidyl transferase dUTP nick end labeling ratio in hippocampal neural precursor cells significantly increased, and the apoptotic rates of glial cells reduced, and neuron-like cell differentiation from neural precursor cells significantly increased. Our experimental findings indicate that Jiaweisinisan promotes hippocampal neurogenesis after stress damage. PMID:25206403

  17. Hormonal disturbances in visceral leishmaniasis (kala-azar).

    PubMed

    Verde, Frederico Araujo Lima; Verde, Francisco Agenor Araujo Lima; Neto, Augusto Saboia; Almeida, Paulo César; Verde, Emir Mendonça Lima

    2011-05-01

    This study presents a cross-sectional analysis of the hormonal alterations of patients with visceral leishmaniasis. The diagnosis was established by the bone marrow aspiration and polymerase chain reaction test. Primary adrenal insufficiency was observed in 45.8% of patients; low aldosterone/renin plasma ratio in 69.4%; low daily urinary aldosterone excretion in 61.1%; and low transtubular potassium gradient in 68.0%. All patients had normal plasma antidiuretic hormone (ADH) concentrations, hyponatremia, and high urinary osmolality. Plasma parathyroid hormone was low in 63%; hypomagnesemia was present in 46.4%, and increased Mg(++)(EF) in 100%. Primary thyroid insufficiency was observed in 24.6%, and secondary thyroid insufficiency in 14.1%. Normal follicle-stimulating hormone plasma levels were present in 81.4%; high luteinizing hormone and low testosterone plasma levels in 58.2% of men. There are evidences of hypothalamus-pituitary-adrenal axis abnormalities, inappropriate aldosterone and ADH secretions, and presence of hypoparathyroidism, magnesium depletion, thyroid and testicular insufficiencies.

  18. Non-syndromic cleft lip and palate: could stress be a causal factor?

    PubMed

    Wallace, Graeme H; Arellano, Jacinta M; Gruner, Tini M

    2011-03-01

    The aetiology of non-syndromic cleft lip and palate has as yet not been clearly defined. Familial relationships, environmental toxins and nutritional status have all been considered without conclusive results, although in some studies a potential link between non-syndromic cleft lip and palate and any one or more of these factors has been proposed. Elevated stress, particularly an extended term of traumatic stress, can lead to oxidative damage at the cellular level via hypothalamus-pituitary-adrenal (HPA) axis dysregulation, high cortisol and cytokine production. The effect of this hormonal shift is to re-direct the blood supply to the mother's muscles, thereby reducing the supply to the placenta, causing a potential nutritional deficiency which may then result in a genetic alteration in the foetus. Mothers with a child aged two years or younger who had been born with a cleft, who were members of CleftPals, a family support group, volunteered to be participants in this qualitative study. The research first called for a survey to be completed by the mother and this was then followed by an interview conducted by the researcher. The study involved families living in the three eastern States of Australia. The results suggest that physical and/or emotional stress may well be implicated in clefting. While little work has been done in considering stress as a causal factor, the existing literature suggests, as does this study, that elevated stress levels at, or soon after, conception appear to affect foetal development.

  19. [Systemic biopsychological perspective of basic emotions].

    PubMed

    Poisson, Benoît

    2015-01-01

    the peripheral nervous system. The latter is divided into two: the sympathetic (norepinephrine) that accelerates the motor response and the parasympathetic (acetylcholine), which slows it down. These two systems work in tandem. As for the second release of information, it is endocrine, thus it will follow the hypothalamus-pituitary-adrenal axis to cortisol, the hypothalamus-pituitary axis to endorphin and oxytocin and the hypothalamus-pineal axis to melatonin. The different emotional behaviours result from one of these two sources of information or from a combination of these two and are then managed by the limbic system, which is in continuous connection with the neocortex.In short, no specific centre totally controls human behaviour. Control is achieved through a group of brain structures and relays, permitting adaptive behaviour and maintenance of balance by means of permanent exchanges. Anger, for instance, is a survival emotion, which allows protecting one's physical integrity. It is very useful as an immediate response in an emergency situation, but it can also be harmful if it is used extensively in all situations, giving way to conduct disorders. Thus, the other neurohormonal circuits will regulate anger.Emotions are an integral part of human behaviour. They allow the individual to constantly adapt to the physical and social environment. This approach brings a new perspective to understand how each person maintains balance to avoid the onset of clinical disorders. The understanding of neurochemical mechanisms underlying basic emotions opens up the door to several clinical applications.

  20. Vertical axis wind turbines

    DOEpatents

    Krivcov, Vladimir [Miass, RU; Krivospitski, Vladimir [Miass, RU; Maksimov, Vasili [Miass, RU; Halstead, Richard [Rohnert Park, CA; Grahov, Jurij [Miass, RU

    2011-03-08

    A vertical axis wind turbine is described. The wind turbine can include a top ring, a middle ring and a lower ring, wherein a plurality of vertical airfoils are disposed between the rings. For example, three vertical airfoils can be attached between the upper ring and the middle ring. In addition, three more vertical airfoils can be attached between the lower ring and the middle ring. When wind contacts the vertically arranged airfoils the rings begin to spin. By connecting the rings to a center pole which spins an alternator, electricity can be generated from wind.

  1. Single Axis Piezoceramic Gimbal

    NASA Technical Reports Server (NTRS)

    Horner, Garnett C.; Taleghani, Barmac K.

    1999-01-01

    This paper describes the fabrication, testing, and analysis of a single axis piezoceramic gimbal. The fabrication process consist of pre-stressing a piezoceramic wafer using a high-temperature thermoplastic polyimide and a metal foil. The differential thermal expansion between the ceramic and metal induces a curvature. The pre-stressed, curved piezoceramic is mounted on a support mechanism and a mirror is attached to the piezoceramic. A plot of gimbal angle versus applied voltage to the piezoceramic is presented. A finite element analysis of the piezoceramic gimbal is described. The predicted gimbal angle versus applied voltage is compared to experimental results.

  2. Stress and the HPA Axis

    PubMed Central

    Stephens, Mary Ann C.; Wand, Gary

    2012-01-01

    Stress has long been suggested to be an important correlate of uncontrolled drinking and relapse. An important hormonal response system to stress—the hypothalamic–pituitary–adrenal (HPA) axis—may be involved in this process, particularly stress hormones known as glucocorticoids and primarily cortisol. The actions of this hormone system normally are tightly regulated to ensure that the body can respond quickly to stressful events and return to a normal state just as rapidly. The main determinants of HPA axis activity are genetic background, early-life environment, and current life stress. Alterations in HPA axis regulation are associated with problematic alcohol use and dependence; however, the nature of this dysregulation appears to vary with respect to stage of alcohol dependence. Much of this research has focused specifically on the role of cortisol in the risk for, development of, and relapse to chronic alcohol use. These studies found that cortisol can interact with the brain’s reward system, which may contribute to alcohol’s reinforcing effects. Cortisol also can influence a person’s cognitive processes, promoting habit-based learning, which may contribute to habit formation and risk of relapse. Finally, cortisol levels during abstinence may be useful clinical indicators of relapse vulnerability in alcohol-dependent people. PMID:23584113

  3. Fibromyxoma of the axis.

    PubMed

    Mavrogenis, Andreas F; Casadei, Roberto; Gambarotti, Marco; Ruggieri, Pietro

    2012-07-01

    Fibromyxoma of bone is a rare benign tumor of fibrous tissue origin. The typical location is the jaws. Sporadic extragnathic cases have been reported, but fibromyxoma of the spine has not been reported. The histological appearance of fibromyxoma is benign and includes abundant extracellular fibrous and myxoid stroma with varying amounts of calcification and ossification. Myxoid changes are usually extensive. Extragnathic fibromyxoma of bone should be distinguished from benign cartilage-forming bone tumors, such as chondromyxoid and myxoid chondrosarcoma and myxoma of bone. It has also been suggested that fibromyxoma is a variant of myxoid fibrous dysplasia, whereas other authors reported extragnathic fibromyxoma resulting from myxoid degeneration of bone tumors, such as chondrosarcoma or fibrosarcoma. The overtreatment of patients with fibromyxoma of bone due to an aggressive imaging appearance should be avoided; the prognosis is excellent compared with the jaw variant and depends on the location and extent of the tumor. This article describes a case of a 21-year-old woman with fibromyxoma of bone originating from the spinous process of the axis. Clinical examination showed a tender mass in the midline of the posterior aspect the neck and slight limitation of neck range of motion; neurologic examination was normal. Diagnosis was obtained with a preoperative biopsy. Marginal excision of the lesion with posterior laminectomy of the axis was performed. The facets were preserved, and no fusion was performed. At last follow-up 2 years after diagnosis and treatment, the patient was asymptomatic with no evidence of local recurrence.

  4. Veratri Nigri Rhizoma et Radix (Veratrum nigrum L.) and Its Constituent Jervine Prevent Adipogenesis via Activation of the LKB1-AMPKα-ACC Axis In Vivo and In Vitro

    PubMed Central

    Park, Jinbong; Jeon, Yong-Deok; Kim, Hye-Lin; Kim, Dae-Seung; Han, Yo-Han; Jung, Yunu; Youn, Dong-Hyun; Kang, JongWook; Yoon, Daeyeon; Jeong, Mi-Young; Lee, Jong-Hyun; Hong, Seung-Heon; Lee, Junhee; Um, Jae-Young

    2016-01-01

    This study was performed in order to investigate the antiobese effects of the ethanolic extract of Veratri Nigri Rhizoma et Radix (VN), a herb with limited usage, due to its toxicology. An HPLC analysis identified jervine as a constituent of VN. By an Oil Red O assay and a Real-Time RT-PCR assay, VN showed higher antiadipogenic effects than jervine. In high-fat diet- (HFD-) induced obese C57BL/6J mice, VN administration suppressed body weight gain. The levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding protein alpha (C/EBPα), adipocyte fatty-acid-binding protein (aP2), adiponectin, resistin, and LIPIN1 were suppressed by VN, while SIRT1 was upregulated. Furthermore, VN activated phosphorylation of the liver kinase B1- (LKB1-) AMP-activated protein kinase alpha- (AMPKα-) acetyl CoA carboxylase (ACC) axis. Further investigation of cotreatment of VN with the AMPK agonist AICAR or AMPK inhibitor Compound C showed that VN can activate the phosphorylation of AMPKα in compensation to the inhibition of Compound C. In conclusion, VN shows antiobesity effects in HFD-induced obese C57BL/6J mice. In 3T3-L1 adipocytes, VN has antiadipogenic features, which is due to activating the LKB1-AMPKα-ACC axis. These results suggest that VN has a potential benefit in preventing obesity. PMID:27143989

  5. Veratri Nigri Rhizoma et Radix (Veratrum nigrum L.) and Its Constituent Jervine Prevent Adipogenesis via Activation of the LKB1-AMPKα-ACC Axis In Vivo and In Vitro.

    PubMed

    Park, Jinbong; Jeon, Yong-Deok; Kim, Hye-Lin; Kim, Dae-Seung; Han, Yo-Han; Jung, Yunu; Youn, Dong-Hyun; Kang, JongWook; Yoon, Daeyeon; Jeong, Mi-Young; Lee, Jong-Hyun; Hong, Seung-Heon; Lee, Junhee; Um, Jae-Young

    2016-01-01

    This study was performed in order to investigate the antiobese effects of the ethanolic extract of Veratri Nigri Rhizoma et Radix (VN), a herb with limited usage, due to its toxicology. An HPLC analysis identified jervine as a constituent of VN. By an Oil Red O assay and a Real-Time RT-PCR assay, VN showed higher antiadipogenic effects than jervine. In high-fat diet- (HFD-) induced obese C57BL/6J mice, VN administration suppressed body weight gain. The levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding protein alpha (C/EBPα), adipocyte fatty-acid-binding protein (aP2), adiponectin, resistin, and LIPIN1 were suppressed by VN, while SIRT1 was upregulated. Furthermore, VN activated phosphorylation of the liver kinase B1- (LKB1-) AMP-activated protein kinase alpha- (AMPKα-) acetyl CoA carboxylase (ACC) axis. Further investigation of cotreatment of VN with the AMPK agonist AICAR or AMPK inhibitor Compound C showed that VN can activate the phosphorylation of AMPKα in compensation to the inhibition of Compound C. In conclusion, VN shows antiobesity effects in HFD-induced obese C57BL/6J mice. In 3T3-L1 adipocytes, VN has antiadipogenic features, which is due to activating the LKB1-AMPKα-ACC axis. These results suggest that VN has a potential benefit in preventing obesity.

  6. Segmentation of dual-axis swallowing accelerometry signals in healthy subjects with analysis of anthropometric effects on duration of swallowing activities.

    PubMed

    Sejdić, Ervin; Steele, Catriona M; Chau, Tom

    2009-04-01

    Dysphagia (swallowing difficulty) is a serious and debilitating condition that often accompanies stroke, acquired brain injury, and neurodegenerative illnesses. Individuals with dysphagia are prone to aspiration (the entry of foreign material into the airway), which directly increases the risk of serious respiratory consequences such as pneumonia. Swallowing accelerometry is a promising noninvasive tool for the detection of aspiration and the evaluation of swallowing. In this paper, dual-axis accelerometry was implemented since the motion of the hyolaryngeal complex occurs in both anterior-posterior and superior-inferior directions during swallowing. Dual-axis cervical accelerometry signals were acquired from 408 healthy subjects during dry, wet, and wet chin tuck swallowing tasks. The proposed segmentation algorithm is based on the idea of sequential fuzzy partitioning of the signal and is well suited for long signals with nonstationary variance. The algorithm was validated with simulated signals with known swallowing locations and a subset of 295 real swallows manually segmented by an experienced speech language pathologist. In both cases, the algorithm extracted individual swallows with over 90% accuracy. The time duration analysis was carried out with respect to gender, body mass index (BMI), and age. Demographic and anthropometric variables influenced the duration of these segmented signals. Male participants exhibited longer swallows than female participants (p=0.05). Older participants and participants with higher BMIs exhibited swallows with significantly longer (p=0.05) duration than younger participants and those with lower BMIs, respectively.

  7. Role of AMP-activated protein kinase activators in antiproliferative multi-drug pituitary tumour therapies: effects of combined treatments with compounds affecting the mTOR-p70S6 kinase axis in cultured pituitary tumour cells.

    PubMed

    Tulipano, G; Faggi, L; Cacciamali, A; Spinello, M; Cocchi, D; Giustina, A

    2015-01-01

    AMP-activated protein kinase (AMPK) is activated under conditions that deplete cellular ATP levels and elevate AMP levels. We have recently shown that AMPK can represent a valid target for improving the medical treatment of growth hormone (GH)-secreting pituitary adenomas and the effects of its activation or inhibition in pituitary tumour cells are worthy of further characterisation. We aimed to determine whether AMPK may have a role in combined antiproliferative therapies based on multiple drugs targeting cell anabolic functions at different levels in pituitary tumour cells to overcome the risk of cell growth escape phenomena. Accordingly, we tried to determine whether a rationale exists in combining compounds activating AMPK with compounds targeting the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR/p70S6K signalling pathway. AMPK down-regulation by specific small-interfering RNAs confirmed that activated AMPK had a role in restraining growth of GH3 cells. Hence, we compared the effects of compounds directly targeting the mTOR-p70S6K axis, namely the mTOR inhibitor rapamycin and the p70S6K inhibitor PF-4708671, with the effects of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on cell signalling and cell growth, in rat pituitary GH3 cells. AICAR was able to reduce growth factor-induced p70S6K activity, as shown by the decrease of phospho-p70S6K levels. However, it was far less effective than rapamycin and PF-4708671. We observed significant differences between the growth inhibitory effects of the three compounds in GH3 and GH1 cells. Interestingly, PF-4708671 was devoid of any effect. AICAR was at least as effective as rapamycin and the co-treatment was more effective than single treatments. AICAR induced apoptosis of GH3 cells, whereas rapamycin caused preferentially a decrease of cell proliferation. Finally, AICAR and rapamycin differed in their actions on growth factor-induced extracellular signal regulated kinase 1/2 phosphorylation

  8. Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2-p27 Axis in Human Colon Cancer Cells.

    PubMed

    Jung, Cholomi; Hong, Ji-Young; Bae, Song Yi; Kang, Sam Sik; Park, Hyen Joo; Lee, Sang Kook

    2015-12-24

    The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.

  9. Anti-neoplastic activity of low-dose endothelial-monocyte activating polypeptide-II results from defective autophagy and G2/M arrest mediated by PI3K/Akt/FoxO1 axis in human glioblastoma stem cells.

    PubMed

    Liu, Jing; Liu, Libo; Xue, Yixue; Meng, Fanjie; Li, Shuai; Wang, Ping; Liu, Yunhui

    2014-06-15

    Glioblastoma multiforme (GBM) is a life-threatening brain tumor with fatal recurrence, for which glioblastoma stem cells (GSCs) are held responsible. Though endothelial-monocyte activating polypeptide-II (EMAP-II) has been confirmed as a possible antitumor agent that can induce apoptosis of endothelial cells and inhibit tumor angiogenesis, the direct cytotoxicity by EMAP-II on tumor cells and its underlying mechanism are largely unknown. In the present study, it was demonstrated that low-dose (0.05 nM) EMAP-II reduces cell viability and mitochondrial membrane potential in vitro. Likewise, EMAP-II suppressed tumor growth in GSC-xenografted mice. Though no apoptosis was detected, all these antitumor effects were attenuated when GSCs were pretreated with 3-methyladenine (3-MA). Analysis of EMAP-II-treated GSCs exhibited the morphological and biochemical changes typical of autophagy, which was further shown to be defective. Moreover, EMAP-II was found to suppress tumor growth by inducing G2/M arrest in GSCs. Our data further showed that EMAP-II inhibited PI3K/Akt activation with concomitant induction of FoxO1 activation. FoxO1 knockdown significantly attenuated the induction of autophagy and G2/M arrest. Excessive accumulation of lipid droplets was intriguingly detected by transmission electron microscope, which was accompanied by autophagosomes. Further investigation indicated that the transcriptional regulation of Atg2B by FoxO1 was responsible for the induction of autophagy and formation of lipid droplets. These results suggest that EMAP-II is an effective anticancer agent for glioblastoma therapy, which can induce direct growth suppression in GSCs through defective autophagy and G2/M arrest mediated by the PI3K/Akt/FoxO1 axis.

  10. Elastic flexure controls magma trajectories and explains the offset of primary volcanic activity upstream of mantle plume axis at la Réunion and Hawaii hotspot islands

    NASA Astrophysics Data System (ADS)

    Gerbault, Muriel; Fontaine, Fabrice J.; Rabinowicz, Michel; Bystricky, Misha

    2017-03-01

    Surface volcanism at la Réunion and Hawaii occurs with an offset of 150-180 km upstream to the plume axis with respect to the plate motion. This striking observation raises questions about the forcing of plume-lithosphere thermo-mechanical interactions on melt trajectories beneath these islands. Based on visco-elasto-plastic numerical models handled at kilometric resolution, we propose to explain this offset by the development of compressional stresses at the base of the lithosphere, that result from elastic plate bending above the upward load exerted by the plume head. This horizontal compression adopts a disc shape centered around the plume axis: (i) it is 20 km thick, (ii) it has a 150 km radius, (iii) it lays at the base of the elastic part of the lithosphere, i.e., around ∼50-70 km depth where the temperature varies from ∼600 °C to ∼750 °C, (iv) it lasts for 5 to 10 My in an oceanic plate of age greater than 70 My, and (vi) it is controlled by the visco-elastic relaxation time at ∼50-70 km depth. This period of time exceeds the time during which both the Somalian/East-African and Pacific plates drift over the Reunion and Hawaii plumes, respectively. This indicates that this basal compression is actually a persistent feature. It is inferred that the buoyant melts percolating in the plume head pond below this zone of compression and eventually spread laterally until the most compressive principal elastic stresses reverse to the vertical, i.e., ∼150 km away from the plume head. There, melts propagate through dikes upwards to ∼35 km depth, where the plate curvature reverses and ambient compression diminishes. This 30-35 km depth may thus host a magmatic reservoir where melts transported by dykes pond. Only after further magmatic differentiation can dykes resume their ascension up to the surface and begin forming a volcanic edifice. As the volcano grows because of melt accumulation at the top of the plate, the lithosphere is flexed downwards

  11. High water temperature impairs ovarian activity and gene expression in the brain-pituitary-gonadal axis in female red seabream during the spawning season.

    PubMed

    Okuzawa, Koichi; Gen, Koichiro

    2013-12-01

    Temperature plays a pivotal role in the control of seasonal reproduction in temperate fish species. It is well known that temperatures that exceed a certain threshold impair gonadal development, maturation, and spawning. However, the endocrine mechanisms that underlie these effects are poorly understood. We evaluated the effect of high water temperature on the brain-pituitary-gonadal (B-P-G) axis of a perciform fish, red seabream, Pagrus (Chrysophrys) major during its spawning season (April-May). Fish were reared at either high (24 °C: H-group) or optimal/control (17 °C: C-group) temperatures for 5 or 10 d. After 5 d, the transcript abundance of gonadotropin-releasing hormone-1 (GnRH1) in the brain and GnRH receptor (GnRH-R) and FSH-β in the pituitary were significantly lower in H-group than in C-group. Conversely, there was no difference in pituitary LH-β mRNA levels, serum concentrations of estradiol-17β (E₂), or the gonadosomatic index (GSIs) between H- and C-groups on Day 5. After 10 d, the ovaries of all H-group fish had completely regressed and were filled with only perinucleolar stage primary oocytes and atretic oocytes. The brain GnRH1 expression, pituitary GnRH-R and pituitary LH-β expression, serum E₂ concentrations, and the GSI were significantly lower in the H-group on Day 10. Our results suggest that high water temperature is the proximate driver of the termination of the spawning season of female red seabream. The effect appears to be mediated by suppression of gene expression in the B-P-G axis.

  12. A users guide to HPA axis research.

    PubMed

    Spencer, Robert L; Deak, Terrence

    2016-11-18

    Glucocorticoid hormones (cortisol and corticosterone - CORT) are the effector hormones of the hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system. CORT is a systemic intercellular signal whose level predictably varies with time of day and dynamically increases with environmental and psychological stressors. This hormonal signal is utilized by virtually every cell and physiological system of the body to optimize performance according to circadian, environmental and physiological demands. Disturbances in normal HPA axis activity profiles are associated with a wide variety of physiological and mental health disorders. Despite numerous studies to date that have identified molecular, cellular and systems-level glucocorticoid actions, new glucocorticoid actions and clinical status associations continue to be revealed at a brisk pace in the scientific literature. However, the breadth of investigators working in this area poses distinct challenges in ensuring common practices across investigators, and a full appreciation for the complexity of a system that is often reduced to a single dependent measure. This Users Guide is intended to provide a fundamental overview of conceptual, technical and practical knowledge that will assist individuals who engage in and evaluate HPA axis research. We begin with examination of the anatomical and hormonal components of the HPA axis and their physiological range of operation. We then examine strategies and best practices for systematic manipulation and accurate measurement of HPA axis activity. We feature use of experimental methods that will assist with better understanding of CORT's physiological actions, especially as those actions impact subsequent brain function. This research approach is instrumental for determining the mechanisms by which alterations of HPA axis function may contribute to pathophysiology.

  13. Psychosocial stress induces working memory impairments in an n-back paradigm.

    PubMed

    Schoofs, Daniela; Preuss, Diana; Wolf, Oliver T

    2008-06-01

    In contrast to the substantial number of studies investigating the effects of stress on declarative memory, effects of stress on working memory have received less attention. We compared working memory (numerical n-back task with single digits) in 40 men exposed either to psychosocial stress (Trier Social Stress Test (TSST)) or a control condition. Task difficulty was varied using two conditions (2-back vs. 3-back). Salivary cortisol (as a marker of hypothalamus-pituitary-adrenal (HPA) activity) and salivary alpha-amylase (sAA as a marker of sympathetic nervous system (SNS) activity) were assessed immediately before and three times after the stress or control condition. As expected stress resulted in an increase in cortisol, sAA, and negative affect. Subjects exposed to stress showed significant working memory impairments in both workload conditions. The analysis of variance indicated a main effect of stress for reaction time as well as accuracy. In addition, for reaction time a stress-block interaction occurred. Follow up tests revealed that only during the first block at each level of difficulty performance was significantly impaired by stress. Thus, the effects of stress became smaller the longer the task was performed. Results provide further evidence for impaired working memory after acute stress and illustrate the time course of this phenomenon.

  14. Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis

    PubMed Central

    Chu, Qiaoqiao; Huang, Hongbing; Huang, Tiejun; Cao, Li; Peng, Lixia; Shi, Simei; Zheng, Lisheng; Xu, Liang; Zhang, Shijun; Huang, Jialing; Li, Xinjian; Qian, Chaonan; Huang, Bijun

    2016-01-01

    Serglycin is a proteoglycan that was first found to be secreted by hematopoietic cells. As an extracellular matrix (ECM) component, serglycin promotes nasopharyngeal carcinoma (NPC) metastasis and serves as an independent, unfavorable NPC prognostic indicator. The detailed mechanism underlying the roles of serglycin in cancer progression remains to be clarified. Here, we report that serglycin knockdown in NPC cells inhibited cell sphere formation and tumor seeding abilities. Serglycin downregulation enhanced high-metastasis NPC cell sensitivity to chemotherapy. It has been reported that serglycin is a novel ligand for the stem cell marker CD44. Interestingly, we found a positive correlation between serglycin expression and CD44 in nasopharyngeal tissues and NPC cell lines. Further study revealed that CD44 was an ERK-dependent downstream effector of serglycin signaling, and serglycin activated the MAPK/β-catenin axis to induce CD44 receptor expression in a positive feedback loop. Taken together, our novel findings suggest that ECM serglycin upregulated CD44 receptor expression to maintain NPC stemness by interacting with CD44 and activating the MAPK/β-catenin pathway, resulting in NPC cell chemoresistance. These findings suggest that the intervention of serglycin/CD44 axis and downstream signaling pathway is a rational strategy for targeting NPC cancer stem cell therapy. PMID:27809309

  15. Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity

    PubMed Central

    León, Silvia; Barroso, Alexia; Vázquez, María J.; García-Galiano, David; Manfredi-Lozano, María; Ruiz-Pino, Francisco; Heras, Violeta; Romero-Ruiz, Antonio; Roa, Juan; Schutz, Günther; Kirilov, Milen; Gaytan, Francisco; Pinilla, Leonor; Tena-Sempere, Manuel

    2016-01-01

    Kisspeptins, ligands of the receptor, Gpr54, are potent stimulators of puberty and fertility. Yet, whether direct kisspeptin actions on GnRH neurons are sufficient for the whole repertoire of their reproductive effects remains debatable. To dissect out direct vs. indirect effects of kisspeptins on GnRH neurons in vivo, we report herein the detailed reproductive/gonadotropic characterization of a Gpr54 null mouse line with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54−/−Tg; rescued). Despite preserved fertility, adult rescued mice displayed abnormalities in gonadal microstructure, with signs of precocious ageing in females and elevated LH levels with normal-to-low testosterone secretion in males. Gpr54−/−Tg rescued mice showed also altered gonadotropin responses to negative feedback withdrawal, while luteinizing hormone responses to various gonadotropic regulators were variably affected, with partially blunted relative (but not absolute) responses to kisspeptin-10, NMDA and the agonist of tachykinin receptors, NK2R. Our data confirm that direct effects of kisspeptins on GnRH cells are sufficient to attain fertility. Yet, such direct actions appear to be insufficient to completely preserve proper functionality of gonadotropic axis, suggesting a role of kisspeptin signaling outside GnRH cells. PMID:26755241

  16. Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity.

    PubMed

    León, Silvia; Barroso, Alexia; Vázquez, María J; García-Galiano, David; Manfredi-Lozano, María; Ruiz-Pino, Francisco; Heras, Violeta; Romero-Ruiz, Antonio; Roa, Juan; Schutz, Günther; Kirilov, Milen; Gaytan, Francisco; Pinilla, Leonor; Tena-Sempere, Manuel

    2016-01-12

    Kisspeptins, ligands of the receptor, Gpr54, are potent stimulators of puberty and fertility. Yet, whether direct kisspeptin actions on GnRH neurons are sufficient for the whole repertoire of their reproductive effects remains debatable. To dissect out direct vs. indirect effects of kisspeptins on GnRH neurons in vivo, we report herein the detailed reproductive/gonadotropic characterization of a Gpr54 null mouse line with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54(-/-)Tg; rescued). Despite preserved fertility, adult rescued mice displayed abnormalities in gonadal microstructure, with signs of precocious ageing in females and elevated LH levels with normal-to-low testosterone secretion in males. Gpr54(-/-)Tg rescued mice showed also altered gonadotropin responses to negative feedback withdrawal, while luteinizing hormone responses to various gonadotropic regulators were variably affected, with partially blunted relative (but not absolute) responses to kisspeptin-10, NMDA and the agonist of tachykinin receptors, NK2R. Our data confirm that direct effects of kisspeptins on GnRH cells are sufficient to attain fertility. Yet, such direct actions appear to be insufficient to completely preserve proper functionality of gonadotropic axis, suggesting a role of kisspeptin signaling outside GnRH cells.

  17. Mechanisms underlying hypertriglyceridemia in rats with monosodium L-glutamate-induced obesity: evidence of XBP-1/PDI/MTP axis activation.

    PubMed

    França, Lucas Martins; Freitas, Larissa Nara Costa; Chagas, Vinicyus Teles; Coêlho, Caio Fernando Ferreira; Barroso, Wermerson Assunção; Costa, Graciomar Conceição; Silva, Lucilene Amorim; Debbas, Victor; Laurindo, Francisco Rafael Martins; Paes, Antonio Marcus de Andrade

    2014-01-10

    Non-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium L-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression.

  18. Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis: Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals.

    PubMed

    Breen, Miyuki; Villeneuve, Daniel L; Ankley, Gerald T; Bencic, David; Breen, Michael S; Watanabe, Karen H; Lloyd, Alun L; Conolly, Rory B

    2016-01-01

    There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.

  19. Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine

    PubMed Central

    Suman, Shubhankar; Kumar, Santosh; Fornace, Albert J.; Datta, Kamal

    2016-01-01

    Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as 56Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of 56Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of 56Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract. PMID:27558773

  20. Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells’ Malignancy by Activating miR-370/CCNE2 Axis

    PubMed Central

    Gong, Wei; Zheng, Jian; Liu, Xiaobai; Liu, Yunhui; Guo, Junqing; Gao, Yana; Tao, Wei; Chen, Jiajia; Li, Zhiqing; Ma, Jun; Xue, Yixue

    2017-01-01

    Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. Here, we elucidated the function and possible molecular mechanisms of lncRNA KCNQ1OT1 in human glioma U87 and U251 cells. Quantitative Real-Time polymerase chain reaction (qRT-PCR) demonstrated that KCNQ1OT1 expression was up-regulated in glioma tissues and cells. Knockdown of KCNQ1OT1 exerted tumor-suppressive function in glioma cells. Moreover, a binding region was confirmed between KCNQ1OT1 and miR-370 by dual-luciferase assays. qRT-PCR showed that miR-370 was down-regulated in human glioma tissue and cells. In addition, restoration of miR-370 exerted tumor-suppressive function via inhibiting cell proliferation, migration and invasion, while promoting the apoptosis of human glioma cells. Knockdown of KCNQ1OT1 decreased the expression level of Cyclin E2 (CCNE2) by binding to miR-370. Further, miR-370 bound to CCNE2 3′UTR region and decreased the expression of CCNE2. These results provided a comprehensive analysis of KCNQ1OT1-miR-370-CCNE2 axis in human glioma cells and might provide a novel strategy for glioma treatment. PMID:28381990

  1. Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine.

    PubMed

    Suman, Shubhankar; Kumar, Santosh; Fornace, Albert J; Datta, Kamal

    2016-08-25

    Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as (56)Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of (56)Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of (56)Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract.

  2. Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption.

    PubMed

    Ohdo, Shigehiro

    2010-07-31

    Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. 24h rhythm is demonstrated for the function of physiology and the pathophysiology of diseases. The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The underlying mechanisms are associated with 24h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24h rhythm in the risk of disease plus evidence of 24h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. Morning once-daily administration of corticosteroid tablet medications results in little adrenocortical suppression, while the same daily dose split into four equal administrations to coincide with daily meals and bedtime results in significant hypothalamus-pituitary-adrenal (HPA) axis suppression. However, the drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs by using

  3. TLR and TNF-R1 activation of the MKK3/MKK6–p38α axis in macrophages is mediated by TPL-2 kinase

    PubMed Central

    Pattison, Michael J.; Mitchell, Olivia; Flynn, Helen R.; Chen, Chao-Sheng; Yang, Huei-Ting; Ben-Addi, Hakem; Boeing, Stefan; Snijders, Ambrosius P.; Ley, Steven C.

    2016-01-01

    Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38α MAP kinase (MAPK) is mediated by transforming growth factor-β-activated kinase 1 (TAK1) activation of MAPK kinases, MKK3, MKK4 and MKK6. We used quantitative mass spectrometry to monitor tumour progression locus 2 (TPL-2)-dependent protein phosphorylation following TLR4 stimulation with lipopolysaccharide, comparing macrophages from wild-type mice and Map3k8D270A/D270A mice expressing catalytically inactive TPL-2 (MAP3K8). In addition to the established TPL-2 substrates MKK1/2, TPL-2 kinase activity was required to phosphorylate the activation loops of MKK3/6, but not of MKK4. MKK3/6 activation required IκB kinase (IKK) phosphorylation of the TPL-2 binding partner nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB1) p105, similar to MKK1/2 activation. Tumour necrosis factor (TNF) stimulation of MKK3/6 phosphorylation was similarly dependent on TPL-2 catalytic activity and IKK phosphorylation of NF-κB1 p105. Owing to redundancy of MKK3/6 with MKK4, Map3k8D270A mutation only fractionally decreased lipopolysaccharide activation of p38α. TNF activation of p38α, which is mediated predominantly via MKK3/6, was substantially reduced. TPL-2 catalytic activity was also required for MKK3/6 and p38α activation following macrophage stimulation with Mycobacterium tuberculosis and Listeria monocytogenes. Our experiments demonstrate that the IKK/NF-κB1 p105/TPL-2 signalling pathway, downstream of TAK1, regulates MKK3/6 and p38α activation in macrophages in inflammation. PMID:27402796

  4. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B.

    PubMed

    Reid, Janet C; Bennett, Nigel C; Stephens, Carson R; Carroll, Melanie L; Magdolen, Viktor; Clements, Judith A; Hooper, John D

    2016-12-01

    Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5-10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.

  5. AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas

    PubMed Central

    Elkabets, Moshe; Pazarentzos, Evangelos; Juric, Dejan; Sheng, Qing; Pelossof, Raphael A.; Brook, Samuel; Benzaken, Ana Oaknin; Rodon, Jordi; Morse, Natasha; Yan, Jenny Jiacheng; Liu, Manway; Das, Rita; Chen, Yan; Tam, Angela; Wang, Huiqin; Liang, Jinsheng; Gurski, Joseph M.; Kerr, Darcy A.; Rosell, Rafael; Teixidó, Cristina; Huang, Alan; Ghossein, Ronald A.; Rosen, Neal; Bivona, Trever G.; Scaltriti, Maurizio; Baselga, José

    2015-01-01

    Summary Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous carcinoma (SCC) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance we have observed that SCCs cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC), which in turn activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance. PMID:25873175

  6. Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis.

    PubMed

    Kojima, K; Konopleva, M; Tsao, T; Andreeff, M; Ishida, H; Shiotsu, Y; Jin, L; Tabe, Y; Nakakuma, H

    2010-01-01

    Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.

  7. Priming Endothelial Cells With a Melanoma-Derived Extracellular Matrix Triggers the Activation of αvβ3/VEGFR2 Axis.

    PubMed

    Helal-Neto, Edward; Brandão-Costa, Renata M; Saldanha-Gama, Roberta; Ribeiro-Pereira, Cristiane; Midlej, Victor; Benchimol, Marlene; Morandi, Verônica; Barja-Fidalgo, Christina

    2016-11-01

    The unique composition of tumor-produced extracellular matrix (ECM) can be a determining factor in changing the profile of endothelial cells in the tumor microenvironment. As the main receptor for ECM proteins, integrins can activate a series of signaling pathways related to cell adhesion, migration, and differentiation of endothelial cells that interact with ECM proteins. We studied the direct impact of the decellularized ECM produced by a highly metastatic human melanoma cell line (MV3) on the activation of endothelial cells and identified the intracellular signaling pathways associated with cell differentiation. Our data show that compared to the ECM derived from a human melanocyte cell line (NGM-ECM), ECM produced by a melanoma cell line (MV3-ECM) is considerably different in ultrastructural organization and composition and possesses a higher content of tenascin-C and laminin and a lower expression of fibronectin. When cultured directly on MV3-ECM, endothelial cells change morphology and show increased adhesion, migration, proliferation, and tubulogenesis. Interaction of endothelial cells with MV3-ECM induces the activation of integrin signaling, increasing FAK phosphorylation and its association with Src, which activates VEGFR2, potentiating the receptor response to VEGF. The blockage of αvβ3 integrin inhibited the FAK-Src association and VEGFR activation, thus reducing tubulogenesis. Together, our data suggest that the interaction of endothelial cells with the melanoma-ECM triggers integrin-dependent signaling, leading to Src pathway activation that may potentiate VEGFR2 activation and up-regulate angiogenesis. J. Cell. Physiol. 231: 2464-2473, 2016. © 2016 Wiley Periodicals, Inc.

  8. MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression.

    PubMed

    Huth, Hugo W; Albarnaz, Jonas D; Torres, Alice A; Bonjardim, Claudio A; Ropert, Catherine

    2016-09-01

    The Ras-Raf-MEK-ERK1/2 signaling pathway regulates fundamental processes in malignant cells. However, the exact contributions of MEK1 and MEK2 to the development of cancer remain to be established. We studied the effects of MEK small-molecule inhibitors (PD98059 and U0126) and MEK1 and MEK2 knock-down on cell proliferation, apoptosis and MAPK activation. We showed a diminution of cell viability that was associated with a downregulation of cyclin D1 expression and an increase of apoptosis marker in MEK2 silenced cells; by contrast, a slight increase of cell survival was observed in the absence of MEK1 that correlated with an augment of cyclin D1 expression. These data indicate that MEK2 but not MEK1 is essential for MDA-MB-231 cell survival. Importantly, the role of MEK2 in cell survival appeared independent on ERK1/2 phosphorylation since its absence did not alter the level of activated ERK1/2. Indeed, we have reported an unrevealed link between MEK2 and MKK3/MKK6-p38 MAPK axis where MEK2 was essential for the phosphorylation of MKK3/MKK6 and p38 MAPK that directly impacted on cyclin D1 expression. Importantly, the MEK1 inhibitor PD98059, like MEK1 silencing, induced an augment of cyclin D1 expression that correlated with an increase of MDA-MB-231 cell proliferation suggesting that MEK1 may play a regulatory role in these cells. In sum, the crucial role of MEK2 in MDA-MB-231 cell viability and the unknown relationship between MEK2 and MKK3/MKK6-p38 axis here revealed may open new therapeutic strategies for aggressive breast cancer.

  9. SHP2 phosphatase promotes mast cell chemotaxis toward stem cell factor via enhancing activation of the Lyn/Vav/Rac signaling axis.

    PubMed

    Sharma, Namit; Everingham, Stephanie; Ramdas, Baskar; Kapur, Reuben; Craig, Andrew W B

    2014-05-15

    SHP2 protein-tyrosine phosphatase (encoded by Ptpn11) positively regulates KIT (CD117) signaling in mast cells and is required for mast cell survival and homeostasis in mice. In this study, we uncover a role of SHP2 in promoting chemotaxis of mast cells toward stem cell factor (SCF), the ligand for KIT receptor. Using an inducible SHP2 knockout (KO) bone marrow-derived mast cell (BMMC) model, we observed defects in SCF-induced cell spreading, polarization, and chemotaxis. To address the mechanisms involved, we tested whether SHP2 promotes activation of Lyn kinase that was previously shown to promote mast cell chemotaxis. In SHP2 KO BMMCs, SCF-induced phosphorylation of the inhibitory C-terminal residue (pY507) was elevated compared with control cells, and phosphorylation of activation loop (pY396) was diminished. Because Lyn also was detected by substrate trapping assays, these results are consistent with SHP2 activating Lyn directly by dephosphorylation of pY507. Further analyses revealed a SHP2- and Lyn-dependent pathway leading to phosphorylation of Vav1, Rac activation, and F-actin polymerization in SCF-treated BMMCs. Treatment of BMMCs with a SHP2 inhibitor also led to impaired chemotaxis, consistent with SHP2 promoting SCF-induced chemotaxis of mast cells via a phosphatase-dependent mechanism. Thus, SHP2 inhibitors may be useful to limit SCF/KIT-induced mast cell recruitment to inflamed tissues or the tumor microenvironment.

  10. Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis.

    PubMed

    Pant, Ila; Rao, S Girish; Kondaiah, Paturu

    2016-10-06

    Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca(2+)/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

  11. Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis

    PubMed Central

    Pant, Ila; Rao, S. Girish; Kondaiah, Paturu

    2016-01-01

    Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF. PMID:27708346

  12. A TGFβ-PRMT5-MEP50 Axis Regulates Cancer Cell Invasion through Histone H3 and H4 Arginine Methylation Coupled Transcriptional Activation and Repression

    PubMed Central

    Chen, Hongshan; Lorton, Benjamin; Gupta, Varun; Shechter, David

    2016-01-01

    Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for transcriptional regulation promoting cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. RNA-Seq transcriptome analysis demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and Epithelial-to-mesenchymal transition (EMT) markers and to potentiate an epigenetic mechanism of the TGFβ response. We show that PRMT5-MEP50 activity both positively and negatively regulates expression of a wide range of genes. Exogenous TGFβ promotes EMT in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity. PRMT5 methylation of histone H3R2me1 induced transcriptional activation by recruitment of WDR5 and concomitant H3K4 methylation at targeted genes. In parallel, PRMT5 methylation of histone H4R3me2s suppressed transcription at distinct genomic loci. Our decoding of histone methylarginine at key genes supports a critical role for complementary PRMT5-MEP50 transcriptional activation and repression in cancer invasion pathways and in response to TGFβ stimulation and therefore and orients future chemotherapeutic opportunities. PMID:27270440

  13. CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism

    PubMed Central

    Klampfl, Stefanie M.; Brunton, Paula J.; Bayerl, Doris S.; Bosch, Oliver J.

    2016-01-01

    Adequate maternal behavior in rats requires minimal corticotropin-releasing factor receptor (CRF-R) activation in the medial-posterior bed nucleus of the stria terminalis (mpBNST). Based on the architectural heterogeneity of the BNST and its distinct inter-neural connectivity, we tested whether CRF-R manipulation in another functional part, the anterior-dorsal BNST (adBNST), differentially modulates maternal behavior. We demonstrate that in the adBNST, activation of CRF-R1 reduced arched back nursing (ABN) and nursing, whereas activation of CRF-R2 resulted in an initial reduction in nursing but significantly increased the incidence of ABN 5 h after the treatment. Following stressor exposure, which is detrimental to maternal care, ABN tended to be protected by CRF-R1 blockade. Maternal motivation, maternal aggression, and anxiety were unaffected by any manipulation. Furthermore, under basal and stress conditions, activation of adBNST CRF-R1 increased plasma ACTH and corticosterone concentrations, whereas stimulation of adBNST CRF-R2 increased basal plasma ACTH and corticosterone concentrations, but blocked the stress-induced increase in plasma corticosterone secretion. Moreover, both the CRF-R1 and -R2 antagonists prevented the stress-induced increase in plasma corticosterone secretion. Importantly, elevated levels of circulating corticosterone induced by intra-adBNST administration of CRF-R1 or -R2 agonist did not impact maternal care. Finally, Crf mRNA expression in the adBNST was increased during lactation; however, Crfr1 mRNA expression was similar between lactating and virgin rats. In conclusion, maternal care is impaired by adBNST CRF-R1 activation, and this appears to be the result of a central action, rather than an effect of elevated circulating levels of CORT. These data provide new insights into potential causes of disturbed maternal behavior postpartum. PMID:26630389

  14. Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil.

    PubMed

    Gao, Jing; Gao, Jin; Qian, Lan; Wang, Xia; Wu, Mingyuan; Zhang, Yang; Ye, Hao; Zhu, Shunying; Yu, Yan; Han, Wei

    2014-08-01

    Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.

  15. Method for spinning up a three-axis controlled spacecraft

    NASA Technical Reports Server (NTRS)

    Vorlicek, Preston L. (Inventor)

    1988-01-01

    A three-axis controlled spacecraft (1), typically a satellite, is spun up about its roll axis (20) prior to firing a motor (2), i.e., a perigee kick motor, to achieve the requisite degree of angular momentum stiffness. Thrusters (21) for imparting rotation about the roll axis (20) are activated in open-loop fashion, typically at less than full duty cycle. Cross-axis torques induced by this rotational motion are compensated for by means of closed control loops for each of the pitch and yaw axes (30, 40, respectively). Each closed control loop combines a prebias torque (72) with torques (75, 74) representative of position and rate feedback information, respectively. A deadband (52) within each closed control loop can be widened during the spinup, to conserve fuel. Position feedback information (75) in each of the control loops is disabled upon saturation of the gyroscope associated with the roll axis (20).

  16. Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells.

    PubMed

    Li, Hongyu; Hu, Jing; Wu, Shuhong; Wang, Li; Cao, Xiaobo; Zhang, Xiaoshan; Dai, Bingbing; Cao, Mengru; Shao, Ruping; Zhang, Ran; Majidi, Mourad; Ji, Lin; Heymach, John V; Wang, Michael; Pan, Shiyang; Minna, John; Mehran, Reza J; Swisher, Stephen G; Roth, Jack A; Fang, Bingliang

    2016-01-19

    Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer.

  17. Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain.

    PubMed

    Finn, D P; Beckett, S R G; Roe, C H; Madjd, A; Fone, K C F; Kendall, D A; Marsden, C A; Chapman, V

    2004-02-01

    The antinociceptive effects of Delta9-tetrahydrocannabinol (Delta9-THC) have been widely described; however, its therapeutic potential may be limited by secondary effects. We investigated whether coadministration of low doses of cannabinoids or cannabinoids and morphine produced antinociception in the absence of side-effects. Effects of preadministration (i.p.) of Delta9-THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), Delta9-THC + morphine, Delta9-THC + cannabidiol or vehicle on formalin-evoked nociceptive behaviour were studied over 60 min. Trunk blood and brains were collected 60 min after formalin injection and assayed for corticosterone and tissue levels of monoamines and metabolites, respectively. Drug effects on locomotor activity, core body temperature and grooming were assessed. Delta9-THC reduced both phases of formalin-evoked nociceptive behaviour, enhanced the formalin-evoked corticosterone response and increased the 4-hydroxy-3-methoxyphenylglycol : noradrenaline ratio in the hypothalamus. Cannabidiol alone had no effect on these indices and did not modulate the effects of Delta9-THC. Morphine reduced both phases of formalin-evoked nociceptive behaviour. Coadministration of Delta9-THC and morphine reduced the second phase of formalin-evoked nociceptive behaviour to a greater extent than either drug alone, and increased levels of thalamic 5-hydroxytryptamine. While the antinociceptive effects of Delta9-THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of Delta9-THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with Delta9-THC, increased antinociception and 5-hydroxytryptamine levels in the thalamus in a model of persistent nociception. Nevertheless, these enhanced antinociceptive effects were associated with increased secondary effects on locomotor activity.

  18. Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis.

    PubMed

    Ljubicic, Vladimir; Burt, Matthew; Lunde, John A; Jasmin, Bernard J

    2014-07-01

    Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ~100 mg·kg(-1)·day(-1)) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ~500 mg·kg(-1)·day(-1) across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1α activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients.

  19. Polychlorinated biphenyl quinone induces oxidative DNA damage and repair responses: The activations of NHEJ, BER and NER via ATM-p53 signaling axis

    SciTech Connect

    Dong, Hui; Shi, Qiong; Song, Xiufang; Fu, Juanli; Hu, Lihua; Xu, Demei; Su, Chuanyang; Xia, Xiaomin; Song, Erqun; Song, Yang

    2015-07-01

    Our previous studies demonstrated that polychlorinated biphenyl (PCB) quinone induced oxidative DNA damage in HepG2 cells. To promote genomic integrity, DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair and apoptosis. PCB quinone-induced cell cycle arrest and apoptosis have been documented, however, whether PCB quinone insult induce DNA repair signaling is still unknown. In this study, we identified the activation of DDR and corresponding signaling events in HepG2 cells upon the exposure to a synthetic PCB quinone, PCB29-pQ. Our data illustrated that PCB29-pQ induces the phosphorylation of p53, which was mediated by ataxia telangiectasia mutated (ATM) protein kinase. The observed phosphorylated histone H2AX (γ-H2AX) foci and the elevation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) indicated that DDR was stimulated by PCB29-pQ treatment. Additionally, we found PCB29-pQ activates non-homologous end joining (NHEJ), base excision repair (BER) and nucleotide excision repair (NER) signalings. However, these repair pathways are not error-free processes and aberrant repair of DNA damage may cause the potential risk of carcinogenesis and mutagenesis. - Highlights: • Polychlorinated biphenyl quinone induces oxidative DNA damage in HepG2 cells. • The elevation of γ-H2AX and 8-OHdG indicates the activation of DNA damage response. • ATM-p53 signaling acts as the DNA damage sensor and effector. • Polychlorinated biphenyl quinone activates NHEJ, BER and NER signalings.

  20. Alleviation of Microglial Activation Induced by p38 MAPK/MK2/PGE2 Axis by Capsaicin: Potential Involvement of other than TRPV1 Mechanism/s.

    PubMed

    Bhatia, Harsharan S; Roelofs, Nora; Muñoz, Eduardo; Fiebich, Bernd L

    2017-12-01

    Exaggerated inflammatory responses in microglia represent one of the major risk factors for various central nervous system's (CNS) associated pathologies. Release of excessive inflammatory mediators such as prostaglandins and cytokines are the hallmark of hyper-activated microglia. Here we have investigated the hitherto unknown effects of capsaicin (cap) - a transient receptor potential vanilloid 1 (TRPV1) agonist- in murine primary microglia, organotypic hippocampal slice cultures (OHSCs) and human primary monocytes. Results demonstrate that cap (0.1-25 µM) significantly (p < 0.05) inhibited the release of prostaglandin E2 (PGE2), 8-iso-PGF2α, and differentially regulated the levels of cytokines (TNF-α, IL-6 & IL-1β). Pharmacological blockade (via capsazepine & SB366791) and genetic deficiency of TRPV1 (TRPV1(-/-)) did not prevent cap-mediated suppression of PGE2 in activated microglia and OHSCs. Inhibition of PGE2 was partially dependent on the reduced levels of PGE2 synthesising enzymes, COX-2 and mPGES-1. To evaluate potential molecular targets, we discovered that cap significantly suppressed the activation of p38 MAPK and MAPKAPK2 (MK2). Altogether, we demonstrate that cap alleviates excessive inflammatory events by targeting the PGE2 pathway in in vitro and ex vivo immune cell models. These findings have broad relevance in understanding and paving new avenues for ongoing TRPV1 based drug therapies in neuroinflammatory-associated diseases.

  1. Childhood stressful events, HPA axis and anxiety disorders.

    PubMed

    Faravelli, Carlo; Lo Sauro, Carolina; Godini, Lucia; Lelli, Lorenzo; Benni, Laura; Pietrini, Francesco; Lazzeretti, Lisa; Talamba, Gabriela Alina; Fioravanti, Giulia; Ricca, Valdo

    2012-02-22

    Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal (HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder (OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders.

  2. Protein kinase C alpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells.

    PubMed

    Mahanivong, C; Chen, H M; Yee, S W; Pan, Z K; Dong, Z; Huang, S

    2008-02-21

    We reported previously that a signaling pathway consisting of G(i)-Ras-NF-kappaB mediates lysophosphatidic acid (LPA)-induced urokinase plasminogen activator (uPA) upregulation in ovarian cancer cells. However, it is not clear what signaling components link Ras to nuclear factor (NF)-kappaB for this LPA-induced event. In the present study, we found that treatment of protein kinase C (PKC) inhibitors including conventional PKC (cPKC) inhibitor Gö6976 abolished LPA-induced uPA upregulation in ovarian cancer cell lines tested, indicating the importance of cPKC activity in this LPA-induced event. Indeed, LPA stimulation led to the activation of PKCalpha and Ras-PKCalpha interaction. Although constitutively active mutants of PKCalpha (a cPKC), PKCtheta (a novel PKC (nPKC)) and PKCzeta (an atypical PKC (aPKC)) were all able to activate NF-kappaB and upregulate uPA expression, only dominant-negative PKCalpha mutant attenuated LPA-induced NF-kappaB activation and uPA upregulation. These results suggest that PKCalpha, rather than PKC isoforms in other PKC classes, participates in LPA-induced NF-kappaB activation and uPA upregulation in ovarian cancer cells. To determine the signaling components downstream of PKCalpha mediating LPA-induced uPA upregulation, we showed that forced expression of dominant-negative CARMA3 or silencing CARMA3, Bcl10 and MALT1 with specific siRNAs diminished these LPA-induced events. Furthermore, we demonstrated that PKCalpha/CARMA3 signaling axis is important in LPA-induced ovarian cancer cell in vitro invasion.

  3. A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages.

    PubMed

    Thyer, Lynda; Ward, Emma; Smith, Rodney; Fiore, Maria Giulia; Magherini, Stefano; Branca, Jacopo J V; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco; Pacini, Stefania

    2013-07-08

    The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This allows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.

  4. A Novel Role for a Major Component of the Vitamin D Axis: Vitamin D Binding Protein-Derived Macrophage Activating Factor Induces Human Breast Cancer Cell Apoptosis through Stimulation of Macrophages

    PubMed Central

    Thyer, Lynda; Ward, Emma; Smith, Rodney; Fiore, Maria Giulia; Magherini, Stefano; Branca, Jacopo J. V.; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco; Pacini, Stefania

    2013-01-01

    The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This al1ows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects. PMID:23857228

  5. Regulation of APC(Cdh1) E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7.

    PubMed

    Lau, Alan W; Inuzuka, Hiroyuki; Fukushima, Hidefumi; Wan, Lixin; Liu, Pengda; Gao, Daming; Sun, Yi; Wei, Wenyi

    2013-07-01

    Fbw7 and Cdh1 are substrate-recognition subunits of the SCF- and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF(Fbw7) substrates, including cyclin E, but also have increased expression of various APC(Cdh1) substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC(Cdh1) activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC(Cdh1) substrates to levels comparable to those in wild-type (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC(Cdh1) substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC(Cdh1) substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF(Fbw7) and APC(Cdh1) substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.

  6. Adolescent Survivors of Hurricane Katrina: A Pilot Study of Hypothalamic-Pituitary-Adrenal Axis Functioning

    ERIC Educational Resources Information Center

    Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal

    2015-01-01

    Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…

  7. Asynchrony of mother-infant hypothalamic-pituitary-adrenal axis activity following extinction of infant crying responses induced during the transition to sleep.

    PubMed

    Middlemiss, Wendy; Granger, Douglas A; Goldberg, Wendy A; Nathans, Laura

    2012-04-01

    This study examines change in the synchrony between mothers' and infants' physiology as 25 infants (11 males; 4 to 10 months of age) participate in a 5-day inpatient sleep training program in which they learn to self-settle through extinction of crying responses during the transition to sleep. The mothers' and infants' experience during the extinction protocol was "yoked" by the infants' behavioral signaling during the sleep transition period. Saliva was sampled for mothers and infants at initiation of infants' nighttime sleep and following infants' falling to sleep on two program days and later assayed for cortisol. As expected on the first day of the program, mothers' and infants' cortisol levels were positively associated at initiation of nighttime sleep following a day of shared activities. Also, when infants expressed distress in response to the sleep transition, mother and infant cortisol responses were again positively associated. On the third day of the program, however, results showed that infants' physiological and behavioral responses were dissociated. They no longer expressed behavioral distress during the sleep transition but their cortisol levels were elevated. Without the infants' distress cue, mothers' cortisol levels decreased. The dissociation between infants' behavioral and physiological responses resulted in asynchrony in mothers' and infants' cortisol levels. The findings are discussed in relation to understanding the determinants and implications of maternal-infant physiological synchrony in early childhood.

  8. Vertical axis wind turbine airfoil

    DOEpatents

    Krivcov, Vladimir; Krivospitski, Vladimir; Maksimov, Vasili; Halstead, Richard; Grahov, Jurij Vasiljevich

    2012-12-18

    A vertical axis wind turbine airfoil is described. The wind turbine airfoil can include a leading edge, a trailing edge, an upper curved surface, a lower curved surface, and a centerline running between the upper surface and the lower surface and from the leading edge to the trailing edge. The airfoil can be configured so that the distance between the centerline and the upper surface is the same as the distance between the centerline and the lower surface at all points along the length of the airfoil. A plurality of such airfoils can be included in a vertical axis wind turbine. These airfoils can be vertically disposed and can rotate about a vertical axis.

  9. Gut Microbiota-brain Axis

    PubMed Central

    Wang, Hong-Xing; Wang, Yu-Ping

    2016-01-01

    Objective: To systematically review the updated information about the gut microbiota-brain axis. Data Sources: All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of “gut microbiota”, “gut-brain axis”, and “neuroscience”. Study Selection: All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. Results: It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. Conclusions: Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future. PMID:27647198

  10. Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis

    SciTech Connect

    Song, Lingqin; Liu, Di; Zhao, Yang; He, Jianjun; Kang, Huafeng; Dai, Zhijun; Wang, Xijing; Zhang, Shuqun; Zan, Ying

    2015-08-28

    Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a vital transcription factor that regulates multiple important biological processes, including the epithelial–mesenchymal transition (EMT) and metastasis of breast cancer. Sinomenine is an isoquinoline well known for its remarkable curative effect on rheumatic and arthritic diseases and can induce apoptosis of several cancer cell types. Recently, sinomenine was reported as a tumor suppressor via inhibiting cell proliferation and inducing apoptosis. However, the role and mechanism of sinomenine in invasion and metastasis of breast cancer are largely unknown. Here, we report that sinomenine suppressed the invasion and migration of MDA-MB-231 and 4T1 breast cancer cells in a dose-dependent manner. We detected binding of NF-κB to the inhibitor of NF-κB (IκB) after the MDA-MB-231 cells were treated with 0.25, 0.5, and 1 mM sinomenine. Co-IP analysis revealed that sinomenine enhanced the binding of NF-κB and IκB in a dose-dependent manner, suggesting that sinomenine had an effect on inactivation of NF-κB. Western blotting and ELISA approaches indicated that the suppression effect was closely associated with the phosphorylation of IκB kinase (IKK) and its negative regulator CUEDC2. Sinomenine treatment decreased miR-324-5p expression, thus increased the level of its target gene CUEDC2, and then blocked the phosphorylation of IKK through altering the upstream axis. Finally, transfection of a miR-324-5p mimic inhibited the suppression of invasion and metastasis of MDA-MB-231 and 4T1 cell by sinomenine, providing evidence that sinomenine treatment suppressed breast cancer cell invasion and metastasis via regulation of the IL4/miR-324-5p/CUEDC2 axis. Our findings reveal a novel mechanism by which sinomenine suppresses cancer cell invasion and metastasis, i.e., blocking NF-κB activation. - Highlights: • Sinomenine reduced invasion and migration of MDA-MB-231 and 4T1 breast cancer cells.

  11. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.

    PubMed

    Galeano, F; Rossetti, C; Tomaselli, S; Cifaldi, L; Lezzerini, M; Pezzullo, M; Boldrini, R; Massimi, L; Di Rocco, C M; Locatelli, F; Gallo, A

    2013-02-21

    Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.

  12. Helical axis stellarator equilibrium model

    SciTech Connect

    Koniges, A.E.; Johnson, J.L.

    1985-02-01

    An asymptotic model is developed to study MHD equilibria in toroidal systems with a helical magnetic axis. Using a characteristic coordinate system based on the vacuum field lines, the equilibrium problem is reduced to a two-dimensional generalized partial differential equation of the Grad-Shafranov type. A stellarator-expansion free-boundary equilibrium code is modified to solve the helical-axis equations. The expansion model is used to predict the equilibrium properties of Asperators NP-3 and NP-4. Numerically determined flux surfaces, magnetic well, transform, and shear are presented. The equilibria show a toroidal Shafranov shift.

  13. Two-axis angular effector

    DOEpatents

    Vaughn, Mark R.; Robinett, III, Rush D.; Phelan, John R.; Van Zuiden, Don M.

    1997-01-21

    A new class of coplanar two-axis angular effectors. These effectors combine a two-axis rotational joint analogous to a Cardan joint with linear actuators in a manner to produce a wider range of rotational motion about both axes defined by the joint. This new class of effectors also allows design of robotic manipulators having very high strength and efficiency. These effectors are particularly suited for remote operation in unknown surroundings, because of their extraordinary versatility. An immediate application is to the problems which arise in nuclear waste remediation.

  14. Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.

    PubMed

    van Heusden, A M; Fauser, B C

    1999-04-01

    EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.

  15. The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis

    PubMed Central

    Shao, Xuejing; Liu, Yujia; Li, Yangling; Xian, Miao; Zhou, Qian; Yang, Bo; Ying, Meidan; He, Qiaojun

    2016-01-01

    The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). However, AML, with the exception of APL, fails to respond to differentiation therapy. Therefore, research strategies to further sensitize cells to retinoids and to extend the range of AMLs that respond to retinoids beyond APLs are urgently needed. In this study, we showed that TAK165, a HER2 inhibitor, exhibited a strong synergy with ATRA to promote AML cell differentiation. We observed that TAK165 sensitized the AML cells to ATRA-induced cell growth inhibition, G0/G1 phase arrest, CD11b expression, mature morphologic changes, NBT reduction and myeloid regulator expression. Unexpectedly, HER2 pathway might not be essential for TAK165-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of the RARα/STAT1 axis. Furthermore, the MEK/ERK cascade regulated the activation of STAT1. Taken together, our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy. PMID:27074819

  16. Discrimination and the HPA axis: current evidence and future directions.

    PubMed

    Busse, David; Yim, Ilona S; Campos, Belinda; Marshburn, Christopher K

    2017-02-02

    Numerous studies suggest that discrimination is associated with poor physical and mental health outcomes. Whereas the cardiovascular system has been extensively studied as a potential pathway linking discrimination with disease, the role of the hypothalamic-pituitary-adrenal (HPA) axis remains understudied. We conducted a systematic review of research on discrimination and related constructs as predictors and correlates of HPA axis activity. Twenty seven studies (10 experimental, 17 observational) met inclusion criteria. Studies suggest that discrimination is associated with alterations in HPA axis activity and that the direction of this association depends on the timing and chronicity of the discrimination experience. There is also evidence of important modulating variables (race, socioeconomic status) and contextual confounders (emotional, situational) that warrant further study. Accounting for the HPA axis in addition to the cardiovascular system will contribute to a more comprehensive understanding of the biobehavioral pathways contributing to physical and mental health inequities related to discrimination.

  17. GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes*

    PubMed Central

    Tsuchimochi, Kaneyuki; Otero, Miguel; Dragomir, Cecilia L.; Plumb, Darren A.; Zerbini, Luiz F.; Libermann, Towia A.; Marcu, Kenneth B.; Komiya, Setsuro; Ijiri, Kosei; Goldring, Mary B.

    2010-01-01

    GADD45β (growth arrest- and DNA damage-inducible) interacts with upstream regulators of the JNK and p38 stress response kinases. Previously, we reported that the hypertrophic zone of the Gadd45β−/− mouse embryonic growth plate is compressed, and expression of type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13) genes is decreased. Herein, we report that GADD45β enhances activity of the proximal Col10a1 promoter, which contains evolutionarily conserved AP-1, cAMP-response element, and C/EBP half-sites, in synergism with C/EBP family members, whereas the MMP13 promoter responds to GADD45β together with AP-1, ATF, or C/EBP family members. C/EBPβ expression also predominantly co-localizes with GADD45β in the embryonic growth plate. Moreover, GADD45β enhances C/EBPβ activation via MTK1, MKK3, and MKK6, and dominant-negative p38αapf, but not JNKapf, disrupts the combined trans-activating effect of GADD45β and C/EBPβ on the Col10a1 promoter. Importantly, GADD45β knockdown prevents p38 phosphorylation while decreasing Col10a1 mRNA levels but does not affect C/EBPβ binding to the Col10a1 promoter in vivo, indicating that GADD45β influences the transactivation function of DNA-bound C/EBPβ. In support of this conclusion, we show that the evolutionarily conserved TAD4 domain of C/EBPβ is the target of the GADD45β-dependent signaling. Collectively, we have uncovered a novel molecular mechanism linking GADD45β via the MTK1/MKK3/6/p38 axis to C/EBPβ-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes. PMID:20048163

  18. GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes.

    PubMed

    Tsuchimochi, Kaneyuki; Otero, Miguel; Dragomir, Cecilia L; Plumb, Darren A; Zerbini, Luiz F; Libermann, Towia A; Marcu, Kenneth B; Komiya, Setsuro; Ijiri, Kosei; Goldring, Mary B

    2010-03-12

    GADD45beta (growth arrest- and DNA damage-inducible) interacts with upstream regulators of the JNK and p38 stress response kinases. Previously, we reported that the hypertrophic zone of the Gadd45beta(-/-) mouse embryonic growth plate is compressed, and expression of type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13) genes is decreased. Herein, we report that GADD45beta enhances activity of the proximal Col10a1 promoter, which contains evolutionarily conserved AP-1, cAMP-response element, and C/EBP half-sites, in synergism with C/EBP family members, whereas the MMP13 promoter responds to GADD45beta together with AP-1, ATF, or C/EBP family members. C/EBPbeta expression also predominantly co-localizes with GADD45beta in the embryonic growth plate. Moreover, GADD45beta enhances C/EBPbeta activation via MTK1, MKK3, and MKK6, and dominant-negative p38alphaapf, but not JNKapf, disrupts the combined trans-activating effect of GADD45beta and C/EBPbeta on the Col10a1 promoter. Importantly, GADD45beta knockdown prevents p38 phosphorylation while decreasing Col10a1 mRNA levels but does not affect C/EBPbeta binding to the Col10a1 promoter in vivo, indicating that GADD45beta influences the transactivation function of DNA-bound C/EBPbeta. In support of this conclusion, we show that the evolutionarily conserved TAD4 domain of C/EBPbeta is the target of the GADD45beta-dependent signaling. Collectively, we have uncovered a novel molecular mechanism linking GADD45beta via the MTK1/MKK3/6/p38 axis to C/EBPbeta-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes.

  19. Anatomical study of the gastrointestinal tract in free-living axis deer (Axis axis).

    PubMed

    Pérez, W; Erdogan, S; Ungerfeld, R

    2015-02-01

    The macroscopic anatomy of the stomach and intestines of adult axis deer (Axis axis), a cervid species considered intermediate/mixed feeder, was observed and recorded. Nine adult wild axis deers of both sexes were used and studied by simple dissection. The ruminal papillae were distributed unevenly in the overall area of the inner surface of rumen and primarily were more large and abundant within the atrium. The ruminal pillars had no papillae. There was an additional ruminal pillar located between the right longitudinal and right coronary ventral pillars connected to the caudal pillar. No dorsal coronary pillars were found, and the ventral coronary pillars are connected. The reticulum was the third compartment in size, and the maximum height of the reticular crests was 1.0 mm. The Cellulae reticuli were not divided and rarely contained secondary crests. There were no Papillae unguiculiformes. The omasum was the smallest gastric compartment. The abomasum had about twelve spiral plicae, and a small pyloric torus was present. The intraruminal papillation was similar to those species that are characterized by a higher proportion of grass in their natural diet. The finding of the small reticular crests is typical for browser ruminants and was coincident with data reported for other deer. The comparative ratio of the small intestine to the large intestine was 1.69, in terms of length measurements in axis deer and appears below of the 'browser range'. We concluded that the gastrointestinal system of axis deer reflected similar morphological characteristics of the both types of ruminants: browser and grazer, and we consider it as an intermediate feeder.

  20. Three axis velocity probe system

    DOEpatents

    Fasching, George E.; Smith, Jr., Nelson S.; Utt, Carroll E.

    1992-01-01

    A three-axis velocity probe system for determining three-axis positional velocities of small particles in fluidized bed systems and similar applications. This system has a sensor head containing four closely-spaced sensing electrodes of small wires that have flat ends to establish a two axis plane, e.g. a X-Y plane. Two of the sensing electrodes are positioned along one of the axes and the other two are along the second axis. These four sensing electrodes are surrounded by a guard electrode, and the outer surface is a ground electrode and support member for the sensing head. The electrodes are excited by, for example, sinusoidal voltage having a peak-to-peak voltage of up to 500 volts at a frequency of 2 MHz. Capacitive currents flowing between the four sensing electrodes and the ground electrode are influenced by the presence and position of a particle passing the sensing head. Any changes in these currents due to the particle are amplified and synchronously detected to produce positional signal values that are converted to digital form. Using these digital forms and two values of time permit generation of values of the three components of the particle vector and thus the total velocity vector.

  1. No evidence for an effect of traffic noise on the development of the corticosterone stress response in an urban exploiter.

    PubMed

    Angelier, Frédéric; Meillère, Alizée; Grace, Jacquelyn K; Trouvé, Colette; Brischoux, François

    2016-06-01

    Anthropogenic noise can have important physiological and behavioral effects on wild animals. For example, urban noise could lead to a state of chronic stress and could alter the development of the hypothalamus-pituitary-adrenal (HPA) axis. Supporting this hypothesis, several studies have found that human disturbance is associated with increased circulating corticosterone (CORT) levels. However, it remains unclear whether increased CORT levels are the result of anthropogenic noise or other anthropogenic factors. Here, we experimentally tested the impact of urban noise on the CORT stress response in an urban exploiter (the house sparrow, Passer domesticus) by exposing chicks to a traffic noise ('disturbed chicks') or not ('control chicks'). If noise exposure has a negative impact on developing chicks, we predicted that (1) disturbed chicks will grow slower, will be in poorer condition, and will have a lower fledging probability than controls; (2) disturbed chicks will have higher baseline CORT levels than control; (3) the CORT stress response will be affected by this noise exposure. Contrary to these predictions, we found no effect of our experiment on growth, body condition, and fledging success, suggesting that house sparrow chicks were not negatively affected by this noise exposure. Moreover, we did not find any effect of noise exposure on either baseline CORT levels or the CORT stress response of chicks. This suggests not only that house sparrow chicks did not perceive this noise as stressful, but also that the development of the HPA axis was not affected by such noise exposure. Our study suggests that, contrary to urban avoiders, urban exploiters might be relatively insensitive to urban noise during their development. Further comparative studies are now needed to understand whether such insensitivity to anthropogenic noise is a consistent phenomenon in urban exploiters and whether this is a major requirement of an urban way of life.

  2. Layer and broiler chicks exhibit similar hypothalamic expression of orexigenic neuropeptides but distinct expression of genes related to energy homeostasis and obesity.

    PubMed

    Yuan, Lixia; Ni, Yingdong; Barth, Stephan; Wang, Yufeng; Grossmann, Roland; Zhao, Ruqian

    2009-06-01

    Layer and broiler chickens demonstrate striking differences in body weight and body composition. However, the mechanism underlying such difference is elusive. Hypothalamus-pituitary-adrenal (HPA) axis regulates energy homeostasis and body size in mammals, but information in birds is scarce. Here we test the hypothesis that such breed difference is more associated with hypothalamic expression of genes related to HPA axis, rather than orexigenic neuropeptides. Broiler chicks exhibit significantly higher body weight and food intake at day (D) 7 posthatching, but the food intake relative to body weight gain was actually lower. No breed differences were observed for hypothalamic expression of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), orexin (ORX), leptin receptor (LEPR), acetyl-CoA carboxylase (ACC) or fatty acid synthase (FAS). However, broiler chicks expressed significantly higher glucocorticoid receptor (GR) mRNA (P<0.05) and protein (P<0.01) in hypothalamus compared to layer chicks, which is associated with lower corticotropin-releasing hormone (CRH) mRNA (P<0.05) yet higher accumulation of CRH peptide in hypothalamus, suggesting an augmented GR-mediated negative feedback regulation of CRH transcription and release in broiler chicks. Furthermore, fat mass and obesity associated (FTO) gene was also more highly expressed in hypothalamus of broiler chicks (P<0.05). These results suggest that the genes related to energy homeostasis and obesity, such as GR, CRH and FTO, rather than orexigenic neuropeptides, are impacted by the genetic selection practices and play a role in breed-specific body weight setpoint regulation in the chicken.

  3. Prenatal and Postpartum Evening Salivary Cortisol Levels in Association with Peripartum Depressive Symptoms

    PubMed Central

    Iliadis, Stavros I.; Comasco, Erika; Sylvén, Sara; Hellgren, Charlotte; Sundström Poromaa, Inger; Skalkidou, Alkistis

    2015-01-01

    Background The biology of peripartum depression remains unclear, with altered stress and the Hypothalamus-Pituitary-Adrenal axis response having been implicated in its pathophysiology. Methods The current study was undertaken as a part of the BASIC project (Biology, Affect, Stress, Imaging, Cognition), a population-based longitudinal study of psychological wellbeing during pregnancy and the postpartum period in Uppsala County, Sweden, in order to assess the association between evening salivary cortisol levels and depressive symptoms in the peripartum period. Three hundred and sixty-five pregnant women from the BASIC cohort were recruited at pregnancy week 18 and instructed to complete a Swedish validated version of the Edinburgh Postnatal Depression Scale at the 36th week of pregnancy as well as the sixth week after delivery. At both times, they were also asked to provide evening salivary samples for cortisol analysis. A comprehensive review of the relevant literature is also provided. Results Women with postpartum EPDS score ≥ 10 had higher salivary evening cortisol at six weeks postpartum compared to healthy controls (median cortisol 1.19 vs 0.89 nmol/L). A logistic regression model showed a positive association between cortisol levels and depressive symptoms postpartum (OR = 4.1; 95% CI 1.7–9.7). This association remained significant even after controlling for history of depression, use of tobacco, partner support, breastfeeding, stressful life events, and sleep problems, as possible confounders (aOR = 4.5; 95% CI 1.5–14.1). Additionally, women with postpartum depressive symptoms had higher postpartum cortisol levels compared to both women with depressive symptoms antenatally and controls (p = 0.019 and p = 0.004, respectively). Conclusions Women with depressive symptoms postpartum had higher postpartum cortisol levels, indicating an altered response of the HPA-axis in postpartum depression. PMID:26322643

  4. Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior.

    PubMed

    Wu, Ting-Ching; Chen, Han-Ting; Chang, Han-Ying; Yang, Ching-Yao; Hsiao, Mei-Chun; Cheng, Mei-Ling; Chen, Jin-Chung

    2013-06-01

    High level of serum corticosteroid is frequently associated with depression, in which a notable HPA (hypothalamus-pituitary-adrenal) axis hyperactivity is often observed. There are two types of corticosteroid receptors expressed in the hippocampus that provide potent negative feedback regulation on the HPA axis but dysfunction during depression, i.e. the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The balance between hippocampal MR and GR during chronic stress plays an important role in the occurrence of depression. The aim of this study is to explore if chronic corticosterone administration would induce depression-like behavior and affect the expression and function of hippocampal MR and GR, in addition to assess whether manipulation of corticosteroid receptors would modulate depressive behaviors. Hence, mice were treated with corticosterone (40 mg/kg) for 21 days followed by assessment in a battery of depression-like behaviors. The results show that chronic corticosterone-treated animals displayed an increased immobility time in a forced-swimming test, decreased preference to sucrose solution and novel object recognition performance, and enhanced hippocampal serotonin but decreased MR expression in both hippocampus and hypothalamus. On the other hand, co-administration of MR antagonist, spironolactone (25mg/kg, i.p. × 7 days) in corticosteroid-treated animals reduced immobility time in a forced-swimming test and improved performance in a novel object recognition test. In conclusion, we demonstrate that chronic corticosterone treatment triggers several depression-like behaviors, and in parallel, down-regulates MR expression in the hippocampus and hypothalamus. Administration of an MR antagonist confers an anti-depressant effect in chronic corticosterone-treated animals.

  5. Influence of maternal ingestion of Aroclor 1254[reg sign] (PCB) or FireMaster BP-6[reg sign] (PBB) on unstimulated and stimulated corticosterone levels in young rats

    SciTech Connect

    Meserve, L.A.; Murray, B.A.; Landis, J.A. )

    1992-05-01

    The organohalides polychlorinated biphenyl (PCB) and polybrominated biphenyl (PBB) remain troublesome environmental pollutants. For example, the percentage of the population in which PCB is detectable in adipose tissue remains high. These compounds are of particular interest to residents of the North Central United States, especially in regions surrounding the Great Lakes where contaminated fish may be a regular component of the diet. Additionally, PBB was mistakenly fed to cattle and chickens in Michigan during the early 1970s, products of which were ingested by humans. Among the physiological effects of ingestion of PCB or PBB is the depression of thyroid status, which has been reported in adult humans, in adult experimental animals, and in the offspring of these animals. In adult rats, circulating levels of thyroid hormones are inversely proportional to dose of PCB or PBB in the diet. On the other hand, reports of effects of these organohalides on adrenocortical function remain equivocal, describing both PCB- and PBB-induced depression, and absence of effect in rats and monkeys. Despite the possible consequences of maternal ingestion of PCB or PBB on future generations, little work has been done previously to determine whether consumption of these materials by pregnant and lactating animals confers hypothyroidism on their offspring, and/or influences other mechanisms of endocrine control in the young. Since early studies showed that hypothyroidism induced by feeding pregnant rats the goitrogen thiouracil altered the functional capabilities in their young of the hypothalamus-pituitary-adrenal (HPA) axis, as revealed by circulating corticosterone levels, the present study was done to determine whether ingestion of either PCB (Aroclor 1254[reg sign]) or PBB (FireMaster BP-6[reg sign]) by pregnant and lactating rats resulted in depressed thyroid status and/or modified HPA axis function in their 15 day old young. 19 refs., 1 fig., 1 tab.

  6. Integrated Evaluation of Latent Viral Reactivation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Pierson, Duane L.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    This application proposes a continuation of our current effort, which has provided the first demonstration of viral reactivation during space flight. We have used the herpesvirus EBV as a model for latent viral reactivation and have shown that increased amounts of EBV DNA were shed by astronauts during space flight. Analysis of the Antarctic space flight analog indicated that the frequency of viral shedding may also increase (along with the increased numbers of virus) during long periods of isolation. However, a number of critical questions remain before the findings may be considered a significant health risk during extended space flight. These include: Are other latent viruses (e.g., other herpesviruses and polyornaviruses) in addition to EBV also reactivated and shed more frequently and/or in higher numbers during space flight? Is the viral reactivation observed in space flight and ground-based analogs mediated through the hypothalamus-pituitary-adrenal (HPA) axis resulting in a decreased cell-mediated immune response? How does detection of viral DNA by PCR analysis correlate with infectious virus? How does the amount of virus found during flight compare with viral levels observed in acute/chronic viral illnesses and in control individuals? This expanded study will examine the phenomenon of viral reactivation from the initiating stress through the HPA axis with the accompanying suppression of the immune system resulting in viral reactivation. This information is essential to determine if latent viral reactivation among crewmembers represents a sufficient medical risk to space travel to require the development of suitable countermeasures.

  7. Pro-TRH and pro-CRF expression in paraventricular nucleus of small litter-reared fasted adult rats.

    PubMed

    Aréchiga-Ceballos, F; Alvarez-Salas, E; Matamoros-Trejo, G; Amaya, M I; García-Luna, C; de Gortari, P

    2014-04-01

    Neuroendocrine axes adapt to nutrient availability. During fasting, the function of the hypothalamus-pituitary-thyroid axis (HPT) is reduced, whereas that of the hypothalamus-pituitary-adrenal axis (HPA) is increased. Overfeeding-induced hyperleptinemia during lactation may alter the regulatory set point of neuroendocrine axes and their adaptability to fasting in adulthood. Hyperleptinemia is developed in rodents by litter size reduction during lactation; adult rats from small litters become overweight, but their paraventricular nucleus (PVN) TRH synthesis is unchanged. It is unclear whether peptide expression still responds to nutrient availability. PVN corticotropin-releasing factor (CRF) expression has not been evaluated in this model. We analyzed adaptability of HPT and HPA axes to fasting-induced low leptin levels of reduced-litter adult rats. Offspring litters were reduced to 2-3/dam (early-overfed) or maintained at 8/dam (controls, C). At 10 weeks old, a subset of animals from each group was fasted for 48 h and leptin, corticosterone, and thyroid hormones serum levels were analyzed. In brain, expressions of leptin receptor, NPY and SOCS3, were evaluated in arcuate nucleus, and those of proTRH and proCRF in PVN by real-time PCR. ProTRH expression in anterior and medial PVN subcompartments was assayed by in situ hybridization. Early-overfed adults developed hyperphagia and excessive weight, together with decreased proTRH expression in anterior PVN, supporting the anorexigenic effects of TRH. Early-overfed rats presented low PVN proTRH synthesis, whereas fasting did not induce a further reduction. Fasting-induced stress was unable to increase corticosterone levels, contributing to reduced body weight loss in early-overfed rats. We concluded that early overfeeding impaired the adaptability of HPT and HPA axes to excess weight and fasting in adults.

  8. Angle interferometer cross axis errors

    SciTech Connect

    Bryan, J.B.; Carter, D.L.; Thompson, S.L.

    1994-01-01

    Angle interferometers are commonly used to measure surface plate flatness. An error can exist when the centerline of the double comer cube mirror assembly is not square to the surface plate and the guide bar for the mirror sled is curved. Typical errors can be one to two microns per meter. A similar error can exist in the calibration of rotary tables when the centerline of the double comer cube mirror assembly is not square to the axes of rotation of the angle calibrator and the calibrator axis is not parallel to the rotary table axis. Commercial double comer cube assemblies typically have non-parallelism errors of ten milli-radians between their centerlines and their sides and similar values for non-squareness between their centerlines and end surfaces. The authors have developed a simple method for measuring these errors and correcting them by remachining the reference surfaces.

  9. Angle interferometer cross axis errors

    NASA Astrophysics Data System (ADS)

    Bryan, J. B.; Carter, D. L.; Thompson, S. L.

    1994-01-01

    Angle interferometers are commonly used to measure surface plate flatness. An error can exist when the centerline of the double comer cube mirror assembly is not square to the surface plate and the guide bar for the mirror sled is curved. Typical errors can be one to two microns per meter. A similar error can exist in the calibration of rotary tables when the centerline of the double comer cube mirror assembly is not square to the axes of rotation of the angle calibrator and the calibrator axis is not parallel to the rotary table axis. Commercial double comer cube assemblies typically have non-parallelism errors of ten milli-radians between their centerlines and their sides and similar values for non-squareness between their centerlines and end surfaces. The authors have developed a simple method for measuring these errors and correcting them.