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Sample records for circadian disruption induced

  1. Disrupting circadian rhythms in rats induces retrograde amnesia

    NARCIS (Netherlands)

    Fekete, Mátyás; Ree, J.M. van; Niesink, Raymond J.M.; Wied, D. de

    1985-01-01

    Disrupting circadian organization in rats by phase-shifting the illumination cycle or by exposure to a reversed day/night cycle or to continuous light, resulted in retrograde amnesia for passive avoidance behavior. This retrograde amnesia induced by phase-shifting lasted at least 2 days, and gradual

  2. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats

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    Vinogradova, Irina A.; Anisimov, Vladimir N.; Bukalev, Andrey V.; Semenchenko, Anna V.; Zabezhinski, Mark A.

    2009-01-01

    We evaluated the effect of various light/dark regimens on the survival, life span and tumorigenesis in rats. Two hundred eight male and 203 females LIO rats were subdivided into 4 groups and kept at various light/dark regimens: standard 12:12 light/dark (LD); natural lighting of the North-West of Russia (NL); constant light (LL), and constant darkness (DD) since the age of 25 days until natural death. We found that exposure to NL and LL regimens accelerated development of metabolic syndrome and spontaneous tumorigenesis, shortened life span both in male and females rats as compared to the standard LD regimen. We conclude that circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans. PMID:20157558

  3. Endocrine Effects of Circadian Disruption.

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    Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J

    2016-01-01

    Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems. PMID:26208951

  4. Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal.

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    Xiang, Shulin; Dauchy, Robert T; Hauch, Adam; Mao, Lulu; Yuan, Lin; Wren, Melissa A; Belancio, Victoria P; Mondal, Debasis; Frasch, Tripp; Blask, David E; Hill, Steven M

    2015-08-01

    Chemotherapeutic resistance, particularly to doxorubicin (Dox), represents a major impediment to successfully treating breast cancer and is linked to elevated tumor metabolism and tumor over-expression and/or activation of various families of receptor- and non-receptor-associated tyrosine kinases. Disruption of circadian time structure and suppression of nocturnal melatonin production by dim light exposure at night (dLEN), as occurs with shift work, and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of an array of diseases, including breast cancer. Melatonin inhibits human breast cancer growth via mechanisms that include the suppression of tumor metabolism and inhibition of expression or phospho-activation of the receptor kinases AKT and ERK1/2 and various other kinases and transcription factors. We demonstrate in tissue-isolated estrogen receptor alpha-positive (ERα+) MCF-7 human breast cancer xenografts, grown in nude rats maintained on a light/dark cycle of LD 12:12 in which dLEN is present during the dark phase (suppressed endogenous nocturnal melatonin), a significant shortening of tumor latency-to-onset, increased tumor metabolism and growth, and complete intrinsic resistance to Dox therapy. Conversely, a LD 12:12 dLEN environment incorporating nocturnal melatonin replacement resulted in significantly lengthened tumor latency-to-onset, tumor regression, suppression of nighttime tumor metabolism, and kinase and transcription factor phosphorylation, while Dox sensitivity was completely restored. Melatonin acts as both a tumor metabolic inhibitor and circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to Dox and drive tumor regression, indicating that dLEN-induced circadian disruption of nocturnal melatonin production contributes to a complete loss of tumor sensitivity to Dox chemotherapy. PMID:25857269

  5. Sleep and circadian rhythm disruption in schizophrenia†

    OpenAIRE

    Wulff, Katharina; Dijk, Derk-Jan; Middleton, Benita; Foster, Russell G.; Joyce, Eileen M.

    2012-01-01

    Background Sleep disturbances comparable with insomnia occur in up to 80% of people with schizophrenia, but very little is known about the contribution of circadian coordination to these prevalent disruptions. Aims A systematic exploration of circadian time patterns in individuals with schizophrenia with recurrent sleep disruption. Method We examined the relationship between sleep-wake activity, recorded actigraphically over 6 weeks, along with ambient light exposure and simultaneous circadia...

  6. Circadian disruption and breast cancer: an epigenetic link?

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    Kochan, David Z; Kovalchuk, Olga

    2015-07-10

    Breast cancer is already the most common malignancy affecting women worldwide, and evidence is mounting that breast cancer induced by circadian disruption (CD) is a warranted concern. Numerous studies have investigated various aspects of the circadian clock in relation to breast cancer, and evidence from these studies indicates that melatonin and the core clock genes can play a crucial role in breast cancer development. Even though epigenetics has been increasingly recognized as a key player in the etiology of breast cancer and linked to circadian rhythms, and there is evidence of overlap between epigenetic deregulation and breast cancer induced by circadian disruption, only a handful of studies have directly investigated the role of epigenetics in CD-induced breast cancer. This review explores the circadian clock and breast cancer, and the growing role of epigenetics in breast cancer development and circadian rhythms. We also summarize the current knowledge and next steps for the investigation of the epigenetic link in CD-induced breast cancer. PMID:26220712

  7. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in young but not in old rats

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    Vinogradova, Irina A.; Anisimov, Vladimir N.; Bukalev, Andrey V.; Ilyukha, Viktor A.; Khizhkin, Evgeniy A.; Lotosh, Tatiana A.; Semenchenko, Anna V.; Zabezhinski, Mark A.

    2010-01-01

    We evaluated the effect of exposure to constant light started at the age of 1 month and at the age of 14 months on the survival, life span, tumorigenesis and age-related dynamics of antioxidant enzymes activity in various organs in comparison to the rats maintained at the standard (12:12 light/dark) light/dark regimen. We found that exposure to constant light started at the age of 1 month accelerated spontaneous tumorigenesis and shortened life span both in male and female rats as compared to the standard regimen. At the same time, the exposure to constant light started at the age of 14 months failed to influence survival of male and female rats. While delaying tumors in males, constant light accelerated tumors in females. We conclude that circadian disruption induced by light-at-night started at the age of 1 month accelerates aging and promotes tumorigenesis in rats, however failed affect survival when started at the age of 14 months. PMID:20354269

  8. Circadian Disruption and Diet-Induced Obesity Synergize to Promote Development of β-Cell Failure and Diabetes in Male Rats.

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    Qian, Jingyi; Yeh, Bonnie; Rakshit, Kuntol; Colwell, Christopher S; Matveyenko, Aleksey V

    2015-12-01

    There are clear epidemiological associations between circadian disruption, obesity, and pathogenesis of type 2 diabetes. The mechanisms driving these associations are unclear. In the current study, we hypothesized that continuous exposure to constant light (LL) compromises pancreatic β-cell functional and morphological adaption to diet-induced obesity leading to development of type 2 diabetes. To address this hypothesis, we studied wild type Sprague Dawley as well as Period-1 luciferase reporter transgenic rats (Per1-Luc) for 10 weeks under standard light-dark cycle (LD) or LL with concomitant ad libitum access to either standard chow or 60% high-fat diet (HFD). Exposure to HFD led to a comparable increase in food intake, body weight, and adiposity in both LD- and LL-treated rats. However, LL rats displayed profound loss of behavioral circadian rhythms as well as disrupted pancreatic islet clock function characterized by the impairment in the amplitude and the phase islet clock oscillations. Under LD cycle, HFD did not adversely alter diurnal glycemia, diurnal insulinemia, β-cell secretory function as well as β-cell survival, indicating successful adaptation to increased metabolic demand. In contrast, concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of diurnal changes in insulin secretion, compromised β-cell function, and induction of β-cell apoptosis. This study suggests that circadian disruption and diet-induced obesity synergize to promote development of β-cell failure, likely mediated as a consequence of impaired islet clock function. PMID:26348474

  9. Carcinogenic effects of circadian disruption: an epigenetic viewpoint.

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    Salavaty, Abbas

    2015-08-08

    Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.

  10. Social memory in the rat: circadian variation and effect of circadian rhythm disruption

    NARCIS (Netherlands)

    Reijmers, L.G.J.E.; Leus, I.E.; Burbach, J.P.H.; Spruijt, B.M.; Ree, van J.M.

    2001-01-01

    Disruption of circadian rhythm can impair long-term passive avoidance memory of rats and mice. The present study investigated whether disruption of circadian rhythm can also impair social memory of male rats. Social memory was assessed using the social discrimination test, in which a short-term olfa

  11. Sleep Deprivation and Circadian Disruption: Stress, Allostasis, and Allostatic Load.

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    McEwen, Bruce S; Karatsoreos, Ilia N

    2015-03-01

    Sleep has important homeostatic functions, and circadian rhythms organize physiology and behavior on a daily basis to insure optimal function. Sleep deprivation and circadian disruption can be stressors, enhancers of other stressors that have consequences for the brain and many body systems. Whether the origins of circadian disruption and sleep disruption and deprivation are from anxiety, depression, shift work, long-distance air travel, or a hectic lifestyle, there are consequences that impair brain functions and contribute to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation. PMID:26055668

  12. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice.

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    Susie Lee

    Full Text Available BACKGROUND: Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per or Cryptochrome1 and 2 (Cry are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. CONCLUSIONS/SIGNIFICANCE: Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.

  13. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

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    Udoh, Uduak S.; Valcin, Jennifer A.; Gamble, Karen L.; Bailey, Shannon M.

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. PMID:26473939

  14. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

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    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  15. Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury.

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    Li, Dongpeng; Ma, Shanshan; Guo, Dewei; Cheng, Tian; Li, Hongwei; Tian, Yi; Li, Jianbin; Guan, Fangxia; Yang, Bo; Wang, Jian

    2016-10-01

    Circadian rhythms modulate many physiologic processes and behaviors. Therefore, their disruption causes a variety of potential adverse effects in humans and animals. Circadian disruption induced by constant light exposure has been discovered to produce pathophysiologic consequences after brain injury. However, the underlying mechanisms that lead to more severe impairment and disruption of neurophysiologic processes are not well understood. Here, we evaluated the effect of constant light exposure on the neurobehavioral impairment and survival of neurons in rats after traumatic brain injury (TBI). Sixty adult male Sprague-Dawley rats were subjected to a weight-drop model of TBI and then exposed to either a standard 12-/12-h light/dark cycle or a constant 24-h light/light cycle for 14 days. Our results showed that 14 days of constant light exposure after TBI significantly worsened the sensorimotor and cognitive deficits, which were associated with decreased body weight, impaired water and food intake, increased cortical lesion volume, and decreased neuronal survival. Furthermore, environmental circadian disruption inhibited cell proliferation and newborn cell survival and decreased immature cell production in rats subjected to the TBI model. We conclude that circadian disruption induced by constant light exposure worsens histologic and neurobehavioral impairment and inhibits neurogenesis in adult TBI rats. Our novel findings suggest that light exposure should be decreased and circadian rhythm reestablished in hospitalized TBI patients and that drugs and strategies that maintain circadian rhythm would offer a novel therapeutic option. PMID:26886755

  16. Circadian Disruption Alters the Effects of Lipopolysaccharide Treatment on Circadian and Ultradian Locomotor Activity and Body Temperature Rhythms of Female Siberian Hamsters.

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    Prendergast, Brian J; Cable, Erin J; Stevenson, Tyler J; Onishi, Kenneth G; Zucker, Irving; Kay, Leslie M

    2015-12-01

    The effect of circadian rhythm (CR) disruption on immune function depends on the method by which CRs are disrupted. Behavioral and thermoregulatory responses induced by lipopolysaccharide (LPS) treatment were assessed in female Siberian hamsters in which circadian locomotor activity (LMA) rhythms were eliminated by exposure to a disruptive phase-shifting protocol (DPS) that sustains arrhythmicity even when hamsters are housed in a light-dark cycle. This noninvasive treatment avoids genome manipulations and neurological damage associated with other models of CR disruption. Circadian rhythmic (RHYTH) and arrhythmic (ARR) hamsters housed in a 16L:8D photocycle were injected with bacterial LPS near the onset of the light (zeitgeber time 1; ZT1) or dark (ZT16) phase. LPS injections at ZT16 and ZT1 elicited febrile responses in both RHYTH and ARR hamsters, but the effect was attenuated in the arrhythmic females. In ZT16, LPS inhibited LMA in the dark phase immediately after injection but not on subsequent nights in both chronotypes; in contrast, LPS at ZT1 elicited more enduring (~4 day) locomotor hypoactivity in ARR than in RHYTH hamsters. Power and period of dark-phase ultradian rhythms (URs) in LMA and Tb were markedly altered by LPS treatment, as was the power in the circadian waveform. Disrupted circadian rhythms in this model system attenuated responses to LPS in a trait- and ZT-specific manner; changes in UR period and power are novel components of the acute-phase response to infection that may affect energy conservation.

  17. Biomarkers for Circadian Rhythm Disruption Independent of Time of Day

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    Van Dycke, Kirsten C. G.; Pennings, Jeroen L. A.; van Oostrom, Conny T. M.; van Kerkhof, Linda W. M.; van Steeg, Harry; van der Horst, Gijsbertus T. J.; Rodenburg, Wendy

    2015-01-01

    Frequent shift work causes disruption of the circadian rhythm and might on the long-term result in increased health risk. Current biomarkers evaluating the presence of circadian rhythm disturbance (CRD), including melatonin, cortisol and body temperature, require 24-hr (“around the clock”) measurements, which is tedious. Therefore, these markers are not eligible to be used in large-scale (human) studies. The aim of the present study was to identify universal biomarkers for CRD independent of time of day using a transcriptomics approach. Female FVB mice were exposed to six shifts in a clockwise (CW) and counterclockwise (CCW) CRD protocol and sacrificed at baseline and after 1 shift, 6 shifts, 5 days recovery and 14 days recovery, respectively. At six time-points during the day, livers were collected for mRNA microarray analysis. Using a classification approach, we identified a set of biomarkers able to classify samples into either CRD or non-disrupted based on the hepatic gene expression. Furthermore, we identified differentially expressed genes 14 days after the last shift compared to baseline for both CRD protocols. Non-circadian genes differentially expressed upon both CW and CCW protocol were considered useful, universal markers for CRD. One candidate marker i.e. CD36 was evaluated in serum samples of the CRD animals versus controls. These biomarkers might be useful to measure CRD and can be used later on for monitoring the effectiveness of intervention strategies aiming to prevent or minimize chronic adverse health effects. PMID:25984797

  18. Facilitated physiological adaptation to prolonged circadian disruption through dietary supplementation with essence of chicken.

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    Wu, Tao; Yao, Cencen; Tsang, Fai; Huang, Liangfeng; Zhang, Wanjing; Jiang, Jianguo; Mao, Youxiang; Shao, Yujian; Kong, Boda; Singh, Paramjeet; Fu, Zhengwei

    2015-01-01

    Synchrony between circadian and metabolic processes is critical to the maintenance of energy homeostasis. Studies on essence of chicken (EC), a chicken meat extract rich in proteins, amino acids and peptides, showed its effectiveness in alleviating fatigue and promoting metabolism. A recent study revealed that it facilitated the re-entrainment of clock genes (Bmal1, Cry1, Dec1, Per1 and Per2) in the pineal gland and liver in a rat model of circadian disruption. Here, we investigated the role of EC-facilitated circadian synchrony in the maintenance of the energy homeostasis using a mouse model of prolonged circadian disruption. Prolonged circadian disruption (12 weeks) resulted in hepatic maladaptation, manifested by a mild but significant (p maladaptation. When supplemented with EC, the functional impairment and inflammation were abolished. The protective effects could be linked to its effectiveness in maintaining the synchrony between the master and hepatic clocks, and the resultant improved coupling of the circadian oscillators (Per1, Cry1, Dec1, Bmal1) and metabolic regulators (mTOR, AMPK). Overall, EC supplementation promoted the physiological adaptation to the prolonged circadian disruption through facilitation of endogenous circadian synchrony and the coupling of circadian oscillators and metabolic regulators. This forms an important basis for further elucidation of the physiological benefits of EC-facilitated circadian synchrony. PMID:26595385

  19. Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Depression

    OpenAIRE

    Roberto Salgado-Delgado; Araceli Tapia Osorio; Nadia Saderi; Carolina Escobar

    2011-01-01

    Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationsh...

  20. The Circadian Timing System and Environmental Circadian Disruption: From Follicles to Fertility.

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    Sen, Aritro; Sellix, Michael T

    2016-09-01

    The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility. PMID:27501186

  1. Circadian clock genes Per1 and Per2 regulate the response of metabolism-associated transcripts to sleep disruption.

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    Jana Husse

    Full Text Available Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction--TSR. We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects

  2. Hypergravity disruption of homeorhetic adaptations to lactation in rat dams include changes in circadian clocks

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    Theresa Casey

    2012-04-01

    Altered gravity load induced by spaceflight (microgravity and centrifugation (hypergravity is associated with changes in circadian, metabolic, and reproductive systems. Exposure to 2-g hypergravity (HG during pregnancy and lactation decreased rate of mammary metabolic activity and increased pup mortality. We hypothesize HG disrupted maternal homeorhetic responses to pregnancy and lactation are due to changes in maternal metabolism, hormone concentrations, and maternal behavior related to gravity induced alterations in circadian clocks. Effect of HG exposure on mammary, liver and adipose tissue metabolism, plasma hormones and maternal behavior were analyzed in rat dams from mid-pregnancy (Gestational day [G]11 through early lactation (Postnatal day [P]3; comparisons were made across five time-points: G20, G21, P0 (labor and delivery, P1 and P3. Blood, mammary, liver, and adipose tissue were collected for analyzing plasma hormones, glucose oxidation to CO2 and incorporation into lipids, or gene expression. Maternal behavioral phenotyping was conducted using time-lapse videographic analyses. Dam and fetal-pup body mass were significantly reduced in HG in all age groups. HG did not affect labor and delivery; however, HG pups experienced a greater rate of mortality. PRL, corticosterone, and insulin levels and receptor genes were altered by HG. Mammary, liver and adipose tissue metabolism and expression of genes that regulate lipid metabolism were altered by HG exposure. Exposure to HG significantly changed expression of core clock genes in mammary and liver and circadian rhythms of maternal behavior. Gravity load alterations in dam's circadian system may have impacted homeorhetic adaptations needed for a successful lactation.

  3. Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Depression

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    Roberto Salgado-Delgado

    2011-01-01

    Full Text Available Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.

  4. Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.

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    Yoshihiro Yasuniwa

    Full Text Available Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L, the other is a more "normal" 12-hour light/dark cycle (L/D. We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF. DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

  5. Melatonin attenuates photic disruption of circadian rhythms in Siberian hamsters.

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    Ruby, N F; Kang, T; Heller, H C

    1997-10-01

    Body temperature (Tb) was recorded via a biotelemetry system from 28 adult male Siberian hamsters maintained in a light-dark (LD) cycle of 16 h light/day for several months. After Tb was recorded for 3 wk, the LD cycle was phase delayed by extending the light phase by 5 h for 1 day; animals remained on a 16:8 LD cycle for the remainder of the experiment. Hamsters were injected daily with melatonin or vehicle solution for several weeks, beginning either 2 mo after (experiment 1) or on the day of (experiment 2) the phase shift; injections occurred within 30 min of dark onset. In experiment 1, 75% of animals free ran with circadian periods >24 h, beginning on the day of the phase shift, and never reentrained to the LD cycle; no hamsters unambiguously entrained to daily injections. In contrast, 78% of animals in experiment 2 entrained to melatonin injections, and 71% of those animals subsequently reentrained to the photocycle when the injection regimen ended. No vehicle-treated animals entrained to the injection schedule. Melatonin had no effect on daily mean Tb and Tb rhythm amplitude in either experiment; however, melatonin doubled the duration of a hyperthermic response that occurred after each injection. Thus melatonin can prevent loss of entrainment induced by a phase shift of the LD cycle but cannot restore entrainment to free-running animals. Failure to reentrain in the presence of two appropriately coordinated entraining agents also suggests that a phase shift of the photocycle can diminish the sensitivity of the circadian system to both photic and nonphotic input.

  6. Disruption of circadian rhythm increases the risk of cancer, metabolic syndrome and cardiovascular disease

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    Vignesh Shanmugam

    2013-03-01

    Full Text Available Incidents of non-communicable diseases (NCD like cardiovascular diseases, cancer, diabetes, and chronic respiratory disease have increased dramatically and are currently the leading causes of death worldwide. Their rising incidents coincide with the dramatic changes in industrialization and development of societies over the past few hundred years. Therefore, current lifestyle practices should be further explored to uncover novel risk factors for certain cancers (i.e. colon, prostate, and breast cancer, metabolic syndrome (i.e. diabetes and obesity, and cardiovascular disease (i.e. coronary artery disease. This review discusses how a disruption of the “biological clock” or circadian rhythms could be involved in the development of these diseases as circadian rhythms control multiple physiological processes such as wake/sleep cycles, hormonal levels, body temperature, metabolism, and immune system.Several environmental factors that disrupt circadian rhythms can be identified including exposure to artificial light and electromagnetic (EM waves, unbalanced diet and night shift work. The mechanisms of how these “chronodisruptors” are associated with NCDs will be discussed. Furthermore, the involvement of genetic factors in the disturbance of circadian rhythms and predisposition to NCDs will be highlighted.Overall there is strong evidence from animal models and epidemiological studies underlining that circadian disruption is a significant player in several diseases particularly the multifactorial diseases that pose a significant public health challenge in contemporary society. A circadian disruption-based model of cancer, metabolic syndrome and cardiovascular disease etiology can be proposed. But, to fully understand the complex interactions of the different components in the network of disease development due to disruption of circadian rhythms, more investigations are needed to unravel the causal relationship between modern lifestyle

  7. Environmental perturbation of the circadian clock disrupts pregnancy in the mouse.

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    Keith C Summa

    Full Text Available BACKGROUND: The circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD cycle, adversely affects reproductive success in mice. METHODOLOGY/PRINCIPAL FINDINGS: Young adult female C57BL/6J (B6 mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were subjected to 6-hr delays or advances in the LD cycle every 5-6 days, respectively. The number of copulations resulting in term pregnancies was determined. Control females had a full-term pregnancy success rate of 90% (11/12, which fell to 50% (9/18; p<0.1 in the phase-delay group and 22% (4/18; p<0.01 in the phase-advance group. CONCLUSIONS/SIGNIFICANCE: Repeated shifting of the LD cycle, which disrupts endogenous circadian timekeeping, dramatically reduces pregnancy success in mice. Advances of the LD cycle have a greater negative impact on pregnancy outcomes and, in non-pregnant female mice, require longer for circadian re-entrainment, suggesting that the magnitude or duration of circadian misalignment may be related to the severity of the adverse impact on pregnancy. These results explicitly link disruptions of circadian entrainment to adverse pregnancy outcomes in mammals, which may have important implications for the reproductive health of female shift workers, women with circadian rhythm sleep disorders and/or women with disturbed circadian rhythms for other

  8. When clocks go bad: neurobehavioural consequences of disrupted circadian timing.

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    Alun R Barnard

    2008-05-01

    Full Text Available Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain's critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.

  9. The relationship between circadian disruption and the development of metabolic syndrome and type 2 diabetes

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    Karatsoreos IN

    2014-12-01

    Full Text Available Ilia N Karatsoreos Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Abstract: Circadian (daily rhythms are pervasive in nature, and expressed in nearly every behavioral and physiological process. In mammals, circadian rhythms are regulated by the master brain clock in the suprachiasmatic nucleus of the hypothalamus that coordinates the activity of “peripheral” oscillators throughout the brain and body. While much progress has been made in understanding the basic functioning of the circadian clock at the level of genes, molecules, and cells, our understanding of how these clocks interact with complex systems is still in its infancy. Much recent work has focused on the role of circadian clocks in the etiology of disorders as diverse as cancer, diabetes, and obesity. Given the rapid rise in obesity, and the economic costs involved in treating its associated cardiometabolic disorders such as heart disease and diabetes mellitus, understanding the development of obesity and metabolic dysregulation is crucial. Significant epidemiological data indicate a role for circadian rhythms in metabolic disorders. Shift workers have a higher incidence of obesity and diabetes, and laboratory studies in humans show misaligning sleep and the circadian clock leads to hyperinsulinemia. In animal models, body-wide “clock gene” knockout mice are prone to obesity. Further, disrupting the circadian clock by manipulating the light–dark cycle can result in metabolic dysregulation and development of obesity. At the molecular level, elegant studies have shown that targeted disruption of the genetic circadian clock in the pancreas leads to diabetes, highlighting the fact that the circadian clock is directly coupled to metabolism at the cellular level. Keywords: glucose, metabolism, sleep, rhythms, obesity

  10. Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

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    Stevens, Richard G; Zhu, Yong

    2015-05-01

    Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution. PMID:25780233

  11. Does circadian disruption play a role in the metabolic-hormonal link to delayed lactogenesis II?

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    Manjie eFu

    2015-02-01

    Full Text Available Breastfeeding improves maternal and child health. The American Academy of Pediatrics recommends exclusive breastfeeding for six months, with continued breastfeeding for at least one year. However, in the US, only 18.8% of infants are exclusively breastfed until six months of age. For mothers who initiate breastfeeding, the early postpartum period sets the stage for sustained breastfeeding. Mothers who experience breastfeeding problems in the early postpartum period are more likely to discontinue breastfeeding within two weeks. A major risk factor for shorter breastfeeding duration is delayed lactogenesis II (i.e. onset of milk coming in more than 72 h postpartum. Recent studies report a metabolic-hormonal link to delayed lactogenesis II. This is not surprising because around the time of birth the mother’s entire metabolism changes to direct nutrients to mammary glands. Circadian and metabolic systems are closely linked, and our rodent studies suggest circadian clocks coordinate hormonal and metabolic changes to support lactation. Molecular and environmental disruption of the circadian system decreases a dam’s ability to initiate lactation and negatively impacts milk production. Circadian and metabolic systems evolved to be functional and adaptive when lifestyles and environmental exposures were quite different from modern times. We now have artificial lights, longer work days, and increases in shift work. Disruption in the circadian system due to shift work, jet lag, sleep disorders and other modern life style choices are associated with metabolic disorders, obesity, and impaired reproduction. We hypothesize delayed lactogenesis II is related to disruption of the mother’s circadian system. Here we review literature that supports this hypothesis, and describe interventions that may help to increase breastfeeding success.

  12. Disrupted Circadian Rhythm as a Common Player in Developmental Models of Neuropsychiatric Disorders.

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    Marco, Eva M; Velarde, Elena; Llorente, Ricardo; Laviola, Giovanni

    2016-01-01

    The environment in which individuals develop and mature is critical for their physiological and psychological outcome; in particular, the intrauterine environment has reached far more clinical relevance given its potential influence on shaping brain function and thus mental health. Gestational stress and/or maternal infection during pregnancy has been related with an increased incidence of neuropsychiatric disorders, including depression and schizophrenia. In this framework, the use of animal models has allowed a formal and deep investigation of causal determinants. Despite disruption of circadian clocks often represents a hallmark of several neuropsychiatric disorders, the relationship between disruption of brain development and the circadian system has been scarcely investigated. Nowadays, there is an increasing amount of studies suggesting a link between circadian system malfunction, early-life insults and the appearance of neuropsychiatric diseases at adulthood. Here, we briefly review evidence from clinical literature and animal models suggesting that the exposure to prenatal insults, i.e. severe gestational stress or maternal immune activation, changes the foetal hormonal milieu increasing the circulating levels of both glucocorticoids and pro-inflammatory cytokines. These two biological events have been reported to affect genes expression in experimental models and critically interfere with brain development triggering and/or exacerbating behavioural anomalies in the offspring. Herein, we highlight the importance to unravel the individual components of the body circadian system that might also be altered by prenatal insults and that may be causally associated with the disruption of neural and endocrine developmental programming. PMID:26728169

  13. Neonatal monosodium glutamate treatment counteracts circadian arrhythmicity induced by phase shifts of the light-dark cycle in female and male Siberian hamsters.

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    Prendergast, Brian J; Onishi, Kenneth G; Zucker, Irving

    2013-07-12

    Studies of rats and voles suggest that distinct pathways emanating from the anterior hypothalamic-retrochiasmatic area and the mediobasal hypothalamic arcuate nucleus independently generate ultradian rhythms (URs) in hormone secretion and behavior. We evaluated the hypothesis that destruction of arcuate nucleus (ARC) neurons, in concert with dampening of suprachiasmatic nucleus (SCN) circadian rhythmicity, would compromize the generation of ultradian rhythms (URs) of locomotor activity. Siberian hamsters retain-->of both sexes treated neonatally with monosodium glutamate (MSG) that destroys ARC neurons were subjected in adulthood to a circadian disrupting phase-shift protocol (DPS) that produces SCN arrhythmia. MSG treatments induced hypogonadism and obesity, retain-->and markedly reduced the size of the optic chiasm and optic nerves. MSG-treated hamsters exhibited normal entrainment to the light-dark cycle, but MSG treatretain-->ment counteracted the circadian arrhythmicity induced by the DPS protocol: only 6% of retain-->MSG-treated hamsters exhibited circadian arrhythmia, whereas 50% of control hamsters were circadian disrupted. In MSG-treated hamsters that retained circadian rhythmicity after DPS treatment, quantitative parameters of URs appeared normal, but in the two MSG-treated hamsters that became circadian arrhythmic after DPS, both dark-phase and light-phase URs were abolished. Although preliminary, these data are consistent with reports in voles suggesting that the combined disruption of SCN and ARC function impairs the expression of behavioral URs. The data also suggest that light thresholds for entrainment of circadian rhythms may be lower than those required to disrupt circadian organization.

  14. A metabolomic study of adipose tissue in mice with a disruption of the circadian system.

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    Castro, C; Briggs, W; Paschos, G K; FitzGerald, G A; Griffin, J L

    2015-07-01

    Adipose tissue functions in terms of energy homeostasis as a rheostat for blood triglyceride, regulating its concentration, in response to external stimuli. In addition it acts as a barometer to inform the central nervous system of energy levels which can vary dramatically between meals and according to energy demand. Here a metabolomic approach, combining both Mass Spectrometry and Nuclear Magnetic Resonance spectroscopy, was used to analyse both white and brown adipose tissue in mice with adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component. The results are consistent with a peripheral circadian clock playing a central role in metabolic regulation of both brown and white adipose tissue in rodents and show that Arntl induced global changes in both tissues which were distinct for the two types. In particular, anterior subcutaneous white adipose tissue (ASWAT) tissue was effected by a reduction in the degree of unsaturation of fatty acids, while brown adipose tissue (BAT) changes were associated with a reduction in chain length. In addition the aqueous fraction of metabolites in BAT were profoundly affected by Arntl disruption, consistent with the dynamic role of this tissue in maintaining body temperature across the day-night cycle and an upregulation in fatty acid oxidation and citric acid cycle activity to generate heat during the day when rats are inactive (increases in 3-hydroxybutyrate and glutamate), and increased synthesis and storage of lipids during the night when rats feed more (increased concentrations of glycerol, choline and glycerophosphocholine).

  15. Breast cancer and circadian disruption from electric lighting in the modern world.

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    Stevens, Richard G; Brainard, George C; Blask, David E; Lockley, Steven W; Motta, Mario E

    2014-01-01

    Breast cancer is the leading cause of cancer death among women worldwide, and there is only a limited explanation of why. Risk is highest in the most industrialized countries but also is rising rapidly in the developing world. Known risk factors account for only a portion of the incidence in the high-risk populations, and there has been considerable speculation and many false leads on other possibly major determinants of risk, such as dietary fat. A hallmark of industrialization is the increasing use of electricity to light the night, both within the home and without. It has only recently become clear that this evolutionarily new and, thereby, unnatural exposure can disrupt human circadian rhythmicity, of which three salient features are melatonin production, sleep, and the circadian clock. A convergence of research in cells, rodents, and humans suggests that the health consequences of circadian disruption may be substantial. An innovative experimental model has shown that light at night markedly increases the growth of human breast cancer xenografts in rats. In humans, the theory that light exposure at night increases breast cancer risk leads to specific predictions that are being tested epidemiologically: evidence has accumulated on risk in shift workers, risk in blind women, and the impact of sleep duration on risk. If electric light at night does explain a portion of the breast cancer burden, then there are practical interventions that can be implemented, including more selective use of light and the adoption of recent advances in lighting technology and application.

  16. Breast cancer and circadian disruption from electric lighting in the modern world.

    Science.gov (United States)

    Stevens, Richard G; Brainard, George C; Blask, David E; Lockley, Steven W; Motta, Mario E

    2014-01-01

    Breast cancer is the leading cause of cancer death among women worldwide, and there is only a limited explanation of why. Risk is highest in the most industrialized countries but also is rising rapidly in the developing world. Known risk factors account for only a portion of the incidence in the high-risk populations, and there has been considerable speculation and many false leads on other possibly major determinants of risk, such as dietary fat. A hallmark of industrialization is the increasing use of electricity to light the night, both within the home and without. It has only recently become clear that this evolutionarily new and, thereby, unnatural exposure can disrupt human circadian rhythmicity, of which three salient features are melatonin production, sleep, and the circadian clock. A convergence of research in cells, rodents, and humans suggests that the health consequences of circadian disruption may be substantial. An innovative experimental model has shown that light at night markedly increases the growth of human breast cancer xenografts in rats. In humans, the theory that light exposure at night increases breast cancer risk leads to specific predictions that are being tested epidemiologically: evidence has accumulated on risk in shift workers, risk in blind women, and the impact of sleep duration on risk. If electric light at night does explain a portion of the breast cancer burden, then there are practical interventions that can be implemented, including more selective use of light and the adoption of recent advances in lighting technology and application. PMID:24604162

  17. Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction.

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    Jaeger, Cassie; Tischkau, Shelley A

    2016-01-01

    The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. AhR binds a range of ligands, which prompts protein-protein interactions with other Per-Arnt-Sim (PAS)-domain-containing proteins and subsequent transcriptional activity. This review focuses on the reciprocal crosstalk between the activated AhR and the molecular circadian clock. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR activation influences the amplitude and phase of expression of circadian clock genes, hormones, and the behavioral responses of the clock system to changes in environmental illumination. Both the clock and AhR status and activation play significant and underappreciated roles in metabolic homeostasis. This review highlights the state of knowledge regarding how AhR may act together with the circadian clock to influence energy metabolism. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism. PMID:27559298

  18. Circadian dysfunction in a rotenone-induced parkinsonian rodent model.

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    Lax, Pedro; Esquiva, Gema; Esteve-Rudd, Julian; Otalora, Beatriz Baño; Madrid, Juan Antonio; Cuenca, Nicolás

    2012-03-01

    Parkinson's disease (PD) is a neurodegenerative disorder that also involves circadian rhythm alterations. Modifications of circadian rhythm parameters have been shown to occur in both PD patients and toxin-induced PD animal models. In the latter case, rotenone, a potent inhibitor of mitochondrial complex I (nicotinamide adenine dinucleotide [NADH]-quinone reductase), has been used to elicit degeneration of dopaminergic neurons and development of parkinsonian syndrome. The present work addresses alterations induced by rotenone on both locomotor and body temperature circadian rhythms in rats. Rotenone-treated rats exhibited abnormalities in equilibrium, postural instability, and involuntary movements. Long-term subcutaneous administration of rotenone significantly reduced mean daily locomotor activity in most animals. During rotenone administration, mean body temperatures (BTs) and BT rhythm amplitudes were significantly lower than those observed in the control group. After long-term rotenone administration, the circadian rhythms of both locomotor activity (LA) and BT displayed decreased amplitudes, lower interdaily phase stability, and higher rhythm fragmentation, as compared to the control rats. The magnitude of the LA and BT circadian rhythm alterations induced by rotenone positively correlated with degree of motor impairment. These results indicate that rotenone induces circadian dysfunction in rats through some of the same mechanisms as those responsible for the development of motor disturbances.

  19. Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.

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    Arble, Deanna M; Bass, Joseph; Behn, Cecilia Diniz; Butler, Matthew P; Challet, Etienne; Czeisler, Charles; Depner, Christopher M; Elmquist, Joel; Franken, Paul; Grandner, Michael A; Hanlon, Erin C; Keene, Alex C; Joyner, Michael J; Karatsoreos, Ilia; Kern, Philip A; Klein, Samuel; Morris, Christopher J; Pack, Allan I; Panda, Satchidananda; Ptacek, Louis J; Punjabi, Naresh M; Sassone-Corsi, Paolo; Scheer, Frank A; Saxena, Richa; Seaquest, Elizabeth R; Thimgan, Matthew S; Van Cauter, Eve; Wright, Kenneth P

    2015-12-01

    A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

  20. Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver.

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    Wang, Danfeng; Chen, Siyu; Liu, Mei; Liu, Chang

    2015-06-01

    Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.

  1. Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention.

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    Smolensky, Michael H; Hermida, Ramon C; Reinberg, Alain; Sackett-Lundeen, Linda; Portaluppi, Francesco

    2016-01-01

    Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ τ 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood

  2. Nocturnal light pollution and underexposure to daytime sunlight: Complementary mechanisms of circadian disruption and related diseases.

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    Smolensky, Michael H; Sackett-Lundeen, Linda L; Portaluppi, Francesco

    2015-01-01

    Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like--now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children--is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm λ) spectrum synchronizes the CTS and whose UV-B (290-315 nm λ) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light

  3. Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans.

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    Cuesta, Marc; Boudreau, Philippe; Dubeau-Laramée, Geneviève; Cermakian, Nicolas; Boivin, Diane B

    2016-03-15

    Recent research unveiled a circadian regulation of the immune system in rodents, yet little is known about rhythms of immune functions in humans and how they are affected by circadian disruption. In this study, we assessed rhythms of cytokine secretion by immune cells and tested their response to simulated night shifts. PBMCs were collected from nine participants kept in constant posture over 24 h under a day-oriented schedule (baseline) and after 3 d under a night-oriented schedule. Monocytes and T lymphocytes were stimulated with LPS and PHA, respectively. At baseline, a bimodal rhythmic secretion was detected for IL-1β, IL-6, and TNF-α: a night peak was primarily due to a higher responsiveness of monocytes, and a day peak was partly due to a higher proportion of monocytes. A rhythmic release was also observed for IL-2 and IFN-γ, with a nighttime peak due to a higher cell count and responsiveness of T lymphocytes. Following night shifts, with the exception of IL-2, cytokine secretion was still rhythmic but with peak levels phase advanced by 4.5-6 h, whereas the rhythm in monocyte and T lymphocyte numbers was not shifted. This suggests distinct mechanisms of regulation between responsiveness to stimuli and cell numbers of the human immune system. Under a night-oriented schedule, only cytokine release was partly shifted in response to the change in the sleep-wake cycle. This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers. PMID:26873990

  4. Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention.

    Science.gov (United States)

    Blask, David E; Dauchy, Robert T; Dauchy, Erin M; Mao, Lulu; Hill, Steven M; Greene, Michael W; Belancio, Victoria P; Sauer, Leonard A; Davidson, Leslie

    2014-01-01

    The central circadian clock within the suprachiasmatic nucleus (SCN) plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect) and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN)-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor. PMID:25099274

  5. Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention.

    Directory of Open Access Journals (Sweden)

    David E Blask

    Full Text Available The central circadian clock within the suprachiasmatic nucleus (SCN plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor.

  6. Sleep loss and the inflammatory response in mice under chronic environmental circadian disruption.

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    Allison J Brager

    Full Text Available Shift work and trans-time zone travel lead to insufficient sleep and numerous pathologies. Here, we examined sleep/wake dynamics during chronic exposure to environmental circadian disruption (ECD, and if chronic partial sleep loss associated with ECD influences the induction of shift-related inflammatory disorder. Sleep and wakefulness were telemetrically recorded across three months of ECD, in which the dark-phase of a light-dark cycle was advanced weekly by 6 h. A three month regimen of ECD caused a temporary reorganization of sleep (NREM and REM and wake processes across each week, resulting in an approximately 10% net loss of sleep each week relative to baseline levels. A separate group of mice were subjected to ECD or a regimen of imposed wakefulness (IW aimed to mimic sleep amounts under ECD for one month. Fos-immunoreactivity (IR was quantified in sleep-wake regulatory areas: the nucleus accumbens (NAc, basal forebrain (BF, and medial preoptic area (MnPO. To assess the inflammatory response, trunk blood was treated with lipopolysaccharide (LPS and subsequent release of IL-6 was measured. Fos-IR was greatest in the NAc, BF, and MnPO of mice subjected to IW. The inflammatory response to LPS was elevated in mice subjected to ECD, but not mice subjected to IW. Thus, the net sleep loss that occurs under ECD is not associated with a pathological immune response.

  7. Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease.

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    Yao, Hongwei; Sundar, Isaac K; Huang, Yadi; Gerloff, Janice; Sellix, Michael T; Sime, Patricia J; Rahman, Irfan

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBβ, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.

  8. Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity

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    Jonathan eShelton

    2015-01-01

    Full Text Available Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6 induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg. Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15 or advance (CT22 wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light-induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals.

  9. Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light.

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    Natalia Mendez

    Full Text Available Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a 'time giver' for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further

  10. The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer

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    Braun Donald P

    2011-05-01

    Full Text Available Abstract Background Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer. Methods We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months. Results We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health

  11. Genetic Disruption of the Core Circadian Clock Impairs Hippocampus-Dependent Memory

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    Wardlaw, Sarah M.; Phan, Trongha X.; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R.

    2014-01-01

    Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1[superscript -/-] mice, which are arrhythmic…

  12. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.

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    Dauchy, Robert T; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G; Blask, David E; Hill, Steven M

    2014-08-01

    Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ERα(+)) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

  13. Circadian Modulation of Alcohol-Induced Sedation and Recovery in Male and Female Drosophila.

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    De Nobrega, Aliza K; Lyons, Lisa C

    2016-04-01

    Delineating the factors that affect behavioral and neurological responses to alcohol is critical to facilitate measures for preventing or treating alcohol abuse. The high degree of conserved molecular and physiological processes makes Drosophila melanogaster a valuable model for investigating circadian interactions with alcohol-induced behaviors and examining sex-specific differences in alcohol sensitivity. We found that wild-type Drosophila exhibited rhythms in alcohol-induced sedation under light-dark and constant dark conditions with considerably greater alcohol exposure necessary to induce sedation during the late (subjective) day and peak sensitivity to alcohol occurring during the late (subjective) night. The circadian clock also modulated the recovery from alcohol-induced sedation with flies regaining motor control significantly faster during the late (subjective) day. As predicted, the circadian rhythms in sedation and recovery were absent in flies with a mutation in the circadian gene period or arrhythmic flies housed in constant light conditions. Flies lacking a functional circadian clock were more sensitive to the effects of alcohol with significantly longer recovery times. Similar to other animals and humans, Drosophila exhibit sex-specific differences in alcohol sensitivity. We investigated whether the circadian clock modulated the rhythms in the loss-of-righting reflex, alcohol-induced sedation, and recovery differently in males and females. We found that both sexes demonstrated circadian rhythms in the loss-of-righting reflex and sedation with the differences in alcohol sensitivity between males and females most pronounced during the late subjective day. Recovery of motor reflexes following alcohol sedation also exhibited circadian modulation in male and female flies, although the circadian clock did not modulate the difference in recovery times between the sexes. These studies provide a framework outlining how the circadian clock modulates alcohol-induced

  14. High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring.

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    Sarah J Borengasser

    Full Text Available The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER and metabolic (PPARα, SIRT1 genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i decreased mRNA synthesis rates; and ii increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPAR

  15. Postnatal constant light compensates Cryptochrome1 and 2 double deficiency for disruption of circadian behavioral rhythms in mice under constant dark.

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    Daisuke Ono

    Full Text Available Clock genes Cryptochrome (Cry1 and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD. However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN of neonatal Cry1 and Cry2 double deficient (Cry1 (-/-/Cry2 (-/- mice. A lack of circadian rhythms in adult Cry1 (-/-/Cry2 (-/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1 (-/-/Cry2 (-/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1 (-/-/Cry2 (-/- mice, but failed to detect the rhythms in Cry1 (-/-/Cry2 (-/- mice raised under light-dark cycles (LD. By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1 (-/-/Cry2 (-/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1(-/-/Cry2(-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1(-/-/Cry2(-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in

  16. Circadian mechanisms in the regulation of melatonin synthesis: disruption with light at night and the pathophysiological consequences

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    Ahmet Korkmaz

    2011-02-01

    Full Text Available In the past two decades, the results of a number of epidemiological studies have uncovered an association between excessive light exposure at night and the prevalence of cancer. Whereas the evidence supporting this link is strongest between nighttime light and female breast and male prostate cancer, the frequency of other tumor types may also be elevated. Individuals who have the highest reported increase in cancer are chronic night shift workers and flight attendants who routinely fly across numerous time zones. There are at least two obvious physiological consequences of nighttime light exposure, i.e., a reduction in circulating melatonin levels and disruption of the circadian system (chronodisruption. Both these perturbations in experimental animals aggravate tumor growth. Melatonin has a long investigative history in terms of its ability to stymie the growth of many tumor types. Likewise, in the last decade chronodisruption has been unequivocally linked to a variety of abnormal metabolic conditions including excessive tumor growth. This brief review summarizes the processes by which light after darkness onset impedes melatonin production and disturbs circadian rhythms. The survey also reviews the evidence associating the ostensible danger of excessive nighttime light pollution to cancer risk. If an elevated tumor frequency is definitively proven to be a consequence of light at night and/or chronodisruption, it seems likely that cancer will not be the exclusive pathophysiological change associated with the rampant light pollution characteristic of modern societies. [J Exp Integr Med 2011; 1(1: 13-22

  17. Minimum criteria for DNA damage-induced phase advances in circadian rhythms.

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    Christian I Hong

    2009-05-01

    Full Text Available Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK, and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1. It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa. However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs from either dexamethasone (Dex or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1 existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2 Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK.

  18. Circadian clocks and breast cancer

    OpenAIRE

    Blakeman, Victoria; Jack L. Williams; Meng, Qing-Jun; Streuli, Charles H

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, an...

  19. Emergence of noise-induced oscillations in the central circadian pacemaker.

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    Caroline H Ko

    Full Text Available Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

  20. Relative metabolic stability, but disrupted circadian cortisol secretion during the fasting month of Ramadan.

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    Suhad Bahijri

    Full Text Available BACKGROUND: Chronic feeding and sleep schedule disturbances are stressors that exert damaging effects on the organism. Practicing Muslims in Saudi Arabia go through strict Ramadan fasting from dawn till sunset for one month yearly. Modern era Ramadan practices in Saudi Arabia are associated with disturbed feeding and sleep patterns, namely abstaining from food and water and increasing daytime sleep, and staying awake and receiving food and water till dawn. HYPOTHESIS: Strict Ramadan practices in Saudi Arabia may influence metabolism, sleep and circadian cortisol secretion. PROTOCOL: Young, male Ramadan practitioners were evaluated before and two weeks into the Ramadan. Blood samples were collected at 9.00 am and 9.00 pm for measurements of metabolic parameters and cortisol. Saliva was collected serially during the day for cortisol determinations. RESULTS: Ramadan practitioners had relative metabolic stability or changes expected by the pattern of feeding. However, the cortisol circadian rhythm was abolished and circulating insulin levels and HOMA index were increased during this period. DISCUSSION: The flattening of the cortisol rhythm is typical of conditions associated with chronic stress or endogenous hypercortisolism and associated with insulin resistance. CONCLUSIONS: Modern Ramadan practices in Saudi Arabia are associated with evening hypercortisolism and increased insulin resistance. These changes might contribute to the high prevalence of chronic stress-related conditions, such as central obesity, hypertension, metabolic syndrome and diabetes mellitus type 2, and their cardiovascular sequelae observed in the Kingdom.

  1. Modelling and analysis of the feeding regimen induced entrainment of hepatocyte circadian oscillators using petri nets.

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    Samar Hayat Khan Tareen

    Full Text Available Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.

  2. Sleep loss and circadian disruption in shift work: health burden and management.

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    Rajaratnam, Shantha M W; Howard, Mark E; Grunstein, Ronald R

    2013-10-21

    About 1.5 million Australians are shift workers. Shift work is associated with adverse health, safety and performance outcomes. Circadian rhythm misalignment, inadequate and poor-quality sleep, and sleep disorders such as sleep apnoea, insomnia and shift work disorder (excessive sleepiness and/or insomnia temporally associated with the work schedule) contribute to these associations. Falling asleep at work at least once a week occurs in 32%-36% of shift workers. Risk of occupational accidents is at least 60% higher for non-day shift workers. Shift workers also have higher rates of cardiometabolic diseases and mood disturbances. Road and workplace accidents related to excessive sleepiness, to which shift work is a significant contributor, are estimated to cost $71-$93 billion per annum in the United States. There is growing evidence that understanding the interindividual variability in sleep-wake responses to shift work will help detect and manage workers vulnerable to the health consequences of shift work. A range of approaches can be used to enhance alertness in shift workers, including screening and treating sleep disorders, melatonin treatment to promote sleep during the daytime, and avoidance of inappropriate use of sedatives and wakefulness-promoters such as modafinil and caffeine. Short naps, which minimise sleep inertia, are generally effective. Shifting the circadian pacemaker with appropriately timed melatonin and/or bright light may be used to facilitate adjustment to a shift work schedule in some situations, such as a long sequence of night work. It is important to manage the health risk of shift workers by minimising vascular risk factors through dietary and other lifestyle approaches.

  3. Dominant-negative CK2alpha induces potent effects on circadian rhythmicity.

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    Elaine M Smith

    2008-01-01

    Full Text Available Circadian clocks organize the precise timing of cellular and behavioral events. In Drosophila, circadian clocks consist of negative feedback loops in which the clock component PERIOD (PER represses its own transcription. PER phosphorylation is a critical step in timing the onset and termination of this feedback. The protein kinase CK2 has been linked to circadian timing, but the importance of this contribution is unclear; it is not certain where and when CK2 acts to regulate circadian rhythms. To determine its temporal and spatial functions, a dominant negative mutant of the catalytic alpha subunit, CK2alpha(Tik, was targeted to circadian neurons. Behaviorally, CK2alpha(Tik induces severe period lengthening (approximately 33 h, greater than nearly all known circadian mutant alleles, and abolishes detectable free-running behavioral rhythmicity at high levels of expression. CK2alpha(Tik, when targeted to a subset of pacemaker neurons, generates period splitting, resulting in flies exhibiting both long and near 24-h periods. These behavioral effects are evident even when CK2alpha(Tik expression is induced only during adulthood, implicating an acute role for CK2alpha function in circadian rhythms. CK2alpha(Tik expression results in reduced PER phosphorylation, delayed nuclear entry, and dampened cycling with elevated trough levels of PER. Heightened trough levels of per transcript accompany increased protein levels, suggesting that CK2alpha(Tik disturbs negative feedback of PER on its own transcription. Taken together, these in vivo data implicate a central role of CK2alpha function in timing PER negative feedback in adult circadian neurons.

  4. Heterogeneity induces rhythms of weakly coupled circadian neurons.

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    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H T

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574

  5. Sympathetic Activation Induces Skeletal Fgf23 Expression in a Circadian Rhythm-dependent Manner*

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    Kawai, Masanobu; Kinoshita, Saori; Shimba, Shigeki; Ozono, Keiichi; Michigami, Toshimi

    2014-01-01

    The circadian clock network is well known to link food intake and metabolic outputs. Phosphorus is a pivotal nutritional factor involved in energy and skeletal metabolisms and possesses a circadian profile in the circulation; however, the precise mechanisms whereby phosphate metabolism is regulated by the circadian clock network remain largely unknown. Because sympathetic tone, which displays a circadian profile, is activated by food intake, we tested the hypothesis that phosphate metabolism was regulated by the circadian clock network through the modification of food intake-associated sympathetic activation. Skeletal Fgf23 expression showed higher expression during the dark phase (DP) associated with elevated circulating FGF23 levels and enhanced phosphate excretion in the urine. The peaks in skeletal Fgf23 expression and urine epinephrine levels, a marker for sympathetic tone, shifted from DP to the light phase (LP) when mice were fed during LP. Interestingly, β-adrenergic agonist, isoproterenol (ISO), induced skeletal Fgf23 expression when administered at ZT12, but this was not observed in Bmal1-deficient mice. In vitro reporter assays revealed that ISO trans-activated Fgf23 promoter through a cAMP responsive element in osteoblastic UMR-106 cells. The mechanism of circadian regulation of Fgf23 induction by ISO in vivo was partly explained by the suppressive effect of Cryptochrome1 (Cry1) on ISO signaling. These results indicate that the regulation of skeletal Fgf23 expression by sympathetic activity is dependent on the circadian clock system and may shed light on new regulatory networks of FGF23 that could be important for understanding the physiology of phosphate metabolism. PMID:24302726

  6. Melanopsin resets circadian rhythms in cells by inducing clock gene Period1

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    Yamashita, Shuhei; Uehara, Tomoe; Matsuo, Minako; Kikuchi, Yo; Numano, Rika

    2014-02-01

    The biochemical, physiological and behavioral processes are under the control of internal clocks with the period of approximately 24 hr, circadian rhythms. The expression of clock gene Period1 (Per1) oscillates autonomously in cells and is induced immediately after a light pulse. Per1 is an indispensable member of the central clock system to maintain the autonomous oscillator and synchronize environmental light cycle. Per1 expression could be detected by Per1∷luc and Per1∷GFP plasmid DNA in which firefly luciferase and Green Fluorescence Protein were rhythmically expressed under the control of the mouse Per1 promoter in order to monitor mammalian circadian rhythms. Membrane protein, MELANOPSIN is activated by blue light in the morning on the retina and lead to signals transduction to induce Per1 expression and to reset the phase of circadian rhythms. In this report Per1 induction was measured by reporter signal assay in Per1∷luc and Per1∷GFP fibroblast cell at the input process of circadian rhythms. To the result all process to reset the rhythms by Melanopsin is completed in single cell like in the retina projected to the central clock in the brain. Moreover, the phase of circadian rhythm in Per1∷luc cells is synchronized by photo-activated Melanopsin, because the definite peak of luciferase activity in one dish was found one day after light illumination. That is an available means that physiological circadian rhythms could be real-time monitor as calculable reporter (bioluminescent and fluorescent) chronological signal in both single and groups of cells.

  7. Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse.

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    Tsuchiya, Yoshiki; Minami, Yoichi; Umemura, Yasuhiro; Watanabe, Hitomi; Ono, Daisuke; Nakamura, Wataru; Takahashi, Tomoyuki; Honma, Sato; Kondoh, Gen; Matsuishi, Toyojiro; Yagita, Kazuhiro

    2015-12-01

    Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.

  8. Interaction of circadian rhythm and opiate-induced thermic and kinetic responses: a biotelemetric investigation.

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    Dafters, R I; Taggart, P

    1990-01-01

    The thermic and kinetic effects of a low dose of morphine sulphate (5mg/kg) were monitored using a remote biotelemetric procedure. Drug and control (saline) injections were administered at two times of day, during the high and low phases of the circadian temperature/activity cycle respectively. Standard measures of the responses revealed that the effect of a dose of morphine differs significantly according to the phase of the circadian rhythm in which it is administered. In contrast to previous studies employing standard stress-inducing rectal probing techniques of temperature measurement, the direction and time-course of thermic and kinetic responses were uncorrelated. The implications for research on physiological and behavioral drug effects and for theories of drug tolerance/dependence are considered. PMID:2266784

  9. The circadian rhythm induced by the heterogeneous network structure of the suprachiasmatic nucleus

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    Gu, Changgui; Yang, Huijie

    2016-05-01

    In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure.

  10. Lmo mutants reveal a novel role for circadian pacemaker neurons in cocaine-induced behaviors.

    Directory of Open Access Journals (Sweden)

    Linus T-Y Tsai

    2004-12-01

    Full Text Available Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LN(vs, is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LN(vfunction,Lmomutants also show defects in circadian rhythms of behavior. However, the role for LN(vs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LN(vs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LN(vs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug.

  11. Depletion of white adipose tissue in cancer cachexia syndrome is associated with inflammatory signaling and disrupted circadian regulation.

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    Maria Tsoli

    Full Text Available Involuntary weight loss in patients with cancer is the hallmark of cancer cachexia. The etiology of cachexia is multifactorial involving loss of skeletal muscle and adipose tissue associated with high systemic levels of acute phase proteins and inflammatory cytokines. While muscle wasting overtly impacts on cancer patient quality of life, loss of lipid depots represents a sustained energy imbalance. In this study fat depletion was examined in Colon-26 model of cancer cachexia, which is a widely used rodent model of this syndrome. We investigated diurnal expression of circadian rhythm regulators as well as key mediators of energy metabolism and cytokine signaling. Mice bearing the C26 tumour exhibited reduced adipose mass, elevated adipose tissue lipolysis and a 5-fold increase in plasma levels of free fatty acids. These changes were associated with activated IL-6 signaling in WAT through a 3-fold increase in phosphorylated STAT3 and high SOCS3 gene expression levels. In addition perturbations in circadian regulation of lipid metabolism were also observed. Lipid catabolism did not appear to be influenced by the classical PKA pathway activating the lipase HSL. ATGL protein levels were elevated 2-fold in cachectic mice while 4-fold increase phosphorylated ACC and a 2-fold decrease in phosphorylated 4EBP1 was observed indicating that lipid metabolism is modulated by the ATGL & AMPK/mTOR pathways. This study provides evidence for activation of cytokine signaling and concomitant alterations in circadian rhythm and regulators of lipid metabolism in WAT of cachectic animals.

  12. Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking.

    Science.gov (United States)

    Swanson, Garth R; Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Kaminsky, Thomas; Van Den Berg, Jolice; Murphy, Terrence; Raeisi, Shohreh; Fogg, Louis; Vitaterna, Martha Hotz; Forsyth, Christopher; Turek, Fred; Burgess, Helen J; Keshavarzian, Ali

    2016-07-01

    Alcohol-induced intestinal hyperpermeability (AIHP) is a known risk factor for alcoholic liver disease (ALD), but only 20-30% of heavy alcoholics develop AIHP and ALD. The hypothesis of this study is that circadian misalignment would promote AIHP. We studied two groups of healthy subjects on a stable work schedule for 3 mo [day workers (DW) and night workers (NW)]. Subjects underwent two circadian phase assessments with sugar challenge to access intestinal permeability between which they drank 0.5 g/kg alcohol daily for 7 days. Sleep architecture by actigraphy did not differ at baseline or after alcohol between either group. After alcohol, the dim light melatonin onset (DLMO) in the DW group did not change significantly, but in the NW group there was a significant 2-h phase delay. Both the NW and DW groups had no change in small bowel permeability with alcohol, but only in the NW group was there an increase in colonic and whole gut permeability. A lower area under the curve of melatonin inversely correlated with increased colonic permeability. Alcohol also altered peripheral clock gene amplitude of peripheral blood mononuclear cells in CLOCK, BMAL, PER1, CRY1, and CRY2 in both groups, and inflammatory markers lipopolysaccharide-binding protein, LPS, and IL-6 had an elevated mesor at baseline in NW vs. DW and became arrhythmic with alcohol consumption. Together, our data suggest that central circadian misalignment is a previously unappreciated risk factor for AIHP and that night workers may be at increased risk for developing liver injury with alcohol consumption. PMID:27198191

  13. Treatment of Sleep Deprivation-induced Circadian Rhythm Disorder by Applying Garlic Cream on Acupoint Shenque(CV 8)

    Institute of Scientific and Technical Information of China (English)

    WU Dong; SHI Na; ZHU Chong-tian; HUANG Yong; ZHU Zhong-chun

    2007-01-01

    To observe the regulative effect of applying garlic cream on acupoint Shenque (CV8) on circadian rhythm disorder induced by sleep deprivation.Methods:Twenty healthy adult men were randomly divided into normal group(group A),sleep deprivation group (group B) and treatment group (group C).Subjects in group B and C received 48-hour sleep deprivation,and in the meantime subjects in group C were treated by applying garlic cream on acupoint Shenque(CV8),while subjects in group A received no any treatment,then contents of serum noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were detected.Results:The contents of NA in three groups all appeared typical circadian rhythm(P<0.01 when group A is compared with group C,and P<0.05 when group A is compared with group B).The peak value in group A was 158.377 and appeared at 10:56,peak value in group B was 291.529 and appeared at 19:44,peak value in group C was 255.964 and appeared at 17:06.The peak phase in group B shifted more obviously when compared with group A,and the peak phase in group C recovered slightly when compared with group B.The contents of 5-HT in group A showed typical circadian rhythm (P<0.01) and the circadian rhythms in group B and C disappeared (P>0.05).the peak value in group A was 196.563 and appeared at about13:10.Conclusion:The application of garlic cream on acupoint Shenque (CV8) Can adjust the disturbed circadian rhythm and accelerate the recovery of circadian rhythm.It is a simple and effective therapeutic method for adjusting circadian rhythm disorder.

  14. Chromatin Dynamics of Circadian Transcription

    OpenAIRE

    Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

    2015-01-01

    The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Disruption of this transcriptional program leads to a variety of pathologies, including insomnia, depression and metabolic disorders. Circadian rhythms in gene expression rely on specific chromatin transitions which are ultimately coordinated by the molecular clock. As a consequence, a highly plastic and dynamic circadian epigenome can be delineated across different tissues and cell types. Intrigui...

  15. Circadian Rhythms and Breast Cancer: The Role of Per2 in Doxorubicin-Induced Cell Death

    Directory of Open Access Journals (Sweden)

    Megan I. Mitchell

    2015-01-01

    a need for more effective adjuvant therapies to increase cancer cell susceptibility has arisen. This study was therefore aimed at characterizing the role of Per2 in normal breast epithelia (MCF-12A and in ER− breast cancer cells (MDA-MB-231 and also at determining the role of Per2 in doxorubicin-induced cell death. In both cell lines Per2 protein expression displayed a 24-hour circadian rhythm in both cell lines. Per2 was located predominantly in the cytoplasm, with nuclear localization observed with lower cytoplasmic fluorescent intensities. Our results show that Per2 silencing effectively sensitizes the chemoresistant MDA-MB-231 breast cancer cells to the cytotoxic effects of doxorubicin.

  16. Deletion of the secretory vesicle proteins IA-2 and IA-2β disrupts circadian rhythms of cardiovascular and physical activity

    OpenAIRE

    Kim, Soo Mi; Power, Andrea; Brown, Timothy M.; Constance, Cara M.; Coon, Steven L.; Nishimura, Takuya; Hirai, Hiroki; Cai, Tao; Eisner, Christoph; David R Weaver; Piggins, Hugh D.; Klein, David C.; Schnermann, Jürgen; Notkins, Abner L.

    2009-01-01

    Targeted deletion of IA-2 and IA-2β, major autoantigens in type 1 diabetes and transmembrane secretory vesicle proteins, results in impaired secretion of hormones and neurotransmitters. In the present study, we evaluated the effect of these deletions on daily rhythms in blood pressure, heart rate, core body temperature, and spontaneous physical and neuronal activity. We found that deletion of both IA-2 and IA-2β profoundly disrupts the usual diurnal variation of each of these parameters, wher...

  17. Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis.

    Science.gov (United States)

    Gagnidze, Khatuna; Hajdarovic, Kaitlyn H; Moskalenko, Marina; Karatsoreos, Ilia N; McEwen, Bruce S; Bulloch, Karen

    2016-05-17

    Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERBα mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERBα may mediate the circadian effect on survival following VSV infection. Blocking REV-ERBα activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERBα-mediated inhibition of CCL2 expression during viral-induced encephalitis may have a protective effect. PMID:27143721

  18. The role of the endocrine system in feeding-induced tissue-specific circadian entrainment.

    Science.gov (United States)

    Sato, Miho; Murakami, Mariko; Node, Koichi; Matsumura, Ritsuko; Akashi, Makoto

    2014-07-24

    The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type-dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding-mediated tissue-specific entrainment.

  19. Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.

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    Jorien Laermans

    Full Text Available BACKGROUND: In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF, a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS: Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD. Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test. Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS: The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. CONCLUSIONS: This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and

  20. Circadian rhythm modulates long-term potentiation induced at CA1 in rat hippocampal slices.

    Science.gov (United States)

    Nakatsuka, Hiroki; Natsume, Kiyohisa

    2014-03-01

    Circadian rhythm affects neuronal plasticity. Consistent with this, some forms of synaptic long-term potentiation (LTP) are modulated by the light/dark cycle (LD cycle). For example, this type of modulation is observed in hippocampal slices. In rodents, which are nocturnal, LTP is usually facilitated in the dark phase, but the rat hippocampal CA1 is an exception. The reason why LTP in the dark phase is suppressed in CA1 remains unknown. Previously, LTP was induced with high-frequency stimulation. In this study, we found that in the dark phase, theta-burst stimulation-induced LTP is indeed facilitated in CA1, similar to other regions in the rodent brain. Population excitatory postsynaptic potentials (pEPSP)-LTP and population spikes (PS)-LTP were recorded at CA1. The magnitude of PS-LTP in dark-phase slices was significantly larger than in light-phase slices, while that of pEPSP-LTP was unchanged. Using antidromic-orthodromic stimulation, we found that recurrent inhibition is suppressed in the dark phase. Local gabazine-application to stratum pyramidale in light-phase slices mimicked this disinhibition and facilitated LTP in dark-phase slices. These results suggest that the disinhibition of a GABAA recurrent inhibitory network can be induced in the dark phase, thereby facilitating LTP.

  1. Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis.

    Science.gov (United States)

    Rao, R; DuBois, D; Almon, R; Jusko, W J; Androulakis, I P

    2016-08-01

    The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology. PMID:27221115

  2. Hydrogen sulfide induced disruption of Na+ homeostasis in the cortex.

    Science.gov (United States)

    Chao, Dongman; He, Xiaozhou; Yang, Yilin; Balboni, Gianfranco; Salvadori, Severo; Kim, Dong H; Xia, Ying

    2012-07-01

    Maintenance of ionic balance is essential for neuronal functioning. Hydrogen sulfide (H(2)S), a known toxic environmental gaseous pollutant, has been recently recognized as a gasotransmitter involved in numerous biological processes and is believed to play an important role in the neural activities under both physiological and pathological conditions. However, it is unclear if it plays any role in maintenance of ionic homeostasis in the brain under physiological/pathophysiological conditions. Here, we report by directly measuring Na(+) activity using Na(+) selective electrodes in mouse cortical slices that H(2)S donor sodium hydrosulfide (NaHS) increased Na(+) influx in a concentration-dependent manner. This effect could be partially blocked by either Na(+) channel blocker or N-methyl-D-aspartate receptor (NMDAR) blocker alone or almost completely abolished by coapplication of both blockers but not by non-NMDAR blocker. These data suggest that increased H(2)S in pathophysiological conditions, e.g., hypoxia/ischemia, potentially causes a disruption of ionic homeostasis by massive Na(+) influx through Na(+) channels and NMDARs, thus injuring neural functions. Activation of delta-opioid receptors (DOR), which reduces Na(+) currents/influx in normoxia, had no effect on H(2)S-induced Na(+) influx, suggesting that H(2)S-induced disruption of Na(+) homeostasis is resistant to DOR regulation and may play a major role in neuronal injury in pathophysiological conditions, e.g., hypoxia/ischemia.

  3. Activity/inactivity circadian rhythm shows high similarities between young obesity-induced rats and old rats.

    Science.gov (United States)

    Bravo Santos, R; Delgado, J; Cubero, J; Franco, L; Ruiz-Moyano, S; Mesa, M; Rodríguez, A B; Uguz, C; Barriga, C

    2016-03-01

    The objective of the present study was to compare differences between elderly rats and young obesity-induced rats in their activity/inactivity circadian rhythm. The investigation was motivated by the differences reported previously for the circadian rhythms of both obese and elderly humans (and other animals), and those of healthy, young or mature individuals. Three groups of rats were formed: a young control group which was fed a standard chow for rodents; a young obesity-induced group which was fed a high-fat diet for four months; and an elderly control group with rats aged 2.5 years that was fed a standard chow for rodents. Activity/inactivity data were registered through actimetry using infrared actimeter systems in each cage to detect activity. Data were logged on a computer and chronobiological analysis were performed. The results showed diurnal activity (sleep time), nocturnal activity (awake time), amplitude, acrophase, and interdaily stability to be similar between the young obesity-induced group and the elderly control group, but different in the young control group. We have concluded that obesity leads to a chronodisruption status in the body similar to the circadian rhythm degradation observed in the elderly.

  4. Activity/inactivity circadian rhythm shows high similarities between young obesity-induced rats and old rats.

    Science.gov (United States)

    Bravo Santos, R; Delgado, J; Cubero, J; Franco, L; Ruiz-Moyano, S; Mesa, M; Rodríguez, A B; Uguz, C; Barriga, C

    2016-03-01

    The objective of the present study was to compare differences between elderly rats and young obesity-induced rats in their activity/inactivity circadian rhythm. The investigation was motivated by the differences reported previously for the circadian rhythms of both obese and elderly humans (and other animals), and those of healthy, young or mature individuals. Three groups of rats were formed: a young control group which was fed a standard chow for rodents; a young obesity-induced group which was fed a high-fat diet for four months; and an elderly control group with rats aged 2.5 years that was fed a standard chow for rodents. Activity/inactivity data were registered through actimetry using infrared actimeter systems in each cage to detect activity. Data were logged on a computer and chronobiological analysis were performed. The results showed diurnal activity (sleep time), nocturnal activity (awake time), amplitude, acrophase, and interdaily stability to be similar between the young obesity-induced group and the elderly control group, but different in the young control group. We have concluded that obesity leads to a chronodisruption status in the body similar to the circadian rhythm degradation observed in the elderly. PMID:27030628

  5. Circadian Rhythms

    Science.gov (United States)

    ... body function and health? Circadian rhythms can influence sleep-wake cycles, hormone release, body temperature and other important bodily functions. They have been linked to various sleep disorders, such as insomnia. Abnormal circadian rhythms have also ...

  6. Circadian systems biology in Metazoa.

    Science.gov (United States)

    Lin, Li-Ling; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2015-11-01

    Systems biology, which can be defined as integrative biology, comprises multistage processes that can be used to understand components of complex biological systems of living organisms and provides hierarchical information to decoding life. Using systems biology approaches such as genomics, transcriptomics and proteomics, it is now possible to delineate more complicated interactions between circadian control systems and diseases. The circadian rhythm is a multiscale phenomenon existing within the body that influences numerous physiological activities such as changes in gene expression, protein turnover, metabolism and human behavior. In this review, we describe the relationships between the circadian control system and its related genes or proteins, and circadian rhythm disorders in systems biology studies. To maintain and modulate circadian oscillation, cells possess elaborative feedback loops composed of circadian core proteins that regulate the expression of other genes through their transcriptional activities. The disruption of these rhythms has been reported to be associated with diseases such as arrhythmia, obesity, insulin resistance, carcinogenesis and disruptions in natural oscillations in the control of cell growth. This review demonstrates that lifestyle is considered as a fundamental factor that modifies circadian rhythm, and the development of dysfunctions and diseases could be regulated by an underlying expression network with multiple circadian-associated signals.

  7. Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior

    OpenAIRE

    Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B.; Singewald, Nicolas; Pollak, Daniela D.

    2015-01-01

    ABSTRACT Introduction Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs – also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. Materials and methods The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular leve...

  8. Pregnancy-induced changes in ultradian rhythms persist in circadian arrhythmic Siberian hamsters

    OpenAIRE

    Wang, Z. Yan; Cable, Erin J.; Zucker, Irving; Prendergast, Brian J.

    2014-01-01

    The impact of pregnancy and lactation on ultradian rhythms (URs) and circadian rhythms (CRs) of locomotor activity was assessed in circadian rhythmic and arrhythmic Siberian hamsters maintained in a long-day photoperiod (16 h light/day). Progressive decrements in CR robustness and amplitude over the course of gestation were accompanied by enhanced URs. Dark-phase UR period and amplitude increased during early gestation and complexity and robustness increased during late gestation. The persist...

  9. Pregnancy-induced changes in ultradian rhythms persist in circadian arrhythmic Siberian hamsters.

    Science.gov (United States)

    Wang, Z Yan; Cable, Erin J; Zucker, Irving; Prendergast, Brian J

    2014-07-01

    The impact of pregnancy and lactation on ultradian rhythms (URs) and circadian rhythms (CRs) of locomotor activity was assessed in circadian rhythmic and arrhythmic Siberian hamsters maintained in a long-day photoperiod (16h light/day). Progressive decrements in CR robustness and amplitude over the course of gestation were accompanied by enhanced URs. Dark-phase UR period and amplitude increased during early gestation and complexity and robustness increased during late gestation. The persistence of pregnancy-associated enhancements of URs in circadian arrhythmic (ARR) hamsters suggests that reproductive modulation of the UR waveform is not dependent on coherent circadian organization. The increased incidence of dark-phase URs appeared more rapidly in ARR dams than entrained (ENTR) dams. Throughout gestation, the percentage of dams with dark-phase URs was significantly greater in the ARR group. Gestational increases in UR complexity and robustness emerged earlier and were greater in ARR than ENTR dams. The attenuation of CRs during lactation is correlated with increased expression of URs. Relaxation of circadian control of the dam's behavior may increase fitness by permitting more efficient interactions with circadian arrhythmic pups.

  10. Shift work and circadian dysregulation of reproduction

    Directory of Open Access Journals (Sweden)

    Karen L. Gamble

    2013-08-01

    Full Text Available Health impairments, including reproductive issues, are associated with working nights or rotating shifts. For example, shift work has been associated with an increased risk of irregular menstrual cycles, endometriosis, infertility, miscarriage, low birth weight or pre-term delivery, and reduced incidence of breastfeeding. Based on what is known about circadian regulation of endocrine rhythms in rodents (and much less in humans, the circadian clock is an integral regulatory part of the reproductive system. When this 24-h program is disordered by environmental perturbation (such as shift work or genetic alterations, the endocrine system can be impaired. The purpose of this review is to explore the hypothesis that misalignment of reproductive hormones with the environmental light-dark cycle and/or sleep wake rhythms can disrupt menstrual cycles, pregnancy, and parturition. We highlight the role of the circadian clock in regulating human reproductive physiology and shift work-induced pathology within each step of the reproductive axis while exploring potential mechanisms from the animal model literature. In addition to documenting the reproductive hazards of shift work, we also point out important gaps in our knowledge as critical areas for future investigation. For example, future studies should examine whether forced desynchronization disrupts gonadotropin secretion rhythms and whether there are sleep/wake schedules that are better or worse for the adaptation of the reproductive system to shift work. These studies are necessary in order to define not only whether or not shift-work induced circadian misalignment impairs reproductive capacity, but also to identify strategies for the future that can minimize this desynchronization.

  11. Metabolic consequences of sleep and circadian disorders

    OpenAIRE

    Depner, Christopher M.; Stothard, Ellen R.; Wright, Kenneth P.

    2014-01-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight g...

  12. The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

    Directory of Open Access Journals (Sweden)

    Tae Won Kim

    2015-01-01

    Full Text Available The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity.

  13. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice

    Science.gov (United States)

    Poroyko, Valeriy A.; Carreras, Alba; Khalyfa, Abdelnaby; Khalyfa, Ahamed A.; Leone, Vanessa; Peris, Eduard; Almendros, Isaac; Gileles-Hillel, Alex; Qiao, Zhuanhong; Hubert, Nathaniel; Farré, Ramon; Chang, Eugene B.; Gozal, David

    2016-01-01

    Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF. PMID:27739530

  14. Consequences of circadian dysregulation on metabolism

    Directory of Open Access Journals (Sweden)

    Cissé YM

    2016-09-01

    Full Text Available Yasmine M Cissé, Randy J Nelson Department of Neuroscience, Neuroscience Research Institute, Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH, USA Abstract: Most organisms display endogenously produced rhythms in physiology and behavior of ~24 hours in duration. These rhythms, termed circadian rhythms, are entrained to precisely 24 hours by the daily extrinsic light–dark cycle. Circadian rhythms are driven by a transcriptional–translational feedback loop that is hierarchically expressed throughout the brain and body; the suprachiasmatic nucleus of the hypothalamus is the master circadian oscillator at the top of the hierarchy. Precise timing of the circadian clocks is critical for many homeostatic processes, including energy regulation and metabolism. Many genes involved in metabolism display rhythmic oscillations. Because circadian rhythms are most potently synchronized with the external environment by light, exposure to light at night potentially disrupts circadian regulation. Other potential disruptors of circadian organization include night shift work, social jet lag, restricted sleep, and misaligned feeding. Each of these environmental conditions has been associated with metabolic changes and obesity. The goal of this review is to highlight how disruption of circadian organization, primarily due to night shift work and exposure to light at night, has downstream effects on metabolic function. Keywords: circadian disruption, light at night, obesity, shift work

  15. 2016 Arte Poster Competition First Place Winner: Circadian Rhythm and UV-Induced Skin Damage: An In Vivo Study.

    Science.gov (United States)

    Guan, Linna; Suggs, Amanda; Ahsanuddin, Sayeeda; Tarrillion, Madeline; Selph, Jacqueline; Lam, Minh; Baron, Elma

    2016-09-01

    Exposure of the skin to ultraviolet (UV) irradiation causes many detrimental effects through mechanisms related to oxidative stress and DNA damage. Excessive oxidative stress can cause apoptosis and cellular dysfunction of epidermal cells leading to cellular senescence and connective tissue degradation. Direct and indirect damage to DNA predisposes the skin to cancer formation. Chronic UV exposure also leads to skin aging manifested as wrinkling, loss of skin tone, and decreased resilience. Fortunately, human skin has several natural mechanisms for combating UV-induced damage. The mechanisms operate on a diurnal rhythm, a cycle that repeats approximately every 24 hours. It is known that the circadian rhythm is involved in many skin physiologic processes, including water regulation and epidermal stem cell function. This study evaluated whether UV damage and the skin's natural mechanisms of inflammation and repair are also affected by circadian rhythm. We looked at UV-induced erythema on seven human subjects irradiated with simulated solar radiation in the morning (at 08:00 h) versus in the afternoon (at 16:00 h). Our data suggest that the same dose of UV radiation induces significantly more inflammation in the morning than in the afternoon. Changes in protein expression relevant to DNA damage, such as xeroderma pigmentosum, complementation group A (XPA), and cyclobutane pyrimidine dimers (CPD) from skin biopsies correlated with our clinical results. Both XPA and CPD levels were higher after the morning UV exposure compared with the afternoon exposure. J Drugs Dermatol. 2016;15(9):1124-1130. PMID:27602977

  16. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    Directory of Open Access Journals (Sweden)

    Sharabi Shirley

    2016-03-01

    Full Text Available Electroporation-based therapies such as electrochemotherapy (ECT and irreversible electroporation (IRE are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning.

  17. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    OpenAIRE

    Sharabi Shirley; Kos Bor; Last David; Guez David; Daniels Dianne; Harnof Sagi; Mardor Yael; Miklavcic Damijan

    2016-01-01

    Background Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This m...

  18. Circadian rhythm sleep disorders

    Directory of Open Access Journals (Sweden)

    Morgenthaler TI

    2012-05-01

    Full Text Available Bhanu P Kolla,1,2 R Robert Auger,1,2 Timothy I Morgenthaler11Mayo Center for Sleep Medicine, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Misalignment between endogenous circadian rhythms and the light/dark cycle can result in pathological disturbances in the form of erratic sleep timing (irregular sleep–wake rhythm, complete dissociation from the light/dark cycle (circadian rhythm sleep disorder, free-running type, delayed sleep timing (delayed sleep phase disorder, or advanced sleep timing (advanced sleep phase disorder. Whereas these four conditions are thought to involve predominantly intrinsic mechanisms, circadian dysrhythmias can also be induced by exogenous challenges, such as those imposed by extreme work schedules or rapid transmeridian travel, which overwhelm the ability of the master clock to entrain with commensurate rapidity, and in turn impair approximation to a desired sleep schedule, as evidenced by the shift work and jet lag sleep disorders. This review will focus on etiological underpinnings, clinical assessments, and evidence-based treatment options for circadian rhythm sleep disorders. Topics are subcategorized when applicable, and if sufficient data exist. The length of text associated with each disorder reflects the abundance of associated literature, complexity of management, overlap of methods for assessment and treatment, and the expected prevalence of each condition within general medical practice.Keywords: circadian rhythm sleep disorders, assessment, treatment

  19. Sleep and circadian rhythms

    Science.gov (United States)

    Monk, Timothy H.

    1991-01-01

    Three interacting processes are involved in the preservation of circadian rhythms: (1) endogenous rhythm generation mechanisms, (2) entrainment mechanisms to keep these rhythms 'on track', and (3) exogenous masking processes stemming from changes in environment and bahavior. These processes, particularly the latter two, can be dramatically affected in individuals of advanced age and in space travelers, with a consequent disruption in sleep and daytime functioning. This paper presents results of a phase-shift experiment investigating the age-related effects of the exogeneous component of circadian rhythms in various physiological and psychological functions by comparing these functions in middle aged and old subjects. Dramatic differences were found between the two age groups in measures of sleep, mood, activation, and performance efficiency.

  20. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  1. Structure of the runaway electron loss during induced disruptions in TEXTOR

    Science.gov (United States)

    Wongrach, K.; Finken, K. H.; Abdullaev, S. S.; Willi, O.; Zeng, L.; Xu, Y.

    2015-10-01

    The loss of runaway electrons during an induced disruption is recorded by a synchrotron imaging technique using a fast infrared CCD camera. The loss is predominantly diffuse. During the "spiky-loss phase", when the runaway beam moves close to the wall, a narrow channel between the runaway column and a scintillator probe is formed and lasts until the runaway beam is terminated. In some cases, the processed images show a stripe pattern at the plasma edge. A comparison between the MHD dominated disruptions and the MHD-free disruption is performed. A new mechanism of plasma disruptions with the runaway electron generation and a novel model which reproduces many characteristic features of the plasma beam evolution during a disruption is briefly described.

  2. Structure of the runaway electron loss during induced disruptions in TEXTOR

    Energy Technology Data Exchange (ETDEWEB)

    Wongrach, K.; Finken, K. H.; Willi, O. [Institut für Laser- und Plasmaphysik, Heinrich-Heine Universität Düsseldorf, Düsseldorf 40225 (Germany); Abdullaev, S. S. [Institut für Energie- und Klimaforschung, Forschungszentrum Jülich GmbH, Jülich 52428 (Germany); Zeng, L. [Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui 230031 (China); Xu, Y. [Southwestern Institute of Physics, Chengdu 610041 (China)

    2015-10-15

    The loss of runaway electrons during an induced disruption is recorded by a synchrotron imaging technique using a fast infrared CCD camera. The loss is predominantly diffuse. During the “spiky-loss phase”, when the runaway beam moves close to the wall, a narrow channel between the runaway column and a scintillator probe is formed and lasts until the runaway beam is terminated. In some cases, the processed images show a stripe pattern at the plasma edge. A comparison between the MHD dominated disruptions and the MHD-free disruption is performed. A new mechanism of plasma disruptions with the runaway electron generation and a novel model which reproduces many characteristic features of the plasma beam evolution during a disruption is briefly described.

  3. Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress-induced alcohol drinking

    OpenAIRE

    Soyka, Michael; Henriksson, Richard; Albrecht, Urs; Spanagel, Rainer; Michael N Smolka; Rietschel, Marcella; Bilbao, Ainhoa; Treutlein, Jens; Schumann, Gunter; Ridinger, Monika; Wodarz, Norbert; Blomeyer, Dorothea; Witt, Stephanie,; Lathrop, Mark; Dong, Li

    2011-01-01

    Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking.Method: In...

  4. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  5. Effects of (± 3,4-Methylenedioxymethamphetamine (MDMA on Sleep and Circadian Rhythms

    Directory of Open Access Journals (Sweden)

    Una D. McCann

    2007-01-01

    Full Text Available Abuse of stimulant drugs invariably leads to a disruption in sleep-wake patterns by virtue of the arousing and sleep-preventing effects of these drugs. Certain stimulants, such as 3,4-methylenedioxymethamphetamine (MDMA, may also have the potential to produce persistent alterations in circadian regulation and sleep because they can be neurotoxic toward brain monoaminergic neurons involved in normal sleep regulation. In particular, MDMA has been found to damage brain serotonin (5-HT neurons in a variety of animal species, including nonhuman primates, with growing evidence that humans are also susceptible to MDMA-induced brain 5-HT neurotoxicity. 5-HT is an important modulator of sleep and circadian rhythms and, therefore, individuals who sustain MDMA-induced 5-HT neurotoxicity may be at risk for developing chronic abnormalities in sleep and circadian patterns. In turn, such abnormalities could play a significant role in other alterations reported in abstinent in MDMA users (e.g., memory disturbance. This paper will review preclinical and clinical studies that have explored the effects of prior MDMA exposure on sleep, circadian activity, and the circadian pacemaker, and will highlight current gaps in knowledge and suggest areas for future research.

  6. Neuroimaging, cognition, light and circadian rhythms

    OpenAIRE

    Gaggioni, Giulia; Maquet, Pierre; Schmidt, Christina, 1984-; Dijk, Derk-Jan; Vandewalle, Gilles

    2014-01-01

    In humans, sleep and wakefulness and the associated cognitive processes are regulated through interactions between sleep homeostasis and the circadian system. Chronic disruption of sleep and circadian rhythmicity is common in our society and there is a need for a better understanding of the brain mechanisms regulating sleep, wakefulness and associated cognitive processes. This review summarizes recent investigations which provide first neural correlates of the combined influence of sleep home...

  7. The role of circadian rhythm in breast cancer

    Science.gov (United States)

    Li, Shujing; Ao, Xiang

    2013-01-01

    The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer. PMID:23997531

  8. Nutrition and the circadian system.

    Science.gov (United States)

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-08-01

    The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157

  9. Rapid Adjustment of Circadian Clocks to Simulated Travel to Time Zones across the Globe.

    Science.gov (United States)

    Harrison, Elizabeth M; Gorman, Michael R

    2015-12-01

    Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure-based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules.

  10. Circadian and Circalunar Clock Interactions in a Marine Annelid

    Directory of Open Access Journals (Sweden)

    Juliane Zantke

    2013-10-01

    Full Text Available Life is controlled by multiple rhythms. Although the interaction of the daily (circadian clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1δ/ε. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function.

  11. Circadian Clock Genes: Effects on Dopamine, Reward and Addiction

    OpenAIRE

    Parekh, Puja K.; Ozburn, Angela R; McClung, Colleen A.

    2015-01-01

    Addiction is a widespread public health issue with social and economic ramifications. Substance abuse disorders are often accompanied by disruptions in circadian rhythms including sleep/wake cycles, which can exacerbate symptoms of addiction and dependence. Additionally, genetic disturbance of circadian molecular mechanisms can predispose some individuals to substance abuse disorders. In this review, we will discuss how circadian genes can regulate midbrain dopaminergic activity and subsequen...

  12. Insulin Restores an Altered Corneal Epithelium Circadian Rhythm in Mice with Streptozotocin-induced Type 1 Diabetes

    Science.gov (United States)

    Song, Fang; Xue, Yunxia; Dong, Dong; Liu, Jun; Fu, Ting; Xiao, Chengju; Wang, Hanqing; Lin, Cuipei; Liu, Peng; Zhong, Jiajun; Yang, Yabing; Wang, Zhaorui; Pan, Hongwei; Chen, Jiansu; Li, Yangqiu; Cai, Dongqing; Li, Zhijie

    2016-01-01

    The mechanisms of corneal epithelial lesions and delayed wound repair, as well as their association with diabetes mellitus, are critical issues for clinical ophthalmologists. To test whether the diabetic condition alters the circadian rhythm in a mouse cornea and whether insulin can synchronise the corneal clock, we studied the effects of streptozotocin-induced diabetes on the mitosis of epithelial cells, the recruitment of leukocytes to the cornea, and the expression of main core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the corneal epithelium. We also assessed the possible effect of insulin on these modifications. Diabetes downregulated Clock, Bmal1, and Per2 expression, upregulated Cry1 and Rev-erbα expression, reduced corneal epithelial mitosis, and increased leukocyte (neutrophils and γδ T-cells) recruitment to the cornea. Early treatments with insulin partially restored the altered rhythmicity in the diabetic cornea. In conclusion, insulin-dependent diabetes altered the normal rhythmicity of the cornea, and insulin administration had a beneficial effect on restoring normal rhythmicity in the diabetic cornea. PMID:27611469

  13. Insulin Restores an Altered Corneal Epithelium Circadian Rhythm in Mice with Streptozotocin-induced Type 1 Diabetes.

    Science.gov (United States)

    Song, Fang; Xue, Yunxia; Dong, Dong; Liu, Jun; Fu, Ting; Xiao, Chengju; Wang, Hanqing; Lin, Cuipei; Liu, Peng; Zhong, Jiajun; Yang, Yabing; Wang, Zhaorui; Pan, Hongwei; Chen, Jiansu; Li, Yangqiu; Cai, Dongqing; Li, Zhijie

    2016-01-01

    The mechanisms of corneal epithelial lesions and delayed wound repair, as well as their association with diabetes mellitus, are critical issues for clinical ophthalmologists. To test whether the diabetic condition alters the circadian rhythm in a mouse cornea and whether insulin can synchronise the corneal clock, we studied the effects of streptozotocin-induced diabetes on the mitosis of epithelial cells, the recruitment of leukocytes to the cornea, and the expression of main core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the corneal epithelium. We also assessed the possible effect of insulin on these modifications. Diabetes downregulated Clock, Bmal1, and Per2 expression, upregulated Cry1 and Rev-erbα expression, reduced corneal epithelial mitosis, and increased leukocyte (neutrophils and γδ T-cells) recruitment to the cornea. Early treatments with insulin partially restored the altered rhythmicity in the diabetic cornea. In conclusion, insulin-dependent diabetes altered the normal rhythmicity of the cornea, and insulin administration had a beneficial effect on restoring normal rhythmicity in the diabetic cornea. PMID:27611469

  14. Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro.

    Science.gov (United States)

    Mou, Xiang; Peterson, Cynthia B; Prosser, Rebecca A

    2009-10-01

    The mammalian circadian clock in the suprachiasmatic nucleus (SCN) maintains environmental synchrony through light signals transmitted by glutamate released from retinal ganglion terminals. Brain-derived neurotrophic factor (BDNF) is required for light/glutamate to reset the clock. In the hippocampus, BDNF is activated by the extracellular protease, plasmin, which is produced from plasminogen by tissue-type plasminogen activator (tPA). We provide data showing expression of proteins from the plasminogen activation cascade in the SCN and their involvement in circadian clock phase-resetting. Early night glutamate application to SCN-containing brain slices resets the circadian clock. Plasminogen activator inhibitor-1 (PAI-1) blocked these shifts in slices from wild-type mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha(2)-antiplasmin inhibition of glutamate-induced shifts. alpha(2)-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Finally, both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential 'gating' mechanism for photic phase-resetting. These data also demonstrate a functional interaction between PAI-1 and VN in adult brain. Given the usual association of these proteins with the extracellular matrix, these data suggest new lines of investigation into the locations and processes modulating mammalian circadian clock phase-resetting.

  15. Three-Dimensional Simulation of Ultrasound-Induced Microalgal Cell Disruption.

    Science.gov (United States)

    Wang, M; Yuan, W; Hale, Andy

    2016-03-01

    The three-dimensional distribution (x, y, and z) of ultrasound-induced microalgal cell disruption in a sonochemical reactor was predicted by solving the Helmholtz equation using a three-dimensional acoustic module in the COMSOL Multiphysics software. The simulated local ultrasound pressure at any given location (x, y, and z) was found to correlate with cell disruption of a freshwater alga, Scenedesmus dimorphus, represented by the change of algal cell particle/debris concentration, chlorophyll-a fluorescence density (CAFD), and Nile red stained lipid fluorescence density (LFD), which was also validated by the model reaction of potassium iodide oxidation (the Weissler reaction). Furthermore, the effect of ultrasound power intensity and processing duration on algal cell disruption was examined to address the limitation of the model. PMID:26660670

  16. CRY links the circadian clock and CREB-mediated gluconeogenesis

    Institute of Scientific and Technical Information of China (English)

    Megumi Hatori; Satchidananda Panda

    2010-01-01

    @@ Circadian oscillators based on a transcriptional feedback loop exist in almost all cells of animals. The cellular oscillators synchronize each other via paracrine or systemic communications,resulting in rhythmic changes of tissue- and whole body-level physiologies and behaviors. Circadian regulation of metabolism is well documented and disruption of such temporal regulation is known to predispose organisms to metabolic diseases.

  17. The effect of constant darkness and circadian resynchronization on the recovery of alcohol hangover.

    Science.gov (United States)

    Karadayian, Analía G; Lores-Arnaiz, Silvia; Cutrera, Rodolfo A

    2014-07-15

    Alcohol hangover (AH) is a particular state after binge-like drinking. AH begins when ethanol is absent in plasma and is characterized by a cluster of physical and psychological symptoms. Alcohol disrupts circadian patterns of behavioral and physiological parameters; however, the involvement of circadian clock on the recovery of AH was not explored. Our aim was to study the effect of continuous darkness and the possible involvement of the circadian clock in the recovery time of neuromuscular impairment and anxiety related-behavior due to AH. Male Swiss mice were habituated to 12:12 L:D or continuous darkness. Each group was injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Motor performance and anxiety phenotype were evaluated at a basal point (ZT0) and every 2 h up to 20 h after blood alcohol levels were close to zero (hangover onset). A third group was subjected to a phase advance during which a hangover episode was induced and behavioral tests were carried out for each group of treatment and resynchronization day. Constant darkness resulted to be in a faster recovery of both motor and anxiety impairments in AH compared with the recovery pattern observed under normal light-dark conditions. Mice suffering from a phase shift exhibited behavioral disruptions due to both AH and phase advance. Results indicated that a synchronized circadian clock is necessary for an adequate recovery of alcohol hangover symptoms. PMID:24717330

  18. Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring.

    Directory of Open Access Journals (Sweden)

    Costas D Arvanitis

    Full Text Available The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001 larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2 = 0.78. Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology.

  19. Circadian Rhythms and Mood Disorders: Are The Phenomena and Mechanisms Causally Related?

    Directory of Open Access Journals (Sweden)

    William eBechtel

    2015-08-01

    Full Text Available This paper reviews some of the compelling evidence of disrupted circadian rhythms in individuals with mood disorders (major depressive disorder, seasonal affective disorder, and bipolar disorder and that treatments such as bright light, designed to alter circadian rhythms, are effective in treating these disorders. Neurotransmitters in brain regions implicated in mood regulation exhibit circadian rhythms. A mouse model originally employed to identify a circadian gene has proven a potent model for mania. While this evidence is suggestive of an etiological role for altered circadian rhythms in mood disorders, it is compatible with other explanations, including that disrupted circadian rhythms and mood disorders are effects of a common cause and that genes and proteins implicated in both simply have pleiotropic effects. In light of this, the paper advances a proposal as to what evidence would be needed to establish a direct causal link between disruption of circadian rhythms and mood disorders.

  20. Circadian Rhythms and Mood Disorders: Are the Phenomena and Mechanisms Causally Related?

    Science.gov (United States)

    Bechtel, William

    2015-01-01

    This paper reviews some of the compelling evidence of disrupted circadian rhythms in individuals with mood disorders (major depressive disorder, seasonal affective disorder, and bipolar disorder) and that treatments such as bright light, designed to alter circadian rhythms, are effective in treating these disorders. Neurotransmitters in brain regions implicated in mood regulation exhibit circadian rhythms. A mouse model originally employed to identify a circadian gene has proven a potent model for mania. While this evidence is suggestive of an etiological role for altered circadian rhythms in mood disorders, it is compatible with other explanations, including that disrupted circadian rhythms and mood disorders are effects of a common cause and that genes and proteins implicated in both simply have pleiotropic effects. In light of this, the paper advances a proposal as to what evidence would be needed to establish a direct causal link between disruption of circadian rhythms and mood disorders. PMID:26379559

  1. Poor quality of life, depressed mood, and memory impairment may be mediated by sleep disruption in patients with Addison's disease

    OpenAIRE

    Henry, Michelle; Wolf, Pedro S. A.; Ross, Ian L.; Thomas, Kevin G.F.

    2015-01-01

    Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. In fact, hydrocortisone replacement in AD patients likely induces disrupted sleep. Given that healthy sleep plays an important role in improving quality of life, optimizing cognition, and ensuring affect regulation, the aim of this study was to investigate whether poor quality of life, mood alterations, and memory complaints reported by AD patients are associated with their disrupted sleep patt...

  2. Protective effect of taurine on the light-induced disruption of isolated frog rod outer segments

    International Nuclear Information System (INIS)

    Isolated frog rod outer segments (ROS) incubated in a Krebs-bicarbonate medium, and illuminated for 2 h, show a profound alteration in their structure. This is characterized by distention of discs, vesiculation, and a marked swelling. The light-induced ROS disruption requires the presence of bicarbonate and sodium chloride. Replacement of bicarbonate by TRIS or HEPES protects ROS structure. Also, substitution of sodium chloride by sucrose or choline chloride maintains unaltered the ROS structure. Deletion of calcium, magnesium, or phosphate does not modify the effect produced by illumination. An increased accumulation of labeled bicarbonate and tritiated water is observed in illuminated ROS, as compared with controls in the dark. The presence of taurine, GABA, or glycine, at concentrations of 5-25 mM, effectively counteracts the light-induced ROS disruption. Taurine (25 mM) reduces labeled bicarbonate and tritiated water levels to those observed in the dark incubated ROS

  3. Circadian Rhythms and Mood Disorders: Are the Phenomena and Mechanisms Causally Related?

    OpenAIRE

    Bechtel, William

    2015-01-01

    This paper reviews some of the compelling evidence of disrupted circadian rhythms in individuals with mood disorders (major depressive disorder, seasonal affective disorder, and bipolar disorder) and that treatments such as bright light, designed to alter circadian rhythms, are effective in treating these disorders. Neurotransmitters in brain regions implicated in mood regulation exhibit circadian rhythms. A mouse model originally employed to identify a circadian gene has proven a potent mode...

  4. Circadian Rhythms and Mood Disorders: Are The Phenomena and Mechanisms Causally Related?

    OpenAIRE

    William eBechtel

    2015-01-01

    This paper reviews some of the compelling evidence of disrupted circadian rhythms in individuals with mood disorders (major depressive disorder, seasonal affective disorder, and bipolar disorder) and that treatments such as bright light, designed to alter circadian rhythms, are effective in treating these disorders. Neurotransmitters in brain regions implicated in mood regulation exhibit circadian rhythms. A mouse model originally employed to identify a circadian gene has proven a potent mode...

  5. Microtubule Disruption in Keratinocytes Induces Cell-Cell Adhesion through Activation of Endogenous E-Cadherin

    OpenAIRE

    Kee, Sun-Ho; Steinert, Peter M.

    2001-01-01

    The association of the cytoskeleton with the cadherin–catenin complex is essential for strong cell-cell adhesion in epithelial cells. In this study, we have investigated the effect of microtubule organization on cell-cell adhesion in differentiating keratinocytes. When microtubules of normal human epidermal keratinocytes (NHEKs) grown in low calcium media (0.05 mM) were disrupted with nocodazole or colcemid, cell-cell adhesion was induced through relocalization of the ...

  6. Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides.

    Science.gov (United States)

    Schweitzer, Kelly S; Hatoum, Hadi; Brown, Mary Beth; Gupta, Mehak; Justice, Matthew J; Beteck, Besem; Van Demark, Mary; Gu, Yuan; Presson, Robert G; Hubbard, Walter C; Petrache, Irina

    2011-12-01

    The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione

  7. Targeting one carbon metabolism with an antimetabolite disrupts pyrimidine homeostasis and induces nucleotide overflow

    OpenAIRE

    Ser, Zheng; GAO, XIA; Johnson, Christelle; Mehrmohamadi, Mahya; Liu, Xiaojing; Li, SiQi; Locasale, Jason W.

    2016-01-01

    Anti-metabolite agents that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used anti-metabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of ...

  8. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Fu [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Chambon, Pierre [Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U596, ULP, Collége de France) and Institut Clinique de la Souris, ILLKIRCH, Strasbourg (France); Tellides, George [Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (United States); Kong, Wei [Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing (China); Zhang, Xiaoming, E-mail: rmygxgwk@163.com [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Li, Wei [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China)

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  9. Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, Shawn S. [McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705 (United States); Medical Scientist Training Program, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States); Cellular and Molecular Biology Program, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States); Oberley, Christopher [McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705 (United States); Hooper, Christopher P. [McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705 (United States); Cellular and Molecular Biology Program, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States); Grindle, Kreg [Department of Medicine, Division of Hematology and Oncology, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States); Wuerzberger-Davis, Shelly [McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705 (United States); Wolff, Jared [Department of Medicine, Division of Hematology and Oncology, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States); and others

    2015-02-01

    The NF-κB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-κB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-κB activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-κB activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO–IKKβ interaction and was a poor direct IKKβ inhibitor, but prevented the formation of TNF-induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMO{sup Y308S} mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo. - Highlights: • Withaferin A, a NF-κB inhibitor, disrupts signaling induced NEMO localization, a novel point of inhibition. • NEMO can be localized to distinct signaling foci after treatment with TNF. • ABC-type DLCBL cells can be sensitized to apoptosis after treatment with Withaferin A.

  10. Circadian arrhythmia dysregulates emotional behaviors in aged Siberian hamsters.

    Science.gov (United States)

    Prendergast, Brian J; Onishi, Kenneth G; Patel, Priyesh N; Stevenson, Tyler J

    2014-03-15

    Emotional behaviors are influenced by the circadian timing system. Circadian disruptions are associated with depressive-like symptoms in clinical and preclinical populations. Circadian rhythm robustness declines markedly with aging and may contribute to susceptibility to emotional dysregulation in aged individuals. The present experiments used a model of chronic circadian arrhythmia generated noninvasively, via a series of circadian-disruptive light treatments, to investigate interactions between circadian desynchrony and aging on depressive- and anxiety-like behaviors, and on limbic neuroinflammatory gene expression that has been linked with emotionality. We also examined whether a social manipulation (group housing) would attenuate effects of arrhythmia on emotionality. In aged (14-18 months of age) male Siberian hamsters, circadian arrhythmia increased behavioral despair and decreased social motivation, but decreased exploratory anxiety. These effects were not evident in younger (5-9 months of age) hamsters. Social housing (3-5 hamsters/cage) abolished the effects of circadian arrhythmia on emotionality. Circadian arrhythmia alone was without effect on hippocampal or cortical interleukin-1β (IL-1β) and indoleamine 2,3-dioxygenase (Ido) mRNA expression in aged hamsters, but social housing decreased hippocampal IL-1β and Ido mRNAs. The data demonstrate that circadian disruption can negatively impact affective state, and that this effect is pronounced in older individuals. Although clear associations between circadian arrhythmia and constitutive limbic proinflammatory activity were not evident, the present data suggest that social housing markedly inhibits constitutive hippocampal IL-1β and Ido activity, which may contribute to the ameliorating effects of social housing on a number of emotional behaviors.

  11. MRI study on reversible and irreversible electroporation induced blood brain barrier disruption.

    Directory of Open Access Journals (Sweden)

    Mohammad Hjouj

    Full Text Available Electroporation, is known to induce cell membrane permeabilization in the reversible (RE mode and cell death in the irreversible (IRE mode. Using an experimental system designed to produce a continuum of IRE followed by RE around a single electrode we used MRI to study the effects of electroporation on the brain. Fifty-four rats were injected with Gd-DOTA and treated with a G25 electrode implanted 5.5 mm deep into the striata. MRI was acquired immediately after treatment, 10 min, 20 min, 30 min, and up to three weeks following the treatment using: T1W, T2W, Gradient echo (GE, serial SPGR (DCE-MRI with flip angles ranging over 5-25°, and diffusion-weighted MRI (DWMRI. Blood brain barrier (BBB disruption was depicted as clear enhancement on T1W images. The average signal intensity in the regions of T1-enhancement, representing BBB disruption, increased from 1887±83 (arbitrary units immediately post treatment to 2246±94 20 min post treatment, then reached a plateau towards the 30 min scan where it reached 2289±87. DWMRI at 30 min showed no significant effects. Early treatment effects and late irreversible damage were clearly depicted on T2W. The enhancing volume on T2W has increased by an average of 2.27±0.27 in the first 24-48 hours post treatment, suggesting an inflammatory tissue response. The permanent tissue damage, depicted as an enhancing region on T2W, 3 weeks post treatment, decreased to an average of 50±10% of the T2W enhancing volumes on the day of the treatment which was 33±5% of the BBB disruption volume. Permanent tissue damage was significantly smaller than the volume of BBB disruption, suggesting, that BBB disruption is associated with RE while tissue damage with IRE. These results demonstrate the feasibility of applying reversible and irreversible electroporation for transient BBB disruption or permanent damage, respectively, and applying MRI for planning/monitoring disruption volume/shape by optimizing electrode positions

  12. Circadian rhythms in liver metabolism and disease

    Directory of Open Access Journals (Sweden)

    Jessica M. Ferrell

    2015-03-01

    Full Text Available Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.

  13. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    Science.gov (United States)

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension.

  14. A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Hayashi, Akane; Matsunaga, Naoya; Okazaki, Hiroyuki; Kakimoto, Keisuke; Kimura, Yoshinori; Azuma, Hiroki; Ikeda, Eriko; Shiba, Takeshi; Yamato, Mayumi; Yamada, Ken-Ichi; Koyanagi, Satoru; Ohdo, Shigehiro

    2013-06-01

    Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP(+)) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP(+)-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

  15. Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

    Science.gov (United States)

    Heidegger, Simon; Anz, David; Stephan, Nicolas; Bohn, Bernadette; Herbst, Tina; Fendler, Wolfgang Peter; Suhartha, Nina; Sandholzer, Nadja; Kobold, Sebastian; Hotz, Christian; Eisenächer, Katharina; Radtke-Schuller, Susanne; Endres, Stefan; Bourquin, Carole

    2013-10-10

    Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens. PMID:23823318

  16. Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice.

    Science.gov (United States)

    Farfán-García, E D; Pérez-Rodríguez, M; Espinosa-García, C; Castillo-Mendieta, N T; Maldonado-Castro, M; Querejeta, E; Trujillo-Ferrara, J G; Soriano-Ursúa, M A

    2016-09-15

    The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥200mg/kg, and involving granular cell damage at doses of 400mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system. PMID:27495897

  17. Circadian Rhythm Abnormalities

    OpenAIRE

    Zee, Phyllis C.; Attarian, Hrayr; Videnovic, Aleksandar

    2013-01-01

    Purpose: This article reviews the recent advances in understanding of the fundamental properties of circadian rhythms and discusses the clinical features, diagnosis, and treatment of circadian rhythm sleep disorders (CRSDs).

  18. Conversion between two conformational states of KaiC is induced by ATP hydrolysis as a trigger for cyanobacterial circadian oscillation.

    Science.gov (United States)

    Oyama, Katsuaki; Azai, Chihiro; Nakamura, Kaori; Tanaka, Syun; Terauchi, Kazuki

    2016-01-01

    The cyanobacterial circadian oscillator can be reconstituted in vitro by mixing three clock proteins, KaiA, KaiB and KaiC, with ATP. KaiC is the only protein with circadian rhythmic activities. In the present study, we tracked the complex formation of the three Kai proteins over time using blue native (BN) polyacrylamide gel electrophoresis (PAGE), in which proteins are charged with the anionic dye Coomassie brilliant blue (CBB). KaiC was separated as three bands: the KaiABC complex, KaiC hexamer and KaiC monomer. However, no KaiC monomer was observed using gel filtration chromatography and CBB-free native PAGE. These data indicate two conformational states of KaiC hexamer and show that the ground-state KaiC (gs-KaiC) is stable and competent-state KaiC (cs-KaiC) is labile and degraded into monomers by the binding of CBB. Repeated conversions from gs-KaiC to cs-KaiC were observed over 24 h using an in vitro reconstitution system. Phosphorylation of KaiC promoted the conversion from gs-KaiC to cs-KaiC. KaiA sustained the gs-KaiC state, and KaiB bound only cs-KaiC. An E77Q/E78Q-KaiC variant that lacked N-terminal ATPase activity remained in the gs-KaiC state. Taken together, ATP hydrolysis induces the formation of cs-KaiC and promotes the binding of KaiB, which is a trigger for circadian oscillations. PMID:27580682

  19. Cold-Induced Cysts of the Photosynthetic Dinoflagellate Lingulodinium polyedrum Have an Arrested Circadian Bioluminescence Rhythm and Lower Levels of Protein Phosphorylation1[C][W

    Science.gov (United States)

    Roy, Sougata; Letourneau, Louis; Morse, David

    2014-01-01

    Dinoflagellates are microscopic, eukaryotic, and primarily marine plankton. Temporary cyst formation is a well-known physiological response of dinoflagellate cells to environmental stresses. However, the molecular underpinnings of cold-induced cyst physiology have never been described. Cultures of the photosynthetic dinoflagellate Lingulodinium polyedrum readily form temporary cysts when placed at low (8°C ± 1°C) temperature and excyst to form normal motile cells following a return to normal temperature (18°C ± 1°C). The normal circadian bioluminescence rhythm and the expected changes in Luciferin Binding Protein abundance were arrested in L. polyedrum cysts. Furthermore, after excystment, the bioluminescence rhythm initiates at a time corresponding to zeitgeber 12, independent of the time when the cells encysted. Phosphoprotein staining after two-dimensional polyacrylamide gel electrophoresis, as well as column-based phosphoprotein enrichment followed by liquid chromatography tandem mass spectrometry, showed cyst proteins are hypophosphorylated when compared with those from motile cells, with the most marked decreases found for predicted Casein Kinase2 target sites. In contrast to the phosphoproteome, the cyst proteome is not markedly different from motile cells, as assessed by two-dimensional polyacrylamide gel electrophoresis. In addition to changes in the phosphoproteome, RNA sequencing revealed that cysts show a significant decrease in the levels of 132 RNAs. Of the 42 RNAs that were identified by sequence analysis, 21 correspond to plastid-encoded gene products and 11 to nuclear-encoded cell wall/plasma membrane components. Our data are consistent with a model in which the highly reduced metabolism in cysts is achieved primarily by alterations in the phosphoproteome. The stalling of the circadian rhythm suggests temporary cysts may provide an interesting model to address the circadian system of dinoflagellates. PMID:24335505

  20. Neuroimaging, cognition, light and circadian rhythms

    Directory of Open Access Journals (Sweden)

    Giulia eGaggioni

    2014-07-01

    Full Text Available In humans, sleep and wakefulness and the associated cognitive processes are regulated through interactions between sleep homeostasis and the circadian system. Chronic disruption of sleep and circadian rhythmicity is common in our society and there is a need for a better understanding of the brain mechanisms regulating sleep, wakefulness and associated cognitive processes. This review summarizes recent investigations which provide first neural correlates of the combined influence of sleep homeostasis and circadian rhythmicity on cognitive brain activity. Markers of interindividual variations in sleep-wake regulation, such as chronotype and polymorphisms in sleep and clock genes, are associated with changes in cognitive brain responses in subcortical and cortical areas in response to manipulations of the sleep-wake cycle. This review also includes recent data showing that cognitive brain activity is regulated by light, which is a powerful modulator of cognition and alertness and also directly impacts sleep and circadian rhythmicity. The effect of light varied with age, psychiatric status, PERIOD3 genotype and changes in sleep homeostasis and circadian phase. These data provide new insights into the contribution of demographic characteristics, the sleep-wake cycle, circadian rhythmicity and light to brain functioning.

  1. Interactions between the circadian clock and metabolism: there are good times and bad times

    Institute of Scientific and Technical Information of China (English)

    Mi Shi; Xiangzhong Zheng

    2013-01-01

    An endogenous circadian (~24 h) clock regulates rhythmic processes of physiology,metabolism and behavior in most living organisms.While able to free-run under constant conditions,the circadian clock is coupled to day:night cycles to increase its amplitude and align the phase of circadian rhythms to the right time of the day.Disruptions of the circadian clock are correlated with brain dysfunctions,cardiovascular diseases and metabolic disorders.In this review,we focus on the interactions between the circadian clock and metabolism.We discuss recent findings on circadian clock regulation of feeding behavior and rhythmic expression of metabolic genes,and present evidence of metabolic input to the circadian clock.We emphasize how misalignment of circadian clocks within the body and with environmental cycles or daily schedules leads to the increasing prevalence of metabolic syndromes in modern society.

  2. Circadian Systems and Metabolism

    NARCIS (Netherlands)

    Roenneberg, Till; Merrow, Martha

    1999-01-01

    Circadian systems direct many metabolic parameters and, at the same time, they appear to be exquisitely shielded from metabolic variations. Although the recent decade of circadian research has brought insights into how circadian periodicity may be generated at the molecular level, little is known ab

  3. Reversible disruption of pre-pulse inhibition in hypomorphic-inducible and reversible CB1-/- mice.

    Directory of Open Access Journals (Sweden)

    Maria Franca Marongiu

    Full Text Available Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes. Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout ((-/- mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1(-/- mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1(-/- only in absence of doxycycline (Dox. In such mice, under Dox(+ or vehicle, as well as in wild-type (WT and CB1(-/-, two endophenotypes motor activity (increased in animal models of schizophrenia and pre-pulse inhibition (PPI of startle reflex (disrupted in schizophrenia were analyzed. Both CB1(-/- and IRh-CB1(-/- showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1(-/- animals, was on the contrary highly and significantly disrupted only in Dox(+ IRh-CB1(-/- mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1(-/- mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1(-/- mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in

  4. Mechanistic study of chlordecone-induced endocrine disruption: Based on an adverse outcome pathway network.

    Science.gov (United States)

    Yang, Lihua; Zhou, Bingsheng; Zha, Jinmiao; Wang, Zijian

    2016-10-01

    The adverse outcome pathway (AOP) framework could be helpful for chemical risk assessment and mechanistic research. The aim of the present study was to unravel the mechanism of chlordecone-induced endocrine disruption by illustrating the main molecular initiating event (MIE)/perturbations responsible for the observed effects. In silico simulations were performed to predict the MIE(s), and the results pointed to agonistic interaction with estrogen receptors (ERα, ERβ), androgen receptor (AR), cytochrome P450 (CYP19A) by chlordecone. In vivo endocrine disruptions were evaluated in rare minnow (Gobiocypris rarus) exposed to 0.01, 0.1, 1 and 10 μg L(-1) chlordecone from 2 h post-fertilization until sexually mature. In the females, increases of vitellogenin (vtg) mRNA levels in liver and gonad, plasma estradiol (E2), testosterone (T) and E2/T, and renalsomatic index confirmed the role of agonism of ER and CYP19A as MIEs, but the decreased gonadosomatic index, degenerated ovaries as well as the feed-forward response pointed to other potential but important MIEs and corresponding AOPs. In the males, increased E2/T ratio, increased testis vtg mRNA levels and occurrence of intersex confirmed the roles of agonism of ERα and CYP19A as main MIEs in chlordecone-induced endocrine disruptions. Our results also fetches out the limit of AOPs in predicting the adverse outcomes and explaining the mechanism of chemicals at present, thus reflected a critical need for expanding AOPs and AOP network before using it in chemical risk assessment. PMID:27448318

  5. Obesity induced by cafeteria diet disrupts fertility in the rat by affecting multiple ovarian targets.

    Science.gov (United States)

    Bazzano, M V; Torelli, C; Pustovrh, M C; Paz, D A; Elia, E M

    2015-11-01

    Obesity constitutes a health problem of increasing worldwide prevalence. Among the health detriments caused by obesity, reproduction is disrupted. However, the mechanisms involved in this disruption are not fully understood. Animals fed a cafeteria diet constitute the model for the study of obesity that most closely reflects Western diet habits. The aims of this study were to evaluate whether a cafeteria diet affects ovarian function and to contribute to the understanding of the mechanisms involved. For that purpose, 22-day-old female Wistar rats were fed ad libitum with a standard diet (control group; n = 20) or cafeteria diet (CAF group; n = 20). The cafeteria diet induced obesity and hyperglycaemia, without altering serum triglycerides, cholesterol or C-reactive protein concentrations. This diet also altered ovarian function: the rats showed prolonged dioestrous phases, decreased serum oestradiol concentrations and increased number of antral atretic follicles. Moreover, follicular cysts were detected in the CAF group, concomitantly with a decrease in the number of anti-Müllerian hormone immunoreactive pre-antral follicles and COX-2-positive antral and pre-ovulatory follicles. The authors conclude that a cafeteria diet reduces ovarian reserve, induces the presence of follicular cysts and disturbs the ovulatory process, leading to the delayed pregnancy observed in these animals.

  6. A role for mixed lineage kinases in granule cell apoptosis induced by cytoskeletal disruption

    DEFF Research Database (Denmark)

    Müller, Georg Johannes; Geist, Marie Aavang; Veng, Lone Merete;

    2006-01-01

    Microtubule disruption by colchicine induces apoptosis in selected neuronal populations. However, little is known about the upstream death signalling events mediating the neurotoxicity. We investigated first whether colchicine-induced granule cell apoptosis activates the c-Jun N-terminal kinase...... (JNK) pathway. Cultured murine cerebellar granule cells were exposed to 1 microm colchicine for 24 h. Activation of the JNK pathway was detected by western blotting as well as immunocytochemistry using antibodies against phospho-c-Jun (p-c-Jun). Next, adult male rats were injected...... intracerebroventricularly with colchicine (10 microg), and JNK pathway activation in dentate granule cells (DGCs) was detected by antibodies against p-c-Jun. The second part of the study tested the involvement of mixed lineage kinases (MLK) as upstream activators of the JNK pathway in colchicine toxicity, using CEP-1347, a...

  7. Development of circadian oscillators in neurosphere cultures during adult neurogenesis.

    Directory of Open Access Journals (Sweden)

    Astha Malik

    Full Text Available Circadian rhythms are common in many cell types but are reported to be lacking in embryonic stem cells. Recent studies have described possible interactions between the molecular mechanism of circadian clocks and the signaling pathways that regulate stem cell differentiation. Circadian rhythms have not been examined well in neural stem cells and progenitor cells that produce new neurons and glial cells during adult neurogenesis. To evaluate circadian timing abilities of cells undergoing neural differentiation, neurospheres were prepared from the mouse subventricular zone (SVZ, a rich source of adult neural stem cells. Circadian rhythms in mPer1 gene expression were recorded in individual spheres, and cell types were characterized by confocal immunofluorescence microscopy at early and late developmental stages in vitro. Circadian rhythms were observed in neurospheres induced to differentiate into neurons or glia, and rhythms emerged within 3-4 days as differentiation proceeded, suggesting that the neural stem cell state suppresses the functioning of the circadian clock. Evidence was also provided that neural stem progenitor cells derived from the SVZ of adult mice are self-sufficient clock cells capable of producing a circadian rhythm without input from known circadian pacemakers of the organism. Expression of mPer1 occurred in high frequency oscillations before circadian rhythms were detected, which may represent a role for this circadian clock gene in the fast cycling of gene expression responsible for early cell differentiation.

  8. cGMP-phosphodiesterase inhibition enhances photic responses and synchronization of the biological circadian clock in rodents.

    Directory of Open Access Journals (Sweden)

    Santiago A Plano

    Full Text Available The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN and is synchronized by several environmental stimuli, mainly the light-dark (LD cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2. The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC, cGMP and its related protein kinase (PKG. Pharmacological manipulation of cGMP by phosphodiesterase (PDE inhibition (e.g., sildenafil increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.

  9. Ginsenoside Rh2 induces ligand-independent Fas activation via lipid raft disruption

    Energy Technology Data Exchange (ETDEWEB)

    Yi, Jae-Sung; Choo, Hyo-Jung [College of Life Sciences and Biotechnology, Korea University, 1, 5-ka, Anam-dong, Sungbuk-gu, Seoul 136-701 (Korea, Republic of); Cho, Bong-Rae [Department of Chemistry, Korea University, Seoul 136-701 (Korea, Republic of); Kim, Hwan-Myung [Department of Chemistry, Ajou University, Suwon, Kyunggi-Do 443-749 (Korea, Republic of); Kim, Yong-Nyun [Division of Specific Organs Center, National Cancer Center, Kyunggi-Do 411-769 (Korea, Republic of); Ham, Young-Mi, E-mail: ymham2@hanmail.net [College of Life Sciences and Biotechnology, Korea University, 1, 5-ka, Anam-dong, Sungbuk-gu, Seoul 136-701 (Korea, Republic of); Ko, Young-Gyu, E-mail: ygko@korea.ac.kr [College of Life Sciences and Biotechnology, Korea University, 1, 5-ka, Anam-dong, Sungbuk-gu, Seoul 136-701 (Korea, Republic of)

    2009-07-24

    Lipid rafts are plasma membrane platforms mediating signal transduction pathways for cellular proliferation, differentiation and apoptosis. Here, we show that membrane fluidity was increased in HeLa cells following treatment with ginsenoside Rh2 (Rh2), as determined by cell staining with carboxy-laurdan (C-laurdan), a two-photon dye designed for measuring membrane hydrophobicity. In the presence of Rh2, caveolin-1 appeared in non-raft fractions after sucrose gradient ultracentrifugation. In addition, caveolin-1 and GM1, lipid raft landmarkers, were internalized within cells after exposure to Rh2, indicating that Rh2 might disrupt lipid rafts. Since cholesterol overloading, which fortifies lipid rafts, prevented an increase in Rh2-induced membrane fluidity, caveolin-1 internalization and apoptosis, lipid rafts appear to be essential for Rh2-induced apoptosis. Moreover, Rh2-induced Fas oligomerization was abolished following cholesterol overloading, and Rh2-induced apoptosis was inhibited following treatment with siRNA for Fas. This result suggests that Rh2 is a novel lipid raft disruptor leading to Fas oligomerization and apoptosis.

  10. Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer.

    Science.gov (United States)

    Truong, Kimberly K; Lam, Michael T; Grandner, Michael A; Sassoon, Catherine S; Malhotra, Atul

    2016-07-01

    Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption. PMID:27104378

  11. Circadian clock: linking epigenetics to aging.

    Science.gov (United States)

    Orozco-Solis, Ricardo; Sassone-Corsi, Paolo

    2014-06-01

    Circadian rhythms are generated by an intrinsic cellular mechanism that controls a large array of physiological and metabolic processes. There is erosion in the robustness of circadian rhythms during aging, and disruption of the clock by genetic ablation of specific genes is associated with aging-related features. Importantly, environmental conditions are thought to modulate the aging process. For example, caloric restriction is a very strong environmental effector capable of delaying aging. Intracellular pathways implicating nutrient sensors, such as SIRTs and mTOR complexes, impinge on cellular and epigenetic mechanisms that control the aging process. Strikingly, accumulating evidences indicate that these pathways are involved in both the modulation of the aging process and the control of the clock. Hence, innovative therapeutic strategies focused at controlling the circadian clock and the nutrient sensing pathways might beneficially influence the negative effects of aging. PMID:25033025

  12. Links between circadian rhythms and psychiatric disease

    Directory of Open Access Journals (Sweden)

    Ilia N Karatsoreos

    2014-05-01

    Full Text Available Determining the cause of psychiatric disorders is a goal of modern neuroscience, and will hopefully lead to the discovery of treatments to either prevent or alleviate the suffering caused by these diseases. One roadblock to attaining this goal is the realization that neuropsychiatric diseases are rarely due to a single gene polymorphism, environmental exposure, or developmental insult. Rather, it is a complex interaction between these various influences that likely leads to the development of clinically relevant syndromes. Our lab is exploring the links between environmental exposures and neurobehavioral function by investigating how disruption of the circadian (daily clock alters the structure and function of neural circuits, with the hypothesis that disrupting this crucial homeostatic system can directly contribute to altered vulnerability of the organism to other factors that interact to produce psychiatric illness. This review explores some historical and more recent findings that link disrupted circadian clocks to neuropsychiatric disorders, particularly depression, mania, and schizophrenia. We take a comparative approach by exploring the effects observed in human populations, as well as some experimental models used in the laboratory to unravel mechanistic and causal relationships between disruption of the circadian clock and behavioral abnormalities. This is a rich area of research that we predict will contribute greatly to our understanding of how genes, environment, and development interact to modulate an individual’s vulnerability to psychiatric disorders.

  13. Hantavirus-induced disruption of the endothelial barrier: neutrophils are on the payroll.

    Science.gov (United States)

    Schönrich, Günther; Krüger, Detlev H; Raftery, Martin J

    2015-01-01

    Viral hemorrhagic fever caused by hantaviruses is an emerging infectious disease for which suitable treatments are not available. In order to improve this situation a better understanding of hantaviral pathogenesis is urgently required. Hantaviruses infect endothelial cell layers in vitro without causing any cytopathogenic effect and without increasing permeability. This implies that the mechanisms underlying vascular hyperpermeability in hantavirus-associated disease are more complex and that immune mechanisms play an important role. In this review we highlight the latest developments in hantavirus-induced immunopathogenesis. A possible contribution of neutrophils has been neglected so far. For this reason, we place special emphasis on the pathogenic role of neutrophils in disrupting the endothelial barrier. PMID:25859243

  14. Hantavirus-induced disruption of the endothelial barrier: Neutrophils are on the payroll

    Directory of Open Access Journals (Sweden)

    Günther eSchönrich

    2015-03-01

    Full Text Available Viral hemorrhagic fever caused by hantaviruses is an emerging infectious disease for which suita-ble treatments are not available. In order to improve this situation a better understanding of han-taviral pathogenesis is urgently required. Hantaviruses infect endothelial cell layers in vitro with-out causing any cytopathogenic effect and without increasing permeability. This implies that the mechanisms underlying vascular hyperpermeability in hantavirus-associated disease are more complex and that immune mechanisms play an important role. In this review we highlight the lat-est developments in hantavirus-induced immunopathogenesis. A possible contribution of neutro-phils has been neglected so far. For this reason, we place special emphasis on the pathogenic role of neutrophils in disrupting the endothelial barrier.

  15. The circadian clock and cell cycle: Interconnected biological circuits

    OpenAIRE

    Masri, Selma; Cervantes, Marlene; Sassone-Corsi, Paolo

    2013-01-01

    The circadian clock governs biological timekeeping on a systemic level, helping to regulate and maintain physiological processes, including endocrine and metabolic pathways with a periodicity of 24-hours. Disruption within the circadian clock machinery has been linked to numerous pathological conditions, including cancer, suggesting that clock-dependent regulation of the cell cycle is an essential control mechanism. This review will highlight recent advances on the ‘gating’ controls of the ci...

  16. Pentachlorophenol-Induced Cytotoxic, Mitogenic, and Endocrine-Disrupting Activities in Channel Catfish, Ictalurus punctatus

    Directory of Open Access Journals (Sweden)

    Paul B. Tchounwou

    2004-09-01

    Full Text Available Pentachlorophenol (PCP is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Although it has been shown to induce systemic toxicity and carcinogenesis in several experimental studies, the literature is scarce regarding its toxic mechanisms of action at the cellular and molecular levels. Recent investigations in our laboratory have shown that PCP induces cytotoxicity and transcriptionally activates stress genes in human liver carcinoma (HepG2 cells [1]. In this research, we hypothesize that environmental exposure to PCP may trigger cytotoxic, mitogenic, and endocrine-disrupting activities in aquatic organisms including fish. To test this hypothesis, we carried out in vitro cultures of male channel catfish hepatocytes, and performed the fluorescein diacetate assay (FDA to assess for cell viability, and the Western Blot analysis to assess for vitellogenin expression following exposure to PCP. Data obtained from FDA experiments indicated a strong dose-response relationship with respect to PCP cytotoxicity. Upon 48 hrs of exposure, the chemical dose required to cause 50% reduction in cell viability (LD50 was computed to be 1,987.0 + 9.6 μg PCP/mL. The NOAEL and LOAEL were 62.5 + 10.3 μg PCP/mL and 125.0+15.2 μg PCP/mL, respectively. At lower levels of exposure, PCP was found to be mitogenic, showing a strong dose- and time-dependent response with regard to cell proliferation. Western Blot analysis demonstrated the potential of PCP to cause endocrine-disrupting activity, as evidenced by the up regulation of the 125-kDa vitellogenin protein the hepatocytes of male channel catfish.

  17. Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine

    OpenAIRE

    Duncan, Marilyn J.; Bruce-Keller, Annadora J.; Conner, Clayton; Knapp, Pamela E.; Xu, Ruquiang; Nath, Avindra; Hauser, Kurt F.

    2008-01-01

    Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their en...

  18. Aging and Circadian Rhythms.

    Science.gov (United States)

    Duffy, Jeanne F; Zitting, Kirsi-Marja; Chinoy, Evan D

    2015-12-01

    Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. This article reviews key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. PMID:26568120

  19. Integration of human sleep-wake regulation and circadian rhythmicity

    Science.gov (United States)

    Dijk, Derk-Jan; Lockley, Steven W.

    2002-01-01

    The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.

  20. Immunity’s fourth dimension: approaching the circadian-immune connection

    OpenAIRE

    Arjona, Alvaro; Adam C Silver; Walker, Wendy E; Fikrig, Erol

    2012-01-01

    The circadian system ensures the generation and maintenance of self-sustained ~24 h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related di...

  1. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism

    DEFF Research Database (Denmark)

    Feng, Dan; Liu, Tao; Sun, Zheng;

    2011-01-01

    Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when...... hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis....

  2. Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy.

    Science.gov (United States)

    van Almen, Geert C; Swinnen, Melissa; Carai, Paolo; Verhesen, Wouter; Cleutjens, Jack P M; D'hooge, Jan; Verheyen, Fons K; Pinto, Yigal M; Schroen, Blanche; Carmeliet, Peter; Heymans, Stephane

    2011-09-01

    Clinical use of the antineoplastic agent doxorubicin (DOX) is limited by its cardiomyocyte toxicity. Attempts to decrease cardiomyocyte injury showed promising results in vitro, but failed to reduce the adverse effects of DOX in vivo, suggesting that other mechanisms contribute to its cardiotoxicity as well. Evidence that DOX also induces cardiac injury by compromising extracellular matrix integrity is lacking. The matricellular protein thrombospondin-2 (TSP-2) is known for its matrix-preserving function, and for modulating cellular function. Here, we investigated whether TSP-2 modulates the process of doxorubicin-induced cardiomyopathy (DOX-CMP). TSP-2-knockout (TSP-2-KO) and wild-type (WT) mice were treated with DOX (2 mg/kg/week) for 12 weeks to induce DOX-CMP. Mortality was significantly increased in TSP-2-KO compared to WT mice. Surviving DOX-treated TSP-2-KO mice had depressed cardiac function compared to WT animals, accompanied by increased cardiomyocyte apoptosis and matrix damage. Enhanced myocyte damage in the absence of TSP-2 was associated with impaired activation of the Akt signaling pathway in TSP-2-KO compared to WT. The absence of TSP-2, in vivo and in vitro, reduced Akt activation both under non-treated conditions and after DOX. Importantly, inhibition of Akt phosphorylation in cardiomyocytes significantly reduced TSP-2 expression, unveiling a unique feedback loop between Akt and TSP-2. Finally, enhanced matrix disruption in DOX-treated TSP-2-KO hearts went along with increased matrix metalloproteinase-2 levels. Taken together, this study is the first to provide evidence for the implication of the matrix element TSP-2 in protecting against DOX-induced cardiac injury and dysfunction. PMID:21624372

  3. Disruption of the ribosomal P complex leads to stress-induced autophagy.

    Science.gov (United States)

    Artero-Castro, Ana; Perez-Alea, Mileidys; Feliciano, Andrea; Leal, Jose A; Genestar, Mónica; Castellvi, Josep; Peg, Vicente; Ramón Y Cajal, Santiago; Lleonart, Matilde E L

    2015-01-01

    The human ribosomal P complex, which consists of the acidic ribosomal P proteins RPLP0, RPLP1, and RPLP2 (RPLP proteins), recruits translational factors, facilitating protein synthesis. Recently, we showed that overexpression of RPLP1 immortalizes primary cells and contributes to transformation. Moreover, RPLP proteins are overexpressed in human cancer, with the highest incidence in breast carcinomas. It is thought that disruption of the P complex would directly affect protein synthesis, causing cell growth arrest and eventually apoptosis. Here, we report a distinct mechanism by which cancer cells undergo cell cycle arrest and induced autophagy when RPLP proteins are downregulated. We found that absence of RPLP0, RPLP1, or RPLP2 resulted in reactive oxygen species (ROS) accumulation and MAPK1/ERK2 signaling pathway activation. Moreover, ROS generation led to endoplasmic reticulum (ER) stress that involved the EIF2AK3/PERK-EIF2S1/eIF2α-EIF2S2-EIF2S3-ATF4/ATF-4- and ATF6/ATF-6-dependent arms of the unfolded protein response (UPR). RPLP protein-deficient cells treated with autophagy inhibitors experienced apoptotic cell death as an alternative to autophagy. Strikingly, antioxidant treatment prevented UPR activation and autophagy while restoring the proliferative capacity of these cells. Our results indicate that ROS are a critical signal generated by disruption of the P complex that causes a cellular response that follows a sequential order: first ROS, then ER stress/UPR activation, and finally autophagy. Importantly, inhibition of the first step alone is able to restore the proliferative capacity of the cells, preventing UPR activation and autophagy. Overall, our results support a role for autophagy as a survival mechanism in response to stress due to RPLP protein deficiency.

  4. Chronic estrogen and progesterone treatment inhibits ketamine-induced disruption of prepulse inhibition in rats.

    Science.gov (United States)

    van den Buuse, Maarten; Mingon, Rebecca L; Gogos, Andrea

    2015-10-21

    Ketamine is a dissociative anesthetic and antagonist of N-methyl-d-aspartate receptors (NMDAr). Hypofunction of NMDAr may underlie some schizophrenia symptoms and the psychotomimetic effects of ketamine have been used to model this hypofunction. Gender differences exist in the age of onset and symptom profile of schizophrenia and sex steroid hormones have been successfully trialed as adjunctive treatment in this illness; however, the mechanism of action of these hormone treatment strategies remains unclear. The aim of this study was therefore to investigate the effect of sex steroid hormones on ketamine-induced disruption of prepulse inhibition (PPI), an endophenotype of schizophrenia. Female ovariectomized (OVX) rats did not show altered effects of ketamine compared to intact rats. There were also no significant changes in the effect of ketamine on PPI in OVX rats implanted with a high dose of estrogen. In contrast, in OVX rats implanted with a low dose of estrogen plus progesterone, the effect of 10mg/kg ketamine was significantly reduced. There were no parallel changes in startle amplitude. These results differ from previous studies on the effect of sex steroid hormones on the disruption of PPI by treatment with the NMDAr antagonist, MK-801, or dopaminergic drugs, such as apomorphine. We speculate that this differential effect of sex steroids on the action of ketamine is mediated by mechanisms other than dopaminergic stimulation or NMDA receptor blockade, for example GABAA receptors. These results extend our understanding of the effects of sex steroid hormones on PPI and their use as potential treatments in schizophrenia. PMID:26391745

  5. Circadian Gene Variants and Susceptibility to Type 2 Diabetes : A Pilot Study

    NARCIS (Netherlands)

    Kelly, M. Ann; Rees, Simon D.; Hydrie, M. Zafar I.; Shera, A. Samad; Bellary, Srikanth; O'Hare, J. Paul; Kumar, Sudhesh; Taheri, Shahrad; Basit, Abdul; Barnett, Anthony H.

    2012-01-01

    Background: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diab

  6. Neisseria gonorrhoeae induced disruption of cell junction complexes in epithelial cells of the human genital tract.

    Science.gov (United States)

    Rodríguez-Tirado, Carolina; Maisey, Kevin; Rodríguez, Felipe E; Reyes-Cerpa, Sebastián; Reyes-López, Felipe E; Imarai, Mónica

    2012-03-01

    Pathogenic microorganisms, such as Neisseria gonorrhoeae, have developed mechanisms to alter epithelial barriers in order to reach subepithelial tissues for host colonization. The aim of this study was to examine the effects of gonococci on cell junction complexes of genital epithelial cells of women. Polarized Ishikawa cells, a cell line derived from endometrial epithelium, were used for experimental infection. Infected cells displayed a spindle-like shape with an irregular distribution, indicating potential alteration of cell-cell contacts. Accordingly, analysis by confocal microscopy and cellular fractionation revealed that gonococci induced redistribution of the adherens junction proteins E-cadherin and its adapter protein β-catenin from the membrane to a cytoplasmic pool, with no significant differences in protein levels. In contrast, gonococcal infection did not induce modification of either expression or distribution of the tight junction proteins Occludin and ZO-1. Similar results were observed for Fallopian tube epithelia. Interestingly, infected Ishikawa cells also showed an altered pattern of actin cytoskeleton, observed in the form of stress fibers across the cytoplasm, which in turn matched a strong alteration on the expression of fibronectin, an adhesive glycoprotein component of extracellular matrix. Interestingly, using western blotting, activation of the ERK pathway was detected after gonococcal infection while p38 pathway was not activated. All effects were pili and Opa independent. Altogether, results indicated that gonococcus, as a mechanism of pathogenesis, induced disruption of junction complexes with early detaching of E-cadherin and β-catenin from the adherens junction complex, followed by a redistribution and reorganization of actin cytoskeleton and fibronectin within the extracellular matrix. PMID:22146107

  7. Illuminating the circadian clock in monarch butterfly migration.

    Science.gov (United States)

    Froy, Oren; Gotter, Anthony L; Casselman, Amy L; Reppert, Steven M

    2003-05-23

    Migratory monarch butterflies use a time-compensated Sun compass to navigate to their overwintering grounds in Mexico. Here, we report that constant light, which disrupts circadian clock function at both the behavioral and molecular levels in monarchs, also disrupts the time-compensated component of flight navigation. We further show that ultraviolet light is important for flight navigation but is not required for photic entrainment of circadian rhythms. Tracing these distinct light-input pathways into the brain should aid our understanding of the clock-compass mechanisms necessary for successful migration. PMID:12764200

  8. Keeping the right time in space:importance of circadian clock and sleep for physiology and performance of astronauts

    Institute of Scientific and Technical Information of China (English)

    Jin-Hu Guo; Wei-Min Qu; Shan-Guang Chen; Xiao-Ping Chen; Ke Lv; Zhi-Li Huang; Yi-Lan Wu

    2014-01-01

    The circadian clock and sleep are essential for human physiology and behavior; deregulation of circadian rhythms impairs health and performance. Circadian clocks and sleep evolved to adapt to Earth’s environment, which is characterized by a 24-hour light–dark cycle. Changes in gravity load, lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, in turn jeopardizing the mood, cognition and performance of orbiting astronauts. In this review, we summarize our understanding of both the influence of the space environment on the circadian timing system and sleep and the impact of these changes on astronaut physiology and performance.

  9. Malathion exposure induces the endocrine disruption and growth retardation in the catfish, Clarias batrachus (Linn.).

    Science.gov (United States)

    Lal, Bechan; Sarang, Mukesh Kumar; Kumar, Pankaj

    2013-01-15

    Many hormones are known for their role in the regulation of metabolic activities and somatic growth in fishes. The present study deals with the effects of malathion (an organophosphorous pesticide) on the levels of metabolic hormones that are responsible for promotion of somatic and ovarian growth of the freshwater catfish, Clarias batrachus. Malathion treatment for thirty days drastically reduced the food intake and body weight of fish. These fish also exhibited a great avoidance to food. Exposure of catfish to malathion reduced the levels of thyroxine (T(4)), triiodothyronine (T(3)), growth hormone (GH), insulin like growth factor-I (IGF-I), testosterone (T) and estradiol-17β (E(2)) in a dose dependent manner during all the studied reproductive phases, in general, except that malathion increased the level of GH during the quiescence phase. Significant reduction in muscle and hepatic protein content also occurred in the malathion-treated fish. Malathion exposure induced lipolysis too in the liver and muscle. The results thus support that malathion treatment disrupts the endocrine functions and the olfactory sensation responsible for food intake and gustatory feeding behavior, which ultimately leads to retardation of fish growth. PMID:23174696

  10. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.

    Directory of Open Access Journals (Sweden)

    Christel Gumy

    Full Text Available BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK and tyrosine-aminotransferase (TAT and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6 and TNF-alpha production in lipopolysaccharide (LPS-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

  11. Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

    Energy Technology Data Exchange (ETDEWEB)

    Liou, Jong-Shian; Wu, Yi-Chen; Yen, Wen-Yen; Tang, Yu-Shuan [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China); Kakadiya, Rajesh B.; Su, Tsann-Long [Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC (China); Yih, Ling-Huei, E-mail: lhyih@gate.sinica.edu.tw [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China)

    2014-08-01

    DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest.

  12. Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

    International Nuclear Information System (INIS)

    DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest

  13. Altered circadian rhythm and metabolic gene profile in rats subjected to advanced light phase shifts.

    Directory of Open Access Journals (Sweden)

    Laura Herrero

    Full Text Available The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT, brown adipose tissue (BAT and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level.

  14. Role for circadian clock genes in seasonal timing: testing the Bunning hypothesis.

    Directory of Open Access Journals (Sweden)

    Mirko Pegoraro

    2014-09-01

    Full Text Available A major question in chronobiology focuses around the "Bünning hypothesis" which implicates the circadian clock in photoperiodic (day-length measurement and is supported in some systems (e.g. plants but disputed in others. Here, we used the seasonally-regulated thermotolerance of Drosophila melanogaster to test the role of various clock genes in day-length measurement. In Drosophila, freezing temperatures induce reversible chill coma, a narcosis-like state. We have corroborated previous observations that wild-type flies developing under short photoperiods (winter-like exhibit significantly shorter chill-coma recovery times (CCRt than flies that were raised under long (summer-like photoperiods. Here, we show that arrhythmic mutant strains, per01, tim01 and ClkJrk, as well as variants that speed up or slow down the circadian period, disrupt the photoperiodic component of CCRt. Our results support an underlying circadian function mediating seasonal daylength measurement and indicate that clock genes are tightly involved in photo- and thermo-periodic measurements.

  15. Dissociation of ultradian and circadian phenotypes in female and male Siberian hamsters.

    Science.gov (United States)

    Prendergast, Brian J; Cisse, Yasmine M; Cable, Erin J; Zucker, Irving

    2012-08-01

    Three experiments addressed whether pronounced alterations in the circadian system yielded concomitant changes in ultradian timing. Female Siberian hamsters were housed in a 16L:8D photoperiod after being subjected to a disruptive phase-shifting protocol that produced 3 distinct permanent circadian phenotypes: some hamsters entrained their circadian rhythms (CRs) with predominantly nocturnal locomotor activity (ENTR), others displayed free-running CRs (FR), and a third cohort was circadian arrhythmic (ARR). The period of the ultradian locomotor rhythm (UR) did not differ among the 3 circadian phenotypes; neuroendocrine generation of URs remains viable in the absence of coherent circadian organization and appears to be mediated by substrates functionally and anatomically distinct from those that generate CRs. Pronounced light-dark differences in several UR characteristics in ENTR hamsters were completely absent in circadian arrhythmic hamsters. The disruptive phase-shifting protocol may compromise direct visual input to ultradian oscillators but more likely indirectly affects URs by interrupting visual afference to the circadian system. Additional experiments documented that deuterium oxide and constant light, each of which substantially lengthened the period of free-running CRs, failed to change the period of concurrently monitored URs. The resistance of URs to deuteration contrasts with the slowing of virtually all other biological timing processes, including CRs. Considered together, the present results point to the existence of separable control mechanisms for generation of circadian and ultradian rhythms.

  16. Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.

    Science.gov (United States)

    Mukherjee, Subhendu; Ayaub, Ehab A; Murphy, James; Lu, Chao; Kolb, Martin; Ask, Kjetil; Janssen, Luke J

    2015-10-01

    Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis.

  17. Methylmercury-induced changes in gene transcription associated with neuroendocrine disruption in largemouth bass (Micropterus salmoides)

    Science.gov (United States)

    Richter, Catherine A.; Martyniuk, Christopher J.; Annis, Mandy L.; Brumbaugh, William G.; Chasar, Lia C.; Denslow, Nancy D.; Tillitt, Donald E.

    2014-01-01

    Methyl-mercury (MeHg) is a potent neuroendocrine disruptor that impairs reproductive processes in fish. The objectives of this study were to (1) characterize transcriptomic changes induced by MeHg exposure in the female largemouth bass (LMB) hypothalamus under controlled laboratory conditions, (2) investigate the health and reproductive impacts of MeHg exposure on male and female largemouth bass (LMB) in the natural environment, and (3) identify MeHg-associated gene expression patterns in whole brain of female LMB from MeHg-contaminated habitats. The laboratory experiment was a single injection of 2.5 μg MeHg/g body weight for 96 h exposure. The field survey compared river systems in Florida, USA with comparably lower concentrations of MeHg (Wekiva, Santa Fe, and St. Johns Rivers) in fish and one river system with LMB that contained elevated concentrations of MeHg (St. Marys River). Microarray analysis was used to quantify transcriptomic responses to MeHg exposure. Although fish at the high-MeHg site did not show overt health or reproductive impairment, there were MeHg-responsive genes and pathways identified in the laboratory study that were also altered in fish from the high-MeHg site relative to fish at the low-MeHg sites. Gene network analysis suggested that MeHg regulated the expression targets of neuropeptide receptor and steroid signaling, as well as structural components of the cell. Disease-associated gene networks related to MeHg exposure, based upon expression data, included cerebellum ataxia, movement disorders, and hypercalcemia. Gene responses in the CNS are consistent with the documented neurotoxicological and neuroendocrine disrupting effects of MeHg in vertebrates.

  18. Efficiency of drug delivery enhanced by acoustic pressure during blood–brain barrier disruption induced by focused ultrasound

    OpenAIRE

    Yang, Feng-Yi

    2012-01-01

    Feng-Yi Yang, Pei-Yi LeeDepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, TaiwanPurpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood–brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters.Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction...

  19. Hypo-osmotic shock-induced subclinical inflammation of skin in a rat model of disrupted skin barrier function.

    Science.gov (United States)

    Kishi, Chihiro; Minematsu, Takeo; Huang, Lijuan; Mugita, Yuko; Kitamura, Aya; Nakagami, Gojiro; Yamane, Takumi; Yoshida, Mikako; Noguchi, Hiroshi; Funakubo, Megumi; Mori, Taketoshi; Sanada, Hiromi

    2015-03-01

    Aging disrupts skin barrier function and induces xerosis accompanied by pruritus. In many cases, elderly patients complain of pruritus during skin hygiene care, a condition called aquagenic pruritus of the elderly (APE). To date, the pathophysiology and mechanism of action of APE have not been elucidated. We conducted the present study to test the hypothesis that hypo-osmotic shock of epidermal cells induces skin inflammation and elongation of C-fibers by nerve growth factor β (NGFβ) as a basic mechanism of APE. The dorsal skin of HWY rats, which are a model for disrupted skin barrier function, was treated with distilled water (hypotonic treatment [Hypo] group) or normal saline (isotonic treatment [Iso] group) by applying soaked gauze for 7 days. Untreated rats were used as a control (no-treatment [NT] group). Histochemical and immunohistochemical analyses revealed inflammatory responses in the epidermis and the dermal papillary layer in the Hypo group, while no alterations were observed in the Iso or NT groups. Induction of expression and secretion of NGFβ and elongation of C-fibers into the epidermis were found in the Hypo group. In contrast, secretion of NGFβ was significantly lower and elongation of C-fibers was not observed in the Iso group. These results suggest that hypo-osmotic shock-induced inflammatory reactions promote hypersensitivity to pruritus in skin with disrupted barrier function. PMID:25681269

  20. Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP/TIMP in aged rats

    Directory of Open Access Journals (Sweden)

    Zhengqian eLi

    2016-04-01

    Full Text Available Reversible BBB disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD. Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2 and -9 (MMP-9, as well as three of their endogenous tissue inhibitors (TIMP-1, -2, -3, and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II and Ang II receptor type 1 (AT1 after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1, as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.

  1. Circadian Misalignment and Health

    OpenAIRE

    Baron, Kelly Glazer; Reid, Kathryn J.

    2014-01-01

    Circadian rhythms are near 24-hour patterns of physiology and behavior that are present independent of external cues including hormones, body temperature, mood, and sleep propensity. The term “circadian misalignment” describes a variety of circumstances, such as inappropriately timed sleep and wake, misalignment of sleep/wake with feeding rhythms, or misaligned central and peripheral rhythms. The predominance of early research focused on misalignment of sleep to the biological night. However,...

  2. Synergetic Effects of Runaway and Disruption Induced by VDE on the First Wall Damage in HL-2A

    Institute of Scientific and Technical Information of China (English)

    宋先瑛; 杨进蔚; 李旭; 袁国梁; 张轶泼

    2012-01-01

    The plasma facing component in HL-2A has been damaged seriously after disruption, and for this reason its operation is suspended for maintenance. The experimental phenomena and plasma configurations, calculated by the current filament code (CF-code) using the plasma parameters measured by diagnostics and the signals of the magnetic probes, confirm that the first wall is damaged by the synergetic effects of runaway electrons and disruption induced by a vertical displacement event (VDE). When the plasma column is displaced upward/downward, the strong runaway electrons normally hit the baffle plate of the MP3 or MP1 coil in the upper and lower divertor during the disruption, causing the baffle plates to be holed and wrinkled by the energetic runaway current, and water (for cooling or heating the baffle plates) to leak into the vacuum vessel. Another disastrous consequence is that bellows underlying the baffle plate and outside the coil of MP3 for connecting two segments of the jacket casing pipe are punctured by arcing. The arc may be part of the halo current that forms a complete circuit. The experimental phenomena are indirect but compelling evidence for the existence of a halo current during the disruption and VDE, though the halo current has not been measured by the diagnostics in the HL-2A tokamak.

  3. AMPK regulates circadian rhythms in a tissue- and isoform-specific manner.

    Directory of Open Access Journals (Sweden)

    Jee-Hyun Um

    Full Text Available BACKGROUND: AMP protein kinase (AMPK plays an important role in food intake and energy metabolism, which are synchronized to the light-dark cycle. In vitro, AMPK affects the circadian rhythm by regulating at least two clock components, CKIα and CRY1, via direct phosphorylation. However, it is not known whether the catalytic activity of AMPK actually regulates circadian rhythm in vivo. METHODOLOGY/PRINCIPAL FINDING: THE CATALYTIC SUBUNIT OF AMPK HAS TWO ISOFORMS: α1 and α2. We investigate the circadian rhythm of behavior, physiology and gene expression in AMPKα1-/- and AMPKα2-/- mice. We found that both α1-/- and α2-/- mice are able to maintain a circadian rhythm of activity in dark-dark (DD cycle, but α1-/- mice have a shorter circadian period whereas α2-/- mice showed a tendency toward a slightly longer circadian period. Furthermore, the circadian rhythm of body temperature was dampened in α1-/- mice, but not in α2-/- mice. The circadian pattern of core clock gene expression was severely disrupted in fat in α1-/- mice, but it was severely disrupted in the heart and skeletal muscle of α2-/- mice. Interestingly, other genes that showed circadian pattern of expression were dysreguated in both α1-/- and α2-/- mice. The circadian rhythm of nicotinamide phosphoryl-transferase (NAMPT activity, which converts nicotinamide (NAM to NAD+, is an important regulator of the circadian clock. We found that the NAMPT rhythm was absent in AMPK-deficient tissues and cells. CONCLUSION/SIGNIFICANCE: This study demonstrates that the catalytic activity of AMPK regulates circadian rhythm of behavior, energy metabolism and gene expression in isoform- and tissue-specific manners.

  4. Circadian rhythm and cell population growth

    CERN Document Server

    Clairambault, Jean; Lepoutre, Thomas

    2010-01-01

    Molecular circadian clocks, that are found in all nucleated cells of mammals, are known to dictate rhythms of approximately 24 hours (circa diem) to many physiological processes. This includes metabolism (e.g., temperature, hormonal blood levels) and cell proliferation. It has been observed in tumor-bearing laboratory rodents that a severe disruption of these physiological rhythms results in accelerated tumor growth. The question of accurately representing the control exerted by circadian clocks on healthy and tumour tissue proliferation to explain this phenomenon has given rise to mathematical developments, which we review. The main goal of these previous works was to examine the influence of a periodic control on the cell division cycle in physiologically structured cell populations, comparing the effects of periodic control with no control, and of different periodic controls between them. We state here a general convexity result that may give a theoretical justification to the concept of cancer chronothera...

  5. Diurnal oscillations of soybean circadian clock and drought responsive genes.

    Directory of Open Access Journals (Sweden)

    Juliana Marcolino-Gomes

    Full Text Available Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis-elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i drought stress affects gene expression of circadian clock components and (ii several stress responsive genes display diurnal oscillation in soybeans.

  6. Basic Sleep and Circadian Science as Building Blocks for Behavioral Interventions: A Translational Approach for Mood Disorders

    OpenAIRE

    Asarnow, Lauren D.; Soehner, Adriane M.; Harvey, Allison G.

    2014-01-01

    Sleep and circadian functioning has been of particular interest to researchers focused on improving treatments for psychiatric illness. The goal of the present paper is to highlight the exciting research that utilizes basic sleep and circadian science as building blocks for intervention in the mood disorders. The reviewed evidence suggests that the sleep and circadian systems are 1) disrupted in the mood disorders and linked to symptoms, 2) open systems that can be modified, 3) the focus of i...

  7. Pharmacokinetics of BPA in Gliomas with Ultrasound Induced Blood-Brain Barrier Disruption as Measured by Microdialysis

    Science.gov (United States)

    Yang, Feng-Yi; Lin, Yi-Li; Chou, Fong-In; Lin, Yu-Chuan; Hsueh Liu, Yen-Wan; Chang, Lun-Wei; Hsieh, Yu-Ling

    2014-01-01

    The blood-brain barrier (BBB) can be transiently disrupted by focused ultrasound (FUS) in the presence of microbubbles for targeted drug delivery. Previous studies have illustrated the pharmacokinetics of drug delivery across the BBB after sonication using indirect visualization techniques. In this study, we investigated the in vivo extracellular kinetics of boronophenylalanine-fructose (BPA-f) in glioma-bearing rats with FUS-induced BBB disruption by microdialysis. After simultaneous intravenous administration of BPA and FUS exposure, the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. With FUS, the mean peak concentration of BPA-f in the glioma dialysate was 3.6 times greater than without FUS, and the area under the concentration-time curve was 2.1 times greater. This study demonstrates that intracerebral microdialysis can be used to assess local BBB transport profiles of drugs in a sonicated site. Applying microdialysis to the study of metabolism and pharmacokinetics is useful for obtaining selective information within a specific brain site after FUS-induced BBB disruption. PMID:24936788

  8. Pharmacokinetics of BPA in gliomas with ultrasound induced blood-brain barrier disruption as measured by microdialysis.

    Directory of Open Access Journals (Sweden)

    Feng-Yi Yang

    Full Text Available The blood-brain barrier (BBB can be transiently disrupted by focused ultrasound (FUS in the presence of microbubbles for targeted drug delivery. Previous studies have illustrated the pharmacokinetics of drug delivery across the BBB after sonication using indirect visualization techniques. In this study, we investigated the in vivo extracellular kinetics of boronophenylalanine-fructose (BPA-f in glioma-bearing rats with FUS-induced BBB disruption by microdialysis. After simultaneous intravenous administration of BPA and FUS exposure, the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. With FUS, the mean peak concentration of BPA-f in the glioma dialysate was 3.6 times greater than without FUS, and the area under the concentration-time curve was 2.1 times greater. This study demonstrates that intracerebral microdialysis can be used to assess local BBB transport profiles of drugs in a sonicated site. Applying microdialysis to the study of metabolism and pharmacokinetics is useful for obtaining selective information within a specific brain site after FUS-induced BBB disruption.

  9. Eddy current induced electromagnetic loads on shield blankets during plasma disruptions in ITER: A benchmark exercise

    International Nuclear Information System (INIS)

    According to recent updates of ITER shield blanket design, electromagnetic loads during the plasma disruption are being evaluated to verify the mechanical confidence and reliability. As a course of such evaluations, a benchmark activity for the electromagnetic analysis, coordinated by ITER Organization, is underway between ITER parties to compare the calculation results for disruption loads on the blankets. In this paper, we present calculation results for the electromagnetic loads on the simplified but practical model of ITER shield blankets with respect to six representative disruption scenarios of which ITER distributes simulation results based on the DINA code as a reference of the design and analysis. Commercial finite element method software, ANSYS/EmagTM, was employed to evaluate the eddy current on the blanket modules with the 40o sector model for major conducting structure of the tokamak including double-walled vacuum vessel, triangular support, and vertical targets of divertors. An interface between ANSYS/EmagTM and plasma simulator was implemented with a conversion tool assigning the plasma current density on the ANSYS elements corresponding to the current filaments in DINA outputs. Discussions are made of the possible improvement of the blanket model taking more realistic blanket configuration into account at the cost of the moderate increase in computational time. A final remark is given of the possibility of incorporating halo currents into ANSYS disruption simulations, which are major sources of electromagnetic loads on in-vessel components including blankets.

  10. Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

    DEFF Research Database (Denmark)

    Petersen, Marta Axelstad; Christiansen, Sofie; Boberg, Julie;

    2014-01-01

    Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine-disrupting contaminants, including pesticides, plastic and cosmetic ingredients, and paracetamol. The mixture was composed on the basis of information about high-end human exposures...

  11. Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis.

    Science.gov (United States)

    Cheng, Bo; Anea, Ciprian B; Yao, Lin; Chen, Feng; Patel, Vijay; Merloiu, Ana; Pati, Paramita; Caldwell, R William; Fulton, David J; Rudic, R Daniel

    2011-10-11

    The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.

  12. Postoperative circadian disturbances

    DEFF Research Database (Denmark)

    Gögenur, Ismail

    2010-01-01

    in patients with lower than median pain levels for a three days period after laparoscopic cholecystectomy. In the series of studies included in this thesis we have systematically shown that circadian disturbances are found in the secretion of hormones, the sleep-wake cycle, core body temperature rhythm......An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention...... these endogenous rhythms have been investigated in relation to surgery we performed a series of studies exploring different endogenous rhythms and factors affecting these rhythms. We also wanted to examine whether the disturbances in the postoperative circadian rhythms could be correlated to postoperative recovery...

  13. The habitat disruption induces immune-suppression and oxidative stress in honey bees

    OpenAIRE

    Morimoto, Tomomi; Kojima, Yuriko; Toki, Taku; Komeda, Yayoi; YOSHIYAMA, Mikio; Kimura, Kiyoshi; Nirasawa, Keijiro; Kadowaki, Tatsuhiko

    2011-01-01

    The honey bee is a major insect used for pollination of many commercial crops worldwide. Although the use of honey bees for pollination can disrupt the habitat, the effects on their physiology have never been determined. Recently, honey bee colonies have often collapsed when introduced in greenhouses for pollination in Japan. Thus, suppressing colony collapses and maintaining the number of worker bees in the colonies is essential for successful long-term pollination in greenhouses and recycli...

  14. The period length of fibroblast circadian gene expression varies widely among human individuals.

    Directory of Open Access Journals (Sweden)

    Steven A Brown

    2005-10-01

    Full Text Available Mammalian circadian behavior is governed by a central clock in the suprachiasmatic nucleus of the brain hypothalamus, and its intrinsic period length is believed to affect the phase of daily activities. Measurement of this period length, normally accomplished by prolonged subject observation, is difficult and costly in humans. Because a circadian clock similar to that of the suprachiasmatic nucleus is present in most cell types, we were able to engineer a lentiviral circadian reporter that permits characterization of circadian rhythms in single skin biopsies. Using it, we have determined the period lengths of 19 human individuals. The average value from all subjects, 24.5 h, closely matches average values for human circadian physiology obtained in studies in which circadian period was assessed in the absence of the confounding effects of light input and sleep-wake cycle feedback. Nevertheless, the distribution of period lengths measured from biopsies from different individuals was wider than those reported for circadian physiology. A similar trend was observed when comparing wheel-running behavior with fibroblast period length in mouse strains containing circadian gene disruptions. In mice, inter-individual differences in fibroblast period length correlated with the period of running-wheel activity; in humans, fibroblasts from different individuals showed widely variant circadian periods. Given its robustness, the presented procedure should permit quantitative trait mapping of human period length.

  15. CIRCADIAN GENES AND REGULATION OF DIAPAUSE IN INSECT

    OpenAIRE

    Bajgar, Adam

    2013-01-01

    This thesis considers various roles of circadian clock genes in insect physiology. Application of molecular-biology methods in Pyrrhocoris apterus, non-model insect species, enable us to investigate involvement of circadian clock genes in photoperiod induced physiological responses. We discover involvement of neuroendocrine cells, and a role of Juvenile hormone (JH) signalization in transduction of photoperiodic signalization to peripheral tissues. We found new principles of JH signal diversi...

  16. Carbendazim has the potential to induce oxidative stress, apoptosis, immunotoxicity and endocrine disruption during zebrafish larvae development.

    Science.gov (United States)

    Jiang, Jinhua; Wu, Shenggan; Wang, Yanhua; An, Xuehua; Cai, Leiming; Zhao, Xueping; Wu, Changxing

    2015-10-01

    Increasing evidence have suggested deleterious effects of carbendazim on reproduction, apoptosis, immunotoxicity and endocrine disruption in mice and rats, however, the developmental toxicity of carbendazim to aquatic organisms remains obscure. In the present study, we utilized zebrafish as an environmental monitoring model to characterize the effects of carbendazim on expression of genes related to oxidative stress, apoptosis, immunotoxicity and endocrine disruption during larval development. Different trends in gene expression were observed upon exposing the larvae to 4, 20, 100, and 500 μg/L carbendazim for 4 and 8d. The mRNA levels of catalase, glutathione peroxidase and manganese superoxide dismutase (CAT, GPX, and Mn/SOD) were up-regulated after exposure to different concentrations of carbendazim for 4 or 8d. The up-regulation of p53, Apaf1, Cas8 and the down-regulation of Bcl2, Mdm2, Cas3 in the apoptosis pathway, as well as the increased expression of cytokines and chemokines, including CXCL-C1C, CCL1, IL-1b, IFN, IL-8, and TNFα, suggested carbendazim might trigger apoptosis and immune response during zebrafish larval development. In addition, the alteration of mRNA expression of VTG, ERα, ERβ1, ERβ2, TRα, TRβ, Dio1, and Dio2 indicated the potential of carbendazim to induce endocrine disruption in zebrafish larvae. These data suggested that carbendazim could simultaneously induce multiple responses during zebrafish larval development, and bidirectional interactions among oxidative stress, apoptosis pathway, immune and endocrine systems might be present. PMID:26055223

  17. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms.

    Science.gov (United States)

    Landgraf, Dominic; Joiner, William J; McCarthy, Michael J; Kiessling, Silke; Barandas, Rita; Young, Jared W; Cermakian, Nicolas; Welsh, David K

    2016-08-01

    Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian

  18. Bifidobacteria Prevent Tunicamycin-Induced Endoplasmic Reticulum Stress and Subsequent Barrier Disruption in Human Intestinal Epithelial Caco-2 Monolayers.

    Science.gov (United States)

    Akiyama, Takuya; Oishi, Kenji; Wullaert, Andy

    2016-01-01

    Endoplasmic reticulum (ER) stress is caused by accumulation of unfolded and misfolded proteins in the ER, thereby compromising its vital cellular functions in protein production and secretion. Genome wide association studies in humans as well as experimental animal models linked ER stress in intestinal epithelial cells (IECs) with intestinal disorders including inflammatory bowel diseases. However, the mechanisms linking the outcomes of ER stress in IECs to intestinal disease have not been clarified. In this study, we investigated the impact of ER stress on intestinal epithelial barrier function using human colon carcinoma-derived Caco-2 monolayers. Tunicamycin-induced ER stress decreased the trans-epithelial electrical resistance of Caco-2 monolayers, concomitant with loss of cellular plasma membrane integrity. Epithelial barrier disruption in Caco-2 cells after ER stress was not caused by caspase- or RIPK1-dependent cell death but was accompanied by lysosomal rupture and up-regulation of the ER stress markers Grp78, sXBP1 and Chop. Interestingly, several bifidobacteria species inhibited tunicamycin-induced ER stress and thereby diminished barrier disruption in Caco-2 monolayers. Together, these results showed that ER stress compromises the epithelial barrier function of Caco-2 monolayers and demonstrate beneficial impacts of bifidobacteria on ER stress in IECs. Our results identify epithelial barrier loss as a potential link between ER stress and intestinal disease development, and suggest that bifidobacteria could exert beneficial effects on this phenomenon. PMID:27611782

  19. CCL2 mediates the circadian response to low dose endotoxin.

    Science.gov (United States)

    Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A

    2016-09-01

    The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation. PMID:27178133

  20. Circadian gating of neuronal functionality: a basis for iterative metaplasticity.

    Science.gov (United States)

    Iyer, Rajashekar; Wang, Tongfei A; Gillette, Martha U

    2014-01-01

    Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID:25285070

  1. Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin▿

    OpenAIRE

    Caridha, D.; Yourick, D.; Cabezas, M.; De Wolf, L.; Hudson, T. H.; Dow, G. S.

    2007-01-01

    In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-d-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Sec...

  2. Circadian Phase Preference in Pediatric Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Kerri L. Kim

    2014-03-01

    Full Text Available Pediatric bipolar disorder (BD rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine one component of sleep—i.e., circadian phase preference with the behavioral construct of morningness/eveningness (M/E. In comparing 30 BD and 45 typically developing control (TDC participants, ages 7–17 years, on the Morningness-Eveningness Scale for Children (MESC, no between-group differences emerged. Similar results were found when comparing three groups (BD−ADHD; BD+ADHD; TDC. Consistent with data available on circadian phase preference in adults with BD, however, we found that BD adolescents, ages 13 years and older, endorsed significantly greater eveningness compared to their TDC peers. While the current findings are limited by reliance on subjective report and the high-rate of comorbid ADHD among the BD group, this finding that BD teens demonstrate an exaggerated shift towards eveningness than would be developmentally expected is important. Future studies should compare the circadian rhythms across the lifespan for individuals diagnosed with BD, as well as identify the point at which BD youth part ways with their healthy peers in terms of phase preference. In addition, given our BD sample was overall euthymic, it may be that M/E is more state vs. trait specific in latency age youth. Further work would benefit from assessing circadian functioning using a combination of rating forms and laboratory-based measures. Improved understanding of sleep in BD may identify behavioral targets for inclusion in prevention and intervention protocols.

  3. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis

    Science.gov (United States)

    Pekovic-Vaughan, Vanja; Gibbs, Julie; Yoshitane, Hikari; Yang, Nan; Pathiranage, Dharshika; Guo, Baoqiang; Sagami, Aya; Taguchi, Keiko; Bechtold, David; Loudon, Andrew; Yamamoto, Masayuki; Chan, Jefferson; van der Horst, Gijsbertus T.J.; Fukada, Yoshitaka; Meng, Qing-Jun

    2014-01-01

    The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock “gated” pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis. PMID:24637114

  4. Oral Gingival Cell Cigarette Smoke Exposure Induces Muscle Cell Metabolic Disruption

    Directory of Open Access Journals (Sweden)

    Andrea C. Baeder

    2016-01-01

    Full Text Available Cigarette smoke exposure compromises health through damaging multiple physiological systems, including disrupting metabolic function. The purpose of this study was to determine the role of oral gingiva in mediating the deleterious metabolic effects of cigarette smoke exposure on skeletal muscle metabolic function. Using an in vitro conditioned medium cell model, skeletal muscle cells were incubated with medium from gingival cells treated with normal medium or medium containing suspended cigarette smoke extract (CSE. Following incubation of muscle cells with gingival cell conditioned medium, muscle cell mitochondrial respiration and insulin signaling and action were determined as an indication of overall muscle metabolic health. Skeletal muscle cells incubated with conditioned medium of CSE-treated gingival cells had a profound reduction in mitochondrial respiration and respiratory control. Furthermore, skeletal muscle cells had a greatly reduced response in insulin-stimulated Akt phosphorylation and glycogen synthesis. Altogether, these results provide a novel perspective on the mechanism whereby cigarette smoke affects systemic metabolic function. In conclusion, we found that oral gingival cells treated with CSE create an altered milieu that is sufficient to both disrupted skeletal muscle cell mitochondrial function and insulin sensitivity.

  5. Dysregulation of circadian rhythms following prolactin-secreting pituitary microadenoma.

    Science.gov (United States)

    Borodkin, Katy; Ayalon, Liat; Kanety, Hanna; Dagan, Yaron

    2005-01-01

    A patient who developed an irregular sleep-wake pattern following prolactin-secreting pituitary microadenoma is described. The patient reported difficulties in sleep onset and awakening at the desired time, which caused major dysfunction in his daily life activities. Despite these difficulties, the sleep-related complaints of the patient remained unrecognized for as long as three yrs. Statistical analyses of the patient's rest-activity patterns revealed that the disruption of the sleep-wake circadian rhythm originated from a disharmony between ultradian (semicircadian) and circadian components. The circadian component displayed shorter than 24 h periodicity most of the time, but the semicircadian component fluctuated between longer and shorter than 12 h periods. Additionally, desynchrony in terms of period length was found in the tentative analyses of the rest-activity pattern, salivary melatonin, and oral temperature. While the salivary melatonin time series data could be characterized by a best-fit cosine curve of 24 h, the time series data of oral temperature was more compatible with 28 h best-fit curve. The rest-activity cycle during the simultaneous measurements, however, was best approximated by a best-fit curve of 21 h. The dysregulation of circadian rhythms occurred concomitantly, but not beforehand, with the onset of pituitary disease, thus suggesting an association between the two phenomena. This association may have interesting implications to the modeling of the circadian time-keeping system. This case also highlights the need to raise the awareness to circadian rhythm sleep disorders and to consider disruptions of sleep-wake cycle in patients with pituitary adenoma. PMID:15865328

  6. κ Opioid Receptor Antagonism and Prodynorphin Gene Disruption Block Stress-Induced Behavioral Responses

    OpenAIRE

    McLaughlin, Jay P.; Marton-Popovici, Monica; Chavkin, Charles

    2003-01-01

    Previous studies have demonstrated that stress may increase prodynorphin gene expression, and κ opioid agonists suppress drug reward. Therefore, we tested the hypothesis that stress-induced release of endogenous dynorphin may mediate behavioral responses to stress and oppose the rewarding effects of cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a modified Porsolt procedure at 30°C showed a characteristic stress-induced immobility response and a stress-induced ana...

  7. Circadian molecular clock in lung pathophysiology.

    Science.gov (United States)

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology.

  8. Prospective evaluation of the Circadian Efficacy of (Day)Light in Rooms

    OpenAIRE

    Pechacek, C.; Andersen, Marilyne; Lockley, S. W.

    2008-01-01

    Recent studies have attempted to link environmental cues, such as lighting, with human performance and health, and initial findings seem to indicate a positive correlation between the two. Light is the major environmental time cue that resets the human circadian pacemaker, an endogenous clock in the hypothalamus that controls the timing of many 24-hour rhythms in physiology and behavior. Insufficient or inappropriate light exposure can disrupt normal circadian rhythms which may result in adve...

  9. Circadian Rhythms and Mood Regulation: Insights from Pre-Clinical Models

    OpenAIRE

    McClung, Colleen A.

    2011-01-01

    Affective disorders such as major depression, bipolar disorder, and seasonal affective disorder are associated with major disruptions in circadian rhythms. Indeed, altered sleep/wake cycles are a critical feature for diagnosis in the DSM IV and several of the therapies used to treat these disorders have profound effects on rhythm length and stabilization in human populations. Furthermore, multiple human genetic studies have identified polymorphisms in specific circadian genes that associate w...

  10. Research on sleep, circadian rhythms and aging - Applications to manned spaceflight

    Science.gov (United States)

    Czeisler, Charles A.; Chiasera, August J.; Duffy, Jeanne F.

    1991-01-01

    Disorders of sleep and circadian rhythmicity are characteristic of both advancing age and manned spaceflight. Sleep fragmentation, reduced nocturnal sleep tendency and sleep efficiency, reduced daytime alertness, and increased daytime napping are common to both of these conditions. Recent research on the pathophysiology and treatment of disrupted sleep in older people has led to a better understanding of how the human circadian pacemaker regulates the timing of the daily sleep-wake cycle and how it responds to the periodic changes in the light-dark cycle to which we are ordinarily exposed. These findings have led to new treatments for some of the sleep disorders common to older individuals, using carefully timed exposure to bright light and darkness to manipulate the phase and/or amplitude of the circadian timing system. These insights and treatment approaches have direct applications in the design of countermeasures allowing astronauts to overcome some of the challenges which manned spaceflight poses for the human circadian timing system. We have conducted an operational feasibility study on the use of scheduled exposure to bright light and darkness prior to launch in order to facilitate adaptation of the circadian system of a NASA Space Shuttle crew to the altered sleep-wake schedule required for their mission. The results of this study illustrate how an understanding of the properties of the human circadian timing system and the consequences of circadian disruption can be applied to manned spaceflight.

  11. Protein/lipid coaggregates are formed during α-synuclein-induced disruption of lipid bilayers

    DEFF Research Database (Denmark)

    van Maarschalkerweerd, Andreas; Vetri, Valeria; Langkilde, Annette Eva;

    2014-01-01

    Amyloid formation is associated with neurodegenerative diseases such as Parkinson's disease (PD). Significant α-synuclein (αSN) deposition in lipid-rich Lewy bodies is a hallmark of PD. Nonetheless, an unraveling of the connection between neurodegeneration and amyloid fibrils, including...... the molecular mechanisms behind potential amyloid-mediated toxic effects, is still missing. Interaction between amyloid aggregates and the lipid cell membrane is expected to play a key role in the disease progress. Here, we present experimental data based on hybrid analysis of two-photon-microscopy, solution...... small-angle X-ray scattering and circular dichroism data. Data show in real time changes in liposome morphology and stability upon protein addition and reveal that membrane disruption mediated by amyloidogenic αSN is associated with dehydration of anionic lipid membranes and stimulation of protein...

  12. Endothelial Cell Permeability and Adherens Junction Disruption Induced by Junín Virus Infection

    Science.gov (United States)

    Lander, Heather M.; Grant, Ashley M.; Albrecht, Thomas; Hill, Terence; Peters, Clarence J.

    2014-01-01

    Junín virus (JUNV) is endemic to the fertile Pampas of Argentina, maintained in nature by the rodent host Calomys musculinus, and the causative agent of Argentine hemorrhagic fever (AHF), which is characterized by vascular dysfunction and fluid distribution abnormalities. Clinical as well as experimental studies implicate involvement of the endothelium in the pathogenesis of AHF, although little is known of its role. JUNV has been shown to result in productive infection of endothelial cells (ECs) in vitro with no visible cytopathic effects. In this study, we show that direct JUNV infection of primary human ECs results in increased vascular permeability as measured by electric cell substrate impedance sensing and transwell permeability assays. We also show that EC adherens junctions are disrupted during virus infection, which may provide insight into the role of the endothelium in the pathogenesis of AHF and possibly, other viral hemorrhagic fevers. PMID:24710609

  13. Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

    Science.gov (United States)

    Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

    2015-02-01

    Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection.

  14. Effects of ZnO nanoparticles on perfluorooctane sulfonate induced thyroid-disrupting on zebrafish larvae.

    Science.gov (United States)

    Du, Jia; Wang, Shutao; You, Hong; Liu, Zhongqiang

    2016-09-01

    Perfluorooctane sulfonate (PFOS) and ZnO nanoparticles (nano-ZnO) are widely distributed in the environment. However, the potential toxicity of co-exposure to PFOS and nano-ZnO remains to be fully elucidated. The test investigated the effects of co-exposure to PFOS and nano-ZnO on the hypothalamic-pituitary-thyroid (HPT) axis in zebrafish. Zebrafish embryos were exposed to a combination of PFOS (0.2, 0.4, 0.8mg/L) and nano-ZnO (50mg/L) from their early stages of life (0-14days). The whole-body content of TH and the expression of genes and proteins related to the HPT axis were analyzed. The co-exposure decreased the body length and increased the malformation rates compared with exposure to PFOS alone. Co-exposure also increased the triiodothyronine (T3) levels, whereas the thyroxine (T4) content remained unchanged. Compared with the exposure to PFOS alone, exposure to both PFOS (0.8mg/L) and nano-ZnO (50mg/L) significantly up-regulated the expression of corticotropin-releasing factor, sodium/iodidesymporter, iodothyronine deiodinases and thyroid receptors and significantly down-regulated the expression of thyroid-stimulating hormone, thyroglobulin (TG), transthyretin (TTR) and thyroid receptors. The protein expression levels of TG and TTR were also significantly down-regulated in the co-exposure groups. In addition, the expression of the thyroid peroxidase gene was unchanged in all groups. The results demonstrated that PFOS and nano-ZnO co-exposure could cause more serious thyroid-disrupting effects in zebrafish than exposure to PFOS alone. Our results also provide insight into the mechanism of disruption of the thyroid status by PFOS and nano-ZnO. PMID:27593282

  15. Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours.

    Directory of Open Access Journals (Sweden)

    Robert Keers

    Full Text Available BACKGROUND: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh, an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long circadian rhythm of approximately 27 hours. METHODOLOGY: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. PRINCIPAL FINDINGS: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009. CONCLUSIONS: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.

  16. Circadian malfunctions in depression - neurobiological and psychosocial approaches.

    Science.gov (United States)

    Nechita, Florina; Pîrlog, Mihail Cristian; ChiriŢă, Anca Livia

    2015-01-01

    Depression leads to disturbances in physiological rhythms, which result in disturbances in circadian sleep-wake cycles, hormonal secretion patterns and fluctuations in mood, all of which can be objectively measured. These disturbances, which are associated with depression, can be also used to define depression. Beyond these "transversal" time-related symptoms, there are the "longitudinal" time-related symptoms, since depression evolves over a long period of time, with a profound impact on a person's life and is often associated with long-term psychosocial consequences (Mendlewicz, 2010). The circadian rhythm reflects an approximate 24-hour cycle in the biochemical, physiological and behavioral processes of living entities, which crucially influences human well-being and health. Increasing evidence from clinical and neurobiological research suggests that disrupted temporal organization impairs behavior, cognition, mood, sleep and social activity and may be implicated in mental disorders. It has been proposed that circadian malfunction is a major core feature of mood disorders, depression in particular. In depressed patients, circadian rhythms and homeostatic processes are disrupted, thereby affecting mood, sleep, activity and a variety of biological functions such as hormone secretion and body temperature (Hajak & Landgrebe, 2010). Sleep difficulties are among the most current symptoms in depressed patients. Insomnia is often the reason why depressed patients seek help and relief of sleep disturbance may encourage compliance with antidepressant treatment. Apart from the discomfort that sleep problems produce, they may lead to exhaustion, poor functioning and they are associated with an increase in suicide risk (Wilson et al., 2013). PMID:26662127

  17. Role of hypoxia-induced VEGF in blood-spinal cord barrier disruption in chronic spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Hou-Qing Long; Guang-Sheng Li; Xing Cheng; Jing-Hui Xu; Fo-Bao Li

    2015-01-01

    Chronic spinal cord lesions (CSCL) which result in irreversible neurologic deficits remain one of the most devastating clinical problems.Its pathophysiological mechanism has not been fully clarified.As a crucial factor in the outcomes following traumatic spinal cord injury (SCI),the blood-spinal cord barrier (BSCB) disruption is considered as an important pathogenic factor contributing to the neurologic impairment in SCI.Vascular endothelial growth factor (VEGF) is a multirole element in the spinal cord vascular event.On one hand,VEGF administrations can result in rise of BSCB permeability in acute or sub-acute periods and even last for chronic process.On the other hand,VEGF is regarded to be correlated with angiogenesis,neurogenesis and improvement of locomotor ability.Hypoxia inducible factor-1 (HIF-1) is a primary regulator of VEGF during hypoxic conditions.Therefore,hypoxia-mediated up-regulation of VEGF may play multiple roles in the BSCB disruption and react on functional restoration of CSCL,The purpose of this article is to further explore the relationship among HIF-1,hypoxia-mediated VEGF and BSCB dysfunction,and investigate the roles of these elements on CSCL.

  18. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

    Science.gov (United States)

    The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

  19. Non-Saccharomyces yeasts protect against epithelial cell barrier disruption induced by Salmonella enterica subsp. enterica serovar Typhimurium

    DEFF Research Database (Denmark)

    Smith, Ida Mosbech; Baker, A; Arneborg, Nils;

    2015-01-01

    . In addition, probiotic strains may be able to reduce epithelial barrier disruption caused by pathogenic species. The aim of this study was to explore non-Saccharomyces yeast modulation of epithelial cell barrier function in vitro. Benchmarking against established probiotic strains, we evaluated the ability...... of four nonpathogenic yeast species to modulate transepithelial electrical resistance (TER) across a monolayer of differentiated human colonocytes (Caco-2 cells). Further, we assessed yeast modulation of a Salmonella Typhimurium-induced epithelial cell barrier function insult. Our findings demonstrate...... distinct patterns of non-Saccharomyces yeast modulation of epithelial cell barrier function. While the established probiotic yeast Saccharomyces boulardii increased TER across a Caco-2 monolayer by 30%, Kluyveromyces marxianus exhibited significantly stronger properties of TER enhancement (50% TER increase...

  20. Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude

    DEFF Research Database (Denmark)

    Oranje, Bob; Gispen-de Wied, Christine C; Westenberg, Herman G M;

    2009-01-01

    Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought....... Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. Can haloperidol (D2 antagonist) counteract the disruptive effects of ketamine on psychophysiological parameters of human attention? In a randomized, double-blind, placebo-controlled experiment...... 18 healthy male volunteers received placebo/placebo, placebo/ketamine (0.3 mg/kg i.v.) and haloperidol (2 mg)/ketamine (0.3 mg/kg i.v.) on three separate test days, after which they were tested in an auditory selective-attention paradigm. Haloperidol/ketamine reduced task performance compared...

  1. Embryonic exposure to carbendazim induces the transcription of genes related to apoptosis, immunotoxicity and endocrine disruption in zebrafish (Danio rerio).

    Science.gov (United States)

    Jiang, Jinhua; Wu, Shenggan; Wu, Changxing; An, Xuehua; Cai, Leiming; Zhao, Xueping

    2014-12-01

    Carbendazim is one of the most widespread environmental contaminant that can cause major concern to human and animal reproductive system. To date, very few studies have been conducted on the toxic effect of carbendazim in the non-target organism zebrafish (Danio rerio). The study presented here aimed to assess how carbendazim triggers apoptosis, immunotoxicity and endocrine disruption pathways in zebrafish during its embryo development. Our results demonstrated that the expression patterns of many key genes involved in cell apoptosis pathway (e.g. P53, Mdm2, Bbc3 and Cas8) were significantly up-regulated upon the exposure to carbendazim at the concentration of 500 μg/L, while the Bcl2 and Cas3 were down-regulated at the same concentration, interestingly, the expression level of Ogg1 decreased at all the exposure concentrations. It was also observed that the mRNA levels of CXCL-C1C, CCL1, IL-1b and TNFα which were closely related to the innate immune system, were affected in newly hatched zebrafish after exposed to different concentrations of carbendazim. Moreover, the expression of genes that are involved in the hypothalamic-pituitary-gonadal/thyroid (HPG/HPT) axis including VTG, ERα, ERβ2, Dio1, Dio2, Thraa and Thrb were all down-regulated significantly after the exposure to carbendazim. The expression levels of two cytochrome P450 aromatases CYP19a and CYP19b were increased significantly after 20 and 100 μg/L carbendazim exposure, respectively. Taken together, our results indicated that carbendazim had the potential to induce cell apoptosis and cause immune toxicity as well as endocrine disruption in zebrafish during the embryo developmental stage. The information presented here also help to elucidate the environmental risks caused by the carbendazim-induced toxicity in aquatic organisms. PMID:25304545

  2. Estradiol administration to ovariectomized rats potentiates mephedrone-induced disruptions of nonspatial learning.

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    Weed, Peter F; Leonard, Stuart T; Sankaranarayanan, Ananthakrishnan; Winsauer, Peter J

    2014-03-01

    Mephedrone (4-methylmethcathinone) has been found in several over-the-counter products that are abused by humans, but very little is known about its behavioral effects and abuse liability. The present study examined the effects of mephedrone (1-10 mg/kg) on learning in female rats, as well as its interaction with the ovarian hormone estradiol. More specifically, female rats were trained to respond under a multiple schedule of repeated acquisition and performance of response sequences and then ovariectomized. Following ovariectomy, mephedrone dose-effect curves were obtained during periods of 17β-estradiol administration and periods without estradiol administration. Unlike mephedrone, which was administered acutely (i.p.) before the experimental sessions, 17β-estradiol was administered via subcutaneous Silastic capsules containing 25% 17β-estradiol and 75% cholesterol. In general, mephedrone produced dose-dependent rate-decreasing and error-increasing effects in the acquisition and performance components of the schedule in all subjects. However, when estradiol was present, three of the four rats were more sensitive to the rate-decreasing effects of mephedrone, and all of the subjects were more sensitive to its error-increasing effects. These data indicate that estradiol can potentiate the disruptive effects of mephedrone on both the acquisition and performance of complex behavior in female rats.

  3. Potentiation of phorbol ester-induced coronary vasoconstriction in dogs following endothelium disruption

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, R.B.; Ku, D.D.

    1986-03-05

    In the present study, the effect of phorbol ester, 12-0-tetradecanoylphorbol 13-acetate (TPA), activation of protein kinase C on coronary vascular reactivity was studied in isolated dog coronary arteries. Addition of TPA (10-100 nM) produced a slow, time- and dose-dependent contraction reaching a maximum at approx 2-3 hrs and was essentially irreversible upon washing. Disruption of the endothelium(EC) greatly accelerated the development as well as increase the magnitude of TPA contraction (50-100%). Prior treatment of vessels with phentolamine (1..mu..M), cyproheptadine (1..mu..H) and ibuprofen (1..mu..g/ml) did not alter the TPA contraction. Furthermore, in contrast to previously reported calcium-dependence of TPA contraction in other vessels, complete removal of extracellular calcium (Ca/sub 0/) or addition of 1..mu..M nimodipine after TPA(30nM) resulted in only 32 +/- 4% and 25 +/- 3% reversal of TPA contraction, respectively. Addition of amiloride (10..mu..M to 1mM), however, resulted in a dose-dependent reversal of TPA contraction. The results of the present study indicate that a similar activation of protein kinase C by TPA leads to potent coronary vasoconstriction, which is not completely dependent on Ca/sub 0/. More importantly, these results further support their hypothesis that EC also functions as an inhibitory barrier to prevent circulating vasoconstrictors from exerting their deleterious constrictory effects.

  4. Interaction with diurnal and circadian regulation results in dynamic metabolic and transcriptional changes during cold acclimation in Arabidopsis.

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    Carmen Espinoza

    Full Text Available In plants, there is a large overlap between cold and circadian regulated genes and in Arabidopsis, we have shown that cold (4°C affects the expression of clock oscillator genes. However, a broader insight into the significance of diurnal and/or circadian regulation of cold responses, particularly for metabolic pathways, and their physiological relevance is lacking. Here, we performed an integrated analysis of transcripts and primary metabolites using microarrays and gas chromatography-mass spectrometry. As expected, expression of diurnally regulated genes was massively affected during cold acclimation. Our data indicate that disruption of clock function at the transcriptional level extends to metabolic regulation. About 80% of metabolites that showed diurnal cycles maintained these during cold treatment. In particular, maltose content showed a massive night-specific increase in the cold. However, under free-running conditions, maltose was the only metabolite that maintained any oscillations in the cold. Furthermore, although starch accumulates during cold acclimation we show it is still degraded at night, indicating significance beyond the previously demonstrated role of maltose and starch breakdown in the initial phase of cold acclimation. Levels of some conventional cold induced metabolites, such as γ-aminobutyric acid, galactinol, raffinose and putrescine, exhibited diurnal and circadian oscillations and transcripts encoding their biosynthetic enzymes often also cycled and preceded their cold-induction, in agreement with transcriptional regulation. However, the accumulation of other cold-responsive metabolites, for instance homoserine, methionine and maltose, did not have consistent transcriptional regulation, implying that metabolic reconfiguration involves complex transcriptional and post-transcriptional mechanisms. These data demonstrate the importance of understanding cold acclimation in the correct day-night context, and are further

  5. Pre-treatment with amifostine protects against cyclophosphamide-induced disruption of taste in mice.

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    Nabanita Mukherjee

    Full Text Available Cyclophosphamide (CYP, a commonly prescribed chemotherapy drug, has multiple adverse side effects including alteration of taste. The effects on taste are a cause of concern for patients as changes in taste are often associated with loss of appetite, malnutrition, poor recovery and reduced quality of life. Amifostine is a cytoprotective agent that was previously shown to be effective in preventing chemotherapy-induced mucositis and nephrotoxicity. Here we determined its ability to protect against chemotherapy-induced damage to taste buds using a mouse model of CYP injury. We conducted detection threshold tests to measure changes in sucrose taste sensitivity and found that administration of amifostine 30 mins prior to CYP injection protected against CYP-induced loss in taste sensitivity. Morphological studies showed that pre-treatment with amifostine prevented CYP-induced reduction in the number of fungiform taste papillae and increased the number of taste buds. Immunohistochemical assays for markers of the cell cycle showed that amifostine administration prevented CYP-induced inhibition of cell proliferation and also protected against loss of mature taste cells after CYP exposure. Our results indicate that treatment of cancer patients with amifostine prior to chemotherapy may improve their sensitivity for taste stimuli and protect the taste system from the detrimental effects of chemotherapy.

  6. Working around the clock: circadian rhythms and skeletal muscle

    OpenAIRE

    ZHANG, XIPING; Dube, Thomas J.; Esser, Karyn A.

    2009-01-01

    The study of the circadian molecular clock in skeletal muscle is in the very early stages. Initial research has demonstrated the presence of the molecular clock in skeletal muscle and that skeletal muscle of a clock-compromised mouse, Clock mutant, exhibits significant disruption in normal expression of many genes required for adult muscle structure and metabolism. In light of the growing association between the molecular clock, metabolism, and metabolic disease, it will also be important to ...

  7. Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

    OpenAIRE

    McClung, Colleen A.

    2007-01-01

    Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for spe...

  8. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

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    Hideaki Nishihara

    Full Text Available OBJECTIVE: Effect of fingolimod in multiple sclerosis (MS is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB. However, brain microvascular endothelial cells (BMECs represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera. METHODS: Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR MS, stable phase of RRMS and secondary progressive MS (SPMS, on the function of BBB in the presence of fingolimod-phosphate were assessed. RESULTS: Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera. CONCLUSIONS: Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.

  9. Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta

    Science.gov (United States)

    Xie, Lishi; Chiang, Eddie T.; Kelly, Gabriel T.; Kanteti, Prasad; Singleton, Patrick A.; Camp, Sara M.; Zhou, Tingting; Dudek, Steven M.; Natarajan, Viswanathan; Wang, Ting; Black, Steven M.; Garcia, Joe G. N.; Jacobson, Jeffrey R.

    2016-01-01

    Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue–specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin), dominant negative PKCδ construct and PKCδ silencing (siRNA). In addition, we identified PKCδ as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKCδ activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKCμ) and CPI-17, two known PKCδ targets, were found to be activated by PKCδ in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKCδ in EC cytoskeleton regulation, and highlight PKCδ as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis. PMID:27442243

  10. Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta.

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    Lishi Xie

    Full Text Available Protein Kinase C (PKC plays a significant role in thrombin-induced loss of endothelial cell (EC barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin, dominant negative PKCδ construct and PKCδ silencing (siRNA. In addition, we identified PKCδ as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKCδ activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKCμ and CPI-17, two known PKCδ targets, were found to be activated by PKCδ in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKCδ in EC cytoskeleton regulation, and highlight PKCδ as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis.

  11. CARBENDAZIM (MBC) DISRUPTS OOCYTE SPINDLE FUNCTION AND INDUCES ANEUPLOIDY IN HAMSTERS EXPOSED DURING FERTILIZATION (MEIOSIS II)

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    Peri-fertilization exposure to Carbendazim (MBC; a microtubule poison) induces infertility and early pregnancy loss (EPL) in hamsters. resently, both in vivo and in vitro techniques were employed to characterize the effects of MBC on cellular aspects of fertilization in hamsters....

  12. Circadian clock dysfunction and psychiatric disease: could fruit flies have a say?

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    Mauro Agostino Zordan

    2015-04-01

    Full Text Available There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system lead to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e. a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.

  13. Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein-coupled inwardly rectifying (GIRK) channels

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    Hablitz, L M; Molzof, H E; Paul, J R; Johnson, R L; Gamble, K L

    2014-01-01

    Abstract G protein signalling within the central circadian oscillator, the suprachiasmatic nucleus (SCN), is essential for conveying time-of-day information. We sought to determine whether G protein-coupled inwardly rectifying potassium channels (GIRKs) modulate SCN physiology and circadian behaviour. We show that GIRK current and GIRK2 protein expression are greater during the day. Pharmacological inhibition of GIRKs and genetic loss of GIRK2 depolarized the day-time resting membrane potential of SCN neurons compared to controls. Behaviourally, GIRK2 knockout (KO) mice failed to shorten free running period in response to wheel access in constant darkness and entrained more rapidly to a 6 h advance of a 12 h:12 h light–dark (LD) cycle than wild-type (WT) littermate controls. We next examined whether these effects were due to disrupted signalling of neuropeptide Y (NPY), which is known to mediate non-photic phase shifts, attenuate photic phase shifts and activate GIRKs. Indeed, GIRK2 KO SCN slices had significantly fewer silent cells in response to NPY, likely contributing to the absence of NPY-induced phase advances of PER2::LUC rhythms in organotypic SCN cultures from GIRK2 KO mice. Finally, GIRK channel activation is sufficient to cause a non-photic-like phase advance of PER2::LUC rhythms on a Per2Luc+/− background. These results suggest that rhythmic regulation of GIRK2 protein and channel function in the SCN contributes to day-time resting membrane potential, providing a mechanism for the fine tuning responses to non-photic and photic stimuli. Further investigation could provide insight into disorders with circadian disruption comorbidities such as epilepsy and addiction, in which GIRK channels have been implicated. PMID:25217379

  14. Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides

    OpenAIRE

    Schweitzer, Kelly S.; Hatoum, Hadi; Brown, Mary Beth; Gupta, Mehak; Justice, Matthew J.; Beteck, Besem; Van Demark, Mary; Gu, Yuan; Presson, Robert G.; Hubbard, Walter C.; Petrache, Irina

    2011-01-01

    The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithel...

  15. Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis.

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    Seong-Jun Kim

    Full Text Available Human hepatitis B virus (HBV causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1 by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2, a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.

  16. Pre-Treatment with Amifostine Protects against Cyclophosphamide-Induced Disruption of Taste in Mice

    OpenAIRE

    Nabanita Mukherjee; Carroll, Brittany L.; Spees, Jeffrey L.; Delay, Eugene R.

    2013-01-01

    Cyclophosphamide (CYP), a commonly prescribed chemotherapy drug, has multiple adverse side effects including alteration of taste. The effects on taste are a cause of concern for patients as changes in taste are often associated with loss of appetite, malnutrition, poor recovery and reduced quality of life. Amifostine is a cytoprotective agent that was previously shown to be effective in preventing chemotherapy-induced mucositis and nephrotoxicity. Here we determined its ability to protect aga...

  17. Social disruption stress exacerbates alpha-galactosylceramide-induced hepatitis in mice

    OpenAIRE

    Sonoda, J.; Chida, Y; Sudo, N.; Kubo, C

    2005-01-01

    Objective: Psychosocial stress has been suggested as a possible aggravating factor in liver diseases, however, the underlying mechanism has yet to be clarified. Recently, our research revealed that electric foot-shock stress aggravated NK1.1 Ag+ T cell-dependent a-galactosylceramide (alpha-GalCer)-induced hepatitis in mice via a mechanism mediated by endogenous glucocorticoids. In this study, we examined whether or not such aggravation could be applied to a psychosocially stressful situation,...

  18. The Fungicidal Activity of Thymol against Fusarium graminearum via Inducing Lipid Peroxidation and Disrupting Ergosterol Biosynthesis

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    Tao Gao

    2016-06-01

    Full Text Available Thymol is a natural plant-derived compound that has been widely used in pharmaceutical and food preservation applications. However, the antifungal mechanism for thymol against phytopathogens remains unclear. In this study, we identified the antifungal action of thymol against Fusarium graminearum, an economically important phytopathogen showing severe resistance to traditional chemical fungicides. The sensitivity of thymol on different F. graminearum isolates was screened. The hyphal growth, as well as conidial production and germination, were quantified under thymol treatment. Histochemical, microscopic, and biochemical approaches were applied to investigate thymol-induced cell membrane damage. The average EC50 value of thymol for 59 F. graminearum isolates was 26.3 μg·mL−1. Thymol strongly inhibited conidial production and hyphal growth. Thymol-induced cell membrane damage was indicated by propidium iodide (PI staining, morphological observation, relative conductivity, and glycerol measurement. Thymol induced a significant increase in malondialdehyde (MDA concentration and a remarkable decrease in ergosterol content. Taken together, thymol showed potential antifungal activity against F. graminearum due to the cell membrane damage originating from lipid peroxidation and the disturbance of ergosterol biosynthesis. These results not only shed new light on the antifungal mechanism of thymol, but also imply a promising alternative for the control of Fusarium head blight (FHB disease caused by F. graminearum.

  19. The Fungicidal Activity of Thymol against Fusarium graminearum via Inducing Lipid Peroxidation and Disrupting Ergosterol Biosynthesis.

    Science.gov (United States)

    Gao, Tao; Zhou, Hao; Zhou, Wei; Hu, Liangbin; Chen, Jian; Shi, Zhiqi

    2016-01-01

    Thymol is a natural plant-derived compound that has been widely used in pharmaceutical and food preservation applications. However, the antifungal mechanism for thymol against phytopathogens remains unclear. In this study, we identified the antifungal action of thymol against Fusarium graminearum, an economically important phytopathogen showing severe resistance to traditional chemical fungicides. The sensitivity of thymol on different F. graminearum isolates was screened. The hyphal growth, as well as conidial production and germination, were quantified under thymol treatment. Histochemical, microscopic, and biochemical approaches were applied to investigate thymol-induced cell membrane damage. The average EC50 value of thymol for 59 F. graminearum isolates was 26.3 μg·mL(-1). Thymol strongly inhibited conidial production and hyphal growth. Thymol-induced cell membrane damage was indicated by propidium iodide (PI) staining, morphological observation, relative conductivity, and glycerol measurement. Thymol induced a significant increase in malondialdehyde (MDA) concentration and a remarkable decrease in ergosterol content. Taken together, thymol showed potential antifungal activity against F. graminearum due to the cell membrane damage originating from lipid peroxidation and the disturbance of ergosterol biosynthesis. These results not only shed new light on the antifungal mechanism of thymol, but also imply a promising alternative for the control of Fusarium head blight (FHB) disease caused by F. graminearum. PMID:27322238

  20. Circadian rhythms of fetal liver transcription persist in the absence of canonical circadian clock gene expression rhythms in vivo.

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    Chengwei Li

    Full Text Available The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture. To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny.

  1. Microcystin-LR induced reactive oxygen species mediate cytoskeletal disruption and apoptosis of hepatocytes in Cyprinus carpio L.

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    Jinlin Jiang

    Full Text Available Microcystins (MCs are a group of cyclic hepatotoxic peptides produced by cyanobacteria. Microcystin-LR (MC-LR contains Leucine (L and Arginine (R in the variable positions, and is one of the most common and potently toxic peptides. MC-LR can inhibit protein phosphatase type 1 and type 2A (PP1 and PP2A activities and induce excessive production of reactive oxygen species (ROS. The underlying mechanism of the inhibition of PP1 and PP2A has been extensively studied. The over-production of ROS is considered to be another main mechanism behind MC-LR toxicity; however, the detailed toxicological mechanism involved in over-production of ROS in carp (Cyprinus carpio L. remains largely unclear. In our present study, the hydroxyl radical (•OH was significantly induced in the liver of carp after a relatively short-term exposure to MC-LR. The elevated reactive oxygen species (ROS production may play an important role in the disruption of microtubule structure. Pre-injection of the antioxidant N-acetyl-cysteine (NAC provided significant protection to the cytoskeleton, however buthionine sulfoximine (BSO exacerbated cytoskeletal destruction. In addition, the elevated ROS formation induced the expression of apoptosis-related genes, including p38, JNKa, and bcl-2. A significant increase in apoptotic cells was observed at 12-48 hours. Our study further supports evidence that ROS are involved in MC-LR induced damage to liver cells in carp, and indicates the need for further study of the molecular mechanisms behind MC-LR toxicity.

  2. Circadian rhythms in microalgae production

    NARCIS (Netherlands)

    Winter, de L.

    2015-01-01

    Abstract Thesis: Circadian rhythms in microalgae production Lenneke de Winter The sun imposes a daily cycle of light and dark on nearly all organisms. The circadian clock evolved to help organisms program their activities at an appropriate time during this daily cycle. For example,

  3. Circadian Pacemaker – Temperature Compensation

    NARCIS (Netherlands)

    Gerkema, Menno P.; Binder, Marc D.; Hirokawa, Nobutaka; Windhorst, Uwe

    2009-01-01

    One of the defining characteristics of circadian pacemakers and indicates the independence of the speed of circadian clock processes of environmental temperature. Mechanisms involved, so far not elucidated in full detail, entail at least two processes that are similarly affected by temperature chang

  4. Exposure of male mice to two kinds of organophosphate flame retardants (OPFRs) induced oxidative stress and endocrine disruption.

    Science.gov (United States)

    Chen, Guanliang; Jin, Yuanxiang; Wu, Yan; Liu, Ling; Fu, Zhengwei

    2015-07-01

    Triphenyl phosphate (TPP) and tris(2-chloroethyl) phosphate (TCEP) are two of the most common organophosphate flame retardants in the ecosystem. Effects of TPP and TCEP on the induction of oxidative stress and endocrine disruption were evaluated in five weeks old male mice. After receiving 100, 300 mg/kg/bodyweight oral exposure to TPP and TCEP for 35 days, the body and testis weights decreased in 300 mg/kg TPP and TCEP treated groups. Hepatic malondialdehyde (MDA) contents increased significantly in both TPP treated groups, while the contents of glutathione (GSH) decreased significantly in 300 mg/kg TPP and both TCEP treated groups. In addition, the hepatic activities of antioxidant enzymes including glutathione peroxidase (GPX), catalase (CAT) and glutathione S-transferase (GST) as well as their related gene expression were affected by TPP or TECP exposure. On the other hand, 300 mg/kg of TPP or TECP treatment resulted in histopathological damage and the decrease of testicular testosterone levels. Moreover, the expression of main genes related to testosterone synthesis including steroidogenic acute regulatory protein (StAR), low-density lipoprotein receptor (LDL-R), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and cytochrome P450 17α-hydroxysteroid dehydrogenase (P450-17α) in the testes also decreased after the exposure to 300 mg/kg TPP or TCEP for 35 days. Combined with the effects on physiology, histopathology and the expression of genes, TPP and TCEP can induce oxidative stress and endocrine disruption in mice.

  5. Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain.

    Science.gov (United States)

    Lamason, Rebecca L; McCully, Ryan R; Lew, Stefanie M; Pomerantz, Joel L

    2010-09-28

    The regulated activation of NF-κB by antigen receptor signaling is required for normal B and T lymphocyte activation during the adaptive immune response. Dysregulated NF-κB activation is associated with several types of lymphoma, including diffuse large B cell lymphoma (DLBCL). During normal antigen receptor signaling, the multidomain scaffold protein CARD11 undergoes a transition from a closed, inactive state to an open, active conformation that recruits several signaling proteins into a complex, leading to IKK kinase activation. This transition is regulated by the CARD11 inhibitory domain (ID), which participates in intramolecular interactions that prevent cofactor binding to CARD11 prior to signaling, but which is neutralized after receptor engagement by phosphorylation. Several oncogenic CARD11 mutations have been identified in DLBCL that enhance activity and that are mostly found in the coiled-coil domain. However, the mechanisms by which these mutations cause CARD11 hyperactivity and spontaneous NF-κB activation are poorly understood. In this report, we provide several lines of evidence that oncogenic mutations F123I and L225LI induce CARD11 hyperactivity by disrupting autoinhibition by the CARD11 ID. These mutations disrupt ID-mediated intramolecular interactions and ID-dependent inhibition and bypass the requirement for ID phosphorylation during T cell receptor signaling. Intriguingly, these mutations selectively enhance the apparent affinity of CARD11 for Bcl10, but not for other signaling proteins that are recruited to CARD11 in an ID-dependent manner during normal antigen receptor signaling. Our results establish a mechanism that explains how DLBCL-associated mutations in CARD11 can initiate spontaneous, receptor-independent activation of NF-κB.

  6. Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo.

    Science.gov (United States)

    Deb, Paromita; Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I; Bobzean, Samara A; Pandita, Tej K; Perrotti, Linda I; Mandal, Subhrangsu S

    2016-09-30

    HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression. Estrogen-receptors (ERs) and ER-co-regulators such as MLL-histone methylase (MLL3), histone acetylases, CBP/P300, bind to the HOXB9 promoter EREs in the presence of BPA, modify chromatin (histone methylation and acetylation) and lead to gene activation. In summary, our results demonstrate that BPA exposure, like estradiol, increases HOXB9 expression in breast cells both in vitro and in vivo through a mechanism that involves increased recruitment of transcription and chromatin modification factors. PMID:27182052

  7. Pretilachlor has the potential to induce endocrine disruption, oxidative stress, apoptosis and immunotoxicity during zebrafish embryo development.

    Science.gov (United States)

    Jiang, Jinhua; Chen, Yanhong; Yu, Ruixian; Zhao, Xueping; Wang, Qiang; Cai, Leiming

    2016-03-01

    The objectives of the present study were to investigate the toxic effects of pretilachlor on zebrafish during its embryo development. The results demonstrated that the transcription of genes involved in the hypothalamic-pituitary-gonadal/thyroid (HPG/HPT) axis was increased after exposure to 50, 100, 200 μg/L pretilachlor for 96 h, the aromatase activity, vitellogenin (VTG) and thyroid hormones T3 and T4 levels in zebrafish were also up-regulated simultaneously. Pretilachlor exposure induced a noticeable increase in ROS level, increased the transcription and level of antioxidant proteins (e.g., CAT, SOD and GPX). Moreover, the up-regulation of P53, Mdm2, Bbc3 expression and Caspase3 and Caspase9 activities in the apoptosis pathway suggested pretilachlor might trigger cell apoptosis in zebrafish. In addition, the transcription of CXCL-C1C, IL-1β and IL-8 related to the innate immunity was down-regulated after pretilachlor exposure. These data suggested that pretilachlor could simultaneously induce endocrine disruption, apoptosis, oxidative stress and immunotoxicity during zebrafish embryo development. PMID:26851375

  8. Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.

    Science.gov (United States)

    Melland-Smith, Megan; Ermini, Leonardo; Chauvin, Sarah; Craig-Barnes, Hayley; Tagliaferro, Andrea; Todros, Tullia; Post, Martin; Caniggia, Isabella

    2015-04-01

    Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

  9. Inducible Cardiomyocyte-Specific Gene Disruption Directed by the Rat Tnnt2 Promoter in the Mouse

    OpenAIRE

    Wu, Bingruo; Wang, Yidong; Cheng, Hsiu-Ling; Hang, Calvin T.; Pu, William T.; Chang, Ching-Pin; Zhou, Bin

    2010-01-01

    We developed a conditional and inducible gene knockout methodology that allows effective gene deletion in mouse cardiomyocytes. This transgenic mouse line was generated by co-injection of two transgenes, a “reverse” tetracycline-controlled transactivator (rtTA) directed by a rat cardiac troponin T (Tnnt2) promoter and a Cre recombinase driven by a tetracycline-responsive promoter (TetO). Here, Tnnt2-rtTA activated TetO-Cre expression takes place in cardiomyocytes following doxycycline treatme...

  10. A Long Noncoding RNA Perturbs the Circadian Rhythm of Hepatoma Cells to Facilitate Hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Ming Cui

    2015-01-01

    Full Text Available Clock circadian regulator (CLOCK/brain and muscle arnt-like protein-1 (BMAL1 complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC remains unclear. Here, we report that a long noncoding RNA (lncRNA, highly upregulated in liver cancer (HULC, contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC.

  11. Laser-induced disruption of systemically administered liposomes for targeted drug delivery

    Science.gov (United States)

    Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

    2009-07-01

    Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

  12. FMDV-induced stress granules are disrupted by the viral L-protease

    DEFF Research Database (Denmark)

    Polacek, Charlotta; Belsham, Graham; McInerney, Gerald

    2014-01-01

    have found that foot-and-mouth disease virus (FMDV) triggers SG formation early during infection in IBRS-2 cells. These SGs contain G3BP and TIA-1, but not dsRNA. However, the presence of the FMDV-induced SGs is transient due to the cleavage of G3BP by the viral L-protease (Lpro), which results...... in subsequent SG dispersal. Cells infected with an Lpro-deficient mutant FMDV are not subjected to G3BP cleavage and the SGs formed upon infection with this mutant maintain throughout the infection. In vitro studies using different variants of the Lpro show different G3BP cleavage efficiencies, suggesting...... a superior function of the full length Lpro for this substrate. Furthermore, the Lpro-directed G3BP cleavage is not dependent on virus replication, as investigated by transfecting FMDV RNAs lacking a functional 3D-polymerase. Finally, FMDV RNAs that contain Lpro, but lack the FMDV 3C-protease, also induce...

  13. Methoxychlor induced biochemical alterations and disruption of spermatogenesis in adult rats.

    Science.gov (United States)

    Aly, Hamdy A A; Azhar, Ahmad S

    2013-09-01

    Adult male albino rats were treated orally with methoxychlor at doses of 0, 50, 100 or 200 mg/kg/day for 15 consecutive days. Testicular weight, sperm count and motility were significantly decreased. Methoxychlor at doses of 100 and 200 mg/kg significantly inhibited α-glucosidase activity, while plasma testosterone was significantly decrease by the three dose levels in a dose-related pattern. Testicular activities of 3β-HSD, 17β-HSD, SDH were significantly decreased, while ACP, ALP (except for 50 mg/kg), and LDH were significantly increased. H2O2 production and LPO were significantly increased while the enzymic (SOD, CAT and GPx) and non-enzymic antioxidants (thiol content) were significantly decreased. Caspase-3 activity was significantly increased in a dose related manner. The findings of this study indicate that methoxychlor induces oxidative stress associated with impairment of spermatogenesis, in addition to apoptosis. These data provide insight into the mode of action of methoxychlor-induced toxicity in the rat testis.

  14. Circadian polymorphisms associated with affective disorders

    OpenAIRE

    Kripke, Daniel F; Nievergelt, Caroline M; Joo, EJ; Shekhtman, Tatyana; Kelsoe, John R.

    2009-01-01

    Background: Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies.Methods:...

  15. Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice.

    Science.gov (United States)

    Chaudhry, Kamaljit K; Shukla, Pradeep K; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E; Rao, RadhaKrishna

    2016-01-01

    Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of Gln in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed with Gln-free diet and absent in mice fed with Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury. PMID:26365579

  16. Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice.

    Science.gov (United States)

    Chaudhry, Kamaljit K; Shukla, Pradeep K; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E; Rao, RadhaKrishna

    2016-01-01

    Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of Gln in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed with Gln-free diet and absent in mice fed with Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury.

  17. The role of chronobiology and circadian rhythms in type 2 diabetes mellitus: implications for management of diabetes

    Directory of Open Access Journals (Sweden)

    Kurose T

    2014-07-01

    Full Text Available Takeshi Kurose, Takanori Hyo, Daisuke Yabe, Yutaka Seino Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Fukushima, Osaka, Japan Abstract: Circadian clocks regulate cellular to organic and individual behavior levels of all organisms. Almost all cells in animals have self-sustained clocks entrained by environmental signals. Recent progress in genetic research has included identification of clock genes whose disruption causes metabolic abnormalities such as diabetes, obesity, and hyperlipidemia. Here we review recent advances in research on circadian disruption, shift work, altered eating behaviors, and disrupted sleep-wake cycles, with reference to management of type 2 diabetes. Keywords: diabetes, clock gene, shift work, eating behavior, sleep loss

  18. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.

    Science.gov (United States)

    Cubeddu, Luigi X

    2016-01-01

    Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

  19. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

  20. Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria.

    Science.gov (United States)

    Shaki, Fatemeh; Hosseini, Mir-Jamal; Ghazi-Khansari, Mahmoud; Pourahmad, Jalal

    2013-06-01

    Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 μM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome. PMID:23629690

  1. Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring

    Science.gov (United States)

    Bruns, Cristin R.; Barnett, Deborah K.; Dunaif, Andrea; Goodfriend, Theodore L.; Dumesic, Daniel A.; Tarantal, Alice F.

    2010-01-01

    Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155–175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in

  2. Entrainment of the mouse circadian clock by sub-acute physical and psychological stress.

    Science.gov (United States)

    Tahara, Yu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Kuriki, Daisuke; Sasaki, Hiroyuki; Motohashi, Hiroaki; Sakai, Tomoko; Shibata, Shigenobu

    2015-01-01

    The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo.

  3. Circadian behaviour in neuroglobin deficient mice.

    Directory of Open Access Journals (Sweden)

    Christian A Hundahl

    Full Text Available Neuroglobin (Ngb, a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN. The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1 and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.

  4. Circadian behaviour in neuroglobin deficient mice.

    Science.gov (United States)

    Hundahl, Christian A; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.

  5. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

    Science.gov (United States)

    Grabner, Beatrice; Schramek, Daniel; Mueller, Kristina M.; Moll, Herwig P.; Svinka, Jasmin; Hoffmann, Thomas; Bauer, Eva; Blaas, Leander; Hruschka, Natascha; Zboray, Katalin; Stiedl, Patricia; Nivarthi, Harini; Bogner, Edith; Gruber, Wolfgang; Mohr, Thomas; Zwick, Ralf Harun; Kenner, Lukas; Poli, Valeria; Aberger, Fritz; Stoiber, Dagmar; Egger, Gerda; Esterbauer, Harald; Zuber, Johannes; Moriggl, Richard; Eferl, Robert; Győrffy, Balázs; Penninger, Josef M.; Popper, Helmut; Casanova, Emilio

    2015-01-01

    STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3–NF-κB–IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance. PMID:25734337

  6. Dimethylaminopyridine derivatives of lupane triterpenoids cause mitochondrial disruption and induce the permeability transition.

    Science.gov (United States)

    Bernardo, Telma C; Cunha-Oliveira, Teresa; Serafim, Teresa L; Holy, Jon; Krasutsky, Dmytro; Kolomitsyna, Oksana; Krasutsky, Pavel; Moreno, António M; Oliveira, Paulo J

    2013-12-01

    Triterpenoids are a large class of naturally occurring compounds, and some potentially interesting as anticancer agents have been found to target mitochondria. The objective of the present work was to investigate the mechanisms of mitochondrial toxicity induced by novel dimethylaminopyridine (DMAP) derivatives of pentacyclic triterpenes, which were previously shown to inhibit the growth of melanoma cells in vitro. MCF-7, Hs 578T and BJ cell lines, as well as isolated hepatic mitochondria, were used to investigate direct mitochondrial effects. On isolated mitochondrial hepatic fractions, respiratory parameters, mitochondrial transmembrane electric potential, induction of the mitochondrial permeability transition (MPT) pore and ion transport-dependent osmotic swelling were measured. Our results indicate that the DMAP triterpenoid derivatives lead to fragmentation and depolarization of the mitochondrial network in situ, and to inhibition of uncoupled respiration, induction of the permeability transition pore and depolarization of isolated hepatic mitochondria. The results show that mitochondrial toxicity is an important component of the biological interaction of DMAP derivatives, which can explain the effects observed in cancer cells. PMID:24156937

  7. Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure.

    Science.gov (United States)

    Alejandro, Emilyn U; Bozadjieva, Nadejda; Kumusoglu, Doga; Abdulhamid, Sarah; Levine, Hannah; Haataja, Leena; Vadrevu, Suryakiran; Satin, Leslie S; Arvan, Peter; Bernal-Mizrachi, Ernesto

    2015-12-22

    Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to "fine-tune" intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function is unclear. Here, we reveal that mice lacking β cell OGT (βOGT-KO) develop diabetes and β cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of β cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling. PMID:26673325

  8. Hippocampal activity mediates the relationship between circadian activity rhythms and memory in older adults.

    Science.gov (United States)

    Sherman, Stephanie M; Mumford, Jeanette A; Schnyer, David M

    2015-08-01

    Older adults experience parallel changes in sleep, circadian rhythms, and episodic memory. These processes appear to be linked such that disruptions in sleep contribute to deficits in memory. Although more variability in circadian patterns is a common feature of aging and predicts pathology, little is known about how alterations in circadian activity rhythms within older adults influence new episodic learning. Following 10 days of recording sleep-wake patterns using actigraphy, healthy older adults underwent fMRI while performing an associative memory task. The results revealed better associative memory was related to more consistent circadian activity rhythms, independent of total sleep time, sleep efficiency, and level of physical activity. Moreover, hippocampal activity during successful memory retrieval events was positively correlated with associative memory accuracy and circadian activity rhythm (CAR) consistency. We demonstrated that the link between consistent rhythms and associative memory performance was mediated by hippocampal activity. These findings provide novel insight into how the circadian rhythm of sleep-wake cycles are associated with memory in older adults and encourage further examination of circadian activity rhythms as a biomarker of cognitive functioning. PMID:26205911

  9. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma

    2015-01-01

    The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

  10. Hyperthermia-induced disruption of functional connectivity in the human brain network.

    Directory of Open Access Journals (Sweden)

    Gang Sun

    executive control reaction time. CONCLUSIONS/SIGNIFICANCE: We first identified the hyperthermia-induced altered functional connectivity patterns. The changes in the functional connectivity network might be a possible explanation for the cognitive performance and work behavior alteration.

  11. Circadian regulation of metabolic homeostasis: causes and consequences

    Directory of Open Access Journals (Sweden)

    McGinnis GR

    2016-05-01

    Full Text Available Graham R McGinnis, Martin E Young Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Abstract: Robust circadian rhythms in metabolic processes have been described in both humans and animal models, at the whole body, individual organ, and even cellular level. ­Classically, these time-of-day-dependent rhythms have been considered secondary to fluctuations in energy/nutrient supply/demand associated with feeding/fasting and wake/sleep cycles. Renewed interest in this field has been fueled by studies revealing that these rhythms are driven, at least in part, by intrinsic mechanisms and that disruption of metabolic synchrony invariably increases the risk of cardiometabolic disease. The objectives of this paper are to provide a comprehensive review regarding rhythms in glucose, lipid, and protein/amino acid metabolism, the relative influence of extrinsic (eg, neurohumoral factors versus intrinsic (eg, cell autonomous circadian clocks mediators, the physiologic roles of these rhythms in terms of daily fluctuations in nutrient availability and activity status, as well as the pathologic consequences of dyssynchrony. Keywords: circadian rhythm, circadian clocks, metabolic homeostasis, neurohumoral factors, dyssynchrony, time-of-day-dependent rhythms

  12. Nullbasic, a potent anti-HIV tat mutant, induces CRM1-dependent disruption of HIV rev trafficking.

    Directory of Open Access Journals (Sweden)

    Min-Hsuan Lin

    Full Text Available Nullbasic, a mutant of the HIV-1 Tat protein, has anti-HIV-1 activity through mechanisms that include inhibition of Rev function and redistribution of the HIV-1 Rev protein from the nucleolus to the nucleoplasm and cytoplasm. Here we investigate the mechanism of this effect for the first time, establishing that redistribution of Rev by Nullbasic is not due to direct interaction between the two proteins. Rather, Nullbasic affects subcellular localization of cellular proteins that regulate Rev trafficking. In particular, Nullbasic induced redistribution of exportin 1 (CRM1, nucleophosmin (B23 and nucleolin (C23 from the nucleolus to the nucleus when Rev was coexpressed, but never in its absence. Inhibition of the Rev:CRM1 interaction by leptomycin B or a non-interacting RevM10 mutant completely blocked redistribution of Rev by Nullbasic. Finally, Nullbasic did not inhibit importin β- or transportin 1-mediated nuclear import, suggesting that cytoplasmic accumulation of Rev was due to increased export by CRM1. Overall, our data support the conclusion that CRM1-dependent subcellular redistribution of Rev from the nucleolus by Nullbasic is not through general perturbation of either nuclear import or export. Rather, Nullbasic appears to interact with and disrupt specific components of a Rev trafficking complex required for its nucleocytoplasmic shuttling and, in particular, its nucleolar accumulation.

  13. Atomistic MD simulations reveal the protective role of cholesterol in dimeric beta-amyloid induced disruptions in neuronal membrane mimics

    Science.gov (United States)

    Qiu, Liming; Buie, Creighton; Cheng, Sara; Chou, George; Vaughn, Mark; Cheng, K.

    2011-10-01

    Interactions of oligomeric beta-amyloid peptides with neuronal membranes have been linked to the pathogenesis of Alzheimer's disease (AD). The molecular details of the interactions of different lipid components, particularly cholesterol (CHOL), of the membranes with the peptides are not clear. Using an atomistic MD simulations approach, the water permeability barrier, structural geometry and order parameters of binary phosphatidylcholine (PC) and PC/CHOL lipid bilayers were examined from various 200 ns-simulation replicates. Our results suggest that the longer length dimer (2 x 42 residues) perturbs the membrane more than the shorter one (2 x 40 residues). In addition, we discovered a significant protective role of cholesterol in protein-induced disruptions of the membranes. The use of a new Monte-Carlo method in characterizing the structures of the conformal annular lipids in close proximity with the proteins will be introduced. We propose that the neurotoxicity of beta-amyloid peptide may be associated with the nanodomain or raft-like structures of the neuronal membranes in-vivo in the development of AD.

  14. Does non-steroidal anti-inflammatory (NSAID) ibuprofen induce antioxidant stress and endocrine disruption in mussel Mytilus galloprovincialis?

    Science.gov (United States)

    Gonzalez-Rey, Maria; Bebianno, Maria João

    2012-03-01

    Ibuprofen (IBU) is one of the most sold over-the-counter non-steroidal anti-inflammatory drugs (NSAID) and widely detected in the aquatic ecosystems. Nevertheless, the information regarding IBU effects in biota is still sparse. The goal of this study was to assess IBU potential effect as oxidative stress and endocrine disruption inducer in mussel Mytilus galloprovincialis applying a battery of biomarkers. Over two weeks of exposure to IBU (250 ngL(-1)), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), phase II glutathione S-transferase (GST) activities and lipid peroxidation (LPO) levels were determined in the digestive gland and alkali-labile phosphates (ALP) were carried out in sex-differentiated mussels' gonads. The results confirm a transitory induction of antioxidant activities responses concomitant to lipid peroxide formation outline and an increase of ALP levels over time, particularly in exposed males which may lead to mussels' reproductive fitness impairment highlighting a higher impact of IBU as an endocrine disruptor than as a short-term reactive oxygen species (ROS)-generator. PMID:22301165

  15. CYP450-dependent biotransformation of the insecticide fipronil into fipronil sulfone can mediate fipronil-induced thyroid disruption in rats.

    Science.gov (United States)

    Roques, Béatrice B; Lacroix, Marlène Z; Puel, Sylvie; Gayrard, Véronique; Picard-Hagen, Nicole; Jouanin, Isabelle; Perdu, Elisabeth; Martin, Pascal G; Viguié, Catherine

    2012-05-01

    In rats, the widely used insecticide fipronil increases the clearance of thyroxine (T(4)). This effect is associated with a high plasma concentration of fipronil sulfone, the fipronil main metabolite in several species including rats and humans. In sheep, following fipronil treatment, fipronil sulfone plasma concentration and thyroid disruption are much lower than in rats. We postulated that fipronil biotransformation into fipronil sulfone by hepatic cytochromes P450 (CYP) could act as a potential thyroid disruptor. The aim of this study was to determine if fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and CYP induction in rats. Fipronil and fipronil sulfone treatments (3.4 μmol/kg/day per os, 14 days) increased total and free T(4) clearances to the same extent in THX + T(3), euthyroid-like rats. Both treatments induced a 2.5-fold increase in Ugt1a1 and Sult1b1 messenger RNA (mRNA) expressions and a twofold increase in UGT1A activity suggesting that T(4) elimination was mediated, at least in part, by hepatic uridine 5'-diphospho-glucuronosyltransferases (UGT) and/or sulfotransferases (SULT) induction. Both treatments induced a 10-fold increase in Cyp3a1 and Cyp2b2 mRNA expressions concomitant with a threefold increase in CYP3A immunoreactivity and a 1.7-fold increase in antipyrine clearance, a biomarker of CYP3A activity. All these results showed that fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and hepatic enzyme induction in rats. The potential of fipronil sulfone to act as a thyroid disruptor is all the more critical because it persists much longer in the organism than fipronil itself.

  16. Efficiency of drug delivery enhanced by acoustic pressure during blood–brain barrier disruption induced by focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-05-01

    Full Text Available Feng-Yi Yang, Pei-Yi LeeDepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, TaiwanPurpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood–brain barrier (BBB-D, induced by focused ultrasound (FUS using various acoustic parameters.Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to

  17. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    International Nuclear Information System (INIS)

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP

  18. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    Energy Technology Data Exchange (ETDEWEB)

    Eum, Sung Yong, E-mail: seum@miami.edu; Jaraki, Dima; András, Ibolya E.; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP

  19. Circadian transitions in radiation dose-dependent augmentation of mRNA levels for DNA damage-induced genes elicited by accurate real-time RT-PCR quantification

    International Nuclear Information System (INIS)

    Molecular mechanisms of intracellular response after DNA-damage by exposure to ionizing radiation have been studied. In the case of cells isolated from living body of human and experimental animals, alteration of the responsiveness by physiological oscillation such as circadian rhythm must be considered. To examine the circadian variation in the response of p53-responsible genes p21, mdm2, bax, and puma, we established a method to quantitate their mRNA levels with high reproducibility and accuracy based on real-time reverse transcription polymerase chain reaction (RT-PCR) and compared the levels of responsiveness in mouse hemocytes after diurnal irradiation to that after nocturnal irradiation. Augmentations of p21 and mdm2 mRNA levels with growth-arrest and of puma mRNA before apoptosis were confirmed by time-course experiment in RAW264.7, and dose-dependent increases in the peak levels of all the RNA were shown. Similarly, the relative RNA levels of p21, mdm2, bax, and puma per glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also increased dose-dependently in peripheral blood and bone marrow cells isolated from whole-body-irradiated mice. Induction levels of all messages reduced by half after nighttime irradiation as compared with daytime irradiation in blood cells. In marrow cells, nighttime irradiation enhanced the p21 and mdm2 mRNA levels than daytime irradiation. No significant difference in bax or puma mRNA levels was observed between nighttime and daytime irradiation in marrow cells. This suggests that early-stage cellular responsiveness in DNA damage-induced genes is modulated between diurnal and nocturnal irradiation. (author)

  20. Circadian and behavioural responses to shift work-like schedules of light/dark in the mouse

    OpenAIRE

    McGowan, Niall M; Coogan, Andrew

    2013-01-01

    Background: Disruption of circadian rhythms is associated with several deleterious health consequences and cognitive impairment. It is estimated that as many as one in five workers are exposed to this risk factor due to experiencing some degree of chronodisruption by way of recurring patterns of shift work. It is not presently clear therefore how efficiently the mammalian circadian system entrains to alternative light/dark cycles such as those found in shift work schedules. Met...

  1. Circadian Rhythm Management System Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The value of measuring sleep-wake cycles is significantly enhanced by measuring other physiological signals that depend on circadian rhythms (such as heart rate and...

  2. Circadian Control of Global Transcription

    Science.gov (United States)

    Li, Shujing; Zhang, Luoying

    2015-01-01

    Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. PMID:26682214

  3. Circadian Control of Global Transcription

    Directory of Open Access Journals (Sweden)

    Shujing Li

    2015-01-01

    Full Text Available Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs. CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions.

  4. Endocrine regulation of circadian physiology.

    Science.gov (United States)

    Tsang, Anthony H; Astiz, Mariana; Friedrichs, Maureen; Oster, Henrik

    2016-07-01

    Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis. PMID:27106109

  5. Postoperative circadian disturbances

    DEFF Research Database (Denmark)

    Gögenur, Ismail

    2010-01-01

    night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively......An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention...... surgery was increased on the fourth day after surgery and the total excretion of AMT6s in urine was correlated to sleep efficiency and wake time after sleep onset, but was not correlated to the occurrence of postoperative cognitive dysfunction. We could only prove an effect of melatonin substitution...

  6. Gene-environment factors in depressive disorders with a focus on circadian genes

    OpenAIRE

    Sjöholm, Louise

    2010-01-01

    Depressive disorders have a multifactorial etiology, where both environmental and genetic risk factors contribute. Depression is characterized by a depressed mood and accompanied by e.g. loss of interest and pleasure, disturbed sleep and appetite and difficulties in concentrating. A disturbed sleep-wake pattern as well as disruptions of other biological (circadian) rhythms is a hallmark of depression. This fact has led researchers to believe that disruptions of biological ...

  7. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    Directory of Open Access Journals (Sweden)

    Ramesh Vijay

    2012-05-01

    Full Text Available Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who have disrupted sleep as a result of obstructive sleep apnea, a condition associated with prominent sleep fragmentation. The aim of this study was to examine role of the TNF-α pathway after long-term sleep fragmentation in mice. Methods The effect of chronic sleep fragmentation during the sleep-predominant period on sleep architecture, sleep latency, cognitive function, behavior, and inflammatory markers was assessed in C57BL/6 J and in mice lacking the TNF-α receptor (double knockout mice. In addition, we also assessed the above parameters in C57BL/6 J mice after injection of a TNF-α neutralizing antibody. Results Mice subjected to chronic sleep fragmentation had preserved sleep duration, sleep state distribution, and cumulative delta frequency power, but also exhibited excessive sleepiness, altered cognitive abilities and mood correlates, reduced cyclic AMP response element-binding protein phosphorylation and transcriptional activity, and increased phosphodiesterase-4 expression, in the absence of AMP kinase-α phosphorylation and ATP changes. Selective increases in cortical expression of TNF-α primarily circumscribed to neurons emerged. Consequently, sleepiness and cognitive dysfunction were absent in TNF-α double receptor knockout mice subjected to sleep fragmentation, and similarly, treatment with a TNF-α neutralizing antibody abrogated sleep fragmentation-induced learning deficits and increases in sleep propensity. Conclusions Taken together

  8. The molecular clock regulates circadian transcription of tissue factor gene.

    Science.gov (United States)

    Oishi, Katsutaka; Koyanagi, Satoru; Ohkura, Naoki

    2013-02-01

    Tissue factor (TF) is involved in endotoxin-induced inflammation and mortality. We found that the circadian expression of TF mRNA, which peaked at the day to night transition (activity onset), was damped in the liver of Clock mutant mice. Luciferase reporter and chromatin immunoprecipitation analyses using embryonic fibroblasts derived from wild-type or Clock mutant mice showed that CLOCK is involved in transcription of the TF gene. Furthermore, the results of real-time luciferase reporter experiments revealed that the circadian expression of TF mRNA is regulated by clock molecules through a cell-autonomous mechanism via an E-box element located in the promoter region.

  9. The circadian clock in mammals

    OpenAIRE

    Zordan, Mauro; Kyriacou, Charalambos P

    2000-01-01

    The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship be...

  10. The circadian clock in mammals

    OpenAIRE

    Zordan, M. A.; Kyriacou, C P

    2005-01-01

    The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship be...

  11. Die circadiane Uhr im Immunsystem

    OpenAIRE

    Keller, Maren

    2010-01-01

    Daily rhythms of a variety of immunological phenomena and functions are well known, but so far they have largely been neglected. Examples of daily rhythms in the immune system are: circadian differences in susceptibility to bacterial infection and daily variations in the symptoms of diseases such as rheumatoid arthritis or asthma. Therefore, it is very important for clinical diagnosis and pharmacological therapies to elucidate the connections between the circadian clock and the immune system....

  12. A baculovirus photolyase with DNA repair activity and circadian clock regulatory function

    NARCIS (Netherlands)

    Biernat, M.A.; Eker, A.P.M.; Oers, van M.M.; Vlak, J.M.; Horst, van der G.T.J.; Chaves, I.

    2012-01-01

    Cryptochromes and photolyases belong to the same family of flavoproteins but, despite being structurally conserved, display distinct functions. Photolyases use visible light to repair ultraviolet-induced DNA damage. Cryptochromes, however, function as blue-light receptors, circadian photoreceptors,

  13. GRK2: putting the brakes on the circadian clock

    Science.gov (United States)

    Mendoza-Viveros, Lucia; Cheng, Arthur H.

    2016-01-01

    G protein-coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that terminate G protein-coupled receptor (GPCR) signaling by phosphorylating the receptor and inducing its internalization. In addition to their canonical function, some GRKs can phosphorylate non-GPCR substrates and regulate GPCR signaling in a kinase-independent manner. GPCRs are abundantly expressed in the suprachiasmatic nucleus (SCN), a structure in the mammalian brain that serves as the central circadian pacemaker. Various facets of circadian timekeeping are under the influence of GPCR signaling, and thus are potential targets for GRK regulation. Despite this, little attention has been given to the role of GRKs in circadian rhythms. In this research highlight, we discuss our latest findings on the functional involvement of GRK2 in mammalian circadian timekeeping in the SCN. Using grk2 knockout mice, we demonstrate that GRK2 is critical for maintaining proper clock speed and ensuring that the clock is appropriately synchronized to environmental light cycles. Although grk2 deficiency expectedly alters the expression of a key GPCR in the SCN, our study also reveals that GRK2 has a more direct function that touches the heart of the circadian clock. PMID:27088110

  14. Coupling between the circadian clock and cell cycle oscillators: Implication for healthy cells and malignant growth

    NARCIS (Netherlands)

    C. Feillet (Céline); G.T.J. van der Horst (Gijsbertus); F.A. Lévi (Francis); D.A. Rand (David); F. Delaunay (Franck)

    2015-01-01

    textabstractUncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift wor

  15. Gremlin-2 is a BMP antagonist that is regulated by the circadian clock

    DEFF Research Database (Denmark)

    Yeung, Ching-Yan Chloé; Gossan, Nicole; Lu, Yinhui;

    2014-01-01

    of human tenocytes in vitro. We observed dampened Grem2 expression, deregulated BMP signaling, and spontaneously calcifying tendons in young CLOCKΔ19 arrhythmic mice and aged wild-type mice. Thus, disruption of circadian control, through mutations or aging, of Grem2/BMP signaling becomes a new focus...

  16. Circadian Transcription from Beta Cell Function to Diabetes Pathophysiology.

    Science.gov (United States)

    Perelis, Mark; Ramsey, Kathryn Moynihan; Marcheva, Biliana; Bass, Joseph

    2016-08-01

    The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease. PMID:27440914

  17. Moderate Stress-Induced Social Bonding and Oxytocin Signaling are Disrupted by Predator Odor in Male Rats.

    Science.gov (United States)

    Muroy, Sandra E; Long, Kimberly L P; Kaufer, Daniela; Kirby, Elizabeth D

    2016-07-01

    In times of stress, social support can serve as a potent buffering mechanism that enhances resilience. In humans, stress can promote protective affiliative interactions and prosocial behavior. Yet, stress also precipitates psychopathologies characterized by social withdrawal such as post-traumatic stress disorder (PTSD) and depression. The factors that drive adaptive vs maladaptive social responses to stress are not yet clear. Rodent studies have focused on pair-bonded, opposite-sex mates and suggest that a variety of stressors can induce social support-like behaviors. However, between same-sex conspecifics-particularly males-stress effects on social bonding are less understood and often associated with aggression and social unrest. We thus sought to investigate if a moderate stressor-3 h of acute immobilization-impacts social-support behaviors differently when experienced in a neutral vs more innately threatening context (ie, paired with predator odor). We found that moderate stress increased social support-seeking behavior in rat cagemates and facilitated long-term sharing of a limited water resource, decreased aggression, and strongly defined dominance ranks (an indicator of home cage stability). In contrast, experiencing the same stressor in the presence of predator odor eliminated the positive behavioral effects of moderate stress. Importantly, hypothalamic oxytocin (OT) signaling increased coincident with stress in a neutral-but not a predator odor-context. Our results define a novel rodent model of divergent stress effects on social affiliation and OT signaling dependent on odor context with particularly strong relevance to stress-related disorders such as PTSD, which are characterized by a disrupted ability to seek and maintain social bonds. PMID:26830961

  18. Chronic Subordination Stress Induces Hyperphagia and Disrupts Eating Behavior in Mice Modeling Binge-Eating-Like Disorder

    Science.gov (United States)

    Razzoli, Maria; Sanghez, Valentina; Bartolomucci, Alessandro

    2015-01-01

    Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge-eating disorder (BED) is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress-induced hyperphagia associated with the development of obesity. Here, we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress (CSS) associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol we tested the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or to the acute application of a social defeat. Notably, the obese phenotype but not the fasting hyperglycemia of subordinate mice was abrogated by preventing hyperphagia in a pair-feeding paradigm. Conclusion: Overall, these results support the validity of our CSS to model BED allowing for the determination of the underlying molecular mechanisms and the generation of testable predictions for innovative therapies, based on the understanding of the regulation and the control of food intake. PMID:25621284

  19. Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder

    Directory of Open Access Journals (Sweden)

    Maria eRazzoli

    2015-01-01

    Full Text Available Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge eating disorder (BED is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress induced hyperphagia associated with the development of obesity. Here we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol was test the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or to the acute application of a social defeat. Notably, the obese phenotype but not the fasting hyperglycemia of subordinate mice was abrogated by preventing hyperphagia in a pair feeding paradigm. Conclusion: Overall these results support the validity of our chronic subordination stress to model binge eating disorder allowing for the determination of the underlying molecular mechanisms and the generation of testable predictions for innovative therapies, based on the understanding of the regulation and the control of food

  20. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells.

    Directory of Open Access Journals (Sweden)

    Mini Balakrishnan

    Full Text Available HIV-1 integrase (IN is the target for two classes of antiretrovirals: i the integrase strand-transfer inhibitors (INSTIs and ii the non-catalytic site integrase inhibitors (NCINIs. NCINIs bind at the IN dimer interface and are thought to interfere primarily with viral DNA (vDNA integration in the target cell by blocking IN-vDNA assembly as well as the IN-LEDGF/p75 interaction. Herein we show that treatment of virus-producing cells, but not of mature virions or target cells, drives NCINI antiviral potency. NCINIs target an essential late-stage event in HIV replication that is insensitive to LEDGF levels in the producer cells. Virus particles produced in the presence of NCINIs displayed normal Gag-Pol processing and endogenous reverse transcriptase activity, but were defective at initiating vDNA synthesis following entry into the target cell. NCINI-resistant virus carrying a T174I mutation in the IN dimer interface was less sensitive to the compound-induced late-stage effects, including the reverse transcription block. Wild-type, but not T174I virus, produced in the presence of NCINIs exhibited striking defects in core morphology and an increased level of IN oligomers that was not observed upon treatment of mature cell-free particles. Collectively, these results reveal that NCINIs act through a novel mechanism that is unrelated to the previously observed inhibition of IN activity or IN-LEDGF interaction, and instead involves the disruption of an IN function during HIV-1 core maturation and assembly.

  1. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells.

    Science.gov (United States)

    Balakrishnan, Mini; Yant, Stephen R; Tsai, Luong; O'Sullivan, Christopher; Bam, Rujuta A; Tsai, Angela; Niedziela-Majka, Anita; Stray, Kirsten M; Sakowicz, Roman; Cihlar, Tomas

    2013-01-01

    HIV-1 integrase (IN) is the target for two classes of antiretrovirals: i) the integrase strand-transfer inhibitors (INSTIs) and ii) the non-catalytic site integrase inhibitors (NCINIs). NCINIs bind at the IN dimer interface and are thought to interfere primarily with viral DNA (vDNA) integration in the target cell by blocking IN-vDNA assembly as well as the IN-LEDGF/p75 interaction. Herein we show that treatment of virus-producing cells, but not of mature virions or target cells, drives NCINI antiviral potency. NCINIs target an essential late-stage event in HIV replication that is insensitive to LEDGF levels in the producer cells. Virus particles produced in the presence of NCINIs displayed normal Gag-Pol processing and endogenous reverse transcriptase activity, but were defective at initiating vDNA synthesis following entry into the target cell. NCINI-resistant virus carrying a T174I mutation in the IN dimer interface was less sensitive to the compound-induced late-stage effects, including the reverse transcription block. Wild-type, but not T174I virus, produced in the presence of NCINIs exhibited striking defects in core morphology and an increased level of IN oligomers that was not observed upon treatment of mature cell-free particles. Collectively, these results reveal that NCINIs act through a novel mechanism that is unrelated to the previously observed inhibition of IN activity or IN-LEDGF interaction, and instead involves the disruption of an IN function during HIV-1 core maturation and assembly. PMID:24040198

  2. Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

    OpenAIRE

    Suemaru, Katsuya; Yasuda, Kayo; Umeda, Kenta; Araki, Hiroaki; Shibata, Kazuhiko; Choshi, Tominari; Hibino, Satoshi; Gomita, Yutaka

    2004-01-01

    Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats.Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrup...

  3. Circadian rhythms, the molecular clock, and skeletal muscle.

    Science.gov (United States)

    Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A

    2011-01-01

    Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1(-/-) and Clock(Δ19) mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle.

  4. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism.

    Science.gov (United States)

    Leone, Vanessa; Gibbons, Sean M; Martinez, Kristina; Hutchison, Alan L; Huang, Edmond Y; Cham, Candace M; Pierre, Joseph F; Heneghan, Aaron F; Nadimpalli, Anuradha; Hubert, Nathaniel; Zale, Elizabeth; Wang, Yunwei; Huang, Yong; Theriault, Betty; Dinner, Aaron R; Musch, Mark W; Kudsk, Kenneth A; Prendergast, Brian J; Gilbert, Jack A; Chang, Eugene B

    2015-05-13

    Circadian clocks and metabolism are inextricably intertwined, where central and hepatic circadian clocks coordinate metabolic events in response to light-dark and sleep-wake cycles. We reveal an additional key element involved in maintaining host circadian rhythms, the gut microbiome. Despite persistence of light-dark signals, germ-free mice fed low or high-fat diets exhibit markedly impaired central and hepatic circadian clock gene expression and do not gain weight compared to conventionally raised counterparts. Examination of gut microbiota in conventionally raised mice showed differential diurnal variation in microbial structure and function dependent upon dietary composition. Additionally, specific microbial metabolites induced under low- or high-fat feeding, particularly short-chain fatty acids, but not hydrogen sulfide, directly modulate circadian clock gene expression within hepatocytes. These results underscore the ability of microbially derived metabolites to regulate or modify central and hepatic circadian rhythm and host metabolic function, the latter following intake of a Westernized diet. PMID:25891358

  5. Acute light exposure suppresses circadian rhythms in clock gene expression.

    Science.gov (United States)

    Grone, Brian P; Chang, Doris; Bourgin, Patrice; Cao, Vinh; Fernald, Russell D; Heller, H Craig; Ruby, Norman F

    2011-02-01

    Light can induce arrhythmia in circadian systems by several weeks of constant light or by a brief light stimulus given at the transition point of the phase response curve. In the present study, a novel light treatment consisting of phase advance and phase delay photic stimuli given on 2 successive nights was used to induce circadian arrhythmia in the Siberian hamster ( Phodopus sungorus). We therefore investigated whether loss of rhythms in behavior was due to arrhythmia within the suprachiasmatic nucleus (SCN). SCN tissue samples were obtained at 6 time points across 24 h in constant darkness from entrained and arrhythmic hamsters, and per1, per2 , bmal1, and cry1 mRNA were measured by quantitative RT-PCR. The light treatment eliminated circadian expression of clock genes within the SCN, and the overall expression of these genes was reduced by 18% to 40% of entrained values. Arrhythmia in per1, per2, and bmal1 was due to reductions in the amplitudes of their oscillations. We suggest that these data are compatible with an amplitude suppression model in which light induces singularity in the molecular circadian pacemaker.

  6. Family Disruptions

    Science.gov (United States)

    ... Spread the Word Shop AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care ... Life Listen Español Text Size Email Print Share Family Disruptions Page Content Article Body No matter how ...

  7. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development...

  8. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...

  9. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  10. Circadian molecular clocks and cancer.

    Science.gov (United States)

    Kelleher, Fergal C; Rao, Aparna; Maguire, Anne

    2014-01-01

    Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors; Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular examples exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock. PMID:24099911

  11. Lithium impacts on the amplitude and period of the molecular circadian clockwork.

    Directory of Open Access Journals (Sweden)

    Jian Li

    Full Text Available Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions.

  12. Circadian variation of the human metabolome captured by real-time breath analysis.

    Directory of Open Access Journals (Sweden)

    Pablo Martinez-Lozano Sinues

    Full Text Available Circadian clocks play a significant role in the correct timing of physiological metabolism, and clock disruption might lead to pathological changes of metabolism. One interesting method to assess the current state of metabolism is metabolomics. Metabolomics tries to capture the entirety of small molecules, i.e. the building blocks of metabolism, in a given matrix, such as blood, saliva or urine. Using mass spectrometric approaches we and others have shown that a significant portion of the human metabolome in saliva and blood exhibits circadian modulation; independent of food intake or sleep/wake rhythms. Recent advances in mass spectrometry techniques have introduced completely non-invasive breathprinting; a method to instantaneously assess small metabolites in human breath. In this proof-of-principle study, we extend these findings about the impact of circadian clocks on metabolomics to exhaled breath. As previously established, our method allows for real-time analysis of a rich matrix during frequent non-invasive sampling. We sampled the breath of three healthy, non-smoking human volunteers in hourly intervals for 24 hours during total sleep deprivation, and found 111 features in the breath of all individuals, 36-49% of which showed significant circadian variation in at least one individual. Our data suggest that real-time mass spectrometric "breathprinting" has high potential to become a useful tool to understand circadian metabolism, and develop new biomarkers to easily and in real-time assess circadian clock phase and function in experimental and clinical settings.

  13. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2.

    Science.gov (United States)

    Eum, Sung Yong; Jaraki, Dima; András, Ibolya E; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.

  14. Analysis of Circadian Leaf Movements.

    Science.gov (United States)

    Müller, Niels A; Jiménez-Gómez, José M

    2016-01-01

    The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato. PMID:26867616

  15. Circadian systems : different levels of complexity

    NARCIS (Netherlands)

    Roenneberg, Till; Merrow, Martha

    2001-01-01

    After approximately 50 years of circadian research, especially in selected circadian model systems (Drosophila, Neurospora, Gonyaulax and, more recently, cyanobacteria and mammals), we appreciate the enormous complexity of the circadian programme in organisms and cells, as well as in physiological a

  16. Circadian rhythms of photorefractory siberian hamsters remain responsive to melatonin.

    Science.gov (United States)

    Butler, Matthew P; Paul, Matthew J; Turner, Kevin W; Park, Jin Ho; Driscoll, Joseph R; Kriegsfeld, Lance J; Zucker, Irving

    2008-04-01

    Short day lengths increase the duration of nocturnal melatonin (Mel) secretion, which induces the winter phenotype in Siberian hamsters. After several months of continued exposure to short days, hamsters spontaneously revert to the spring-summer phenotype. This transition has been attributed to the development of refractoriness of Mel-binding tissues, including the suprachiasmatic nucleus (SCN), to long-duration Mel signals. The SCN of Siberian hamsters is required for the seasonal response to winter-like Mel signals, and becomes refractory to previously effective long-duration Mel signals restricted to this area. Acute Mel treatment phase shifts circadian locomotor rhythms of photosensitive Siberian hamsters, presumably by affecting circadian oscillators in the SCN. We tested whether seasonal refractoriness of the SCN to long-duration Mel signals also renders the circadian system of Siberian hamsters unresponsive to Mel. Males manifesting free-running circadian rhythms in constant dim red light were injected with Mel or vehicle for 5 days on a 23.5-h T-cycle beginning at circadian time 10. Mel injections caused significantly larger phase advances in activity onset than did the saline vehicle, but the magnitude of phase shifts to Mel did not differ between photorefractory and photosensitive hamsters. Similarly, when entrained to a 16-h light/8-h dark photocycle, photorefractory and photosensitive hamsters did not differ in their response to Mel injected 4 h before the onset of the dark phase. Activity onset in Mel-injected hamsters was masked by light but was revealed to be significantly earlier than in vehicle-injected hamsters upon transfer to constant dim red light. The acute effects of melatonin on circadian behavioral rhythms are preserved in photorefractory hamsters.

  17. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    Science.gov (United States)

    Jim, Heather S.L.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Vierkant, Robert A.; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Schernhammer, Eva; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Ramus, Susan J.; Monteiro, Alvaro N.A.; Goode, Ellen L.; Narod, Steven A.; Gayther, Simon A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. PMID:26807442

  18. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-08-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

  19. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, HongSeok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-01-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs. PMID:27510760

  20. Millisecond flashes of light phase delay the human circadian clock during sleep

    Science.gov (United States)

    Zeitzer, Jamie M.; Fisicaro, Ryan A.; Ruby, Norman F.; Heller, H. Craig

    2016-01-01

    The human circadian timing system is most sensitive to the phase shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a two-week circadian stabilization protocol followed by a two-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n=7) or a sequence of 2-msec light flashes given every 30 seconds (n=6) from hours 2–3 after habitual bed time. Changes in circadian timing (phase), micro- and macroarchitecture of sleep were all assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm as compared to the control dark condition (P0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 seconds of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether there is an effect of these light flashes on sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. PMID:25227334

  1. Millisecond flashes of light phase delay the human circadian clock during sleep.

    Science.gov (United States)

    Zeitzer, Jamie M; Fisicaro, Ryan A; Ruby, Norman F; Heller, H Craig

    2014-10-01

    The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. PMID:25227334

  2. The Circadian Clock Is a Key Driver of Steroid Hormone Production in Drosophila.

    Science.gov (United States)

    Di Cara, Francesca; King-Jones, Kirst

    2016-09-26

    Biological clocks allow organisms to anticipate daily environmental changes such as temperature fluctuations, abundance of daylight, and nutrient availability. Many circadian-controlled physiological states are coordinated by the release of systemically acting hormones, including steroids and insulin [1-7]. Thus, hormones relay circadian outputs to target tissues, and disrupting these endocrine rhythms impairs human health by affecting sleep patterns, energy homeostasis, and immune functions [8-10]. It is largely unclear, however, whether circadian circuits control hormone levels indirectly via central timekeeping neurons or whether peripheral endocrine clocks can modulate hormone synthesis directly. We show here that perturbing the circadian clock, specifically in the major steroid hormone-producing gland of Drosophila, the prothoracic gland (PG), unexpectedly blocks larval development due to an inability to produce sufficient steroids. This is surprising, because classic circadian null mutants are viable and result in arrhythmic adults [4, 11-14]. We found that Timeless and Period, both core components of the insect clock [15], are required for transcriptional upregulation of steroid hormone-producing enzymes. Timeless couples the circadian machinery directly to the two canonical pathways that regulate steroid synthesis in insects, insulin and PTTH signaling [16], respectively. Activating insulin signaling directly modulates Timeless function, suggesting that the local clock in the PG is normally synced with systemic insulin cues. Because both PTTH and systemic insulin signaling are themselves under circadian control, we conclude that de-synchronization of a local endocrine clock with external circadian cues is the primary cause for steroid production to fail. PMID:27546572

  3. An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA.

    Directory of Open Access Journals (Sweden)

    Guo-Xiang Ruan

    2008-10-01

    Full Text Available The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER

  4. Egg parasitoid attraction toward induced plant volatiles is disrupted by a non-host herbivore attacking above or belowground plant organs.

    Directory of Open Access Journals (Sweden)

    Rihem eMoujahed

    2014-11-01

    Full Text Available Plants respond to insect oviposition by emission of oviposition-induced plant volatiles (OIPVs which can recruit egg parasitoids of the attacking herbivore. To date, studies demonstrating egg parasitoid attraction to OIPVs have been carried out in tritrophic systems consisting of one species each of plant, herbivore host, and the associated egg parasitoid. Less attention has been given to plants experiencing multiple attacks by host and non-host herbivores that potentially could interfere with the recruitment of egg parasitoids as a result of modifications to the OIPV blend. Egg parasitoid attraction could also be influenced by the temporal dynamics of multiple infestations, when the same non-host herbivore damages different organs of the same plant species. In this scenario we investigated the responses of egg parasitoids to feeding and oviposition damage using a model system consisting of Vicia faba, the above-ground insect herbivore Nezara viridula, the above- and below-ground insect herbivore Sitona lineatus, and Trissolcus basalis, a natural enemy of N. viridula. We demonstrated that the non-host S. lineatus disrupts wasp attraction toward plant volatiles induced by the host N. viridula. Interestingly, V. faba damage inflicted by either adults (i.e. leaf-feeding or larvae (i.e. root-feeding of S. lineatus, had a similar disruptive effect on T. basalis host location, suggesting that a common interference mechanism might be involved. Neither naïve wasps or wasps with previous oviposition experience were attracted to plant volatiles induced by N. viridula when V. faba plants were concurrently infested with S. lineatus adults or larvae. Analysis of the volatile blends among healthy plants and above-ground treatments show significant differences in terms of whole volatile emissions. Our results demonstrate that induced plant responses caused by a non-host herbivore can disrupt the attraction of an egg parasitoid to a plant that is also infested

  5. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  6. Chronobesity: role of the circadian system in the obesity epidemic.

    Science.gov (United States)

    Laermans, J; Depoortere, I

    2016-02-01

    Although obesity is considered to result from an imbalance between energy uptake and energy expenditure, the strategy of dietary changes and physical exercise has failed to tackle the global obesity epidemic. In search of alternative and more adequate treatment options, research has aimed at further unravelling the mechanisms underlying this excessive weight gain. While numerous studies are focusing on the neuroendocrine alterations that occur after bariatric Roux-en-Y gastric bypass surgery, an increasing amount of chronobiological studies have started to raise awareness concerning the pivotal role of the circadian system in the development and exacerbation of obesity. This internal timekeeping mechanism rhythmically regulates metabolic and physiological processes in order to meet the fluctuating demands in energy use and supply throughout the 24-h day. This review elaborates on the extensive bidirectional interaction between the circadian system and metabolism and explains how disruption of body clocks by means of shift work, frequent time zone travelling or non-stop consumption of calorie-dense foods can evoke detrimental metabolic alterations that contribute to obesity. Altering the body's circadian rhythms by means of time-related dietary approaches (chrononutrition) or pharmacological substances (chronobiotics) may therefore represent a novel and interesting way to prevent or treat obesity and associated comorbidities.

  7. A multi-oscillatory circadian system times female reproduction

    Directory of Open Access Journals (Sweden)

    Valerie eSimonneaux

    2015-10-01

    Full Text Available Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei as an indicator of the time of the day. Herein we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the suprachiasmatic nucleus, arginine vasopressin and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis (kisspeptin neurons, GnRH neurons, gonadotropic cells, the ovary and the uterus. This review will point to the critical position of the kisspeptin neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift work conditions on female reproductive performance and fertility in both animal model and humans.

  8. Effects of chronic forced circadian desynchronization on body weight and metabolism in male mice.

    Science.gov (United States)

    Casiraghi, Leandro P; Alzamendi, Ana; Giovambattista, Andrés; Chiesa, Juan J; Golombek, Diego A

    2016-04-01

    Metabolic functions are synchronized by the circadian clock setting daily patterns of food intake, nutrient delivery, and behavioral activity. Here, we study the impact of chronic jet-lag (CJL) on metabolism, and test manipulations aimed to overcome potential alterations. We recorded weight gain in C57Bl/6 mice under chronic 6 h advances or delays of the light-dark cycle every 2 days (ChrA and ChrD, respectively). We have previously reported ChrA, but not ChrD, to induce forced desynchronization of locomotor activity rhythms in mice (Casiraghi et al. 2012). Body weight was rapidly increased under ChrA, with animals tripling the mean weight gain observed in controls by day 10, and doubling it by day 30 (6% vs. 2%, and 15% vs. 7%, respectively). Significant increases in retroperitoneal and epidydimal adipose tissue masses (172% and 61%, respectively), adipocytes size (28%), and circulating triglycerides (39%) were also detected. Daily patterns of food and water intake were abolished under ChrA In contrast, ChrD had no effect on body weight. Wheel-running, housing of animals in groups, and restriction of food availability to hours of darkness prevented abnormal increase in body weight under ChrA Our findings suggest that the observed alterations under ChrA may arise either from a direct effect of circadian disruption on metabolism, from desynchronization between feeding and metabolic rhythms, or both. Direction of shifts, timing of feeding episodes, and other reinforcing signals deeply affect the outcome of metabolic function under CJL Such features should be taken into account in further studies of shift working schedules in humans. PMID:27125665

  9. Individual differences in circadian waveform of Siberian hamsters under multiple lighting conditions.

    Science.gov (United States)

    Evans, Jennifer A; Elliott, Jeffrey A; Gorman, Michael R

    2012-10-01

    Because the circadian clock in the mammalian brain derives from a network of interacting cellular oscillators, characterizing the nature and bases of circadian coupling is fundamental to understanding how the pacemaker operates. Various phenomena involving plasticity in circadian waveform have been theorized to reflect changes in oscillator coupling; however, it remains unclear whether these different behavioral paradigms reference a unitary underlying process. To test whether disparate coupling assays index a common mechanism, we examined whether there is covariation among behavioral responses to various lighting conditions that produce changes in circadian waveform. Siberian hamsters, Phodopus sungorus, were transferred from long to short photoperiods to distinguish short photoperiod responders (SP-R) from nonresponders (SP-NR). Short photoperiod chronotyped hamsters were subsequently transferred, along with unselected controls, to 24-h light:dark:light: dark cycles (LDLD) with dim nighttime illumination, a procedure that induces bifurcated entrainment. Under LDLD, SP-R hamsters were more likely to bifurcate their rhythms than were SP-NR hamsters or unselected controls. After transfer from LDLD to constant dim light, SP-R hamsters were also more likely to become arrhythmic compared to SP-NR hamsters and unselected controls. In contrast, short photoperiod chronotype did not influence more transient changes in circadian waveform. The present data reveal a clear relationship in the plasticity of circadian waveform across 3 distinct lighting conditions, suggesting a common mechanism wherein individual differences reflect variation in circadian coupling.

  10. Protein phosphatase-dependent circadian regulation of intermediate-term associative memory.

    Science.gov (United States)

    Michel, Maximilian; Gardner, Jacob S; Green, Charity L; Organ, Chelsea L; Lyons, Lisa C

    2013-03-01

    The endogenous circadian clock is a principal factor modulating memory across species. Determining the processes through which the circadian clock modulates memory formation is a key issue in understanding and identifying mechanisms to improve memory. We used the marine mollusk Aplysia californica to investigate circadian modulation of intermediate-term memory (ITM) and the mechanisms through which the circadian clock phase specifically suppresses memory using the operant learning paradigm, learning that food is inedible. We found that ITM, a temporally and mechanistically distinct form of memory, is rhythmically expressed under light-dark and constant conditions when induced by either massed or spaced training. Strong circadian regulation of ITM occurs with memory exhibited only by animals trained during the early subjective day; no apparent memory is expressed when training occurs during the late subjective day or night. Given the necessity of multiple persistent kinase cascades for ITM, we investigated whether protein phosphatase activity affected circadian modulation. Inhibition of protein phosphatases 1 and 2A blocked ITM when animals were trained during the early (subjective) day while resulting in phase-specific memory rescue when animals were trained late in the subjective day and early night. In contrast, inhibition of calcineurin did not block ITM when animals were trained during the early day and permitted ITM when animals were trained during the late subjective day, early evening, and throughout the night. These results demonstrate that levels of protein phosphatase activity are critical regulators of ITM and one mechanism through which the circadian clock regulates memory formation.

  11. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential.

    Science.gov (United States)

    Xiao, Dong; Lew, Karen L; Zeng, Yan; Xiao, Hui; Marynowski, Stanley W; Dhir, Rajiv; Singh, Shivendra V

    2006-11-01

    The present study was undertaken to gain insights into the molecular mechanism of apoptosis induction by phenethyl isothiocyanate (PEITC), which is a cancer chemopreventive constituent of cruciferous vegetables, using PC-3 human prostate cancer cells as a model. The PEITC-induced cell death in PC-3 cells was associated with disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria to the cytosol and generation of reactive oxygen species (ROS), which were blocked in the presence of a combined mimetic of superoxide dismutase and catalase (Euk134). Ectopic expression of Bcl-xL, whose protein level is reduced markedly on treatment of PC-3 cells with PEITC, conferred partial protection against PEITC-induced apoptosis only at higher drug concentrations (>10 microM). Administration of 12 micromol PEITC/day (Monday through Friday) by oral gavage significantly retarded growth of PC-3 xenografts in athymic mice. For instance, 31 days after the initiation of PEITC administration, the average tumor volume in control mice (721 +/- 153 mm3) was approximately 2-fold higher compared with mice receiving 12 micromol PEITC/day. The PEITC-mediated inhibition of PC-3 xenograft growth was associated with induction of Bax and Bid proteins. In conclusion, the present study indicates that the PEITC-induced apoptosis in PC-3 cells is mediated by ROS-dependent disruption of the mitochondrial membrane potential and regulated by Bax and Bid. PMID:16774948

  12. Pesticide- and sex steroid analogue-induced endocrine disruption differentially targets hypothalamo-hypophyseal-gonadal system during gametogenesis in teleosts - A review.

    Science.gov (United States)

    Senthilkumaran, Balasubramanian

    2015-08-01

    Pesticide-induced endocrine disruption often mimics sex steroidal action resulting in physiological functional disarray of hypothalamo-hypophyseal-gonadal (HHG) system at multiple levels. Among various group of pesticides, organochlorine and organophosphate family of pesticides are known to impart sex steroidal mimicking activity with slightly higher resemblance to estrogens when compared to androgenic action. This review will highlight the effects of organochlorine (for e.g. endosulfan) and organophosphate (for e.g. malathion) pesticides in comparison with sex-steroid analogue-induced changes on HHG axis during gametogenesis in few teleost fish models. Interestingly, the effects of these compounds have produced differential effects in juveniles and adults which also vary based on exposure dosage and duration. Further, the treatments had caused at times sexually dimorphic effects indicating that the action of these compounds bring out serious implications in sexual development. A comprehensive overview has been provided by considering all these aspects to recognize the adverse impacts of pesticide-induced endocrine disruption with special reference to endosulfan and malathion as those had been applied even today or used before for controlling agricultural pests in several Asian countries including India. This review also compares the effects of sex-steroid analogues where in sex reversal to reproductive dysfunction is evident, which may imply the extent of sexual plasticity in teleosts compared to other vertebrates.

  13. Monoclonal antibodies against DNA-binding tips of DNABII proteins disrupt biofilms in vitro and induce bacterial clearance in vivo

    Directory of Open Access Journals (Sweden)

    Laura A. Novotny

    2016-08-01

    Full Text Available The vast majority of chronic and recurrent bacterial diseases are attributed to the presence of a recalcitrant biofilm that contributes significantly to pathogenesis. As such, these diseases will require an innovative therapeutic approach. We targeted DNABII proteins, an integral component of extracellular DNA (eDNA which is universally found as part of the pathogenic biofilm matrix to develop a biofilm disrupting therapeutic. We show that a cocktail of monoclonal antibodies directed against specific epitopes of a DNABII protein is highly effective to disrupt diverse biofilms in vitro as well as resolve experimental infection in vivo, in both a chinchilla and murine model. Combining this monoclonal antibody cocktail with a traditional antibiotic to kill bacteria newly released from the biofilm due to the action of the antibody cocktail was highly effective. Our results strongly support these monoclonal antibodies as attractive candidates for lead optimization as a therapeutic for resolution of bacterial biofilm diseases.

  14. Circadian influences on myocardial infarction.

    Science.gov (United States)

    Virag, Jitka A I; Lust, Robert M

    2014-01-01

    Components of circadian rhythm maintenance, or "clock genes," are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  15. Experience-independent development of the hamster circadian visual system.

    Directory of Open Access Journals (Sweden)

    August Kampf-Lassin

    Full Text Available Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduction of a light-dark cycle. In adulthood, previously-occluded eyes were challenged with visual stimuli. Whereas image-formation and motion-detection were markedly impaired by monocular occlusion, neither entrainment to a light-dark cycle, nor phase-resetting responses to shifts in the light-dark cycle were affected by prior monocular deprivation. Cholera toxin-b subunit fluorescent tract-tracing revealed that in monocularly-deprived hamsters the density of fibers projecting from the retina to the suprachiasmatic nucleus (SCN was comparable regardless of whether such fibers originated from occluded or exposed eyes. In addition, long-term monocular deprivation did not attenuate light-induced c-Fos expression in the SCN. Thus, in contrast to the thalamocortical projections of the primary visual system, retinohypothalamic projections terminating in the SCN develop into normal adult patterns and mediate circadian responses to light largely independent of light experience during development. The data identify a categorical difference in the requirement for light input during postnatal development between circadian and non-circadian visual systems.

  16. The circadian clock regulates auxin signaling and responses in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Michael F Covington

    2007-08-01

    Full Text Available The circadian clock plays a pervasive role in the temporal regulation of plant physiology, environmental responsiveness, and development. In contrast, the phytohormone auxin plays a similarly far-reaching role in the spatial regulation of plant growth and development. Went and Thimann noted 70 years ago that plant sensitivity to auxin varied according to the time of day, an observation that they could not explain. Here we present work that explains this puzzle, demonstrating that the circadian clock regulates auxin signal transduction. Using genome-wide transcriptional profiling, we found many auxin-induced genes are under clock regulation. We verified that endogenous auxin signaling is clock regulated with a luciferase-based assay. Exogenous auxin has only modest effects on the plant clock, but the clock controls plant sensitivity to applied auxin. Notably, we found both transcriptional and growth responses to exogenous auxin are gated by the clock. Thus the circadian clock regulates some, and perhaps all, auxin responses. Consequently, many aspects of plant physiology not previously thought to be under circadian control may show time-of-day-specific sensitivity, with likely important consequences for plant growth and environmental responses.

  17. Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease.

    Science.gov (United States)

    van Wamelen, Daniel J; Roos, Raymund Ac; Aziz, Nasir A

    2015-12-01

    Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.

  18. Toxicity of perfluorooctane sulfonate and perfluorooctanoic acid to Escherichia coli: Membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death.

    Science.gov (United States)

    Liu, Gesheng; Zhang, Shuai; Yang, Kun; Zhu, Lizhong; Lin, Daohui

    2016-07-01

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two widely used polyfluorinated compounds (PFCs) and are persistent in the environment. This study for the first time systematically investigated their toxicities and the underlying mechanisms to Escherichia coli. Much higher toxicity was observed for PFOA than PFOS, with the 3 h half growth inhibition concentrations (IC50) determined to be 10.6 ± 1.0 and 374 ± 3 mg L(-1), respectively, while the bacterial accumulation of PFOS was much greater than that of PFOA. The PFC exposures disrupted cell membranes as evidenced by the dose-dependent variations of cell structures (by transmission electron microscopy observations), surface properties (electronegativity, hydrophobicity, and membrane fluidity), and membrane compositions (by gas chromatogram and Fourier transform infrared spectroscopy analyses). The increases in the contents of intracellular reactive oxygen species (ROS) and malondialdehyde and the activity of superoxide dismutase indicated the increment of oxidative stress induced by the PFCs in the bacterial cells. The fact that the cell growth inhibition was mitigated by the addition of ROS scavenger (N-acetyl cysteine) further evidenced the important role of oxidative damage in the toxicities of PFOS and PFOA. Eighteen genes involved in cell division, membrane instability, oxidative stress, and DNA damage of the exposed cells were up or down expressed, indicating the DNA damage by the PFCs. The toxicities of PFOS and PFOA to E. coli were therefore ascribed to the membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death. The difference in the bactericidal effect between PFOS and PFOA was supposed to be related to their different dominating toxicity mechanisms, i.e., membrane disruption and oxidative damage, respectively. The outcomes will shed new light on the assessment of ecological effects of PFCs. PMID:27155098

  19. Tualang Honey Protects against BPA-Induced Morphological Abnormalities and Disruption of ERα, ERβ, and C3 mRNA and Protein Expressions in the Uterus of Rats

    Directory of Open Access Journals (Sweden)

    Siti Sarah Mohamad Zaid

    2015-01-01

    Full Text Available Bisphenol A (BPA is an endocrine disrupting chemical (EDC that can disrupt the normal functions of the reproductive system. The objective of the study is to investigate the potential protective effects of Tualang honey against BPA-induced uterine toxicity in pubertal rats. The rats were administered with BPA by oral gavage over a period of six weeks. Uterine toxicity in BPA-exposed rats was determined by the degree of the morphological abnormalities, increased lipid peroxidation, and dysregulated expression and distribution of ERα, ERβ, and C3 as compared to the control rats. Concurrent treatment of rats with BPA and Tualang honey significantly improved the uterine morphological abnormalities, reduced lipid peroxidation, and normalized ERα, ERβ, and C3 expressions and distribution. There were no abnormal changes observed in rats treated with Tualang honey alone, comparable with the control rats. In conclusion, Tualang honey has potential roles in protecting the uterus from BPA-induced toxicity, possibly accounted for by its phytochemical properties.

  20. Circadian clock proteins control adaptation to novel environment and memory formation

    Science.gov (United States)

    A.Kondratova, Anna; V.Dubrovsky, Yuliya; Antoch, Marina P.; Kondratov, Roman V.

    2010-01-01

    Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning. PMID:20519775

  1. Phone phobia, phact or phantasy? An operant approach to a child's disruptive behavior induced by telephone usage.

    Science.gov (United States)

    Babbitt, R L; Parrish, J M

    1991-06-01

    The clinical efficacy of a contingency management program for treating a developmentally disabled girl referred for telephone phobia was evaluated using both a multiple baseline across settings design and a reversal design. A descriptive analysis indicated that the 'phobia' was in all probability an operant, rather than a respondent. The treatment, consisting of differential reinforcement, extinction and time-out, was effective in reducing the frequency and intensity of disruptive behaviors in response to telephone usage. Follow-up assessments at 1, 3, and 6 months revealed that treatment gains were maintained.

  2. ROS stress resets circadian clocks to coordinate pro-survival signals.

    Directory of Open Access Journals (Sweden)

    Teruya Tamaru

    Full Text Available Dysfunction of circadian clocks exacerbates various diseases, in part likely due to impaired stress resistance. It is unclear how circadian clock system responds toward critical stresses, to evoke life-protective adaptation. We identified a reactive oxygen species (ROS, H2O2 -responsive circadian pathway in mammals. Near-lethal doses of ROS-induced critical oxidative stress (cOS at the branch point of life and death resets circadian clocks, synergistically evoking protective responses for cell survival. The cOS-triggered clock resetting and pro-survival responses are mediated by transcription factor, central clock-regulatory BMAL1 and heat shock stress-responsive (HSR HSF1. Casein kinase II (CK2 -mediated phosphorylation regulates dimerization and function of BMAL1 and HSF1 to control the cOS-evoked responses. The core cOS-responsive transcriptome includes CK2-regulated crosstalk between the circadian, HSR, NF-kappa-B-mediated anti-apoptotic, and Nrf2-mediated anti-oxidant pathways. This novel circadian-adaptive signaling system likely plays fundamental protective roles in various ROS-inducible disorders, diseases, and death.

  3. Relationships between the circadian system and Alzheimer's disease-like symptoms in Drosophila.

    Directory of Open Access Journals (Sweden)

    Dani M Long

    Full Text Available Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD, are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01. No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism.

  4. Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal.

    Science.gov (United States)

    Putker, Marrit; O'Neill, John Stuart

    2016-01-01

    Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redox-sensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian time-keeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological time-keeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.

  5. Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements

    Science.gov (United States)

    Torres, Manon; Becquet, Denis; Blanchard, Marie-Pierre; Guillen, Séverine; Boyer, Bénédicte; Moreno, Mathias; Franc, Jean-Louis; François-Bellan, Anne-Marie

    2016-01-01

    Paraspeckles are nuclear bodies form around the long non-coding RNA, Neat1, and RNA-binding proteins. While their role is not fully understood, they are believed to control gene expression at a post-transcriptional level by means of the nuclear retention of mRNA containing in their 3’-UTR inverted repeats of Alu sequences (IRAlu). In this study, we found that, in pituitary cells, all components of paraspeckles including four major proteins and Neat1 displayed a circadian expression pattern. Furthermore the insertion of IRAlu at the 3’-UTR of the EGFP cDNA led to a rhythmic circadian nuclear retention of the egfp mRNA that was lost when paraspeckles were disrupted whereas insertion of a single antisense Alu had only a weak effect. Using real-time video-microscopy, these IRAlu were further shown to drive a circadian expression of EGFP protein. This study shows that paraspeckles, thanks to their circadian expression, control circadian gene expression at a post-transcriptional level. DOI: http://dx.doi.org/10.7554/eLife.14837.001 PMID:27441387

  6. Pet-1 deficiency alters the circadian clock and its temporal organization of behavior.

    Directory of Open Access Journals (Sweden)

    Christopher M Ciarleglio

    Full Text Available The serotonin and circadian systems are two important interactive regulatory networks in the mammalian brain that regulate behavior and physiology in ways that are known to impact human mental health. Previous work on the interaction between these two systems suggests that serotonin modulates photic input to the central circadian clock (the suprachiasmatic nuclei; SCN from the retina and serves as a signal for locomotor activity, novelty, and arousal to shift the SCN clock, but effects of disruption of serotonergic signaling from the raphe nuclei on circadian behavior and on SCN function are not fully characterized. In this study, we examined the effects on diurnal and circadian behavior, and on ex vivo molecular rhythms of the SCN, of genetic deficiency in Pet-1, an ETS transcription factor that is necessary to establish and maintain the serotonergic phenotype of raphe neurons. Pet-1⁻/⁻ mice exhibit loss of rhythmic behavioral coherence and an extended daily activity duration, as well as changes in the molecular rhythms expressed by the clock, such that ex vivo SCN from Pet-1⁻/⁻ mice exhibit period lengthening and sex-dependent changes in rhythmic amplitude. Together, our results indicate that Pet-1 regulation of raphe neuron serotonin phenotype contributes to the period, precision and light/dark partitioning of locomotor behavioral rhythms by the circadian clock through direct actions on the SCN clock itself, as well as through non-clock effects.

  7. Circadian rhythms of liver physiology and disease: experimental and clinical evidence.

    Science.gov (United States)

    Tahara, Yu; Shibata, Shigenobu

    2016-04-01

    The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.

  8. Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

    Directory of Open Access Journals (Sweden)

    Chun Wang

    2014-07-01

    Full Text Available The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function.

  9. Clock is important for food and circadian regulation of macronutrient absorption in mice.

    Science.gov (United States)

    Pan, Xiaoyue; Hussain, M Mahmood

    2009-09-01

    Clock genes respond to external stimuli and exhibit circadian rhythms. This study investigated the expression of clock genes in the small intestine and their contribution in the regulation of nutrient absorption by enterocytes. We examined expression of clock genes and macronutrient transport proteins in the small intestines of wild-type and Clock mutant (Clk(mt/mt)) mice with free or limited access to food. In addition, we studied absorption of macronutrients in these mice. Intestinal clock genes show circadian expression and respond to food entrainment in wild-type mice. Dominant negative Clock in Clk(mt/mt) mice disrupts circadian expression and food entrainment of clock genes. The absorption of lipids and monosaccharides was high in Clk(mt/mt) mice whereas peptide absorption was reduced. Molecular studies revealed that Clock regulates several transport proteins involved in nutrient absorption. Clock plays an important role in light and food entrainment of intestinal functions by regulating nutrient transport proteins. Disruptions in intestinal circadian activity may contribute to hyperlipidemia and hyperglycemia.

  10. Effect of melatonin on endogenous circadian rhythm

    Institute of Scientific and Technical Information of China (English)

    XU Feng; WANG Min; ZANG Ling-he

    2008-01-01

    Objective To further authenticate the role of melatonin on endogenous biologic clock system. Methods Pinealectomized mice were used in the experiments, a series of circadian rhythm of physiology index, such as glucocorticoid, amino acid neurotransmitter, immune function, sensitivity of algesia and body temperature were measured. Results Effects of melatonin on endogenous circadian rhythm roughly appeared four forms: 1) The model of inherent rhythm was invariant, but midvalue was removed. 2) Pacing function: pinealectomy and melatonin administration changed amplitude of the circadian vibration of aspartate, peripheral blood WBC and serum hemolysin. 3) Phase of rhythm changed, such as the effects on percentage of lymphocyte and sensitivity of algesia. 4) No effect, the circadian rhythm of body temperature belong to this form Conclusions Melatonin has effects some circadian rhythm, and it can adjust endogenous inherent rhythm and make the rhythm keep step with environmental cycle. Melatonin may be a kind of Zeitgeber, Pineal gland might being a rhythm bearing organ to some circadian rhythm.

  11. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

    Science.gov (United States)

    Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

    2016-02-16

    Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders. PMID:26839413

  12. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

    Science.gov (United States)

    Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

    2016-02-16

    Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

  13. Circadian clocks are designed optimally

    CERN Document Server

    Hasegawa, Yoshihiko

    2014-01-01

    Circadian rhythms are acquired through evolution to increase the chances for survival by synchronizing to the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. Since both properties have been tuned through natural selection, their adaptation can be formalized in the framework of mathematical optimization. By using a succinct model, we found that simultaneous optimization of regularity and entrainability entails inherent features of the circadian mechanism irrespective of model details. At the behavioral level we discovered the existence of a dead zone, a time during which light pulses neither advance nor delay the clock. At the molecular level we demonstrate the role-sharing of two light inputs, phase advance and delay, as is well observed in mammals. We also reproduce the results of phase-controlling experiments and predict molecular elements responsible for the clockwork...

  14. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    Directory of Open Access Journals (Sweden)

    Astha Malik

    Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte

  15. The Drosophila melanogaster circadian pacemaker circuit

    Indian Academy of Sciences (India)

    Vasu Sheeba

    2008-12-01

    As an experimental model system, the fruit fly Drosophila melanogaster has been seminal in shaping our understanding of the circadian clockwork. The wealth of genetic tools at our disposal over the past four decades has enabled discovery of the genetic and molecular bases of circadian rhythmicity. More recently, detailed investigation leading to the anatomical, neurochemical and electrophysiological characterization of the various neuronal subgroups that comprise the circadian machinery has revealed pathways through which these neurons come together to act as a neuronal circuit. Thus the D. melanogaster circadian pacemaker circuit presents a relatively simple and attractive model for the study of neuronal circuits and their functions.

  16. Design principles underlying circadian clocks.

    OpenAIRE

    Rand, D.A.; Shulgin, B. V.; D. Salazar; Millar, A. J.

    2004-01-01

    A fundamental problem for regulatory networks is to understand the relation between form and function: to uncover the underlying design principles of the network. Circadian clocks present a particularly interesting instance, as recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. While several authors have speculated on the reasons for this, a convincing explanation is still lacking.We analyse both t...

  17. Circadian influences on myocardial infarction

    OpenAIRE

    Virag, Jitka A. I.; Lust, Robert M.

    2014-01-01

    Components of circadian rhythm maintenance, or “clock genes,” are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial...

  18. Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.

    Directory of Open Access Journals (Sweden)

    Tadakazu Okoshi

    Full Text Available Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid

  19. Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice.

    Directory of Open Access Journals (Sweden)

    Thomas E Sussan

    Full Text Available BACKGROUND: Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice (Nrf2(-/- causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis. PRINCIPAL FINDINGS: To investigate the role of Nrf2 in the development of atherosclerosis, we crossed Nrf2(-/- mice with apoliporotein E-deficient (ApoE(-/- mice. ApoE(-/- and ApoE(-/-Nrf2(-/- mice were fed an atherogenic diet for 20 weeks, and plaque area was assessed in the aortas. Surprisingly, ApoE(-/-Nrf2(-/- mice exhibited significantly smaller plaque area than ApoE(-/- controls (11.5% vs 29.5%. This decrease in plaque area observed in ApoE(-/-Nrf2(-/- mice was associated with a significant decrease in uptake of modified low density lipoproteins (AcLDL by isolated macrophages from ApoE(-/-Nrf2(-/- mice. Furthermore, atherosclerotic plaques and isolated macrophages from ApoE(-/-Nrf2(-/- mice exhibited decreased expression of the scavenger receptor CD36. CONCLUSIONS: Nrf2 is pro-atherogenic in mice, despite its antioxidative function. The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.

  20. Tight Junction Disruption Induced by Type 3 Secretion System Effectors Injected by Enteropathogenic and Enterohemorrhagic Escherichia coli.

    Science.gov (United States)

    Ugalde-Silva, Paul; Gonzalez-Lugo, Octavio; Navarro-Garcia, Fernando

    2016-01-01

    The intestinal epithelium consists of a single cell layer, which is a critical selectively permeable barrier to both absorb nutrients and avoid the entry of potentially harmful entities, including microorganisms. Epithelial cells are held together by the apical junctional complexes, consisting of adherens junctions, and tight junctions (TJs), and by underlying desmosomes. TJs lay in the apical domain of epithelial cells and are mainly composed by transmembrane proteins such as occludin, claudins, JAMs, and tricellulin, that are associated with the cytoplasmic plaque formed by proteins from the MAGUK family, such as ZO-1/2/3, connecting TJ to the actin cytoskeleton, and cingulin and paracingulin connecting TJ to the microtubule network. Extracellular bacteria such as EPEC and EHEC living in the intestinal lumen inject effectors proteins directly from the bacterial cytoplasm to the host cell cytoplasm, where they play a relevant role in the manipulation of the eukaryotic cell functions by modifying or blocking cell signaling pathways. TJ integrity depends on various cell functions such as actin cytoskeleton, microtubule network for vesicular trafficking, membrane integrity, inflammation, and cell survival. EPEC and EHEC effectors target most of these functions. Effectors encoded inside or outside of locus of enterocyte effacement (LEE) disrupt the TJ strands. EPEC and EHEC exploit the TJ dynamics to open this structure, for causing diarrhea. EPEC and EHEC secrete effectors that mimic host proteins to manipulate the signaling pathways, including those related to TJ dynamics. In this review, we focus on the known mechanisms exploited by EPEC and EHEC effectors for causing TJ disruption. PMID:27606286

  1. A circadian biosignature in the labeled release data from Mars?

    Science.gov (United States)

    Van Dongen, Hans P. A.; Miller, Joseph D.; Levin, Gilbert V.; Straat, Patricia A.

    2005-09-01

    Organisms on Earth commonly exhibit a circadian rhythm, which is synchronized to the 24-hour day-night (diurnal) cycle of the planet. However, if isolated from strong environmental time cues (e.g., light-dark, temperature, etc.), many organisms revert to a "free-running" rhythm that is close to, but significantly different from, the diurnal cycle. Such a free-running rhythm is a distinct biological feature, as it requires an endogenous pacemaker that is not just passively driven by rhythms in the environment. On Mars, a free-running rhythm (i.e., significantly different from the Martian diurnal cycle of 24.66 hours) would constitute independent proof of the presence of living organisms. Evidence for such a circadian biosignature from Mars has been sought in the data sent by the 1976 Viking Labeled Release (LR) life detection experiment . In the search for circadian rhythmicity, oscillatory fluctuations in the amount of radiolabeled gas in the headspace of the LR test cell of Viking Lander 2, test cycle 3, were studied. The cycle duration of the LR oscillations examined did not differ significantly from that of the daily cell temperature oscillations controlled ultimately by the Martian diurnal cycle. Thus, these specific LR oscillations produced no independent evidence for an endogenous biological origin. However, it was found that the amplitudes of the oscillations in the gas (presumably CO2) were greater than could be accounted for by the most likely non-biological mechanism (i.e., temperature-induced changes in soil solubility of CO2). The possibility thus remained that biological activity, synchronized to the Martian diurnal cycle, could be responsible for at least part of the oscillatory activity in the LR signals. We now propose to consider all data from the nine active and control cycles of the Martian LR experiment. A comprehensive set of null and alternative hypotheses is proposed for statistical testing using the digitized data. Advanced, statistically

  2. Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid

    Directory of Open Access Journals (Sweden)

    Takashi Kudo

    2014-01-01

    Full Text Available Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP. We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP-treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.

  3. Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells

    Directory of Open Access Journals (Sweden)

    Zheng Hu

    2014-01-01

    Full Text Available High-risk human papillomavirus (HR-HPV has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR- associated protein system (CRISPR/Cas system, a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.

  4. The circadian system is a target and modulator of prenatal cocaine effects.

    Directory of Open Access Journals (Sweden)

    Eva H Shang

    Full Text Available BACKGROUND: Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. METHODOLOGY AND PRINCIPLE FINDINGS: Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH and neurotransmission (dopamine transporter, zDAT. Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR, demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1 and genes encoding melatonin receptors (zMelR that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily

  5. The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S.

    Science.gov (United States)

    Hayashi, Yoshinori; Koyanagi, Satoru; Kusunose, Naoki; Okada, Ryo; Wu, Zhou; Tozaki-Saitoh, Hidetoshi; Ukai, Kiyoharu; Kohsaka, Shinichi; Inoue, Kazuhide; Ohdo, Shigehiro; Nakanishi, Hiroshi

    2013-09-25

    Microglia are thought to play important roles in the maintenance of neuronal circuitry and the regulation of behavior. We found that the cortical microglia contain an intrinsic molecular clock and exhibit a circadian expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain. The genetic deletion of CatS causes mice to exhibit hyperlocomotor activity and removes diurnal variations in the synaptic activity and spine density of the cortical neurons, which are significantly higher during the dark (waking) phase than the light (sleeping) phase. Furthermore, incubation with recombinant CatS significantly reduced the synaptic activity of the cortical neurons. These results suggest that CatS secreted by microglia during the dark-phase decreases the spine density of the cortical neurons by modifying the perisynaptic environment, leading to downscaling of the synaptic strength during the subsequent light-phase. Disruption of CatS therefore induces hyperlocomotor activity due to failure to downscale the synaptic strength.

  6. Pinealectomy abolishes circadian behavior and interferes with circadian clock gene oscillations in brain and liver but not retina in a migratory songbird.

    Science.gov (United States)

    Trivedi, Amit Kumar; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod

    2016-03-15

    In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings. PMID:26801391

  7. Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast-myeloma hybrid cells

    DEFF Research Database (Denmark)

    Andersen, Thomas L; Søe, Kent; Søndergaard, Teis Esben;

    2010-01-01

    Osteolytic lesions are a hallmark of multiple myeloma. They are due to the hyperactivity of bone resorbing osteoclasts and hypoactivity of bone forming osteoblasts, in response to neighbouring myeloma cells. This study identified a structure that deeply affects this response, because of its impact...... on the physical organisation of the myeloma cell microenvironment. The proximity between myeloma cells and osteoclasts or osteoblasts was shown to be conditioned by the recently discovered layer of flat cells that separates the osteoclasts and osteoblasts from the bone marrow, by forming a canopy over bone......, this disruption and increased proximity and density of myeloma cells coincides with key myeloma-induced bone events, such as osteolytic lesions, impaired bone formation despite increased bone resorption, and fusion of myeloma cells with osteoclasts thereby forming myeloma-osteoclast hybrid cells. These findings...

  8. The octarepeat region of hamster PrP (PrP51-91) enhances the formation of microtubule and antagonize Cu~(2+)-induced microtubule-disrupting activity

    Institute of Scientific and Technical Information of China (English)

    Xiaoli Li; Chenfang Dong; Song Shi; Guirong Wang; Yuan Li; Xin Wang; Qi Shi; Chan Tian; Ruimin Zhou; Chen Gao; Xiaoping Dong

    2009-01-01

    Prion protein (PrP) is considered to associate with microtubule and its major component, tubulin. In the present study, octarepeat region of PrP (PrP51-91) was expressed in prokaryotic-expressing system. Using GST pull-down assay and co-immunoprecipitation, the mol-ecular interaction between PrP51-91 and tubulin was observed. Our data also demonstrated that PrP51-91 could efficiently stimulate microtubule assembly in vitro, indicating a potential effect of PrP on microtu-bule dynamics. Moreover, PrP51-91 was confirmed to be able to antagonize Cu~(2+)-induced microtubule-disrupt-ing activity in vivo, partially protecting against Cu~(2+) intoxication to culture cells and stabilize cellular micro-tubule structure. The association of the octarepeat region of PrP with tubulin may further provide insight into the biological function of PrP in the neurons.

  9. A circadian clock in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Eelderink-Chen, Zheng; Mazzotta, Gabriella; Sturre, Marcel; Bosman, Jasper; Roenneberg, Till; Merrow, Martha

    2010-01-01

    Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily cha

  10. A colorful model of the circadian clock.

    Science.gov (United States)

    Reppert, Steven M

    2006-01-27

    The migration of the colorful monarch butterfly provides biologists with a unique model system with which to study the cellular and molecular mechanisms underlying a sophisticated circadian clock. The monarch circadian clock is involved in the induction of the migratory state and navigation over long distances, using the sun as a compass. PMID:16439193

  11. Circadian oscillators in the mouse brain

    DEFF Research Database (Denmark)

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-01-01

    The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators resi...

  12. Arecoline induced disruption of expression and localization of the tight junctional protein ZO-1 is dependent on the HER 2 expression in human endometrial Ishikawa cells

    Directory of Open Access Journals (Sweden)

    Sundar Shyam N

    2010-07-01

    Full Text Available Abstract Background Approximately 600 million people chew Betel nut, making this practice the fourth most popular oral habit in the world. Arecoline, the major alkaloid present in betel nut is one of the causative agents for precancerous lesions and several cancers of mouth among those who chew betel nut. Arecoline can be detected in the human embryonic tissue and is correlated to low birth weight of newborns whose mothers chew betel nut during pregnancy, suggesting that arecoline can induce many systemic effects. However, few reports exist as to the effects of arecoline in human tissues other than oral cancer cell lines. Furthermore, in any system, virtually nothing is known about the cellular effects of arecoline treatment on membrane associated signaling components of human cancer cells. Results Using the human Ishikawa endometrial cancer cell line, we investigated the effects of arecoline on expression, localization and functional connections between the ZO-1 tight junction protein and the HER2 EGF receptor family member. Treatment of Ishikawa cells with arecoline coordinately down-regulated expression of both ZO-1 and HER2 protein and transcripts in a dose dependent manner. Biochemical fractionation of cells as well as indirect immunofluorescence revealed that arecoline disrupted the localization of ZO-1 to the junctional complex at the cell periphery. Compared to control transfected cells, ectopic expression of exogenous HER2 prevented the arecoline mediated down-regulation of ZO-1 expression and restored the localization of ZO-1 to the cell periphery. Furthermore, treatment with dexamethasone, a synthetic glucocorticoid reported to up-regulate expression of HER2 in Ishikawa cells, precluded arecoline from down-regulating ZO-1 expression and disrupting ZO-1 localization. Conclusion Arecoline is known to induce precancerous lesions and cancer in the oral cavity of betel nut users. The arecoline down-regulation of ZO-1 expression and

  13. The protective effect of Borago Officinalis extract on amyloid β (25-35)-induced long term potentiation disruption in the dentate gyrus of male rats.

    Science.gov (United States)

    Zargooshnia, Somayeh; Shahidi, Siamak; Ghahremanitamadon, Fatemeh; Nikkhah, Ali; Mehdizadeh, Mehdi; Soleimani Asl, Sara

    2015-02-01

    Alzheimer's disease (AD) begins with impairment in synaptic functions before developing into later neurodegeneration and neural loss. In the present study we have examined the protective effects of Borago Officinalis (borage) extract on amyloid β (Aβ)--Induced long term potentiation (LTP) disruption in hippocampal dentate gyrus (DG). Wistar male rats received intrahippocampal (IHP) injection of the Aβ (25-35) and borage extract throughout gestation (100 mg/kg). LTP in perforant path- DG synapses was assessed using electrophysiology method and field excitatory post- synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured by 400 Hz tetanization. Finally, the total thiol content of hippocampus was measured using colorimetric reaction based on the Ellman's method. The results showed that Aβ (25-35) significantly decreased fEPSP slope and SP amplitude comparing with the control and sham group, whereas borage extract administration increased these parameters compared to the Aβ group. Aβ induced a remarkable decrease in total thiol content of hippocampus and borage prevented the decrease of the hippocampal total sulfhydryl (SH) groups. This data suggest that Aβ (25-35) can effectively inhibit LTP in the granular cells of the DG in hippocampus, and borage supplementation reverse the synaptic plasticity in DG following Aβ treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction. PMID:25060965

  14. Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role in β-Cell Death in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Lucie Khemtémourian

    2008-01-01

    Full Text Available The presence of fibrillar protein deposits (amyloid of human islet amyloid polypeptide (hIAPP in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2. The mechanism of hIAPP-induced β-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of β-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer’s disease, Parkinson’s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to β-cell death in DM2.

  15. Disruption of the blood-brain interface in neonatal rat neocortex induces a transient expression of metallothionein in reactive astrocytes

    DEFF Research Database (Denmark)

    Penkowa, M; Moos, T

    1995-01-01

    Exposure of the adult rat brain parenchyma to zinc induces an increase in the intracerebral expression of the metal-binding protein, metallothionein, which is normally confined to astrocytes, ependymal cells, choroid plexus epithelial cells, and brain endothelial cells. Metallothionein is express...... induces a transient expression of metallothionein in reactive astrocytes, probably as a response to metals released from the site of the brain injury.......Exposure of the adult rat brain parenchyma to zinc induces an increase in the intracerebral expression of the metal-binding protein, metallothionein, which is normally confined to astrocytes, ependymal cells, choroid plexus epithelial cells, and brain endothelial cells. Metallothionein is expressed...... only in diminutive amounts in astrocytes of the neonatal rat brain, which could imply that neonatal rats are devoid of the capacity to detoxify free metals released from a brain wound. In order to examine the influence of a brain injury on the expression of metallothionein in the neonatal brain, PO...

  16. Circadian regulation of human cortical excitability.

    Science.gov (United States)

    Ly, Julien Q M; Gaggioni, Giulia; Chellappa, Sarah L; Papachilleos, Soterios; Brzozowski, Alexandre; Borsu, Chloé; Rosanova, Mario; Sarasso, Simone; Middleton, Benita; Luxen, André; Archer, Simon N; Phillips, Christophe; Dijk, Derk-Jan; Maquet, Pierre; Massimini, Marcello; Vandewalle, Gilles

    2016-01-01

    Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp electroencephalography (EEG) responses to transcranial magnetic stimulation in 22 participants during 29 h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that are strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlates with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homoeostasis alone. These findings have implications for clinical applications such as non-invasive brain stimulation in neurorehabilitation. PMID:27339884

  17. The circadian clock coordinates ribosome biogenesis.

    Directory of Open Access Journals (Sweden)

    Céline Jouffe

    Full Text Available Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.

  18. Poor quality of life, depressed mood, and memory impairment may be mediated by sleep disruption in patients with Addison's disease.

    Science.gov (United States)

    Henry, Michelle; Wolf, Pedro S A; Ross, Ian L; Thomas, Kevin G F

    2015-11-01

    Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. In fact, hydrocortisone replacement in AD patients likely induces disrupted sleep. Given that healthy sleep plays an important role in improving quality of life, optimizing cognition, and ensuring affect regulation, the aim of this study was to investigate whether poor quality of life, mood alterations, and memory complaints reported by AD patients are associated with their disrupted sleep patterns. Sixty patients with AD and 60 matched healthy controls completed a battery of self-report questionnaires assessing perceived physical and mental health (Short-Form 36), mood (Beck Depression Inventory-II), sleep quality (Pittsburgh Sleep Quality Index), and cognition (Cognitive Failures Questionnaire). A latent variable model revealed that although AD had a significant direct effect on quality of life, the indirect effect of sleep was significantly greater. Furthermore, although AD had no direct effect on cognitive functioning, the indirect effect of sleep was significant. The overall model showed a good fit (comparative fit index = 0.91, root mean square of approximation = 0.09, and standardized root mean square residual = 0.05). Our findings suggest that disrupted sleep, and not the disease per se, may induce poor quality of life, memory impairment, and affect dysregulation in patients with AD. We think that improving sleep architecture may improve cognitive, affective, and physical functioning. PMID:26256520

  19. Divergent roles of clock genes in retinal and suprachiasmatic nucleus circadian oscillators.

    Directory of Open Access Journals (Sweden)

    Guo-Xiang Ruan

    Full Text Available The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per 1 and 2, Cryptochrome (Cry 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN, the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC or Period1::luciferase (Per1::luc circadian reporters. Per1-, Cry1- and Clock-deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period.

  20. Differential contribution of rod and cone circadian clocks in driving retinal melatonin rhythms in Xenopus.

    Directory of Open Access Journals (Sweden)

    Naoto Hayasaka

    Full Text Available BACKGROUND: Although an endogenous circadian clock located in the retinal photoreceptor layer governs various physiological events including melatonin rhythms in Xenopus laevis, it remains unknown which of the photoreceptors, rod and/or cone, is responsible for the circadian regulation of melatonin release. METHODOLOGY/PRINCIPAL FINDINGS: We selectively disrupted circadian clock function in either the rod or cone photoreceptor cells by generating transgenic Xenopus tadpoles expressing a dominant-negative CLOCK (XCLΔQ under the control of a rod or cone-specific promoter. Eyecup culture and continuous melatonin measurement revealed that circadian rhythms of melatonin release were abolished in a majority of the rod-specific XCLΔQ transgenic tadpoles, although the percentage of arrhythmia was lower than that of transgenic tadpole eyes expressing XCLΔQ in both rods and cones. In contrast, whereas a higher percentage of arrhythmia was observed in the eyes of the cone-specific XCLΔQ transgenic tadpoles compare to wild-type counterparts, the rate was significantly lower than in rod-specific transgenics. The levels of the transgene expression were comparable between these two different types of transgenics. In addition, the average overall melatonin levels were not changed in the arrhythmic eyes, suggesting that CLOCK does not affect absolute levels of melatonin, only its temporal expression pattern. CONCLUSIONS/SIGNIFICANCE: These results suggest that although the Xenopus retina is made up of approximately equal numbers of rods and cones, the circadian clocks in the rod cells play a dominant role in driving circadian melatonin rhythmicity in the Xenopus retina, although some contribution of the clock in cone cells cannot be excluded.

  1. Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude

    NARCIS (Netherlands)

    Oranje, Bob; Gispen-de Wied, Christine C.; Westenberg, Herman G. M.; Kemner, Chantal; Verbaten, Marinus N.; Kahn, Rene S.

    2009-01-01

    Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought. B

  2. Toward a detailed computational model for the mammalian circadian clock

    Science.gov (United States)

    Leloup, Jean-Christophe; Goldbeter, Albert

    2003-06-01

    We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erb and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.

  3. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    OpenAIRE

    Ramesh Vijay; Nair Deepti; Zhang Shelley X L; Hakim Fahed; Kaushal Navita; Kayali Foaz; Wang Yang; Li Richard C; Carreras Alba; Gozal David

    2012-01-01

    Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who...

  4. The lysosomotropic drug LeuLeu-OMe induces lysosome disruption and autophagy-independent cell death in Trypanosoma brucei

    OpenAIRE

    Hazel Xinyu Koh; Htay Mon Aye; Tan, Kevin S W; He, Cynthia Y.

    2015-01-01

    Background: Trypanosoma brucei is a blood-borne, protozoan parasite that causes African sleeping sickness in humans and nagana in animals. The current chemotherapy relies on only a handful of drugs that display undesirable toxicity, poor efficacy and drug-resistance. In this study, we explored the use of lysosomotropic drugs to induce bloodstream form T. brucei cell death via lysosome destabilization. Methods: We measured drug concentrations that inhibit cell proliferation by 50% (...

  5. Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells

    OpenAIRE

    Viñas, René; WATSON, CHERYL S.

    2013-01-01

    Background Our study examines the effects of xenoestrogen mixtures on estradiol-induced non-genomic signaling and associated functional responses. Bisphenol-A, used to manufacture plastic consumer products, and nonylphenol, a surfactant, are estrogenic by a variety of assays, including altering many intracellular signaling pathways; bisphenol-S is now used as a bisphenol-A substitute. All three compounds contaminate the environment globally. We previously showed that bisphenol-S, bisphenol-A,...

  6. Evidence for Time-of-Day Dependent Effect of Neurotoxic Dorsomedial Hypothalamic Lesions on Food Anticipatory Circadian Rhythms in Rats

    OpenAIRE

    Landry, Glenn J.; Kent, Brianne A.; Patton, Danica F.; Mark Jaholkowski; Marchant, Elliott G.; Mistlberger, Ralph E.

    2011-01-01

    The dorsomedial hypothalamus (DMH) is a site of circadian clock gene and immediate early gene expression inducible by daytime restricted feeding schedules that entrain food anticipatory circadian rhythms in rats and mice. The role of the DMH in the expression of anticipatory rhythms has been evaluated using different lesion methods. Partial lesions created with the neurotoxin ibotenic acid (IBO) have been reported to attenuate food anticipatory rhythms, while complete lesions made with radiof...

  7. Effect of Modafinil on Impairments in Neurobehavioral Performance and Learning Associated with Extended Wakefulness and Circadian Misalignment

    OpenAIRE

    Grady, Scott; Aeschbach, Daniel; Wright, Kenneth P.; Czeisler, Charles A.

    2010-01-01

    Although worldwide millions of people work prolonged hours, at adverse circadian phases, evidence suggests that cognitive function is impaired under these conditions with important societal consequences. In a double-blind placebo-controlled laboratory-based study, we investigated the effect of the wakefulness-promoting drug modafinil as a countermeasure against such neurobehavioral impairments induced by both prolonged wakefulness and circadian misalignment. Neurobehavioral performance, alert...

  8. The circadian molecular clock creates epidermal stem cell heterogeneity.

    Science.gov (United States)

    Janich, Peggy; Pascual, Gloria; Merlos-Suárez, Anna; Batlle, Eduard; Ripperger, Jürgen; Albrecht, Urs; Cheng, Hai-Ying M; Obrietan, Karl; Di Croce, Luciano; Benitah, Salvador Aznar

    2011-11-09

    Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.

  9. Two Trichothecene Mycotoxins from Myrothecium roridum Induce Apoptosis of HepG-2 Cells via Caspase Activation and Disruption of Mitochondrial Membrane Potential.

    Science.gov (United States)

    Ye, Wei; Chen, Yuchan; Li, Haohua; Zhang, Weimin; Liu, Hongxin; Sun, Zhanghua; Liu, Taomei; Li, Saini

    2016-01-01

    Trichothecene mycotoxins are a type of sesquiterpenoid produced by various kinds of plantpathogenic fungi. In this study, two trichothecene toxins, namely, a novel cytotoxic epiroridin acid and a known trichothecene, mytoxin B, were isolated from the endophytic fungus Myrothecium roridum derived from the medicinal plant Pogostemon cablin. The two trichothecene mytoxins were confirmed to induce the apoptosis of HepG-2 cells by cytomorphology inspection, DNA fragmentation detection, and flow cytometry assay. The cytotoxic mechanisms of the two mycotoxins were investigated by quantitative real time polymerase chain reaction, western blot, and detection of mitochondrial membrane potential. The results showed that the two trichothecene mycotoxins induced the apoptosis of cancer cell HepG-2 via activation of caspase-9 and caspase-3, up-regulation of bax gene expression, down-regulation of bcl-2 gene expression, and disruption of the mitochondrial membrane potential of the HepG-2 cell. This study is the first to report on the cytotoxic mechanism of trichothecene mycotoxins from M. roridum. This study provides new clues for the development of attenuated trichothecene toxins in future treatment of liver cancer. PMID:27322225

  10. Disruption of the HPA-axis through corticosterone-release pellets induces robust depressive-like behavior and reduced BDNF levels in mice.

    Science.gov (United States)

    Demuyser, Thomas; Bentea, Eduard; Deneyer, Lauren; Albertini, Giulia; Massie, Ann; Smolders, Ilse

    2016-07-28

    The corticosterone mouse model is widely used in preclinical research towards a better understanding of mechanisms of major depression. One particular administration procedure is the subcutaneous implantation of corticosterone slow-release pellets. In this report we want to provide basic evidence, regarding behavioral changes, neurotransmitter and -modulator levels and some other relevant biomolecules after hypothalamic-pituitary-adrenal-axis distortion. We show that three weeks of corticosterone pellet exposure robustly induces depressive-like but not anxiety-like behavior in mice, accompanied by a significant decrease in hippocampal brain-derived neurotrophic factor levels, at five weeks after the start of treatment. Furthermore there is an overall decrease in plasma corticosterone levels after three weeks of treatment that lasts up until the five weeks' time point. On the other hand, no differences are observed in total monoamine, glutamate or d-serine levels, nor in glucocorticoid receptor expression, in various depression-related brain areas. Altogether this characterization delivers vital information, supplementary to existing literature, regarding the phenotyping of pellet-induced hypothalamic-pituitary-adrenal-axis disruption in mice following three weeks of continuous corticosterone exposure. PMID:27208833

  11. Circadian Clock Regulates Bone Resorption in Mice.

    Science.gov (United States)

    Xu, Cheng; Ochi, Hiroki; Fukuda, Toru; Sato, Shingo; Sunamura, Satoko; Takarada, Takeshi; Hinoi, Eiichi; Okawa, Atsushi; Takeda, Shu

    2016-07-01

    The circadian clock controls many behavioral and physiological processes beyond daily rhythms. Circadian dysfunction increases the risk of cancer, obesity, and cardiovascular and metabolic diseases. Although clinical studies have shown that bone resorption is controlled by circadian rhythm, as indicated by diurnal variations in bone resorption, the molecular mechanism of circadian clock-dependent bone resorption remains unknown. To clarify the role of circadian rhythm in bone resorption, aryl hydrocarbon receptor nuclear translocator-like (Bmal1), a prototype circadian gene, was knocked out specifically in osteoclasts. Osteoclast-specific Bmal1-knockout mice showed a high bone mass phenotype due to reduced osteoclast differentiation. A cell-based assay revealed that BMAL1 upregulated nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (Nfatc1) transcription through its binding to an E-box element located on the Nfatc1 promoter in cooperation with circadian locomotor output cycles kaput (CLOCK), a heterodimer partner of BMAL1. Moreover, steroid receptor coactivator (SRC) family members were shown to interact with and upregulate BMAL1:CLOCK transcriptional activity. Collectively, these data suggest that bone resorption is controlled by osteoclastic BMAL1 through interactions with the SRC family and binding to the Nfatc1 promoter. © 2016 American Society for Bone and Mineral Research. PMID:26841172

  12. Nonphotic entrainment of the human circadian pacemaker

    Science.gov (United States)

    Klerman, E. B.; Rimmer, D. W.; Dijk, D. J.; Kronauer, R. E.; Rizzo, J. F. 3rd; Czeisler, C. A.

    1998-01-01

    In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

  13. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms.

    Science.gov (United States)

    Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu; Shan, Yongli; Fan, Junmei; Izumo, Mariko; Ikeda, Yuichi; Motoike, Toshiyuki; Dixon, Shelley; Seinfeld, Jeffrey E; Takahashi, Joseph S; Yanagisawa, Masashi

    2015-03-01

    Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. PMID:25741729

  14. Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus.

    Directory of Open Access Journals (Sweden)

    Ashley N Filiano

    Full Text Available Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease. However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2 and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN. These results were confirmed in Per2(Luciferase knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to

  15. Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus.

    Science.gov (United States)

    Filiano, Ashley N; Millender-Swain, Telisha; Johnson, Russell; Young, Martin E; Gamble, Karen L; Bailey, Shannon M

    2013-01-01

    Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease). However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef) were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN). These results were confirmed in Per2(Luciferase) knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to cause steatosis

  16. Circadian rhythms of women with fibromyalgia

    Science.gov (United States)

    Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.

    2001-01-01

    Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.

  17. Characterisation of circadian rhythms of various duckweeds.

    Science.gov (United States)

    Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T

    2015-01-01

    The plant circadian clock controls various physiological phenomena that are important for adaptation to natural day-night cycles. Many components of the circadian clock have been identified in Arabidopsis thaliana, the model plant for molecular genetic studies. Recent studies revealed evolutionary conservation of clock components in green plants. Homologues of clock-related genes have been isolated from Lemna gibba and Lemna aequinoctialis, and it has been demonstrated that these homologues function in the clock system in a manner similar to their functioning in Arabidopsis. While clock components are widely conserved, circadian phenomena display diversity even within the Lemna genus. In order to survey the full extent of diversity in circadian rhythms among duckweed plants, we characterised the circadian rhythms of duckweed by employing a semi-transient bioluminescent reporter system. Using a particle bombardment method, circadian bioluminescent reporters were introduced into nine strains representing five duckweed species: Spirodela polyrhiza, Landoltia punctata, Lemna gibba, L. aequinoctialis and Wolffia columbiana. We then monitored luciferase (luc+) reporter activities driven by AtCCA1, ZmUBQ1 or CaMV35S promoters under entrainment and free-running conditions. Under entrainment, AtCCA1::luc+ showed similar diurnal rhythms in all strains. This suggests that the mechanism of biological timing under day-night cycles is conserved throughout the evolution of duckweeds. Under free-running conditions, we observed circadian rhythms of AtCCA1::luc+, ZmUBQ1::luc+ and CaMV35S::luc+. These circadian rhythms showed diversity in period length and sustainability, suggesting that circadian clock mechanisms are somewhat diversified among duckweeds. PMID:24942699

  18. Disruption of dopamine D1 receptor phosphorylation at serine 421 attenuates cocaine-induced behaviors in mice.

    Science.gov (United States)

    Zhang, Ying; Wang, Ning; Su, Ping; Lu, Jie; Wang, Yun

    2014-12-01

    Dopamine D1 receptors (D1Rs) play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1R in the forebrain. These transgenic mice showed reduced phospho-D1R (S421) and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders. PMID:25304015

  19. Circadian Rhythm Regulates Development of Enamel in Mouse Mandibular First Molar

    Science.gov (United States)

    Tao, Jiang; Zhai, Yue; Park, Hyun; Han, Junli; Dong, Jianhui; Xie, Ming; Gu, Ting; Lewi, Keidren; Ji, Fang; Jia, William

    2016-01-01

    Rhythmic incremental growth lines and the presence of melatonin receptors were discovered in tooth enamel, suggesting possible role of circadian rhythm. We therefore hypothesized that circadian rhythm may regulate enamel formation through melatonin receptors. To test this hypothesis, we examined expression of melatonin receptors (MTs) and amelogenin (AMELX), a maker of enamel formation, during tooth germ development in mouse. Using qRT-PCR and immunocytochemistry, we found that mRNA and protein levels of both MTs and AMELX in normal mandibular first molar tooth germs increased gradually after birth, peaked at 3 or 4 day postnatal, and then decreased. Expression of MTs and AMELX by immunocytochemistry was significantly delayed in neonatal mice raised in all-dark or all-light environment as well as the enamel development. Furthermore, development of tooth enamel was also delayed showing significant immature histology in those animals, especially for newborn mice raised in all daylight condition. Interestingly, disruption in circadian rhythm in pregnant mice also resulted in delayed enamel development in their babies. Treatment with melatonin receptor antagonist 4P-PDOT in pregnant mice caused underexpression of MTs and AMELX associated with long-lasting deficiency in baby enamel tissue. Electromicroscopic evidence demonstrated increased necrosis and poor enamel mineralization in ameloblasts. The above results suggest that circadian rhythm is important for normal enamel development at both pre- and postnatal stages. Melatonin receptors were partly responsible for the regulation. PMID:27494172

  20. Circadian metabolic regulation through crosstalk between casein kinase 1δ and transcriptional coactivator PGC-1α.

    Science.gov (United States)

    Li, Siming; Chen, Xiao-Wei; Yu, Lei; Saltiel, Alan R; Lin, Jiandie D

    2011-12-01

    Circadian clock coordinates behavior and physiology in mammals in response to light and feeding cycles. Disruption of normal clock function is associated with increased risk for cardiovascular and metabolic diseases, underscoring the emerging concept that temporal regulation of tissue metabolism is a fundamental aspect of energy homeostasis. We have previously demonstrated that transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), coordinates circadian metabolic rhythms through simultaneous regulation of metabolic and clock gene expression. In this study, we found that PGC-1α physically interacts with, and is phosphorylated by, casein kinase 1δ (CK1δ), a core component of the circadian pacemaker. CK1δ represses the transcriptional function of PGC-1α in cultured hepatocytes, resulting in decreased gluconeogenic gene expression and glucose secretion. At the molecular level, CK1δ phosphorylation of PGC-1α within its arginine/serine-rich domain enhances its degradation through the proteasome system. Together, these results elucidate a novel mechanism through which circadian pacemaker transduces timing signals to the metabolic regulatory network that controls hepatic energy metabolism.

  1. Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth

    Directory of Open Access Journals (Sweden)

    Celine eFeillet

    2015-05-01

    Full Text Available Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumour growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.

  2. Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth

    Science.gov (United States)

    Feillet, Celine; van der Horst, Gijsbertus T. J.; Levi, Francis; Rand, David A.; Delaunay, Franck

    2015-01-01

    Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer. PMID:26029155

  3. Basic sleep and circadian science as building blocks for behavioral interventions: a translational approach for mood disorders.

    Science.gov (United States)

    Asarnow, Lauren D; Soehner, Adriane M; Harvey, Allison G

    2014-06-01

    Sleep and circadian functioning has been of particular interest to researchers focused on improving treatments for psychiatric illness. The goal of the present paper is to highlight the exciting research that utilizes basic sleep and circadian science as building blocks for intervention in the mood disorders. The reviewed evidence suggests that the sleep and circadian systems are a) disrupted in the mood disorders and linked to symptoms, b) open systems that can be modified, c) the focus of interventions which have been developed to effectively treat sleep disturbance within mood disorders, and d) intimately linked with mood, such that improvements in sleep are associated with improvements in mood. Although significant positive treatment effects are evident, more research is needed to fill the gap in our basic understanding of the relationship between sleep and mood. PMID:24773429

  4. Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model

    DEFF Research Database (Denmark)

    Amrutkar, Manoj; Cansby, Emmelie; Chursa, Urszula;

    2015-01-01

    Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator...... of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia...... and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25−/− mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid...

  5. Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

    Directory of Open Access Journals (Sweden)

    Xu L

    2015-09-01

    Full Text Available Liming Xu,1,2,* Mo Dan,1,* Anliang Shao,1 Xiang Cheng,1,3 Cuiping Zhang,4 Robert A Yokel,5 Taro Takemura,6 Nobutaka Hanagata,6 Masami Niwa,7,8 Daisuke Watanabe7,81National Institutes for Food and Drug Control, No 2, Temple of Heaven, Beijing, 2School of Information and Engineering, Wenzhou Medical University, Wenzhou, 3School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 4Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 5College of Pharmacy, University of Kentucky, Lexington, KY, USA; 6Nanotechnology Innovation Station for Nanoscale Science and Technology, National Institute for Materials Science, Tsukuba, Ibaraki, 7Department of Pharmacology, Nagasaki University, 8BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, Japan*These authors contributed equally to this workBackground: Silver nanoparticles (Ag-NPs can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB and the underlying mechanism(s of action on the BBB and the brain are not well understood.Method: To investigate Ag-NP suspension (Ag-NPS-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM. Global gene expression of astrocytes was measured using a DNA microarray.Results: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the

  6. Neurobiological disruptions induced in brains of the rats fed with mercury contaminated rice collected from experimental fields in Guizhou Province, China

    Institute of Scientific and Technical Information of China (English)

    CHENG Jinping; YUAN Tao; YANG Liu; HU Weixuan; ZHENG Min; WANG Wenhua; LIU Xiaojie; QU Liya

    2005-01-01

    Guizhou Province, located in the southwestern China, is an important mercury (Hg) production center. High levels of Hg were found in local environmental and biomass samples. The neurobiological disruptions induced in brains of rats fed with Hg polluted rice collected from two experimental plots in Guizhou Province were studied. The plots are close to the Hg mine of Wanshang area and a chemical plant (where Hg is used as a catalyst for the production of acetaldehyde) of Qingzhen area. Rats were fed for 30 d before toxicological end points were tested. The results showed that the accumulations of Hg in rat's brain of Qingzhen chemical plant group and Wanshang mine group were significantly higher than those of Shanghai group (control group) (P<0.01). The neural transmitters, including acetylcholine (Ach), acetylcholine enzyme (AchE), nitric oxide and nitricoxide synthase (NOS), in rat's brain were significantly affected. Oxidative stress was observed in the exposure groups. The expression levels of the immediately early gene (IEG), c-fos and c-FOS proteins were induced by the Hg polluted rice. It was noted that the IEG (c-fos) participated in the neurotoxic process induced by the Hg polluted rice. IEG response to Hg might be dependent on interactions between neural transmitter and oxidative damage. c-fos could be used as an effective index of detecting and assessing the neurotoxicity of Hg. The results suggested that it should be alert to mental health problem in human beings eating Hg-polluted food. More efforts are necessary to protect the local ecosystem and human health in the Hg polluted areas such as Wangshan and Qingzhen in Guizhou Province of China.

  7. Disruption of BSEP Function in HepaRG Cells Alters Bile Acid Disposition and Is a Susceptive Factor to Drug-Induced Cholestatic Injury.

    Science.gov (United States)

    Qiu, Xi; Zhang, Yueping; Liu, Tongtong; Shen, Hong; Xiao, Yongling; Bourner, Maureen J; Pratt, Jennifer R; Thompson, David C; Marathe, Punit; Humphreys, W Griffith; Lai, Yurong

    2016-04-01

    In the present study, we characterized in vitro biosynthesis and disposition of bile acids (BAs) as well as hepatic transporter expression followed by ABCB11 (BSEP) gene knockout in HepaRG cells (HepaRG-KO cells). BSEP KO in HepaRG cells led to time-dependent BA accumulation, resulting in reduced biosynthesis of BAs and altered BA disposition. In HepaRG-KO cells, the expression of NTCP, OATP1B1, OATP2B1, BCRP, P-gp, and MRP2 were reduced, whereas MRP3 and OCT1 were up-regulated. As a result, BSEP KO altered the disposition of BAs and subsequently underwent adaptive regulations of BA synthesis and homeostasis to enable healthy growth of the cells. Although BSEP inhibitors caused no or slight increase of BAs in HepaRG wild type cells (HepaRG-WT cells), excessive intracellular accumulation of BAs was observed in HepaRG-KO cells exposed to bosentan and troglitazone, but not dipyridamole. LDH release in the medium was remarkably increased in HepaRG-KO cultures exposed to troglitazone (50 μM), suggesting drug-induced cellular injury. The results revealed that functional impairment of BSEP predisposes the cells to altered BA disposition and is a susceptive factor to drug-induced cholestatic injury. In total, BSEP inhibition might trigger the processes but is not a sole determinant of cholestatic cellular injury. As intracellular BA accumulation is determined by BSEP function and the subsequent adaptive gene regulation, assessment of intracellular BA accumulation in HepaRG-KO cells could be a useful approach to evaluate drug-induced liver injury (DILI) potentials of drugs that could disrupt other BA homeostasis pathways beyond BSEP inhibition. PMID:26910619

  8. Acute myocardial infarction and infarct size: do circadian variations play a role?

    Directory of Open Access Journals (Sweden)

    Ibáñez B

    2012-08-01

    Full Text Available Aída Suárez-Barrientos,1 Borja Ibáñez1,21Cardiovascular Institute, Hospital Clínico San Carlos, 2Centro Nacional de Investigaciones Cardiovasculares, Madrid, SpainAbstract: The circadian rhythm influences cardiovascular system physiology, inducing diurnal variations in blood pressure, heart rate, cardiac output, endothelial functions, platelet aggregation, and coronary arterial flow, among other physiological parameters. Indeed, an internal circadian network modulates cardiovascular physiology by regulating heart rate, metabolism, and even myocyte growth and repair ability. Consequently, cardiovascular pathology is also controlled by circadian oscillations, with increased morning incidence of cardiovascular events. The potential circadian influence on the human tolerance to ischemia/reperfusion has not been systematically scrutinized until recently. It has since been proven, in both animals and humans, that infarct size varies during the day depending on the symptom onset time, while circadian fluctuations in spontaneous cardioprotection in humans with ST-segment elevation myocardial infarction (STEMI have also been demonstrated. Furthermore, several studies have proposed that the time of day at which revascularization occurs in patients with STEMI may also influence infarct size and reperfusion outcomes. The potential association of the circadian clock with infarct size advocates the acknowledgment of time of day as a new prognostic factor in patients suffering acute myocardial infarction, which would open up a new field for chronotherapeutic targets and lead to the inclusion of time of day as a variable in clinical trials that test novel cardioprotective strategies.Keywords: cardioprotection, circadian rhythm, reperfusion injury, ST-segment elevation myocardial infarction

  9. The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity.

    Science.gov (United States)

    Plikus, Maksim V; Van Spyk, Elyse N; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S; Andersen, Bogi

    2015-06-01

    Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration: the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell type-specific circadian mutants. Also, due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Skin also provides opportunities to interrogate the clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model

  10. The output signal of Purkinje cells of the cerebellum and circadian rhythmicity.

    Directory of Open Access Journals (Sweden)

    Jérôme Mordel

    Full Text Available Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.

  11. The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila.

    Directory of Open Access Journals (Sweden)

    Elizabeth F Stone

    2012-01-01

    Full Text Available Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim and Period (Per are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load or tolerance (endurance of the pathogenic effects of infection. Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim-independent; moreover, infection-induced AMP gene expression is not circadian-regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis can have significant effects on long-term survival of infection.

  12. Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington's Disease.

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    Dika A Kuljis

    Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHD males, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differences are associated with a smaller suprachiasmatic nucleus (SCN in BACHD male mice at age of symptom onset (3 months, but are not associated with sex-specific differences in SCN daytime electrical activity deficits, or peptide expression (arginine vasopressin, vasoactive intestinal peptide within the SCN. Notably, BACHD females exhibited delayed motor coordination deficits, as measured using rotarod and challenge beam. These findings suggest a sex specific factor plays a role both in non-motor and motor symptom progression for the BACHD mouse.

  13. Darinaparsin is a multivalent chemotherapeutic which induces incomplete stress response with disruption of microtubules and Shh signaling.

    Directory of Open Access Journals (Sweden)

    Twila A Mason

    Full Text Available Chemotherapeutics and other pharmaceuticals are common sources of cellular stress. Darinaparsin (ZIO-101 is a novel organic arsenical under evaluation as a cancer chemotherapeutic, but the drug's precise mechanism of action is unclear. Stress granule formation is an important cellular stress response, but the mechanisms of formation, maintenance, and dispersal of RNA-containing granules are not fully understood. During stress, small, diffuse granules initially form throughout the cytoplasm. These granules then coalesce near the nucleus into larger granules that disperse once the cellular stress is removed. Complete stress granule formation is dependent upon microtubules. Human cervical cancer (HeLa cells, pre-treated with nocodazole for microtubule depolymerization, formed only small, diffuse stress granules upon sodium arsenite treatment. Darinaparsin, as a single agent, also induced the formation of small, diffuse stress granules, an effect similar to that of the combination of nocodazole with sodium arsenite. Darinaparsin inhibited the polymerization of microtubules both in vivo and in vitro. Interestingly, upon removal of darinaparsin, the small, diffuse stress granules completed formation with coalescence in the perinuclear region prior to disassembly. These results indicate that RNA stress granules must complete formation prior to disassembly, and completion of stress granule formation is dependent upon microtubules. Finally, treatment of cells with darinaparsin led to a reduction in Sonic hedgehog (Shh stimulated activation of Gli1 and a loss of primary cilia. Therefore, darinaparsin represents a unique multivalent chemotherapeutic acting on stress induction, microtubule polymerization, and Shh signaling.

  14. Radiation-induced reduction of the glial population during development disrupts the formation of olfactory glomeruli in an insect

    Energy Technology Data Exchange (ETDEWEB)

    Oland, L.A.; Tolbert, L.P.; Mossman, K.L.

    1988-01-01

    Interactions between neurons and between neurons and glial cells have been shown by a number of investigators to be critical for normal development of the nervous system. In the olfactory system of Manduca sexta, sensory axons have been shown to induce the formation of synaptic glomeruli in the antennal lobe of the brain. Oland and Tolbert (1987) found that the growth of sensory axons into the developing antennal lobe causes changes in glial shape and disposition that presage the establishment of glomeruli, each surrounded by a glial envelope. Several lines of evidence lead us to hypothesize that the glial cells of the lobe may be acting as intermediaries in developmental interactions between sensory axons and neurons of the antennal lobe. In the present study, we have tested this hypothesis by using gamma-radiation to reduce the number of glial cells at a time when neurons of the antennal system are postmitotic but glomeruli have not yet developed. When glial numbers are severely reduced, the neuropil of the resulting lobe lacks glomeruli. Despite the presence of afferent axons, the irradiated lobe has many of the features of a lobe that developed in the absence of afferent axons. Our findings indicate that the glial cells must play a necessary role in the inductive influence of the afferent axons.

  15. Heat-induced phytohormone changes are associated with disrupted early reproductive development and reduced yield in rice

    Science.gov (United States)

    Wu, Chao; Cui, Kehui; Wang, Wencheng; Li, Qian; Fahad, Shah; Hu, Qiuqian; Huang, Jianliang; Nie, Lixiao; Peng, Shaobing

    2016-01-01

    Heat stress causes morphological and physiological changes and reduces crop yield in rice (Oryza sativa). To investigate changes in phytohormones and their relationships with yield and other attributes under heat stress, four rice varieties (Nagina22, Huanghuazhan, Liangyoupeijiu, and Shanyou 63) were grown in pots and subjected to three high temperature treatments plus control in temperature-controlled greenhouses for 15 d during the early reproductive phase. Yield reductions in Nagina22, Huanghuazhan, and Liangyoupeijiu were attributed to reductions in spikelet fertility, spikelets per panicle, and grain weight. The adverse effects of high temperature were alleviated by application of exogenous 6-benzylaminopurine (6-BA) in the heat-susceptible Liangyoupeijiu. High temperature stress reduced active cytokinins, gibberellin A1 (GA1), and indole-3-acetic acid (IAA), but increased abscisic acid (ABA) and bound cytokinins in young panicles. Correlation analyses and application of exogenous 6-BA revealed that high temperature-induced cytokinin changes may regulate yield components by modulating the differentiation and degradation of branches and spikelets, panicle exsertion, pollen vigor, anther dehiscence, and grain size. Heat-tolerant Shanyou 63 displayed minor changes in phytohormones, panicle formation, and grain yield under high temperature compared with those of the other three varieties. These results suggest that phytohormone changes are closely associated with yield formation, and a small reduction or stability in phytohormone content is required to avoid large yield losses under heat stress. PMID:27713528

  16. γ-H2AX induced by linear alkylbenzene sulfonates is due to deoxyribonuclease-1 translocation to the nucleus via actin disruption

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xiaoxu; Toyooka, Tatsushi; Kubota, Toru; Yang, Guang; Ibuki, Yuko, E-mail: ibuki@u-shizuoka-ken.ac.jp

    2015-07-15

    Graphical abstract: - Highlights: • Non-genotoxic linear alkylbenzene sulfonates (LAS) generated γ-H2AX. • The γ-H2AX was not induced through direct LAS-induced DNA damage. • LAS weakened interactions between actin and DNase I. • Released DNase I translocated to nucleus and broke DNA strands, generating γ-H2AX. • This is a novel pathway for chemically induced γ-H2AX. - Abstract: Phosphorylation of histone H2AX (γ-H2AX) occurs following formation of DNA double strand breaks (DSBs). Other types of DNA damage also generate DSBs through DNA replication and repair, leading to the production of γ-H2AX. In the present study, we demonstrated that linear alkylbenzene sulfonates (LAS), the most widely used and non-genotoxic anionic surfactants, could generate γ-H2AX via a novel pathway. Breast adenocarcinoma MCF-7 cells were treated with five kinds of LAS with alkyl chains ranging from 10 to 14 carbon units (C{sub 10}–C{sub 14}LAS). The generation of DSBs and subsequent production of γ-H2AX increased in a manner that depended on the number of carbon units in LAS. γ-H2AX could also be generated with non-cytotoxic doses of LAS and was independent of the cell cycle, indicating the non-apoptotic and DNA replication-independent formation of DSBs. The generation of γ-H2AX could be attenuated by EGTA and ZnCl{sub 2}, deoxyribonuclease-1 (DNase I) inhibitors, as well as by the knockdown of DNase I. LAS weakened the interaction between DNase I and actin, and the enhanced release of DNase I was dependent on the number of carbon units in LAS. DNase I released by the LAS treatment translocated to the nucleus, in which DNase I attacked DNA and generated γ-H2AX. These results suggested that the LAS-induced generation of γ-H2AX could be attributed to the translocation of DNase I to the nucleus through the disruption of actin, and not to LAS-induced DNA damage.

  17. Entrainment of the Neurospora circadian clock

    NARCIS (Netherlands)

    Merrow, M; Boesl, C; Ricken, J; Messerschmitt, M; Goedel, M; Roenneberg, T

    2006-01-01

    Neurospora crassa has been systematically investigated for circadian entrainment behavior. Many aspects of synchronization can be investigated in this simple, cellular system, ranging from systematic entrainment and drivenness to masking. Clock gene expression during entrainment and entrainment with

  18. Functional conservation of clock-related genes in flowering plants: overexpression and RNA interference analyses of the circadian rhythm in the monocotyledon Lemna gibba.

    Science.gov (United States)

    Serikawa, Masayuki; Miwa, Kumiko; Kondo, Takao; Oyama, Tokitaka

    2008-04-01

    Circadian rhythms are found in organisms from cyanobacteria to plants and animals. In flowering plants, the circadian clock is involved in the regulation of various physiological phenomena, including growth, leaf movement, stomata opening, and floral transitions. Molecular mechanisms underlying the circadian clock have been identified using Arabidopsis (Arabidopsis thaliana); the functions and genetic networks of a number of clock-related genes, including CIRCADIAN CLOCK ASSOCIATED1, LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION1, GIGANTEA (GI), and EARLY FLOWERING3 (ELF3), have been analyzed. The degree to which clock systems are conserved among flowering plants, however, is still unclear. We previously isolated homologs for Arabidopsis clock-related genes from monocotyledon Lemna plants. Here, we report the physiological roles of these Lemna gibba genes (LgLHYH1, LgLHYH2, LgGIH1, and LgELF3H1) in the circadian system. We studied the effects of overexpression and RNA interference (RNAi) of these genes on the rhythmic expression of morning- and evening-specific reporters. Overexpression of each gene disrupted the rhythmicity of either or both reporters, suggesting that these four homologs can be involved in the circadian system. RNAi of each of the genes except LgLHYH2 affected the bioluminescence rhythms of both reporters. These results indicated that these homologs are involved in the circadian system of Lemna plants and that the structure of the circadian clock is likely to be conserved between monocotyledons and dicotyledons. Interestingly, RNAi of LgGIH1 almost completely abolished the circadian rhythm; because this effect appeared to be much stronger than the phenotype observed in an Arabidopsis gi loss-of-function mutant, the precise role of each clock gene may have diverged in the clock systems of Lemna and Arabidopsis. PMID:18281417

  19. Neuroanatomy of the Extended Circadian Rhythm System

    OpenAIRE

    Morin, Lawrence P

    2012-01-01

    The suprachiasmatic nucleus (SCN), site of the primary clock in the circadian rhythm system, has three major afferent connections. The most important consists of a retinohypothalamic projection through which photic information, received by classical rod/cone photoreceptors and intrinsically photoreceptive retinal ganglion cells, gains access to the clock. This information influences phase and period of circadian rhythms. The two other robust afferent projections are the median raphe serotoner...

  20. Circadian clock proteins in mood regulation

    Directory of Open Access Journals (Sweden)

    Timo ePartonen

    2015-01-01

    Full Text Available Mood regulation is known to be affected by the change of seasons. Recent research findings have suggested that mood regulation may be influenced by the function of circadian clocks. In addition, the activity of brown adipocytes has been hypothesized to contribute to mood regulation. Here, the overarching link to mood disorders might be the circadian clock protein NR1D1 (nuclear receptor subfamily 1, group D, member 1.

  1. Evolution of circadian organization in vertebrates

    Directory of Open Access Journals (Sweden)

    M. Menaker

    1997-03-01

    Full Text Available Circadian organization means the way in which the entire circadian system above the cellular level is put together physically and the principles and rules that determine the interactions among its component parts which produce overt rhythms of physiology and behavior. Understanding this organization and its evolution is of practical importance as well as of basic interest. The first major problem that we face is the difficulty of making sense of the apparently great diversity that we observe in circadian organization of diverse vertebrates. Some of this diversity falls neatly into place along phylogenetic lines leading to firm generalizations: i in all vertebrates there is a "circadian axis" consisting of the retinas, the pineal gland and the suprachiasmatic nucleus (SCN, ii in many non-mammalian vertebrates of all classes (but not in any mammals the pineal gland is both a photoreceptor and a circadian oscillator, and iii in all non-mammalian vertebrates (but not in any mammals there are extraretinal (and extrapineal circadian photoreceptors. An interesting explanation of some of these facts, especially the differences between mammals and other vertebrates, can be constructed on the assumption that early in their evolution mammals passed through a "nocturnal bottleneck". On the other hand, a good deal of the diversity among the circadian systems of vertebrates does not fall neatly into place along phylogenetic lines. In the present review we will consider how we might better understand such "phylogenetically incoherent" diversity and what sorts of new information may help to further our understanding of the evolution of circadian organization in vertebrates

  2. Circadian Gene Networks In Bone Regeneration

    OpenAIRE

    Hassan, Nathaniel

    2012-01-01

    BACKGROUND: Previous studies suggested that vitamin D played a significant role in bone regeneration, facilitating the establishment of implant osseointegration. A whole genome microarray study further suggested that the vitamin D axis might involve circadian rhythm gene expression in the bone peripheral tissue.OBJECTIVES: To identify key gene networks involved with vitamin D receptor in the bone regeneration process and to explore any correlation with circadian rhythm gene expression in bone...

  3. Acute and phase-shifting effects of ocular and extraocular light in human circadian physiology

    NARCIS (Netherlands)

    Ruger, M; Gordijn, MCM; Beersma, DGM; de Vries, B; Daan, S

    2003-01-01

    Light can influence physiology and performance of humans in two distinct ways. It can acutely change the level of physiological and behavioral parameters, and it can induce a phase shift in the circadian oscillators underlying variations in these levels. Until recently, both effects were thought to

  4. Circadian phase resetting in response to light-dark and dark-light transitions

    NARCIS (Netherlands)

    Comas, M.; Beersma, D. G. M.; Hut, R. A.; Daan, S.

    2008-01-01

    Phase shifting of circadian systems by light has been attributed both to parametric effects on angular velocity elicited by a tonic response to the luminance level and to nonparametric instantaneous shifts induced by a phasic response to the dark-light (D>L) and light-dark (L>D) transitions. Claims

  5. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila.

    Science.gov (United States)

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-08-31

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species.

  6. The Effects of Kidney Transplantation on Sleep, Melatonin, Circadian Rhythm and Quality of Life in Kidney Transplant Recipients and Living Donors

    NARCIS (Netherlands)

    Russcher, Marije; Nagtegaal, J. Elsbeth; Nurmohamed, S. Azam; Koch, Birgit C. P.; van der Westerlaken, Monique M. L.; van Someren, Eus J. W.; Bakker, Stephan J. L.; ter Wee, Pieter M.; Gaillard, Carlo A. J. M.

    2015-01-01

    Background: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal

  7. The effects of kidney transplantation on sleep, melatonin, circadian rhythm and quality of life in kidney transplant recipients and living donors

    NARCIS (Netherlands)

    Russcher, Marije; Nagtegaal, J Elsbeth; Nurmohamed, S Azam; Koch, Birgit C P; van der Westerlaken, Monique M L; van Someren, Eus J W; Bakker, Stephan J L; Ter Wee, Pieter M; Gaillard, Carlo A J M

    2015-01-01

    BACKGROUND: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal

  8. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  9. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy. PMID:26886341

  10. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light

    Science.gov (United States)

    Boivin, D. B.; Czeisler, C. A.

    1998-01-01

    The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p < or = 0.003). After light-induced phase advances, the circadian rhythms of plasma melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.

  11. [Impact of age-related cataract on regulation of circadian rhythm in elderly].

    Science.gov (United States)

    Wang, M S; Liu, M Y; Dong, X R; Wang, W

    2016-04-11

    This review presented an introduction of the visual pathway related circadian rhythm regulation system: the intrinsically photosensitive retinal ganglion cells-suprachiasmatic nucleus-pineal gland-melatonin axis, and discussed the impact of light with different wave length and irradiation received by retina on circadian rhythm and sleep habit. A hypothesis was proposed consequently that the high morbidity of sleep disorder in elderly might be partially attributable to the long-term blue light blocking status induced by age-related cataract. A number of relative literatures were reviewed and a novel research direction was advanced on improving circadian rhythm and sleep condition in elderly based on the current knowledge. (Chin J Ophthalmol, 2016, 52: 309-314). PMID:27094070

  12. Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease.

    Science.gov (United States)

    Richardson, Katie; Livieratos, Achilleas; Dumbill, Richard; Hughes, Steven; Ang, Gauri; Smith, David A; Morris, Lauren; Brown, Laurence A; Peirson, Stuart N; Platt, Frances M; Davies, Kay E; Oliver, Peter L

    2016-01-15

    Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1(nih)) and Sandhoff (Hexb knockout, Hexb(-/-)) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb(-/-) mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1(nih) mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level. PMID:26467605

  13. Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease

    Science.gov (United States)

    Richardson, Katie; Livieratos, Achilleas; Dumbill, Richard; Hughes, Steven; Ang, Gauri; Smith, David A.; Morris, Lauren; Brown, Laurence A.; Peirson, Stuart N.; Platt, Frances M.; Davies, Kay E.; Oliver, Peter L.

    2016-01-01

    Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1nih) and Sandhoff (Hexb knockout, Hexb−/−) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb−/− mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1nih mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level. PMID:26467605

  14. Cloning of the Koi Herpesvirus Genome as an Infectious Bacterial Artificial Chromosome Demonstrates That Disruption of the Thymidine Kinase Locus Induces Partial Attenuation in Cyprinus carpio koi▿

    Science.gov (United States)

    Costes, B.; Fournier, G.; Michel, B.; Delforge, C.; Raj, V. Stalin; Dewals, B.; Gillet, L.; Drion, P.; Body, A.; Schynts, F.; Lieffrig, F.; Vanderplasschen, A.

    2008-01-01

    Koi herpesvirus (KHV) is the causative agent of a lethal disease in koi and common carp. In the present study, we describe the cloning of the KHV genome as a stable and infectious bacterial artificial chromosome (BAC) clone that can be used to produce KHV recombinant strains. This goal was achieved by the insertion of a loxP-flanked BAC cassette into the thymidine kinase (TK) locus. This insertion led to a BAC plasmid that was stably maintained in bacteria and was able to regenerate virions when permissive cells were transfected with the plasmid. Reconstituted virions free of the BAC cassette but carrying a disrupted TK locus (the FL BAC-excised strain) were produced by the transfection of Cre recombinase-expressing cells with the BAC. Similarly, virions with a wild-type revertant TK sequence (the FL BAC revertant strain) were produced by the cotransfection of cells with the BAC and a DNA fragment encoding the wild-type TK sequence. Reconstituted recombinant viruses were compared to the wild-type parental virus in vitro and in vivo. The FL BAC revertant strain and the FL BAC-excised strain replicated comparably to the parental FL strain. The FL BAC revertant strain induced KHV infection in koi carp that was indistinguishable from that induced by the parental strain, while the FL BAC-excised strain exhibited a partially attenuated phenotype. Finally, the usefulness of the KHV BAC for recombination studies was demonstrated by the production of an ORF16-deleted strain by using prokaryotic recombination technology. The availability of the KHV BAC is an important advance that will allow the study of viral genes involved in KHV pathogenesis, as well as the production of attenuated recombinant candidate vaccines. PMID:18337580

  15. Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation.

    Science.gov (United States)

    Zika, Eleni; Greer, Susanna F; Zhu, Xin-Sheng; Ting, Jenny P-Y

    2003-05-01

    The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-gamma) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-gamma-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-gamma- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs.

  16. Parvin overexpression uncovers tissue-specific genetic pathways and disrupts F-actin to induce apoptosis in the developing epithelia in Drosophila.

    Directory of Open Access Journals (Sweden)

    Maria Chountala

    Full Text Available Parvin is a putative F-actin binding protein important for integrin-mediated cell adhesion. Here we used overexpression of Drosophila Parvin to uncover its functions in different tissues in vivo. Parvin overexpression caused major defects reminiscent of metastatic cancer cells in developing epithelia, including apoptosis, alterations in cell shape, basal extrusion and invasion. These defects were closely correlated with abnormalities in the organization of F-actin at the basal epithelial surface and of integrin-matrix adhesion sites. In wing epithelium, overexpressed Parvin triggered increased Rho1 protein levels, predominantly at the basal side, whereas in the developing eye it caused a rough eye phenotype and severely disrupted F-actin filaments at the retina floor of pigment cells. We identified genes that suppressed these Parvin-induced dominant effects, depending on the cell type. Co-expression of both ILK and the apoptosis inhibitor DIAP1 blocked Parvin-induced lethality and apoptosis and partially ameliorated cell delamination in epithelia, but did not rescue the elevated Rho1 levels, the abnormal organization of F-actin in the wing and the assembly of integrin-matrix adhesion sites. The rough eye phenotype was suppressed by coexpression of either PTEN or Wech, or by knock-down of Xrp1. Two main conclusions can be drawn from our studies: (1, high levels of cytoplasmic Parvin are toxic in epithelial cells; (2 Parvin in a dose dependent manner affects the organization of actin cytoskeleton in both wing and eye epithelia, independently of its role as a structural component of the ILK-PINCH-Parvin complex that mediates the integrin-actin link. Thus, distinct genetic interactions of Parvin occur in different cell types and second site modifier screens are required to uncover such genetic circuits.

  17. Disease and degeneration of aging neural systems that integrate sleep drive and circadian oscillations

    Directory of Open Access Journals (Sweden)

    Kris eSingletary

    2011-10-01

    Full Text Available Sleep and circadian activity rhythms become irregular with age which are characterized by fragmented sleep during the night and increased daytime sleepiness. These changes lead to a reduction in the quality of life due to cognitive impairments and emotional stress. More importantly, severely disrupted sleep and circadian rhythms have been associated with an increase in disease susceptibility. Many of the same brain areas affected by neurodegenerative diseases include the sleep and wake promoting systems. Any advances in our knowledge of these sleep/wake networks are necessary to target neural areas or connections for therapy. This review will discuss research that uses molecular, behavioral, genetic and anatomical methods to further our understanding of the interaction of these systems.

  18. Rapid changes in the light/dark cycle disrupt memory of conditioned fear in mice.

    Directory of Open Access Journals (Sweden)

    Dawn H Loh

    Full Text Available BACKGROUND: Circadian rhythms govern many aspects of physiology and behavior including cognitive processes. Components of neural circuits involved in learning and memory, e.g., the amygdala and the hippocampus, exhibit circadian rhythms in gene expression and signaling pathways. The functional significance of these rhythms is still not understood. In the present study, we sought to determine the impact of transiently disrupting the circadian system by shifting the light/dark (LD cycle. Such "jet lag" treatments alter daily rhythms of gene expression that underlie circadian oscillations as well as disrupt the synchrony between the multiple oscillators found within the body. METHODOLOGY/PRINCIPAL FINDINGS: We subjected adult male C57Bl/6 mice to a contextual fear conditioning protocol either before or after acute phase shifts of the LD cycle. As part of this study, we examined the impact of phase advances and phase delays, and the effects of different magnitudes of phase shifts. Under all conditions tested, we found that recall of fear conditioned behavior was specifically affected by the jet lag. We found that phase shifts potentiated the stress-evoked corticosterone response without altering baseline levels of this hormone. The jet lag treatment did not result in overall sleep deprivation, but altered the temporal distribution of sleep. Finally, we found that prior experience of jet lag helps to compensate for the reduced recall due to acute phase shifts. CONCLUSIONS/SIGNIFICANCE: Acute changes to the LD cycle affect the recall of fear-conditioned behavior. This suggests that a synchronized circadian system may be broadly important for normal cognition and that the consolidation of memories may be particularly sensitive to disruptions of circadian timing.

  19. Circadian control of glucose metabolism

    NARCIS (Netherlands)

    Kalsbeek, A.; la Fleur, Susanne; Fliers, Eric

    2014-01-01

    The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which h

  20. Systemic inflammation disrupts oligodendrocyte gap junctions and induces ER stress in a model of CNS manifestations of X-linked Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Olympiou, Margarita; Sargiannidou, Irene; Markoullis, Kyriaki; Karaiskos, Christos; Kagiava, Alexia; Kyriakoudi, Styliana; Abrams, Charles K; Kleopa, Kleopas A

    2016-01-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset of CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions of systemic inflammation and metabolic stress. To clarify the underlying mechanisms of CNS phenotypes in CMT1X we studied a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) injection to compare wild type (WT), connexin32 (Cx32) knockout (KO), and KO T55I mice expressing the T55I Cx32 mutation associated with CNS phenotypes. Following a single intraperitoneal LPS or saline (controls) injection at the age of 40-60 days systemic inflammatory response was documented by elevated TNF-α and IL-6 levels in peripheral blood and mice were evaluated 1 week after injection. Behavioral analysis showed graded impairment of motor performance in LPS treated mice, worse in KO T55I than in Cx32 KO and in Cx32 KO worse than WT. Iba1 immunostaining revealed widespread inflammation in LPS treated mice with diffusely activated microglia throughout the CNS. Immunostaining for the remaining major oligodendrocyte connexin Cx47 and for its astrocytic partner Cx43 revealed widely reduced expression of Cx43 and loss of Cx47 GJs in oligodendrocytes. Real-time PCR and immunoblot analysis indicated primarily a down regulation of Cx43 expression with secondary loss of Cx47 membrane localization. Inflammatory changes and connexin alterations were most severe in the KO T55I group. To examine why the presence of the T55I mutant exacerbates pathology even more than in Cx32 KO mice, we analyzed the expression of ER-stress markers BiP, Fas and CHOP by immunostaining, immunoblot and Real-time PCR. All markers were increased in LPS treated KO T55I mice more than in other genotypes. In conclusion, LPS induced neuroinflammation causes disruption of the main astrocyte

  1. The role of chronobiology and circadian rhythms in type 2 diabetes mellitus: implications for management of diabetes

    OpenAIRE

    Kurose, Takeshi; Hyo,Takanori; Seino, Yutaka; Yabe, Daisuke

    2014-01-01

    Takeshi Kurose, Takanori Hyo, Daisuke Yabe, Yutaka Seino Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Fukushima, Osaka, Japan Abstract: Circadian clocks regulate cellular to organic and individual behavior levels of all organisms. Almost all cells in animals have self-sustained clocks entrained by environmental signals. Recent progress in genetic research has included identification of clock genes whose disruption causes metabolic abnormalities such as d...

  2. Disruption of Inducible 6-Phosphofructo-2-kinase Ameliorates Diet-induced Adiposity but Exacerbates Systemic Insulin Resistance and Adipose Tissue Inflammatory Response*

    OpenAIRE

    Huo, Yuqing; Guo, Xin; Li, Honggui; Wang, Huan; Zhang, Weiyu; Wang, Ying; Zhou, Huaijun; Gao, Zhanguo; Telang, Sucheta; Chesney, Jason; Chen, Y. Eugene; Ye, Jianping; Chapkin, Robert S.; Wu, Chaodong

    2009-01-01

    Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3+/− mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high...

  3. Natural selection against a circadian clock gene mutation in mice

    NARCIS (Netherlands)

    Spoelstra, K.; Wikelski, Martin; Daan, Serge; Loudon, Andrew; Hau, Michaela

    2015-01-01

    Circadian rhythms with an endogenous period close or equal to the natural light-dark cycle are considered evolutionarily adaptive (‘circadian resonance hypothesis’). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural c

  4. Phase resetting of the mammalian circadian clock by DNA damage

    NARCIS (Netherlands)

    Oklejewicz, Malgorzata; Destici, Eugin; Tamanini, Filippo; Hut, Roelof A.; Janssens, Roel; van der Horst, Gijsbertus T. J.

    2008-01-01

    To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian

  5. An electrochemical DNA-sensor developed with the use of methylene blue as a redox indicator for the detection of DNA damage induced by endocrine-disrupting compounds

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Xiaoyun [State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047 (China); College of Chemistry, Nanchang University, Nanchang 330031 (China); Ni, Yongnian, E-mail: ynni@ncu.edu.cn [State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047 (China); College of Chemistry, Nanchang University, Nanchang 330031 (China); Kokot, Serge, E-mail: s.kokot@qut.edu.au [School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane 4001 (Australia)

    2015-03-31

    Highlights: • A new method for detecting DNA damage was successfully developed. • A novel biosensor, MB/dsDNA/GO-CS/AuNPs/GCE biosensor was constructed. • Loading/release of MB in/out of dsDNA/GO-CS/AuNPs film was investigated. • DNA damage induced by BPA, NP and OP was detected and estimated. - Abstract: An electrochemical biosensor capable of indirect detection of DNA damage induced by any one of the three endocrine-disrupting compounds (EDCs) – bisphenol A (BPA), 4-nonylphenol (NP) and 4-t-octylphenol (OP), has been researched and developed. The methylene blue (MB) dye was used as the redox indicator. The glassy carbon electrode (GCE) was modified by the assembled dsDNA/graphene oxide-chitosan/gold nano-particles to produce a dsDNA/GO-CS/AuNPs/GCE sensor. It was characterized with the use of electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and scanning electron microscopy (SEM) techniques. The loading/release of the MB dye by the dsDNA/GO-CS/AuNPs film was investigated, and the results showed that the process was reversible. Based on this, the sensor was used to measure the difference between the loading capabilities of intact and damaged dsDNA in the films. The sensor was then successfully applied to detect DNA damage electrochemically. The differential pulse voltammetry (DPV) peak current ratio for MB, observed before and after DNA damage, increased linearly in the presence the BPA, NP or OP compounds; the treatment range was 10–60 min, and the respective damage rates were 0.0069, 0.0044 and 0.0031 min{sup −1}, respectively. These results were confirmed by the binding constants: 2.09 × 10{sup 6} M{sup −1} (BPA-DNA), 1.28 × 10{sup 6} M{sup −1} (NP-DNA) and 9.33 × 10{sup 5} M{sup −1} (OP-DNA), all of which were obtained with the use of differential pulse stripping voltammetry (DPSV)

  6. An electrochemical DNA-sensor developed with the use of methylene blue as a redox indicator for the detection of DNA damage induced by endocrine-disrupting compounds

    International Nuclear Information System (INIS)

    Highlights: • A new method for detecting DNA damage was successfully developed. • A novel biosensor, MB/dsDNA/GO-CS/AuNPs/GCE biosensor was constructed. • Loading/release of MB in/out of dsDNA/GO-CS/AuNPs film was investigated. • DNA damage induced by BPA, NP and OP was detected and estimated. - Abstract: An electrochemical biosensor capable of indirect detection of DNA damage induced by any one of the three endocrine-disrupting compounds (EDCs) – bisphenol A (BPA), 4-nonylphenol (NP) and 4-t-octylphenol (OP), has been researched and developed. The methylene blue (MB) dye was used as the redox indicator. The glassy carbon electrode (GCE) was modified by the assembled dsDNA/graphene oxide-chitosan/gold nano-particles to produce a dsDNA/GO-CS/AuNPs/GCE sensor. It was characterized with the use of electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and scanning electron microscopy (SEM) techniques. The loading/release of the MB dye by the dsDNA/GO-CS/AuNPs film was investigated, and the results showed that the process was reversible. Based on this, the sensor was used to measure the difference between the loading capabilities of intact and damaged dsDNA in the films. The sensor was then successfully applied to detect DNA damage electrochemically. The differential pulse voltammetry (DPV) peak current ratio for MB, observed before and after DNA damage, increased linearly in the presence the BPA, NP or OP compounds; the treatment range was 10–60 min, and the respective damage rates were 0.0069, 0.0044 and 0.0031 min−1, respectively. These results were confirmed by the binding constants: 2.09 × 106 M−1 (BPA-DNA), 1.28 × 106 M−1 (NP-DNA) and 9.33 × 105 M−1 (OP-DNA), all of which were obtained with the use of differential pulse stripping voltammetry (DPSV)

  7. CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock.

    Directory of Open Access Journals (Sweden)

    Brigitte Grima

    Full Text Available Eukaryotic circadian clocks rely on transcriptional feedback loops. In Drosophila, the PERIOD (PER and TIMELESS (TIM proteins accumulate during the night, inhibit the activity of the CLOCK (CLK/CYCLE (CYC transcriptional complex, and are degraded in the early morning. The control of PER and TIM oscillations largely depends on post-translational mechanisms. They involve both light-dependent and light-independent pathways that rely on the phosphorylation, ubiquitination, and proteasomal degradation of the clock proteins. SLMB, which is part of a CULLIN-1-based E3 ubiquitin ligase complex, is required for the circadian degradation of phosphorylated PER. We show here that CULLIN-3 (CUL-3 is required for the circadian control of PER and TIM oscillations. Expression of either Cul-3 RNAi or dominant negative forms of CUL-3 in the clock neurons alters locomotor behavior and dampens PER and TIM oscillations in light-dark cycles. In constant conditions, CUL-3 deregulation induces behavioral arrhythmicity and rapidly abolishes TIM cycling, with slower effects on PER. CUL-3 affects TIM accumulation more strongly in the absence of PER and forms protein complexes with hypo-phosphorylated TIM. In contrast, SLMB affects TIM more strongly in the presence of PER and preferentially associates with phosphorylated TIM. CUL-3 and SLMB show additive effects on TIM and PER, suggesting different roles for the two ubiquitination complexes on PER and TIM cycling. This work thus shows that CUL-3 is a new component of the Drosophila clock, which plays an important role in the control of TIM oscillations.

  8. Modeling an evolutionary conserved circadian cis-element.

    Directory of Open Access Journals (Sweden)

    Eric R Paquet

    2008-02-01

    Full Text Available Circadian oscillator networks rely on a transcriptional activator called CLOCK/CYCLE (CLK/CYC in insects and CLOCK/BMAL1 or NPAS2/BMAL1 in mammals. Identifying the targets of this heterodimeric basic-helix-loop-helix (bHLH transcription factor poses challenges and it has been difficult to decipher its specific sequence affinity beyond a canonical E-box motif, except perhaps for some flanking bases contributing weakly to the binding energy. Thus, no good computational model presently exists for predicting CLK/CYC, CLOCK/BMAL1, or NPAS2/BMAL1 targets. Here, we use a comparative genomics approach and first study the conservation properties of the best-known circadian enhancer: a 69-bp element upstream of the Drosophila melanogaster period gene. This fragment shows a signal involving the presence of two closely spaced E-box-like motifs, a configuration that we can also detect in the other four prominent CLK/CYC target genes in flies: timeless, vrille, Pdp1, and cwo. This allows for the training of a probabilistic sequence model that we test using functional genomics datasets. We find that the predicted sequences are overrepresented in promoters of genes induced in a recent study by a glucocorticoid receptor-CLK fusion protein. We then scanned the mouse genome with the fly model and found that many known CLOCK/BMAL1 targets harbor sequences matching our consensus. Moreover, the phase of predicted cyclers in liver agreed with known CLOCK/BMAL1 regulation. Taken together, we built a predictive model for CLK/CYC or CLOCK/BMAL1-bound cis-enhancers through the integration of comparative and functional genomics data. Finally, a deeper phylogenetic analysis reveals that the link between the CLOCK/BMAL1 complex and the circadian cis-element dates back to before insects and vertebrates diverged.

  9. Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

    Directory of Open Access Journals (Sweden)

    Norman F Ruby

    Full Text Available Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN, but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

  10. Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

    Science.gov (United States)

    Ruby, Norman F; Fernandez, Fabian; Garrett, Alex; Klima, Jessy; Zhang, Pei; Sapolsky, Robert; Heller, H Craig

    2013-01-01

    Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

  11. Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3.

    Science.gov (United States)

    Jarosch, Marlene S; Gebhardt, Christine; Fano, Silvia; Huchzermeyer, Christine; Ul Haq, Rizwan; Behrens, Christoph J; Heinemann, Uwe

    2015-07-01

    We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3 min. The prolongation of hypoxic periods to 6 min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6 min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3. PMID:25959377

  12. Coordination of the maize transcriptome by a conserved circadian clock

    Directory of Open Access Journals (Sweden)

    Harmon Frank G

    2010-06-01

    Full Text Available Abstract Background The plant circadian clock orchestrates 24-hour rhythms in internal physiological processes to coordinate these activities with daily and seasonal changes in the environment. The circadian clock has a profound impact on many aspects of plant growth and development, including biomass accumulation and flowering time. Despite recent advances in understanding the circadian system of the model plant Arabidopsis thaliana, the contribution of the circadian oscillator to important agronomic traits in Zea mays and other cereals remains poorly defined. To address this deficit, this study investigated the transcriptional landscape of the maize circadian system. Results Since transcriptional regulation is a fundamental aspect of circadian systems, genes exhibiting circadian expression were identified in the sequenced maize inbred B73. Of the over 13,000 transcripts examined, approximately 10 percent displayed circadian expression patterns. The majority of cycling genes had peak expression at subjective dawn and dusk, similar to other plant circadian systems. The maize circadian clock organized co-regulation of genes participating in fundamental physiological processes, including photosynthesis, carbohydrate metabolism, cell wall biogenesis, and phytohormone biosynthesis pathways. Conclusions Circadian regulation of the maize genome was widespread and key genes in several major metabolic pathways had circadian expression waveforms. The maize circadian clock coordinated transcription to be coincident with oncoming day or night, which was consistent with the circadian oscillator acting to prepare the plant for these major recurring environmental changes. These findings highlighted the multiple processes in maize plants under circadian regulation and, as a result, provided insight into the important contribution this regulatory system makes to agronomic traits in maize and potentially other C4 plant species.

  13. Circadian Control of the Estrogenic Circuits Regulating GnRH Secretion and the Preovulatory Luteinizing Hormone Surge

    Directory of Open Access Journals (Sweden)

    Lance J Kriegsfeld

    2012-05-01

    Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

  14. Circadian Metabolism in the Light of Evolution

    DEFF Research Database (Denmark)

    Gerhart-Hines, Zachary; Lazar, Mitchell A.

    2015-01-01

    -tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery......A review. Circadian rhythm, or daily oscillation, of behaviors and biol. processes is a fundamental feature of mammalian physiol. that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine...

  15. Circadian aspects of post-operative morbidity and mortality

    DEFF Research Database (Denmark)

    Kvaslerud, T.; Hansen, M.V.; Rosenberg, J.;

    2010-01-01

    concerning post-operative circadian disturbances. We also present the literature concerning circadian variation in post-operative morbidity and mortality. PubMed and the Cochrane database were searched for papers using a combination of 'circadian,' 'surgery,' 'post-operative,' 'mortality' and 'morbidity....... There is a peak incidence of myocardial ischemia, fatal thromboembolism and sudden unexpected death in the morning hours. A circadian variation exists in post-operative morbidity and mortality. The observed circadian variation in post-operative morbidity and mortality may warrant a chronopharmacological approach...

  16. Modelling of intercellular synchronization in the Drosophila circadian clock

    Institute of Scientific and Technical Information of China (English)

    Wang Jun-Wei; Chen Ai-Min; Zhang Jia-Jun; Yuan Zhan-Jiang; Zhou Tian-Shou

    2009-01-01

    In circadian rhythm generation, intercellular signaling factors are shown to play a crucial role in both sustaining intrinsic cellular rhythmicity and acquiring collective behaviours across a population of circadian neurons. However, the physical mechanism behind their role remains to be fully understood. In this paper, we propose an indirectly coupled multicellular model for the synchronization of Drosophila circadian oscillators combining both intracellular and intercellular dynamics. By simulating different experimental conditions, we find that such an indirect coupling way can synchronize both heterogeneous self-sustained circadian neurons and heterogeneous mutational damped circadian neurons. Moreover, they can also be entrained to ambient light-dark (LD) cycles depending on intercellular signaling.

  17. Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer's Disease?

    Directory of Open Access Journals (Sweden)

    Brianne Alyssia Kent

    2014-09-01

    Full Text Available Alzheimer’s disease (AD is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behaviour and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.

  18. Progestins alter photo-transduction cascade and circadian rhythm network in eyes of zebrafish (Danio rerio)

    Science.gov (United States)

    Zhao, Yanbin; Fent, Karl

    2016-02-01

    Environmental progestins are implicated in endocrine disruption in vertebrates. Additional targets that may be affected in organisms are poorly known. Here we report that progesterone (P4) and drospirenone (DRS) interfere with the photo-transduction cascade and circadian rhythm network in the eyes of zebrafish. Breeding pairs of adult zebrafish were exposed to P4 and DRS for 21 days with different measured concentrations of 7–742 ng/L and 99-13´650 ng/L, respectively. Of totally 10 key photo-transduction cascade genes analyzed, transcriptional levels of most were significantly up-regulated, or normal down-regulation was attenuated. Similarly, for some circadian rhythm genes, dose-dependent transcriptional alterations were also observed in the totally 33 genes analyzed. Significant alterations occurred even at environmental relevant levels of 7 ng/L P4. Different patterns were observed for these transcriptional alterations, of which, the nfil3 family displayed most significant changes. Furthermore, we demonstrate the importance of sampling time for the determination and interpretation of gene expression data, and put forward recommendations for sampling strategies to avoid false interpretations. Our results suggest that photo-transduction signals and circadian rhythm are potential targets for progestins. Further studies are required to assess alterations on the protein level, on physiology and behavior, as well as on implications in mammals.

  19. Neurospora COP9 signalosome integrity plays major roles for hyphal growth, conidial development, and circadian function.

    Directory of Open Access Journals (Sweden)

    Zhipeng Zhou

    Full Text Available The COP9 signalosome (CSN is a highly conserved multifunctional complex that has two major biochemical roles: cleaving NEDD8 from cullin proteins and maintaining the stability of CRL components. We used mutation analysis to confirm that the JAMM domain of the CSN-5 subunit is responsible for NEDD8 cleavage from cullin proteins in Neurospora crassa. Point mutations of key residues in the metal-binding motif (EX(nHXHX(10D of the CSN-5 JAMM domain disrupted CSN deneddylation activity without interfering with assembly of the CSN complex or interactions between CSN and cullin proteins. Surprisingly, CSN-5 with a mutated JAMM domain partially rescued the phenotypic defects observed in a csn-5 mutant. We found that, even without its deneddylation activity, the CSN can partially maintain the stability of the SCF(FWD-1 complex and partially restore the degradation of the circadian clock protein FREQUENCY (FRQ in vivo. Furthermore, we showed that CSN containing mutant CSN-5 efficiently prevents degradation of the substrate receptors of CRLs. Finally, we found that deletion of the CAND1 ortholog in N. crassa had little effect on the conidiation circadian rhythm. Our results suggest that CSN integrity plays major roles in hyphal growth, conidial development, and circadian function in N. crassa.

  20. Progestins alter photo-transduction cascade and circadian rhythm network in eyes of zebrafish (Danio rerio)

    Science.gov (United States)

    Zhao, Yanbin; Fent, Karl

    2016-02-01

    Environmental progestins are implicated in endocrine disruption in vertebrates. Additional targets that may be affected in organisms are poorly known. Here we report that progesterone (P4) and drospirenone (DRS) interfere with the photo-transduction cascade and circadian rhythm network in the eyes of zebrafish. Breeding pairs of adult zebrafish were exposed to P4 and DRS for 21 days with different measured concentrations of 7-742 ng/L and 99-13´650 ng/L, respectively. Of totally 10 key photo-transduction cascade genes analyzed, transcriptional levels of most were significantly up-regulated, or normal down-regulation was attenuated. Similarly, for some circadian rhythm genes, dose-dependent transcriptional alterations were also observed in the totally 33 genes analyzed. Significant alterations occurred even at environmental relevant levels of 7 ng/L P4. Different patterns were observed for these transcriptional alterations, of which, the nfil3 family displayed most significant changes. Furthermore, we demonstrate the importance of sampling time for the determination and interpretation of gene expression data, and put forward recommendations for sampling strategies to avoid false interpretations. Our results suggest that photo-transduction signals and circadian rhythm are potential targets for progestins. Further studies are required to assess alterations on the protein level, on physiology and behavior, as well as on implications in mammals.

  1. The RNA-binding Protein TDP-43 Selectively Disrupts MicroRNA-1/206 Incorporation into the RNA-induced Silencing Complex*♦

    Science.gov (United States)

    King, Isabelle N.; Yartseva, Valeria; Salas, Donaldo; Kumar, Abhishek; Heidersbach, Amy; Ando, D. Michael; Stallings, Nancy R.; Elliott, Jeffrey L.; Srivastava, Deepak; Ivey, Kathryn N.

    2014-01-01

    MicroRNA (miRNA) maturation is regulated by interaction of particular miRNA precursors with specific RNA-binding proteins. Following their biogenesis, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) where they interact with mRNAs to negatively regulate protein production. However, little is known about how mature miRNAs are regulated at the level of their activity. To address this, we screened for proteins differentially bound to the mature form of the miR-1 or miR-133 miRNA families. These muscle-enriched, co-transcribed miRNA pairs cooperate to suppress smooth muscle gene expression in the heart. However, they also have opposing roles, with the miR-1 family, composed of miR-1 and miR-206, promoting myogenic differentiation, whereas miR-133 maintains the progenitor state. Here, we describe a physical interaction between TDP-43, an RNA-binding protein that forms aggregates in the neuromuscular disease, amyotrophic lateral sclerosis, and the miR-1, but not miR-133, family. Deficiency of the TDP-43 Drosophila ortholog enhanced dmiR-1 activity in vivo. In mammalian cells, TDP-43 limited the activity of both miR-1 and miR-206, but not the miR-133 family, by disrupting their RISC association. Consistent with TDP-43 dampening miR-1/206 activity, protein levels of the miR-1/206 targets, IGF-1 and HDAC4, were elevated in TDP-43 transgenic mouse muscle. This occurred without corresponding Igf-1 or Hdac4 mRNA increases and despite higher miR-1 and miR-206 expression. Our findings reveal that TDP-43 negatively regulates the activity of the miR-1 family of miRNAs by limiting their bioavailability for RISC loading and suggest a processing-independent mechanism for differential regulation of miRNA activity. PMID:24719334

  2. The Pentose Phosphate Pathway Regulates the Circadian Clock.

    Science.gov (United States)

    Rey, Guillaume; Valekunja, Utham K; Feeney, Kevin A; Wulund, Lisa; Milev, Nikolay B; Stangherlin, Alessandra; Ansel-Bollepalli, Laura; Velagapudi, Vidya; O'Neill, John S; Reddy, Akhilesh B

    2016-09-13

    The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.

  3. Circadian Variation in Coronary Stent Thrombosis

    NARCIS (Netherlands)

    Mahmoud, Karim D.; Lennon, Ryan J.; Ting, Henry H.; Rihal, Charanjit S.; Holmes, David R.

    2011-01-01

    Objectives We sought to determine the circadian, weekly, and seasonal variation of coronary stent thrombosis. Background Other adverse cardiovascular events such as acute myocardial infarction are known to have higher incidences during the early morning hours, Mondays, and winter months. Methods The

  4. Impact of nutrients on circadian rhythmicity

    NARCIS (Netherlands)

    Oosterman, Johanneke E; Kalsbeek, A.; la Fleur, Susanne E; Belsham, Denise D

    2015-01-01

    The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to th

  5. Light and the human circadian clock

    NARCIS (Netherlands)

    Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V

    2013-01-01

    The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the f

  6. Circadian systems biology: When time matters

    Directory of Open Access Journals (Sweden)

    Luise Fuhr

    2015-01-01

    In this manuscript we review the combination of experimental methodologies, bioinformatics and theoretical models that have been essential to explore this remarkable timing-system. Such an integrative and interdisciplinary approach may provide new strategies with regard to chronotherapeutic treatment and new insights concerning the restoration of the circadian timing in clock-associated diseases.

  7. How Temperature Changes Reset a Circadian Oscillator

    NARCIS (Netherlands)

    Merrow, Martha; Loros, Jennifer J.; Dunlap, Jay C.

    1998-01-01

    Circadian rhythms control many physiological activities. The environmental entrainment of rhythms involves the immediate responses of clock components. Levels of the clock protein FRQ were measured in Neurospora at various temperatures; at higher temperatures, the amount of FRQ oscillated around hig

  8. Harmonics of circadian gene transcription in mammals.

    Directory of Open Access Journals (Sweden)

    Michael E Hughes

    2009-04-01

    Full Text Available The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse.

  9. The Potorous CPD photolyase rescues a cryptochrome-deficient mammalian circadian clock.

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    Inês Chaves

    Full Text Available Despite the sequence and structural conservation between cryptochromes and photolyases, members of the cryptochrome/photolyase (flavoprotein family, their functions are divergent. Whereas photolyases are DNA repair enzymes that use visible light to lesion-specifically remove UV-induced DNA damage, cryptochromes act as photoreceptors and circadian clock proteins. To address the functional diversity of cryptochromes and photolyases, we investigated the effect of ectopically expressed Arabidopsis thaliana (6-4PP photolyase and Potorous tridactylus CPD-photolyase (close and distant relatives of mammalian cryptochromes, respectively, on the performance of the mammalian cryptochromes in the mammalian circadian clock. Using photolyase transgenic mice, we show that Potorous CPD-photolyase affects the clock by shortening the period of behavioral rhythms. Furthermore, constitutively expressed CPD-photolyase is shown to reduce the amplitude of circadian oscillations in cultured cells and to inhibit CLOCK/BMAL1 driven transcription by interacting with CLOCK. Importantly, we show that Potorous CPD-photolyase can restore the molecular oscillator in the liver of (clock-deficient Cry1/Cry2 double knockout mice. These data demonstrate that a photolyase can act as a true cryptochrome. These findings shed new light on the importance of the core structure of mammalian cryptochromes in relation to its function in the circadian clock and contribute to our further understanding of the evolution of the cryptochrome/photolyase protein family.

  10. Harmine lengthens circadian period of the mammalian molecular clock in the suprachiasmatic nucleus.

    Science.gov (United States)

    Kondoh, Daisuke; Yamamoto, Saori; Tomita, Tatsunosuke; Miyazaki, Koyomi; Itoh, Nanako; Yasumoto, Yuki; Oike, Hideaki; Doi, Ryosuke; Oishi, Katsutaka

    2014-01-01

    The circadian clock is a cell-autonomous endogenous system that generates circadian rhythms in the behavior and physiology of most organisms. We previously reported that the harmala alkaloid, harmine, lengthens the circadian period of Bmal1 transcription in NIH 3T3 fibroblasts. Clock protein dynamics were examined using real-time reporter assays of PER2::LUC to determine the effects of harmine on the central clock in the suprachiasmatic nucleus (SCN). Harmine significantly lengthened the period of PER2::LUC expression in embryonic fibroblasts, in neuronal cells differentiated from neuronal progenitor cells and in SCN slices obtained from PER2::LUC mice. Although harmine did not induce the transient mRNA expression of clock genes such as Per1, Per2 and Bmal1 in embryonic fibroblasts, it significantly extended the half-life of PER2::LUC protein in neuronal cells and SCN slices. Harmine might lengthen the circadian period of the molecular clock by increasing PER2 protein stability in the SCN.

  11. Adaptive and Pathological Inhibition of Neuroplasticity Associated with Circadian Rhythms and Sleep

    Science.gov (United States)

    Heller, H. Craig; Ruby, Norman F.; Rolls, Asya; Makam, Megha; Colas, Damien

    2014-01-01

    The circadian system organizes sleep and wake through imposing a daily cycle of sleep propensity on the organism. Sleep has been shown to play an important role in learning and memory. Apart from the daily cycle of sleep propensity, however, direct effects of the circadian system on learning and memory also have been well documented. Many mechanistic components of the memory consolidation process ranging from the molecular to the systems level have been identified and studied. The question that remains is how do these various processes and components work together to produce cycles of increased and decreased learning abilities, and why should there be times of day when neural plasticity appears to be restricted? Insights into this complex problem can be gained through investigations of the learning disabilities caused by circadian disruption in Siberian hamsters and by aneuploidy in Down syndrome mice. A simple working hypothesis that has been explored in this work is that the observed learning disabilities are due to an altered excitation/inhibition balance in the CNS. Excessive inhibition is the suspected cause of deficits in memory consolidation. In this paper we present the evidence that excessive inhibition in these cases of learning disability involves GABAergic neurotransmission, that treatment with GABA receptor inhibitors can reverse the learning disability, and that the efficacy of the treatment is time sensitive coincident with the major daily sleep phase, and that it depends on sleep. The evidence we present leads us to hypothesize that a function of the circadian system is to reduce neuroplasticity during the daily sleep phase when processes of memory consolidation are taking place. PMID:24886189

  12. Temporal requirements of the fragile X mental retardation protein in modulating circadian clock circuit synaptic architecture

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    Cheryl L Gatto

    2009-08-01

    Full Text Available Loss of fragile X mental retardation 1 (FMR1 gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs, a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity.

  13. Determination of reference genes for circadian studies in different tissues and mouse strains

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    Kosir Rok

    2010-08-01

    Full Text Available Abstract Background Circadian rhythms have a profound effect on human health. Their disruption can lead to serious pathologies, such as cancer and obesity. Gene expression studies in these pathologies are often studied in different mouse strains by quantitative real time polymerase chain reaction (qPCR. Selection of reference genes is a crucial step of qPCR experiments. Recent studies show that reference gene stability can vary between species and tissues, but none has taken circadian experiments into consideration. Results In the present study the expression of ten candidate reference genes (Actb, Eif2a, Gapdh, Hmbs, Hprt1, Ppib, Rn18s, Rplp0, Tbcc and Utp6c was measured in 131 liver and 97 adrenal gland samples taken from three mouse strains (C57BL/6JOlaHsd, 129Pas plus C57BL/6J and Crem KO on 129Pas plus C57BL/6J background every 4 h in a 24 h period. Expression stability was evaluated by geNorm and NormFinder programs. Differences in ranking of the most stable reference genes were observed both between individual mouse strains as well as between tissues within each mouse strain. We show that selection of reference gene (Actb that is often used for analyses in individual mouse strains leads to errors if used for normalization when different mouse strains are compared. We identified alternative reference genes that are stable in these comparisons. Conclusions Genetic background and circadian time influence the expression stability of reference genes. Differences between mouse strains and tissues should be taken into consideration to avoid false interpretations. We show that the use of a single reference gene can lead to false biological conclusions. This manuscript provides a useful reference point for researchers that search for stable reference genes in the field of circadian biology.

  14. Circadian adaptations to meal timing: Neuroendocrine mechanisms

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    Danica F Patton

    2013-10-01

    Full Text Available Circadian rhythms of behavior and physiology are generated by central and peripheral circadian oscillators entrained by periodic environmental or physiological stimuli. A master circadian pacemaker in the hypothalamic suprachiasmatic nucleus is directly entrained by daily light-dark cycles, and coordinates the timing of other oscillators by direct and indirect neural, hormonal and behavioral outputs. The daily rhythm of food intake provides stimuli that entrain most peripheral and central oscillators, some of which can drive a daily rhythm of food anticipatory activity if food is restricted to one daily mealtime. The location of food-entrainable oscillators (FEOs that drive food anticipatory rhythms, and the food-related stimuli that entrain these oscillators, remain to be clarified. Here, we critically examine the role of peripheral metabolic hormones as potential internal entrainment stimuli or outputs for FEOs controlling food anticipatory rhythms in rats and mice. Hormones for which data are available include corticosterone, ghrelin, leptin, insulin, glucagon, and glucagon-like peptide 1. All of these hormones exhibit daily rhythms of synthesis and secretion that are synchronized by meal timing. There is some evidence that ghrelin and leptin modulate the expression of food anticipatory rhythms, but none of the hormones examined so far are necessary for entrainment. Ghrelin and leptin likely modulate food-entrained rhythms by actions in hypothalamic circuits utilizing melanocortin and orexin signaling, although again food-entrained behavioral rhythms can persist in lesion and gene knockout models in which these systems are disabled. Actions of these hormones on circadian oscillators in central reward circuits remain to be evaluated. Food-entrained activity rhythms are likely mediated by a distributed system of circadian oscillators sensitive to multiple feeding related inputs. Metabolic hormones appear to play a modulatory role within this

  15. Circadian Entrainment, Sleep-Wake Regulation and Neurobehavioral Performance During Extended Duration Space Flight

    Science.gov (United States)

    Czeisler, Charles A.

    1999-01-01

    Long-duration manned space flight requires crew members to maintain a high level of cognitive performance and vigilance while operating and monitoring sophisticated instrumentation. However, the reduction in the strength of environmental synchronizers in the space environment leads to misalignment of circadian phase among crew members, coupled with restricted time available to sleep, results in sleep deprivation and consequent deterioration of neurobehavioral function. Crew members are provided, and presently use, long-acting benzodiazepine hypnotics on board the current, relatively brief space shuttle missions to counteract such sleep disruption, a situation that is only likely to worsen during extended duration missions. Given the known carry-over effects of such compounds on daytime performance, together with the reduction in emergency readiness associated with their use at night, NASA has recognized the need to develop effective but safe countermeasures to allow crew members to obtain an adequate amount of sleep. Over the past eight years, we have successfully implemented a new technology for shuttle crew members involving bright light exposure during the pre-launch period to facilitate adaptation of the circadian timing system to the inversions of the sleep-wake schedule often required during dual shift missions. However for long duration space station missions it will be necessary to develop effective and attainable countermeasures that can be used chronically to optimize circadian entrainment. Our current research effort is to study the effects of light-dark cycles with reduced zeitgeber strength, such as are anticipated during long-duration space flight, on the entrainment of the endogenous circadian timing system and to study the effects of a countermeasure that consists of scheduled brief exposures to bright light on the human circadian timing system. The proposed studies are designed to address the following Specific Aims: (1) test the hypothesis that

  16. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age

    International Nuclear Information System (INIS)

    Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks

  17. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age

    Energy Technology Data Exchange (ETDEWEB)

    Keith, Dove; Finlay, Liam; Butler, Judy [Linus Pauling Institute, Oregon State University (United States); Gómez, Luis; Smith, Eric [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States); Moreau, Régis [Linus Pauling Institute, Oregon State University (United States); Hagen, Tory, E-mail: Tory.Hagen@oregonstate.edu [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States)

    2014-07-18

    Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.

  18. period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock

    Energy Technology Data Exchange (ETDEWEB)

    Emerson, Jillian M.; Bartholomai, Bradley M.; Ringelberg, Carol; Baker, Scott E.; Loros, Jennifer J.; Dunlap, Jay C.

    2015-12-22

    Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 and DDX17 in humans and Dbp2p in yeast, are implicated in various processes including transcriptional regulation, elongation, and termination, 23 ribosome biogenesis, and RNA decay. Although prdi-1smutantssiois an ATP-dependent RNA helicase, member of a sub-family display a long period (~25 hrs) circadian developmental cycle, they interestingly display a wild type period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator runs with a long period under glucose-sufficient conditions. Thus PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose PRD-1 is in the nucleus until glucose runs out which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd­-1 may be formally viewed as clock mutant with defective nutritional compensation of circadian period length.

  19. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    R Daniel Rudic

    2004-11-01

    Full Text Available Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3 and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

  20. Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy.

    OpenAIRE

    Shiga, N.; Takeshima, Y; Sakamoto, H; Inoue, K.; Y. Yokota; Yokoyama, M.; Matsuo, M.

    1997-01-01

    The mechanism of exon skipping induced by nonsense mutations has not been well elucidated. We now report results of in vitro splicing studies which disclosed that a particular example of exon skipping is due to disruption of a splicing enhancer sequence located within the exon. A nonsense mutation (E1211X) due to a G to T transversion at the 28th nucleotide of exon 27 (G3839T) was identified in the dystrophin gene of a Japanese Becker muscular dystrophy case. Partial skipping of the exon resu...

  1. Stochastic models of cellular circadian rhythms in plants help to understand the impact of noise on robustness and clock structure

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    Maria Luisa eGuerriero

    2014-10-01

    Full Text Available Rhythmic behavior is essential for plants; for example, daily (circadian rhythms control photosynthesis and seasonal rhythms regulate their life cycle. The core of the circadian clock is a genetic network that coordinates the expression of specific clock genes in a circadian rhythm reflecting the 24-hour day/night cycle.Circadian clocks exhibit stochastic noise due to the low copy numbers of clock genes and the consequent cell-to-cell variation: this intrinsic noise plays a major role in circadian clocks by inducing more robust oscillatory behavior. Another source of noise is the environment, which causes variation in temperature and light intensity: this extrinsic noise is part of the requirement for the structural complexity of clock networks.Advances in experimental techniques now permit single-cell measurements and the development of single-cell models. Here we present some modeling studies showing the importance of considering both types of noise in understanding how plants adapt to regular and irregular light variations. Stochastic models have proven useful for understanding the effect of regular variations. By contrast, the impact of irregular variations and the interaction of different noise sources are less studied.

  2. Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters.

    Science.gov (United States)

    Ikeno, Tomoko; Nelson, Randy J

    2015-02-01

    In the hippocampus of Siberian hamsters, dendritic length and dendritic complexity increase in the CA1 region whereas dendritic spine density decreases in the dentate gyrus region at night. However, the underlying mechanism of the diurnal rhythmicity in hippocampal neuronal remodeling is unknown. In mammals, most daily rhythms in physiology and behaviors are regulated by a network of circadian clocks. The central clock, located in the hypothalamus, controls melatonin secretion at night and melatonin modifies peripheral clocks by altering expression of circadian clock genes. In this study, we examined the effects of acute melatonin treatment on the circadian clock system as well as on morphological changes of hippocampal neurons. Male Siberian hamsters were injected with melatonin in the afternoon; 4 h later, mRNA levels of hypothalamic and hippocampal circadian clock genes and hippocampal neuron dendritic morphology were assessed. In the hypothalamus, melatonin treatment did not alter Period1 and Bmal1 expression. However, melatonin treatment increased both Period1 and Bmal1 expression in the hippocampus, suggesting that melatonin affected molecular oscillations in the hippocampus. Melatonin treatment also induced rapid remodeling of hippocampal neurons; melatonin increased apical dendritic length and dendritic complexity in the CA1 region and reduced the dendritic spine density in the dentate gyrus region. These data suggest that structural changes in hippocampal neurons are regulated by a circadian clock and that melatonin functions as a nighttime signal to coordinate the diurnal rhythm in neuronal remodeling.

  3. Reconnaissance of 17 beta-estradiol, 11-ketotestosterone, vitellogenin, and gonad histopathology in common carp of United States streams; potential for contaminant-induced endocrine disruption

    Science.gov (United States)

    Goodbred, Steven L.; Gilliom, Robert J.; Gross, Timothy S.; Denslow, Nancy P.; Bryant, Wade B.; Schoeb, Trenton R.

    1997-01-01

    A reconnaissance of sex steroid hormones and other biomarkers in common carp was used to assess whether endocrine disruption may be occurring in fish in United States streams, to evaluate relations between endocrine disruption and contaminant levels, and to determine requirements for further studies. 17?-estradiol, 11-ketotestosterone, vitellogenin, and gonadal histopathology were measured in adult carp (usually 10--15 for each sex) at 25 sites (647 fish), representing a wide range of environmental settings typical of major regions of the nation. Fish were collected during August--December 1994, a period of gonadal maturation after spawning. Contaminants evaluated were organochlorine pesticides and polychlorinated biphenyls in tissue; phthalates, phenols, and polycyclic aromatic hydrocarbons in bed sediment; and dissolved pesticides in water. Mean