Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems.

PubMed

Fedorova, I; Hashimoto, A; Fecik, R A; Hedrick, M P; Hanus, L O; Boger, D L; Rice, K C; Basile, A S

2001-10-01

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)1A, 5HT2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.

Enhanced radiosensitization of p53 mutant cells by oleamide.

PubMed

Lee, Yoon-Jin; Chung, Da Yeon; Lee, Su-Jae; Ja Jhon, Gil; Lee, Yun-Sil

2006-04-01

Effect of oleamide, an endogenous fatty-acid primary amide, on tumor cells exposed to ionizing radiation (IR) has never before been explored. NCI H460, human lung cancer cells, and human astrocytoma cell lines, U87 and U251, were used. The cytotoxicity of oleamide alone or in combination with IR was determined by clonogenic survival assay, and induction of apoptosis was estimated by FACS analysis. Protein expressions were confirmed by Western blotting, and immunofluorescence analysis of Bax by use of confocal microscopy was also performed. The combined effect of IR and oleamide to suppress tumor growth was studied by use of xenografts in the thighs of nude mice. Oleamide in combination with IR had a synergistic effect that decreased clonogenic survival of lung-carcinoma cell lines and also sensitized xenografts in nude mice. Enhanced induction of apoptosis of the cells by the combined treatment was mediated by loss of mitochondrial membrane potential, which resulted in the activation of caspase-8, caspase-9, and caspase-3 accompanied by cytochrome c release and Bid cleavage. The synergistic effects of the combined treatment were more enhanced in p53 mutant cells than in p53 wild-type cells. In p53 wild-type cells, both oleamide and radiation induced Bax translocation to mitochondria. On the other hand, in p53 mutant cells, radiation alone slightly induced Bax translocation to mitochondria, whereas oleamide induced a larger translocation. Oleamide may exhibit synergistic radiosensitization in p53 mutant cells through p53-independent Bax translocation to mitochondria.

Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?

PubMed

Hiley, C Robin; Hoi, Pui Man

2007-01-01

Oleamide (cis-9,10-octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep-deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system. The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine alpha-amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage-gated Na(+) channels and allosterically with GABA(A) and 5-HT(7) receptors as well as having cannabinoid-like actions. The latter have been suggested to be due to potentiation of the effects of endocannabinoids such as anandamide by inhibiting FAAH-mediated hydrolysis. This might underlie an "entourage effect" whereby co-released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH. However, oleamide has direct agonist actions at CB(1) cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap-junctional communication, and this might give oleamide a role in myocardial development. Many of these actions are absent from the trans isomer of 9,10-octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response does not involve CB(1) cannabinoid receptors but another pertussis toxin-sensitive, G protein-coupled receptor, as yet unidentified. This receptor is sensitive to rimonabant and O-1918, an antagonist at the putative "abnormal-cannabidiol" or endothelial "anandamide" receptors. Vasodilation is mediated by endothelium-derived nitric oxide, endothelium-dependent hyperpolarization, and also through activation of TRPV1 receptors. A physiological role for oleamide in the heart and circulation has yet to be demonstrated, as has production by cells of the cardiovascular system, but

[INFLUENCE OF OLEAMIDE OF WATER AND ION TRANSPORT IN THE OSMOREGULATORY ORGANS].

PubMed

Shakhmatova, E I; Bogolepova, A E; Dubina, M V; Natochin, Yu V

2015-01-01

Application of oleamide (final concentration of 10 μM) at the skin basal surface of the frog, Rana temporaria L., augmented the short-circuit current (SCC) from 59.8 ± 2.5 to 78.2 ± 1.4 μA/cm2. Oleamide added to the serous membrane of the frog urinary bladder at a final dose of 1 μM induced more than 30-fold increase of osmotic permeability. The addition of arginine-vasotocin on the background of oleamide action further increased SCC across the isolated frog skin and osmotic permeability of the frog urinary bladder. Intraperitoneal injection of oleamide at a dose of 0.1 mM/100 g BW to water-loaded non-anesthetized Wistar rats decreased diuresis by 22%, enhanced solute-free water reabsorption and urinary sodium excretion by 31% and 55% respectively, but did not affect the renal potassium excretion. The results obtained provide evidence of similarity of oleamide and neurohypophyseal hormones effects on water and ion transport in epithelial cells of osmoregulatory organs in vertebrates.

Sleep-inducing factors.

PubMed

García-García, Fabio; Acosta-Peña, Eva; Venebra-Muñoz, Arturo; Murillo-Rodríguez, Eric

2009-08-01

Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.

Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol and Lipid Peroxidation in the Rat Plasma.

PubMed

Olayaki, L A; Sulaiman, S O; Anoba, N B

2015-12-20

Sleep deprivation (SD) is biological stressor that alters metabolic parameters, induced oxidative stress and lipid peroxidation. Previous studies have shown that antioxidants substances such as melatonin, tryptophan, vitamin E and vitamin C improved stress tolerance in laboratory animals. In this study, we examined the potential protective effects of administration of vitamin C on acute and chronic sleep deprivation-induced metabolic derangement. In addition, possible processes involved in vitamin C effects on acute and chronic sleep deprivation-induced metabolic derangement were determined. Thirty-five rats (120-250g) were used. The rats were divided into 7 groups of 5 rats each as Control (CTRL), Acute sleep deprived untreated with vitamin C (AC), Acute sleep deprived treated with vitamin C (AWC), Chronic sleep deprived untreated with vitamin C (CC), Chronic sleep deprived treated with vitamin C (CWC), Chronic sleep deprived + Recovery untreated with vitamin C (RC), and Chronic sleep deprived + Recovery treated with vitamin C (RWC). The SD was carried out for 20h for 1 day on the acute groups, and for 20h/day for 5 days on the chronic group, using the Multiple Modified Platforms (MMP) after oral administration of 300mg/kg of vitamin C to all vitamin C-treated groups. The recovery groups were further observed for five days after SD. The control group were treated with vitamin C and without stress in their home cages. At the end of the experiment, the animals were sacrificed and blood was collected for estimation of plasma glucose, insulin, cortisol and malondialdehyde (MDA). The results showed that acute and chronic SDs significantly  increased MDA and cortisol levels, while significantly reduced the levels of insulin. Treatment with vitamin C reversed the changes in the MDA, cortisol and plasma insulin levels. Additionally, allowing the rats to recover for 5 days after sleep deprivation corrected the observed changes. Plasma glucose was significantly

Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

PubMed

Cravatt, B F; Giang, D K; Mayfield, S P; Boger, D L; Lerner, R A; Gilula, N B

1996-11-07

Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.

Inhibitory action of linoleamide and oleamide toward sarco/endoplasmic reticulum Ca2+-ATPase.

PubMed

Yamamoto, Sachiko; Takehara, Munenori; Ushimaru, Makoto

2017-01-01

SERCA maintains intracellular Ca 2+ homeostasis by sequestering cytosolic Ca 2+ into SR/ER stores. Two primary fatty acid amides (PFAAs), oleamide (18:1 9-cis ) and linoleamide (18:2 9,12-cis ), induce an increase in intracellular Ca 2+ levels, which might be caused by their inhibition of SERCA. Three major SERCA isoforms, rSERCA1a, hSERCA2b, and hSERCA3a, were individually overexpressed in COS-1 cells, and the inhibitory action of PFAAs on Ca 2+ -ATPase activity of SERCA was examined. The Ca 2+ -ATPase activity of each SERCA was inhibited in a concentration-dependent manner strongly by linoleamide (IC 50 15-53μM) and partially by oleamide (IC 50 8.3-34μM). Inhibition by other PFAAs, such as stearamide (18:0) and elaidamide (18:1 9-trans ), was hardly or slightly observed. With increasing dose, linoleamide decreased the apparent affinity for Ca 2+ and the apparent maximum velocity of Ca 2+ -ATPase activity of all SERCAs tested. Oleamide also lowered these values for hSERCA3a. Meanwhile, oleamide uniquely reduced the apparent Ca 2+ affinity of rSERCA1a and hSERCA2b: the reduction was considerably attenuated above certain concentrations of oleamide. The dissociation constants for SERCA interaction varied from 6 to 45μM in linoleamide and from 1.6 to 55μM in oleamide depending on the isoform. Linoleamide and oleamide inhibit SERCA activity in the micromolar concentration range, and in a different manner. Both amides mainly suppress SERCA activity by lowering the Ca 2+ affinity of the enzyme. Our findings imply a novel role of these PFAAs as modulators of intracellular Ca 2+ homeostasis via regulation of SERCA activity. Copyright © 2016 Elsevier B.V. All rights reserved.

The perilipin homologue, lipid storage droplet 2, regulates sleep homeostasis and prevents learning impairments following sleep loss.

PubMed

Thimgan, Matthew S; Suzuki, Yasuko; Seugnet, Laurent; Gottschalk, Laura; Shaw, Paul J

2010-08-31

Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking.

Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension.

PubMed

Hopps, Jamie J; Dunn, William R; Randall, Michael D

2012-06-05

Oleamide is an endocannabinoid-like, fatty acid amide with structural similarities to anandamide. The cardiovascular effects of anandamide are enhanced in hypertension and we have now examined how hypertension affects responses to oleamide. Vasorelaxant responses to oleamide were significantly (P<0.001) enhanced in aortic rings from spontaneously hypertensive rats (SHRs), such that the maximal relaxation to oleamide was 40.3 ± 3.5%, compared to 15.7 ± 3.9% in normotensive Wistar Kyoto (WKY) controls. The augmented responses to oleamide in SHR arteries were unaffected by either inhibition of nitric oxide synthase (300 μM l-NAME) or fatty acid amide hydrolase (1 μM URB597) and independent of cannabinoid CB(1) receptors or the endothelium. The enhanced responses to oleamide were opposed by pre-treatment with capsaicin (such that R(max) was reduced to 9.8 ± 1.5%) and this occurred independently of TRPV1 receptor and sensory nerve activity, as the TRPV1 antagonist capsazepine (1-5 μM) and the cation channel inhibitor ruthenium red (10 μM) had no effect on the responses to oleamide. However, inhibition of cyclooxygenase (10 μM indomethacin) enhanced the responses in the WKY aortae, such that the responses were comparable to those in the SHR. The results suggest that the cyclooxygenase pathway has a role in modulating vasorelaxation caused by oleamide in normotensive aortae and that this is lost in hypertension, possibly as an adaptation to the increase in blood pressure. Copyright © 2012 Elsevier B.V. All rights reserved.

Oleic acid derived metabolites in mouse neuroblastoma N18TG2 cells.

PubMed

Merkler, David J; Chew, Geoffrey H; Gee, Andrew J; Merkler, Kathleen A; Sorondo, Jean-Paul O; Johnson, Mitchell E

2004-10-05

Oleamide is an endogenous sleep-inducing lipid that has been isolated from the cerebrospinal fluid of sleep-deprived mammals. Oleamide is the best-understood member of the primary fatty acid amide family. One key unanswered question regarding oleamide and all other primary acid amides is the pathway by which these molecules are produced. One proposed pathway involves oleoyl-CoA and N-oleoylglycine as intermediates: oleic acid --> oleoyl-CoA --> N-oleoylglycine --> oleamide. The first and third reactions are known reactions, catalyzed by acyl-CoA synthetase and peptidylglycine alpha-amidating monooxygenase (PAM). Oleoyl-CoA formation from oleic acid has been demonstrated in vitro and in vivo while, to date, N-oleoylglycine cleavage to oleamide has been established only in vitro. PAM catalyzes the final step in alpha-amidated peptide biosynthesis, and its proposed role in primary fatty acid amide biosynthesis has been controversial. Mouse neuroblastoma N(18)TG(2) cells are an excellent model system for the study of oleamide biosynthesis because these cells convert [(14)C]-oleic acid to [(14)C]-oleamide and express PAM in a regulated fashion. We report herein that growth of the N(18)TG(2) cells in the presence of [(14)C]-oleic acid under conditions known to stimulate PAM expression generates an increase in [(14)C]-oleamide or in the presence of a PAM inhibitor generates [(14)C]-N-oleoylglycine. This represents the first identification of N-oleoylglycine from a biological source. In addition, N(18)TG(2) cell growth in the presence of N-oleoylglycine yields oleamide. These results strongly indicate that N-oleoylglycine is an intermediate in oleamide biosynthesis and provide further evidence that PAM does have a role in primary fatty acid amide production in vivo.

Polygonatum sibiricum rhizome promotes sleep by regulating non-rapid eye movement and GABAergic/serotonergic receptors in rodent models.

PubMed

Jo, Kyungae; Suh, Hyung Joo; Choi, Hyeon-Son

2018-05-29

The aim of this study is to investigate the sleep-promoting effect of a water extract of the Polygonatum sibiricum rhizome (PSE) in rodent models. PSE contained oleamide (0.10 mg/g extract) and glyceryl monolinoleate (0.17 mg/g extract), which are recognized as sleep-promoting substances. In pentobarbital-induced sleep model at hypnotic level, PSE (160 mg/kg) administration significantly decreased sleep latency time by 29% (2.7 min) and increased sleep duration time by 70% (68.4 min) compared with the normal control (3.8 min and 40.7 min, respectively). In the electroencephalography (EEG) analysis of rats, PSE-mediated sleep promotion accompanied the change of sleep architecture including increase of non-rapid eye movement (NREM) and decrease of REM. This sleep promoting effect was more obvious in caffeine-induced awakening model; total sleep time was increased by 40% along with increased NREM by PSE treatment at 160 mg/kg. In addition, PSE significantly increased the protein and mRNA levels of GABA A -R2 and 5-HT1A receptor, the major sleep-related neurotransmitter receptors. Furthermore, glyceryl monolinoleate and oleamide effectively bound to GABA A receptor in a competitive binding assay. These results indicate that PSE-mediated sleep-promoting effect is associated with the extension of NREM and upregulation of GABA A -R2 and 5-HT1A, and is mediated by binding to the GABA A receptor in vertebrate models. Copyright © 2018. Published by Elsevier Masson SAS.

Differential proteomic analysis of the anti-depressive effects of oleamide in a rat chronic mild stress model of depression.

PubMed

Ge, Lin; Zhu, Ming-Ming; Yang, Jing-Yu; Wang, Fang; Zhang, Rong; Zhang, Jing-Hai; Shen, Jing; Tian, Hui-Fang; Wu, Chun-Fu

2015-04-01

Depression is a complex psychiatric disorder, and its etiology and pathophysiology are not completely understood. Depression involves changes in many biogenic amine, neuropeptide, and oxidative systems, as well as alterations in neuroendocrine function and immune-inflammatory pathways. Oleamide is a fatty amide which exhibits pharmacological effects leading to hypnosis, sedation, and anti-anxiety effects. In the present study, the chronic mild stress (CMS) model was used to investigate the antidepressant-like activity of oleamide. Rats were exposed to 10weeks of CMS or control conditions and were then subsequently treated with 2weeks of daily oleamide (5mg/kg, i.p.), fluoxetine (10mg/kg, i.p.), or vehicle. Protein extracts from the hippocampus were then collected, and hippocampal maps were generated by way of two-dimensional gel electrophoresis (2-DE). Altered proteins induced by CMS and oleamide were identified through mass spectrometry and database searches. Compared to the control group, the CMS rats exhibited significantly less body weight gain and decreased sucrose consumption. Treatment with oleamide caused a reversal of the CMS-induced deficit in sucrose consumption. In the proteomic analysis, 12 protein spots were selected and identified. CMS increased the levels of adenylate kinase isoenzyme 1 (AK1), nucleoside diphosphate kinase B (NDKB), histidine triad nucleotide-binding protein 1 (HINT1), acyl-protein thioesterase 2 (APT-2), and glutathione S-transferase A4 (GSTA4). Compared to the CMS samples, seven spots changed significantly following treatment with oleamide, including GSTA4, glutathione S-transferase A6 (GSTA6), GTP-binding nuclear protein Ran (Ran-GTP), ATP synthase subunit d, transgelin-3, small ubiquitin-related modifier 2 (SUMO2), and eukaryotic translation initiation factor 5A-1 (eIF5A1). Of these seven proteins, the level of eIF5A1 was up-regulated, whereas the remaining proteins were down-regulated. In conclusion, oleamide has antidepressant

Changes in Plasma Lipids during Exposure to Total Sleep Deprivation.

PubMed

Chua, Eric Chern-Pin; Shui, Guanghou; Cazenave-Gassiot, Amaury; Wenk, Markus R; Gooley, Joshua J

2015-11-01

The effects of sleep loss on plasma lipids, which play an important role in energy homeostasis and signaling, have not been systematically examined. Our aim was to identify lipid species in plasma that increase or decrease reliably during exposure to total sleep deprivation. Twenty individuals underwent sleep deprivation in a laboratory setting. Blood was drawn every 4 h and mass spectrometry techniques were used to analyze concentrations of 263 lipid species in plasma, including glycerolipids, glycerophospholipids, sphingolipids, and sterols. Chronobiology and Sleep Laboratory, Duke-NUS Graduate Medical School. Healthy ethnic-Chinese males aged 21-28 y (n = 20). Subjects were kept awake for 40 consecutive hours. Each metabolite time series was modeled as a sum of sinusoidal (circadian) and linear components, and we assessed whether the slope of the linear component differed from zero. More than a third of all individually analyzed lipid profiles exhibited a circadian rhythm and/or a linear change in concentration during sleep deprivation. Twenty-five lipid species showed a linear and predominantly unidirectional trend in concentration levels that was consistent across participants. Choline plasmalogen levels decreased, whereas several phosphatidylcholine (PC) species and triacylglycerides (TAG) carrying polyunsaturated fatty acids increased. The decrease in choline plasmalogen levels during sleep deprivation is consistent with prior work demonstrating that these lipids are susceptible to degradation by oxidative stress. The increase in phosphatidylcholines and triacylglycerides suggests that sleep loss might modulate lipid metabolism, which has potential implications for metabolic health in individuals who do not achieve adequate sleep. © 2015 Associated Professional Sleep Societies, LLC.

[Natural factors influencing sleep].

PubMed

Jurkowski, Marek K; Bobek-Billewicz, Barbara

2007-01-01

Sleep is a universal phenomenon of human and animal lives, although the importance of sleep for homeo-stasis is still unknown. Sleep disturbances influence many behavioral and physiologic processes, leading to health complications including death. On the other hand, sleep improvement can beneficially influence the course of healing of many disorders and can be a prognostic of health recovery. The factors influencing sleep have different biological and chemical origins. They are classical hormones, hypothalamic releasing and inhibitory hormones, neuropeptides, peptides and others as cytokines, prostaglandins, oleamid, adenosine, nitric oxide. These factors regulate most physiologic processes and are likely elements integrating sleep with physiology and physiology with sleep in health and disorders.

Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor.

PubMed

Hoi, Pui Man; Hiley, C Robin

2006-03-01

Oleamide (cis-9-octadecenoamide) exhibits some cannabimimetic responses despite its low affinities at the currently known cannabinoid receptors. Here we have investigated whether or not it is a vasorelaxant in rat small mesenteric arteries. Oleamide elicited vasorelaxation (EC50=1.2+/-0.2 microM, Rmax=99.1+/-3.9%, n=8) which was reduced by endothelial removal. Nitric oxide synthase inhibition reduced the response (EC50=5.3+/-1.6 microM, Rmax=59.2+/-7.7%, n=7; P<0.01) as did blockade of Ca2+-sensitive K+ channels (KCa) with apamin plus charybdotoxin (both 50 nM) (EC50=2.1+/-0.2 microM, Rmax=58.4+/-1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 microM for 30 min) shifted the oleamide concentration-response curve approximately 30-fold to the right (n=7; P<0.01). Pertussis toxin (400 ng ml-1 for 2 h) caused a two-fold shift in the response curve (EC50=2.2+/-0.4 microM, Rmax=66.8+/-4.5%, n=6; P<0.01). Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 microM) significantly inhibited relaxation induced by oleamide (EC50=3.5+/-0.3 microM, Rmax=75.1+/-1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 microM), nor the CB2 antagonist, SR144528 (1 microM), had significant effects. O-1918 (10 microM), a putative antagonist at a novel endothelial cannabinoid receptor (abnormal-cannabidiol site), markedly reduced the relaxation to oleamide (n=7; P<0.01). It is concluded that oleamide responses in the rat isolated small mesenteric artery are partly dependent on the presence of the endothelium, activation of Ca2+-sensitive K+ channels (KC)) and involve capsaicin-sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O-1918, and coupled to KC) and Gi/o) with anandamide in this vessel. This might be distinct from both of the known cannabinoid receptors and the novel abnormal-cannabidiol site.

Oleamide derivatives suppress the spontaneous metastasis by inhibiting connexin 26.

PubMed

Ohba, Yusuke; Kanao, Yukiko; Morita, Nobuyoshi; Fujii, Eri; Hohrai, Mai; Takatsuji, Mayuko; Hirose, Hideki; Miura, Daisaku; Watari, Akihiro; Yutsudo, Masuo; Zhao, Hanjun; Yabuta, Norikazu; Ito, Akihiko; Kita, Yasuyuki; Nojima, Hiroshi

2007-07-01

We previously reported that overexpressing connexin 26 (Cx26) enhances the spontaneous metastasis of mouse BL6 melanoma cells. In contrast, daily intraperitoneal injections of an oleamide derivative named MI-18 potently inhibits the spontaneous metastasis of BL6 cells. In the present study, we chemically synthesized a novel oleamide derivative named MI-22 and found that it also efficiently suppressed the spontaneous metastasis of BL6 cells. Both MI-18 and MI-22 inhibited the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of the hCx26 and hCx32 human connexin subtypes; however, they had no effect on GJIC mediated by hCx40, hCx43 or hCx45. Fluorescently labeled MI-18 primarily localized not only at plasma membrane but also at Golgi/endosome. This suggests that this oleamide derivative may also act on the Cx26 molecules that accumulate in the Golgi/endosome because of their overexpression. Notably, neither derivative had a cytotoxic effect on HeLa cells when they were added into the tissue culture medium. Taken together, we propose that the MI-18 and MI-22 oleamide derivatives may serve as prototypes for novel and clinically important anticancer drugs.

Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor

PubMed Central

Hoi, Pui Man; Hiley, C Robin

2006-01-01

Oleamide (cis-9-octadecenoamide) exhibits some cannabimimetic responses despite its low affinities at the currently known cannabinoid receptors. Here we have investigated whether or not it is a vasorelaxant in rat small mesenteric arteries. Oleamide elicited vasorelaxation (EC50=1.2±0.2 μM, Rmax=99.1±3.9%, n=8) which was reduced by endothelial removal. Nitric oxide synthase inhibition reduced the response (EC50=5.3±1.6 μM, Rmax=59.2±7.7%, n=7; P<0.01) as did blockade of Ca2+-sensitive K+ channels (KCa) with apamin plus charybdotoxin (both 50 nM) (EC50=2.1±0.2 μM, Rmax=58.4±1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 μM for 30 min) shifted the oleamide concentration–response curve ∼30-fold to the right (n=7; P<0.01). Pertussis toxin (400 ng ml−1 for 2 h) caused a two-fold shift in the response curve (EC50=2.2±0.4 μM, Rmax=66.8±4.5%, n=6; P<0.01). Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 μM) significantly inhibited relaxation induced by oleamide (EC50=3.5±0.3 μM, Rmax=75.1±1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 μM), nor the CB2 antagonist, SR144528 (1 μM), had significant effects. O-1918 (10 μM), a putative antagonist at a novel endothelial cannabinoid receptor (abnormal-cannabidiol site), markedly reduced the relaxation to oleamide (n=7; P<0.01). It is concluded that oleamide responses in the rat isolated small mesenteric artery are partly dependent on the presence of the endothelium, activation of Ca2+-sensitive K+ channels (KCa) and involve capsaicin-sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O-1918, and coupled to KCa and Gi/o) with anandamide in this vessel. This might be distinct from both of the known cannabinoid receptors and the novel abnormal-cannabidiol site. PMID:16415907

Growth inhibition and possible mechanism of oleamide against the toxin-producing cyanobacterium Microcystis aeruginosa NIES-843.

PubMed

Shao, Jihai; He, Yaxian; Li, Fan; Zhang, Huiling; Chen, Anwei; Luo, Si; Gu, Ji-Dong

2016-01-01

Oleamide, a fatty acid derivative, shows inhibitory effect against the bloom-forming cyanobacterium Microcystis aeruginosa. The EC50 of oleamide on the growth of M. aeruginosa NIES-843 was 8.60 ± 1.20 mg/L. In order to elucidate the possible mechanism of toxicity of oleamide against M. aeruginosa, chlorophyll fluorescence transient, cellular ultrastructure, fatty acids composition and the transcription of the mcyB gene involved in microcystins synthesis were studied. The results of chlorophyll fluorescence transient showed that oleamide could destruct the electron accepting side of the photosystem II of M. aeruginosa NIES-843. Cellular ultrastructure examination indicated that the destruction of fatty acid constituents, the distortion of thylakoid membrane and the loss of integrity of cell membrane were associated with oleamide treatment and concentration. The damage of cellular membrane increased the release of microcystins from intact cells into the medium. Results presented in this study provide new information on the possible mechanisms involved and potential utilization of oleamide as an algicide in cyanobacterial bloom control.

Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro.

PubMed

Dionisi, Mauro; Alexander, Stephen P H; Bennett, Andrew J

2012-05-14

Oleamide (ODA) is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs) as potential targets for ODA action. Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

On the lipid composition of human meibum and tears: comparative analysis of nonpolar lipids.

PubMed

Butovich, Igor A

2008-09-01

To qualitatively compare the nonpolar lipids present in meibomian gland (MG) secretions (samples T1) with aqueous tears (AT) collected from the lower tear menisci of healthy, non-dry eye volunteers using either glass microcapillaries (samples T2) or Schirmer test strips (samples T3). Samples T1 to T3 were analyzed with the use of high-pressure liquid chromatography/positive ion mode atmospheric pressure chemical ionization mass spectrometry. Where possible, the unknown lipids were compared with known standards. Samples T1 had the simplest lipid composition among all the tested specimens. Samples T2 and T3 were similar to each other but were noticeably different from samples T1. In addition to all the compounds detected in samples T1, lower molecular weight wax esters and other compounds were found in samples T2 and T3. No appreciable amounts of fatty acid amides (e.g., oleamide), ceramides, or monoacyl glycerols were routinely detected. The occasionally observed minor signals of oleamide (m/z 282) in samples T3 were attributed to the contamination of the samples with common plasticizers routinely found in plastic ware extractives and organic solvents. The MG is a prominent source of lipids for the tear film. However, it would have been a mistake to exclude from consideration other likely sources of lipids such as conjunctiva, cornea, and tears produced by the lacrimal glands. These data showed that lipids in AT are more complex than MG secretions, which necessitates more cautious interpretation of the functions of the latter in the tear film.

Separate and Joint Associations of Shift Work and Sleep Quality with Lipids.

PubMed

Charles, Luenda E; Gu, Ja K; Tinney-Zara, Cathy A; Fekedulegn, Desta; Ma, Claudia C; Baughman, Penelope; Hartley, Tara A; Andrew, Michael E; Violanti, John M; Burchfiel, Cecil M

2016-06-01

Shift work and/or sleep quality may affect health. We investigated whether shift work and sleep quality, separately and jointly, were associated with abnormal levels of triglycerides, total cholesterol (TC), and low-and high-density lipoprotein cholesterol in 360 police officers (27.5% women). Triglycerides, TC, and high-density lipoprotein were analyzed on the Abbott Architect; low-density lipoprotein was calculated. Shift work was assessed using City of Buffalo payroll work history records. Sleep quality (good, ≤ 5; intermediate, 6-8; poor, ≥ 9) was assessed using the Pittsburgh Sleep Quality Index questionnaire. A shift work + sleep quality variable was created: day plus good sleep; day plus poor sleep; afternoon/night plus good; and poor sleep quality. Mean values of lipid biomarkers were compared across categories of the exposures using analysis of variance/analysis of covariance. Shift work was not significantly associated with lipids. However, as sleep quality worsened, mean levels of triglycerides and TC gradually increased but only among female officers (age- and race-adjusted p = 0.013 and 0.030, respectively). Age significantly modified the association between sleep quality and TC. Among officers ≥ 40 years old, those reporting poor sleep quality had a significantly higher mean level of TC (202.9 ± 3.7 mg/dL) compared with those reporting good sleep quality (190.6 ± 4.0 mg/dL) (gender- and race-adjusted p = 0.010). Female officers who worked the day shift and also reported good sleep quality had the lowest mean level of TC compared with women in the other three categories (p = 0.014). Sleep quality and its combined influence with shift work may play a role in the alteration of some lipid measures.

Human longevity is associated with regular sleep patterns, maintenance of slow wave sleep, and favorable lipid profile

PubMed Central

Mazzotti, Diego Robles; Guindalini, Camila; Moraes, Walter André dos Santos; Andersen, Monica Levy; Cendoroglo, Maysa Seabra; Ramos, Luiz Roberto; Tufik, Sergio

2014-01-01

Some individuals are able to successfully reach very old ages, reflecting higher adaptation against age-associated effects. Sleep is one of the processes deeply affected by aging; however few studies evaluating sleep in long-lived individuals (aged over 85) have been reported to date. The aim of this study was to characterize the sleep patterns and biochemical profile of oldest old individuals (N = 10, age 85–105 years old) and compare them to young adults (N = 15, age 20–30 years old) and older adults (N = 13, age 60–70 years old). All subjects underwent full-night polysomnography, 1-week of actigraphic recording and peripheral blood collection. Sleep electroencephalogram spectral analysis was also performed. The oldest old individuals showed lower sleep efficiency and REM sleep when compared to the older adults, while stage N3 percentage and delta power were similar across the groups. Oldest old individuals maintained strictly regular sleep-wake schedules and also presented higher HDL-cholesterol and lower triglyceride levels than older adults. The present study revealed novel data regarding specific sleep patterns and maintenance of slow wave sleep in the oldest old group. Taken together with the favorable lipid profile, these results contribute with evidence to the importance of sleep and lipid metabolism regulation in the maintenance of longevity in humans. PMID:25009494

Sustained Sleep Fragmentation Induces Sleep Homeostasis in Mice

PubMed Central

Baud, Maxime O.; Magistretti, Pierre J.; Petit, Jean-Marie

2015-01-01

Study Objectives: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. Design: N/A. Setting: Animal sleep research laboratory. Participants : Sixty-six C57BL6/J adult mice. Interventions: Instrumental sleep disruption at a rate of 60/h during 14 days Measurements and Results: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1–4 Hz) and other frequencies as well (4–40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Conclusions: Chronic sleep fragmentation (SF) increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF. Citation: Baud MO, Magistretti PJ, Petit JM. Sustained sleep fragmentation induces sleep homeostasis in mice. SLEEP 2015;38(4):567–579. PMID:25325477

On the Lipid Composition of Human Meibum and Tears: Comparative Analysis of Nonpolar Lipids

PubMed Central

Butovich, Igor A.

2009-01-01

PURPOSE To qualitatively compare the nonpolar lipids present in meibomian gland (MG) secretions (samples T1) with aqueous tears (AT) collected from the lower tear menisci of healthy, non-dry eye volunteers using either glass microcapillaries (samples T2) or Schirmer test strips (samples T3). METHODS Samples T1 to T3 were analyzed with the use of high-pressure liquid chromatography/positive ion mode atmospheric pressure chemical ionization mass spectrometry. Where possible, the unknown lipids were compared with known standards. RESULTS Samples T1 had the simplest lipid composition among all the tested specimens. Samples T2 and T3 were similar to each other but were noticeably different from samples T1. In addition to all the compounds detected in samples T1, lower molecular weight wax esters and other compounds were found in samples T2 and T3. No appreciable amounts of fatty acid amides (e.g., oleamide), ceramides, or monoacyl glycerols were routinely detected. The occasionally observed minor signals of oleamide (m/z 282) in samples T3 were attributed to the contamination of the samples with common plasticizers routinely found in plastic ware extractives and organic solvents. CONCLUSIONS The MG is a prominent source of lipids for the tear film. However, it would have been a mistake to exclude from consideration other likely sources of lipids such as conjunctiva, cornea, and tears produced by the lacrimal glands. These data showed that lipids in AT are more complex than MG secretions, which necessitates more cautious interpretation of the functions of the latter in the tear film. PMID:18487374

Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice.

PubMed

Singh, Anant; Kumar, Anil

2008-04-01

Sleep deprivation is considered as a risk factor for various diseases. Sleep deprivation leads to behavioral, hormonal, neurochemical and biochemical alterations in the animals. The present study was designed to explore the possible involvement of GABAergic mechanism in protective effect of alprazolam against 72h sleep deprivation-induced behavior alterations and oxidative damage in mice. In the present study, sleep deprivation caused anxiety-like behavior, weight loss, impaired ambulatory movements and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep-deprived mice brain. Treatment with alprazolam (0.25 and 0.5 mg/kg, ip) significantly improved behavioral alterations. Biochemically, alprazolam treatment significantly restored depleted reduced glutathione, catalase activity, reversed raised lipid peroxidation and nitrite level. Combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of alprazolam (0.25mg/kg) significantly antagonized protective effect of alprazolam. However, combination of muscimol (0.05 mg/kg) with alprazolam (0.25 mg/kg, ip) potentiated protective effect of alprazolam. On the basis of these results, it might be suggested that alprazolam might produce protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.

Determination of oleamide and erucamide in polyethylene films by pressurised fluid extraction and gas chromatography.

PubMed

Garrido-López, Alvaro; Esquiu, Vanesa; Tena, María Teresa

2006-08-18

A pressurized fluid extraction (PFE) and gas chromatography-flame ionization detection (GC-FID) method is proposed to determine the slip agents in polyethylene (PE) films. The study of PFE variables was performed using a fractional factorial design (FFD) for screening and a central composite design (CCD) for optimizing the main variables obtained from the Pareto charts. The variables that were studied include temperature, static time, percentage of cyclohexane and the number of extraction cycles. The final condition selected was pure isopropanol (two times) at 105 degrees C for 16min. The recovery of spiked oleamide and erucamide was around 100%. The repeatability of the method was between 9.6% for oleamide and 8% for erucamide, expressed as relative standard deviation. Finally, the method was applied to determine oleamide and erucamide in several polyethylene films and the results were statistically equal to those obtained by pyrolysis and gas-phase chemiluminescence (CL).

Identification of fatty acids and fatty acid amides in human meibomian gland secretions.

PubMed

Nichols, Kelly K; Ham, Bryan M; Nichols, Jason J; Ziegler, Corrie; Green-Church, Kari B

2007-01-01

The complex superficial lipid layer of the tear film functions to prevent evaporation and maintain tear stability. Although classes of lipids found in the tear film have been reported, individual lipid species are currently being studied with more sophisticated. The purpose of this work was to show the identification of fatty acids and the fatty acid amides in human meibomian gland secretions by using electrospray mass spectrometry. methods. Human meibomian gland secretions (meibum) were analyzed by electrospray quadrupole time-of-flight mass spectrometry (positive- and negative-ion mode). Accurate mass determination and collision-induced dissociation of meibum, and lipid standards were used to identify lipid species. Mass analysis of meibum in an acidic chloroform-methanol solution in positive-ion mode revealed a mass peak of m/z 282.3, which was identified as the protonated molecule of oleamide [C(18)H(35)NO+H](+). The high-resolution mass analysis of the m/z 282.2788 peak (oleamide) demonstrated a mass accuracy of 3.2 parts per million (ppm). Collision-induced dissociation of this species from meibum, compared with an oleamide standard, confirmed its identification. Myristic, palmitic, stearic, and oleic free fatty acids were identified in a similar manner, as were the other fatty acid amides (myristamide, palmitamide, stearamide, and erucamide). The findings indicate that oleamide (cis-9-octadecenamide), an endogenous fatty acid primary amide, is a predominant component of meibum when examined by electrospray mass spectrometry. The novel finding of oleamide and other members of the fatty acid amide family in the tear film could lead to additional insights into the role of fatty acid amide activity in human biological systems and may indicate a new function for this lipid class of molecules in ocular surface signaling and/or in the maintenance of the complex tear film.

Proteins regulating the biosynthesis and inactivation of neuromodulatory fatty acid amides.

PubMed

Patricelli, M P; Cravatt, B F

2001-01-01

Fatty acid amides (FAAs) represent a growing family of biologically active lipids implicated in a diverse range of cellular and physiological processes. At present, two general types of fatty acid amides, the N-acylethanolamines (NAEs) and the fatty acid primary amides (FAPAs), have been identified as potential physiological neuromodulators/neurotransmitters in mammals. Representative members of these two subfamilies include the endocannabinoid NAE anandamide and the sleep-inducing FAPA oleamide. In this Chapter, molecular mechanisms proposed for the biosynthesis and inactivation of FAAs are critically evaluated, with an emphasis placed on the biochemical and cell biological properties of proteins thought to mediate these processes.

Obstructive sleep apnoea treatment and fasting lipids: a comparative effectiveness study.

PubMed

Keenan, Brendan T; Maislin, Greg; Sunwoo, Bernie Y; Arnardottir, Erna Sif; Jackson, Nicholas; Olafsson, Isleifur; Juliusson, Sigurdur; Schwab, Richard J; Gislason, Thorarinn; Benediktsdottir, Bryndis; Pack, Allan I

2014-08-01

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes. Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified. At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed. Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA. ©ERS 2014.

Characterization of the sleep-wake patterns in mice lacking fatty acid amide hydrolase.

PubMed

Huitron-Resendiz, Salvador; Sanchez-Alavez, Manuel; Wills, Derek N; Cravatt, Benjamin F; Henriksen, Steven J

2004-08-01

Oleamide and anandamide are fatty acid amides implicated in the regulatory mechanisms of sleep processes. However, due to their prompt catabolism by fatty acid amide hydrolase (FAAH), their pharmacologic and behavioral effects, in vivo, disappear rapidly. To determine if, in the absence of FAAH, the hypnogenic fatty acid amides induce an increase of sleep, we characterized the sleep-wake patters in FAAH-knockout mice [FAAH (-/-)] before and after sleep deprivation. FAAH (-/-), FAAH (+/-), and FAAH (+/+) mice were implanted chronically for sleep, body temperature (Tb), and locomotor activity (LMA) recordings. Sleep-wake states were recorded during a 24-hour baseline session followed by 8 hours of sleep deprivation. Recovery recordings were done during the 16 hours following sleep deprivation. Total amount of wake, slow-wave sleep, and rapid eye movement sleep were calculated and compared between genotypes. The electroencephalographic spectral analysis was performed by fast Fourier transform analysis. Telemetry recordings of Tb and LMA were carried out continuously during 4 days under baseline conditions. N/A. FAAH (-/-) mice and their heterozygote (+/-) and control (+/+) littermates were used. Sleep deprivation. FAAH (-/-) mice possess higher values of slow-wave sleep and more intense episodes of slow-wave sleep than do control littermates under baseline conditions that are not related to differences in Tb and LMA. A rebound of slow-wave sleep and rapid eye movement sleep as well an increase in the levels of slow-wave activity were observed after sleep deprivation in all genotypes. These findings support the role of fatty acid amides as possible modulators of sleep and indicate that the homeostatic mechanisms of sleep in FAAH (-/-) mice are not disrupted.

Effects of different periods of paradoxical sleep deprivation and sleep recovery on lipid and glucose metabolism and appetite hormones in rats.

PubMed

Brianza-Padilla, Malinalli; Bonilla-Jaime, Herlinda; Almanza-Pérez, Julio César; López-López, Ana Laura; Sánchez-Muñoz, Fausto; Vázquez-Palacios, Gonzalo

2016-03-01

Sleep has a fundamental role in the regulation of energy balance, and it is an essential and natural process whose precise impacts on health and disease have not yet been fully elucidated. The aim of this study was to assess the consequences of different periods of paradoxical sleep deprivation (PSD) and recovery from PSD on lipid profile, oral glucose tolerance test (OGTT) results, and changes in insulin, corticosterone, ghrelin, and leptin concentrations. Three-month-old male Wistar rats weighing 250-350 g were submitted to 24, 96, or 192 h of PSD or 192 h of PSD with 480 h of recovery. The PSD was induced by the multiple platforms method. Subsequently, the animals were submitted to an OGTT. One day later, the animals were killed and the levels of triglycerides, total cholesterol, lipoproteins (low-density lipoprotein, very-low-density lipoprotein, and high-density lipoprotein), insulin, ghrelin, leptin, and corticosterone in plasma were quantified. There was a progressive decrease in body weight with increasing duration of PSD. The PSD induced basal hypoglycemia over all time periods evaluated. Evaluation of areas under the curve revealed progressive hypoglycemia only after 96 and 192 h of PSD. There was an increase in corticosterone levels after 192 h of PSD. We conclude that PSD induces alterations in metabolism that are reversed after a recovery period of 20 days.

Sleep self-intoxication and sleep driving as rare zolpidem-induced complex behaviour.

PubMed

Paulke, Alexander; Wunder, Cora; Toennes, Stefan W

2015-01-01

The GABA(A) receptor agonist zolpidem has been used for treatment of insomnia since years, but special side effects have been reported. These side effects were called zolpidem-induced sleep-related complex behaviour. Such complex behaviour is associated with somnambulism and includes sleepwalking, sleep eating, sleep conversation and sleep driving. Two cases of zolpidem-induced sleep-related complex behaviour following self-intoxication, sleep driving and amnesia are presented. In both cases, the subjects reported the voluntary intake of only one zolpidem tablet of 10 mg and amnesia for the time afterwards. Shortly after the onset of the drug's action, both individuals drifted into a somnambulism-like state and toxicological blood analysis suggested the intake of the remaining zolpidem tablets which might be called "sleep intoxication". Later, the subjects were arrested by police after driving under drug influence and not realizing the situation. Retrospectively, both subjects suffered from psychiatric disorders and in case 2, the subject was treated for depression with doxepin. Consequently, these co-factors may have increased the risk for the occurrence of the sleep-related complex behaviour. Involuntary self-intoxication should be taken into account in addition to the known pattern of zolpidem-induced complex behaviour. In legal cases, the forensic expert has to assess the blood concentration of zolpidem in evaluating this strange behaviour. Amnesia and incoherence of speech, disorganization of behaviour, inability to realize the situation and mood changes may indicate a zolpidem-induced somnambulism-like state with sleep-related complex behaviour.

Aging induced ER stress alters sleep and sleep homeostasis

PubMed Central

Brown, Marishka K.; Chan, May T.; Zimmerman, John E.; Pack, Allan I.; Jackson, Nicholas E.; Naidoo, Nirinjini

2014-01-01

Alterations in the quality, quantity and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response (UPR). The effectiveness of the adaptive UPR is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of x-box binding protein 1 (XBP1) and upregulation of phosphorylated elongation initiation factor 2 α (p-eIF2α), in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged/sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep/ sleep debt discharge. PMID:24444805

FMRFamide signaling promotes stress-induced sleep in Drosophila

PubMed Central

Lenz, Olivia; Xiong, Jianmei; Nelson, Matthew D.; Raizen, David M.; Williams, Julie A.

2015-01-01

Enhanced sleep in response to cellular stress is a conserved adaptive behavior across multiple species, but the mechanism of this process is poorly understood. Drosophila melanogaster increases sleep following exposure to septic or aseptic injury, and Caenorhabditis elegans displays sleep-like quiescence following exposure to high temperatures that stress cells. We show here that, similar to C. elegans, Drosophila responds to heat stress with an increase in sleep. In contrast to Drosophila infection-induced sleep, heat-induced sleep is not sensitive to the time-of-day of the heat pulse. Moreover, the sleep response to heat stress does not require Relish, the NFκB transcription factor that is necessary for infection-induced sleep, indicating that sleep is induced by multiple mechanisms from different stress modalities. We identify a sleep-regulating role for a signaling pathway involving FMRFamide neuropeptides and their receptor FR. Animals mutant for either FMRFamide or for the FMRFamide receptor (FR) have a reduced recovery sleep in response to heat stress. FR mutants, in addition, show reduced sleep responses following infection with Serratia marcescens, and succumb to infection at a faster rate than wild-type controls. Together, these findings support the hypothesis that FMRFamide and its receptor promote an adaptive increase in sleep following stress. Because an FMRFamide-like neuropeptide plays a similar role in C. elegans, we propose that FRMFamide neuropeptide signaling is an ancient regulator of recovery sleep which occurs in response to cellular stress. PMID:25668617

FMRFamide signaling promotes stress-induced sleep in Drosophila.

PubMed

Lenz, Olivia; Xiong, Jianmei; Nelson, Matthew D; Raizen, David M; Williams, Julie A

2015-07-01

Enhanced sleep in response to cellular stress is a conserved adaptive behavior across multiple species, but the mechanism of this process is poorly understood. Drosophila melanogaster increases sleep following exposure to septic or aseptic injury, and Caenorhabditis elegans displays sleep-like quiescence following exposure to high temperatures that stress cells. We show here that, similar to C. elegans, Drosophila responds to heat stress with an increase in sleep. In contrast to Drosophila infection-induced sleep, heat-induced sleep is not sensitive to the time-of-day of the heat pulse. Moreover, the sleep response to heat stress does not require Relish, the NFκB transcription factor that is necessary for infection-induced sleep, indicating that sleep is induced by multiple mechanisms from different stress modalities. We identify a sleep-regulating role for a signaling pathway involving FMRFamide neuropeptides and their receptor FR. Animals mutant for either FMRFamide or for the FMRFamide receptor (FR) have a reduced recovery sleep in response to heat stress. FR mutants, in addition, show reduced sleep responses following infection with Serratia marcescens, and succumb to infection at a faster rate than wild-type controls. Together, these findings support the hypothesis that FMRFamide and its receptor promote an adaptive increase in sleep following stress. Because an FMRFamide-like neuropeptide plays a similar role in C. elegans, we propose that FRMFamide neuropeptide signaling is an ancient regulator of recovery sleep which occurs in response to cellular stress. Copyright © 2015 Elsevier Inc. All rights reserved.

Membrane protein crystallization in meso: lipid type-tailoring of the cubic phase.

PubMed Central

Cherezov, Vadim; Clogston, Jeffrey; Misquitta, Yohann; Abdel-Gawad, Wissam; Caffrey, Martin

2002-01-01

Hydrated monoolein forms the cubic-Pn3m mesophase that has been used for in meso crystallization of membrane proteins. The crystals have subsequently provided high-resolution structures by crystallographic means. It is possible that the hosting cubic phase created by monoolein alone, which itself is not a common membrane component, will limit the range of membrane proteins crystallizable by the in meso method. With a view to expanding the range of applicability of the method, we investigated by x-ray diffraction the degree to which the reference cubic-Pn3m phase formed by hydrated monoolein could be modified by other lipid types. These included phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylserine, cardiolipin, lyso-PC, a polyethylene glycol-lipid, 2-monoolein, oleamide, and cholesterol. The results show that all nine lipids were accommodated in the cubic phase to some extent without altering phase identity. The positional isomer, 2-monoolein, was tolerated to the highest level. The least well tolerated were the anionic lipids, followed by lyso-PC. The others were accommodated to the extent of 20-25 mol %. Beyond a certain concentration limit, the lipid additives either triggered one or a series of phase transitions or saturated the phase and separated out as crystals, as seen with oleamide and cholesterol. The series of phases observed and their order of appearance were consistent with expectations in terms of interfacial curvature changes. The changes in phase type and microstructure have been rationalized on the basis of lipid molecular shape, interfacial curvature, and chain packing energy. The data should prove useful in the rational design of cubic phase crystallization matrices with different lipid profiles that match the needs of a greater range of membrane proteins. PMID:12496106

Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis.

PubMed

Brown, Marishka K; Chan, May T; Zimmerman, John E; Pack, Allan I; Jackson, Nicholas E; Naidoo, Nirinjini

2014-06-01

Alterations in the quality, quantity, and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response. The effectiveness of the adaptive unfolded protein response is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of X-box binding protein 1 and upregulation of phosphorylated elongation initiation factor 2 α, in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged or sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep or sleep debt discharge. Copyright © 2014 Elsevier Inc. All rights reserved.

Identification of genes associated with resilience/vulnerability to sleep deprivation and starvation in Drosophila.

PubMed

Thimgan, Matthew S; Seugnet, Laurent; Turk, John; Shaw, Paul J

2015-05-01

Flies mutant for the canonical clock protein cycle (cyc(01)) exhibit a sleep rebound that is ∼10 times larger than wild-type flies and die after only 10 h of sleep deprivation. Surprisingly, when starved, cyc(01) mutants can remain awake for 28 h without demonstrating negative outcomes. Thus, we hypothesized that identifying transcripts that are differentially regulated between waking induced by sleep deprivation and waking induced by starvation would identify genes that underlie the deleterious effects of sleep deprivation and/or protect flies from the negative consequences of waking. We used partial complementary DNA microarrays to identify transcripts that are differentially expressed between cyc(01) mutants that had been sleep deprived or starved for 7 h. We then used genetics to determine whether disrupting genes involved in lipid metabolism would exhibit alterations in their response to sleep deprivation. Laboratory. Drosophila melanogaster. Sleep deprivation and starvation. We identified 84 genes with transcript levels that were differentially modulated by 7 h of sleep deprivation and starvation in cyc(01) mutants and were confirmed in independent samples using quantitative polymerase chain reaction. Several of these genes were predicted to be lipid metabolism genes, including bubblegum, cueball, and CG4500, which based on our data we have renamed heimdall (hll). Using lipidomics we confirmed that knockdown of hll using RNA interference significantly decreased lipid stores. Importantly, genetically modifying bubblegum, cueball, or hll resulted in sleep rebound alterations following sleep deprivation compared to genetic background controls. We have identified a set of genes that may confer resilience/vulnerability to sleep deprivation and demonstrate that genes involved in lipid metabolism modulate sleep homeostasis. © 2015 Associated Professional Sleep Societies, LLC.

Involvement of the α1-adrenoceptor in sleep-waking and sleep loss-induced anxiety behavior in zebrafish.

PubMed

Singh, A; Subhashini, N; Sharma, S; Mallick, B N

2013-08-15

Sleep is a universal phenomenon in vertebrates, and its loss affects various behaviors. Independent studies have reported that sleep loss increases anxiety; however, the detailed mechanism is unknown. Because sleep deprivation increases noradrenalin (NA), which modulates many behaviors and induces patho-physiological changes, this study utilized zebrafish as a model to investigate whether sleep loss-induced increased anxiety is modulated by NA. Continuous behavioral quiescence for at least 6s was considered to represent sleep in zebrafish; although some authors termed it as a sleep-like state, in this study we have termed it as sleep. The activity of fish that signified sleep-waking was recorded in light-dark, during continuous dark and light; the latter induced sleep loss in fish. The latency, number of entries, time spent and distance travelled in the light chamber were assessed in a light-dark box test to estimate the anxiety behavior of normal, sleep-deprived and prazosin (PRZ)-treated fish. Zebrafish showed increased waking during light and complete loss of sleep upon continuous exposure to light for 24h. PRZ significantly increased sleep in normal fish. Sleep-deprived fish showed an increased preference for dark (expression of increased anxiety), and this effect was prevented by PRZ, which increased sleep as well. Our findings suggest that sleep loss-induced anxiety-like behavior in zebrafish is likely to be mediated by NA's action on the α1-adrenoceptor. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

PubMed

Brager, Allison J; Yang, Tao; Ehlen, J Christopher; Simon, Roger P; Meller, Robert; Paul, Ketema N

2016-11-01

Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities ( Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome. © 2016 Associated Professional Sleep Societies, LLC.

Effect of sleep-inducing music on sleep in persons with percutaneous transluminal coronary angiography in the cardiac care unit.

PubMed

Ryu, Min-Jung; Park, Jeong Sook; Park, Heeok

2012-03-01

The study compared the effect of earplug-delivered sleep-inducing music on sleep in persons with percutaneous transluminal coronary angiography in the cardiac care unit. Diverse types of music have been claimed to improve sleeping elsewhere, but relatively little is known in South Korea. Most studies investigating the effect of sleep-inducing music on sleep have involved persons with insomnia, even though many persons with cardiovascular disease in the intensive care unit suffer from sleeping problems. There is a need to investigate the effect of sleep-inducing music on sleep disorders in persons with percutaneous transluminal coronary angiography in the cardiac care unit. An experimental research design was used. Data collection was conducted in the cardiac care unit of K University Hospital in D city, from 3 September-4 October 2010. Fifty-eight subjects participated and were randomly assigned to the experimental group (earplug-delivered sleep-inducing music for 52 min beginning at 10:00 pm, while wearing an eyeshield, n = 29) and the control group (no music, but earplugs and eyeshield worn, n = 29). The quantity and quality of sleep were measured using questionnaires at 7 am the next morning for each group. Participants in the experimental group reported that the sleeping quantity and quality were significantly higher than control group (t = 3·181, p = 0·002, t = 5·269, p < 0·001, respectively). Sleep-inducing music significantly improved sleep in patients with percutaneous transluminal coronary angiography at a cardiac care unit. Offering earplugs and playing sleep-inducing music may be a meaningful and easily enacted nursing intervention to improve sleep for intensive care unit patients. Nurses working at cardiac care unit can use music to improve sleeping in clients with percutaneous transluminal coronary angiography. © 2011 Blackwell Publishing Ltd.

Interleukin-1 receptor (IL-1R) mediates epilepsy-induced sleep disruption.

PubMed

Huang, Tzu-Rung; Jou, Shuo-Bin; Chou, Yu-Ju; Yi, Pei-Lu; Chen, Chun-Jen; Chang, Fang-Chia

2016-11-22

Sleep disruptions are common in epilepsy patients. Our previous study demonstrates that homeostatic factors and circadian rhythm may mediate epilepsy-induced sleep disturbances when epilepsy occurs at different zeitgeber hours. The proinflammatory cytokine, interleukin-1 (IL-1), is a somnogenic cytokine and may also be involved in epileptogenesis; however, few studies emphasize the effect of IL-1 in epilepsy-induced sleep disruption. We herein hypothesized that IL-1 receptor type 1 (IL-1R1) mediates the pathogenesis of epilepsy and epilepsy-induced sleep disturbances. We determined the role of IL-1R1 by using IL-1R1 knockout (IL-1R1 -/- KO) mice. Our results elucidated the decrease of non-rapid eye movement (NREM) sleep during the light period in IL-1R -/- mice and confirmed the somnogenic role of IL-1R1. Rapid electrical amygdala kindling was performed to induce epilepsy at the particular zeitgeber time (ZT) point, ZT13. Our results demonstrated that seizure thresholds induced by kindling stimuli, such as the after-discharge threshold and successful kindling rates, were not altered in IL-1R -/- mice when compared to those obtained from the wildtype mice (IL-1R +/+ mice). This result suggests that IL-1R1 is not involved in kindling-induced epileptogenesis. During sleep, ZT13 kindling stimulation significantly enhanced NREM sleep during the subsequent 6 h (ZT13-18) in wildtype mice, and sleep returned to the baseline the following day. However, the kindling-induced sleep alteration was absent in the IL-1R -/- KO mice. These results indicate that the IL-1 signal mediates epilepsy-induced sleep disturbance, but dose not participate in kindling-induced epileptogenesis.

Corneal Neovascularization with Associated Lipid Keratopathy in a Patient with Obstructive Sleep Apnea-Hypopnea Syndrome Using a Continuous Positive Airway Pressure Machine.

PubMed

Oikonomakis, Konstantinos; Petrelli, Myrsini; Andreanos, Konstantinos; Mouchtouris, Andreas; Petrou, Petros; Georgalas, Ilias; Papaconstantinou, Dimitrios; Kymionis, George

2017-01-01

To report a case of corneal neovascularization with secondary lipid keratopathy in a patient treated with continuous positive airway pressure (CPAP) for obstructive sleep apnea-hypopnea syndrome (OSAHS). A 49-year-old male had been diagnosed with obstructive sleep apnea syndrome 10 years ago and has been treated with the application of a CPAP machine during night sleep ever since. For the past year, the patient had been complaining for ocular irritation and excessive tearing of the left eye on awakening. Slit-lamp biomicroscopy revealed the presence of neovascularization and lipid exudation in the inferior third of the cornea of the left eye. Ocular patching during night sleep resulted in recession of the reported symptoms and shrinkage of the neovascularization, while the area of lipid exudation ceased to enlarge. To the best of our knowledge, this is the first report of corneal neovascularization in a patient using a CPAP machine for OSAHS.

Identification of Genes Associated with Resilience/Vulnerability to Sleep Deprivation and Starvation in Drosophila

PubMed Central

Thimgan, Matthew S.; Seugnet, Laurent; Turk, John; Shaw, Paul J.

2015-01-01

Background and Study Objectives: Flies mutant for the canonical clock protein cycle (cyc01) exhibit a sleep rebound that is ∼10 times larger than wild-type flies and die after only 10 h of sleep deprivation. Surprisingly, when starved, cyc01 mutants can remain awake for 28 h without demonstrating negative outcomes. Thus, we hypothesized that identifying transcripts that are differentially regulated between waking induced by sleep deprivation and waking induced by starvation would identify genes that underlie the deleterious effects of sleep deprivation and/or protect flies from the negative consequences of waking. Design: We used partial complementary DNA microarrays to identify transcripts that are differentially expressed between cyc01 mutants that had been sleep deprived or starved for 7 h. We then used genetics to determine whether disrupting genes involved in lipid metabolism would exhibit alterations in their response to sleep deprivation. Setting: Laboratory. Patients or Participants: Drosophila melanogaster. Interventions: Sleep deprivation and starvation. Measurements and Results: We identified 84 genes with transcript levels that were differentially modulated by 7 h of sleep deprivation and starvation in cyc01 mutants and were confirmed in independent samples using quantitative polymerase chain reaction. Several of these genes were predicted to be lipid metabolism genes, including bubblegum, cueball, and CG4500, which based on our data we have renamed heimdall (hll). Using lipidomics we confirmed that knockdown of hll using RNA interference significantly decreased lipid stores. Importantly, genetically modifying bubblegum, cueball, or hll resulted in sleep rebound alterations following sleep deprivation compared to genetic background controls. Conclusions: We have identified a set of genes that may confer resilience/vulnerability to sleep deprivation and demonstrate that genes involved in lipid metabolism modulate sleep homeostasis. Citation: Thimgan MS

Sleep disturbance induces neuroinflammation and impairment of learning and memory.

PubMed

Zhu, Biao; Dong, Yuanlin; Xu, Zhipeng; Gompf, Heinrich S; Ward, Sarah A P; Xue, Zhanggang; Miao, Changhong; Zhang, Yiying; Chamberlin, Nancy L; Xie, Zhongcong

2012-12-01

Hospitalized patients can develop cognitive function decline, the mechanisms of which remain largely to be determined. Sleep disturbance often occurs in hospitalized patients, and neuroinflammation can induce learning and memory impairment. We therefore set out to determine whether sleep disturbance can induce neuroinflammation and impairment of learning and memory in rodents. Five to 6-month-old wild-type C57BL/6J male mice were used in the studies. The mice were placed in rocking cages for 24 h, and two rolling balls were present in each cage. The mice were tested for learning and memory function using the Fear Conditioning Test one and 7 days post-sleep disturbance. Neuroinflammation in the mouse brain tissues was also determined. Of the Fear Conditioning studies at one day and 7 days after sleep disturbance, twenty-four hour sleep disturbance decreased freezing time in the context test, which assesses hippocampus-dependent learning and memory; but not the tone test, which assesses hippocampus-independent learning and memory. Sleep disturbance increased pro-inflammatory cytokine IL-6 levels and induced microglia activation in the mouse hippocampus, but not the cortex. These results suggest that sleep disturbance induces neuroinflammation in the mouse hippocampus, and impairs hippocampus-dependent learning and memory in mice. Pending further studies, these findings suggest that sleep disturbance-induced neuroinflammation and impairment of learning and memory may contribute to the development of cognitive function decline in hospitalized patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Recurrent restriction of sleep and inadequate recuperation induce both adaptive changes and pathological outcomes

PubMed Central

Szabo, Aniko

2009-01-01

Chronic restriction of a basic biological need induces adaptations to help meet requisites for survival. The adaptations to chronic restriction of sleep are unknown. A single episode of 10 days of partial sleep loss in rats previously was shown to be tolerated and to result in increased food intake and loss of body weight as principal signs. The purpose of the present experiment was to investigate the extent to which adaptation to chronic sleep restriction would ameliorate short-term effects and result in a changed internal phenotype. Rats were studied during 10 wk of multiple periods of restricted and unrestricted sleep to allow adaptive changes to develop. Control rats received the same ambulatory requirements only consolidated into periods that lessened interruptions of their sleep. The results indicate a latent period of relatively stable food and water intake without weight gain, followed by a dynamic phase marked by enormous increases in food and water intake and progressive loss of body weight, without malabsorption of calories. Severe consequences ensued, marked especially by changes to the connective tissues, and became fatal for two individuals. The most striking changes to internal organs in sleep-restricted rats included lengthening of the small intestine, decreased size of adipocytes, and increased incidence of multilocular adipocytes. Major organs accounted for an increased proportion of total body mass. These changes to internal tissues appear adaptive in response to high energy production, decomposition of lipids, and increased need to absorb nutrients, but ultimately insufficient to compensate for inadequate sleep. PMID:19692662

Lithium Prevents REM Sleep Deprivation-Induced Impairments on Memory Consolidation

PubMed Central

Ota, Simone M.; Moreira, Karin Di Monteiro; Suchecki, Deborah; Oliveira, Maria Gabriela M.; Tiba, Paula A.

2013-01-01

Background: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. Objective: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. Design: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Subjects: Wistar male rats weighing 300-400 g. Results: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Conclusion: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained. Citation: Ota SM; Moreira KDM; Suchecki D; Oliveira MGM; Tiba PA. Lithium prevents REM sleep deprivation-induced impairments on memory consolidation. SLEEP 2013;36(11):1677-1684. PMID:24179301

Comparison of snoring sounds between natural and drug-induced sleep recorded using a smartphone.

PubMed

Koo, Soo Kweon; Kwon, Soon Bok; Moon, Ji Seung; Lee, Sang Hoon; Lee, Ho Byung; Lee, Sang Jun

2018-08-01

Snoring is an important clinical feature of obstructive sleep apnea (OSA), and recent studies suggest that the acoustic quality of snoring sounds is markedly different in drug-induced sleep compared with natural sleep. However, considering differences in sound recording methods and analysis parameters, further studies are required. This study explored whether acoustic analysis of drug-induced sleep is useful as a screening test that reflects the characteristics of natural sleep in snoring patients. The snoring sounds of 30 male subjects (mean age=41.8years) were recorded using a smartphone during natural and induced sleep, with the site of vibration noted during drug-induced sleep endoscopy (DISE); then, we compared the sound intensity (dB), formant frequencies, and spectrograms of snoring sounds. Regarding the intensity of snoring sounds, there were minor differences within the retrolingual level obstruction group, but there was no significant difference between natural and induced sleep at either obstruction site. There was no significant difference in the F 1 and F 2 formant frequencies of snoring sounds between natural sleep and induced sleep at either obstruction site. Compared with natural sleep, induced sleep was slightly more irregular, with a stronger intensity on the spectrogram, but the spectrograms showed the same pattern at both obstruction sites. Although further studies are required, the spectrograms and formant frequencies of the snoring sounds of induced sleep did not differ significantly from those of natural sleep, and may be used as a screening test that reflects the characteristics of natural sleep according to the obstruction site. Copyright © 2017 Elsevier B.V. All rights reserved.

The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

PubMed Central

Kim, Tae Won; Jeong, Jong-Hyun; Hong, Seung-Chul

2015-01-01

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. PMID:25861266

Aripiprazole-induced sleep-related eating disorder: a case report.

PubMed

Kobayashi, Nobuyuki; Takano, Masahiro

2018-04-05

Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep-related eating disorder. A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient's mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient's nocturnal eating episodes rapidly and completely disappeared. To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects.

Oscillatory brain activity in spontaneous and induced sleep stages in flies.

PubMed

Yap, Melvyn H W; Grabowska, Martyna J; Rohrscheib, Chelsie; Jeans, Rhiannon; Troup, Michael; Paulk, Angelique C; van Alphen, Bart; Shaw, Paul J; van Swinderen, Bruno

2017-11-28

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA A agonist Gaboxadol. We find a transitional sleep stage associated with a 7-10 Hz oscillation in the central brain during spontaneous sleep. Oscillatory activity is also evident when we acutely activate sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila. In contrast, sleep following Gaboxadol exposure is characterized by low-amplitude LFPs, during which dFB-induced effects are suppressed. Sleep in flies thus appears to involve at least two distinct stages: increased oscillatory activity, particularly during sleep induction, followed by desynchronized or decreased brain activity.

Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence

PubMed Central

Schmidt, Michelle A.; Wisor, Jonathan P.

2014-01-01

Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1 β in CD11b-positive monocytes within the brain. Here, we sought to determine whether activation of the interleukin 1 receptor (IL1R) drives the increase in the depth and amount of sleep that occurs subsequent to methamphetamine-induced wakefulness. IL1R-deficient mice and wild type control mice were subjected to systemic methamphetamine (1 and 2mg/kg) and saline treatments. The wake-promoting effect of methamphetamine was modestly potentiated by IL1R-deficiency. Additionally, the increase in time spent in NREMS subsequent to methamphetamine-induced wakefulness in wild type mice was abolished in IL1R-deficient mice. The increase in time spent asleep after 3 h of behaviorally enforced wakefulness was also abolished in IL1R-deficient mice. Increases in EEG slow wave activity triggered by methamphetamine and sleep deprivation were of equal magnitude in IL1R-deficient and wild type mice. These data demonstrate that IL1R activation contributes to hypersomnolence that occurs after sleep loss, whether that sleep loss is triggered pharmacologically by methamphetamine or through behavioral sleep deprivation. PMID:22387068

L-carnitine prevents memory impairment induced by chronic REM-sleep deprivation.

PubMed

Alzoubi, Karem H; Rababa'h, Abeer M; Owaisi, Amani; Khabour, Omar F

2017-05-01

Sleep deprivation (SD) negatively impacts memory, which was related to oxidative stress induced damage. L-carnitine is a naturally occurring compound, synthesized endogenously in mammalian species and known to possess antioxidant properties. In this study, the effect of L-carnitine on learning and memory impairment induced by rapid eye movement sleep (REM-sleep) deprivation was investigated. REM-sleep deprivation was induced using modified multiple platform model (8h/day, for 6 weeks). Simultaneously, L-carnitine was administered (300mg/kg/day) intraperitoneally for 6 weeks. Thereafter, the radial arm water maze (RAWM) was used to assess spatial learning and memory. Additionally, the hippocampus levels of antioxidant biomarkers/enzymes: reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS) were assessed. The results showed that chronic REM-sleep deprivation impaired both short- and long-term memory (P<0.05), whereas L-carnitine treatment protected against this effect. Furthermore, L-carnitine normalized chronic REM-sleep deprivation induced reduction in the hippocampus ratio of GSH/GSSG, activity of catalase, GPx, and SOD. No change was observed in TBARS among tested groups (P>0.05). In conclusion, chronic REM-sleep deprivation induced memory impairment, and treatment with L-carnitine prevented this impairment through normalizing antioxidant mechanisms in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasticity-Related Gene Expression During Eszopiclone-Induced Sleep.

PubMed

Gerashchenko, Dmitry; Pasumarthi, Ravi K; Kilduff, Thomas S

2017-07-01

Experimental evidence suggests that restorative processes depend on synaptic plasticity changes in the brain during sleep. We used the expression of plasticity-related genes to assess synaptic plasticity changes during drug-induced sleep. We first characterized sleep induced by eszopiclone in mice during baseline conditions and during the recovery from sleep deprivation. We then compared the expression of 18 genes and two miRNAs critically involved in synaptic plasticity in these mice. Gene expression was assessed in the cerebral cortex and hippocampus by the TaqMan reverse transcription polymerase chain reaction and correlated with sleep parameters. Eszopiclone reduced the latency to nonrapid eye movement (NREM) sleep and increased NREM sleep amounts. Eszopiclone had no effect on slow wave activity (SWA) during baseline conditions but reduced the SWA increase during recovery sleep (RS) after sleep deprivation. Gene expression analyses revealed three distinct patterns: (1) four genes had higher expression either in the cortex or hippocampus in the group of mice with increased amounts of wakefulness; (2) a large proportion of plasticity-related genes (7 out of 18 genes) had higher expression during RS in the cortex but not in the hippocampus; and (3) six genes and the two miRNAs showed no significant changes across conditions. Even at a relatively high dose (20 mg/kg), eszopiclone did not reduce the expression of plasticity-related genes during RS period in the cortex. These results indicate that gene expression associated with synaptic plasticity occurs in the cortex in the presence of a hypnotic medication. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Neuropeptide glutamic acid-isoleucine (NEI)-induced paradoxical sleep in rats.

PubMed

Fujimoto, Moe; Fukuda, Satoru; Sakamoto, Hidetoshi; Takata, Junko; Sawamura, Shigehito

2017-01-01

Neuropeptideglutamic acid-isoleucine (NEI) as well as melanin concentrating hormone (MCH) is cleaved from the 165 amino acid protein, prepro-melanin concentrating hormone (prepro-MCH). Among many physiological roles of MCH, we demonstrated that intracerebroventricular (icv) injection of MCH induced increases in REM sleep episodes as well as in non REM sleep episodes. However, there are no studies on the effect of NEI on the sleep-wake cycle. As for the sites of action of MCH for induction of REM sleep, the ventrolateral periaqueductal gray (vlPAG) has been reported to be one of its site of action. Although MCH neurons contain NEI, GABA, MCH, and other neuropeptides, we do not know which transmitter(s) might induce REM sleep by acting on the vlPAG. Thus, we first examined the effect of icv injection of NEI on the sleep-wake cycle, and investigated how microinjection of either NEI, MCH, or GABA into the vlPAG affected REM sleep in rats. Icv injection of NEI (0.61μg/5μl: n=7) significantly increased the time spent in REM episodes compared to control (saline: 5μl; n=6). Microinjection of either NEI (61ng/0.2μl: n=7), MCH (100ng/0.2μl: n=6) or GABA (250mM/0.2μl: n=7) into the vlPAG significantly increased the time spent in REM episodes and the AUC. Precise hourly analysis of REM sleep also revealed that after those microinjections, NEI and MCH increased REM episodes at the latter phase, compared to GABA which increased REM episodes at the earlier phase. This result suggests that NEI and MCH may induce sustained REM sleep, while GABA may initiate REM sleep. In conclusion, our findings demonstrate that NEI, a cleaved peptide from the same precursor, prepro-MCH, as MCH, induce REM sleep at least in part through acting on the vlPAG. Copyright © 2016 Elsevier Inc. All rights reserved.

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.

PubMed

Ota, Simone M; Moreira, Karin Di Monteiro; Suchecki, Deborah; Oliveira, Maria Gabriela M; Tiba, Paula A

2013-11-01

Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Wistar male rats weighing 300-400 g. Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Effect of obstructive sleep apnea hypopnea syndrome on lipid profile: a meta-regression analysis.

PubMed

Nadeem, Rashid; Singh, Mukesh; Nida, Mahwish; Waheed, Irfan; Khan, Adnan; Ahmed, Saeed; Naseem, Jawed; Champeau, Daniel

2014-05-15

Obstructive sleep apnea (OSA) is associated with obesity, metabolic syndrome, and dyslipidemia, which may be related to decrease androgen levels found in OSA patients. Dyslipidemia may contribute to atherosclerosis leading to increasing risk of heart disease. Systematic review was conducted using PubMed and Cochrane library by utilizing different combinations of key words; sleep apnea, obstructive sleep apnea, serum lipids, dyslipidemia, cholesterol, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglyceride (TG). Inclusion criteria were: English articles, and studies with adult population in 2 groups of patients (patients with OSA and without OSA). A total 96 studies were reviewed for inclusion, with 25 studies pooled for analysis. Sixty-four studies were pooled for analysis; since some studies have more than one dataset, there were 107 datasets with 18,116 patients pooled for meta-analysis. All studies measured serum lipids. Total cholesterol pooled standardized difference in means was 0.267 (p = 0.001). LDL cholesterol pooled standardized difference in means was 0.296 (p = 0.001). HDL cholesterol pooled standardized difference in means was -0.433 (p = 0.001). Triglyceride pooled standardized difference in means was 0.603 (p = 0.001). Meta-regression for age, BMI, and AHI showed that age has significant effect for TC, LDL, and HDL. BMI had significant effect for LDL and HDL, while AHI had significant effect for LDL and TG. Patients with OSA appear to have increased dyslipidemia (high total cholesterol, LDL, TG, and low HDL).

The protective effect of 20(S)-protopanaxadiol (PPD) against chronic sleep deprivation (CSD)-induced memory impairments in mice.

PubMed

Lu, Cong; Lv, Jingwei; Dong, Liming; Jiang, Ning; Wang, Yan; Fan, Bei; Wang, Fengzhong; Liu, Xinmin

2018-03-01

Sleep deprivation (SD) is associated with oxidative stress that causes learning and memory impairment. 20(S)-Protopanaxadiol (PPD), one of the protopanaxadiol-type saponins, has antioxidant and neuroprotective effect. This study was designed to research the protective effect of PPD against cognitive deficits induced by chronic sleep deprivation (CSD) in mice. The CSD model was induced by subjecting the mice to our self-made Sleep Interruption Apparatus (SIA) continuously for 14 days. The memory enhancing effects of PPD were evaluated by behavioral tests and the related mechanism was further explored by observing the oxidative stress changes in the cortex and hippocampus of mice. The results revealed that PPD (20 and 40 μmol/kg, i.p.) administration significantly improved the cognitive performance of CSD model mice in object location recognition experiment, novel object recognition task and Morris water maze test. Furthermore, PPD effectively restored the levels/activities of antioxidant defense biomarkers in the cortex and hippocampus, including the superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, glutathione (GSH), and lipid peroxidation (LPO). In conclusion, PPD could attenuate cognitive deficits induced by CSD, and the neuroprotective effect of PPD might be mediated by alleviation of oxidative stress. It was assumed that PPD has the potential to be a neuroprotective substance for cognition dysfunction. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of oleamide in Guatteria recurvisepala by LC/MS-based Plasmodium falciparum thioredoxin reductase ligand binding method.

PubMed

Munigunti, Ranjith; Nelson, Nicholas; Mulabagal, Vanisree; Gupta, Mahabir P; Brun, Reto; Calderón, Angela I

2011-10-01

Our current research on applications of mass spectrometry to natural product drug discovery against malaria aims to screen plant extracts for new ligands to Plasmodium falciparum thioredoxin reductase (PfTrxR) followed by their identification and structure elucidation. PfTrxR is involved in the antioxidant defense and redox regulation of the parasite and is validated as a promising target for therapeutic intervention against malaria. In the present study, detannified methanol extracts from Guatteria recurvisepala, Licania kallunkiae, and Topobea watsonii were screened for ligands to PfTrxR using ultrafiltration and liquid chromatography/mass spectrometry-based binding experiments. The PfTrxR ligand identified in the extract of Guatteria recurvisepala displayed a relative binding affinity of 3.5-fold when incubated with 1 μM PfTrxR. The ligand corresponding to the protonated molecule m/z 282.2792 [M+ H]+ was eluted at a retention time of 17.95 min in a 20-min gradient of 95% B consisting of (A) 0.1%formic acid in 95% H₂O-5% ACN, and (B) 0.1% formic acid in 95% ACN-5% H₂O in an LC-QTOF-MS.Tandem MS of the protonated molecule m/z 282.2792 [M + H]+, C₁₈H₃₆NO (DBE: 2; error: 1.13 ppm) resulted in two daughter ions m/z 265.2516[M + H-NH₃]+ (DBE: 3; error: 0.35 ppm) and m/z 247.2405 [M + H-NH₃-H₂O] +, (DBE: 4; error:2.26 ppm). The PfTrxR ligand was identified as oleamide and confirmed by comparison of the retention time, molecular formula, accurate mass,and double bond equivalence with the standard oleamide. This is the first report on the identification of oleamide as a PfTrxR ligand from Guatteria recurvisepala R. E. Fr. and the corresponding in vitro activity against P. falciparum strain K1 (IC₅₀ 4.29 μg/mL). © Georg Thieme Verlag KG Stuttgart · New York.

Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome.

PubMed

Marti, Isabelle; Valko, Philipp O; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

2009-12-01

Short mean latencies to the first epoch of non-rapid eye movement sleep stage 1 (NREM1) and the presence of >or= 2 sleep onset REM (SOREM) periods on multiple sleep latency test (MSLT) occur in both narcolepsy-cataplexy (NC) and behaviourally induced insufficient sleep syndrome (BIISS). It is not known whether specific MSLT findings help differentiate the two disorders. We analyzed MSLT data including sleep latencies to and between different sleep stages of 60 age-, gender- and body mass index (BMI)-matched subjects (hypocretin-deficient NC, actigraphy-confirmed BIISS, healthy controls: each 20). Mean latency (in minutes) to NREM1 sleep was significantly shorter in NC (1.8+/-1.5) than in BIISS (4.7+/-2.1, p<0.001) and controls (11.4+/-3.3, p<0.001). Mean latency to NREM2 sleep was similar in NC (8.6+/-4.7) and BIISS (8.1+/-2.7, p=0.64); latency to either NREM2 or rapid eye movement (REM) sleep (i.e., the sum of the sleep latency to NREM1 and the duration of the first NREM1 sleep sequence), however, was shorter in NC (4.4+/-2.9) than in BIISS (7.9+/-3.5, p<0.001). Referring to all naps with SOREM periods, the sequence NREM1-REM-NREM2 was more common (71%) in NC than in BIISS (15%, p<0.001), reflecting the shorter latency from NREM1 to NREM2 in BIISS (3.7+/-2.5) than in NC (6.1+/-5.9, p<0.001). Our findings show that both sleepiness (as measured by NREM1 sleep latency) and REM sleep propensity are higher in NC than in BIISS. Furthermore, our finding of frequent REM sleep prior to NREM2 sleep in NC is in line with the recent assumption of an insufficient NREM sleep intensity in NC. Together with detailed clinical interviews, sleep logs, actigraphy, and nocturnal polysomnography, mean sleep latencies to NREM1

Lipid domains in zwitterionic-anionic lipid mixtures induced by combined effect of monovalent and divalent ions

NASA Astrophysics Data System (ADS)

Xu, Hongcheng; Ganesan, Sai; Matysiak, Silvina

Lipid domain formation is an important process for many cellular processes. In experiment, the effects of Ba2+, Sr2+, Ca2+ and Mg2+ in inducing lateral phase separation in the binary phosphatidylcholine-phosphatidylserine (PC-PS) bilayer are quite different, of which the molecular mechanism remains to be understood. We have explored the effect of monovalent (MI) and divalent (MII) cationic radii on lipid domain formation in mixed zwitterionic-anionic lipid bilayers. We propose a mechanism for the formation of divalent-cation-induced lipid domains based on MD simulations with our Water-Explicit Polarizable MEMbrane (WEPMEM) coarse-grained model, which uses PC as the model for zwitterionic and PS for anionic lipids. Lipid aggregation only occurs with limited range of monovalent and divalent ion sizes in agreement with experimental observations. More ordering and closer packing of the lipids are noted within the domains, which correlate with bilayer thickness, curvature and lipid asymmetry. The results of the simulations reveal that the lipid domain consists of MII-mediated anionic lipid dimer/trimer complexes bridged by monovalent ions MI and provide a stereochemical insight in understanding the experimentally observed calcium-induced phase separation.

Endoscopic examination of obstructive sleep apnea syndrome patients during drug-induced sleep.

PubMed

Iwanaga, Koichi; Hasegawa, Kiyokazu; Shibata, Nobuhiro; Kawakatsu, Kenji; Akita, Yasutaka; Suzuki, Kenji; Yagisawa, Mikio; Nishimura, Tadao

2003-01-01

Sixty patients diagnosed with obstructive sleep apnea syndrome (OSAS) underwent uvulopalatopharyngoplasty (UPPP). The effects of surgery were studied based on endoscopic findings during drug-induced sleep and determination of the apnea-hypopnea index (AHI) before and after the operation. Changes in the form of the airway during sleep in the recumbent position were observed, and the role of upper airway endoscopy in the diagnosis and surgical treatment of OSAS was determined. The site of airway obstruction during sleep induced by i.v. injection of 10 mg of diazepam was classified into five types, and changes in AHI and the site of airway obstruction were compared before and after surgery. Changes in airway morphology during sleep in the supine and recumbent positions were also compared before surgery. The postoperative improvement rate was 74.4% for the soft palatal type of obstruction, 76.2% for the tonsillar type, 53.3% for the circumferential palatal type and 34.0% for the mixed type. Treatment produced excellent or good effects for the soft palatal and tonsillar types of obstruction. However, many patients with the circumferential palatal and mixed types of obstruction showed only some improvement or no change. Good airway morphology was maintained in the recumbent position by patients with the soft palatal type of obstruction. With the circumferential palatal and mixed types of obstruction, improvement can be expected from operations which include surgical treatment of the posterior pharyngeal wall or lateral funiculus, or with midline laser glossectomy. A good operative outcome can be predicted in patients showing improvement of apnea in the recumbent position preoperatively.

Brain prolactin is involved in stress-induced REM sleep rebound.

PubMed

Machado, Ricardo Borges; Rocha, Murilo Ramos; Suchecki, Deborah

2017-03-01

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

PubMed Central

Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

2016-01-01

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID:26235983

DMSO Induces Dehydration near Lipid Membrane Surfaces

PubMed Central

Cheng, Chi-Yuan; Song, Jinsuk; Pas, Jolien; Meijer, Lenny H.H.; Han, Songi

2015-01-01

Dimethyl sulfoxide (DMSO) has been broadly used in biology as a cosolvent, a cryoprotectant, and an enhancer of membrane permeability, leading to the general assumption that DMSO-induced structural changes in cell membranes and their hydration water play important functional roles. Although the effects of DMSO on the membrane structure and the headgroup dehydration have been extensively studied, the mechanism by which DMSO invokes its effect on lipid membranes and the direct role of water in this process are unresolved. By directly probing the translational water diffusivity near unconfined lipid vesicle surfaces, the lipid headgroup mobility, and the repeat distances in multilamellar vesicles, we found that DMSO exclusively weakens the surface water network near the lipid membrane at a bulk DMSO mole fraction (XDMSO) of <0.1, regardless of the lipid composition and the lipid phase. Specifically, DMSO was found to effectively destabilize the hydration water structure at the lipid membrane surface at XDMSO <0.1, lower the energetic barrier to dehydrate this surface water, whose displacement otherwise requires a higher activation energy, consequently yielding compressed interbilayer distances in multilamellar vesicles at equilibrium with unaltered bilayer thicknesses. At XDMSO >0.1, DMSO enters the lipid interface and restricts the lipid headgroup motion. We postulate that DMSO acts as an efficient cryoprotectant even at low concentrations by exclusively disrupting the water network near the lipid membrane surface, weakening the cohesion between water and adhesion of water to the lipid headgroups, and so mitigating the stress induced by the volume change of water during freeze-thaw. PMID:26200868

C. elegans Stress-Induced Sleep Emerges from the Collective Action of Multiple Neuropeptides.

PubMed

Nath, Ravi D; Chow, Elly S; Wang, Han; Schwarz, Erich M; Sternberg, Paul W

2016-09-26

The genetic basis of sleep regulation remains poorly understood. In C. elegans, cellular stress induces sleep through epidermal growth factor (EGF)-dependent activation of the EGF receptor in the ALA neuron. The downstream mechanism by which this neuron promotes sleep is unknown. Single-cell RNA sequencing of ALA reveals that the most highly expressed, ALA-enriched genes encode neuropeptides. Here we have systematically investigated the four most highly enriched neuropeptides: flp-7, nlp-8, flp-24, and flp-13. When individually removed by null mutation, these peptides had little or no effect on stress-induced sleep. However, stress-induced sleep was abolished in nlp-8; flp-24; flp-13 triple-mutant animals, indicating that these neuropeptides work collectively in controlling stress-induced sleep. We tested the effect of overexpression of these neuropeptide genes on five behaviors modulated during sleep-pharyngeal pumping, defecation, locomotion, head movement, and avoidance response to an aversive stimulus-and we found that, if individually overexpressed, each of three neuropeptides (nlp-8, flp-24, or flp-13) induced a different suite of sleep-associated behaviors. These overexpression results raise the possibility that individual components of sleep might be specified by individual neuropeptides or combinations of neuropeptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

Uridine prevents tamoxifen-induced liver lipid droplet accumulation

PubMed Central

2014-01-01

Background Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Methods Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1−/−and UPase1-TG. Results Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1−/−with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had

Uridine prevents tamoxifen-induced liver lipid droplet accumulation.

PubMed

Le, Thuc T; Urasaki, Yasuyo; Pizzorno, Giuseppe

2014-05-23

Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1-/-and UPase1-TG. Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1-/-with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had intrinsic liver lipid droplet

Modeling aircraft noise induced sleep disturbance

NASA Astrophysics Data System (ADS)

McGuire, Sarah M.

occurrence of rapid eye movements, sleep spindles, and slow wave sleep. Using these features an approach for classifying sleep stages every one second during the night was developed. From observation of the results of the sleep stage classification, it was determined how to add faster dynamics to the nonlinear dynamic model. Slow and fast REM activity are modeled separately and the activity in the gamma frequency band of the EEG signal is used to model both spontaneous and noise-induced awakenings. The nonlinear model predicts changes in sleep structure similar to those found by other researchers and reported in the sleep literature and similar to those found in obtained survey data. To compare sleep disturbance model predictions, flight operations data from US airports were obtained and sleep disturbance in communities was predicted for different operations scenarios using the modified Markov model, the nonlinear dynamic model, and other aircraft noise awakening models. Similarities and differences in model predictions were evaluated in order to determine if the use of the developed sleep structure model leads to improved predictions of the impact of nighttime noise on communities.

A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

PubMed

Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

2011-12-01

Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

Cellular stress induces a protective sleep-like state in C. elegans.

PubMed

Hill, Andrew J; Mansfield, Richard; Lopez, Jessie M N G; Raizen, David M; Van Buskirk, Cheryl

2014-10-20

Sleep is recognized to be ancient in origin, with vertebrates and invertebrates experiencing behaviorally quiescent states that are regulated by conserved genetic mechanisms. Despite its conservation throughout phylogeny, the function of sleep remains debated. Hypotheses for the purpose of sleep include nervous-system-specific functions such as modulation of synaptic strength and clearance of metabolites from the brain, as well as more generalized cellular functions such as energy conservation and macromolecule biosynthesis. These models are supported by the identification of synaptic and metabolic processes that are perturbed during prolonged wakefulness. It remains to be seen whether perturbations of cellular homeostasis in turn drive sleep. Here we show that under conditions of cellular stress, including noxious heat, cold, hypertonicity, and tissue damage, the nematode Caenorhabditis elegans engages a behavioral quiescence program. The stress-induced quiescent state displays properties of sleep and is dependent on the ALA neuron, which mediates the conserved soporific effect of epidermal growth factor (EGF) ligand overexpression. We characterize heat-induced quiescence in detail and show that it is indeed dependent on components of EGF signaling, providing physiological relevance to the behavioral effects of EGF family ligands. We find that after noxious heat exposure, quiescence-defective animals show elevated expression of cellular stress reporter genes and are impaired for survival, demonstrating the benefit of stress-induced behavioral quiescence. These data provide evidence that cellular stress can induce a protective sleep-like state in C. elegans and suggest that a deeply conserved function of sleep is to mitigate disruptions of cellular homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice.

PubMed

Kumar, Anil; Singh, Anant

2009-08-01

Sleep is an important physiological process responsible for the maintenance of physical, mental and emotional health of a living being. Sleep deprivation is considered risky for several pathological diseases such as anxiety and motor and cognitive dysfunctions. Sleep deprivation has recently been reported to cause oxidative damage. This study has been designed to explore the possible involvement of the GABAergic mechanism in protective effects of melatonin against 72-h sleep deprivation-induced behaviour modification and oxidative damage in mice. Mice were sleep-deprived for a period of 72 h using the grid over water suspended method. Animals were divided into groups of 6-8 animals each. Melatonin (5 and 10 mg/kg), flumazenil (0.5 mg/kg), picrotoxin (0.5 mg/kg) and muscimol (0.05 mg/kg) were administered for 5 days starting 2 days before 72-h sleep deprivation. Various behavioural tests (plus maze, zero maze, mirror chamber, actophotometer) and body weight assessment followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were carried out. The 72-h sleep deprivation caused significant anxiety-like behaviour, weight loss, impaired locomotor activity and oxidative damage as compared with naïve (without sleep deprivation). Treatment with melatonin (5 mg/kg and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared with control (sleep-deprived). Biochemically, melatonin treatment significantly restored reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared with control animals (72-h sleep-deprived). Flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) pretreatments with a lower dose of melatonin (5 mg/kg) significantly antagonized the protective effect of melatonin. However, muscimol (0.05 mg/kg) pretreatment with melatonin (5 mg/kg, ip) potentiated the protective effect of melatonin which was significant as compared with their

Antiallergic Activity of Ethanol Extracts of Arctium lappa L. Undried Roots and Its Active Compound, Oleamide, in Regulating FcεRI-Mediated and MAPK Signaling in RBL-2H3 Cells.

PubMed

Yang, Woong-Suk; Lee, Sung Ryul; Jeong, Yong Joon; Park, Dae Won; Cho, Young Mi; Joo, Hae Mi; Kim, Inhye; Seu, Young-Bae; Sohn, Eun-Hwa; Kang, Se Chan

2016-05-11

The antiallergic potential of Arctium lappa L. was investigated in Sprague-Dawley rats, ICR mice, and RBL-2H3 cells. Ethanol extract (90%) of A. lappa (ALE, 100 μg/mL) inhibited the degranulation rate by 52.9%, determined by the level of β-hexosaminidase. ALE suppressed passive cutaneous anaphylaxis (PCA) in rats and attenuated anaphylaxis and histamine release in mice. To identify the active compound of ALE, we subsequently fractionated and determined the level of β-hexosaminidase in all subfractions. Oleamide was identified as an active compound of ALE, which attenuated the secretion of histamine and the production of tumor necrosis factor (TNF)-α and interleukin-4 (IL-4) in cells treated with compound 48/80 or A23187/phorbol myristate acetate (PMA). Oleamide suppressed FcεRI-tyrosine kinase Lyn-mediated pathway, c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinases (p38-MAPKs). These results showed that ALE and oleamide attenuated allergic reactions and should serve as a platform to search for compounds with antiallergic activity.

Influence of serial electrical stimulations of perifornical and posterior hypothalamic orexin-containing neurons on regulation of sleep homeostasis and sleep-wakefulness cycle recovery from experimental comatose state and anesthesia-induced deep sleep.

PubMed

Chijavadze, E; Chkhartishvili, E; Babilodze, M; Maglakelidze, N; Nachkebia, N

2013-11-01

The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamic, and brain Orexinergic system in general, are those cellular targets which can speed up recovery of disturbed sleep homeostasis and accelerate restoration of sleep-wakefulness cycle phases during some pathological conditions - experimental comatose state and/or deep anesthesia-induced sleep. Study was carried out on white rats. Modeling of experimental comatose state was made by midbrain cytotoxic lesions at intra-collicular level.Animals were under artificial respiration and special care. Different doses of Sodium Ethaminal were used for deep anesthesia. 30 min after comatose state and/or deep anesthesia induced sleep serial electrical stimulations of posterior and/or perifornical hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts.EEG registration of cortical and hippocampal electrical activity was started immediately after experimental comatose state and deep anesthesia induced sleep and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of posterior and perifornical hypothalamic Orexin-containing neurons significantly accelerate recovery of sleep homeostasis, disturbed because of comatose state and/or deep anesthesia induced sleep. Speed up recovery of sleep homeostasis was manifested in acceleration of coming out from comatose state and deep anesthesia induced sleep and significant early restoration of sleep-wakefulness cycle behavioral states.

Ventilatory response to induced auditory arousals during NREM sleep.

PubMed

Badr, M S; Morgan, B J; Finn, L; Toiber, F S; Crabtree, D C; Puleo, D S; Skatrud, J B

1997-09-01

Sleep state instability is a potential mechanism of central apnea/hypopnea during non-rapid eye movement (NREM) sleep. To investigate this postulate, we induced brief arousals by delivering transient (0.5 second) auditory stimuli during stable NREM sleep in eight normal subjects. Arousal was determined according to American Sleep Disorders Association (ASDA) criteria. A total of 96 trials were conducted; 59 resulted in cortical arousal and 37 did not result in arousal. In trials associated with arousal, minute ventilation (VE) increased from 5.1 +/- 1.24 minutes to 7.5 +/- 2.24 minutes on the first posttone breath (p = 0.001). However, no subsequent hypopnea or apnea occurred as VE decreased gradually to 4.8 +/- 1.5 l/minute (p > 0.05) on the fifth posttone breath. Trials without arousal did not result in hyperpnea on the first breath nor subsequent hypopnea. We conclude that 1) auditory stimulation resulted in transient hyperpnea only if associated with cortical arousal; 2) hypopnea or apnea did not occur following arousal-induced hyperpnea in normal subjects; 3) interaction with fluctuating chemical stimuli or upper airway resistance may be required for arousals to cause sleep-disordered breathing.

Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice

PubMed Central

Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Hee Jin; Choung, Se Young

2015-01-01

γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice. PMID:25995826

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

PubMed

Yi, Pei-Lu; Lu, Chin-Yu; Jou, Shuo-Bin; Chang, Fang-Chia

2015-07-07

The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a μ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

Berberine potentizes apoptosis induced by X-rays irradiation probably through modulation of gap junctions.

PubMed

Liu, Bing; Wang, Qin; Yuan, Dong-dong; Hong, Xiao-ting; Tao, Liang

2011-04-01

Clinical combination of some traditional Chinese medical herbs, including berberine, with irradiation is demonstrated to improve efficacy of tumor radiotherapy, yet the mechanisms for such effect remain largely unknown. The present study investigated the effect of berberine on apoptosis induced by X-rays irradiation and the relation between this effect and gap junction intercellular communication (GJIC). The role of gap junctions in the modulation of X-rays irradiation-induced apoptosis was explored by manipulation of connexin (Cx) expression, and gap junction function, using oleamide, a GJIC inhibitor, and berberine. In transfected HeLa cells, Cx32 expression increased apoptosis induced by X-rays irradiation, while inhibition of gap junction by oleamide reduced the irradiation responses, indicating the dependence of X-rays irradiation-induced apoptosis on GJIC. Berberine, at the concentrations without cytotoxicity, enhanced apoptosis induced by irradiation only in the presence of functional gap junctions. These results suggest that berberine potentizes cell apoptosis induced by X-rays irradiation, probably through enhancement of gap junction activity.

Sleep Loss as a Factor to Induce Cellular and Molecular Inflammatory Variations

PubMed Central

Hurtado-Alvarado, Gabriela; Castillo-García, Stephanie Ariadne; Hernández, María Eugenia; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

2013-01-01

A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's disease, and multiple sclerosis). Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate data from recent published reports (2002–2013) on the effects of sleep loss on the immune response. This review may allow readers to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss. PMID:24367384

Lipid oxidation induced oxidative degradation of cereal beta-glucan.

PubMed

Wang, Yu-Jie; Mäkelä, Noora; Maina, Ndegwa Henry; Lampi, Anna-Maija; Sontag-Strohm, Tuula

2016-04-15

In food systems, lipid oxidation can cause oxidation of other molecules. This research for the first time investigated oxidative degradation of β-glucan induced by lipid oxidation using an oil-in-water emulsion system which simulated a multi-phased aqueous food system containing oil and β-glucan. Lipid oxidation was monitored using peroxide value and hexanal production while β-glucan degradation was evaluated by viscosity and molecular weight measurements. The study showed that while lipid oxidation proceeded, β-glucan degradation occurred. Emulsions containing β-glucan, oil and ferrous ion showed significant viscosity and molecular weight decrease after 1 week of oxidation at room temperature. Elevated temperature (40°C) enhanced the oxidation reactions causing higher viscosity drop. In addition, the presence of β-glucan appeared to retard the hexanal production in lipid oxidation. The study revealed that lipid oxidation may induce the degradation of β-glucan in aqueous food systems where β-glucan and lipids co-exist. Copyright © 2015 Elsevier Ltd. All rights reserved.

Experimental Sleep Restriction Facilitates Pain and Electrically Induced Cortical Responses

PubMed Central

Matre, Dagfinn; Hu, Li; Viken, Leif A.; Hjelle, Ingri B.; Wigemyr, Monica; Knardahl, Stein; Sand, Trond; Nilsen, Kristian Bernhard

2015-01-01

Study Objectives: Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses. Design: A paired crossover study. Intervention: Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS). Setting: Laboratory experiment at research center. Participants: Self-reported healthy volunteers (n = 21, age range: 18–31 y). Measurements and Results: Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017). Conclusion: Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR. Citation: Matre D, Hu L, Viken LA, Hjelle IB, Wigemyr M, Knardahl S, Sand T, Nilsen KB. Experimental sleep restriction facilitates pain and electrically induced cortical responses. SLEEP 2015;38(10):1607–1617. PMID:26194577

Glucose Induces Slow-Wave Sleep by Exciting the Sleep-Promoting Neurons in the Ventrolateral Preoptic Nucleus: A New Link between Sleep and Metabolism.

PubMed

Varin, Christophe; Rancillac, Armelle; Geoffroy, Hélène; Arthaud, Sébastien; Fort, Patrice; Gallopin, Thierry

2015-07-08

Sleep-active neurons located in the ventrolateral preoptic nucleus (VLPO) play a crucial role in the induction and maintenance of slow-wave sleep (SWS). However, the cellular and molecular mechanisms responsible for their activation at sleep onset remain poorly understood. Here, we test the hypothesis that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons. We find that infusion of a glucose concentration into the VLPO of mice promotes SWS and increases the density of c-Fos-labeled neurons selectively in the VLPO. Moreover, we show in patch-clamp recordings from brain slices that VLPO neurons exhibiting properties of sleep-promoting neurons are selectively excited by glucose within physiological range. This glucose-induced excitation implies the catabolism of glucose, leading to a closure of ATP-sensitive potassium (KATP) channels. The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status. Together, these results provide evidence that glucose may participate in the mechanisms of SWS promotion and/or consolidation. Although the brain circuitry underlying vigilance states is well described, the molecular mechanisms responsible for sleep onset remain largely unknown. Combining in vitro and in vivo experiments, we demonstrate that glucose likely contributes to sleep onset facilitation by increasing the excitability of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO). We find here that these neurons integrate energetic signals such as ambient glucose directly to regulate vigilance states accordingly. Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the

Hypnotic Effect of Ocimum basilicum on Pentobarbital-Induced Sleep in Mice.

PubMed

Askari, Vahid Reza; Baradaran Rahimi, Vafa; Ghorbani, Ahmad; Rakhshandeh, Hassan

2016-07-01

Sleep disorders are accompanied by several complications, and currently used soporific drugs can induce unwanted effects such as psychomotor impairment, tolerance, amnesia, and rebound insomnia. The present study was carried out to investigate if Ocimum basilicum has a sleep-prolonging effect. This work was an experimental study on 72 mice which were randomly divided into 9 groups: saline (control); diazepam (3 mg/kg, positive control); hydro-alcoholic extract (HAE) of Ocimum basilicum (25, 50, or 100 mg/kg); ethyl acetate fraction (EAF, 50 mg/kg); n-butanol fraction (NBF, 50 mg/kg); water fraction (WF, 50 mg/kg); and saline containing 10% DMSO (vehicle for EAF and NBF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital-induced sleep were recorded. Also, LD50 of HAE was determined and the cytotoxicity of HAE was tested on neural and fibroblast cells using the MTT assay. HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, and 100 mg/kg (P < 0.001). The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and NBF at 50 mg/kg could increase sleep duration. The sleep latency was decreased by HAE (P < 0.01 - P < 0.001) and NBF (P < 0.001), but not by WF and EAF. The LD50 value for HAE was found to be 2.4 g/kg. HAE had no effect on the viability of neuronal PC12 cells and L929 fibroblast cells. The present data demonstrated that Ocimum basilicum potentiates sleeping behaviors without any cytotoxicity. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in NBF. Isolation of the active constituents may yield a novel sedative drug.

Flurbiprofen in rapid eye movement sleep deprivation induced hyperalgesia.

PubMed

Gürel, Elif Ezgi; Ural, Keremcan; Öztürk, Gülnur; Öztürk, Levent

2014-04-10

Rapid eye movement (REM) sleep deprivation induces hyperalgesia in healthy rats. Here, we evaluated the effects of flurbiprofen, an anti-inflammatory and neuroprotective agent, on the increased thermal responses observed in REM sleep deprived rats. Forty female rats were divided into four groups following 96-hour REM sleep deprivation: intraperitoneal injections of placebo, and flurbiprofen 5 mg/kg, 15 mg/kg and 40 mg/kg were made in CONT (n=10), FBP5, FBP15 and FBP40 groups respectively. Pain threshold measurements were performed three times at baseline (0.hour), at the end of REM sleep deprivation (96.hour) and at 1 h after injections (97.hour) by hot plate and tail-flick tests. REM sleep deprivation induced a significant decrease in pain thresholds of all rats (hotplate: 0.hour vs 96.hour, 9.75±2.85 vs 5.10±2.02, p<0.001; tail flick: 0.hour vs 96.hour, 11.92±4.62 vs 7.92±5.15, p<0.001). Flurbiprofen in 15 mg/kg and 40 mg/kg doses significantly improved pain tolerance measured by tail flick test (tail flick in FBP15 and FBP40 groups: 96.hour vs 97.hour, 7.01±4.97 vs 8.34±3.61 and 5.06±1.57 vs 7.04±2.49, p<0.05 for both). 96 h of REM sleep deprivation resulted in reduced pain thresholds in both hot plate and tail flick tests. Flurbiprofen was used for the first time in a rat model of REM sleep deprivation, and it provided anti-nociceptive effects in 15 mg/kg and 40 mg/kg doses. Flurbiprofen may have the potential for treatment of painful syndromes accompanying insomnia or sleep loss. Copyright © 2014 Elsevier Inc. All rights reserved.

Preventive effects of a fermented dairy product against Alzheimer's disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity.

PubMed

Ano, Yasuhisa; Ozawa, Makiko; Kutsukake, Toshiko; Sugiyama, Shinya; Uchida, Kazuyuki; Yoshida, Aruto; Nakayama, Hiroyuki

2015-01-01

Despite the ever-increasing number of patients with dementia worldwide, fundamental therapeutic approaches to this condition have not been established. Epidemiological studies suggest that intake of fermented dairy products prevents cognitive decline in the elderly. However, the active compounds responsible for the effect remain to be elucidated. The present study aims to elucidate the preventive effects of dairy products on Alzheimer's disease and to identify the responsible component. Here, in a mouse model of Alzheimer's disease (5xFAD), intake of a dairy product fermented with Penicillium candidum had preventive effects on the disease by reducing the accumulation of amyloid β (Aβ) and hippocampal inflammation (TNF-α and MIP-1α production), and enhancing hippocampal neurotrophic factors (BDNF and GDNF). A search for preventive substances in the fermented dairy product identified oleamide as a novel dual-active component that enhanced microglial Aβ phagocytosis and anti-inflammatory activity towards LPS stimulation in vitro and in vivo. During the fermentation, oleamide was synthesized from oleic acid, which is an abundant component of general dairy products owing to lipase enzymatic amidation. The present study has demonstrated the preventive effect of dairy products on Alzheimer's disease, which was previously reported only epidemiologically. Moreover, oleamide has been identified as an active component of dairy products that is considered to reduce Aβ accumulation via enhanced microglial phagocytosis, and to suppress microglial inflammation after Aβ deposition. Because fermented dairy products such as camembert cheese are easy to ingest safely as a daily meal, their consumption might represent a preventive strategy for dementia.

A New Model to Study Sleep Deprivation-Induced Seizure

PubMed Central

Lucey, Brendan P.; Leahy, Averi; Rosas, Regine; Shaw, Paul J.

2015-01-01

Background and Study Objectives: A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. Design: Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB9ed4), and in an adult temperature sensitive seizure mutant seizure (seits1) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB9ed4 flies was also assessed. Setting: Laboratory. Participants: Drosophila melanogaster. Interventions: Sleep deprivation. Measurements and Results: Sleep deprivation increased seizure susceptibility in adult sesB9ed4/+ and seits1 mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB9ed4/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB9ed4/+ became adults. Conclusions: These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. Citation: Lucey BP, Leahy A, Rosas R, Shaw PJ. A new model to study sleep deprivation-induced seizure. SLEEP 2015;38(5):777–785. PMID:25515102

Clusterin deficiency induces lipid accumulation and tissue damage in kidney.

PubMed

Heo, Jung-Yoon; Kim, Ji-Eun; Dan, Yongwook; Kim, Yong-Woon; Kim, Jong-Yeon; Cho, Kyu Hyang; Bae, Young Kyung; Im, Seung-Soon; Liu, Kwang-Hyeon; Song, In-Hwan; Kim, Jae-Ryong; Lee, In-Kyu; Park, So-Young

2018-05-01

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease. © 2018 Society for Endocrinology.

Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat.

PubMed

Garrity, Abigail G; Botta, Simhadri; Lazar, Stephanie B; Swor, Erin; Vanini, Giancarlo; Baghdoyan, Helen A; Lydic, Ralph

2015-01-01

Dexmedetomidine is used clinically to induce states of sedation that have been described as homologous to nonrapid eye movement (NREM) sleep. A better understanding of the similarities and differences between NREM sleep and dexmedetomidine-induced sedation is essential for efforts to clarify the relationship between these two states. This study tested the hypothesis that dexmedetomidine-induced sedation is homologous to sleep. This study used between-groups and within-groups designs. University of Michigan. Adult male Sprague Dawley rats (n = 40). Independent variables were administration of dexmedetomidine and saline or Ringer's solution (control). Dependent variables included time spent in states of wakefulness, sleep, and sedation, electroencephalographic (EEG) power, adenosine levels in the substantia innominata (SI), and activation of pCREB and c-Fos in sleep related forebrain regions. Dexmedetomidine significantly decreased time spent in wakefulness (-49%), increased duration of sedation (1995%), increased EEG delta power (546%), and eliminated the rapid eye movement (REM) phase of sleep for 16 h. Sedation was followed by a rebound increase in NREM and REM sleep. Systemically administered dexmedetomidine significantly decreased (-39%) SI adenosine levels. Dialysis delivery of dexmedetomidine into SI did not decrease adenosine level. Systemic delivery of dexmedetomidine did not alter c-Fos or pCREB expression in the horizontal diagonal band, or ventrolateral, median, and medial preoptic areas of the hypothalamus. Dexmedetomidine significantly altered normal sleep phenotypes, and the dexmedetomidine-induced state did not compensate for sleep need. Thus, in the Sprague Dawley rat, dexmedetomidine-induced sedation is characterized by behavioral, electrographic, and immunohistochemical phenotypes that are distinctly different from similar measures obtained during sleep. © 2014 Associated Professional Sleep Societies, LLC.

Potentiating Effects of Lactuca sativa on Pentobarbital-Induced Sleep.

PubMed

Ghorbani, Ahmad; Rakhshandeh, Hassan; Sadeghnia, Hamid Reza

2013-01-01

Traditionally, Lactuca sativa (lettuce) has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydro-alcoholic extract (HAE) of lettuce and its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF) were administrated (IP) to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD50-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component(s) responsible for this effect is most likely to be non-polar agent(s) which found in NBF of this plant.

Potentiating Effects of Lactuca sativa on Pentobarbital-Induced Sleep

PubMed Central

Ghorbani, Ahmad; Rakhshandeh, Hassan; Sadeghnia, Hamid Reza

2013-01-01

Traditionally, Lactuca sativa (lettuce) has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydro-alcoholic extract (HAE) of lettuce and its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF) were administrated (IP) to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD50-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component(s) responsible for this effect is most likely to be non-polar agent(s) which found in NBF of this plant. PMID:24250615

Morphology-induced defects enhance lipid transfer rates

DOE PAGES

Xia, Yan; Charubin, Kamil; Marquardt, Drew; ...

2016-08-25

Molecular transfer between nanoparticles has been considered to have important implications regarding nanoparticle stability. Recently, the interparticle spontaneous lipid transfer rate constant for discoidal bicelles was found to be very different from spherical, unilamellar vesicles (ULVs). Here, we investigate the mechanism responsible for this discrepancy. Analysis of the data indicates that lipid transfer is entropically favorable, but enthalpically unfavorable with an activation energy that is independent of bicelle size and long- to short-chain lipid molar ratio. Moreover, molecular dynamics simulations reveal a lower lipid dissociation energy cost in the vicinity of interfaces (“defects”) induced by the segregation of the long-more » and short-chain lipids in bicelles; these defects are not present in ULVs. Taken together, these results suggest that the enhanced lipid transfer observed in bicelles arises from interfacial defects as a result of the hydrophobic mismatch between the long- and short-chain lipid species. In conclusion, the observed lipid transfer rate is found to be independent of nanoparticle stability.« less

Preventive Effects of a Fermented Dairy Product against Alzheimer’s Disease and Identification of a Novel Oleamide with Enhanced Microglial Phagocytosis and Anti-Inflammatory Activity

PubMed Central

Ano, Yasuhisa; Ozawa, Makiko; Kutsukake, Toshiko; Sugiyama, Shinya; Uchida, Kazuyuki; Yoshida, Aruto; Nakayama, Hiroyuki

2015-01-01

Despite the ever-increasing number of patients with dementia worldwide, fundamental therapeutic approaches to this condition have not been established. Epidemiological studies suggest that intake of fermented dairy products prevents cognitive decline in the elderly. However, the active compounds responsible for the effect remain to be elucidated. The present study aims to elucidate the preventive effects of dairy products on Alzheimer’s disease and to identify the responsible component. Here, in a mouse model of Alzheimer’s disease (5xFAD), intake of a dairy product fermented with Penicillium candidum had preventive effects on the disease by reducing the accumulation of amyloid β (Aβ) and hippocampal inflammation (TNF-α and MIP-1α production), and enhancing hippocampal neurotrophic factors (BDNF and GDNF). A search for preventive substances in the fermented dairy product identified oleamide as a novel dual-active component that enhanced microglial Aβ phagocytosis and anti-inflammatory activity towards LPS stimulation in vitro and in vivo. During the fermentation, oleamide was synthesized from oleic acid, which is an abundant component of general dairy products owing to lipase enzymatic amidation. The present study has demonstrated the preventive effect of dairy products on Alzheimer’s disease, which was previously reported only epidemiologically. Moreover, oleamide has been identified as an active component of dairy products that is considered to reduce Aβ accumulation via enhanced microglial phagocytosis, and to suppress microglial inflammation after Aβ deposition. Because fermented dairy products such as camembert cheese are easy to ingest safely as a daily meal, their consumption might represent a preventive strategy for dementia. PMID:25760987

A survey of chemicals inducing lipid peroxidation in biological systems.

PubMed

Kappus, H

1987-01-01

A great number of drugs and chemicals are reviewed which have been shown to stimulate lipid peroxidation in any biological system. The underlying mechanisms, as far as known, are also dealt with. Lipid peroxidation induced by iron ions, organic hydroperoxides, halogenated hydrocarbons, redox cycling drugs, glutathione depleting chemicals, ethanol, heavy metals, ozone, nitrogen dioxide and a number of miscellaneous compounds, e.g. hydrazines, pesticides, antibiotics, are mentioned. It is shown that lipid peroxidation is stimulated by many of these compounds. However, quantitative estimates cannot be given yet and it is still impossible to judge the biological relevance of chemical-induced lipid peroxidation.

Therapeutic effects of connexin inhibitors on detrusor overactivity induced by bladder outlet obstruction in rats.

PubMed

Kim, Su Jin; Park, Eun Young; Hwang, Tae-Kon; Kim, Joon Chul

2011-08-01

To investigate the alterations in Connexin 43 (Cx43) and connexin 26 (Cx26) levels in the bladder outlet obstruction (BOO)-induced detrusor overactivity and examine the effect of connexin inhibitors on this condition. Fifty Sprague-Dawley rats were divided into 4 groups: sham-operated control group (n = 10), BOO group (n = 10), and 2 groups that were administered connexin inhibitors. The first of these 2 groups was administered 18β-glycyrrhetinic acid (BOO-18β-GA group, n = 15) and the second group was given oleamide (BOO-oleamide group, n = 15). Cystometrogram was performed in all groups after 2 weeks of obstruction. The expression levels of Cx26 and Cx43 were analyzed using immunohistochemical staining and Western blot. The intercontraction interval was markedly shorter in the BOO group compared with the control group (P <.05). Intercontraction intervals in the BOO-18β-GA and BOO-oleamide groups at 2 weeks were significantly longer than that observed for the BOO group (P <.05). The expression of Cx43 and Cx26 were increased in the BOO group. After administration of connexin inhibitors, downregulation of Cx43 and Cx26 was noted. These results suggest that upregulation of Cx43 and Cx26 induce detrusor overactivity after BOO, and connexin inhibitors may have some role in relieving BOO-induced detrusor overactivity in rats. Copyright © 2011 Elsevier Inc. All rights reserved.

Lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic doses.

PubMed

Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo; Sohn, Ju-Tae

2013-11-01

Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10(-4) M levobupivacaine, 2×10(-3) M ropivacaine, and 7×10(-3) M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10(-3) M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic.

Hypnotic Effect of Ocimum basilicum on Pentobarbital-Induced Sleep in Mice

PubMed Central

Askari, Vahid Reza; Baradaran Rahimi, Vafa; Ghorbani, Ahmad; Rakhshandeh, Hassan

2016-01-01

Background Sleep disorders are accompanied by several complications, and currently used soporific drugs can induce unwanted effects such as psychomotor impairment, tolerance, amnesia, and rebound insomnia. Objectives The present study was carried out to investigate if Ocimum basilicum has a sleep-prolonging effect. Materials and Methods This work was an experimental study on 72 mice which were randomly divided into 9 groups: saline (control); diazepam (3 mg/kg, positive control); hydro-alcoholic extract (HAE) of Ocimum basilicum (25, 50, or 100 mg/kg); ethyl acetate fraction (EAF, 50 mg/kg); n-butanol fraction (NBF, 50 mg/kg); water fraction (WF, 50 mg/kg); and saline containing 10% DMSO (vehicle for EAF and NBF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital-induced sleep were recorded. Also, LD50 of HAE was determined and the cytotoxicity of HAE was tested on neural and fibroblast cells using the MTT assay. Results HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, and 100 mg/kg (P < 0.001). The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and NBF at 50 mg/kg could increase sleep duration. The sleep latency was decreased by HAE (P < 0.01 - P < 0.001) and NBF (P < 0.001), but not by WF and EAF. The LD50 value for HAE was found to be 2.4 g/kg. HAE had no effect on the viability of neuronal PC12 cells and L929 fibroblast cells. Conclusions The present data demonstrated that Ocimum basilicum potentiates sleeping behaviors without any cytotoxicity. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in NBF. Isolation of the active constituents may yield a novel sedative drug. PMID:27651944

Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila.

PubMed

Dubowy, Christine; Moravcevic, Katarina; Yue, Zhifeng; Wan, Joy Y; Van Dongen, Hans P A; Sehgal, Amita

2016-05-01

Sleep rebound-the increase in sleep that follows sleep deprivation-is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake-promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. We identified two lines that consistently exhibit a blunted increase in the duration and depth of sleep after

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity.

PubMed

Gazea, Mary; Patchev, Alexandre V; Anderzhanova, Elmira; Leidmaa, Este; Pissioti, Anna; Flachskamm, Cornelia; Almeida, Osborne F X; Kimura, Mayumi

2018-01-10

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep. SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY 3-36 can reverse this neurochemical imbalance and

Experimental Sleep Restriction Facilitates Pain and Electrically Induced Cortical Responses.

PubMed

Matre, Dagfinn; Hu, Li; Viken, Leif A; Hjelle, Ingri B; Wigemyr, Monica; Knardahl, Stein; Sand, Trond; Nilsen, Kristian Bernhard

2015-10-01

Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses. A paired crossover study. Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS). Laboratory experiment at research center. Self-reported healthy volunteers (n = 21, age range: 18-31 y). Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017). Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR. © 2015 Associated Professional Sleep Societies, LLC.

Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep.

PubMed

Wisor, J P; Morairty, S R; Huynh, N T; Steininger, T L; Kilduff, T S

2006-08-11

Most hypnotic medications currently on the market target some aspect of GABAergic neurotransmission. Although all such compounds increase sleep, these drugs differentially affect the activity of the cerebral cortex as measured by the electroencephalogram. Whereas benzodiazepine medications such as triazolam tend to suppress slow wave activity in the cortex, the GABA(B) ligand gamma-hydroxybutyrate greatly enhances slow wave activity and the non-benzodiazepine, zolpidem, which binds to the omega1 site on the GABA(A) receptor/Cl(-) ionophore complex, is intermediate in this regard. Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3. Using these genes as a panel of biomarkers associated with sleep, we asked whether hypnotic medications induce similar molecular changes in the rat cerebral cortex to those observed when both sleep continuity and slow wave activity are enhanced during recovery sleep. We find that, although each drug increases the expression of a subset of genes in the panel of biomarkers, no drug fully replicates the molecular changes in the cortex associated with recovery sleep. Furthermore, high levels of slow wave activity in the cortex are correlated with increased expression of fra-2 whereas the expression of grp94 is correlated with body temperature. These results demonstrate that sleep-related changes in gene expression may be affected by physiological covariates of sleep and wakefulness rather than by vigilance state per se.

Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis.

PubMed

Chung, Sook Hee; Park, Young Sook; Kim, Ok Soon; Kim, Ja Hyun; Baik, Haing Woon; Hong, Young Ok; Kim, Sang Su; Shin, Jae-Ho; Jun, Jin-Hyun; Jo, Yunju; Ahn, Sang Bong; Jo, Young Kwan; Son, Byoung Kwan; Kim, Seong Hwan

2014-06-01

Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.

Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila

PubMed Central

Dubowy, Christine; Moravcevic, Katarina; Yue, Zhifeng; Wan, Joy Y.; Van Dongen, Hans P.A.; Sehgal, Amita

2016-01-01

Study Objectives: Sleep rebound—the increase in sleep that follows sleep deprivation—is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. Methods: To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake-promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. Results: We identified two lines that consistently exhibit a blunted increase in the

Pro-Inflammatory Activated Kupffer Cells by Lipids Induce Hepatic NKT Cells Deficiency through Activation-Induced Cell Death

PubMed Central

Tang, Tongfang; Sui, Yongheng; Lian, Min; Li, Zhiping; Hua, Jing

2013-01-01

Background Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response. Aims The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. Methods Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. Results High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. Conclusion High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD. PMID:24312613

Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice.

PubMed

Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Pena, Irene Joy Dela; Park, Se Jin; Lee, Hyung Eun; Woo, Hyun; Kim, Hee Jin; Cheong, Jae Hoon; Hong, Eunyoung; Ryu, Jong Hoon

2015-09-05

Prunella vulgaris is widely used as a herbal medicine for cancers, inflammatory diseases, and other infections. Although it has long been used, few studies have examined its effects on central nervous system function. Here, we first observed that ethanolic extracts of P. vulgaris (EEPV) prolonged pentobarbital-induced sleep duration in mice. It is known that EEPV consists of many active components including triterpenoid (ursolic acid and oleanolic acid), which have many biological activities. Therefore, we evaluated which EEPV components induced sleep extension in pentobarbital-mediated sleeping model in mice. Surprisingly, despite their structural similarity and other common functions such as anti-inflammation, anti-cancer, and tissue protection, only ursolic acid enhanced sleep duration in pentobarbital-treated mice. These results were attenuated by bicuculline treatment, which is a GABAA receptor antagonist. The present results suggest that ursolic acid from P. vulgaris enhances sleep duration through GABAA receptor activation and could be a therapeutic candidate for insomnia treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Academic Performance among Adolescents with Behaviorally Induced Insufficient Sleep Syndrome

PubMed Central

Lee, Yu Jin; Park, Juhyun; Kim, Soohyun; Cho, Seong-Jin; Kim, Seog Ju

2015-01-01

Study Objectives: The present study investigated academic performance among adolescents with behaviorally induced insufficient sleep syndrome (BISS) and attempted to identify independent predictors of academic performance among BISS-related factors. Methods: A total of 51 students with BISS and 50 without BISS were recruited from high schools in South Korea based on self-reported weekday sleep durations, weekend oversleep, and the Epworth Sleepiness Scale (ESS). Participants reported their academic performance in the form of class quartile ranking. The Korean version of the Composite Scale (KtCS) for morningness/eveningness, the Beck Depression Inventory (BDI) for depression, and the Barratt Impulsiveness Scale-II (BIS-II) for impulsivity were administered. Results: Adolescents with BISS reported poorer academic performance than adolescents without BISS (p = 0.02). Adolescents with BISS also exhibited greater levels of eveningness (p < 0.001), depressive symptoms (p < 0.001), and impulsiveness (p < 0.01). Longer weekend oversleep predicted poorer academic performance among adolescents with BISS even after controlling for ESS, KtCS, BDI, and BIS-II (β = 0.42, p < 0.01). Conclusions: BISS among adolescents is associated with poor academic performance and that sleep debt, as represented by weekend oversleep, predicts poorer academic performance independent of depression, impulsiveness, weekday sleep duration, daytime sleepiness, and morningness/eveningness among adolescents with BISS. Citation: Lee YJ, Park J, Kim S, Cho SJ, Kim SJ. Academic performance among adolescents with behaviorally induced insufficient sleep syndrome. J Clin Sleep Med 2015;11(1):61–68. PMID:25515277

Brief Report: Behaviorally Induced Insufficient Sleep Syndrome in Older Adolescents: Prevalence and Correlates

ERIC Educational Resources Information Center

Pallesen, Stale; Saxvig, Ingvild West; Molde, Helge; Sorensen, Eli; Wilhelmsen-Langeland, Ane; Bjorvatn, Bjorn

2011-01-01

The aim of the present study was to investigate the prevalence of "behaviorally induced insufficient sleep syndrome (BIISS)" which is a newly defined hypersomnia, among adolescents. BIISS is characterized by excessive daytime sleepiness, short habitual sleep duration and sleeping considerably longer than usual during weekend/vacations.…

[Pharmacology of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (II). Sleep-inducing activity and effect on the motor system].

PubMed

Yamamoto, K; Matsushita, A; Sawada, T; Naito, Y; Yoshimura, K; Takesue, H; Utsumi, S; Kawasaki, K; Hirono, S; Koshida, H

1984-07-01

The sleep-inducing activity and effect on the motor system of the 1H-1,2,4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for 1 to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the

Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations.

PubMed

Tubert-Brohman, Ivan; Acevedo, Orlando; Jorgensen, William L

2006-12-27

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that degrades anandamide, an endocannabinoid, and oleamide, a sleep-inducing lipid, and has potential applications as a therapeutic target for neurological disorders. Remarkably, FAAH hydrolyzes amides and esters with similar rates; however, the normal preference for esters reemerges when Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and the causes behind this variation of selectivity, mixed quantum and molecular mechanics (QM/MM) calculations were carried out to obtain free-energy profiles for alternative mechanisms for the enzymatic hydrolyses. The methodology features free-energy perturbation calculations in Monte Carlo simulations with PDDG/PM3 as the QM method. For wild-type FAAH, the results support a mechanism, which features proton transfer from Ser217 to Lys142, simultaneous proton transfer from Ser241 to Ser217, and attack of Ser241 on the substrate's carbonyl carbon to yield a tetrahedral intermediate, which subsequently undergoes elimination with simultaneous protonation of the leaving group by a Lys142-Ser217 proton shuttle. For the Lys142Ala mutant, a striking multistep sequence is proposed with simultaneous proton transfer from Ser241 to Ser217, attack of Ser241 on the carbonyl carbon of the substrate, and elimination of the leaving group and its protonation by Ser217. Support comes from the free-energy results, which well reproduce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis for oleamide significantly more than for methyl oleate.

Bicarbonate trigger for inducing lipid accumulation in algal systems

DOEpatents

Gardner, Robert; Peyton, Brent; Cooksey, Keith E.

2015-08-04

The present invention provides bicarbonate containing and/or bicarbonate-producing compositions and methods to induce lipid accumulation in an algae growth system, wherein the algae growth system is under light-dark cycling condition. By adding said compositions at a specific growth stage, said methods lead to much higher lipid accumulation and/or significantly reduced total time required for accumulating lipid in the algae growth system.

Possible Involvement of Nitric Oxide Modulatory Mechanisms in the Neuroprotective Effect of Centella asiatica Against Sleep Deprivation Induced Anxiety Like Behaviour, Oxidative Damage and Neuroinflammation.

PubMed

Chanana, Priyanka; Kumar, Anil

2016-04-01

Sleep deprivation (SD) is an experience of inadequate or poor quality of sleep that may produce significant alterations in multiple neural systems. Centella asiatica (CA) is a psychoactive medicinal herb with immense therapeutic potential. The present study was designed to explore the possible nitric oxide (NO) modulatory mechanism in the neuroprotective effect of CA against SD induced anxiety like behaviour, oxidative damage and neuroinflammation. Male laca mice were sleep deprived for 72 h, and CA (150 and 300 mg/kg) was administered alone and in combination with NO modulators for 8 days, starting five days before 72-h SD exposure. Various behavioural (locomotor activity, elevated plus maze) and biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels and superoxide dismutase activity), neuroinflammation marker (TNF-alpha) were assessed subsequently. CA (150 and 300 mg/kg) treatment for 8 days significantly improved locomotor activity, anti-anxiety like effect and attenuated oxidative damage and TNF α level as compared to sleep-deprived 72-h group. Also while the neuroprotective effect of CA was increased by NO antagonists, it was diminished by NO agonists. The present study suggests that NO modulatory mechanism could be involved in the protective effect of CA against SD-induced anxiety-like behaviour, oxidative damage and neuroinflammation in mice. Copyright © 2016 John Wiley & Sons, Ltd.

Chronic Sleep Fragmentation During the Sleep Period Induces Hypothalamic Endoplasmic Reticulum Stress and PTP1b-Mediated Leptin Resistance in Male Mice

PubMed Central

Hakim, Fahed; Wang, Yang; Carreras, Alba; Hirotsu, Camila; Zhang, Jing; Peris, Eduard; Gozal, David

2015-01-01

Background: Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. Methods: Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP −/+ transgenic mice. Results: Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP −/+ mice. Conclusions: Sleep fragmentation (SF) induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of endoplasmic reticulum (ER) stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target. Citation: Hakim F, Wang Y, Carreras A, Hirotsu C, Zhang J, Peris E, Gozal D. Chronic sleep

Decreased inducibility of TNF expression in lipid-loaded macrophages

PubMed Central

Ares, Mikko PS; Stollenwerk, Maria; Olsson, Anneli; Kallin, Bengt; Jovinge, Stefan; Nilsson, Jan

2002-01-01

Background Inflammation and immune responses are considered to be very important in the pathogenesis of atherosclerosis. Lipid accumulation in macrophages of the arterial intima is a characteristic feature of atherosclerosis which can influence the inflammatory potential of macrophages. We studied the effects of lipid loading on the regulation of TNF expression in human monocyte-derived macrophages. Results In macrophages incubated with acetylated low density lipoprotein (ac-LDL) for 2 days, mRNA expression of TNF in cells stimulated with TNF decreased by 75%. In cell cultures stimulated over night with IL-1β, lipid loading decreased secretion of TNF into culture medium by 48%. These results suggest that lipid accumulation in macrophages makes them less responsive to inflammatory stimuli. Decreased basal activity and inducibility of transcription factor AP-1 was observed in lipid-loaded cells, suggesting a mechanism for the suppression of cytokine expression. NF-κB binding activity and inducibility were only marginally affected by ac-LDL. LDL and ac-LDL did not activate PPARγ. In contrast, oxidized LDL stimulated AP-1 and PPARγ but inhibited NF-κB, indicating that the effects of lipid loading with ac-LDL were not due to oxidation of lipids. Conclusions Accumulation of lipid, mainly cholesterol, results in down-regulation of TNF expression in macrophages. Since monocytes are known to be activated by cell adhesion, these results suggest that foam cells in atherosclerotic plaques may contribute less potently to an inflammatory reaction than newly arrived monocytes/macrophages. PMID:12366867

The structure of oleamide films at the aluminum/oil interface and aluminum/air interface studied by Sum Frequency Generation (SFG) vibrational spectroscopy and Reflection Absorption Infrared Spectroscopy (RAIRS).

PubMed

Casford, Michael T L; Davies, Paul B

2009-08-01

The structure of oleamide (cis-9-octadecenamide) films on aluminum has been investigated by sum frequency generation vibrational spectroscopy (SFG) and reflection absorption infrared spectroscopy (RAIRS). Three different film deposition strategies were investigated: (i) films formed by equilibrium adsorption from oleamide solutions in oil, (ii) Langmuir-Blodgett films cast at 1 and 25 mN m(-1), (iii) thick spin-cast films. Both L-B and spin-cast films were examined in air and under oil. The adsorbate formed in the 1 mN m(-1) film in air showed little orientational order. For this film, the spectroscopic results and the ellipsometric thickness point to a relatively conformationally disordered monolayer that is oriented principally in the plane of the interface. Direct adsorption to the metal interface from oil results in SFG spectra of oleamide that are comparable to those observed for the 1 mN m(-1) L-B film in air. In contrast, SFG and RAIRS results for the 25 mN m(-1) film in air and SFG spectra of the spin-cast film in air both show strong conformational ordering and orientational alignment normal to the interface. The 25 mN m(-1) film has an ellipsometric thickness almost twice that of the 1 mN m(-1) L-B film. Taken in combination with the spectroscopic results, this is indicative of a well packed monolayer in air in which the hydrocarbon chain is in an essentially defect-free extended conformation with the methyl terminus oriented away from the surface. A similar structure is also deduced for the surface of the spin-cast film in air. Upon immersion of the 25 mN m(-1) L-B film in oil the SFG spectra show that this film rapidly adopts a relatively disordered structure similar to that seen for the 1 mN m(-1) L-B film in air. Immersion of the spin-cast film in oil results in the gradual disordering of the amide film over a period of several days until the observed spectra become essentially identical to those observed for direct adsorption of oleamide from oil.

Lipid-protein interaction induced domains: Kinetics and conformational changes in multicomponent vesicles

NASA Astrophysics Data System (ADS)

Sreeja, K. K.; Sunil Kumar, P. B.

2018-04-01

The spatio-temporal organization of proteins and the associated morphological changes in membranes are of importance in cell signaling. Several mechanisms that promote the aggregation of proteins at low cell surface concentrations have been investigated in the past. We show, using Monte Carlo simulations, that the affinity of proteins for specific lipids can hasten their aggregation kinetics. The lipid membrane is modeled as a dynamically triangulated surface with the proteins defined as in-plane fields at the vertices. We show that, even at low protein concentrations, strong lipid-protein interactions can result in large protein clusters indicating a route to lipid mediated signal amplification. At high protein concentrations, the domains form buds similar to that seen in lipid-lipid interaction induced phase separation. Protein interaction induced domain budding is suppressed when proteins act as anisotropic inclusions and exhibit nematic orientational order. The kinetics of protein clustering and resulting conformational changes are shown to be significantly different for the isotropic and anisotropic curvature inducing proteins.

Sleep-Active Neurons: Conserved Motors of Sleep

PubMed Central

Bringmann, Henrik

2018-01-01

Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

No effect of odor-induced memory reactivation during REM sleep on declarative memory stability

PubMed Central

Cordi, Maren J.; Diekelmann, Susanne; Born, Jan; Rasch, Björn

2014-01-01

Memory reactivations in hippocampal brain areas are critically involved in memory consolidation processes during sleep. In particular, specific firing patterns of hippocampal place cells observed during learning are replayed during subsequent sleep and rest in rodents. In humans, experimentally inducing hippocampal memory reactivations during slow-wave sleep (but not during wakefulness) benefits consolidation and immediately stabilizes declarative memories against future interference. Importantly, spontaneous hippocampal replay activity can also be observed during rapid eye movement (REM) sleep and some authors have suggested that replay during REM sleep is related to processes of memory consolidation. However, the functional role of reactivations during REM sleep for memory stability is still unclear. Here, we reactivated memories during REM sleep and examined its consequences for the stability of declarative memories. After 3 h of early, slow-wave sleep (SWS) rich sleep, 16 healthy young adults learned a 2-D object location task in the presence of a contextual odor. During subsequent REM sleep, participants were either re-exposed to the odor or to an odorless vehicle, in a counterbalanced within subject design. Reactivation was followed by an interference learning task to probe memory stability after awakening. We show that odor-induced memory reactivation during REM sleep does not stabilize memories against future interference. We propose that the beneficial effect of reactivation during sleep on memory stability might be critically linked to processes characterizing SWS including, e.g., slow oscillatory activity, sleep spindles, or low cholinergic tone, which are required for a successful redistribution of memories from medial temporal lobe regions to neocortical long-term stores. PMID:25225474

Venlafaxine-induced REM sleep behavioral disorder presenting as two fractures.

PubMed

Ryan Williams, R; Sandigo, Gustavo

2017-10-01

Rapid eye movement (REM) sleep behavioral disorder is characterized by the absence of muscular atonia during REM sleep. In this disorder, patients can violently act out their dreams, placing them at risk for traumatic fractures during these episodes. REM sleep behavioral disorder (RBD) can be a sign of future neurodegenerative disease and has also been found to be a side effect of certain psychiatric medications. We present a case of venlafaxine-induced RBD in a 55 year old female who presented with a 13 year history of intermittent parasomnia and dream enactment in addition to a recent history of two fractures requiring intervention.

Positive effects of β-amyrin on pentobarbital-induced sleep in mice via GABAergic neurotransmitter system.

PubMed

Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Lee, Hyung Eun; Park, Se Jin; Hong, Eunyoung; Jang, Dae Sik; Shin, Chan Young; Cheong, Jae Hoon; Ryu, Jong Hoon

2015-09-15

Sleep loss, insomnia, is considered a sign of imbalance of physiological rhythm, which can be used as pre-clinic diagnosis of various neuropsychiatric disorders. The aim of the present study is to understand the pharmacological actions of α- or β-amyrin, natural triterpene compound, on the sleep in mice. To analyze the sleeping behavior, we used the well-known pentobarbital-induced sleeping model after single administration of either α- or β-amyrin. The sleeping onset time was remarkably decreased and duration was prolonged by β-amyrin (1, 3, or 10mg/kg) but not by α-amyrin (1, 3, or 10mg/kg). These effects were significantly blocked by GABAA receptor antagonist, bicuculline. Moreover, β-amyrin increased brain GABA level compared to the vehicle administration. Overall, the present study suggests that β-amyrin would enhance the total sleeping behavior in pentobarbital-induced sleeping model via the activation of GABAergic neurotransmitter system through GABA content in the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

Torque Induced on Lipid Microtubules with Optical Tweezers

NASA Astrophysics Data System (ADS)

wichean, T. Na; Charrunchon, S.; Pattanaporkratana, A.; Limtrakul, J.; Chattham, N.

2017-09-01

Chiral Phospholipids are found self-assembled into cylindrical tubules of 500 nm in diameter by helical winding of bilayer stripes under cooling in ethanol and water solution. Theoretical prediction and experimental evidence reported so far confirmed the modulated tilt direction in a helical striped pattern of the tubules. This molecular orientation morphology results in optically birefringent tubules. We investigate an individual lipid microtubule under a single optical trap of 532 nm linearly polarized laser. Spontaneous rotation of a lipid tubule induced by radiation torque was observed with only one sense of rotation caused by chirality of a lipid tubule. Rotation discontinued once the high refractive index axis of a lipid tubule aligned with a polarization axis of the laser. We further explored a lipid tubule under circularly polarized optical trap. It was found that a lipid tubule was continuously rotated confirming the tubule birefringent property. We modified the shape of optical trap by cylindrical lens obtaining an elliptical profile optical trap. A lipid tubule can be aligned along the elongated length of optical trap. We reported an investigation of competition between polarized light torque on a birefringent lipid tubule versus torque from intensity gradient of an elongated optical trap.

Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome.

PubMed

Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

2015-01-01

Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon's and patients' satisfaction, postoperative Aldrete score and side effects were recorded. Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia.

Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome

PubMed Central

Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

2015-01-01

Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. Aims: We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. Methods: A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon’s and patients’ satisfaction, postoperative Aldrete score and side effects were recorded. Results: Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Conclusion: Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia. PMID:26131153

Dorsal Raphe Serotonin Neurons Mediate CO2-Induced Arousal from Sleep.

PubMed

Smith, Haleigh R; Leibold, Nicole K; Rappoport, Daniel A; Ginapp, Callie M; Purnell, Benton S; Bode, Nicole M; Alberico, Stephanie L; Kim, Young-Cho; Audero, Enrica; Gross, Cornelius T; Buchanan, Gordon F

2018-02-21

Arousal from sleep in response to CO 2 is a critical protective phenomenon. Dysregulation of CO 2 -induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO 2 -induced arousal is unknown. Because CO 2 is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO 2 -induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO 2 could cause arousal from sleep independently of enhancing breathing. Dialysis of CO 2 -rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO 2 can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality. SIGNIFICANCE STATEMENT Although CO 2 -induced arousal is critical to a number of diseases, the specific mechanism is not well understood. We previously demonstrated that serotonin (5-HT) neurons are important for CO 2 -induced arousal, as mice without 5-HT neurons do not arouse to CO 2 Many have interpreted this to mean that medullary 5-HT neurons that regulate breathing are important in this arousal mechanism. Here we found that direct application of CO 2

Down-regulation of lipid raft-associated onco-proteins via cholesterol-dependent lipid raft internalization in docosahexaenoic acid-induced apoptosis.

PubMed

Lee, Eun Jeong; Yun, Un-Jung; Koo, Kyung Hee; Sung, Jee Young; Shim, Jaegal; Ye, Sang-Kyu; Hong, Kyeong-Man; Kim, Yong-Nyun

2014-01-01

Lipid rafts, plasma membrane microdomains, are important for cell survival signaling and cholesterol is a critical lipid component for lipid raft integrity and function. DHA is known to have poor affinity for cholesterol and it influences lipid rafts. Here, we investigated a mechanism underlying the anti-cancer effects of DHA using a human breast cancer cell line, MDA-MB-231. We found that DHA decreased cell surface levels of lipid rafts via their internalization, which was partially reversed by cholesterol addition. With DHA treatment, caveolin-1, a marker for rafts, and EGFR were colocalized with LAMP-1, a lysosomal marker, in a cholesterol-dependent manner, indicating that DHA induces raft fusion with lysosomes. DHA not only displaced several raft-associated onco-proteins, including EGFR, Hsp90, Akt, and Src, from the rafts but also decreased total levels of those proteins via multiple pathways, including the proteasomal and lysosomal pathways, thereby decreasing their activities. Hsp90 overexpression maintained its client proteins, EGFR and Akt, and attenuated DHA-induced cell death. In addition, overexpression of Akt or constitutively active Akt attenuated DHA-induced apoptosis. All these data indicate that the anti-proliferative effect of DHA is mediated by targeting of lipid rafts via decreasing cell surface lipid rafts by their internalization, thereby decreasing raft-associated onco-proteins via proteasomal and lysosomal pathways and decreasing Hsp90 chaperone function. © 2013.

Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats

PubMed Central

Tarasiuk, Ariel; Levi, Avishag; Assadi, Mohammad H.; Troib, Ariel; Segev, Yael

2016-01-01

Study Objectives: The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. Methods: The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. Results: The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. Conclusions: In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. Citation: Tarasiuk A, Levi A, Assadi MH, Troib A, Segev Y. Orexin plays a role in growth impediment induced by obstructive sleep breathing in rats. SLEEP 2016;39(4):887–897. PMID:26943473

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

PubMed Central

Velázquez-Moctezuma, J.

2016-01-01

Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins. PMID:27738642

Organization and logistics of drug-induced sleep endoscopy in a training hospital.

PubMed

Benoist, L B L; de Vries, N

2015-09-01

Drug-induced sleep endoscopy (DISE) is a rapidly growing method to evaluate airway collapse in patients receiving non-CPAP therapies for sleep-disordered breathing (SDB). The growing number of DISEs has consequences for the organization of clinical protocols. In this paper we present our recent experiences with DISE, performed by an ENT resident, with sedation given by a nurse anesthetist, in an outpatient endoscopy setting, while the staff member/sleep surgeon discusses the findings and the recommended treatment proposal on the same day.

Polystyrene nanoparticle exposure induces ion-selective pores in lipid bilayers

PubMed Central

Negoda, Alexander; Kim, Kwang-Jin; Crandall, Edward D.; Worden, Robert M.

2014-01-01

A diverse range of molecular interactions can occur between engineered nanomaterials (ENM) and biomembranes, some of which could lead to toxic outcomes following human exposure to ENM. In this study, we adapted electrophysiology methods to investigate the ability of 20 nm polystyrene nanoparticles (PNP) to induce pores in model bilayer lipid membranes (BLM) that mimic biomembranes. PNP charge was varied using PNP decorated with either positive (amidine) groups or negative (carboxyl) groups, and BLM charge was varied using dioleoyl phospholipids having cationic (ethylphosphocholine), zwitterionic (phosphocholine), or anionic (phosphatidic acid) headgroups. Both positive and negative PNP induced BLM pores for all lipid compositions studied, as evidenced by current spikes and integral conductance. Stable PNP-induced pores exhibited ion selectivity, with the highest selectivity for K+ (PK/PCl ~ 8.3) observed when both the PNP and lipids were negatively charged, and the highest selectivity for Cl− (PK/PCl ~ 0.2) observed when both the PNP and lipids were positively charged. This trend is consistent with the finding that selectivity for an ion in channel proteins is imparted by oppositely charged functional groups within the channel’s filter region. The PK/PCl value was unaffected by the voltage-ramp method, the pore conductance, or the side of the BLM to which the PNP were applied. These results demonstrate for the first time that PNP can induce ion-selective pores in BLM, and that the degree of ion selectivity is influenced synergistically by the charges of both the lipid headgroups and functional groups on the PNP. PMID:23747366

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

PubMed

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Domain Formation Induced by the Adsorption of Charged Proteins on Mixed Lipid Membranes

PubMed Central

Mbamala, Emmanuel C.; Ben-Shaul, Avinoam; May, Sylvio

2005-01-01

Peripheral proteins can trigger the formation of domains in mixed fluid-like lipid membranes. We analyze the mechanism underlying this process for proteins that bind electrostatically onto a flat two-component membrane, composed of charged and neutral lipid species. Of particular interest are membranes in which the hydrocarbon lipid tails tend to segregate owing to nonideal chain mixing, but the (protein-free) lipid membrane is nevertheless stable due to the electrostatic repulsion between the charged lipid headgroups. The adsorption of charged, say basic, proteins onto a membrane containing anionic lipids induces local lipid demixing, whereby charged lipids migrate toward (or away from) the adsorption site, so as to minimize the electrostatic binding free energy. Apart from reducing lipid headgroup repulsion, this process creates a gradient in lipid composition around the adsorption zone, and hence a line energy whose magnitude depends on the protein's size and charge and the extent of lipid chain nonideality. Above a certain critical lipid nonideality, the line energy is large enough to induce domain formation, i.e., protein aggregation and, concomitantly, macroscopic lipid phase separation. We quantitatively analyze the thermodynamic stability of the dressed membrane based on nonlinear Poisson-Boltzmann theory, accounting for both the microscopic characteristics of the proteins and lipid composition modulations at and around the adsorption zone. Spinodal surfaces and critical points of the dressed membranes are calculated for several different model proteins of spherical and disk-like shapes. Among the models studied we find the most substantial protein-induced membrane destabilization for disk-like proteins whose charges are concentrated in the membrane-facing surface. If additional charges reside on the side faces of the proteins, direct protein-protein repulsion diminishes considerably the propensity for domain formation. Generally, a highly charged flat face

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

PubMed Central

Chanana, Priyanka; Kumar, Anil

2016-01-01

Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems. Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation. Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed. Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel

Oxidized lipids and lipid-mediators are involved in cardiovascular injury induced by diesel exhaust particles and ozone

EPA Science Inventory

The mechanisms by which air pollutants induce cardiac and vascular injuries are unknown. We hypothesized that these injuries involve alterations in'aortic membrane lipids and lipid-mediators. We exposed male Wistar Kyoto rats (12-15 wk old), nose-only to air, ozone (03; 0.5 ppm),...

Oral mucosal lipids are antibacterial against Porphyromonas gingivalis, induce ultrastructural damage, and alter bacterial lipid and protein compositions.

PubMed

Fischer, Carol L; Walters, Katherine S; Drake, David R; Dawson, Deborah V; Blanchette, Derek R; Brogden, Kim A; Wertz, Philip W

2013-09-01

Oral mucosal and salivary lipids exhibit potent antimicrobial activity for a variety of Gram-positive and Gram-negative bacteria; however, little is known about their spectrum of antimicrobial activity or mechanisms of action against oral bacteria. In this study, we examine the activity of two fatty acids and three sphingoid bases against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Minimal inhibitory concentrations, minimal bactericidal concentrations, and kill kinetics revealed variable, but potent, activity of oral mucosal and salivary lipids against P. gingivalis, indicating that lipid structure may be an important determinant in lipid mechanisms of activity against bacteria, although specific components of bacterial membranes are also likely important. Electron micrographs showed ultrastructural damage induced by sapienic acid and phytosphingosine and confirmed disruption of the bacterial plasma membrane. This information, coupled with the association of treatment lipids with P. gingivalis lipids revealed via thin layer chromatography, suggests that the plasma membrane is a likely target of lipid antibacterial activity. Utilizing a combination of two-dimensional in-gel electrophoresis and Western blot followed by mass spectroscopy and N-terminus degradation sequencing we also show that treatment with sapienic acid induces upregulation of a set of proteins comprising a unique P. gingivalis stress response, including proteins important in fatty acid biosynthesis, metabolism and energy production, protein processing, cell adhesion and virulence. Prophylactic or therapeutic lipid treatments may be beneficial for intervention of infection by supplementing the natural immune function of endogenous lipids on mucosal surfaces.

ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness.

PubMed

Mikhail, Cyril; Vaucher, Angélique; Jimenez, Sonia; Tafti, Mehdi

2017-01-24

Wakefulness is accompanied by experience-dependent synaptic plasticity and an increase in activity-regulated gene transcription. Wake-induced genes are certainly markers of neuronal activity and may also directly regulate the duration of and need for sleep. We stimulated murine cortical cultures with the neuromodulatory signals that are known to control wakefulness in the brain and found that norepinephrine alone or a mixture of these neuromodulators induced activity-regulated gene transcription. Pharmacological inhibition of the various signaling pathways involved in the regulation of gene expression indicated that the extracellular signal-regulated kinase (ERK) pathway is the principal one mediating the effects of waking neuromodulators on gene expression. In mice, ERK phosphorylation in the cortex increased and decreased with wakefulness and sleep. Whole-body or cortical neuron-specific deletion of Erk1 or Erk2 significantly increased the duration of wakefulness in mice, and pharmacological inhibition of ERK phosphorylation decreased sleep duration and increased the duration of wakefulness bouts. Thus, this signaling pathway, which is highly conserved from Drosophila to mammals, is a key pathway that links waking experience-induced neuronal gene expression to sleep duration and quality. Copyright © 2017, American Association for the Advancement of Science.

Polar Lipids of Burkholderia pseudomallei Induce Different Host Immune Responses

PubMed Central

Gonzalez-Juarrero, Mercedes; Mima, Naoko; Trunck, Lily A.; Schweizer, Herbert P.; Bowen, Richard A.; Dascher, Kyle; Mwangi, Waithaka; Eckstein, Torsten M.

2013-01-01

Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs) and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor) molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster. PMID:24260378

Sleep loss and acute drug abuse can induce DNA damage in multiple organs of mice.

PubMed

Alvarenga, T A; Ribeiro, D A; Araujo, P; Hirotsu, C; Mazaro-Costa, R; Costa, J L; Battisti, M C; Tufik, S; Andersen, M L

2011-09-01

The purpose of the present study was to characterize the genetic damage induced by paradoxical sleep deprivation (PSD) in combination with cocaine or ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in multiple organs of male mice using the single cell gel (comet) assay. C57BL/6J mice were submitted to PSD by the platform technique for 72 hours, followed by drug administration and evaluation of DNA damage in peripheral blood, liver and brain tissues. Cocaine was able to induce genetic damage in the blood, brain and liver cells of sleep-deprived mice at the majority of the doses evaluated. Ecstasy also induced increased DNA migration in peripheral blood cells for all concentrations tested. Analysis of damaged cells by the tail moment data suggests that ecstasy is a genotoxic chemical at the highest concentrations tested, inducing damage in liver or brain cells after sleep deprivation in mice. Taken together, our results suggest that cocaine and ecstasy/MDMA act as potent genotoxins in multiple organs of mice when associated with sleep loss.

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

PubMed

Aho, Vilma; Ollila, Hanna M; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S A; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

2016-04-22

Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

PubMed

Wodarski, R; Schuh-Hofer, S; Yurek, D A; Wafford, K A; Gilmour, G; Treede, R-D; Kennedy, J D

2015-04-01

Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity. © 2014 European Pain Federation - EFIC®

Review of field studies of aircraft noise-induced sleep disturbance.

PubMed

Michaud, David S; Fidell, Sanford; Pearsons, Karl; Campbell, Kenneth C; Keith, Stephen E

2007-01-01

Aircraft noise-induced sleep disturbance (AN-ISD) is potentially among the more serious effects of aircraft noise on people. This literature review of recent field studies of AN-ISD finds that reliable generalization of findings to population-level effects is complicated by individual differences among subjects, methodological and analytic differences among studies, and predictive relationships that account for only a small fraction of the variance in the relationship between noise exposure and sleep disturbance. It is nonetheless apparent in the studied circumstances of residential exposure that sleep disturbance effects of nighttime aircraft noise intrusions are not dramatic on a per-event basis, and that linkages between outdoor aircraft noise exposure and sleep disturbance are tenuous. It is also apparent that AN-ISD occurs more often during later than earlier parts of the night; that indoor sound levels are more closely associated with sleep disturbance than outdoor measures; and that spontaneous awakenings, or awakenings attributable to nonaircraft indoor noises, occur more often than awakenings attributed to aircraft noise. Predictions of sleep disturbance due to aircraft noise should not be based on over-simplifications of the findings of the reviewed studies, and these reports should be treated with caution in developing regulatory policy for aircraft noise.

Trigeminal induced arousals during human sleep.

PubMed

Heiser, Clemens; Baja, Jan; Lenz, Franziska; Sommer, J Ulrich; Hörmann, Karl; Herr, Raphael M; Stuck, Boris A

2015-05-01

Arousals caused by external stimuli during human sleep have been studied for most of the sensorial systems. It could be shown that a pure nasal trigeminal stimulus leads to arousals during sleep. The frequency of arousals increases dependent on the stimulus concentration. The aim of the study was to evaluate the influence of different stimulus durations on arousal frequency during different sleep stages. Ten young healthy volunteers with 20 nights of polysomnography were included in the study. Pure trigeminal stimulation with both different concentrations of CO2 (0, 10, 20, 40% v/v) and different stimulus durations (1, 3, 5, and 10 s) were applied during different sleep stages to the volunteers using an olfactometer. The application was performed during different sleep stages (light sleep, deep sleep, REM sleep). The number of arousals increased with rising stimulus duration and stimulus concentration during each sleep stage. Trigeminal stimuli during sleep led to arousals in dose- and time-dependent manner.

Profiling over 1500 lipids in induced lung sputum and the implications in studying lung diseases.

PubMed

t'Kindt, Ruben; Telenga, Eef D; Jorge, Lucie; Van Oosterhout, Antoon J M; Sandra, Pat; Ten Hacken, Nick H T; Sandra, Koen

2015-01-01

Induced lung sputum is a valuable matrix in the study of respiratory diseases. Although the methodology of sputum collection has evolved to a point where it is repeatable and responsive to inflammation, its use in molecular profiling studies is still limited. Here, an in-depth lipid profiling of induced lung sputum using high-resolution liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS) is described. An enormous complexity in lipid composition could be revealed. Over 1500 intact lipids, originating from 6 major lipid classes, have been accurately identified in 120 μL of induced sputum. By number and measured intensity, glycerophospholipids represent the largest lipid class, followed by sphingolipids, glycerolipids, fatty acyls, sterol lipids, and prenol lipids. Several prenol lipids, originating from tobacco, could be detected in the lung sputum of smokers. To illustrate the utility of the methodology in studying respiratory diseases, a comparative lipid screening was performed on lung sputum extracts in order to study the effect of Chronic Obstructive Pulmonary Disease (COPD) on the lung barrier lipidome. Results show that sphingolipid expression in induced sputum significantly differs between smokers with and without COPD.

Effects of one night of induced night-wakings versus sleep restriction on sustained attention and mood: a pilot study.

PubMed

Kahn, Michal; Fridenson, Shimrit; Lerer, Reut; Bar-Haim, Yair; Sadeh, Avi

2014-07-01

Despite their high prevalence in daily life, repeated night-wakings and their cognitive and emotional consequences have received less research attention compared to other types of sleep disturbances. Our aim was to experimentally compare the effects of one night of induced infrequent night-wakings (of ∼15 min, each requiring a purposeful response) and sleep restriction on sustained attention and mood in young adults. In a within-between subjects counterbalanced design, 61 healthy adults (40 females; aged 20-29 years) underwent home assessments of sustained attention and self-reported mood at two times: after a normal (control) sleep night, and after a night of either sleep restriction (4h in bed) or induced night-wakings (four prolonged awakenings across 8h in bed). Sleep was monitored using actigraphy and sleep diaries. Sustained attention was assessed using an online continuous performance test (OCPT), and mood was reported online using the Profile of Mood States (POMS). Actigraphic data revealed good compliance with experimental sleep requirements. Induced night-wakings and sleep restriction both resulted in more OCPT omission and commission errors, and in increased depression, fatigue and confusion levels and reduced vigor compared to the normal sleep night. Moreover, there were no significant differences between the consequences of induced awakenings and sleep restriction. Our pilot study indicates that, similar to sleep restriction, one night of life-like repeated night-wakings negatively affects mood and sustained attention. Copyright © 2014 Elsevier B.V. All rights reserved.

Obstructive sleep apnea syndrome (OSAS) and hypertension: Pathogenic mechanisms and possible therapeutic approaches

PubMed Central

Zhang, Wang

2012-01-01

Obstructive sleep apnea syndrome (OSAS), a chronic condition characterized by collapse of the pharynx during sleep, has been increasingly recognized as a health issue of growing importance over the last decade. Recently emerging evidence suggests that there is a causal link between OSAS and hypertension, and hypertension represents an independent risk factor in OSAS patients. However, the pathophysiological basis for patients with OSAS having an increased risk for hypertension remains to be elucidated. The main acute physiological outcomes of OSAS are intermittent hypoxia, intrapleural pressure changes, and arousal from sleep, which might induce endothelial dysfunction, sympathetic activation, renin–angiotensin–aldosterone system activation, lipid metabolism dysfunction, and increased oxidative stress. This brief review focuses on the current understanding of the complex association between OSAS and hypertension. PMID:23009224

Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

PubMed Central

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-01-01

Study Objectives: Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Design: Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Participants: Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Measurements: Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. Results: In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Conclusions: Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. Citation: Huang CT, Chiang RP, Chen CL, Tsai YJ. Sleep

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alters Mitochondrial Membrane Lipids

PubMed Central

Sandra, Ferry; Esposti, Mauro Degli; Ndebele, Kenneth; Gona, Philimon; Knight, David; Rosenquist, Magnus; Khosravi-Far, Roya

2010-01-01

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been shown to have selective antitumor activity. TRAIL induces ubiquitous pathways of cell death in which caspase activation is mediated either directly or via the release of apoptogenic factors from mitochondria; however, the precise components of the mitochondrial signaling pathway have not been well defined. Notably, mitochondria constitute an important target in overcoming resistance to TRAIL in many types of tumors. Bid is considered to be fundamental in engaging mitochondria during death receptor–mediated apoptosis, but this action is dependent on mitochondrial lipids. Here, we report that TRAIL signaling induces an alteration in mitochondrial membrane lipids, particularly cardiolipin. This occurs independently of caspase activation and primes mitochondrial membranes to the proapoptotic action of Bid. We unveil a link between TRAIL signaling and alteration of membrane lipid homeostasis that occurs in parallel to apical caspase activation but does not take over the mode of cell death because of the concurrent activation of caspase-8. In particular, TRAIL-induced alteration of mitochondrial lipids follows an imbalance in the cellular homeostasis of phosphatidylcholine, which results in an elevation in diacylglycerol (DAG). Elevated DAG in turn activates the δ isoform of phospholipid-dependent serine/threonine protein kinase C, which then accelerates the cleavage of caspase-8. We also show that preservation of phosphatidylcholine homeostasis by inhibition of lipid-degrading enzymes almost completely impedes the activation of pro-caspase-9 while scarcely changing the activation of caspase-8. PMID:16166305

Dynamic upper airway changes during sleep in patients with obstructive sleep apnea syndrome.

PubMed

Chuang, Li-Pang; Chen, Ning-Hung; Li, Hsueh-Yu; Lin, Shih-Wei; Chou, Yu-Ting; Wang, Chao-Jan; Liao, Yu-Fang; Tsai, Ying-Huang

2009-12-01

The narrowing pattern of the upper airway in obstructive sleep apnea patients may be different in sleep as compared with awake. Three different types of obstruction were observed in these subjects during drug-induced sleep. The different obstruction pattern during drug-induced sleep suggests that different strategies should be selected in upper airway management. To identify the sites of narrowing and evaluate dynamic upper airway movement in patients with obstructive sleep apnea syndrome (OSAS) while awake and asleep. This study included 10 patients treated for OSAS between August 2003 and June 2004. Overnight polysomnography was performed on all patients. Parameters including gender, age, neck circumference, and body mass index were recorded. Ultra-fast MRI during awake and drug-induced sleep was arranged to evaluate the dynamic motion of the upper airway. The narrowing pattern of the upper airway during awake differed from the narrowing pattern during drug-induced sleep in 3 of 10 subjects. Three different types, palatal obstruction, combined upper and lower pharyngeal obstruction, and circumferential obstruction of the upper airway, were observed in these patients during drug-induced sleep.

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

PubMed Central

Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

2015-01-01

Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

A Rodent Model of Night-Shift Work Induces Short-Term and Enduring Sleep and Electroencephalographic Disturbances.

PubMed

Grønli, Janne; Meerlo, Peter; Pedersen, Torhild T; Pallesen, Ståle; Skrede, Silje; Marti, Andrea R; Wisor, Jonathan P; Murison, Robert; Henriksen, Tone E G; Rempe, Michael J; Mrdalj, Jelena

2017-02-01

Millions of people worldwide are working at times that overlap with the normal time for sleep. Sleep problems related to the work schedule may mediate the well-established relationship between shift work and increased risk for disease, occupational errors and accidents. Yet, our understanding of causality and the underlying mechanisms that explain this relationship is limited. We aimed to assess the consequences of night-shift work for sleep and to examine whether night-shift work-induced sleep disturbances may yield electrophysiological markers of impaired maintenance of the waking brain state. An experimental model developed in rats simulated a 4-day protocol of night-work in humans. Two groups of rats underwent 8-h sessions of enforced ambulation, either at the circadian time when the animal was physiologically primed for wakefulness (active-workers, mimicking day-shift) or for sleep (rest-workers, mimicking night-shift). The 4-day rest-work schedule induced a pronounced redistribution of sleep to the endogenous active phase. Rest-work also led to higher electroencephalogram (EEG) slow-wave (1-4 Hz) energy in quiet wakefulness during work-sessions, suggesting a degraded waking state. After the daily work-sessions, being in their endogenous active phase, rest-workers slept less and had higher gamma (80-90 Hz) activity during wake than active-workers. Finally, rest-work induced an enduring shift in the main sleep period and attenuated the accumulation of slow-wave energy during NREM sleep. A comparison of recovery data from 12:12 LD and constant dark conditions suggests that reduced time in NREM sleep throughout the recorded 7-day recovery phase induced by rest-work may be modulated by circadian factors. Our data in rats show that enforced night-work-like activity during the normal resting phase has pronounced acute and persistent effects on sleep and waking behavior. The study also underscores the potential importance of animal models for future studies on the

Noise-Induced Sleep Disturbance in Residences Near Two Civil Airports

NASA Technical Reports Server (NTRS)

Fidell, Sanford; Howe, Richard R.; Tabachnick, Barbara G.; Pearsons, Karl S.; Sneddon, Matthew D.

1995-01-01

A large-scale field study of noise-induced sleep disturbance was conducted in the vicinities of Stapleton International Airport (DEN) and Denver International Airport (DIA) in anticipation of the closure of the former and opening of the latter. Both indoor and outdoor measurements of aircraft and other nighttime noises were made during four time periods. Measurements were made in 57 homes located as close as feasible to the runway ends of the two airports. Sleep disturbance was measured by several indices of behaviorally confirmed awakening (button pushes upon awakening) and body movement (as measured with wrist-worn actimeters). A total of 2717 subject-nights of observations were made over the course of the study. Although average noise event levels measured outdoors decreased markedly at DEN after closure of the airport and increased slightly at DIA after its opening, indoor noise event levels varied much less in homes near both airports. No large differences were observed in noise-induced sleep disturbance at either airport. Indoor sound exposure levels of noise events were, however, closely related to and good predictors of actimetrically defined motility and arousal.

AMPA receptors mediate passive avoidance deficits induced by sleep deprivation.

PubMed

Dubiela, Francisco Paulino; Queiroz, Claudio Marcos; Moreira, Karin Di Monteiro; Nobrega, Jose N; Sita, Luciane Valéria; Tufik, Sergio; Hipolide, Debora Cristina

2013-11-15

The present study addressed the effects of sleep deprivation (SD) on AMPA receptor (AMPAR) binding in brain regions associated with learning and memory, and investigated whether treatment with drugs acting on AMPAR could prevent passive avoidance deficits in sleep deprived animals. [(3)H]AMPA binding and GluR1 in situ hybridization signals were quantified in different brain regions of male Wistar rats either immediately after 96 h of sleep deprivation or after 24h of sleep recovery following 96 h of sleep deprivation. Another group of animals were sleep deprived and then treated with either the AMPAR potentiator, aniracetam (25, 50 and 100mg/kg, acute administration) or the AMPAR antagonist GYKI-52466 (5 and 10mg/kg, acute and chronic administration) before passive avoidance training. Task performance was evaluated 2h and 24h after training. A significant reduction in [(3)H]AMPA binding was found in the hippocampal formation of SD animals, while no alterations were observed in GluR1 mRNA levels. The highest dose of aniracetam (100mg/kg) reverted SD-induced impairment of passive avoidance performance in both retention tests, whereas GYKI-52466 treatment had no effect. Pharmacological enhancement of AMPAR function may revert hippocampal-dependent learning impairments produced after SD. We argue that such effects might be associated with reduced AMPAR binding in the hippocampus of sleep deprived animals. Copyright © 2013 Elsevier B.V. All rights reserved.

The effects of anandamide and oleamide on cognition depend on diurnal variations.

PubMed

Rueda-Orozco, Pavel E; Montes-Rodriguez, Corinne J; Ruiz-Contreras, Alejandra E; Mendez-Diaz, Monica; Prospero-Garcia, Oscar

2017-10-01

Cannabinergic receptor 1 (CB1r) is highly expressed in almost the entire brain; hence, its activation affects diverse functions, including cognitive processes such as learning and memory. On the other hand, it has been demonstrated that CB1r expression fluctuates along the light-dark cycle. In this context, the objective of this work was to characterize the cannabinergic influence over cognitive processes and its relationship with the light-dark cycle. To this aim we studied the effects of two endogenous cannabinoids, anandamide (AEA) and oleamide (ODA), on the consolidation of memory and event-related potentials (ERPs) depending on the light-dark cycle. Our results indicate that AEA and ODA impair the consolidation of spatial and emotional memories and reduce the amplitude of several components of the ERP complex, depending on the phase of the light-dark cycle. This study further supports the notion that endocannabinoids participate in the regulation of cognitive processes with strong influence of environmental variables such as the light-dark cycle. Copyright © 2017 Elsevier B.V. All rights reserved.

Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study.

PubMed

Murillo-Rodriguez, Eric; Blanco-Centurion, Carlos; Sanchez, Cristina; Piomelli, Daniele; Shiromani, Priyattam J

2003-12-15

The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.

Linalool Ameliorates Memory Loss and Behavioral Impairment Induced by REM-Sleep Deprivation through the Serotonergic Pathway.

PubMed

Lee, Bo Kyung; Jung, An Na; Jung, Yi-Sook

2018-07-01

Rapid eye movement (REM) sleep has an essential role in the process of learning and memory in the hippocampus. It has been reported that linalool, a major component of Lavandula angustifolia , has antioxidant, anti-inflammatory, and neuroprotective effects, along with other effects. However, the effect of linalool on the cognitive impairment and behavioral alterations that are induced by REM-sleep deprivation has not yet been elucidated. Several studies have reported that REM-sleep deprivation-induced memory deficits provide a well-known model of behavioral alterations. In the present study, we examined whether linalool elicited an anti-stress effect, reversing the behavioral alterations observed following REM-sleep deprivation in mice. Furthermore, we investigated the underlying mechanism of the effect of linalool. Spatial memory and learning memory were assessed through Y maze and passive avoidance tests, respectively, and the forced swimming test was used to evaluate anti-stress activity. The mechanisms through which linalool improves memory loss and behavioral alterations in sleep-deprived mice appeared to be through an increase in the serotonin levels. Linalool significantly ameliorated the spatial and learning memory deficits, and stress activity observed in sleep-deprived animals. Moreover, linalool led to serotonin release, and cortisol level reduction. Our findings suggest that linalool has beneficial effects on the memory loss and behavioral alterations induced by REM-sleep deprivation through the regulation of serotonin levels.

Delta sleep-inducing peptide (DSIP): a still unresolved riddle.

PubMed

Kovalzon, Vladimir M; Strekalova, Tatyana V

2006-04-01

Delta sleep-inducing peptide (DSIP) was isolated from rabbit cerebral venous blood by Schoenenberger-Monnier group from Basel in 1977 and initially regarded as a candidate sleep-promoting factor. However, the link between DSIP and sleep has never been further characterized, in part because of the lack of isolation of the DSIP gene, protein and possible related receptor. Thus the hypothesis regarding DSIP as a sleep factor is extremely poorly documented and still weak. Although DSIP itself presented a focus of study for a number of researchers, its natural occurrence and biological activity still remains obscure. DSIP structure is different from any other known representative of the various peptide families. In this mini-review we hypothesize the existence of a DSIP-like peptide(s) that is responsible (at least partly) for DSIP-like immunoreactivity and DSIP biological activity. This assumption is based on: (i) a highly specific distribution of DSIP-like immunoreactivity in the neurosecretory hypothalamic nuclei of various vertebrate species that are not particularly relevant for sleep regulation, as revealed by the histochemical studies of the Geneva group (Charnay et al.); (ii) a large spectrum of DSIP biological activity revealed by biochemical and physiological studies in vitro; (iii) significant slow-wave sleep (SWS) promoting activity of certain artificial DSIP structural analogues (but not DSIP itself!) in rabbits and rats revealed by our early studies; and (iv) significant SWS-promoting activity of a naturally occurring dermorphin-decapeptide that is structurally similar to DSIP (in five of the nine positions) and the sleep-suppressing effect of its optical isomer, as revealed in rabbits. Potential future studies are outlined, including natural synthesis and release of this DSIP-like peptide and its role in neuroendocrine regulation.

Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

PubMed

Cedernaes, Jonathan; Fanelli, Flaminia; Fazzini, Alessia; Pagotto, Uberto; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Schiöth, Helgi B; Benedict, Christian

2016-12-01

Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, p<0.05) when participants were sleep-deprived. This coincided with increased hunger ratings (+25% vs. normal sleep, p<0.05). Moreover, plasma 2AG was elevated 15min post-exercise (+44%, p<0.05). Sleep duration did not however modulate this exercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (p<0.05). Given that activation of the endocannabinoid system has been previously shown to acutely increase appetite and mood, our results could suggest that behavioral effects of acute sleep loss, such as increased hunger and transiently improved psychological state, may partially result from activation of this signaling pathway. In contrast, more pronounced exercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

PubMed

Deacon, Naomi L; McEvoy, R Doug; Stadler, Daniel L; Catcheside, Peter G

2017-09-01

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO 2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO 2 and 3.0 ± 0.2% O 2 ) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO 2 , O 2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea. NEW & NOTEWORTHY Both arousal state and concomitant CO 2 levels are known modulators of the effects of intermittent hypoxia on

Hypnotic Effect of Portulaca oleracea L on Pentobarbital-Induced Sleep in Mice.

PubMed

Hamedi, Shokouhsadat; Forouzanfar, Fatemeh; Rakhshandeh, Hasan; Arian, Amirali

2018-03-08

In Iranian Traditional Medicine, the herbs with cold and wet temperament can help to improve insomnia. Portulaca oleracea has cold and wet temperament, so the present study was carried out to investigate the sleep-prolonging effect of Portulaca oleracea. This work was an experimental study on mice which were randomly divided into these groups: saline (control); Diazepam:) positive control); hydro-alcoholic extract of Portulaca oleracea (12.5, 25, 50, 75 and 100 mg/kg) by Soxhlet apparatus and maceration; in the effective (dose25 mg/kg), different fractions of extract were tested. Ethyl acetate fraction (EAF:); n-Hexane fraction (n-HF); water fraction (WF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital-induced sleep were recorded. Also, LD50 of Portulaca oleracea extract was determined and the possible neurotoxicity of the extract was tested on neural PC12 cells. Besides, 30 min after administration of hydro alcoholic extract (HAE) motor coordination (rota-rod test) were assessed. HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, 75 and 100 mg/kg The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and n-HF at 25 mg/kg could increase sleep duration. The sleep latency was decreased by HAE and NHF but not by WF and EAF. The LD50 value for HAE was found to be 4.8 g/Kg. HAE and its fractions did not show neurotoxic effect in cultured PC12-cell line, also HAE did not affect the animals' performance on the rotarod test. The present data demonstrated that Portulaca oleracea potentiates sleeping behaviors. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in n-HF. Isolation of the active constituents may yield a novel sedative drug. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Entropic Anomaly Observed in Lipid Polymorphisms Induced by Surfactant Peptide SP-B(1-25).

PubMed

Tran, Nhi; Kurian, Justin; Bhatt, Avni; McKenna, Robert; Long, Joanna R

2017-10-05

The N-terminal 25 amino-acid residues of pulmonary surfactant protein B (SP-B 1-25 ) induces unusual lipid polymorphisms in a model lipid system, 4:1 DPPC/POPG, mirroring the lipid composition of native pulmonary surfactant. It is widely suggested that SP-B 1-25 -induced lipid polymorphisms within the alveolar aqueous subphase provide a structural platform for rapid lipid adsorption to the air-water interface. Here, we characterize in detail the phase behavior of DPPC and POPG in hydrated lipid assemblies containing therapeutic levels of SP-B 1-25 using 2 H and 31 P solid state NMR spectroscopy. The appearance of a previously observed isotropic lipid phase is found to be highly dependent on the thermal cycling of the samples. Slow heating of frozen samples leads to phase separation of DPPC into a lamellar phase whereas POPG lipids interact with the peptide to form an isotropic phase at physiologic temperature. Rapid heating of frozen samples to room temperature leads to strongly isotropic phase behavior for both DPPC and POPG lipids, with DPPC in exchange between isotropic and interdigitated phases. 31 P T 2 relaxation times confirm the isotropic phase to be consistent with a lipid cubic phase. The observed phases exhibit thermal stability up to physiologic temperature (37 °C) and are consistent with the formation of a ripple phase containing a large number of peptide-induced membrane structural defects enabling rapid transit of lipids between lipid lamellae. The coexistance of a lipid cubic phase with interdigitated lipids suggests a specific role for the highly conserved N-terminus of SP-B in stabilizing this unusual lipid polymorphism.

Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-α and lipopolysaccharide in mice.

PubMed

Zielinski, Mark R; Dunbrasky, Danielle L; Taishi, Ping; Souza, Gianne; Krueger, James M

2013-08-01

Systemic tumor necrosis factor-α (TNF-α) is linked to sleep and sleep altering pathologies in humans. Evidence from animals indicates that systemic and brain TNF-α have a role in regulating sleep. In animals, TNF-α or lipopolysaccharide (LPS) enhance brain pro-inflammatory cytokine expression and sleep after central or peripheral administration. Vagotomy blocks enhanced sleep induced by systemic TNF-α and LPS in rats, suggesting that vagal afferent stimulation by TNF-α enhances pro-inflammatory cytokines in sleep-related brain areas. However, the effects of systemic TNF-α on brain cytokine expression and mouse sleep remain unknown. We investigated the role of vagal afferents on brain cytokines and sleep after systemically applied TNF-α or LPS in mice. Spontaneous sleep was similar in vagotomized and sham-operated controls. Vagotomy attenuated TNF-α- and LPS-enhanced non-rapid eye movement sleep (NREMS); these effects were more evident after lower doses of these substances. Vagotomy did not affect rapid eye movement sleep responses to these substances. NREMS electroencephalogram delta power (0.5-4 Hz range) was suppressed after peripheral TNF-α or LPS injections, although vagotomy did not affect these responses. Compared to sham-operated controls, vagotomy did not affect liver cytokines. However, vagotomy attenuated interleukin-1 beta (IL-1β) and TNF-α mRNA brain levels after TNF-α, but not after LPS, compared to the sham-operated controls. We conclude that vagal afferents mediate peripheral TNF-α-induced brain TNF-α and IL-1β mRNA expressions to affect sleep. We also conclude that vagal afferents alter sleep induced by peripheral pro-inflammatory stimuli in mice similar to those occurring in other species.

Osmotically Induced Reversible Transitions in Lipid-DNA Mesophases

PubMed Central

Danino, Dganit; Kesselman, Ellina; Saper, Gadiel; Petrache, Horia I.; Harries, Daniel

2009-01-01

We follow the effect of osmotic pressure on isoelectric complexes that self-assemble from mixtures of DNA and mixed neutral and cationic lipids. Using small angle x-ray diffraction and freeze-fracture cryo-electron microscopy, we find that lamellar complexes known to form in aqueous solutions can reversibly transition to hexagonal mesophases under high enough osmotic stress exerted by adding a neutral polymer. Using molecular spacings derived from x-ray diffraction, we estimate the reversible osmotic pressure-volume (Π-V) work needed to induce this transition. We find that the transition free energy is comparable to the work required to elastically bend lipid layers around DNA. Consistent with this, the required work is significantly lowered by an addition of hexanol, which is known to soften lipid bilayers. Our findings not only help to resolve the free-energy contributions associated with lipid-DNA complex formation, but they also demonstrate the importance that osmotic stress can have to the macromolecular phase geometry in realistic biological environments. PMID:19348739

Rodent models of insomnia: a review of experimental procedures that induce sleep disturbances.

PubMed

Revel, Florent G; Gottowik, Juergen; Gatti, Sylvia; Wettstein, Joseph G; Moreau, Jean-Luc

2009-06-01

Insomnia, the most common sleep disorder, is characterized by persistent difficulty in falling or staying asleep despite adequate opportunity to sleep, leading to daytime fatigue and mental dysfunction. As sleep is a sophisticated physiological process generated by a network of neuronal systems that cannot be reproduced in-vitro, pre-clinical development of hypnotic drugs requires in-vivo investigations. Accordingly, this review critically evaluates current and putative rodent models of insomnia which could be used to screen novel hypnotics. Only few valid insomnia models are currently available, although many experimental conditions lead to disturbance of physiological sleep. We categorized these conditions as a function of the procedure used to induce perturbation of sleep, and we discuss their respective advantages and pitfalls with respect to validity, feasibility and translational value to human research.

Independent Association between Sleep Fragmentation and Dyslipidemia in Patients with Obstructive Sleep Apnea.

PubMed

Qian, Yingjun; Yi, Hongliang; Zou, Jianyin; Meng, Lili; Tang, Xulan; Zhu, Huaming; Yu, Dongzhen; Zhou, Huiqun; Su, Kaiming; Guan, Jian; Yin, Shankai

2016-05-17

Obstructive sleep apnea (OSA) is independently associated with dyslipidemia. Previous studies have demonstrated that sleep fragmentation can impair lipid metabolism. The present study aimed to identify whether sleep fragmentation is independently associated with dyslipidemia, in a large-scale, clinic-based consecutive OSA sample. This cross-sectional study was conducted among 2,686 patients who underwent polysomnography (PSG) for suspicion of OSA from January 2008 to January 2013 at the sleep laboratory. Multivariate regression analyses were performed to evaluate the independent associations between the microarousal index (MAI) and lipid profiles adjusting for potential confounders, including metabolic syndrome components and nocturnal intermittent hypoxia. The adjusted odds ratios (ORs) for various types of dyslipidemia according to MAI quartiles, as determined by logistic regression were also evaluated. MAI was found positively associated with low-density lipoprotein cholesterol (LDL-c) but not with total cholesterol (TC), triglyceride (TG) or high-density lipoprotein cholesterol (HDL-c). Furthermore, the adjusted ORs (95% confidence interval) for hyper-LDL cholesterolemia increased across MAI quartiles, as follows: 1 (reference), 1.3 (1.1-1.7), 1.6 (1.2-2.0), and 1.6 (1.2-2.1) (p = 0.001, linear trend). Sleep fragmentation in OSA is independently associated with hyper-LDL cholesterolemia, which may predispose patients with OSA to a higher risk of cardiovascular disease.

Academic performance among adolescents with behaviorally induced insufficient sleep syndrome.

PubMed

Lee, Yu Jin; Park, Juhyun; Kim, Soohyun; Cho, Seong-Jin; Kim, Seog Ju

2015-01-15

The present study investigated academic performance among adolescents with behaviorally induced insufficient sleep syndrome (BISS) and attempted to identify independent predictors of academic performance among BISS-related factors. A total of 51 students with BISS and 50 without BISS were recruited from high schools in South Korea based on self-reported weekday sleep durations, weekend oversleep, and the Epworth Sleepiness Scale (ESS). Participants reported their academic performance in the form of class quartile ranking. The Korean version of the Composite Scale (KtCS) for morningness/eveningness, the Beck Depression Inventory (BDI) for depression, and the Barratt Impulsiveness Scale-II (BIS-II) for impulsivity were administered. Adolescents with BISS reported poorer academic performance than adolescents without BISS (p = 0.02). Adolescents with BISS also exhibited greater levels of eveningness (p < 0.001), depressive symptoms (p < 0.001), and impulsiveness (p < 0.01). Longer weekend oversleep predicted poorer academic performance among adolescents with BISS even after controlling for ESS, KtCS, BDI, and BIS-II (β = 0.42, p < 0.01). BISS among adolescents is associated with poor academic performance and that sleep debt, as represented by weekend oversleep, predicts poorer academic performance independent of depression, impulsiveness, weekday sleep duration, daytime sleepiness, and morningness/eveningness among adolescents with BISS. © 2015 American Academy of Sleep Medicine.

Technique and Preliminary Analysis of Drug-Induced Sleep Endoscopy With Online Polygraphic Cardiorespiratory Monitoring in Patients With Obstructive Sleep Apnea Syndrome.

PubMed

Gobbi, Riccardo; Baiardi, Simone; Mondini, Susanna; Cerritelli, Luca; Piccin, Ottavio; Scaramuzzino, Giuseppe; Milano, Francesca; Melotti, Maria Rita; Mordini, Francesco; Pirodda, Antonio; Cirignotta, Fabio; Sorrenti, Giovanni

2017-05-01

Drug-induced sleep endoscopy is a diagnostic technique that allows dynamic evaluation of the upper airway during artificial sleep. The lack of a standardized procedure and the difficulties associated with direct visual detection of obstructive events result in poor intraobserver and interobserver reliability, especially when otolaryngology surgeons not experienced in the technique are involved. To describe a drug-induced sleep endoscopy technique implemented with simultaneous polygraphic monitoring of cardiorespiratory parameters (DISE-PG) in patients with a diagnosis of obstructive sleep apnea syndrome and discuss the technique's possible advantages compared with the standard procedure. This prospective cohort study included 50 consecutive patients with obstructive sleep apnea syndrome who underwent DISE-PG from March 1, 2013, to June 30, 2014. A standard protocol was adopted, and all the procedures were carried out in an operation room by an experienced otolaryngology surgeon under the supervision of an anesthesiologist. Endoscopic and polygraphic obstructive respiratory events were analyzed offline in a double-blind setting and randomized order. The feasibility and safety of the DISE-PG technique, as well as its sensitivity in detecting respiratory events compared with that of the standard drug-induced sleep endoscopy procedure. All 50 patients (43 men and 7 women; mean [SD] age, 51.1 [12.1] years) underwent DISE-PG without technical problems or patient difficulties regarding the procedure. As expected, polygraphic scoring was more sensitive than endoscopic scoring in identifying obstructive events (mean [SD] total events, 13.3 [6.8] vs 5.3 [3.6]; mean [SD] difference, 8.8 [5.6]; 95% CI, 7.3 to 10.4; Cohen d, -1.5). This difference was most pronounced in patients with a higher apnea-hypopnea index (AHI) at baseline (mean [SD] difference for AHI >30, 27.1% [31.0%]; 95% CI, -36.2% to 90.4%; Cohen d, 0.2; for AH I >40, 76.0% [35.5%]; 95% CI, 4.6% to 147.4%; Cohen d

Technique and Preliminary Analysis of Drug-Induced Sleep Endoscopy With Online Polygraphic Cardiorespiratory Monitoring in Patients With Obstructive Sleep Apnea Syndrome

PubMed Central

Gobbi, Riccardo; Mondini, Susanna; Cerritelli, Luca; Piccin, Ottavio; Scaramuzzino, Giuseppe; Milano, Francesca; Melotti, Maria Rita; Mordini, Francesco; Pirodda, Antonio; Cirignotta, Fabio; Sorrenti, Giovanni

2017-01-01

Importance Drug-induced sleep endoscopy is a diagnostic technique that allows dynamic evaluation of the upper airway during artificial sleep. The lack of a standardized procedure and the difficulties associated with direct visual detection of obstructive events result in poor intraobserver and interobserver reliability, especially when otolaryngology surgeons not experienced in the technique are involved. Objectives To describe a drug-induced sleep endoscopy technique implemented with simultaneous polygraphic monitoring of cardiorespiratory parameters (DISE-PG) in patients with a diagnosis of obstructive sleep apnea syndrome and discuss the technique’s possible advantages compared with the standard procedure. Design, Setting, and Participants This prospective cohort study included 50 consecutive patients with obstructive sleep apnea syndrome who underwent DISE-PG from March 1, 2013, to June 30, 2014. A standard protocol was adopted, and all the procedures were carried out in an operation room by an experienced otolaryngology surgeon under the supervision of an anesthesiologist. Endoscopic and polygraphic obstructive respiratory events were analyzed offline in a double-blind setting and randomized order. Main Outcomes and Measures The feasibility and safety of the DISE-PG technique, as well as its sensitivity in detecting respiratory events compared with that of the standard drug-induced sleep endoscopy procedure. Results All 50 patients (43 men and 7 women; mean [SD] age, 51.1 [12.1] years) underwent DISE-PG without technical problems or patient difficulties regarding the procedure. As expected, polygraphic scoring was more sensitive than endoscopic scoring in identifying obstructive events (mean [SD] total events, 13.3 [6.8] vs 5.3 [3.6]; mean [SD] difference, 8.8 [5.6]; 95% CI, 7.3 to 10.4; Cohen d, –1.5). This difference was most pronounced in patients with a higher apnea-hypopnea index (AHI) at baseline (mean [SD] difference for AHI >30, 27.1% [31.0%]; 95

The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis.

PubMed

Chung, Ki Wung; Kim, Kyung Mok; Choi, Yeon Ja; An, Hye Jin; Lee, Bonggi; Kim, Dae Hyun; Lee, Eun Kyeong; Im, Eunok; Lee, Jaewon; Im, Dong Soon; Yu, Byung Pal; Chung, Hae Young

2017-07-03

Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 μg/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A 1 or Atg7 knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis.

Cold-induced bradycardia in man during sleep in Arctic winter nights

NASA Astrophysics Data System (ADS)

Buguet, A. G. C.

1987-03-01

Two young male Caucasians volunteered for a study on the effects of cold exposure during night sleep in winter in the Arctic. The 14-day experiment was divided in three consecutive periods, baseline (2 nights), cold exposure (10 night) and recovery (2 nights). Both baseline and recovery data were obtained in neutral thermal conditions in a laboratory. The subjects slept in a sleeping bag under an unheated tent during the cold exposure. Apart from polysomnographic and body temperature recordings, electrocardiograms were taken through a telemetric system for safety purposes. Heart rates were noted at 5-min intervals and averaged hourly. In both environmental conditions, heart rate decreased within the first two hours of sleep. Comparison of the data obtained during cold exposure vs. thermal neutrality revealed lower values of heart rate in the cold, while body temperatures remained within normal range. This cold-induced bradycardia supervening during night sleep is discussed in terms of the occurrence of a vagal reflex preventing central blood pressure to rise.

Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice.

PubMed

Valvassori, Samira S; Resende, Wilson R; Dal-Pont, Gustavo; Sangaletti-Pereira, Heron; Gava, Fernanda F; Peterle, Bruna R; Carvalho, André F; Varela, Roger B; Dal-Pizzol, Felipe; Quevedo, João

2017-06-01

The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons

PubMed Central

Aton, Sara J.; Broussard, Christopher; Dumoulin, Michelle; Seibt, Julie; Watson, Adam; Coleman, Tammi; Frank, Marcos G.

2013-01-01

Ocular dominance plasticity in the developing primary visual cortex is initiated by monocular deprivation (MD) and consolidated during subsequent sleep. To clarify how visual experience and sleep affect neuronal activity and plasticity, we continuously recorded extragranular visual cortex fast-spiking (FS) interneurons and putative principal (i.e., excitatory) neurons in freely behaving cats across periods of waking MD and post-MD sleep. Consistent with previous reports in mice, MD induces two related changes in FS interneurons: a response shift in favor of the closed eye and depression of firing. Spike-timing–dependent depression of open-eye–biased principal neuron inputs to FS interneurons may mediate these effects. During post-MD nonrapid eye movement sleep, principal neuron firing increases and becomes more phase-locked to slow wave and spindle oscillations. Ocular dominance (OD) shifts in favor of open-eye stimulation—evident only after post-MD sleep—are proportional to MD-induced changes in FS interneuron activity and to subsequent sleep-associated changes in principal neuron activity. OD shifts are greatest in principal neurons that fire 40–300 ms after neighboring FS interneurons during post-MD slow waves. Based on these data, we propose that MD-induced changes in FS interneurons play an instructive role in ocular dominance plasticity, causing disinhibition among open-eye–biased principal neurons, which drive plasticity throughout the visual cortex during subsequent sleep. PMID:23300282

Occurrence of epileptiform discharges and sleep during EEG recordings in children after melatonin intake versus sleep-deprivation.

PubMed

Gustafsson, Greta; Broström, Anders; Ulander, Martin; Vrethem, Magnus; Svanborg, Eva

2015-08-01

To determine if melatonin is equally efficient as partial sleep deprivation in inducing sleep without interfering with epileptiform discharges in EEG recordings in children 1-16 years old. We retrospectively analysed 129 EEGs recorded after melatonin intake and 113 EEGs recorded after partial sleep deprivation. Comparisons were made concerning occurrence of epileptiform discharges, the number of children who fell asleep and the technical quality of EEG recordings. Comparison between different age groups was also made. No significant differences were found regarding occurrence of epileptiform discharges (33% after melatonin intake, 36% after sleep deprivation), or proportion of unsuccessful EEGs (8% and 10%, respectively). Melatonin and sleep deprivation were equally efficient in inducing sleep (70% in both groups). Significantly more children aged 1-4 years obtained sleep after melatonin intake in comparison to sleep deprivation (82% vs. 58%, p⩽0.01), and in comparison to older children with melatonin induced sleep (58-67%, p⩽0.05). Sleep deprived children 9-12 years old had higher percentage of epileptiform discharges (62%, p⩽0.05) compared to younger sleep deprived children. Melatonin is equally efficient as partial sleep deprivation to induce sleep and does not affect the occurrence of epileptiform discharges in the EEG recording. Sleep deprivation could still be preferable in older children as melatonin probably has less sleep inducing effect. Melatonin induced sleep have advantages, especially in younger children as they fall asleep easier than after sleep deprivation. The procedure is easier for the parents than keeping a young child awake for half the night. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats.

PubMed

Tarasiuk, Ariel; Levi, Avishag; Assadi, Mohammad H; Troib, Ariel; Segev, Yael

2016-04-01

The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. © 2016 Associated Professional Sleep Societies, LLC.

Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

PubMed Central

Tannenbaum, Pamela L.; Stevens, Joanne; Binns, Jacquelyn; Savitz, Alan T.; Garson, Susan L.; Fox, Steven V.; Coleman, Paul; Kuduk, Scott D.; Gotter, Anthony L.; Marino, Michael; Tye, Spencer J.; Uslaner, Jason M.; Winrow, Christopher J.; Renger, John J.

2014-01-01

The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli. PMID:24904334

Separating the Contribution of Glucocorticoids and Wakefulness to the Molecular and Electrophysiological Correlates of Sleep Homeostasis

PubMed Central

Mongrain, Valérie; Hernandez, Susana A.; Pradervand, Sylvain; Dorsaz, Stéphane; Curie, Thomas; Hagiwara, Grace; Gip, Phung; Heller, H. Craig; Franken, Paul

2010-01-01

Study Objectives: The sleep-deprivation–induced changes in delta power, an electroencephalographical correlate of sleep need, and brain transcriptome profiles have importantly contributed to current hypotheses on sleep function. Because sleep deprivation also induces stress, we here determined the contribution of the corticosterone component of the stress response to the electrophysiological and molecular markers of sleep need in mice. Design: N/A Settings: Mouse sleep facility. Participants: C57BL/6J, AKR/J, DBA/2J mice. Interventions: Sleep deprivation, adrenalectomy (ADX). Measurements and Results: Sleep deprivation elevated corticosterone levels in 3 inbred strains, but this increase was larger in DBA/2J mice; i.e., the strain for which the rebound in delta power after sleep deprivation failed to reach significance. Elimination of the sleep-deprivation–associated corticosterone surge through ADX in DBA/2J mice did not, however, rescue the delta power rebound but did greatly reduce the number of transcripts affected by sleep deprivation. Genes no longer affected by sleep deprivation cover pathways previously implicated in sleep homeostasis, such as lipid, cholesterol (e.g., Ldlr, Hmgcs1, Dhcr7, −24, Fkbp5), energy and carbohydrate metabolism (e.g., Eno3, G6pc3, Mpdu1, Ugdh, Man1b1), protein biosynthesis (e.g., Sgk1, Alad, Fads3, Eif2c2, −3, Mat2a), and some circadian genes (Per1, −3), whereas others, such as Homer1a, remained unchanged. Moreover, several microRNAs were affected both by sleep deprivation and ADX. Conclusions: Our findings indicate that corticosterone contributes to the sleep-deprivation–induced changes in brain transcriptome that have been attributed to wakefulness per se. The study identified 78 transcripts that respond to sleep loss independent of corticosterone and time of day, among which genes involved in neuroprotection prominently feature, pointing to a molecular pathway directly relevant for sleep function. Citation: Mongrain

Oxidation-Induced Increase In Photoreactivity of Bovine Retinal Lipid Extract.

PubMed

Koscielniak, A; Serafin, M; Duda, M; Oles, T; Zadlo, A; Broniec, A; Berdeaux, O; Gregoire, S; Bretillon, L; Sarna, T; Pawlak, A

2017-12-01

The mammalian retina contains a high level of polyunsaturated fatty acids, including docosahexaenoic acid (22:6) (DHA), which are highly susceptible to oxidation. It has been shown that one of the products of DHA oxidation-carboxyethylpyrrole (CEP), generated in situ, causes modifications of retinal proteins and induces inflammation response in the outer retina. These contributing factors may play a role in the development of age-related macular degeneration (AMD). It is also possible that some of the lipid oxidation products are photoreactive, and upon irradiation with blue light may generate reactive oxygen species. Therefore, in this work we analysed oxidation-induced changes in photoreactivity of lipids extracted from bovine neural retinas. Lipid composition of bovine neural retinas closely resembles that of human retinas making the bovine tissue a convenient model for studying the photoreactivity and potential phototoxicity of oxidized human retinal lipids. Lipid composition of bovine neural retinas Folch' extracts (BRex) was determined by gas chromatography (GC) and liquid chromatography coupled to an electrospray ionization source-mass spectrometer (LC-ESI-MS) analysis. Liposomes prepared from BRex, equilibrated with air, were oxidized in the dark at 37 °C for up to 400 h. The photoreactivity of BRex at different stages of oxidation was studied by EPR-oximetry and EPR-spin trapping. Photogeneration of singlet oxygen ( 1 O 2 , 1 Δ g ) by BRex was measured using time-resolved detection of the characteristic phosphorescence at 1270 nm. To establish contribution of lipid components to the analysed photoreactivity of Folch' extract of bovine retinas, a mixture of selected synthetic lipids in percent by weight (w/w %) ratio resembling that of the BRex has been also studied. Folch's extraction of bovine neural retinas was very susceptible to oxidation despite the presence of powerful endogenous antioxidants such as α-tocopherol and zeaxanthin. Non

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae.

PubMed

Ok, Seong-Ho; Lee, Soo Hee; Kwon, Seong-Chun; Choi, Mun Hwan; Shin, Il-Woo; Kang, Sebin; Park, Miyeong; Hong, Jeong-Min; Sohn, Ju-Tae

2017-02-13

The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH₂-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization.

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae

PubMed Central

Ok, Seong-Ho; Lee, Soo Hee; Kwon, Seong-Chun; Choi, Mun Hwan; Shin, Il-Woo; Kang, Sebin; Park, Miyeong; Hong, Jeong-Min; Sohn, Ju-Tae

2017-01-01

The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization. PMID:28208809

Sleep deprivation predisposes liver to oxidative stress and phospholipid damage: a quantitative molecular imaging study

PubMed Central

Chang, Hung-Ming; Mai, Fu-Der; Chen, Bo-Jung; Wu, Un-In; Huang, Yi-Lun; Lan, Chyn-Tair; Ling, Yong-Chien

2008-01-01

Sleep disorders are associated with an increased rate of various metabolic disturbances, which may be related to oxidative stress and consequent lipid peroxidation. Since hepatic phosphatidylcholine plays an important role in metabolic regulation, the aim of the present study was to determine phosphatidylcholine expression in the liver following total sleep deprivation. To determine the effects of total sleep deprivation, we used adult rats implanted for polygraphic recording. Phosphatidylcholine expression was examined molecularly by the use of time-of-flight secondary ion mass spectrometry, along with biochemical solid-phase extraction. The parameters of oxidative stress were investigated by evaluating the hepatic malondialdehyde levels as well as heat shock protein 25 immunoblotting and immunohistochemistry. In normal rats, the time-of-flight secondary ion mass spectrometry spectra revealed specific peaks (m/z 184 and 224) that could be identified as molecular ions for phosphatidylcholine. However, following total sleep deprivation, the signals for phosphatidylcholine were significantly reduced to nearly one-third of the normal values. The results of solid-phase extraction also revealed that the phosphatidylcholine concentration was noticeably decreased, from 15.7 µmol g–1 to 9.4 µmol g–1, after total sleep deprivation. By contrast, the biomarkers for oxidative stress were drastically up-regulated in the total sleep deprivation-treated rats as compared with the normal ones (4.03 vs. 1.58 nmol mg–1 for malondialdehyde levels, and 17.1 vs. 6.7 as well as 1.8 vs. 0.7 for heat shock protein 25 immunoblotting and immunoreactivity, respectively). Given that phosphatidylcholine is the most prominent component of all plasma lipoproteins, decreased expression of hepatic phosphatidylcholine following total sleep deprivation may be attributed to the enhanced oxidative stress and the subsequent lipid peroxidation, which would play an important role in the formation

Intrahippocampal administration of anandamide increases REM sleep.

PubMed

Rueda-Orozco, Pavel Ernesto; Soria-Gómez, Edgar; Montes-Rodríguez, Corinne Jennifer; Pérez-Morales, Marcel; Prospéro-García, Oscar

2010-04-05

A nascent literature has postulated endocannabinoids (eCBs) as strong sleep-inducing lipids, particularly rapid-eye-movement sleep (REMs), nevertheless the exact mechanisms behind this effect remain to be determined. Anandamide and 2-arachidonyl glycerol, two of the most important eCBS, are synthesized in the hippocampus. This structure also expresses a high concentration of cannabinoid receptor 1 (CB1). Recent extensive literature supports eCBs as important regulators of hippocampal activity. It has also been shown that these molecules vary their expression on the hippocampus depending on the light-dark cycle. In this context we decided to analyze the effect of intrahippocampal administration of the eCB anandamide (ANA) on the sleep-waking cycle at two points of the light-dark cycle. Our data indicate that the administration of ANA directly into the hippocampus increases REMs in a dose dependent manner during the dark but not during the light phase of the cycle. The increase of REMs was blocked by the CB1 antagonist AM251. This effect was specific for the hippocampus since ANA administrations in the surrounding cortex did not elicit any change in REMs. These results support the idea of a direct relationship between hippocampal activity and sleep mechanisms by means of eCBs. The data presented here show, for the first time that eCBs administered into the hippocampus trigger REMs and support previous studies where chemical stimulation of limbic areas triggered sleep.

[Localization of upper airway stricture by CT scan in patients with obstructive sleep apnea syndrome during drug-induced sleeping].

PubMed

Hu, Ji-bo; Hu, Hong-jie; Hou, Tie-ning; Gao, Hang-xiang; He, Jian

2010-03-01

To evaluate the feasibility of multi-slice spiral CT scan to localize upper airway stricture in patients with obstructive sleep apnea syndrome (OSAS) during drug-induced sleeping. One hundred and fourteen patients diagnosed as OSAS by polysomnography were included in the study. Multi-slice spiral CT scan covering upper airway was performed at the end of inspiration and clear upper airway images were obtained in waking. After injecting 5 mg of midazolam intravenously slowly in 109 patients, CT scan was performed at apnea and clear upper airway images were obtained in sleeping. Cross-section area and minimal diameter of airway were measured and the parameters were compared under those two states. Upper airway was displayed intuitionisticly by using post-processing techniques. One hundred and nine patients with OSAS finished the examination with a success rate of 100 %. Airway obstruction at retropalatal level was observed in 62 patients, among whom 26 were associated with airway obstruction at retroglossal level, 27 with narrower airway at retroglossal level in sleeping compared with that in waking, and 9 with no significant change of the airway at retroglossal level after sleeping. Narrower airway at retropalatal level in sleeping compared with that in waking was observed in 40 patients, among whom 20 were associated with narrower airway at retroglossal level in sleeping compared with that in waking, 10 with complete airway obstruction at retroglossal level in sleeping, and 7 with no significant change of the airway at both retropalatal and retroglossal levels before and after sleeping. Minimal mean cross-section area of airway at retropalatal level was (72.60 +/-45.15)mm(2) in waking and (8.26 +/-18.16)mm(2) in sleeping; and minimal mean cross-section area of airway at retroglossal level was (133.21 +/-120.36)mm(2)in waking and (16.73 +/-30.21)mm(2) in sleeping (P <0.01). Minimal mean diameter of airway at retropalatal level was (6.91 +/-2.23) mm in waking and (1

Serum lipid profile, sleep-disordered breathing and blood pressure in the elderly: a 10-year follow-up of the PROOF-SYNAPSE cohort.

PubMed

Monneret, Denis; Barthélémy, Jean-Claude; Hupin, David; Maudoux, Delphine; Celle, Sébastien; Sforza, Emilia; Roche, Frédéric

2017-11-01

Dyslipidemia, sleep-disordered breathing (SDB) and hypertension are comorbid factors evidenced in adults, but poorly studied in old people. This study aimed to examine the long-term evolution of the serum lipid profile, and its relationships with SDB and blood pressure (BP) in the elderly. A ten-year follow-up of the prospective Prognostic Indicator of Cardiovascular and Cerebrovascular Events (PROOF) and the Autonomic Nervous System Activity, Aging and Sleep Apnea/Hypopnea (SYNAPSE) cohort, which initially included 1011 elderly subjects from the general population, and who were untreated by continuous positive airway pressure (CPAP). Serum lipid profile, respiratory polygraphy for SDB and ambulatory blood pressure monitoring were performed. A total of 266 subjects (male/female 150/116; age 66.2 ± 0.8 years) were reassessed after 9.6 ± 0.7 years (age 75.8 ± 1.2 years). The prevalence of high-risk dyslipidemia decreased from 61.3 to 44.4%, and hypertension from 57.9 to 27.4%. The nocturnal oxygen desaturation index increased (mean + 2.3 ± 6.7 events/hour; p < 0.001), while the mean SaO 2 and minimal SaO 2 decreased. These variations (Δ) of oxygen desaturation worsened whether or not elderly subjects took anti-hypertensive and lipid-lowering treatments, and were not associated with serum lipid variations. The decrease in diurnal diastolic BP was independently associated with aging, and with the lowering of the waist/hip ratio (ΔW/H) and low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, while the decrease in diurnal systolic BP only depended on aging and ΔW/H. The results suggested that the observed worsening of nocturnal oxygen desaturation after 10 years in the elderly was independent of the change in circulating lipids, and not influenced by lipid-lowering treatments. However, the variation in blood pressure remained associated with aging, waist/hip and LDL-C/HDL-C ratios. NCT00759304 and NCT00766584

Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion.

PubMed

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-09-01

Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. © 2014 Associated Professional Sleep Societies, LLC.

Molecular Approach to Hypothalamic Rhythms

DTIC Science & Technology

1998-06-24

PAGE • PuDiic reoorttnc DUTCH p gather.r.q ar.c n-untai ; COHeCtJO-■ -:r ;-v-rrr.^! ; Davis hiopwa.-, ioiie 1 ■ 1. AGENCY USE AFRL-SR-BL-TR...the same neurons? eharacter"ed „™ „eer ye3f1V 6d ,y the sl" P -^ueing lipid oleamide. He have precursor exeinslvelv H = ’", "^ "W"«1...mapped the anatomical distribution of the degradative enzyme for oleamide within the brain. To identify neuronal populations activated in vivo by 3

Lipid-induced metabolic dysfunction in skeletal muscle.

PubMed

Muoio, Deborah M; Koves, Timothy R

2007-01-01

Insulin resistance is a hallmark of type 2 diabetes and commonly observed in other energy-stressed settings such as obesity, starvation, inactivity and ageing. Dyslipidaemia and 'lipotoxicity'--tissue accumulation of lipid metabolites-are increasingly recognized as important drivers of insulin resistant states. Mounting evidence suggests that lipid-induced metabolic dysfunction in skeletal muscle is mediated in large part by stress-activated serine kinases that interfere with insulin signal transduction. However, the metabolic and molecular events that connect lipid oversupply to stress kinase activation and glucose intolerance are as yet unclear. Application of transcriptomics and targeted mass spectrometry-based metabolomics tools has led to our finding that insulin resistance is a condition in which muscle mitochondria are persistently burdened with a heavy lipid load. As a result, high rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates. In contrast, exercise training enhances mitochondrial performance, favouring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high fat diet. The exercise-activated transcriptional co-activator, PGC1alpha, plays a key role in co-ordinating metabolic flux through these two intersecting metabolic pathways, and its suppression by overfeeding may contribute to obesity-associated mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from mitochondrial lipid stress and a resultant disconnect between beta-oxidation and TCA cycle activity. Understanding this 'disconnect' and its molecular basis may lead to new therapeutic targets for combating metabolic disease.

Circadian rhythms in effects of hypnotics and sleep inducers.

PubMed

Reinberg, A

1986-01-01

Chronopharmacology involves the investigation of drug effects as a function of biological time and the investigation of drug effects on rhythm characteristics. Three new concepts must be considered: (a) the chronokinetics of a drug, embracing rhythmic (circadian) changes in drug bioavailability (or pharmacokinetics) and its excretion (urinary among others); (b) the chronaesthesia of a biosystem to a drug, i.e. circadian changes in the susceptibility of any biosystem to a drug (including organ systems, parasites, etc.); skin and bronchial chronaesthesia to various agents have been documented in man; and (c) the chronergy of a drug, taking into consideration its chronokinetics and the chronaesthesia of the involved organismic biosystems. The term chronergy includes rhythmic changes in the overall effects and in the effectiveness of some drugs. Clinical chronopharmacology is useful for solving problems of drug optimization, i.e. enhancing the desired efficiency of a drug and reducing its undesired effects. Circadian rhythms can be demonstrated in various effects of drugs on sleep, anaesthesia and related processes. For example, in the rat the duration of sleep induced by substances such as pentobarbital, hexobarbital, Althesin (alphaxadone and alphadoline in castor oil) is circadian system stage-dependent. Time-dependent changes of liver enzymes (e.g. hexobarbital oxidase) play a role in these circadian rhythms. The clinical chronopharmacokinetics of benzodiazepines have been documented in man. Chronopharmacologic methods can be used to study desired and undesired hypnotic effects of substances. Such is the case of new antihistamines (anti-H1), which do not induce sleepiness, in either acute or chronic administration. Pertinent also is the problem of intolerance to shift-work. Intolerant shift-workers are subject to internal desynchronization between at least two rhythms (e.g. activity-rest cycle and body temperature). Clinically these workers suffer from sleep

Dynamics of crowding-induced mixing in phase separated lipid bilayers

DOE PAGES

Zeno, Wade F.; Johnson, Kaitlin E.; Sasaki, Darryl Y.; ...

2016-10-10

We use fluorescence microscopy to examine the dynamics of the crowding-induced mixing transition of liquid ordered (L o)–liquid disordered (L d) phase separated lipid bilayers when the following particles of increasing size bind to either the L o or L d phase: Ubiquitin, green fluorescent protein (GFP), and nanolipoprotein particles (NLPs) of two diameters. These proteinaceous particles contained histidine-tags, which were phase targeted by binding to iminodiacetic acid (IDA) head groups, via a Cu 2+ chelating mechanism, of lipids that specifically partition into either the Lo phase or Ld phase. The degree of steric pressure was controlled by varying themore » size of the bound particle (10–240 kDa) and the amount of binding sites present (i.e., DPIDA concentrations of 9 and 12 mol%) in the supported lipid multibilayer platform used here. We develop a mass transfer-based diffusional model to analyze the observed L o phase domain dissolution that, along with visual observations and activation energy calculations, provides insight into the sequence of events in crowding-induced mixing. Furthermore, our results suggest that the degree of steric pressure and target phase influence not only the efficacy of steric-pressure induced mixing, but the rate and controlling mechanism for which it occurs.« less

Neocortical 40 Hz oscillations during carbachol-induced rapid eye movement sleep and cataplexy.

PubMed

Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Chase, Michael H; Falconi, Atilio

2016-02-01

Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice.

PubMed

Hakim, Fahed; Wang, Yang; Carreras, Alba; Hirotsu, Camila; Zhang, Jing; Peris, Eduard; Gozal, David

2015-01-01

Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice. Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice. SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target. © 2014 Associated Professional Sleep Societies, LLC.

Automobile diesel exhaust particles induce lipid droplet formation in macrophages in vitro.

PubMed

Cao, Yi; Jantzen, Kim; Gouveia, Ana Cecilia Damiao; Skovmand, Astrid; Roursgaard, Martin; Loft, Steffen; Møller, Peter

2015-07-01

Exposure to diesel exhaust particles (DEP) has been associated with adverse cardiopulmonary health effects, which may be related to dysregulation of lipid metabolism and formation of macrophage foam cells. In this study, THP-1 derived macrophages were exposed to an automobile generated DEP (A-DEP) for 24h to study lipid droplet formation and possible mechanisms. The results show that A-DEP did not induce cytotoxicity. The production of reactive oxygen species was only significantly increased after exposure for 3h, but not 24h. Intracellular level of reduced glutathione was increased after 24h exposure. These results combined indicate an adaptive response to oxidative stress. Exposure to A-DEP was associated with significantly increased formation of lipid droplets, as well as changes in lysosomal function, assessed as reduced LysoTracker staining. In conclusion, these results indicated that exposure to A-DEP may induce formation of lipid droplets in macrophages in vitro possibly via lysosomal dysfunction. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effects of Massage Therapy to Induce Sleep in Infants Born Preterm

PubMed Central

Yates, Charlotte C.; Mitchell, Anita J.; Booth, Melissa Y.; Williams, D. Keith; Lowe, Leah M.; Hall, Richard Whit

2014-01-01

Purpose The aim of this study was to determine if massage therapy can be used as an adjunct intervention to induce sleep in infants born preterm. Methods Thirty infants born at a minimum of 28 weeks gestational age (GA), who were at the time of the study between 32-48 weeks adjusted GA, were randomly assigned to receive massage therapy on 1 day and not receive massage on an alternate day. The Motionlogger® Micro Sleep Watch® Actigraph recorded lower extremity activity on the morning of each day. Results No significant difference was found between groups for sleep efficiency (P=.13) for the time period evaluated. Groups differed significantly during the time period after the massage ended with more infants sleeping on the non-massage day (Χ2= 4.9802, P=.026). Conclusions Massage is well tolerated in infants born preterm and infants do not fall asleep faster after massage than without massage. PMID:25251794

Sleep Deprivation and Neurobehavioral Dynamics

PubMed Central

Basner, Mathias; Rao, Hengyi; Goel, Namni; Dinges, David F.

2013-01-01

Lifestyles involving sleep deprivation are common, despite mounting evidence that both acute total sleep deprivation and chronically restricted sleep degrade neurobehavioral functions associated with arousal, attention, memory and state stability. Current research suggests dynamic differences in the way the central nervous system responds to acute versus chronic sleep restriction, which is reflected in new models of sleep-wake regulation. Chronic sleep restriction likely induces long-term neuromodulatory changes in brain physiology that could explain why recovery from it may require more time than from acute sleep loss. High intraclass correlations in neurobehavioral responses to sleep loss suggest that these trait-like differences are phenotypic and may include genetic components. Sleep deprivation induces changes in brain metabolism and neural activation that involve distributed networks and connectivity. PMID:23523374

The role of drug-induced sleep endoscopy in surgical planning for obstructive sleep apnea syndrome.

PubMed

Aktas, Ozturk; Erdur, Omer; Cirik, Ahmet Adnan; Kayhan, Fatma Tulin

2015-08-01

This study investigated the role of drug-induced sleep endoscopy (DISE) in the surgical treatment planning of patients with obstructive sleep apnea syndrome (OSAS). This study was conducted using patients diagnosed with OSAS between January 2007 and March 2009, who were scheduled for surgical treatment. DISE was performed using propofol in patients considered to have upper respiratory tract obstruction as indicated by Muller's maneuver. After completing the sleep endoscopy, the patient was intubated and surgery was performed (tonsillectomy and uvulopalatopharyngoplasty). A successful operation was defined as a decrease in the respiratory disturbance index to below 5 or a decrease of ≥50 % following the operation. The study included 20 patients (4 female and 16 male) aged 19-57 years. No statistically significant correlation between modified Mallampati class and operation success or between the polysomnographic stage of disease and operation success was identified. A significantly high operation success rate was found in the group with obstruction of the upper airway according to DISE (p < 0.05), whereas a significantly low operation success rate was found in the group with obstruction of the lower airway according to DISE (p < 0.01). DISE may be used to identify the localization of obstruction for diagnostic purposes, and it can be helpful in selecting the treatment method.

Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption

PubMed Central

Jones, Emmalee M.; Dubey, Manish; Camp, Phillip J.; Vernon, Briana C.; Biernat, Jacek; Mandelkow, Eckhard; Majewski, Jaroslaw; Chi, Eva Y.

2012-01-01

The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's disease. However, the mechanisms of tau aggregation and toxicity remain unknown. Recent work has shown that lipid membrane can induce tau aggregation and that membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity, suggesting that the plasma membrane may play dual roles in tau pathology. This prompted our investigation to assess tau's propensity to interact with membranes and to elucidate the mutually disruptive structural perturbations the interactions induce in both tau and the membrane. We show that although highly charged and soluble, the full-length tau (hTau40) is also highly surface active, selectively inserts into anionic DMPG lipid monolayers and induces membrane morphological changes. To resolve molecular-scale structural details of hTau40 associated with lipid membranes, X-ray and neutron scattering techniques are utilized. X-ray reflectivity indicates hTau40's presence underneath a DMPG monolayer and penetration into the lipid headgroups and tailgroups, whereas grazing incidence X-ray diffraction shows that hTau40 insertion disrupts lipid packing. Moreover, both air/water and DMPG lipid membrane interfaces induce the disordered hTau40 to partially adopt a more compact conformation with density similar to that of a folded protein. Neutron reflectivity shows that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact. Our results show that hTau40's strong interaction with anionic lipids induces tau structural compaction and membrane disruption, suggesting possible membrane-based mechanisms of tau aggregation and toxicity in neurodegenerative diseases. PMID:22401494

Hepatitis C Virus Induces the Localization of Lipid Rafts to Autophagosomes for Its RNA Replication

PubMed Central

Kim, Ja Yeon; Wang, Linya; Lee, Jiyoung

2017-01-01

ABSTRACT Autophagy plays important roles in maintaining cellular homeostasis. It uses double- or multiple-membrane vesicles termed autophagosomes to remove protein aggregates and damaged organelles from the cytoplasm for recycling. Hepatitis C virus (HCV) has been shown to induce autophagy to enhance its own replication. Here we describe a procedure that combines membrane flotation and affinity chromatography for the purification of autophagosomes from cells that harbor an HCV subgenomic RNA replicon. The purified autophagosomes had double- or multiple-membrane structures with a diameter ranging from 200 nm to 600 nm. The analysis of proteins associated with HCV-induced autophagosomes by proteomics led to the identification of HCV nonstructural proteins as well as proteins involved in membrane trafficking. Notably, caveolin-1, caveolin-2, and annexin A2, which are proteins associated with lipid rafts, were also identified. The association of lipid rafts with HCV-induced autophagosomes was confirmed by Western blotting, immunofluorescence microscopy, and immunoelectron microscopy. Their association with autophagosomes was also confirmed in HCV-infected cells. The association of lipid rafts with autophagosomes was specific to HCV, as it was not detected in autophagosomes induced by nutrient starvation. Further analysis indicated that the autophagosomes purified from HCV replicon cells could mediate HCV RNA replication in a lipid raft-dependent manner, as the depletion of cholesterol, a major component of lipid rafts, from autophagosomes abolished HCV RNA replication. Our studies thus demonstrated that HCV could specifically induce the association of lipid rafts with autophagosomes for its RNA replication. IMPORTANCE HCV can cause severe liver diseases, including cirrhosis and hepatocellular carcinoma, and is one of the most important human pathogens. Infection with HCV can lead to the reorganization of membrane structures in its host cells, including the induction of

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

PubMed Central

Wise, Laura E.; Cannavacciulo, Roberta; Cravatt, Benjamin F.; Martin, Billy F.; Lichtman, Aron H.

2008-01-01

While it has long been recognized that Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this

Evaluation of fatty acid amides in the carrageenan-induced paw edema model.

PubMed

Wise, Laura E; Cannavacciulo, Roberta; Cravatt, Benjamin F; Martin, Billy F; Lichtman, Aron H

2008-01-01

While it has long been recognized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild-type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this

D1 Receptor Activation in the Mushroom Bodies Rescues Sleep Loss Induced Learning Impairments in Drosophila

PubMed Central

Seugnet, Laurent; Suzuki, Yasuko; Vine, Lucy; Gottschalk, Laura; Shaw, Paul J

2008-01-01

Background Extended wakefulness disrupts acquisition of short term memories in mammals. However, the underlying molecular mechanisms triggered by extended waking and restored by sleep are unknown. Moreover, the neuronal circuits that depend on sleep for optimal learning remain unidentified. Results Learning was evaluated using Aversive Phototaxic Suppression (APS). In this task, flies learn to avoid light that is paired with an aversive stimulus (quinine /humidity). We demonstrate extensive homology in sleep deprivation induced learning impairment between flies and humans. Both 6 h and 12 h of sleep deprivation are sufficient to impair learning in Canton-S (Cs) flies. Moreover, learning is impaired at the end of the normal waking-day in direct correlation with time spent awake. Mechanistic studies indicate that this task requires intact mushroom bodies (MBs) and requires the Dopamine D1-like receptor (dDA1). Importantly, sleep deprivation induced learning impairments could be rescued by targeted gene expression of the dDA1 receptor to the MBs. Conclusion These data provide direct evidence that extended wakefulness disrupts learning in Drosophila. These results demonstrate that it is possible to prevent the effects of sleep deprivation by targeting a single neuronal structure and identify cellular and molecular targets adversely affected by extended waking in a genetically tractable model organism. PMID:18674913

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 in Caenorhabditis elegans.

PubMed

DeBardeleben, Hilary K; Lopes, Lindsey E; Nessel, Mark P; Raizen, David M

2017-10-01

Stress-induced sleep (SIS) in Caenorhabditis elegans is important for restoration of cellular homeostasis and is a useful model to study the function and regulation of sleep. SIS is triggered when epidermal growth factor (EGF) activates the ALA neuron, which then releases neuropeptides to promote sleep. To further understand this behavior, we established a new model of SIS using irradiation by ultraviolet C (UVC) light. While UVC irradiation requires ALA signaling and leads to a sleep state similar to that induced by heat and other stressors, it does not induce the proteostatic stress seen with heat exposure. Based on the known genotoxic effects of UVC irradiation, we tested two genes, atl-1 and cep-1 , which encode proteins that act in the DNA damage response pathway. Loss-of-function mutants of atl-1 had no defect in UVC-induced SIS but a partial loss-of-function mutant of cep-1 , gk138 , had decreased movement quiescence following UVC irradiation. Germline ablation experiments and tissue-specific RNA interference experiments showed that cep-1 is required somatically in neurons for its effect on SIS. The cep-1 ( gk138 ) mutant suppressed body movement quiescence controlled by EGF, indicating that CEP-1 acts downstream or in parallel to ALA activation to promote quiescence in response to ultraviolet light. Copyright © 2017 by the Genetics Society of America.

Drug-induced sleep endoscopy in the identification of obstruction sites in patients with obstructive sleep apnea: a systematic review.

PubMed

Viana, Alonço da Cunha; Thuler, Luiz Claudio Santos; Araújo-Melo, Maria Helena de

2015-01-01

Obstructive sleep apnea syndrome has multifactorial causes. Although indications for surgery are evaluated by well-known diagnostic tests in the awake state, these do not always correlate with satisfactory surgical results. To undertake a systematic review on endoscopy during sleep, as one element of the diagnosis routine, aiming to identify upper airway obstruction sites in adult patients with OSAS. By means of electronic databases, a systematic review was performed of studies using drug-induced sleep endoscopy to identify obstruction sites in patients with OSAS. Ten articles were selected that demonstrated the importance of identifying multilevel obstruction, especially in relation to retrolingual and laryngeal collapse in OSAS. DISE is an additional method to reveal obstruction sites that have not been detected in awake patients. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss.

PubMed

Graham, Lucia S; Parhami, Farhad; Tintut, Yin; Kitchen, Christina M R; Demer, Linda L; Effros, Rita B

2009-11-01

Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of receptor activator of NFkappaB ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NFkappaB pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis.

Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

PubMed Central

Kim, Hyunbae; Mendez, Roberto; Chen, Xuequn; Fang, Deyu

2015-01-01

Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH. PMID:26438600

Slow Wave Sleep Induced by GABA Agonist Tiagabine Fails to Benefit Memory Consolidation

PubMed Central

Feld, Gordon B.; Wilhelm, Ines; Ma, Ying; Groch, Sabine; Binkofski, Ferdinand; Mölle, Matthias; Born, Jan

2013-01-01

Study Objectives: Slow wave sleep (SWS) plays a pivotal role in consolidating memories. Tiagabine has been shown to increase SWS in favor of REM sleep without impacting subjective sleep. However, it is unknown whether this effect is paralleled by an improved sleep-dependent consolidation of memory. Design: This double-blind within-subject crossover study tested sensitivity of overnight retention of declarative neutral and emotional materials (word pairs, pictures) as well as a procedural memory task (sequence finger tapping) to oral administration of placebo or 10 mg tiagabine (at 22:30). Participants: Fourteen healthy young men aged 21.9 years (range 18-28 years). Measurements and Results: Tiagabine significantly increased the time spent in SWS and decreased REM sleep compared to placebo. Tiagabine also enhanced slow wave activity (0.5-4.0 Hz) and density of < 1 Hz slow oscillations during NREM sleep. Fast (12-15 Hz) and slow (9-12 Hz) spindle activity, in particular that occurring phase-locked to the slow oscillation cycle, was decreased following tiagabine. Despite signs of deeper and more SWS, overnight retention of memory tested after sleep the next evening (19:30) was generally not improved after tiagabine, but on average even lower than after placebo, with this impairing effect reaching significance for procedural sequence finger tapping. Conclusions: Our data show that increasing slow wave sleep with tiagabine does not improve memory consolidation. Possibly this is due to functional differences from normal slow wave sleep, i.e., the concurrent suppressive influence of tiagabine on phase-locked spindle activity. Citation: Feld GB; Wilhelm I; Ma Y; Groch S; Binkofski F; Mölle M; Born J. Slow wave sleep induced by GABA agonist tiagabine fails to benefit memory consolidation. SLEEP 2013;36(9):1317-1326. PMID:23997364

Ion-Induced Defect Permeation of Lipid Membranes

PubMed Central

Vorobyov, Igor; Olson, Timothy E.; Kim, Jung H.; Koeppe, Roger E.; Andersen, Olaf S.; Allen, Toby W.

2014-01-01

We have explored the mechanisms of uncatalyzed membrane ion permeation using atomistic simulations and electrophysiological recordings. The solubility-diffusion mechanism of membrane charge transport has prevailed since the 1960s, despite inconsistencies in experimental observations and its lack of consideration for the flexible response of lipid bilayers. We show that direct lipid bilayer translocation of alkali metal cations, Cl–, and a charged arginine side chain analog occurs via an ion-induced defect mechanism. Contrary to some previous suggestions, the arginine analog experiences a large free-energy barrier, very similar to those for Na+, K+, and Cl–. Our simulations reveal that membrane perturbations, due to the movement of an ion, are central for explaining the permeation process, leading to both free-energy and diffusion-coefficient profiles that show little dependence on ion chemistry and charge, despite wide-ranging hydration energies and the membrane’s dipole potential. The results yield membrane permeabilities that are in semiquantitative agreement with experiments in terms of both magnitude and selectivity. We conclude that ion-induced defect-mediated permeation may compete with transient pores as the dominant mechanism of uncatalyzed ion permeation, providing new understanding for the actions of a range of membrane-active peptides and proteins. PMID:24507599

Effect of nicotinic acid on the sleep time and tolerance induced by ethanol in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basilio, C.; Toro, A.; Yojay, L.

The intraperitoneal (i.p.) administration (50 mg/kg) of nicotinic acid (NA), markedly decreased the sleep time of rats pretreated (10 min before), post-treated (10 min after) or simultaneously treated with ethanol (4 g/Kg i.p.). A similar effect was observed on the sleep time induced by pentobarbital (37 mg/Kg i.p.). Blood alcohol levels (BAL) were the same or slightly higher in the animals pretreated with NA than in the control animals pre-injected with saline. Nicotinamide and NAD had no effect. A total of three doses of ethanol, each one administered weekly or biweekly, induced tolerance, which persisted for approximately six weeks. Aftermore » this period, a hypersensitivity to ethanol appeared to develop. This phenomenon was not observed when NA was pre-injected 10 min before each dose of ethanol. The sleep time of the latter animals did not change neither during the treatment period nor after six weeks without any treatment. BAL were slightly higher in NA treated than in control animals. The authors concluded that the effect of NA on the sleep time and tolerance induced by ethanol is not due to an increased rate of its metabolism and/or elimination but to a long-lasting effect that decreases the sensitivity of the nervous cells to ethanol. The mechanisms involved in the shortening of the sleep time as well as those responsible for the loss of the capacity to develop tolerance are under current investigation.« less

Critical role of CA1 muscarinic receptors on memory acquisition deficit induced by total (TSD) and REM sleep deprivation (RSD).

PubMed

Javad-Moosavi, Bibi-Zahra; Vaezi, Gholamhassan; Nasehi, Mohammad; Haeri-Rouhani, Seyed-Ali; Zarrindast, Mohammad-Reza

2017-10-03

Despite different theories regarding sleep physiological function, an overall census indicates that sleep is useful for neural plasticity which eventually strengthens cognition and brain performance. Different studies show that sleep deprivation (SD) leads to impaired learning and hippocampus dependent memory. According to some studies, cholinergic system plays an important role in sleep (particularly REM sleep), learning, memory, and its retrieval. So this study has been designed to investigate the effect of CA1 Cholinergic Muscarinic Receptors on memory acquisition deficit induced by total sleep deprivation (TSD) and REM sleep deprivation (RSD). A modified water box (locomotor activity may be provide a limiting factor in this method of SD) or multiple platforms were used for induction of TSD or RSD, respectively. Inhibitory passive avoidance apparatus has been used to determine the effects of SD and its changes by physostigmine (as cholinesterase inhibitor) or scopolamine (muscarinic receptor antagonist) on memory formation. Because locomotor activity and pain perception induce critical roles in passive avoidance memory formation, we also measured these factors by open field and hot-plate instruments, respectively. The results showed that TSD and RSD for 24 hours impaired memory formation but they did not alter locomotor activity. TSD also induced analgesia effect, but RSD did not alter it. Intra-CA1 injection of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) did not alter memory acquisition in the sham-TSD or sham-RSD, by themselves. Moreover, intra-CA1 injection of sub-threshold dose of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) could restore the memory acquisition deficit induced by RSD, while scopolamine could restore TSD-induced amnesia. Both drugs reversed analgesia induced by TSD. None of previous interventions altered locomotor activity. According to this study, CA1 cholinergic muscarinic receptors play an important role in

Thermodynamic and fluorescence studies of the underlying factors in benzyl alcohol-induced lipid interdigitated phase.

PubMed

Chen, C H; Hoye, K; Roth, L G

1996-09-15

To further investigate factors contributing to the action of alcohol in the solute-induced lipid interdigitation phase, thermodynamic and fluorescence polarization measurements were carried out to study the interaction of benzyl alcohol with dipalmitoyl phosphatidylcholine bilayer vesicles. The obtained results were compared with those previously reported for ethanol and cyclohexanol (L. G. Roth and C-H. Chen, Arch. Biochem. Biophys. 296, 207, 1992). Similar to ethanol, benzyl alcohol was found to exhibit a biphasic effect on the enthalpy (delta Hm) and the temperature (tm) of the lipid-phase transition and the steady-state fluorescence polarization (P) monitored by 1,6-diphenyl-1,3,5-hexatriene. At a total concentration of benzyl alcohol < 30 mg/ml (the alcohol concentration in lipid phase < 21 mg/ml), benzyl alcohol was found to exhibit large increases in delta Hm and P, which were correlated with the formation of a lipid interdigitated phase, as evidenced by reported X-ray diffraction data. Combining the results with benzyl alcohol and ethanol suggested that simultaneously large changes in delta Hm and P can be used as an indication of the occurrence of a solute-induced lipid interdigitated phase. The overall interacting force in the formation of this lipid phase, as derived from the interactions of the hydroxyl portion of an alcohol with the lipid phosphate head group and the hydrophobic portion of an alcohol with the lipid hydrocarbon chains, may or may not be dominated by hydrophobic interaction. Although lipid/water partition coefficients and the contribution of hydrophobic interaction to the overall interacting force were comparable between benzyl alcohol and cyclohexanol, benzyl alcohol induced lipid interdigitated phase, but not for cyclohexanol. This was due to the ability of benzyl alcohol to be more effective than cyclohexanol in simultaneously interacting with the phosphate head group and the hydrocarbon chains of lipid.

Cholesterol Regulates μ-Opioid Receptor-Induced β-Arrestin 2 Translocation to Membrane Lipid RaftsS⃞

PubMed Central

Qiu, Yu; Wang, Yan; Chen, Hong-Zhuan; Loh, Horace H.

2011-01-01

μ-Opioid receptor (OPRM1) is mainly localized in lipid raft microdomains but internalizes through clathrin-dependent pathways. Our previous studies demonstrated that disruption of lipid rafts by cholesterol-depletion reagent blocked the agonist-induced internalization of OPRM1 and G protein-dependent signaling. The present study demonstrated that reduction of cholesterol level decreased and culturing cells in excess cholesterol increased the agonist-induced internalization and desensitization of OPRM1, respectively. Further analyses indicated that modulation of cellular cholesterol level did not affect agonist-induced receptor phosphorylation but did affect membrane translocation of β-arrestins. The translocation of β-arrestins was blocked by cholesterol reduction, and the effect could be reversed by incubating with cholesterol. OptiPrep gradient separation of lipid rafts revealed that excess cholesterol retained more receptors in lipid raft domains and facilitated the recruitment of β-arrestins to these microdomains upon agonist activation. Moreover, excess cholesterol could evoke receptor internalization and protein kinase C-independent extracellular signal-regulated kinases activation upon morphine treatment. Therefore, these results suggest that cholesterol not only can influence OPRM1 localization in lipid rafts but also can effectively enhance the recruitment of β-arrestins and thereby affect the agonist-induced trafficking and agonist-dependent signaling of OPRM1. PMID:21518774

Adverse Effects of Induced Hot Flashes on Objectively Recorded and Subjectively Reported Sleep: Results of a Gonadotropin-Releasing Hormone Agonist Experimental Protocol

PubMed Central

Joffe, Hadine; White, David P.; Crawford, Sybil L.; McCurnin, Kristin E.; Economou, Nicole; Connors, Stephanie; Hall, Janet E.

2013-01-01

Objectives The impact of hot flashes on sleep is of great clinical interest, but results are inconsistent, especially when both hot flashes and sleep are measured objectively. Using objective and subjective measurements, we examined the impact of hot flashes on sleep by inducing hot flashes with a gonadotropin-releasing hormone agonist (GnRHa). Methods The GnRHa leuprolide was administered to 20 healthy premenopausal volunteers without hot flashes or sleep disturbances. Induced hot flashes were assessed objectively (skin-conductance monitor) and subjectively (daily diary) during one-month follow-up. Changes from baseline in objective (actigraphy) and subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) were compared between women who did and did not develop objective hot flashes, and, in parallel analyses, subjective hot flashes. Results New-onset hot flashes were recorded in 14 (70%) and reported by 14 (70%) women (80% concordance). Estradiol was universally suppressed. Objective sleep efficiency worsened in women with objective hot flashes and improved in women without objective hot flashes (median decrease 2.6%, increase 4.2%, p=0.005). Subjective sleep quality worsened more in those with than without subjective hot flashes (median increase PSQI 2.5 vs. 1.0, p=0.03). Objective hot flashes were not associated with subjective sleep quality, nor were subjective symptoms linked to objective sleep measures. Conclusions This experimental model of induced hot flashes demonstrates a causal relationship between hot flashes and poor sleep quality. Objective hot flashes result in worse objective sleep efficiency, while subjective hot flashes worsen perceived sleep quality. PMID:23481119

Sleep and Physiological Dysregulation: A Closer Look at Sleep Intraindividual Variability.

PubMed

Bei, Bei; Seeman, Teresa E; Carroll, Judith E; Wiley, Joshua F

2017-09-01

Variable daily sleep (ie, higher intraindividual variability; IIV) is associated with negative health consequences, but potential physiological mechanisms are poorly understood. This study examined how the IIV of sleep timing, duration, and quality is associated with physiological dysregulation, with diurnal cortisol trajectories as a proximal outcome and allostatic load (AL) as a multisystem distal outcome. Participants are 436 adults (Mage ± standard deviation = 54.1 ± 11.7, 60.3% women) from the Midlife in the United States study. Sleep was objectively assessed using 7-day actigraphy. Diurnal cortisol was measured via saliva samples (four/day for 4 consecutive days). AL was measured using 23 biomarkers from seven systems (inflammatory, hypothalamic-pituitary-adrenal axis, metabolic glucose and lipid, cardiovascular, parasympathetic, sympathetic) using a validated bifactor model. Linear and quadratic effects of sleep IIV were estimated using a validated Bayesian model. Controlling for covariates, more variable sleep timing (p = .04 for risetime, p = .097 for bedtime) and total sleep time (TST; p = .02), but not mean sleep variables, were associated with flatter cortisol diurnal slope. More variable sleep onset latency and wake after sleep onset, later average bedtime, and shorter TST were associated with higher AL adjusting for age and sex (p-values < .05); after controlling for all covariates, however, only later mean bedtime remained significantly associated with higher AL (p = .04). In a community sample of adults, more variable sleep patterns were associated with blunted diurnal cortisol trajectories but not with higher multisystem physiological dysregulation. The associations between sleep IIV and overall health are likely complex, including multiple biopsychosocial determinants and require further investigation. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For

Dopamine agonist suppression of rapid-eye-movement sleep is secondary to sleep suppression mediated via limbic structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miletich, R.S.

The effects of pergolide, a direct dopamine receptor agonist, on sleep and wakefulness, motor behavior and /sup 3/H-spiperone specific binding in limbic structures and striatum in rats was studied. The results show that pergolide induced a biphasic dose effect, with high doses increasing wakefulness and suppressing sleep while low dose decreased wakefulness, but increased sleep. It was shown that pergolide-induced sleep suppression was blocked by ..cap alpha..-glupenthixol and pimozide, two dopamine receptor antagonists. It was further shown that pergolide merely delayed the rebound resulting from rapid-eye-movement (REM) sleep deprivation, that dopamine receptors stimulation had no direct effect on the period,more » phase or amplitude of the circadian rhythm of REM sleep propensity and that there was no alteration in the coupling of REM sleep episodes with S/sub 2/ episodes. Rapid-eye-movement sleep deprivation resulted in increased sensitivity to the pergolide-induced wakefulness stimulation and sleep suppression and pergolide-induced motor behaviors of locomotion and head bobbing. /sup 3/H-spiperone specific binding to dopamine receptors was shown to be altered by REM sleep deprivation in the subcortical limbic structures. It is concluded that the REM sleep suppressing action of dopamine receptor stimulation is secondary to sleep suppression per se and not secondary to a unique effect on the REM sleep. Further, it is suggested that the wakefulness stimulating action of dopamine receptor agonists is mediated by activation of the dopamine receptors in the terminal areas of the mesolimbocortical dopamine projection system.« less

Sleep-inducing N-alkyl-5-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinones and N-alkyl-3-(trifluoromethyl)cinnamamides.

PubMed

Houlihan, W J; Gogerty, J H; Ryan, E A; Schmitt, G

1985-01-01

A series of N-alkyl-3-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinones and N-alkyl-3-(trifluoromethyl)-cinnamamides were prepared and screened in a series of tests designed to detect potential sleep inducers. The more active members of the series were evaluated for their ability to induce sleep in Cebus monkeys. The most active compound, N-methyl-5-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinone, was equal to methaqualone.

Interspecific variability in phosphorus-induced lipid remodelling among marine eukaryotic phytoplankton.

PubMed

Cañavate, José Pedro; Armada, Isabel; Hachero-Cruzado, Ismael

2017-01-01

The response of marine microalgal lipids to phosphorus is of central importance in phytoplankton ecology but remains poorly understood. We determined how taxonomically diverse microalgal species remodelled their lipid class profile in response to phosphorus availability and whether these changes coincided with those already known to occur in land plants and in the limited number of phytoplankton species for which data are available. The complete lipid class profile and specific lipid ratios influenced by phosphorus availability were quantified in two green microalgae and seven Chromalveolates exposed to phosphorus repletion, deprivation and replenishment. Lipid class cell quota changes in the two green microalgae resembled the currently described pattern of betaine lipids substituting for phospholipids under phosphorus depletion, whereas only two of the studied Chromalveolates showed this pattern. Sulpholipids counterbalanced phosphatidylglycerol only in Picochlorum atomus. In all other species, both lipids decreased simultaneously under phosphorus deprivation, although sulpholipids declined more slowly. Phosphorus deprivation always induced a decrease in digalactosyl-diacylglycerol. However, the ratio of digalactosyl-diacylglycerol to total phospholipids increased in eight species and remained unchanged in Isochrysis galbana. Marine phytoplankton seems to have evolved a diversified mechanism for remodelling its lipid class profile under the influence of phosphorus, with cryptophytes and particularly haptophytes exhibiting previously unobserved lipid responses to phosphorus. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males.

PubMed

de Souza, Jorge F T; Dáttilo, Murilo; de Mello, Marco T; Tufik, Sergio; Antunes, Hanna K M

2017-01-01

Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT) is emerging as a potential strategy. Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation. Method: Eleven healthy male volunteers were recruited, aged 18-35 years, who declared taking 7-8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition), 24 h of total sleep deprivation ( SD condition), HIIT training followed by regular sleep (HIIT+RS condition), and HIIT training followed by 24 h of total sleep deprivation (HIIT+ SD condition). They performed six training sessions over 2 weeks and each session consisted of 8-12 × 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT), were performed. Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids. Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition.

High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males

PubMed Central

de Souza, Jorge F. T.; Dáttilo, Murilo; de Mello, Marco T.; Tufik, Sergio; Antunes, Hanna K. M.

2017-01-01

Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT) is emerging as a potential strategy. Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation. Method: Eleven healthy male volunteers were recruited, aged 18–35 years, who declared taking 7–8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition), 24 h of total sleep deprivation (SD condition), HIIT training followed by regular sleep (HIIT+RS condition), and HIIT training followed by 24 h of total sleep deprivation (HIIT+SD condition). They performed six training sessions over 2 weeks and each session consisted of 8–12 × 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT), were performed. Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids. Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition. PMID:29270126

Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory.

PubMed

Guo, Lengqiu; Guo, Zhuangli; Luo, Xiaoqing; Liang, Rui; Yang, Shui; Ren, Haigang; Wang, Guanghui; Zhen, Xuechu

2016-12-02

Sleep, particularly rapid eye movement (REM) sleep, is implicated in the consolidation of emotional memories. In the present study, we investigated the protective effects of a phosphodiesterase 10A (PDE10A) inhibitor MP-10 on deficits in long-term fear memory induced by REM sleep deprivation (REM-SD). REM-SD caused deficits in long-term fear memory, however, MP-10 administration ameliorated the deleterious effects of REM-SD on long term fear memory. Brain-derived neurotropic factor (BDNF) and phosphorylated cAMP response element-binding protein (pCREB) were altered in specific brain regions associated with learning and memory in REM-SD rats. Accordingly, REM-SD caused a significant decrease of pCREB in hippocampus and striatum and a significant decrease of BDNF in the hippocampus, striatum and amygdala, however, MP-10 reversed the effects of REM-SD in a dose-dependent manner. Our findings suggest that REM-SD disrupts the consolidation of long-term fear memory and that administration of MP-10 protects the REM-SD-induced deficits in fear memory, which may be due to the MP-10-induced expression of BDNF in the hippocampus, striatum and amygdala, and phosphorylation of CREB in the hippocampus and striatum. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Choline and betaine ameliorate liver lipid accumulation induced by vitamin B6 deficiency in rats.

PubMed

Kitagawa, Erina; Yamamoto, Tatsuya; Fujishita, Mayuko; Ota, Yuki; Yamamoto, Kohei; Nakagawa, Tomoyuki; Hayakawa, Takashi

2017-02-01

We investigated the efficacy of supplementing the diet with choline or betaine in ameliorating lipid accumulation induced by vitamin B 6 (B 6 ) deficiency in rat liver. Male Wistar rats were fed a control, B 6 -deficient, choline-supplemented (2, 4, or 6 g choline bitartrate/kg diet) B 6 -deficient diet or betaine-supplemented (1, 2, or 4 g betaine anhydrous/kg diet) B 6 -deficient diet for 35 d; all diets contained 9 g L-methionine (Met)/kg diet. Choline or betaine supplementation attenuated liver lipid deposition and restored plasma lipid profiles to control levels. These treatments restored the disruptions in Met metabolism and the phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio induced by B 6 deficiency in liver microsomes. These results suggest that choline and betaine ameliorated liver lipid accumulation induced by B 6 deficiency via recovery of Met metabolism and very low-density lipoprotein secretion by restoring the supply of PC derived from PE.

Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage

PubMed Central

2016-01-01

The excessive intake of alcohol is a serious public health problem, especially given the severe damage provoked by chronic or prenatal exposure to alcohol that affects many physiological processes, such as memory, motor function, and cognitive abilities. This damage is related to the ethanol oxidation in the brain. The metabolism of ethanol to acetaldehyde and then to acetate is associated with the production of reactive oxygen species that accentuate the oxidative state of cells. This metabolism of ethanol can induce the oxidation of the fatty acids in phospholipids, and the bioactive aldehydes produced are known to be associated with neurotoxicity and neurodegeneration. As such, here we will review the role of lipids in the neuronal damage induced by ethanol-related oxidative stress and the role that lipids play in the related compensatory or defense mechanisms. PMID:26949445

Cuticular lipids and odors induce sex-specific behaviors in the male cricket Gryllus bimaculatus.

PubMed

Iwasaki, Masazumi; Katagiri, Chihiro

2008-03-01

Male crickets display sex-specific (e.g., mating and agonistic) behaviors towards conspecific individuals. One of the key signals for these behaviors is the chemical substance on the cricket body surface. In the present study, we analyzed female and male cuticular substances in behavioral assays. Antennal contact stimulation using female forewings elicited a mating behavior in males, while that using male forewings elicited an agonistic behavior in males. Thin-layer-chromatographic and other techniques analysis showed that saturated cuticular lipids were present in both female and male cuticles and that unsaturated lipids were present only in the male cuticle. Filter papers soaked with saturated or unsaturated cuticular lipids were applied to antennae of male crickets. Males showed mating behavior in response to stimulation with saturated lipids from both females and males but showed avoidance behavior in response to stimulation with male unsaturated lipids. Because cuticular lipids did not induce agonistic behavior in males, we collected odors from male crickets and found that these odors induced agonistic behavior in males. Therefore, we concluded that the key signals for mating, avoidance and agonistic behaviors of male crickets are comprised of at least three different components, saturated and unsaturated cuticular lipids and male odors, respectively.

Lipid-induced Signaling Causes Release of Inflammatory Extracellular Vesicles from Hepatocytes

PubMed Central

Hirsova, Petra; Ibrahim, Samar H.; Krishnan, Anuradha; Verma, Vikas K.; Bronk, Steven F.; Werneburg, Nathan W.; Charlton, Michael R.; Shah, Vijay H.; Malhi, Harmeet; Gores, Gregory J.

2016-01-01

BACKGROUND & AIMS Hepatocyte cellular dysfunction and death induced by lipids, and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in release of extracellular vesicles (EV) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype. METHODS Primary mouse and human hepatocytes and Huh7 cells were incubated with palmitate, its metabolite lysophosphatidylcholine, or diluent (control). The released EV were isolated, characterized, quantified, and applied to macrophages. C57BL/6 mice were placed on chow or a diet high in fat, fructose, and cholesterol to induce NASH. Some mice were also given the ROCK1 inhibitor fasudil; 2 weeks later, serum EVs were isolated and characterized by immunoblot and nanoparticle-tracking analyses. Livers were collected and analyzed by histology, immunohistochemistry, and quantitative PCR. RESULTS Incubation of primary hepatocytes and Huh7 cells with palmitate or lysophosphatidylcholine increased their release of EV, compared with control cells. This release was reduced by inactivating mediators of the DR5 signaling pathway or ROCK1 inhibition. Hepatocyte-derived EV contained TRAIL and induced expression of interleukin-1, beta (Il1b) and Il6 mRNAs in mouse bone marrow-derived macrophages. Activation of macrophages required DR5 and RIP1. Administration of the ROCK1 inhibitor fasudil to mice with NASH reduced serum levels of EV; this reduction was associated with decreased liver injury, inflammation, and fibrosis. CONCLUSIONS Lipids, which stimulate DR5, induce release of hepatocyte EV, which activate an inflammatory phenotype in macrophages. Strategies to inhibit ROCK1-dependent release of EV by hepatocytes might be

Corticotropin Releasing Factor (CRF) Modulates Fear-Induced Alterations in Sleep in Mice

PubMed Central

Yang, Linghui; Tang, Xiangdong; Wellman, Laurie L.; Liu, Xianling; Sanford, Larry D.

2009-01-01

Contextual fear significantly reduces rapid eye movement sleep (REM) during post-exposure sleep in mice and rats. Corticotropin releasing factor (CRF) plays a major role in CNS responses to stressors. We examined the influence of CRF and astressin (AST), a non-specific CRF antagonist, on sleep after contextual fear in BALB/c mice. Male mice were implanted with transmitters for recording sleep via telemetry and with a guide cannula aimed into the lateral ventricle. Recordings for vehicle and handling control were obtained after ICV microinjection of saline (SAL) followed by exposure to a novel chamber. Afterwards, the mice were subjected to shock training (20 trials, 0.5 mA, 0.5 s duration) for 2 sessions. After training, separate groups of mice received ICV microinjections of SAL (0.2 microl, n=9), CRF (0.4 microg, n=8), or AST (1.0 microg, n=8) prior to exposure to the shock context alone. Sleep was then recorded for 20 hours (8-hour light and 12-hour dark period). Compared to handling control, contextual fear significantly decreased REM during the 8-h light period in mice receiving SAL and in mice receiving CRF, but not in the mice receiving AST. Mice receiving CRF exhibited reductions in REM during the 12-h dark period after contextual fear, whereas mice receiving SAL or AST did not. CRF also reduced non-REM (NREM) delta (slow wave) amplitude in the EEG. Only mice receiving SAL prior to contextual fear exhibited significant reductions in NREM and total sleep. These findings demonstrate a role for the central CRF system in regulating alterations in sleep induced by contextual fear. PMID:19376095

Conical Lipids in Flat Bilayers Induce Packing Defects Similar to that Induced by Positive Curvature

PubMed Central

Vamparys, Lydie; Gautier, Romain; Vanni, Stefano; Bennett, W.F. Drew; Tieleman, D. Peter; Antonny, Bruno; Etchebest, Catherine; Fuchs, Patrick F.J.

2013-01-01

In biological membranes, changes in lipid composition or mechanical deformations produce defects in the geometrical arrangement of lipids, thus allowing the adsorption of certain peripheral proteins. Here, we perform molecular dynamics simulations on bilayers containing a cylindrical lipid (PC) and a conical lipid (DOG). Profiles of atomic density and lateral pressure across the bilayer show differences in the acyl chain region due to deeper partitioning of DOG compared to PC. However, such analyses are less informative for the interfacial region where peripheral proteins adsorb. To circumvent this limitation, we develop, to our knowledge, a new method of membrane surface analysis. This method allows the identification of chemical defects, where hydrocarbon chains are accessible to the solvent, and geometrical defects, i.e., voids deeper than the glycerol backbone. The size and number of both types of defects increase with the number of monounsaturated acyl chains in PC and with the introduction of DOG, although the defects do not colocalize with the conical lipid. Interestingly, the size and probability of the defects promoted by DOG resemble those induced by positive curvature, thus explaining why conical lipids and positive curvature can both drive the adsorption of peripheral proteins that use hydrophobic residues as membrane anchors. PMID:23442909

Fatty acids from VLDL lipolysis products induce lipid droplet accumulation in human monocytes

PubMed Central

den Hartigh, Laura J; Connolly-Rohrbach, Jaime E; Fore, Samantha; Huser, Thomas R; Rutledge, John C

2010-01-01

One mechanism by which monocytes become activated postprandially is by exposure to triglyceride (TG)-rich lipoproteins such as very low-density lipoproteins (VLDL). VLDL are hydrolyzed by lipoprotein lipase (LpL) at the blood-endothelial cell interface, releasing free fatty acids. In this study, we examined postprandial monocyte activation in more detail, and found that lipolysis products generated from postprandial VLDL induce the formation of lipid-filled droplets within cultured THP-1 monocytes, characterized by coherent anti-stokes Raman spectroscopy. Organelle-specific stains revealed an association of lipid droplets with the endoplasmic reticulum, confirmed by electron microscopy. Lipid droplet formation was reduced when LpL-released fatty acids were bound by bovine serum albumin, which also reduced cellular inflammation. Furthermore, saturated fatty acids induced more lipid droplet formation in monocytes compared to mono- and polyunsaturated fatty acids. Monocytes treated with postprandial VLDL lipolysis products contained lipid droplets with more intense saturated Raman spectroscopic signals than monocytes treated with fasting VLDL lipolysis products. In addition, we found that human monocytes isolated during the peak postprandial period contain more lipid droplets compared to those from the fasting state, signifying that their development is not limited to cultured cells but also occurs in vivo. In summary, circulating free fatty acids can mediate lipid droplet formation in monocytes and potentially be used as a biomarker to assess an individual’s risk of developing atherosclerotic cardiovascular disease. PMID:20208007

Effects of carotenoids on damage of biological lipids induced by gamma irradiation

NASA Astrophysics Data System (ADS)

Saito, Takeshi; Fujii, Noriko

2014-05-01

Carotenoids are considered to be involved in the radioresistant mechanisms of radioresistant bacteria. In these bacterial cells, carotenoids are present in biological lipids, and therefore may be related to the radiation-induced damage of lipids. However, only limited data are available for the role of carotenoids in such damage. In this study, we irradiated an α-linolenic acid-benzene solution with gamma rays and analyzed the resulting oxidative degradation and peroxidation damage in the presence or absence of two typical carotenoids: β-carotene and astaxanthin. The analyses revealed that oxidative degradation and peroxidation of α-linolenic acid, as evaluated by the amount of malondialdehyde and conjugated diene formed, respectively, increased in a dose-dependent manner. Moreover, 8.5×10-3 M β-carotene inhibited gamma radiation-induced oxidative degradation of α-linolenic acid, whereas 5.0×10-5 and 5.0×10-6 M β-carotene, and 5.0×10-7 and 5.0×10-8 M astaxanthin promoted degradation. In contrast, neither β-carotene nor astaxanthin affected peroxidation of α-linolenic acid. These results suggest that an optimum concentration of carotenoids in radioresistant bacteria protects biological lipid structures from radiation-induced damage.

Protective effect of ascorbic acid on netilmicin-induced lipid profile and peroxidation parameters in rabbit blood plasma.

PubMed

Devbhuti, Pritesh; Sikdar, Debasis; Saha, Achintya; Sengupta, Chandana

2011-01-01

A drug may cause alteration in blood-lipid profile and induce lipid peroxidation phenomena on administration in the body. Antioxidant may play beneficial role to control the negative alteration in lipid profile and lipid peroxidation. In view of this context, the present in vivo study was carried out to evaluate the role of ascorbic acid as antioxidant on netilmicin-induced alteration of blood lipid profile and peroxidation parameters. Rabbits were used as experimental animals and blood was collected to estimate blood-lipid profiles, such as total cholesterol (TCh), high density lipoprotein cholesterol (HDL-Ch), low density lipoprotein cholesterol (LDL-Ch), very low density lipoprotein cholesterol (VLDL-Ch), triglycerides (Tg), phospholipids (PL), and total lipids (TL), as well as peroxidation parameters, such as malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), reduced glutathione (GSH) and nitric oxide (NO). The results revealed that netilmicin caused significant enhancement of MDA, HNE, TCh, LDL-Ch, VLDL-Ch, Tg levels and reduction in GSH, NO, HDL-Ch, PL, TL levels. On co-administration, ascorbic acid was found to be effective in reducing netilmicin-induced negative alterations of the above parameters.

A Case of Concomitant Obstructive Sleep Apnea and Non-Alcoholic Steatohepatitis Treated With CPAP Therapy

PubMed Central

Bajantri, Bharat; Lvovsky, Dmitry

2018-01-01

Obstructive sleep apnea syndrome is a disorder of sleep breathing that is a result of recurrent and intermittent hypoxia during sleep induced by the repeated partial or complete collapse of the upper airway, eventually causing chronic intermittent hypoxia. Non-alcoholic fatty liver disease is divided into non-alcoholic fatty liver and non-alcoholic steatohepatitis. Animal and human studies showed that obesity is associated with chronic liver hypoxia, even in the presence of systemic normoxia causing inflammation and release of cytokines. A “two-hit” model has been proposed. The first hit is characterized by insulin resistance and excess hepatic lipid accumulation secondary to abnormal fatty acid metabolism. Oxidative stress and inflammation are thought to comprise the second hit. Gold standard for the diagnosis of non-alcoholic steatohepatitis is a liver biopsy. Many clinical scores and non-invasive tools are used for the diagnosis of non-alcoholic steatohepatitis. Conservative management with lifestyle modifications including diet, exercise and weight loss remains the therapy of choice today. We present a case report of a 39-year-old man who was diagnosed with concomitant non-alcoholic steatohepatitis and severe obstructive sleep apnea. He was started treatment with continuous positive airway pressure and demonstrated excellent adherence to therapy for 6 years, with concomitant obstructive sleep apnea and non-alcoholic steatohepatitis which reversed with prolonged optimal continuous positive airway pressure therapy. Physical examination remained unremarkable except for morbid obesity. His abdominal girth, as well as body mass index, remained unchanged. After 6 years of optimal continuous positive airway pressure therapy, liver enzymes and relevant lipid panel normalized, suggesting reversal of non-alcoholic steatohepatitis. PMID:29915639

Crowding-Induced Mixing Behavior of Lipid Bilayers: Examination of Mixing Energy, Phase, Packing Geometry, and Reversibility.

PubMed

Zeno, Wade F; Rystov, Alice; Sasaki, Darryl Y; Risbud, Subhash H; Longo, Marjorie L

2016-05-10

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu(2+), chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domains of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10(-22) to 1.5 × 10(-20) J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. The mixing process was reversible, with Lo domains

Crowding-induced mixing behavior of lipid bilayers: Examination of mixing energy, phase, packing geometry, and reversibility

DOE PAGES

Zeno, Wade F.; Rystov, Alice; Sasaki, Darryl Y.; ...

2016-04-20

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu 2+, chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domainsmore » of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10 –22 to 1.5 × 10 –20 J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. Furthermore, the mixing process was reversible

Crowding-induced mixing behavior of lipid bilayers: Examination of mixing energy, phase, packing geometry, and reversibility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeno, Wade F.; Rystov, Alice; Sasaki, Darryl Y.

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu 2+, chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domainsmore » of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10 –22 to 1.5 × 10 –20 J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. Furthermore, the mixing process was reversible

Cationic cell-penetrating peptide binds to planar lipid bilayers containing negatively charged lipids but does not induce conductive pores.

PubMed

Gurnev, Philip A; Yang, Sung-Tae; Melikov, Kamran C; Chernomordik, Leonid V; Bezrukov, Sergey M

2013-05-07

Using a cation-selective gramicidin A channel as a sensor of the membrane surface charge, we studied interactions of oligoarginine peptide R9C, a prototype cationic cell-penetrating peptide (CPP), with planar lipid membranes. We have found that R9C sorption to the membrane depends strongly on its lipid composition from virtually nonexistent for membranes made of uncharged lipids to very pronounced for membranes containing negatively charged lipids, with charge overcompensation at R9C concentrations exceeding 1 μM. The sorption was reversible as it was removed by addition of polyanionic dextran sulfate to the membrane bathing solution. No membrane poration activity of R9C (as would be manifested by increased bilayer conductance) was detected in the charged or neutral membranes, including those with asymmetric negative/neutral and negative/positive lipid leaflets. We conclude that interaction of R9C with planar lipid bilayers does not involve pore formation in all studied lipid combinations up to 20 μM peptide concentration. However, R9C induces leakage of negatively charged but not neutral liposomes in a process that involves lipid mixing between liposomes. Our findings suggest that direct traversing of CPPs through the uncharged outer leaflet of the plasma membrane bilayer is unlikely and that permeabilization necessarily involves both anionic lipids and CPP-dependent fusion between opposing membranes. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The Phospholipid:Diacylglycerol Acyltransferase Lro1 Is Responsible for Hepatitis C Virus Core-Induced Lipid Droplet Formation in a Yeast Model System

PubMed Central

Wang, Chao-Wen; Cheng, Yun-Hsin; Irokawa, Hayato; Hwang, Gi-Wook; Naganuma, Akira; Kuge, Shusuke

2016-01-01

Chronic infection with the hepatitis C virus frequently induces steatosis, which is a significant risk factor for liver pathogenesis. Steatosis is characterized by the accumulation of lipid droplets in hepatocytes. The structural protein core of the virus induces lipid droplet formation and localizes on the surface of the lipid droplets. However, the precise molecular mechanisms for the core-induced formation of lipid droplets remain elusive. Recently, we showed that the expression of the core protein in yeast as a model system could induce lipid droplet formation. In this study, we probed the cellular factors responsible for the formation of core-induced lipid-droplets in yeast cells. We demonstrated that one of the enzymes responsible for triglyceride synthesis, a phospholipid:diacylglycerol acyltransferase (Lro1), is required for the core-induced lipid droplet formation. While core proteins inhibit Lro1 degradation and alter Lro1 localization, the characteristic localization of Lro1 adjacent to the lipid droplets appeared to be responsible for the core-induced lipid droplet formation. RNA virus genomes have evolved using high mutation rates to maintain their ability to replicate. Our observations suggest a functional relationship between the core protein with hepatocytes and yeast cells. The possible interactions between core proteins and the endoplasmic reticulum membrane affect the mobilization of specific proteins. PMID:27459103

Acidic fibroblast growth factor (FGF) but not basic FGF induces sleep and fever in rabbits.

PubMed

Knefati, M; Somogyi, C; Kapás, L; Bourcier, T; Krueger, J M

1995-07-01

Acidic fibroblast growth factor (FGF) and basic FGF belong to a growth factor family. Interleukin-1, another member of that family, is involved in sleep regulation. FGFs and interleukin-1 share structural and functional features. We therefore determined whether acidic FGF and basic FGF were somnogenic. Male New Zealand White rabbits were provided with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular (icv) cannula. The animals were injected icv with isotonic NaCl (control) and on separate days with one of three doses of acidic or basic FGF (0.01, 0.1, or 1.0 micrograms) or with heat-treated acidic FGF (1.0 micrograms). The EEG, brain temperature, and motor activity were recorded for 23 h. The biological activity of basic FGF was determined in vitro by its ability to induce DNA synthesis in rat aortic smooth muscle cells. Acidic FGF induced prolonged dose-related increases in non-rapid eye movement sleep beginning in the 1st postinjection h and continuing for 12-23 h after the treatment. Acidic FGF also induced fevers of approximately 1 degree C after the 1.0 micrograms dose. Both activities of acidic FGF were lost after heat treatment. In contrast, basic FGF lacked somnogenic and pyrogenic activity, although it did induce DNA synthesis. Current results suggest that acidic FGF is part of the complex cytokine network in brain involved in sleep regulation.

Transcriptional program for nitrogen starvation-induced lipid accumulation in Chlamydomonas reinhardtii

DOE PAGES

Garcia de Lomana, Adrian Lopez; Schäuble, Sascha; Valenzuela, Jacob; ...

2015-12-02

Algae accumulate lipids to endure different kinds of environmental stresses including macronutrient starvation. Although this response has been extensively studied, an in depth understanding of the transcriptional regulatory network (TRN) that controls the transition into lipid accumulation remains elusive. In this study, we used a systems biology approach to elucidate the transcriptional program that coordinates the nitrogen starvation-induced metabolic readjustments that drive lipid accumulation in Chlamydomonas reinhardtii. We demonstrate that nitrogen starvation triggered differential regulation of 2147 transcripts, which were co-regulated in 215 distinct modules and temporally ordered as 31 transcriptional waves. An early-stage response was triggered within 12 minmore » that initiated growth arrest through activation of key signaling pathways, while simultaneously preparing the intracellular environment for later stages by modulating transport processes and ubiquitin-mediated protein degradation. Subsequently, central metabolism and carbon fixation were remodeled to trigger the accumulation of triacylglycerols. Further analysis revealed that these waves of genome-wide transcriptional events were coordinated by a regulatory program orchestrated by at least 17 transcriptional regulators, many of which had not been previously implicated in this process. We demonstrate that the TRN coordinates transcriptional downregulation of 57 metabolic enzymes across a period of nearly 4 h to drive an increase in lipid content per unit biomass. Notably, this TRN appears to also drive lipid accumulation during sulfur starvation, while phosphorus starvation induces a different regulatory program. The TRN model described here is available as a community-wide web-resource at http://networks.systemsbiology.net/chlamy-portal. In conclusion, in this work, we have uncovered a comprehensive mechanistic model of the TRN controlling the transition from N starvation to lipid

Transcriptional program for nitrogen starvation-induced lipid accumulation in Chlamydomonas reinhardtii

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garcia de Lomana, Adrian Lopez; Schäuble, Sascha; Valenzuela, Jacob

Algae accumulate lipids to endure different kinds of environmental stresses including macronutrient starvation. Although this response has been extensively studied, an in depth understanding of the transcriptional regulatory network (TRN) that controls the transition into lipid accumulation remains elusive. In this study, we used a systems biology approach to elucidate the transcriptional program that coordinates the nitrogen starvation-induced metabolic readjustments that drive lipid accumulation in Chlamydomonas reinhardtii. We demonstrate that nitrogen starvation triggered differential regulation of 2147 transcripts, which were co-regulated in 215 distinct modules and temporally ordered as 31 transcriptional waves. An early-stage response was triggered within 12 minmore » that initiated growth arrest through activation of key signaling pathways, while simultaneously preparing the intracellular environment for later stages by modulating transport processes and ubiquitin-mediated protein degradation. Subsequently, central metabolism and carbon fixation were remodeled to trigger the accumulation of triacylglycerols. Further analysis revealed that these waves of genome-wide transcriptional events were coordinated by a regulatory program orchestrated by at least 17 transcriptional regulators, many of which had not been previously implicated in this process. We demonstrate that the TRN coordinates transcriptional downregulation of 57 metabolic enzymes across a period of nearly 4 h to drive an increase in lipid content per unit biomass. Notably, this TRN appears to also drive lipid accumulation during sulfur starvation, while phosphorus starvation induces a different regulatory program. The TRN model described here is available as a community-wide web-resource at http://networks.systemsbiology.net/chlamy-portal. In conclusion, in this work, we have uncovered a comprehensive mechanistic model of the TRN controlling the transition from N starvation to lipid

The role of omega-3 on modulation of cognitive deficiency induced by REM sleep deprivation in rats.

PubMed

Nasehi, Mohammad; Nezhad, Seyed Moslem Mousavi; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza

2018-06-02

Prolonged sleep deprivation causes cognitive deficits. In rats, for instance, sleep deprivation weakens spatial learning and long-term potentiation (LTP). We examined the effects of omega-3 on cognitive deficiency induced by REM sleep deprivation (RSD). For this purpose, we used a fear conditioning paradigm, forced swim test (FST) apparatus, and hot plate test. Intravenously omega-3 injection was performed during 3 consecutive days. Rats trained in the fear conditioning apparatus after 24 hours. During conditioning, animals were received foot shocks, either alone or paired with a sound. Sleep deprivation paradigm was carried out in which REM sleep was completely prevented and non-REM sleep was intensely declined for 24 hours. Then, context-dependent retention, anxiety behaviors, and hot plate tests were done. Auditory-dependent retention, anxiety behaviors, and FST were carried out 24 hours later. 24 hours of RSD impaired cognitive function, however intravenously administration of omega-3 improved (0.25, 0.5 and 1 mg/kg) context- or auditory-dependent memory, induced anxiolytic (1 mg/kg), antidepressant (1.25 mg/kg), and anti-nociceptive (0.25 mg/kg) effects. The results revealed that RSD interferes with the neural systems underlying cognitive functions and supports the involvement of omega-3 in the modulation of cognitive functions. Copyright © 2018. Published by Elsevier B.V.

Oleamide derivatives are prototypical anti-metastasis drugs that act by inhibiting Connexin 26.

PubMed

Nojima, Hiroshi; Ohba, Yusuke; Kita, Yasuyuki

2007-09-01

Despite considerable research, metastasis remains a major challenge in the clinical management of cancer. Recent reports show that abnormally augmented expression of Cx26 is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells. The function of Cx26 appears to be responsible for this phenotype since exogenous expression of a dominant-negative form of Cx26 and oleamide derivatives called MI-18 and MI-22 that specifically inhibit Cx26-mediated gap junction-mediated intercellular communications (GJIC) prevent the spontaneous metastasis of BL6 cells. As expected from their structural similarity to oleic acid (the major component of olive oil), both MI-18 and MI-22 are safe drugs; nonetheless, they are potent inhibitors of the spontaneous metastasis of BL6 mouse melanoma cells. Thus, they are a novel prototype of an anti-metastasis drug that has minimal side effects. While the primary tumors do not necessarily show strong Cx26-immunostaining signals, pronounced Cx26 expression is detected in the highly invasive tumor regions; it is also more frequently observed in metastasized tumors. Thus, Cx26 expression may be useful as a prognostic tool that can predict the existence of highly metastatic cancer cells in clinical samples.

Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats.

PubMed

Everson, Carol A; Henchen, Christopher J; Szabo, Aniko; Hogg, Neil

2014-12-01

Increased cell injury would provide the type of change in constitution that would underlie sleep disruption as a risk factor for multiple diseases. The current study was undertaken to investigate cell injury and altered cell fate as consequences of sleep deprivation, which were predicted from systemic clues. Partial (35% sleep reduction) and total sleep deprivation were produced in rats for 10 days, which was tolerated and without overtly deteriorated health. Recovery rats were similarly sleep deprived for 10 days, then allowed undisturbed sleep for 2 days. The plasma, liver, lung, intestine, heart, and spleen were analyzed and compared to control values for damage to DNA, proteins, and lipids; apoptotic cell signaling and death; cell proliferation; and concentrations of glutathione peroxidase and catalase. Oxidative DNA damage in totally sleep deprived rats was 139% of control values, with organ-specific effects in the liver (247%), lung (166%), and small intestine (145%). Overall and organ-specific DNA damage was also increased in partially sleep deprived rats. In the intestinal epithelium, total sleep deprivation resulted in 5.3-fold increases in dying cells and 1.5-fold increases in proliferating cells, compared with control. Recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage. These findings provide physical evidence that sleep loss causes cell damage, and in a manner expected to predispose to replication errors and metabolic abnormalities; thereby providing linkage between sleep loss and disease risk observed in epidemiological findings. Properties of recovery sleep include biochemical and molecular events that restore balance and decrease cell injury. © 2014 Associated Professional Sleep Societies, LLC.

Cell Injury and Repair Resulting from Sleep Loss and Sleep Recovery in Laboratory Rats

PubMed Central

Everson, Carol A.; Henchen, Christopher J.; Szabo, Aniko; Hogg, Neil

2014-01-01

Study Objectives: Increased cell injury would provide the type of change in constitution that would underlie sleep disruption as a risk factor for multiple diseases. The current study was undertaken to investigate cell injury and altered cell fate as consequences of sleep deprivation, which were predicted from systemic clues. Design: Partial (35% sleep reduction) and total sleep deprivation were produced in rats for 10 days, which was tolerated and without overtly deteriorated health. Recovery rats were similarly sleep deprived for 10 days, then allowed undisturbed sleep for 2 days. The plasma, liver, lung, intestine, heart, and spleen were analyzed and compared to control values for damage to DNA, proteins, and lipids; apoptotic cell signaling and death; cell proliferation; and concentrations of glutathione peroxidase and catalase. Measurements and Results: Oxidative DNA damage in totally sleep deprived rats was 139% of control values, with organ-specific effects in the liver (247%), lung (166%), and small intestine (145%). Overall and organ-specific DNA damage was also increased in partially sleep deprived rats. In the intestinal epithelium, total sleep deprivation resulted in 5.3-fold increases in dying cells and 1.5-fold increases in proliferating cells, compared with control. Two days of recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage. Conclusions: These findings provide physical evidence that sleep loss causes cell damage, and in a manner expected to predispose to replication errors and metabolic abnormalities; thereby providing linkage between sleep loss and disease risk observed in epidemiological findings. Properties of recovery sleep include biochemical and molecular events that restore balance and decrease cell injury. Citation: Everson CA, Henchen CJ, Szabo A, Hogg N. Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats

In Search of a Safe Natural Sleep Aid.

PubMed

Rao, Theertham P; Ozeki, Motoko; Juneja, Lekh R

2015-01-01

Sleep deprivation is associated with an elevated risk of various diseases and leads to a poor quality of life and negative socioeconomic consequences. Sleep inducers such as drugs and herbal medicines may often lead to dependence and other side effects. L-Theanine (γ-glutamylethylamide), an amino acid naturally found abundant in tea leaves, has anxiolytic effects via the induction of α brain waves without additive and other side effects associated with conventional sleep inducers. Anxiolysis is required for the initiation of high-quality sleep. In this study, we review the mechanism(s), safety, and efficacy of L-theanine. Collectively, sleep studies based on an actigraph, the obstructive sleep apnea (OSA) sleep inventory questionnaire, wakeup after sleep onset (WASO) and automatic nervous system (ANS) assessment, sympathetic and parasympathetic nerve activities, and a pediatric sleep questionnaire (PSQ) suggest that the administration of 200 mg of L-theanine before bed may support improved sleep quality not by sedation but through anxiolysis. Because L-theanine does not induce daytime drowsiness, it may be useful at any time of the day. The no observable adverse effect level (NOAEL) for the oral administration of L-theanine was determined to be above 2000 mg/kg bw/day. KEY TEACHING POINTS: Sleep deprivation-associated morbidity is an increasing public health concern posing a substantial socioeconomic burden. Chronic sleep disorders may seriously affect quality of life and may be etiological factors in a number of chronic diseases such as depression, obesity, diabetes, and cardiovascular diseases. Most sleep inducers are sedatives and are often associated with addiction and other side effects. L-Theanine promotes relaxation without drowsiness. Unlike conventional sleep inducers, L-theanine is not a sedative but promotes good quality of sleep through anxiolysis. This review suggests that L-theanine is a safe natural sleep aid.

The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans.

PubMed

Iannacone, Michael J; Beets, Isabel; Lopes, Lindsey E; Churgin, Matthew A; Fang-Yen, Christopher; Nelson, Matthew D; Schoofs, Liliane; Raizen, David M

2017-01-17

In response to environments that cause cellular stress, animals engage in sleep behavior that facilitates recovery from the stress. In Caenorhabditis elegans , stress-induced sleep(SIS) is regulated by cytokine activation of the ALA neuron, which releases FLP-13 neuropeptides characterized by an amidated arginine-phenylalanine (RFamide) C-terminus motif. By performing an unbiased genetic screen for mutants that impair the somnogenic effects of FLP-13 neuropeptides, we identified the gene dmsr-1 , which encodes a G-protein coupled receptor similar to an insect RFamide receptor. DMSR-1 is activated by FLP-13 peptides in cell culture, is required for SIS in vivo , is expressed non-synaptically in several wake-promoting neurons, and likely couples to a Gi/o heterotrimeric G-protein. Our data expand our understanding of how a single neuroendocrine cell coordinates an organism-wide behavioral response, and suggest that similar signaling principles may function in other organisms to regulate sleep during sickness.

Propofol inhibits gap junctions by attenuating sevoflurane-induced cytotoxicity against rat liver cells in vitro.

PubMed

Huang, Fei; Li, Shangrong; Gan, Xiaoliang; Wang, Ren; Chen, Zhonggang

2014-04-01

Liver abnormalities are seen in a small proportion of patients following anaesthesia with sevoflurane. To investigate whether the cytotoxicity of sevoflurane against rat liver cells was mediated by gap junction intercellular communications, and the effect of propofol on sevoflurane-induced cytotoxicity. Experimental study. The study was carried out in the central laboratory of The Third Affiliated Hospital, Sun Yat-sen University. BRL-3A rat liver cells. Immortal rat liver cells BRL-3A were grown at low and high density. Colony-forming assays were performed to determine clonogenic growth of these cells. To investigate the effect of oleamide and propofol on gap junction function, we measured fluorescence transmission between cells using parachute dye-coupling assays. Immunoblotting assays were performed to determine connexin32 and connexin43 expression. Our colony formation assays revealed that, in low-density culture, sevoflurane caused no apparent inhibition of clonogenic growth of BRL-3A cells. In high-density culture, 2.2 to 4.4% sevoflurane markedly inhibited clonogenic growth of BRL-3A cells with 67.6 (0.34)% and 61.2 (0.17)% of the cells being viable, respectively (P = 0.003 vs. low-density culture), suggesting cell density dependency of sevoflurane-induced cytotoxicity. Our colony formation assays revealed that propofol markedly attenuated the suppression by sevoflurane of the clonogenic growth of BRL-3A cells (viability: propofol and sevoflurane, 91.5 (0.014)% vs. sevoflurane, 56.6 (0.019)%; P <0.01). Blocking gap junctions with 10 μmol l oleamide significantly attenuated 4.4% sevoflurane-induced suppression with a viability of 83.6 ± 0.138% (oleamide and sevoflurane vs. sevoflurane, P < 0.01). Immunoblotting assays further showed that propofol (3.2 μg ml) markedly reduced CX32 levels and significantly inhibited gap junctional intercellular communications as revealed by parachute dye-coupling assays. Values are mean (SD). This study

Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

PubMed Central

Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

2007-01-01

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048

Effects of Macrophage Depletion on Sleep in Mice

PubMed Central

Ames, Conner; Boland, Erin; Szentirmai, Éva

2016-01-01

The reciprocal interaction between the immune system and sleep regulation has been widely acknowledged but the cellular mechanisms that underpin this interaction are not completely understood. In the present study, we investigated the role of macrophages in sleep loss- and cold exposure-induced sleep and body temperature responses. Macrophage apoptosis was induced in mice by systemic injection of clodronate-containing liposomes (CCL). We report that CCL treatment induced an immediate and transient increase in non-rapid-eye movement sleep (NREMS) and fever accompanied by decrease in rapid-eye movement sleep, motor activity and NREMS delta power. Chronically macrophage-depleted mice had attenuated NREMS rebound after sleep deprivation compared to normal mice. Cold-induced increase in wakefulness and decrease in NREMS, rapid-eye movement sleep and body temperature were significantly enhanced in macrophage-depleted mice indicating increased cold sensitivity. These findings provide further evidence for the reciprocal interaction among the immune system, sleep and metabolism, and identify macrophages as one of the key cellular elements in this interplay. PMID:27442442

Protein-Tyrosine Phosphatase-1B Mediates Sleep Fragmentation-Induced Insulin Resistance and Visceral Adipose Tissue Inflammation in Mice.

PubMed

Gozal, David; Khalyfa, Abdelnaby; Qiao, Zhuanghong; Akbarpour, Mahzad; Maccari, Rosanna; Ottanà, Rosaria

2017-09-01

Sleep fragmentation (SF) is highly prevalent and has emerged as an important contributing factor to obesity and metabolic syndrome. We hypothesized that SF-induced increases in protein tyrosine phosphatase-1B (PTP-1B) expression and activity underlie increased food intake, inflammation, and leptin and insulin resistance. Wild-type (WT) and ObR-PTP-1b-/- mice (Tg) were exposed to SF and control sleep (SC), and food intake was monitored. WT mice received a PTP-1B inhibitor (RO-7d; Tx) or vehicle (Veh). Upon completion of exposures, systemic insulin and leptin sensitivity tests were performed as well as assessment of visceral white adipose tissue (vWAT) insulin receptor sensitivity and macrophages (ATM) polarity. SF increased food intake in either untreated or Veh-treated WT mice. Leptin-induced hypothalamic STAT3 phosphorylation was decreased, PTP-1B activity was increased, and reduced insulin sensitivity emerged both systemic and in vWAT, with the latter displaying proinflammatory ATM polarity changes. All of the SF-induced effects were abrogated following PTP-1B inhibitor treatment and in Tg mice. SF induces increased food intake, reduced leptin signaling in hypothalamus, systemic insulin resistance, and reduced vWAT insulin sensitivity and inflammation that are mediated by increased PTP-1B activity. Thus, PTP-1B may represent a viable therapeutic target in the context of SF-induced weight gain and metabolic dysfunction. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Involvement of lipid rafts in adhesion-induced activation of Met and EGFR.

PubMed

Lu, Ying-Che; Chen, Hong-Chen

2011-10-27

Cell adhesion has been shown to induce activation of certain growth factor receptors in a ligand-independent manner. However, the mechanism for such activation remains obscure. Human epidermal carcinoma A431 cells were used as a model to examine the mechanism for adhesion-induced activation of hepatocyte growth factor receptor Met and epidermal growth factor receptor (EGFR). The cells were suspended and replated on culture dishes under various conditions. The phosphorylation of Met at Y1234/1235 and EGFR at Y1173 were used as indicators for their activation. The distribution of the receptors and lipid rafts on the plasma membrane were visualized by confocal fluorescent microscopy and total internal reflection microscopy. We demonstrate that Met and EGFR are constitutively activated in A431 cells, which confers proliferative and invasive potentials to the cells. The ligand-independent activation of Met and EGFR in A431 cells relies on cell adhesion to a substratum, but is independent of cell spreading, extracellular matrix proteins, and substratum stiffness. This adhesion-induced activation of Met and EGFR cannot be attributed to Src activation, production of reactive oxygen species, and the integrity of the cytoskeleton. In addition, we demonstrate that Met and EGFR are independently activated upon cell adhesion. However, partial depletion of Met and EGFR prevents their activation upon cell adhesion, suggesting that overexpression of the receptors is a prerequisite for their self-activation upon cell adhesion. Although Met and EGFR are largely distributed in 0.04% Triton-insoluble fractions (i.e. raft fraction), their activated forms are detected mainly in 0.04% Triton-soluble fractions (i.e. non-raft fraction). Upon cell adhesion, lipid rafts are accumulated at the cell surface close to the cell-substratum interface, while Met and EGFR are mostly excluded from the membrane enriched by lipid rafts. Our results suggest for the first time that cell adhesion to a

Sleep Habits and Sleep Problems in Healthy Preschoolers.

PubMed

Murthy, C L Srinivasa; Bharti, Bhavneet; Malhi, Prahbhjot; Khadwal, Alka

2015-07-01

To describe the sleep patterns and problems in children aged between 12 and 36 mo of age. This cross sectional survey was collected over a span of 1 y in Advanced Pediatric Centre, PGIMER, Chandigarh and crèches of Chandigarh. Children in the age group of 12 to 36 mo were included in study. Children with chronic illness, developmental delay, seizure disorder and lack of consent were excluded. A total of 368 children were enrolled. Main outcome measures were sleep duration over 1 to 3 y of life; sleep behavior at onset, during and waking of sleep and parent reported sleep problems and their predictors. The average duration of sleep was 12.5 h (S.D = 1.9). The mean total sleep duration and mean day time sleep duration decreased, while mean night time sleep increased as the age advanced from 12 to 36 mo. Following were the frequency of sleep habits seen in the index study; bed time routine was seen only in 68(18.5 %), a regular bed time ritual was seen in 281(76.4 %), 329(89.4 %) children frequently required 0-20 min time to fall asleep, 11(3 %) parents used sleep inducing drugs. Night waking (1 to 3 times a night) was seen in 297(80.7 %) and its frequency declined with age. Parent reported sleep problems were seen in 12.8 % (47/368). Lack of co-sleeping and night waking were considered as strongest predictors of parent reported sleep problems. Toddlers' sleep duration, night waking behavior, and day time naps decrease as the age progress while night time sleep duration increases with age. Lack of co-sleeping and night waking are considered as strongest predictors of parent reported sleep problems.

Zolpidem-Induced Sleepwalking, Sleep Related Eating Disorder, and Sleep-Driving: Fluorine-18-Flourodeoxyglucose Positron Emission Tomography Analysis, and a Literature Review of Other Unexpected Clinical Effects of Zolpidem

PubMed Central

Hoque, Romy; Chesson, Andrew L.

2009-01-01

Zolpidem is a hypnotic which acts at the GABAA receptor and is indicated for short-term insomnia. Sleep related disorders including somnambulism, sleep related eating and sleep-driving have been reported with zolpidem. A 51-year-old insomniac who used zolpidem 10 mg nightly starting at 44 years of age is described. A few weeks after starting zolpidem she began walking, eating, and had one episode of driving while asleep. Episodes of sleep related eating, sleepwalking, and sleeptalking occurred 3 nights per week, 1 to 2 h after sleep onset. After her evaluation, the patient's zolpidem was gradually discontinued, and all sleep related activities immediately ceased. An 18F-FDG-PET was obtained 2 months after discontinuation of zolpidem. The following day, FDG was administered 1 h after oral administration of 10 mg zolpidem, and then a second PET was performed. We report the results and a review of the literature regarding other unintended effects seen with zolpidem use. Citation: Hoque R; Chesson AL. Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem. J Clin Sleep Med 2009;5(5):471-476 PMID:19961034

A new model to study sleep deprivation-induced seizure.

PubMed

Lucey, Brendan P; Leahy, Averi; Rosas, Regine; Shaw, Paul J

2015-05-01

A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB(9ed4)), and in an adult temperature sensitive seizure mutant seizure (sei(ts1)) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB(9ed4) flies was also assessed. Laboratory. Drosophila melanogaster. Sleep deprivation. Sleep deprivation increased seizure susceptibility in adult sesB(9ed4)/+ and sei(ts1) mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB(9ed4)/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB(9ed4)/+ became adults. These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. © 2015 Associated Professional Sleep Societies, LLC.

Analysis of constant tension-induced rupture of lipid membranes using activation energy.

PubMed

Karal, Mohammad Abu Sayem; Levadnyy, Victor; Yamazaki, Masahito

2016-05-11

The stretching of biomembranes and lipid membranes plays important roles in various physiological and physicochemical phenomena. Here we analyzed the rate constant kp of constant tension-induced rupture of giant unilamellar vesicles (GUVs) as a function of tension σ using their activation energy Ua. To determine the values of kp, we applied constant tension to a GUV membrane using the micropipette aspiration method and observed the rupture of GUVs, and then analyzed these data statistically. First, we investigated the temperature dependence of kp for GUVs of charged lipid membranes composed of negatively charged dioleoylphosphatidylglycerol (DOPG) and electrically neutral dioleoylphosphatidylcholine (DOPC). By analyzing this result, the values of Ua of tension-induced rupture of DOPG/DOPC-GUVs were obtained. Ua decreased with an increase in σ, supporting the classical theory of tension-induced pore formation. The analysis of the relationship between Ua and σ using the theory on the electrostatic interaction effects on the tension-induced rupture of GUVs provided the equation of Ua including electrostatic interaction effects, which well fits the experimental data of the tension dependence of Ua. A constant which does not depend on tension, U0, was also found to contribute significantly to Ua. The Arrhenius equations for kp using the equation of Ua and the parameters determined by the above analysis fit well to the experimental data of the tension dependence of kp for DOPG/DOPC-GUVs as well as for DOPC-GUVs. On the basis of these results, we discussed the possible elementary processes underlying the tension-induced rupture of GUVs of lipid membranes. These results indicate that the Arrhenius equation using the experimentally determined Ua is useful in the analysis of tension-induced rupture of GUVs.

Information processing during sleep and stress-related sleep vulnerability.

PubMed

Lin, Yen-Hsuan; Jen, Chun-Hui; Yang, Chien-Ming

2015-02-01

Previous studies showed enhanced attention and decreased inhibitory processes during early non-rapid eye movement sleep in primary insomnia patients, as measured by event-related potentials. The current study aims to examine information processing during sleep in non-insomniac individuals with high vulnerability (HV) to stress-related sleep disturbances. Twenty-seven non-insomniac individuals were recruited, 14 with low vulnerability and 13 with HV. After passing a screening interview and polysomnographic recording, subjects came to the sleep laboratory for 2 nights (a baseline night and a stress-inducing night) for event-related potentials recordings. The HV group demonstrated shorter P2 latency during the first 5 min of stage 2 sleep and higher P900 amplitudes under the stress condition during slow-wave sleep, which indicates an increased level of inhibitory processes. In addition, they had shorter N1 latencies during slow-wave sleep that could indicate an elevated level of attention processing during deep sleep. Unlike patients with chronic insomnia, individuals with high sleep vulnerability to stress show a compensatory process that may prevent external stimulation from interfering with their sleep. This may be one of the factors preventing their acute sleep disturbances from becoming chronic problems. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Betaine attenuates chronic alcohol‑induced fatty liver by broadly regulating hepatic lipid metabolism.

PubMed

Yang, Wenjuan; Huang, Luming; Gao, Jinhang; Wen, Shilei; Tai, Yang; Chen, Meng; Huang, Zhiyin; Liu, Rui; Tang, Chengwei; Li, Jing

2017-10-01

Betaine has previously been demonstrated to protect the liver against alcohol‑induced fat accumulation. However, the mechanism through which betaine affects alcohol‑induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)‑α levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)‑1c, SREBP‑2, fatty acid synthase (FAS), 3‑hydroxy‑3‑methyl‑glutaryl (HMG)‑CoA reductase, peroxisome proliferator-activated receptor λ coactivator (PGC)‑1α, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme‑linked immunoassay. The results demonstrated that alcohol‑induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP‑1c, SREBP‑2, FAS and HMG‑CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol‑induced decreases in hepatic PGC‑1α mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF‑α, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that

The state of the art of predicting noise-induced sleep disturbance in field settings.

PubMed

Fidell, Sanford; Tabachnick, Barbara; Pearsons, Karl S

2010-01-01

Several relationships between intruding noises (largely aircraft) and sleep disturbance have been inferred from the findings of a handful of field studies. Comparisons of sleep disturbance rates predicted by the various relationships are complicated by inconsistent data collection methods and definitions of predictor variables and predicted quantities. None of the relationships is grounded in theory-based understanding, and some depend on questionable statistical assumptions and analysis procedures. The credibility, generalizability, and utility of sleep disturbance predictions are also limited by small and nonrepresentative samples of test participants, and by restricted (airport-specific and relatively short duration) circumstances of exposure. Although expedient relationships may be the best available, their predictions are of only limited utility for policy analysis and regulatory purposes, because they account for very little variance in the association between environmental noise and sleep disturbance, have characteristically shallow slopes, have not been well validated in field settings, are highly context-dependent, and do not squarely address the roles and relative importance of nonacoustic factors in sleep disturbance. Such relationships offer the appearance more than the substance of precision and objectivity. Truly useful, population-level prediction and genuine understanding of noise-induced sleep disturbance will remain beyond reach for the foreseeable future, until the findings of field studies of broader scope and more sophisticated design become available.

C-fos expression in the pons and medulla of the cat during carbachol-induced active sleep.

PubMed

Yamuy, J; Mancillas, J R; Morales, F R; Chase, M H

1993-06-01

Microinjection of carbachol into the rostral pontine tegmentum of the cat induces a state that is comparable to naturally occurring active (REM, rapid eye movement) sleep. We sought to determine, during this pharmacologically induced behavioral state, which we refer to as active sleep-carbachol, the distribution of activated neuron within the pons and medulla using c-fos immunocytochemistry as a functional marker. Compared with control cats, which were injected with saline, active sleep-carbachol cats exhibited higher numbers of c-fos-expressing neurons in (1) the medial and portions of the lateral reticular formation of the pons and medulla, (2) nuclei in the dorsolateral rostral pons, (3) various raphe nuclei, including the dorsal, central superior, magnus, pallidus, and obscurus, (4) the medial and lateral vestibular, prepositus hypoglossi, and intercalatus nuclei, and (5) the abducens nuclei. On the other hand, the mean number of c-fos-expressing neurons found in the masseter, facial, and hypoglossal nuclei was lower in carbachol-injected than in control cats. The data indicate that c-fos expression can be employed as a marker of state-dependent neuronal activity. The specific sites in which there were greater numbers of c-fos-expressing neurons during active sleep-carbachol are discussed in relation to the state of active sleep, as well as the functional role that these sites play in generating the various physiological patterns of activity that occur during this state.

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.

PubMed

Holland, William L; Bikman, Benjamin T; Wang, Li-Ping; Yuguang, Guan; Sargent, Katherine M; Bulchand, Sarada; Knotts, Trina A; Shui, Guanghou; Clegg, Deborah J; Wenk, Markus R; Pagliassotti, Michael J; Scherer, Philipp E; Summers, Scott A

2011-05-01

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

PubMed Central

Holland, William L.; Bikman, Benjamin T.; Wang, Li-Ping; Yuguang, Guan; Sargent, Katherine M.; Bulchand, Sarada; Knotts, Trina A.; Shui, Guanghou; Clegg, Deborah J.; Wenk, Markus R.; Pagliassotti, Michael J.; Scherer, Philipp E.; Summers, Scott A.

2011-01-01

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid–induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes. PMID:21490391

[Lipid changes of fibrinogen and of platelet aggregation induced by etofibrate].

PubMed

Fonseca, F A; Novazzi, J P; Cendoroglo, M S; Duarte, M; Almeida Pinto, L E; Rabelo, L M; da Rocha Martinez, T L

1996-01-01

To evaluate modifications on lipid profile, fibrinogen and platelet aggregation induced by etofibrate. Twenty-one adult patients were studied. They all had primary hyperlipidemia and had already been on the AHA step I diet and placebo. Etofibrate (500mg/day) was administered for 60 days in the active phase, when lipid parameters, fibrinogen and platelet aggregation were measured. The % significant reductions were: total cholesterol (-9.50%), LDL-cholesterol (-7.88%), triglycerides (-19.07%), total cholesterol/HDL-cholesterol(-11.90%), LDL-cholesterol/HDL-cholesterol (-10.20%), fibrinogen (-12.79%), platelet aggregation with adrenaline (-24.02%), with ADP 1 mumol (-30.13%), and ADP 3 mumol (-24.51%). The beneficial effects of etofibrate were observed not only on the lipid profile but also on the thrombogenic parameters measured by fibrinogen and platelet aggregation.

BDNF in sleep, insomnia, and sleep deprivation.

PubMed

Schmitt, Karen; Holsboer-Trachsler, Edith; Eckert, Anne

2016-01-01

The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase. Key messages Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of stress-related mood disorders. The interplay of stress and sleep impacts on BDNF level. Partial sleep deprivation (PSD) shows a fast action on BDNF level increase.

Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain.

PubMed

Kim, Youngsoo; Elmenhorst, David; Weisshaupt, Angela; Wedekind, Franziska; Kroll, Tina; McCarley, Robert W; Strecker, Robert E; Bauer, Andreas

2015-10-01

Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26-31% from SR1 to R1). A decrease in β-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction. © 2015 European Sleep Research Society.

Precipitating factors of somnambulism: impact of sleep deprivation and forced arousals.

PubMed

Pilon, Mathieu; Montplaisir, Jacques; Zadra, Antonio

2008-06-10

Experimental attempts to induce sleepwalking with forced arousals during slow-wave sleep (SWS) have yielded mixed results in children and have not been investigated in adult patients. We hypothesized that the combination of sleep deprivation and external stimulation would increase the probability of inducing somnambulistic episodes in sleepwalkers recorded in the sleep laboratory. The main goal of this study was to assess the effects of forced arousals from auditory stimuli (AS) in adult sleepwalkers and control subjects during normal sleep and following post-sleep deprivation recovery sleep. Ten sleepwalkers and 10 controls were investigated. After a baseline night, participants were presented with AS at predetermined sleep stages either during normal sleep or recovery sleep following 25 hours of sleep deprivation. One week later, the conditions with AS were reversed. No somnambulistic episodes were induced in controls. When compared to the effects of AS during sleepwalkers' normal sleep, the presentation of AS during sleepwalkers' recovery sleep significantly increased their efficacy in experimentally inducing somnambulistic events and a significantly greater proportion of sleepwalkers (100%) experienced at least one induced episode during recovery SWS as compared to normal SWS (30%). There was no significant difference between the mean intensity of AS that induced episodes during sleepwalkers' SWS and the mean intensity of AS that awakened sleepwalkers and controls from SWS. Sleep deprivation and forced arousals during slow-wave sleep can induce somnambulistic episodes in predisposed adults. The results highlight the potential value of this protocol in establishing a video-polysomnographically based diagnosis for sleepwalking.

Short-Term Sleep Disturbance-Induced Stress Does not Affect Basal Pain Perception, but Does Delay Postsurgical Pain Recovery.

PubMed

Wang, Po-Kai; Cao, Jing; Wang, Hongzhen; Liang, Lingli; Zhang, Jun; Lutz, Brianna Marie; Shieh, Kun-Ruey; Bekker, Alex; Tao, Yuan-Xiang

2015-11-01

Chronic sleep disturbance-induced stress is known to increase basal pain sensitivity. However, most surgical patients frequently report short-term sleep disturbance/deprivation during the pre- and postoperation periods and have normal pain perception presurgery. Whether this short-term sleep disturbance affects postsurgical pain is elusive. Here, we report that pre- or postexposure to rapid eye movement sleep disturbance (REMSD) for 6 hours daily for 3 consecutive days did not alter basal responses to mechanical, heat, and cold stimuli, but did delay recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation and paw withdrawal latencies to heat and cold stimuli on the ipsilateral side of male or female rats. This short-term REMSD led to stress shown by an increase in swim immobility time, a decrease in sucrose consumption, and an increase in the level of corticosterone in serum. Blocking this stress via intrathecal RU38486 or bilateral adrenalectomy abolished REMSD-caused delay in recovery of incision-induced reductions in behavioral responses to mechanical, heat, and cold stimuli. Moreover, this short-term REMSD produced significant reductions in the levels of mu opioid receptor and kappa opioid receptor, but not Kv1.2, in the ipsilateral L4/5 spinal cord and dorsal root ganglia on day 9 after incision (but not after sham surgery). Our findings show that short-term sleep disturbance either pre- or postsurgery does not alter basal pain perception, but does exacerbate postsurgical pain hypersensitivity. The latter may be related to the reductions of mu and kappa opioid receptors in the spinal cord and dorsal root ganglia caused by REMSD plus incision. Prevention of short-term sleep disturbance may help recovery from postsurgical pain in patients. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Effects of Antidepressants on Sleep.

PubMed

Wichniak, Adam; Wierzbicka, Aleksandra; Walęcka, Małgorzata; Jernajczyk, Wojciech

2017-08-09

The aim of this review article was to summarize recent publications on effects of antidepressants on sleep and to show that these effects not only depend on the kind of antidepressant drugs but are also related to the dose, the time of drug administration, and the duration of the treatment. Complaints of disrupted sleep are very common in patients suffering from depression, and they are listed among diagnostic criteria for this disorder. Moreover, midnocturnal insomnia is the most frequent residual symptom of depression. Thus, all antidepressants should normalize sleep. However, at least in short-term treatment, many antidepressants with so-called activating effects (e.g. fluoxetine, venlafaxine) may disrupt sleep, while others with sedative properties (e.g., doxepin, mirtazapine, trazodone) rapidly improve sleep, but may cause problems in long-term treatment due to oversedation.For sleep-promoting action, the best effects can frequently be achieved with a very low dose, administered early enough before bedtime and importantly, always as a part of more complex interventions based on the cognitive-behavioral protocol to treat insomnia (CBT-I). For successful treatment of depression, it is necessary to understand the effects of antidepressants on sleep. Each physician should also be aware that some antidepressants may worsen or induce primary sleep disorders like restless legs syndrome, sleep bruxism, REM sleep behavior disorder, nightmares, and sleep apnea, which may result from an antidepressant-induced weight gain.

The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans

PubMed Central

Iannacone, Michael J; Beets, Isabel; Lopes, Lindsey E; Churgin, Matthew A; Fang-Yen, Christopher; Nelson, Matthew D; Schoofs, Liliane; Raizen, David M

2017-01-01

In response to environments that cause cellular stress, animals engage in sleep behavior that facilitates recovery from the stress. In Caenorhabditis elegans, stress-induced sleep(SIS) is regulated by cytokine activation of the ALA neuron, which releases FLP-13 neuropeptides characterized by an amidated arginine-phenylalanine (RFamide) C-terminus motif. By performing an unbiased genetic screen for mutants that impair the somnogenic effects of FLP-13 neuropeptides, we identified the gene dmsr-1, which encodes a G-protein coupled receptor similar to an insect RFamide receptor. DMSR-1 is activated by FLP-13 peptides in cell culture, is required for SIS in vivo, is expressed non-synaptically in several wake-promoting neurons, and likely couples to a Gi/o heterotrimeric G-protein. Our data expand our understanding of how a single neuroendocrine cell coordinates an organism-wide behavioral response, and suggest that similar signaling principles may function in other organisms to regulate sleep during sickness. DOI: http://dx.doi.org/10.7554/eLife.19837.001 PMID:28094002

Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

NASA Astrophysics Data System (ADS)

Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

2016-08-01

Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns.

Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

PubMed Central

Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

2016-01-01

Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns. PMID:27502578

Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis.

PubMed

Pérez-Baos, S; Barrasa, J I; Gratal, P; Larrañaga-Vera, A; Prieto-Potin, I; Herrero-Beaumont, G; Largo, R

2017-09-01

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation. CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg -1 ·day -1 ) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations and then stimulated with IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT. Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis. Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients. © 2017 The British Pharmacological Society.

Drug-induced sleep endoscopy with target-controlled infusion using propofol and monitored depth of sedation to determine treatment strategies in obstructive sleep apnea.

PubMed

Heiser, Clemens; Fthenakis, Phillippe; Hapfelmeier, Alexander; Berger, Sebastian; Hofauer, Benedikt; Hohenhorst, Winfried; Kochs, Eberhard F; Wagner, Klaus J; Edenharter, Guenther M

2017-09-01

Drug-induced sleep endoscopy (DISE) has become an important diagnostic examination tool in the treatment decision process for surgical therapies in the treatment of obstructive sleep apnea (OSA). Currently, there is a variety of regimes for the performance of DISE, which renders comparison and assessment across results difficult. It remains unclear how the different regimes influence the findings of the examination and the resulting conclusions and treatment recommendations. This study aimed to investigate the correlation between increasing levels of sedation (i.e., light, medium, and deep) induced by propofol using a target-controlled infusion (TCI) pump, with the obstruction patterns at the levels of the velum, oropharynx, tongue base, and epiglottis (i.e., VOTE classification). A second goal was the establishment of a sufficient sedation level to enable a reliable decision regarding treatment recommendations. Forty-three patients with OSA underwent a DISE procedure using propofol TCI. Three levels of sedation were defined, depending on entropy levels and assessment of sedation: light sedation, medium sedation, and deep sedation. The evaluation of the upper airway at each level, with increasing sedation, was documented using the VOTE classification. The elapsed time at which each assessment was performed was recorded. Upper airway changes occurred and were measured throughout the DISE procedure. Clinically useful determinations of airway closure occurred at medium sedation; this level of sedation was most probably achieved with a blood propofol concentration of 3.2 μg/ml. In all 43 patients, definite treatment decisions could be made at medium sedation level. Increasing sedation did not result in changes in the treatment decision. Changes in upper airway collapse during DISE with propofol TCI occur at levels of medium sedation. Decisions regarding surgical treatment could be made at this level of sedation. Upper Airway Collapse in Patients with Obstructive

Lipid Emulsion Inhibits Vasodilation Induced by a Toxic Dose of Bupivacaine via Attenuated Dephosphorylation of Myosin Phosphatase Target Subunit 1 in Isolated Rat Aorta

PubMed Central

Ok, Seong-Ho; Byon, Hyo-Jin; Kwon, Seong-Chun; Park, Jungchul; Lee, Youngju; Hwang, Yeran; Baik, Jiseok; Choi, Mun-Jeoung; Sohn, Ju-Tae

2015-01-01

Lipid emulsions are widely used for the treatment of systemic toxicity that arises from local anesthetics. The goal of this in vitro study was to examine the cellular mechanism associated with the lipid emulsion-mediated attenuation of vasodilation induced by a toxic dose of bupivacaine in isolated endothelium-denuded rat aorta. The effects of lipid emulsion on vasodilation induced by bupivacaine, mepivacaine, and verapamil were assessed in isolated aorta precontracted with phenylephrine, the Rho kinase stimulant NaF, and the protein kinase C activator phorbol 12,13-dibutyrate (PDBu). The effects of Rho kinase inhibitor Y-27632 on contraction induced by phenylephrine or NaF were assessed. The effects of bupivacaine on intracellular calcium concentrations ([Ca2+]i) and tension induced by NaF were simultaneously measured. The effects of bupivacaine alone and lipid emulsion plus bupivacaine on myosin phosphatase target subunit 1 (MYPT1) phosphorylation induced by NaF were examined in rat aortic vascular smooth muscle cells. In precontracted aorta, the lipid emulsion attenuated bupivacaine-induced vasodilation but had no effect on mepivacaine-induced vasodilation. Y-27632 attenuated contraction induced by either phenylephrine or NaF. The lipid emulsion attenuated verapamil-induced vasodilation. Compared with phenylephrine-induced precontracted aorta, bupivacaine-induced vasodilation was slightly attenuated in NaF-induced precontracted aorta. The magnitude of the bupivacaine-induced vasodilation was higher than that of a bupivacaine-induced decrease in [Ca2+]i. Bupivacaine attenuated NaF-induced MYPT1 phosphorylation, whereas lipid emulsion pretreatment attenuated the bupivacaine-induced inhibition of MYPT1 phosphorylation induced by NaF. Taken together, these results suggest that lipid emulsions attenuate bupivacaine-induced vasodilation via the attenuation of inhibition of MYPT1 phosphorylation evoked by NaF. PMID:26664257

Lipid peroxidation and cytotoxicity induced by respirable volcanic ash.

PubMed

Cervini-Silva, Javiera; Antonio-Nieto-Camacho; Gomez-Vidales, Virginia; Ramirez-Apan, María Teresa; Palacios, Eduardo; Montoya, Ascención; Kaufhold, Stephan; Abidin, Zeanal; Theng, Benny K G

2014-06-15

This paper reports that the main component of respirable volcanic ash, allophane, induces lipid peroxidation (LP), the oxidative degradation of lipids in cell membranes, and cytotoxicity in murin monocyle/macrophage cells. Naturally-occurring allophane collected from New Zealand, Japan, and Ecuador was studied. The quantification of LP was conducted using the Thiobarbituric Acid Reactive Substances (TBARS) assay. The cytotoxic effect was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide colorimetric assay. Electron-Paramagnetic Resonance (EPR) determinations of naturally-occurring allophane confirmed the incorporation in the structure and clustering of structural Fe(3+), and nucleation and growth of small-sized Fe (oxyhydr)oxide or gibbsite. LP induced by allophane varied with time, and solid concentration and composition, reaching 6.7 ± 0.2 nmol TBARS mg prot(-1). LP was surface controlled but not restricted by structural or surface-bound Fe(3+), because redox processes induced by soluble components other than perferryl iron. The reactivity of Fe(3+) soluble species stemming from surface-bound Fe(3+) or small-sized Fe(3+) refractory minerals in allophane surpassed that of structural Fe(3+) located in tetrahedral or octahedral sites of phyllosilicates or bulk iron oxides. Desferrioxamine B mesylate salt (DFOB) or ethylenediaminetetraacetic acid (EDTA) inhibited LP. EDTA acted as a more effective inhibitor, explained by multiple electron transfer pathways. Registered cell-viability values were as low as 68.5 ± 6.7%. Copyright © 2014 Elsevier B.V. All rights reserved.

Ameliorating reactive oxygen species-induced in vitro lipid peroxidation in brain, liver, mitochondria and DNA damage by Zingiber officinale Roscoe.

PubMed

Ajith, T A

2010-01-01

Iron is an essential nutrient for a number of cellular activities. However, excess cellular iron can be toxic by producing reactive oxygen species (ROS) such as superoxide anion (O(2) (-)) and hydroxyl radical (HO(·)) that damage proteins, lipids and DNA. Mutagenic and genotoxic end products of lipid peroxidation can induce the decline of mitochondrial respiration and are associated with various human ailments including aging, neurodegenerative disorders, cancer etc. Zingiber officinale Roscoe (ginger) is a widely used spice around the world. The protective effect of aqueous ethanol extract of Z. officinale against ROS-induced in vitro lipid peroxidation and DNA damage was evaluated in this study. The lipid peroxidation was induced by hydroxyl radical generated from Fenton's reaction in rat liver and brain homogenates and mitochondrial fraction (isolated from rat liver). The DNA protection was evaluated using H(2)O(2)-induced changes in pBR-322 plasmid and Fenton reaction-induced DNA fragmentation in rat liver. The results indicated that Z. officinale significantly (P<0.001) protected the lipid peroxidation in all the tissue homogenate/mitochondria. The extract at 2 and 0.5 mg/ml could protect 92 % of the lipid peroxidation in brain homogenate and liver mitochondria respectively. The percent inhibition of lipid peroxidation at 1mg/ml of Z. officinale in the liver homogenate was 94 %. However, the extract could partially alleviate the DNA damage. The protective mechanism can be correlated to the radical scavenging property of Z. officinale. The results of the study suggest the possible nutraceutical role of Z. officinale against the oxidative stress induced human ailments.

Sleep deprivation attenuates endotoxin-induced cytokine gene expression independent of day length and circulating cortisol in male Siberian hamsters (Phodopus sungorus).

PubMed

Ashley, Noah T; Walton, James C; Haim, Achikam; Zhang, Ning; Prince, Laura A; Fruchey, Allison M; Lieberman, Rebecca A; Weil, Zachary M; Magalang, Ulysses J; Nelson, Randy J

2013-07-15

Sleep is restorative, whereas reduced sleep leads to negative health outcomes, such as increased susceptibility to disease. Sleep deprivation tends to attenuate inflammatory responses triggered by infection or exposure to endotoxin, such as bacterial lipopolysaccharide (LPS). Previous studies have demonstrated that Siberian hamsters (Phodopus sungorus), photoperiodic rodents, attenuate LPS-induced fever, sickness behavior and upstream pro-inflammatory gene expression when adapted to short day lengths. Here, we tested whether manipulation of photoperiod alters the suppressive effects of sleep deprivation upon cytokine gene expression after LPS challenge. Male Siberian hamsters were adapted to long (16 h:8 h light:dark) or short (8 h:16 h light:dark) photoperiods for >10 weeks, and were deprived of sleep for 24 h using the multiple platform method or remained in their home cage. Hamsters received an intraperitoneal injection of LPS or saline (control) 18 h after starting the protocol, and were killed 6 h later. LPS increased liver and hypothalamic interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) gene expression compared with vehicle. Among LPS-challenged hamsters, sleep deprivation reduced IL-1 mRNA levels in liver and hypothalamus, but not TNF. IL-1 attenuation was independent of circulating baseline cortisol, which did not increase after sleep deprivation. Conversely, photoperiod altered baseline cortisol, but not pro-inflammatory gene expression in sleep-deprived hamsters. These results suggest that neither photoperiod nor glucocorticoids influence the suppressive effect of sleep deprivation upon LPS-induced inflammation.

Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats.

PubMed

Dworak, Markus; Kim, Tae; Mccarley, Robert W; Basheer, Radhika

2017-06-01

Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders. © 2017 European Sleep Research Society.

Short-term sleep disturbance-induced stress does not affect basal pain perception, but does delay postsurgical pain recovery

PubMed Central

Wang, Po-Kai; Cao, Jing; Wang, Hongzhen; Liang, Lingli; Zhang, Jun; Lutz, Brianna Marie; Shieh, Kun-Ruey; Bekker, Alex; Tao, Yuan-Xiang

2015-01-01

Chronic sleep disturbance-induced stress is known to increase basal pain sensitivity. However, most surgical patients frequently report short-term sleep disturbance/deprivation during pre- and post-operation periods and have normal pain perception pre-surgery. Whether this short-term sleep disturbance affects postsurgical pain is elusive. We here reported that pre- or post-exposure to rapid eye movement sleep disturbance (REMSD) 6 h daily for 3 consecutive days did not alter basal responses to mechanical, heat, and cold stimuli, but did delay recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation and paw withdrawal latencies to heat and cold stimuli on the ipsilateral side of male or female rats. This short-term REMSD led to stress evidenced by an increase in swim immobility time, a decrease in sucrose consumption, and an elevation in the level of corticosterone in serum. Blocking this stress via intrathecal RU38486 or bilateral adrenalectomy abolished REMSD-caused delay in recovery of incision-induced reductions in behavioral responses to mechanical, heat, and cold stimuli. Moreover, this short-term REMSD produced significant reductions in the levels of mu opioid receptor and kappa opioid receptor, but not Kv1.2, in the ipsilateral L4/5 spinal cord and dorsal root ganglia on day 9 post-incision (but not post-sham surgery). PMID:26342649

Prompt inhibition of fMLP-induced Ca2+ mobilization by parenteral lipid emulsions in human neutrophils.

PubMed

Wanten, Geert; Rops, Angelique; van Emst-De Vries, Sjenet E; Naber, Ton; Willems, Peter H G M

2002-04-01

It remains unclear whether modulation of immune system functions by lipids contributes to the increased infection rate observed in patients treated with parenteral nutrition. We therefore evaluated the effects of lipid emulsions derived from fish oil [very long chain triglycerides (VLCT)], olive oil [long-chain triglycerides- mono-unsaturated fatty acid (LCT-MUFA)], soya oil [long-chain triglycerides (LCT)], or a physical mixture of coconut and soya oil [mixed long- and medium-chain triglycerides (LCT-MCT)] on neutrophil activation. N-formyl-methionyl-leucyl-phenylalanine (fMLP) evoked an immediate increase of the cytosolic Ca2+ concentration ([Ca2+](i,av)) in a suspension of neutrophils. When added 3 min before fMLP, however, all four lipid emulsions reduced the hormone-induced increase in [Ca2+](i,av) with the same efficacy but with different potency. Half-maximal inhibition was reached at emulsion concentrations of 0.24 mM VLCT, 0.32 mM LCT-MCT, 0.52 mM LCT, and 0.82 mM LCT-MUFA. Similarly to the lipids, the protein kinase C (PKC) activator PMA markedly reduced the fMLP-induced increase in [Ca2+](i,av). PMA inhibition was abolished by the PKC inhibitor staurosporine. In contrast, however, this drug did not interfere with the inhibitory lipid effect, indicating that the lipids act primarily in a PKC-independent manner. In summary, this study shows that nutritional lipids can evoke a prompt and significant attenuation of hormone-induced neutrophil stimulation and that the emulsions based on fish oil and a mixture of coconut oil and soya oil are among the most potent ones in this respect.

Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebrafish (Danio rerio)

PubMed Central

Li, Lin; Yan, Qiaoqiao; Yi, Weijie; Ying, Chenjiang; Wu, Hongmei

2017-01-01

Defective lipid metabolism is associated with increased risk of various chronic diseases, such as obesity, cardiovascular diseases, and diabetes. Resveratrol (RSV), a natural polyphenol, has been shown the potential of ameliorating disregulations of lipid metabolism. The objective of this study was to investigate the effects of feed intake and RSV on lipid metabolism in zebrafish (Danio rerio). The adult males were randomly allocated to 6 groups: control (Con, 8 mg cysts/fish/day), control with 20 μmol/L RSV (Con+RSV), calorie restriction (CR, 5 mg cysts/fish/day), calorie restriction with RSV (CR+RSV), overfeed (OF, 60 mg cysts/fish/day), and overfeed with RSV (OF+RSV) groups. The treatment period was 8 weeks. Results showed that CR reduced body length, body weight, and condition factor of zebrafish. CR reduced levels of plasma triglyceride (TG) and induced protein expression of phosphorylated AMP-activated protein kinase-α (pAMPKα), silent information regulator 2 homolog 1 (Sirt1), and peroxisome proliferator activated receptor gamma coactivator-1α (PGC1α). RSV attenuated CR-induced pAMPKα/AMPKαincreases. RSV increased levels of Sirt1 protein in the OF zebrafish, and decreased OF-induced increase in peroxisome proliferator-activated receptor-γ (PPARγ) protein level. Additionally, RSV down-regulated caveolin-1 and up-regulated microtubule-associated protein 1 light chain 3 -II (LC3-II) protein levels in OF zebrafish. In conclusion, these results suggest that 1) CR reduces plasma TG level through activation of the AMPKα-Sirt1- PGC1α pathway; 2) under different dietary stress conditions RSV might regulate AMPK phosphorylation bi-directionally; 3) RSV might regulate lipid metabolism through the AMPKα-Sirt1-PPARγ pathway in OF zebrafish. PMID:28686680

Musculoskeletal sensitization and sleep: chronic muscle pain fragments sleep of mice without altering its duration.

PubMed

Sutton, Blair C; Opp, Mark R

2014-03-01

Musculoskeletal pain in humans is often associated with poor sleep quality. We used a model in which mechanical hypersensitivity was induced by injection of acidified saline into muscle to study the impact of musculoskeletal sensitization on sleep of mice. A one month pre-clinical study was designed to determine the impact of musculoskeletal sensitization on sleep of C57BL/6J mice. We instrumented mice with telemeters to record the electroencephalogram (EEG) and body temperature. We used an established model of musculoskeletal sensitization in which mechanical hypersensitivity was induced using two unilateral injections of acidified saline (pH 4.0). The injections were given into the gastrocnemius muscle and spaced five days apart. EEG and body temperature recordings started prior to injections (baseline) and continued for three weeks after musculoskeletal sensitization was induced by the second injection. Mechanical hypersensitivity was assessed using von Frey filaments at baseline (before any injections) and on days 1, 3, 7, 14, and 21 after the second injection. Mice injected with acidified saline developed bilateral mechanical hypersensitivity at the hind paws as measured by von Frey testing and as compared to control mice and baseline data. Sleep during the light period was fragmented in experimental mice injected with acidified saline, and EEG spectra altered. Musculoskeletal sensitization did not alter the duration of time spent in wakefulness, non-rapid eye movement sleep, or rapid eye movement sleep. Musculoskeletal sensitization in this model results in a distinct sleep phenotype in which sleep is fragmented during the light period, but the overall duration of sleep is not changed. This study suggests the consequences of musculoskeletal pain include sleep disruption, an observation that has been made in the clinical literature but has yet to be studied using preclinical models.

Insufficient sleep: Enhanced risk-seeking relates to low local sleep intensity.

PubMed

Maric, Angelina; Montvai, Eszter; Werth, Esther; Storz, Matthias; Leemann, Janina; Weissengruber, Sebastian; Ruff, Christian C; Huber, Reto; Poryazova, Rositsa; Baumann, Christian R

2017-09-01

Chronic sleep restriction is highly prevalent in modern society and is, in its clinical form, insufficient sleep syndrome, one of the most prevalent diagnoses in clinical sleep laboratories, with substantial negative impact on health and community burden. It reflects every-day sleep loss better than acute sleep deprivation, but its effects and particularly the underlying mechanisms remain largely unknown for a variety of critical cognitive domains, as, for example, risky decision making. We assessed financial risk-taking behavior after 7 consecutive nights of sleep restriction and after 1 night of acute sleep deprivation compared to a regular sleep condition in a within-subject design. We further investigated potential underlying mechanisms of sleep-loss-induced changes in behavior by high-density electroencephalography recordings during restricted sleep. We show that chronic sleep restriction increases risk-seeking, whereas this was not observed after acute sleep deprivation. This increase was subjectively not noticed and was related to locally lower values of slow-wave energy during preceding sleep, an electrophysiological marker of sleep intensity and restoration, in electrodes over the right prefrontal cortex. This study provides, for the first time, evidence that insufficient sleep restoration over circumscribed cortical areas leads to aberrant behavior. In chronically sleep restricted subjects, low slow-wave sleep intensity over the right prefrontal cortex-which has been shown to be linked to risk behavior-may lead to increased and subjectively unnoticed risk-seeking. Ann Neurol 2017;82:409-418. © 2017 American Neurological Association.

REM sleep deprivation induces endothelial dysfunction and hypertension in middle-aged rats: Roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine.

PubMed

Jiang, Jiaye; Gan, Zhongyuan; Li, Yuan; Zhao, Wenqi; Li, Hanqing; Zheng, Jian-Pu; Ke, Yan

2017-01-01

Sleep loss can induce or aggravate the development of cardiovascular and cerebrovascular diseases. However, the molecular mechanism underlying this phenomenon is poorly understood. The present study was designed to investigate the effects of REM sleep deprivation on blood pressure in rats and the underlying mechanisms of these effects. After Sprague-Dawley rats were subjected to REM sleep deprivation for 5 days, their blood pressures and endothelial function were measured. In addition, one group of rats was given continuous access to L-arginine supplementation (2% in distilled water) for the 5 days before and the 5 days of REM sleep deprivation to reverse sleep deprivation-induced pathological changes. The results showed that REM sleep deprivation decreased body weight, increased blood pressure, and impaired endothelial function of the aortas in middle-aged rats but not young rats. Moreover, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) concentrations as well as endothelial NO synthase (eNOS) phosphorylation in the aorta were decreased by REM sleep deprivation. Supplementation with L-arginine could protect against REM sleep deprivation-induced hypertension, endothelial dysfunction, and damage to the eNOS/NO/cGMP signaling pathway. The results of the present study suggested that REM sleep deprivation caused endothelial dysfunction and hypertension in middle-aged rats via the eNOS/NO/cGMP pathway and that these pathological changes could be inhibited via L-arginine supplementation. The present study provides a new strategy to inhibit the signaling pathways involved in insomnia-induced or insomnia-enhanced cardiovascular diseases.

The effect of Ramadan intermittent fasting on lipid peroxidation in healthy young men while controlling for diet and sleep: A pilot study.

PubMed

BaHammam, Ahmed S; Pandi-Perumal, Seithikurippu R; Alzoghaibi, Mohammed A

2016-01-01

We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. The participants had a mean age of 26.6 ± 4.9 years and a mean body mass index of 23.7 ± 3.5 kg/m(2). No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings.

Chronic sleep restriction induces changes in the mandibular condylar cartilage of rats: roles of Akt, Bad and Caspase-3.

PubMed

Zhu, Yong; Wu, Gaoyi; Zhu, Guoxiong; Ma, Chuan; Zhao, Huaqiang

2014-01-01

The aim of the present study was to observe changes in the temporomandibular joint (TMJ) of rats that had been subjected to chronic sleep restriction and to investigate whether Akt, Bad and Caspase3 play a role in the mechanism underlying the changes. One hundred and eighty male Wistar rats were randomly divided into three groups (n = 60 in each): cage control group, large-platform control group, and sleep restriction group. Each group was divided into three subgroups (n = 20 in each) of three different time points (7, 14 and 21 days), respectively. The modified multiple platform method was used to induce chronic sleep restriction. The TMJ tissue histology was studied by staining with haematoxylin and eosin. The expression of Akt, p-Aktser473, Bad, p-Badser136 and Caspase3 proteins was detected by immunohistochemistry and western blotting. The expression of Akt, Bad and Caspase3 mRNAs was measured by real-time quantitative polymerase chain reaction (RT-qPCR). Compared with the large-platform and cage control groups, condylar cartilage pathological alterations were found in the sleep restriction group. There were significantly decreased expression levels of Akt, p-Aktser473 and p-Badser136 and significantly increased expression levels of Bad and Caspase3 after sleep restriction. These data suggest that sleep restriction may induce pathological alterations in the condylar cartilage of rats. Alterations in Akt, Bad and Caspase3 may be associated with the potential mechanism by which chronic sleep restriction influences the condylar cartilage.

Chronic sleep restriction induces changes in the mandibular condylar cartilage of rats: roles of Akt, Bad and Caspase-3

PubMed Central

Zhu, Yong; Wu, Gaoyi; Zhu, Guoxiong; Ma, Chuan; Zhao, Huaqiang

2014-01-01

Aims: The aim of the present study was to observe changes in the temporomandibular joint (TMJ) of rats that had been subjected to chronic sleep restriction and to investigate whether Akt, Bad and Caspase3 play a role in the mechanism underlying the changes. Main methods: One hundred and eighty male Wistar rats were randomly divided into three groups (n = 60 in each): cage control group, large-platform control group, and sleep restriction group. Each group was divided into three subgroups (n = 20 in each) of three different time points (7, 14 and 21 days), respectively. The modified multiple platform method was used to induce chronic sleep restriction. The TMJ tissue histology was studied by staining with haematoxylin and eosin. The expression of Akt, p-Aktser473, Bad, p-Badser136 and Caspase3 proteins was detected by immunohistochemistry and western blotting. The expression of Akt, Bad and Caspase3 mRNAs was measured by real-time quantitative polymerase chain reaction (RT-qPCR). Key findings: Compared with the large-platform and cage control groups, condylar cartilage pathological alterations were found in the sleep restriction group. There were significantly decreased expression levels of Akt, p-Aktser473 and p-Badser136 and significantly increased expression levels of Bad and Caspase3 after sleep restriction. Significance: These data suggest that sleep restriction may induce pathological alterations in the condylar cartilage of rats. Alterations in Akt, Bad and Caspase3 may be associated with the potential mechanism by which chronic sleep restriction influences the condylar cartilage. PMID:25356113

Aerobic training suppresses exercise-induced lipid peroxidation and inflammation in overweight/obese adolescent girls.

PubMed

Youssef, Hala; Groussard, Carole; Lemoine-Morel, Sophie; Pincemail, Joel; Jacob, Christophe; Moussa, Elie; Fazah, Abdallah; Cillard, Josiane; Pineau, Jean-Claude; Delamarche, Arlette

2015-02-01

This study aimed to determine whether aerobic training could reduce lipid peroxidation and inflammation at rest and after maximal exhaustive exercise in overweight/obese adolescent girls. Thirty-nine adolescent girls (14-19 years old) were classified as nonobese or overweight/obese and then randomly assigned to either the nontrained or trained group (12-week multivariate aerobic training program). Measurements at the beginning of the experiment and at 3 months consisted of body composition, aerobic fitness (VO2peak) and the following blood assays: pre- and postexercise lipid peroxidation (15F2a-isoprostanes [F2-Isop], lipid hydroperoxide [ROOH], oxidized LDL [ox-LDL]) and inflammation (myeloperoxidase [MPO]) markers. In the overweight/ obese group, the training program significantly increased their fat-free mass (FFM) and decreased their percentage of fat mass (%FM) and hip circumference but did not modify their VO2peak. Conversely, in the nontrained overweight/obese group, weight and %FM increased, and VO2peak decreased, during the same period. Training also prevented exercise-induced lipid peroxidation and/or inflammation in overweight/obese girls (F2-Isop, ROOH, ox-LDL, MPO). In addition, in the trained overweight/obese group, exercise-induced changes in ROOH, ox-LDL and F2-Isop were correlated with improvements in anthropometric parameters (waist-to-hip ratio, %FM and FFM). In conclusion aerobic training increased tolerance to exercise-induced oxidative stress in overweight/obese adolescent girls partly as a result of improved body composition.

The Effects of Boron on Arsenic-Induced Lipid Peroxidation and Antioxidant Status in Male and Female Rats.

PubMed

Kucukkurt, Ismail; Ince, Sinan; Demirel, Hasan Huseyin; Turkmen, Ruhi; Akbel, Erten; Celik, Yasemin

2015-12-01

The aim of the present study was to investigate the possible protective effects of boron, an antioxidant agent, against arsenic-induced oxidative stress in male and female rats. In total, 42 Wistar albino male and female rats were divided into three equal groups: The animals in the control group were given normal drinking water, the second group was given drinking water with 100 mg/L arsenic, and the third group was orally administered drinking water with 100 mg/kg boron together with arsenic. At the end of the 28-day experiment, arsenic increased lipid peroxidation and damage in the tissues of rats. However, boron treatment reversed this arsenic-induced lipid peroxidation and activities of antioxidant enzymes in rats. Moreover, boron exhibited a protective action against arsenic-induced histopathological changes in the tissues of rats. In conclusion, boron was found to be effective in protecting rats against arsenic-induced lipid peroxidation by enhancing antioxidant defense mechanisms. © 2015 Wiley Periodicals, Inc.

Pathophysiology of Sleep Apnea

PubMed Central

Veasey, Sigrid C.; Morgan, Barbara J.; O'Donnell, Christopher P.

2010-01-01

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the “metabolic syndrome” remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect

Sleep in elite athletes and nutritional interventions to enhance sleep.

PubMed

Halson, Shona L

2014-05-01

Sleep has numerous important physiological and cognitive functions that may be particularly important to elite athletes. Recent evidence, as well as anecdotal information, suggests that athletes may experience a reduced quality and/or quantity of sleep. Sleep deprivation can have significant effects on athletic performance, especially submaximal, prolonged exercise. Compromised sleep may also influence learning, memory, cognition, pain perception, immunity and inflammation. Furthermore, changes in glucose metabolism and neuroendocrine function as a result of chronic, partial sleep deprivation may result in alterations in carbohydrate metabolism, appetite, food intake and protein synthesis. These factors can ultimately have a negative influence on an athlete's nutritional, metabolic and endocrine status and hence potentially reduce athletic performance. Research has identified a number of neurotransmitters associated with the sleep-wake cycle. These include serotonin, gamma-aminobutyric acid, orexin, melanin-concentrating hormone, cholinergic, galanin, noradrenaline, and histamine. Therefore, nutritional interventions that may act on these neurotransmitters in the brain may also influence sleep. Carbohydrate, tryptophan, valerian, melatonin and other nutritional interventions have been investigated as possible sleep inducers and represent promising potential interventions. In this review, the factors influencing sleep quality and quantity in athletic populations are examined and the potential impact of nutritional interventions is considered. While there is some research investigating the effects of nutritional interventions on sleep, future research may highlight the importance of nutritional and dietary interventions to enhance sleep.

Fos and serotonin immunoreactivity in the raphe nuclei of the cat during carbachol-induced active sleep: a double-labeling study.

PubMed

Yamuy, J; Sampogna, S; López-Rodríguez, F; Luppi, P H; Morales, F R; Chase, M H

1995-07-01

The microinjection of carbachol into the nucleus pontis oralis produces a state which is polygraphically and behaviorally similar to active sleep (rapid eye movement sleep). In the present study, using double-labeling techniques for serotonin and the protein product of c-fos (Fos), we sought to examine whether immunocytochemically identified serotonergic neurons of the raphe nuclei of the cat were activated, as indicated by their expression of c-fos, during this pharmacologically-induced behavioral state (active sleep-carbachol). Compared with control cats, which were injected with saline, active sleep-carbachol cats exhibited a significantly greater number of c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus. Whereas most of the c-fos-expressing neurons in the raphe dorsalis were small, those in the raphe magnus were medium-sized and in the raphe pallidus they were small and medium-sized. The mean number of serotonergic neurons that expressed c-fos (i.e. double-labeled cells) was similar in control and active sleep-carbachol cats. These data indicate that there is an increased number of non-serotonergic, c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus during the carbachol-induced state.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep-induced periodic breathing and apnea: a theoretical study.

PubMed

Khoo, M C; Gottschalk, A; Pack, A I

1991-05-01

To elucidate the mechanisms that lead to sleep-disordered breathing, we have developed a mathematical model that allows for dynamic interactions among the chemical control of respiration, changes in sleep-waking state, and changes in upper airway patency. The increase in steady-state arterial PCO2 accompanying sleep is shown to be inversely related to the ventilatory response to CO2. Chemical control of respiration becomes less stable during the light stage of sleep, despite a reduction in chemoresponsiveness, due to a concomitant increase in "plant gain" (i.e., responsiveness of blood gases to ventilatory changes). The withdrawal of the "wakefulness drive" during sleep onset represents a strong perturbation to respiratory control: higher magnitudes and rates of withdrawal of this drive favor instability. These results may account for the higher incidence of periodic breathing observed during light sleep and sleep onset. Periodic ventilation can also result from repetitive alternations between sleep onset and arousal. The potential for instability is further compounded if the possibility of upper airway occlusion is also included. In systems with high controller gains, instability is mediated primarily through chemoreflex overcompensation. However, in systems with depressed chemoresponsiveness, rapid sleep onset and large blood gas fluctuations trigger repetitive episodes of arousal and hyperpnea alternating with apneas that may or may not be obstructive. Between these extremes, more complex patterns can arise from the interaction between chemoreflex-mediated oscillations of shorter-cycle-duration (approximately 36 s) and longer-wavelength (approximately 60-80 s) state-driven oscillations.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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)more » 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

Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability.

PubMed

Boisramé-Helms, Julie; Delabranche, Xavier; Klymchenko, Andrey; Drai, Jocelyne; Blond, Emilie; Zobairi, Fatiha; Mely, Yves; Hasselmann, Michel; Toti, Florence; Meziani, Ferhat

2014-11-01

The aim of this study was to assess how lipid emulsions for parenteral nutrition affect lipopolysaccharide (LPS)-induced acute monocyte inflammation in vitro. An 18 h long LPS induced human monocyte leukemia cell stimulation was performed and the cell-growth medium was supplemented with three different industrial lipid emulsions: Intralipid(®), containing long-chain triglycerides (LCT--soybean oil); Medialipid(®), containing LCT (soybean oil) and medium-chain triglycerides (MCT--coconut oil); and SMOFlipid(®), containing LCT, MCT, omega-9 and -3 (soybean, coconut, olive and fish oils). Cell viability and apoptosis were assessed by Trypan blue exclusion and flow cytometry respectively. Monocyte composition and membrane remodeling were studied using gas chromatography and NR12S staining. Microparticles released in supernatant were measured by prothrombinase assay. After LPS challenge, both cellular necrosis and apoptosis were increased (threefold and twofold respectively) and microparticle release was enhanced (sevenfold) after supplementation with Medialipid(®) compared to Intralipid(®), SMOFlipid(®) and monocytes in the standard medium. The monocytes differentially incorporated fatty acids after lipid emulsion challenge. Finally, lipid-treated cells displayed microparticles characterized by disrupted membrane lipid order, reflecting lipid remodeling of the parental cell plasma membrane. Our data suggest that lipid emulsions differentially alter cell viability, monocyte composition and thereby microparticle release. While MCT have deleterious effects, we have shown that parenteral nutrition emulsion containing LCT or LCT and MCT associated to n-3 and n-9 fatty acids have no effect on endotoxin-induced cell death and inflammation.

A tryptic hydrolysate from bovine milk αs1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor.

PubMed

Dela Peña, Irene Joy I; Kim, Hee Jin; de la Peña, June Bryan; Kim, Mikyung; Botanas, Chrislean Jun; You, Kyung Yi; Woo, Taeseon; Lee, Yong Soo; Jung, Jae-Chul; Kim, Kyung-Mi; Cheong, Jae Hoon

2016-10-15

Studies have shown that enzymatic hydrolysis of casein, the primary protein component of cow's milk, produces peptides with various biological activities, and some of these peptides may have sleep-promoting effects. In the present study, we evaluated the sedative and sleep-promoting effects of bovine αS1-casein tryptic hydrolysate (CH), containing a decapeptide αS1-casein known as alpha-casozepine. CH was orally administered to ICR mice at various concentrations (75, 150, 300, or 500mg/kg). An hour after administration, assessment of its sedative (open-field and rota-rod tests) and sleep-potentiating effects (pentobarbital-induced sleeping test and EEG monitoring) were conducted. Although a trend can be observed, CH treatment did not significantly alter the spontaneous locomotor activity and motor function of mice in the open-field and rota-rod tests. On the other hand, CH (150mg/kg, respectively) enhanced the sleep induced by pentobarbital sodium in mice. It also promoted slow-wave (delta) EEG activity in rats; a pattern indicative of sleep or relaxation. These behavioral results indicate that CH has sleep-promoting effects, but no or has minimal sedative effects. To elucidate the probable mechanism behind the effects of CH, we examined its action on intracellular chloride ion influx in cultured human neuroblastoma cells. CH dose-dependently increased chloride ion influx, which was blocked by co-administration of bicuculline, a competitive GABAA receptor antagonist. Taken together, the results of the present study suggest that CH has sleep-promoting properties which are probably mediated through the GABAA receptor-chloride ion channel complex. Copyright © 2016 Elsevier B.V. All rights reserved.

Wheel running improves REM sleep and attenuates stress-induced flattening of diurnal rhythms in F344 rats.

PubMed

Thompson, Robert S; Roller, Rachel; Greenwood, Benjamin N; Fleshner, Monika

2016-05-01

Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12 h light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise.

Wheel Running Improves REM Sleep and Attenuates Stress-induced Flattening of Diurnal Rhythms in F344 Rats

PubMed Central

Thompson, Robert S.; Roller, Rachel; Greenwood, Benjamin N.; Fleshner, Monika

2016-01-01

Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12hr light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise. PMID:27124542

Localization and Ordering of Lipids Around Aquaporin-0: Protein and Lipid Mobility Effects.

PubMed

Briones, Rodolfo; Aponte-Santamaría, Camilo; de Groot, Bert L

2017-01-01

Hydrophobic matching, lipid sorting, and protein oligomerization are key principles by which lipids and proteins organize in biological membranes. The Aquaporin-0 channel (AQP0), solved by electron crystallography (EC) at cryogenic temperatures, is one of the few protein-lipid complexes of which the structure is available in atomic detail. EC and room-temperature molecular dynamics (MD) of dimyristoylglycerophosphocholine (DMPC) annular lipids around AQP0 show similarities, however, crystal-packing and temperature might affect the protein surface or the lipids distribution. To understand the role of temperature, lipid phase, and protein mobility in the localization and ordering of AQP0-lipids, we used MD simulations of an AQP0-DMPC bilayer system. Simulations were performed at physiological and at DMPC gel-phase temperatures. To decouple the protein and lipid mobility effects, we induced gel-phase in the lipids or restrained the protein. We monitored the lipid ordering effects around the protein. Reducing the system temperature or inducing lipid gel-phase had a marginal effect on the annular lipid localization. However, restraining the protein mobility increased the annular lipid localization around the whole AQP0 surface, resembling EC. The distribution of the inter-phosphate and hydrophobic thicknesses showed that stretching of the DMPC annular layer around AQP0 surface is the mechanism that compensates the hydrophobic mismatch in this system. The distribution of the local area-per-lipid and the acyl-chain order parameters showed particular fluid- and gel-like areas that involved several lipid layers. These areas were in contact with the surfaces of higher and lower protein mobility, respectively. We conclude that the AQP0 surfaces induce specific fluid- and gel-phase prone areas. The presence of these areas might guide the AQP0 lipid sorting interactions with other membrane components, and is compatible with the squared array oligomerization of AQP0 tetramers

The Degree of Radiation-Induced DNA Strand Breaks Is Altered by Acute Sleep Deprivation and Psychological Stress and Is Associated with Cognitive Performance in Humans.

PubMed

Moreno-Villanueva, Maria; von Scheven, Gudrun; Feiveson, Alan; Bürkle, Alexander; Wu, Honglu; Goel, Namni

2018-03-27

Sleep deprivation is associated with impaired immune responses, cancer, and morbidity and mortality, and can degrade cognitive performance, although individual differences exist in such responses. Sleep deprivation induces DNA strand breaks and DNA base oxidation in animals, and psychological stress is associated with increased DNA damage in humans. It remains unknown whether sleep deprivation or psychological stress in humans affects DNA damage response from environmental stressors, and whether these responses predict cognitive performance during sleep deprivation. Sixteen healthy adults (ages 29-52;mean age±SD, 36.4±7.1 years;7 women) participated in a 5-day experiment involving two 8 hour time-in-bed [TIB] baseline nights, followed by 39 hours total sleep deprivation (TSD), and two 8-10 hour TIB recovery nights. A modified Trier Social Stress Test was conducted on the day after TSD. Psychomotor Vigilance Tests measured behavioral attention. DNA damage was assessed in blood cells collected at 5 time points, and blood cells were irradiated ex-vivo. TSD, alone or in combination with psychological stress, did not induce significant increases in DNA damage. By contrast, radiation-induced DNA damage decreased significantly in response to TSD, but increased back to baseline when combined with psychological stress. Cognitively-vulnerable individuals had more radiation-induced DNA strand breaks before TSD, indicating their greater sensitivity to DNA damage from environmental stressors. Our results provide novel insights into the molecular consequences of sleep deprivation, psychological stress, and performance vulnerability. They are important for situations involving sleep loss, radiation exposure and cognitive deficits, including cancer therapy, environmental toxicology, and space medicine.

Sleep, Torpor and Memory Impairment

NASA Astrophysics Data System (ADS)

Palchykova, S.; Tobler, I.

It is now well known that daily torpor induces a sleep deficit. Djungarian hamsters emerging from this hypometabolic state spend most of the time in sleep. This sleep is characterized by high initial values of EEG slow-wave activity (SWA) that monotonically decline during recovery sleep. These features resemble the changes seen in numerous species during recovery after prolonged wakefulness or sleep deprivation (SD). When hamsters are totally or partially sleep deprived immediately after emerging from torpor, an additional increase in SWA can be induced. It has been therefore postulated, that these slow- waves are homeostatically regulated, as predicted by the two-process model of sleep regulation, and that during daily torpor a sleep deficit is accumulated as it is during prolonged waking. The predominance of SWA in the frontal EEG observed both after SD and daily torpor provides further evidence for the similarity of these conditions. It has been shown in several animal and human studies that sleep can enhance memory consolidation, and that SD leads to memory impairment. Preliminary data obtained in the Djungarian hamster showed that both SD and daily torpor result in object recognition deficits. Thus, animals subjected to SD immediately after learning, or if they underwent an episode of daily torpor between learning and retention, displayed impaired recognition memory for complex object scenes. The investigation of daily torpor can reveal mechanisms that could have important implications for hypometabolic state induction in other mammalian species, including humans.

Temperature induced modulation of lipid oxidation and lipid accumulation in palmitate-mediated 3T3-L1 adipocytes and 3T3-L1 adipocytes.

PubMed

Lin, Xiaofen; Li, Yi; Leung, Polly Hangmei; Li, Jiashen; Hu, Junyan; Liu, Xuan; Li, Zhi

2016-05-01

Human skin temperature can vary widely depending on anatomical location and ambient temperature. It is also known that local changes in skin and subcutaneous temperature can affect fat metabolism. This study aimed to explore the potential effects of surrounding thermal environment on fat by investigating cell viability, lipid oxidation, and lipid accumulation in 3T3-L1 adipocytes and palmitate-treated adipocytes after 4h incubation. No significant differences of viability in 3T3-L1 adipocytes were detected under different temperature conditions. Despite no significant increase being observed under warm temperature (39°C) conditions, a similarly significant suppression of intracellular reactive oxygen species (ROS) and lipid peroxidation were found in 3T3-L1 adipocytes and palmitate-treated adipocytes under 4h exposure to cooler temperatures of 31-33°C (P<0.01). ROS, chemically reactive molecules containing oxygen, are currently understood to be a major contributor to oxidantive stress in obesity. Additionally, cooler temperatures (31-33°C) could improve the size of lipid droplets in 3T3-L1 adipocytes (P<0.01), but no significant effect was generated by temperature change on lipid droplets in palmitate-treated adipocytes. In the palmitate-induced adiposity model, although excessive ROS and lipid peroxidation has been attenuated by temperature decrease (P<0.01), it still does not positively modulate lipid droplet size (P>0.05) and remedy the palmitate damage induced cell death (P<0.01). These findings provide preliminary support for potential interventions based on temperature manipulation for cell metabolism of adipocytes. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Caveolin Dominant Negative Mutant Associates with Lipid Bodies and Induces Intracellular Cholesterol Imbalance

PubMed Central

Pol, Albert; Luetterforst, Robert; Lindsay, Margaret; Heino, Sanna; Ikonen, Elina; Parton, Robert G.

2001-01-01

Recent studies have indicated a role for caveolin in regulating cholesterol-dependent signaling events. In the present study we have analyzed the role of caveolins in intracellular cholesterol cycling using a dominant negative caveolin mutant. The mutant caveolin protein, cav-3DGV, specifically associates with the membrane surrounding large lipid droplets. These structures contain neutral lipids, and are accessed by caveolin 1–3 upon overexpression. Fluorescence, electron, and video microscopy observations are consistent with formation of the membrane-enclosed lipid rich structures by maturation of subdomains of the ER. The caveolin mutant causes the intracellular accumulation of free cholesterol (FC) in late endosomes, a decrease in surface cholesterol and a decrease in cholesterol efflux and synthesis. The amphiphile U18666A acts synergistically with cavDGV to increase intracellular accumulation of FC. Incubation of cells with oleic acid induces a significant accumulation of full-length caveolins in the enlarged lipid droplets. We conclude that caveolin can associate with the membrane surrounding lipid droplets and is a key component involved in intracellular cholesterol balance and lipid transport in fibroblasts. PMID:11238460

ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN

EPA Science Inventory

Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
*CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studie...

Sleep Changes in Older Adults

MedlinePlus

... Kids and Teens Pregnancy and Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life ... CholesterolExercise-induced UrticariaDe Quervain’s Tenosynovitis Home Family Health Seniors Sleep Changes in Older Adults Sleep Changes in ...

The effect of Ramadan intermittent fasting on lipid peroxidation in healthy young men while controlling for diet and sleep: A pilot study

PubMed Central

BaHammam, Ahmed S.; Pandi-Perumal, Seithikurippu R.; Alzoghaibi, Mohammed A.

2016-01-01

AIMS: We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. METHODS: Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. RESULTS: The participants had a mean age of 26.6 ± 4.9 years and a mean body mass index of 23.7 ± 3.5 kg/m2. No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. CONCLUSION: In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings. PMID:26933456

Sleeping on the rubber-hand illusion: Memory reactivation during sleep facilitates multisensory recalibration.

PubMed

Honma, Motoyasu; Plass, John; Brang, David; Florczak, Susan M; Grabowecky, Marcia; Paller, Ken A

2016-01-01

Plasticity is essential in body perception so that physical changes in the body can be accommodated and assimilated. Multisensory integration of visual, auditory, tactile, and proprioceptive signals contributes both to conscious perception of the body's current state and to associated learning. However, much is unknown about how novel information is assimilated into body perception networks in the brain. Sleep-based consolidation can facilitate various types of learning via the reactivation of networks involved in prior encoding or through synaptic down-scaling. Sleep may likewise contribute to perceptual learning of bodily information by providing an optimal time for multisensory recalibration. Here we used methods for targeted memory reactivation (TMR) during slow-wave sleep to examine the influence of sleep-based reactivation of experimentally induced alterations in body perception. The rubber-hand illusion was induced with concomitant auditory stimulation in 24 healthy participants on 3 consecutive days. While each participant was sleeping in his or her own bed during intervening nights, electrophysiological detection of slow-wave sleep prompted covert stimulation with either the sound heard during illusion induction, a counterbalanced novel sound, or neither. TMR systematically enhanced feelings of bodily ownership after subsequent inductions of the rubber-hand illusion. TMR also enhanced spatial recalibration of perceived hand location in the direction of the rubber hand. This evidence for a sleep-based facilitation of a body-perception illusion demonstrates that the spatial recalibration of multisensory signals can be altered overnight to stabilize new learning of bodily representations. Sleep-based memory processing may thus constitute a fundamental component of body-image plasticity.

Managing statin-induced muscle toxicity in a lipid clinic.

PubMed

Blaier, O; Lishner, M; Elis, A

2011-06-01

Muscle toxicity is the most significant adverse effect related to statins. The aim of the study was to analyse the clinical course and achievement of LDL-C target levels in patients with statin-induced muscle toxicity. All patients who were referred to the lipid clinic because of statin-induced muscle toxicity, or developed it during follow-up, or did not reach LDL-C target levels because of its previous occurrence, and attended the clinic for at least three follow-up visits, were eligible. Files were reviewed for demographic and clinical parameters, coronary heart disease risk level, the severity of muscle injury, the type of statin and dose that caused the adverse effects, the clinical approach and outcome, and whether the LDL-C target level was achieved. The study group consisted of 54 patients. Twenty-three (43%) patients complained of myalgia, 23 (43%) had asymptomatic serum creatine kinase (CK) level elevation, five (9%) had myopathy and three (5%) had rhabdomyolysis. Fifty of the patients (93%) continued statin therapy and 43 (80%) achieved the LDL-C target level. We show that for the majority of patients with statin-induced muscle toxicity, statin therapy can be safely and effectively continued. In cases of asymptomatic CK levels <3-5 upper limit of normal (ULN), statin treatment should not be interrupted. When CK levels >3-5 ULN or when various symptomatic muscle adverse reactions are present, statins rechallenge, after a recovery period, should be individualized either by a low dose of a potent statin or by a less potent statin. An additional lipid medication is advised if the target levels are not achieved. © 2011 Blackwell Publishing Ltd.

Lipid-induced thermogenesis is up-regulated by the first cold-water immersions in juvenile penguins.

PubMed

Teulier, Loïc; Rey, Benjamin; Tornos, Jérémy; Le Coadic, Marion; Monternier, Pierre-Axel; Bourguignon, Aurore; Dolmazon, Virginie; Romestaing, Caroline; Rouanet, Jean-Louis; Duchamp, Claude; Roussel, Damien

2016-07-01

The passage from shore to marine life is a critical step in the development of juvenile penguins and is characterized by a fuel selection towards lipid oxidation concomitant to an enhancement of lipid-induced thermogenesis. However, mechanisms of such thermogenic improvement at fledging remain undefined. We used two different groups of pre-fledging king penguins (Aptenodytes patagonicus) to investigate the specific contribution of cold exposure during water immersion to lipid metabolism. Terrestrial penguins that had never been immersed in cold water were compared with experimentally cold-water immersed juveniles. Experimentally immersed penguins underwent ten successive immersions at approximately 9-10 °C for 5 h over 3 weeks. We evaluated adaptive thermogenesis by measuring body temperature, metabolic rate and shivering activity in fully immersed penguins exposed to water temperatures ranging from 12 to 29 °C. Both never-immersed and experimentally immersed penguins were able to maintain their homeothermy in cold water, exhibiting similar thermogenic activity. In vivo, perfusion of lipid emulsion at thermoneutrality induced a twofold larger calorigenic response in experimentally immersed than in never-immersed birds. In vitro, the respiratory rates and the oxidative phosphorylation efficiency of isolated muscle mitochondria were not improved with cold-water immersions. The present study shows that acclimation to cold water only partially reproduced the fuel selection towards lipid oxidation that characterizes penguin acclimatization to marine life.

Notch signaling modulates sleep homeostasis and learning after sleep deprivation in Drosophila.

PubMed

Seugnet, Laurent; Suzuki, Yasuko; Merlin, Gabriel; Gottschalk, Laura; Duntley, Stephen P; Shaw, Paul J

2011-05-24

The role of the transmembrane receptor Notch in the adult brain is poorly understood. Here, we provide evidence that bunched, a negative regulator of Notch, is involved in sleep homeostasis. Genetic evidence indicates that interfering with bunched activity in the mushroom bodies (MBs) abolishes sleep homeostasis. Combining bunched and Delta loss-of-function mutations rescues normal homeostasis, suggesting that Notch signaling may be involved in regulating sensitivity to sleep loss. Preventing the downregulation of Delta by overexpressing a wild-type transgene in MBs reduces sleep homeostasis and, importantly, prevents learning impairments induced by sleep deprivation. Similar resistance to sleep loss is observed with Notch(spl-1) gain-of-function mutants. Immunohistochemistry reveals that the Notch receptor is expressed in glia, whereas Delta is localized in neurons. Importantly, the expression in glia of the intracellular domain of Notch, a dominant activated form of the receptor, is sufficient to prevent learning deficits after sleep deprivation. Together, these results identify a novel neuron-glia signaling pathway dependent on Notch and regulated by bunched. These data highlight the emerging role of neuron-glia interactions in regulating both sleep and learning impairments associated with sleep loss. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mobile phones and sleep - A review

NASA Astrophysics Data System (ADS)

Supe, Sanjay S.

2010-01-01

The increasing use of mobile phones has raised concerns regarding the potential health effects of exposure to the radiofrequency electromagnetic fields. An increasing amount research related to mobile phone use has focussed on the possible effects of mobile phone exposure on human brain activity and function. In particular, the use of sleep research has become a more widely used technique for assessing the possible effects of mobile phones on human health and wellbeing especially in the investigation of potential changes in sleep architecture resulting from mobile phone use. Acute exposure to a mobile phone prior to sleep significantly enhances electroencephalogram spectral power in the sleep spindle frequency range. This mobile phone-induced enhancement in spectral power is largely transitory and does not linger throughout the night. Furthermore, a reduction in rapid eye movement sleep latency following mobile phone exposure was also found, although interestingly, neither this change in rapid eye movement sleep latency or the enhancement in spectral power following mobile phone exposure, led to changes in the overall quality of sleep. In conclusion, a short exposure to the radiofrequency electromagnetic fields emitted by a mobile phone handset immediately prior to sleep is sufficient to induce changes in brain activity in the initial part of sleep. The consequences or functional significance of this effect are currently unknown and it would be premature to draw conclusions about possible health consequences.

Investigating lipids as a source of chemical exchange-induced MRI frequency shifts.

PubMed

Shmueli, K; Dodd, S J; van Gelderen, P; Duyn, J H

2017-04-01

While magnetic susceptibility is a major contributor to NMR resonance frequency variations in the human brain, a substantial contribution may come from the chemical exchange of protons between water and other molecules. Exchange-induced frequency shifts f e have been measured in tissue and protein solutions, but relatively lipid-rich white matter (WM) has a larger f e than gray matter, suggesting that lipids could contribute. Galactocerebrosides (GC) are a prime candidate as they are abundant in WM and susceptible to exchange. To investigate this, f e was measured in a model of WM lipid membranes in the form of multilamellar vesicles (MLVs), consisting of a 1:2 molar ratio of GC and phospholipids (POPC), and in MLVs with POPC only. Chemical shift imaging with 15% volume fraction of dioxane, an internal reference whose protons are assumed not to undergo chemical exchange, was used to remove susceptibility-induced frequency shifts in an attempt to measure f e in MLVs at several lipid concentrations. Initial analysis of these measurements indicated a necessity to correct for small unexpected variations in dioxane concentration due to its effect on the water frequency shift. To achieve this, the actual dioxane concentration was inferred from spectral analysis and its additional contribution to f e was removed through separate experiments which showed that the water-dioxane frequency shift depended linearly on the dioxane concentration at low concentrations with a proportionality constant of -0.021 ± 0.002 ppb/mM in agreement with published experiments. Contrary to expectations and uncorrected results, for GC + POPC vesicles, the dependence of the corrected f e on GC concentration was insignificant (0.023 ± 0.037 ppb/mM; r 2  = 0.085, p > 0.57), whereas for the POPC-only vesicles a small but significant linear increase with POPC concentration was found: 0.044 ± 0.008 ppb/mM (r 2  = 0.877, p < 0.01). These findings suggest that

Sleep Deprivation and Oxidative Stress in Animal Models: A Systematic Review

PubMed Central

Villafuerte, Gabriel; Miguel-Puga, Adán; Murillo Rodríguez, Eric; Machado, Sergio; Manjarrez, Elias; Arias-Carrión, Oscar

2015-01-01

Because the function and mechanisms of sleep are partially clear, here we applied a meta-analysis to address the issue whether sleep function includes antioxidative properties in mice and rats. Given the expansion of the knowledge in the sleep field, it is indeed ambitious to describe all mammals, or other animals, in which sleep shows an antioxidant function. However, in this paper we reviewed the current understanding from basic studies in two species to drive the hypothesis that sleep is a dynamic-resting state with antioxidative properties. We performed a systematic review of articles cited in Medline, Scopus, and Web of Science until March 2015 using the following search terms: Sleep or sleep deprivation and oxidative stress, lipid peroxidation, glutathione, nitric oxide, catalase or superoxide dismutase. We found a total of 266 studies. After inclusion and exclusion criteria, 44 articles were included, which are presented and discussed in this study. The complex relationship between sleep duration and oxidative stress is discussed. Further studies should consider molecular and genetic approaches to determine whether disrupted sleep promotes oxidative stress. PMID:25945148

Computer simulation studies on passive recruitment dynamics of lipids induced by the adsorption of charged nanoparticles.

PubMed

Li, Yang

2014-07-07

The recruitment dynamics of lipids in the biomembrane is believed to play an important role in a variety of cellular processes. In this work, we investigate the nanoparticle-induced recruitment dynamics of lipids in the heterogeneous phospholipid bilayers of distearoyl-phosphatidylcholine (DSPC) and dioleoyl-phosphatidylglycerol (DOPG) via coarse-grained molecular dynamics simulations. Three dynamic modes of individual charged DOPG lipid molecules have been taken into account in the recruitment process: lateral diffusion, protrusions, and flip-flops. Based on analysis of the mobility pattern of lipids, structural variations in the membrane as well as activation energy of the structure of lipid eyelids characterized by the potential of mean force, we have concluded that the electrostatic attraction of nanoparticles plays a crucial role in the recruitment process of lipids in phospholipid bilayers. These studies are consistent with experimental observations and to some extent give insight into the origin of some cellular processes such as signaling, formation of lipid rafts, and endocytosis.

Brief light stimulation during the mouse nocturnal activity phase simultaneously induces a decline in core temperature and locomotor activity followed by EEG-determined sleep

PubMed Central

Studholme, Keith M.; Gompf, Heinrich S.

2013-01-01

Light exerts a variety of effects on mammals. Unexpectedly, one of these effects is the cessation of nocturnal locomotion and the induction of behavioral sleep (photosomnolence). Here, we extend the initial observations in several ways, including the fundamental demonstration that core body temperature (Tc) drops substantially (about 1.5°C) in response to the light stimulation at CT15 or CT18 in a manner suggesting that the change is a direct response to light rather than simply a result of the locomotor suppression. The results show that 1) the decline of locomotion and Tc begin soon after nocturnal light stimulation; 2) the variability in the magnitude and onset of light-induced locomotor suppression is very large, whereas the variability in Tc is very small; 3) Tc recovers from the light-induced decline in advance of the recovery of locomotion; 4) under entrained and freerunning conditions, the daily late afternoon Tc increase occurs in advance of the corresponding increase in wheel running; and 5) toward the end of the subjective night, the nocturnally elevated Tc persists longer than does locomotor activity. Finally, EEG measurements confirm light-induced sleep and, when Tc or locomotion was measured, show their temporal association with sleep onset. Both EEG- and immobility-based sleep detection methods confirm rapid induction of light-induced sleep. The similarities between light-induced loss of locomotion and drop in Tc suggest a common cause for parallel responses. The photosomnolence response may be contingent upon both the absence of locomotion and a simultaneous low Tc. PMID:23364525

Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

PubMed

Song, Qian; Feng, Ge; Huang, Zehua; Chen, Xiaoman; Chen, Zhaohuan; Ping, Yong

2017-10-01

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

Vibrational Studies of Saccharide-Induced Lipid Film Reorganization at Aqueous/Air Interfaces

DOE PAGES

Link, Katie A.; Hsieh, Chia -Yun; Tuladhar, Aashish; ...

2018-02-09

Vibrational sum frequency generation (VSFG) and surface tension experiments were used to examine the effects of aqueous phase soluble saccharides on the structure and organization of insoluble lipid monolayers adsorbed to aqueous-air interfaces. Changes in dipalmitoylphosphocholine (DPPC) chain structure as a function of aqueous phase saccharide concentration and pH are reported. Complementary differential scanning calorimetry (DSC) measurements performed on solutions containing soluble saccharides and DPPC vesicles measured the effects of the saccharides on the lipid membrane phase behavior. Here, data show that the saccharides glucosamine and glucuronic acid induce a higher degree of organization in compressed DPPC monolayers regardless ofmore » the saccharide’s charge.« less

Vibrational Studies of Saccharide-Induced Lipid Film Reorganization at Aqueous/Air Interfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Link, Katie A.; Hsieh, Chia -Yun; Tuladhar, Aashish

Vibrational sum frequency generation (VSFG) and surface tension experiments were used to examine the effects of aqueous phase soluble saccharides on the structure and organization of insoluble lipid monolayers adsorbed to aqueous-air interfaces. Changes in dipalmitoylphosphocholine (DPPC) chain structure as a function of aqueous phase saccharide concentration and pH are reported. Complementary differential scanning calorimetry (DSC) measurements performed on solutions containing soluble saccharides and DPPC vesicles measured the effects of the saccharides on the lipid membrane phase behavior. Here, data show that the saccharides glucosamine and glucuronic acid induce a higher degree of organization in compressed DPPC monolayers regardless ofmore » the saccharide’s charge.« less

Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells.

PubMed

Woo, Seon Min; Seo, Seung Un; Min, Kyoung-Jin; Im, Seung-Soon; Nam, Ju-Ock; Chang, Jong-Soo; Kim, Shin; Park, Jong-Wook; Kwon, Taeg Kyu

2018-04-27

Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti-proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor), necroptosis inhibitor (necrostatin-1), or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO)). Furthermore, corosolic acid significantly induces reactive oxygen species (ROS) levels, but antioxidants ( N -acetyl-l-cysteine (NAC) and trolox) do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti-chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498), breast cancer (MDA-MB231), and hepatocellular carcinoma (SK-Hep1 and Huh7) cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation.

One night of sleep is insufficient to achieve sleep-to-forget emotional decontextualisation processes.

PubMed

Deliens, Gaétane; Peigneux, Philippe

2014-01-01

Neutral memories unbind from their emotional acquisition context when sleep is allowed the night after learning and testing takes place after two additional nights of sleep. However, mood-dependent memory (MDM) effects are not abolished after a restricted sleep episode mostly featuring non rapid-eye-movement (NREM) or rapid-eye-movement (REM) sleep. Here, we tested whether (1) one night of sleep featuring several NREM-REM sleep cycles is sufficient to suppress MDM effects and (2) a neutral mood is a sufficiently contrasting state to induce MDM effects, i.e. interfere with the recall of information learned in happy or sad states. Results disclosed MDM effects both in the post-learning sleep and wake conditions, with better recall in congruent than incongruent emotional contexts. Our findings suggest that the emotional unbinding needs several consecutive nights of sleep to be complete, and that even subtle mood changes are sufficient to produce MDM effects.

Stability and magnetically induced heating behavior of lipid-coated Fe3O4 nanoparticles

NASA Astrophysics Data System (ADS)

Allam, Ayat A.; Sadat, Md Ehsan; Potter, Sarah J.; Mast, David B.; Mohamed, Dina F.; Habib, Fawzia S.; Pauletti, Giovanni M.

2013-10-01

-coated SPIONs on colloidal stability without compromising magnetically induced hyperthermia properties. Since phospholipids are biocompatible, these unique lipid-coated Fe3O4 nanoparticles offer exciting opportunities as thermoresponsive drug delivery carriers for targeted, stimulus-induced therapeutic interventions.

Dose–response study of chronic alcohol induced changes in sleep patterns in rats

PubMed Central

Mukherjee, Sanjib; Kazerooni, Morvarid; Simasko, Steven M.

2008-01-01

The goal of the present study was to determine an optimum exposure regimen for alterations in sleep induced by chronic alcohol treatments in rats. We used two different exposure routes (alcohol in water and alcohol in liquid diet at two different doses in each regimen (6% and 12% alcohol in water and 3% and 6% alcohol in liquid diet)). All treatments were for 6 weeks. We found the effects of the 6% and 12% in water and 3% in liquid diet to be very similar; all three produced increases in slow-wave sleep (SWS) only in the dark period with no changes in rapid-eye-movement sleep (REMS). On the other hand 6% alcohol in liquid diet caused much more dramatic changes, with alterations in both SWS and REMS in both the dark and light periods. These animals spent less time in SWS and REMS during the light period but more time in SWS and REMS in the dark period. Additionally, the variation of slow-wave amplitude (SWA) across day and night in this group of alcoholic animals is blunted with the loss of the peak of SWA at the beginning of light onset compared to the other groups. We conclude that future alcohol treatment regimens used to investigate the effects of alcohol on sleep in adult rats should use an exposure protocol of at least 6 weeks with 6% alcohol in liquid diet. PMID:18387599

Mice Lacking Alternatively Activated (M2) Macrophages Show Impairments in Restorative Sleep after Sleep Loss and in Cold Environment.

PubMed

Massie, Ashley; Boland, Erin; Kapás, Levente; Szentirmai, Éva

2018-06-05

The relationship between sleep, metabolism and immune functions has been described, but the cellular components of the interaction are incompletely identified. We previously reported that systemic macrophage depletion results in sleep impairment after sleep loss and in cold environment. These findings point to the role of macrophage-derived signals in maintaining normal sleep. Macrophages exist either in resting form, classically activated, pro-inflammatory (M1) or alternatively activated, anti-inflammatory (M2) phenotypes. In the present study we determined the contribution of M2 macrophages to sleep signaling by using IL-4 receptor α-chain-deficient [IL-4Rα knockout (KO)] mice, which are unable to produce M2 macrophages. Sleep deprivation induced robust increases in non-rapid-eye-movement sleep (NREMS) and slow-wave activity in wild-type (WT) animals. NREMS rebound after sleep deprivation was ~50% less in IL-4Rα KO mice. Cold exposure induced reductions in rapid-eye-movement sleep (REMS) and NREMS in both WT and KO mice. These differences were augmented in IL-4Rα KO mice, which lost ~100% more NREMS and ~25% more REMS compared to WTs. Our finding that M2 macrophage-deficient mice have the same sleep phenotype as mice with global macrophage depletion reconfirms the significance of macrophages in sleep regulation and suggests that the main contributors are the alternatively activated M2 cells.

Effects of bedding systems selected by manual muscle testing on sleep and sleep-related respiratory disturbances.

PubMed

Tsai, Ling-Ling; Liu, Hau-Min

2008-03-01

In this study, we investigated the feasibility of applying manual muscle testing (MMT) for bedding selection and examined the bedding effect on sleep. Four lay testers with limited training in MMT performed muscle tests for the selection of the bedding systems from five different mattresses and eight different pillows for 14 participants with mild sleep-related respiratory disturbances. For each participant individually, two bedding systems-one inducing stronger muscle forces and the other inducing weaker forces-were selected. The tester-participant pairs showed 85% and 100% agreement, respectively, for the selection of mattresses and pillows that induced the strongest muscle forces. The firmness of the mattress and the height of the pillow were significantly correlated with the body weight and body mass index of the participants for the selected strong bedding system but not for the weak bedding system. Finally, differences were observed between the strong and the weak bedding systems with regard to sleep-related respiratory disturbances and the percentage of slow-wave sleep. It was concluded that MMT can be performed by inexperienced testers for the selection of bedding systems.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

PubMed

Leu-Semenescu, Smaranda; Arnulf, Isabelle; Decaix, Caroline; Moussa, Fathi; Clot, Fabienne; Boniol, Camille; Touitou, Yvan; Levy, Richard; Vidailhet, Marie; Roze, Emmanuel

2010-03-01

A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs.

PubMed Central

Turnbull, M J; Watkins, J W

1976-01-01

A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypertensive rats awakened with lower brain halothane concentrations and were also hypersensitivity to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may be indicative of a drug's potential to produce dependence is discussed. PMID:987820

Ca(2+)-regulated cyclic electron flow supplies ATP for nitrogen starvation-induced lipid biosynthesis in green alga.

PubMed

Chen, Hui; Hu, Jinlu; Qiao, Yaqin; Chen, Weixian; Rong, Junfeng; Zhang, Yunming; He, Chenliu; Wang, Qiang

2015-10-09

We previously showed that both the linear photosynthetic electron transportation rate and the respiration rate dropped significantly during N starvation-induced neutral lipid accumulation in an oil-producing microalga, Chlorella sorokiniana, and proposed a possible role for cyclic electron flow (CEF) in ATP supply. In this study, we further exploited this hypothesis in both Chlorella sorokiniana C3 and the model green alga Chlamydomonas. We found that both the rate of CEF around photosystem I and the activity of thylakoid membrane-located ATP synthetase increased significantly during N starvation to drive ATP production. Furthermore, we demonstrated that the Chlamydomonas mutant pgrl1, which is deficient in PGRL1-mediated CEF, accumulated less neutral lipids and had reduced rates of CEF under N starvation. Further analysis revealed that Ca(2+) signaling regulates N starvation-induced neutral lipid biosynthesis in Chlamydomonas by increasing calmodulin activity and boosting the expression of the calcium sensor protein that regulates Pgrl1-mediated CEF. Thus, Ca(2+)-regulated CEF supplies ATP for N starvation-induced lipid biosynthesis in green alga. The increased CEF may re-equilibrate the ATP/NADPH balance and recycle excess light energy in photosystems to prevent photooxidative damage, suggesting Ca(2+)-regulated CEF also played a key role in protecting and sustaining photosystems.

Sleep deprivation reduces the citalopram-induced inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis of the rat.

PubMed

Prévot, E; Maudhuit, C; Le Poul, E; Hamon, M; Adrien, J

1996-12-01

Sleep deprivation (SD) for one night induces mood improvement in depressed patients. However, relapse often occurs on the day after deprivation subsequently to a sleep episode. In light of the possible involvement of central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission in both depression and sleep mechanisms, we presently investigated, in the rat, the effects of SD and recovery sleep on the electrophysiological response of 5-HT neurons in the nucleus raphe dorsalis (NRD) to an acute challenge with the 5-HT reuptake blocker citalopram. In all rats, citalopram induced a dose-dependent inhibition of the firing of NRD neurons recorded under chloral hydrate anaesthesia. After SD, achieved by placing rats in a slowly rotating cylinder for 24 h, the inhibitory action of citalopram was significantly reduced (with a concomitant 53% increase in its ED50 value). After a recovery period of 4 h, a normal susceptibility of the firing to citalopram was restored. The decreased sensitivity of 5-HT neuronal firing to the inhibitory effect of citalopram after SD probably results in an enhancement of 5-HT neurotransmission. Such an adaptive phenomenon (similar to that reported after chronic antidepressant treatment), and its normalization after recovery sleep, parallel the mood improvement effect of SD and the subsequent relapse observed in depressed patients. These data suggest that the associated changes in 5-HT autocontrol of the firing of NRD serotoninergic neurons are relevant to the antidepressant action of SD.

Nonthermal dielectric-barrier discharge plasma-induced inactivation involves oxidative DNA damage and membrane lipid peroxidation in Escherichia coli.

PubMed

Joshi, Suresh G; Cooper, Moogega; Yost, Adam; Paff, Michelle; Ercan, Utku K; Fridman, Gregory; Friedman, Gary; Fridman, Alexander; Brooks, Ari D

2011-03-01

Oxidative stress leads to membrane lipid peroxidation, which yields products causing variable degrees of detrimental oxidative modifications in cells. Reactive oxygen species (ROS) are the key regulators in this process and induce lipid peroxidation in Escherichia coli. Application of nonthermal (cold) plasma is increasingly used for inactivation of surface contaminants. Recently, we reported a successful application of nonthermal plasma, using a floating-electrode dielectric-barrier discharge (FE-DBD) technique for rapid inactivation of bacterial contaminants in normal atmospheric air (S. G. Joshi et al., Am. J. Infect. Control 38:293-301, 2010). In the present report, we demonstrate that FE-DBD plasma-mediated inactivation involves membrane lipid peroxidation in E. coli. Dose-dependent ROS, such as singlet oxygen and hydrogen peroxide-like species generated during plasma-induced oxidative stress, were responsible for membrane lipid peroxidation, and ROS scavengers, such as α-tocopherol (vitamin E), were able to significantly inhibit the extent of lipid peroxidation and oxidative DNA damage. These findings indicate that this is a major mechanism involved in FE-DBD plasma-mediated inactivation of bacteria.

Nonthermal Dielectric-Barrier Discharge Plasma-Induced Inactivation Involves Oxidative DNA Damage and Membrane Lipid Peroxidation in Escherichia coli▿

PubMed Central

Joshi, Suresh G.; Cooper, Moogega; Yost, Adam; Paff, Michelle; Ercan, Utku K.; Fridman, Gregory; Friedman, Gary; Fridman, Alexander; Brooks, Ari D.

2011-01-01

Oxidative stress leads to membrane lipid peroxidation, which yields products causing variable degrees of detrimental oxidative modifications in cells. Reactive oxygen species (ROS) are the key regulators in this process and induce lipid peroxidation in Escherichia coli. Application of nonthermal (cold) plasma is increasingly used for inactivation of surface contaminants. Recently, we reported a successful application of nonthermal plasma, using a floating-electrode dielectric-barrier discharge (FE-DBD) technique for rapid inactivation of bacterial contaminants in normal atmospheric air (S. G. Joshi et al., Am. J. Infect. Control 38:293-301, 2010). In the present report, we demonstrate that FE-DBD plasma-mediated inactivation involves membrane lipid peroxidation in E. coli. Dose-dependent ROS, such as singlet oxygen and hydrogen peroxide-like species generated during plasma-induced oxidative stress, were responsible for membrane lipid peroxidation, and ROS scavengers, such as α-tocopherol (vitamin E), were able to significantly inhibit the extent of lipid peroxidation and oxidative DNA damage. These findings indicate that this is a major mechanism involved in FE-DBD plasma-mediated inactivation of bacteria. PMID:21199923

Protective effects of boron on cyclophosphamide induced lipid peroxidation and genotoxicity in rats.

PubMed

Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Acaroz, Damla Arslan; Akbel, Erten; Cigerci, Ibrahim Hakki

2014-08-01

The aim of the present study was to evaluate the possible protective effect of boron (B) on cyclophosphamide (CYC) induced oxidative stress in rats. Totally, thirty Wistar albino male rats were fed standard rodent diet and divided into 5 equal groups: physiological saline was given intraperitoneally (i.p.) to the control group (vehicle treated), to the second group only 75 mg kg(-1) CYC was given i.p. on the 14th d, and boron was administered (5, 10, and 20 mg kg(-1), i.p.) to the other groups for 14 d and CYC (75 mg kg(-1), i.p.) on the 14th d. CYC caused increase of malondialdehyde and decrease of glutathione levels, decrease of superoxide dismutase activities in erythrocyte and tissues, decrease of erythrocyte, heart, lung, and brain catalase, and plasma antioxidant activities. Also, CYC treatment caused to DNA damage in mononuclear leukocytes. Moreover, B exhibited protective action against the CYC-induced histopathological changes in tissues. However, treatment of B decreased severity of CYC-induced lipid peroxidation and genotoxicity on tissues. In conclusion, B has ameliorative effects against CYC-induced lipid peroxidation and genotoxicity by enhancing antioxidant defence mechanism in rat. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dysfunction in gap junction intercellular communication induces aberrant behavior of the inner cell mass and frequent collapses of expanded blastocysts in mouse embryos.

PubMed

Togashi, Kazue; Kumagai, Jin; Sato, Emiko; Shirasawa, Hiromitsu; Shimoda, Yuki; Makino, Kenichi; Sato, Wataru; Kumazawa, Yukiyo; Omori, Yasufumi; Terada, Yukihiro

2015-06-01

We investigated the role of gap junctions (GJs) in embryological differentiation, and observed the morphological behavior of the inner cell mass (ICM) by time-lapse movie observation (TLM) with gap junction inhibitors (GJis). ICR mouse embryos were exposed to two types of GJis in CZB medium: oleamide (0 to 50 μM) and 1-heptanol (0 to 10 mM). We compared the rate of blastocyst formation at embryonic day 4.5 (E4.5) with E5.5. We also observed and evaluated the times from the second cleavage to each embryonic developing stage by TLM. We investigated embryonic distribution of DNA, Nanog protein, and Connexin 43 protein with immunofluorescent staining. In the comparison of E4.5 with E5.5, inhibition of gap junction intercellular communication (GJIC) delayed embryonic blastocyst formation. The times from the second cleavage to blastocyst formation were significantly extended in the GJi-treated embryos (control vs with oleamide, 2224 ± 179 min vs 2354 ± 278 min, p = 0.013). Morphological differences were traced in control versus GJi-treated embryos until the hatching stage. Oleamide induced frequent severe collapses of expanded blastocysts (77.4 % versus 26.3 %, p = 0.0001) and aberrant ICM divisions connected to sticky strands (74.3 % versus 5.3 %, p = 0.0001). Immunofluorescent staining indicated Nanog-positive cells were distributed in each divided ICM. GJIC plays an important role in blastocyst formation, collapses of expanded blastocysts, and the ICM construction in mouse embryos.

Mild pressure induces rapid accumulation of neutral lipid (triacylglycerol) in Chlorella spp.

PubMed

Praveenkumar, Ramasamy; Kim, Bohwa; Lee, Jiye; Vijayan, Durairaj; Lee, Kyubock; Nam, Bora; Jeon, Sang Goo; Kim, Dong-Myung; Oh, You-Kwan

2016-11-01

Effective enhancement of neutral lipid (especially triacylglycerol, TAG) content in microalgae is an important issue for commercialization of microalgal biorefineries. Pressure is a key physical factor affecting the morphological, physiological, and biochemical behaviors of organisms. In this paper, we report a new stress-based method for induction of TAG accumulation in microalgae (specifically, Chlorella sp. KR-1 and Ch. sp. AG20150) by very-short-duration application of mild pressure. Pressure treatments of 10-15bar for 2h resulted in a considerable, ∼55% improvement of the 10-100g/Lcells' TAG contents compared with the untreated control. The post-pressure-treatment increase of cytoplasmic TAG granules was further confirmed by transmission electron microscopy (TEM). Notwithstanding the increased TAG content, the total lipid content was not changed by pressurization, implying that pressure stress possibly induces rapid remodeling/transformation of algal lipids rather than de novo biosynthesis of TAG. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurobiological linkage between stress and sleep

NASA Astrophysics Data System (ADS)

Sanford, Larry D.; Wellman, Laurie L.

2012-10-01

Stress can have a significant negative impact on health and stress-induced alterations in sleep are implicated in both human sleep disorders and in psychiatric disorders in which sleep is affected. We have demonstrated that the amygdala, a region critical for regulating emotion, is a key modulator of sleep. Our current research is focused on understanding how the amygdala and stressful emotion affect sleep and on the role sleep plays in recovery from stress. We have implemented animal models to examine the how stress and stress-related memories impact sleep. Experiencing uncontrollable stress and reminders of uncontrollable stress can produce significant reductions in sleep, in particular rapid eye movement sleep. We are using these models to explore the neurobiology linking stress-related emotion and sleep. This research is relevant for sleep disorders such as insomnia and into mental disorders in which sleep is affected such as post-traumatic stress disorder (PTSD), which is typically characterized by a prominent sleep disturbance in the aftermath of exposure to a psychologically traumatic event.

Heart rate variability during carbachol-induced REM sleep and cataplexy.

PubMed

Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Velasquez, Noelia; Brando, Victoria; Falconi, Atilio; Chase, Michael H; Migliaro, Eduardo R

2015-09-15

The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with muscle atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same muscle atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the muscle atonia during this state. Copyright © 2015 Elsevier B.V. All rights reserved.

Diabetes-induced changes in specific lipid molecular species in rat myocardium.

PubMed Central

Han, X; Abendschein, D R; Kelley, J G; Gross, R W

2000-01-01

Intrinsic cardiac dysfunction during the diabetic state has been causally linked to changes in myocardial lipid metabolism. However, the precise alterations in the molecular species of myocardial polar and non-polar lipids during the diabetic state and their responses to insulin have not been investigated. Herein we demonstrate four specific alterations in rat myocardial lipid molecular species after induction of the diabetic state by streptozotocin treatment: (i) a massive remodelling of triacylglycerol molecular species including a >5-fold increase in tripalmitin mass and a 60% decrease in polyunsaturated triacylglycerol molecular species mass (i.e. triacylglycerols containing at least one acyl residue with more than two double bonds); (ii) a 46% increase in myocardial phosphatidylinositol mass; (iii) a 44% increase in myocardial plasmenylethanolamine mass and (iv) a 22% decrease in 1-stearoyl-2-arachidonoyl phosphatidylethanolamine content. Each of the changes in phospholipid classes, subclasses and individual molecular species were prevented by insulin treatment after induction of the diabetic state. In sharp contrast, the alterations in triacylglycerol molecular species were not preventable by peripheral insulin treatment after induction of the diabetic state. These results segregate diabetes-induced alterations in myocardial lipid metabolism into changes that can be remedied or not by routine peripheral insulin treatment and suggest that peripheral insulin therapy alone may not be sufficient to correct all of the metabolic alterations present in diabetic myocardium. PMID:11062060

Lipid-derived free radical production in superantigen-induced interstitial pneumonia

PubMed Central

Miyakawa, Hisako; Mason, Ronald P.; Jiang, JinJie; Kadiiska, Maria B.

2009-01-01

We studied the free radical generation involved in the development of interstitial pneumonia (IP) in an animal model of autoimmune disease. We observed an electron spin resonance (ESR) spectrum of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts detected in the lipid extract of lungs in autoimmune-prone mice after intratracheal instillation of staphylococcal enterotoxin B. The POBN adducts detected by ESR were paralleled by infiltration of macrophages and neutrophils in the bronchoalveolar lavage fluid. To further investigate the mechanism of free radical generation, mice were pretreated with the macrophage toxicant gadolinium chloride, which significantly suppressed the radical generation. Free radical generation was also decreased by pretreatment with the xanthine oxidase (XO) inhibitor allopurinol, the iron chelator Desferal, and the inducible nitric oxide synthase (iNOS) inhibitor 1400W. Histopathologically, these drugs significantly reduced both the cell infiltration to alveolar septal walls and the synthesis of pulmonary collagen fibers. Experiments with NADPH oxidase knockout mice showed that NADPH oxidase did not contribute to lipid radical generation. These results suggest that lipid-derived carbon-centered free radical production is important in the manifestation of IP and that a macrophage toxicant, an XO inhibitor, an iron chelator, and an iNOS inhibitor protect against both radical generation and the manifestation of IP. PMID:19376221

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy.

PubMed

Jaffrès, Paul-Alain; Gajate, Consuelo; Bouchet, Ana Maria; Couthon-Gourvès, Hélène; Chantôme, Aurélie; Potier-Cartereau, Marie; Besson, Pierre; Bougnoux, Philippe; Mollinedo, Faustino; Vandier, Christophe

2016-09-01

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals.

PubMed Central

Coffey, M D; Cole, R A; Colles, S M; Chisolm, G M

1995-01-01

Mounting evidence supports current theories linking lipoprotein oxidation to atherosclerosis. We sought the cellular biochemical mechanism by which oxidized LDL inflicts cell injury. Inhibitors of candidate pathways of cell death were used to treat human fibroblast target cells exposed to oxidized LDL.. Ebselen, which degrades lipid hydroperoxides, inhibited oxidized LDL toxicity, consistent with our recent report that 7 beta-hydroperoxycholesterol (7 beta-OOH chol) is the major cytotoxin of oxidized LDL. Intracellular chelation of metal ions inhibited, while preloading cells with iron enhanced, toxicity, Inhibition of oxidized LDL and 7 beta-OOH chol toxicity by 2-keto-4-thiolmethyl butyric acid, a putative alkoxyl radical scavenger and by vitamin E, probucol and diphenylphenylenediamine, putative scavengers of peroxyl radicals was consistent with the involvement of these radicals in the lethal sequence. Cell death was thus postulated to occur due to lipid peroxidation via a sequence involving lipid hydroperoxide-induced, iron-mediated formation of alkoxyl, lipid, and peroxyl radicals. Pathways involving other reactive oxygen species, new protein synthesis, or altered cholesterol metabolism were considered less likely, since putative inhibitors failed to lessen toxicity. Understanding the mechanism of cell injury by oxidized LDL and its toxic moiety, 7 beta-OOH chol, may indicate specific interventions in the cell injury believed to accompany vascular lesion development. PMID:7560078

Lipid Emulsion Attenuates Acetylcholine-Induced Relaxation in Isolated Rat Aorta

PubMed Central

Ok, Seong-Ho; Lee, Soo Hee; Yu, Jongsun; Park, Jungchul; Shin, Il-Woo; Lee, Youngju; Cho, Hyunhoo; Choi, Mun-Jeoung; Baik, Jiseok; Hong, Jeong-Min; Han, Jeong Yeol; Lee, Heon Keun; Chung, Young-Kyun; Sohn, Ju-Tae

2015-01-01

We investigated the effect of Lipofundin MCT/LCT and Intralipid on acetylcholine-induced nitric oxide- (NO-) mediated relaxation in rat aorta to determine which lipid emulsion (LE) is more potent in terms of inhibition of NO-induced relaxation. Dose-response curves of responses induced by acetylcholine, the calcium ionophore A23187, and sodium nitroprusside were generated using isolated rat aorta with or without LE. The effect of Lipofundin MCT/LCT on acetylcholine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVECs) was investigated using western blotting. Lipofundin MCT/LCT (0.1 and 0.2%) attenuated acetylcholine-induced relaxation in endothelium-intact aorta with or without tiron, whereas 0.2% Intralipid only inhibited relaxation. Lipofundin MCT/LCT inhibited relaxation induced by the calcium ionophore A23187 and sodium nitroprusside in endothelium-intact aorta, but Lipofundin MCT/LCT had no effect on sodium nitroprusside-induced relaxation in the endothelium-denuded aorta. Combined pretreatment with l-arginine plus Lipofundin MCT/LCT increased acetylcholine-induced maximal relaxation in endothelium-intact aorta compared with Lipofundin MCT/LCT alone. l-Arginine attenuated Lipofundin MCT/LCT-mediated inhibition of acetylcholine-induced eNOS phosphorylation in HUVECs. Taken together, Lipofundin MCT/LCT attenuated acetylcholine-induced NO-mediated relaxation via an inhibitory effect on the endothelium including eNOS, which is proximal to activation of guanylyl cyclase. PMID:26273653

Lipid Emulsion Attenuates Acetylcholine-Induced Relaxation in Isolated Rat Aorta.