WorldWideScience

Sample records for barrier function regulate

  1. Karyopherins regulate nuclear pore complex barrier and transport function.

    Science.gov (United States)

    Kapinos, Larisa E; Huang, Binlu; Rencurel, Chantal; Lim, Roderick Y H

    2017-09-01

    Nucleocytoplasmic transport is sustained by karyopherins (Kaps) and a Ran guanosine triphosphate (RanGTP) gradient that imports nuclear localization signal (NLS)-specific cargoes (NLS-cargoes) into the nucleus. However, how nuclear pore complex (NPC) barrier selectivity, Kap traffic, and NLS-cargo release are systematically linked and simultaneously regulated remains incoherent. In this study, we show that Kapα facilitates Kapβ1 turnover and occupancy at the NPC in a RanGTP-dependent manner that is directly coupled to NLS-cargo release and NPC barrier function. This is underpinned by the binding affinity of Kapβ1 to phenylalanine-glycine nucleoporins (FG Nups), which is comparable with RanGTP·Kapβ1, but stronger for Kapα·Kapβ1. On this basis, RanGTP is ineffective at releasing standalone Kapβ1 from NPCs. Depleting Kapα·Kapβ1 by RanGTP further abrogates NPC barrier function, whereas adding back Kapβ1 rescues it while Kapβ1 turnover softens it. Therefore, the FG Nups are necessary but insufficient for NPC barrier function. We conclude that Kaps constitute integral constituents of the NPC whose barrier, transport, and cargo release functionalities establish a continuum under a mechanism of Kap-centric control. © 2017 Kapinos et al.

  2. Hydrogen sulfide metabolism regulates endothelial solute barrier function

    Directory of Open Access Journals (Sweden)

    Shuai Yuan

    2016-10-01

    Full Text Available Hydrogen sulfide (H2S is an important gaseous signaling molecule in the cardiovascular system. In addition to free H2S, H2S can be oxidized to polysulfide which can be biologically active. Since the impact of H2S on endothelial solute barrier function is not known, we sought to determine whether H2S and its various metabolites affect endothelial permeability. In vitro permeability was evaluated using albumin flux and transendothelial electrical resistance. Different H2S donors were used to examine the effects of exogenous H2S. To evaluate the role of endogenous H2S, mouse aortic endothelial cells (MAECs were isolated from wild type mice and mice lacking cystathionine γ-lyase (CSE, a predominant source of H2S in endothelial cells. In vivo permeability was evaluated using the Miles assay. We observed that polysulfide donors induced rapid albumin flux across endothelium. Comparatively, free sulfide donors increased permeability only with higher concentrations and at later time points. Increased solute permeability was associated with disruption of endothelial junction proteins claudin 5 and VE-cadherin, along with enhanced actin stress fiber formation. Importantly, sulfide donors that increase permeability elicited a preferential increase in polysulfide levels within endothelium. Similarly, CSE deficient MAECs showed enhanced solute barrier function along with reduced endogenous bound sulfane sulfur. CSE siRNA knockdown also enhanced endothelial junction structures with increased claudin 5 protein expression. In vivo, CSE genetic deficiency significantly blunted VEGF induced hyperpermeability revealing an important role of the enzyme for barrier function. In summary, endothelial solute permeability is critically regulated via exogenous and endogenous sulfide bioavailability with a prominent role of polysulfides.

  3. Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity

    Directory of Open Access Journals (Sweden)

    Harmit S. Ranhotra

    2016-07-01

    Full Text Available The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.

  4. Update on pulmonary edema: the role and regulation of endothelial barrier function.

    Science.gov (United States)

    Patterson, C E; Lum, H

    2001-01-01

    Discovery of the pathophysiologic mechanisms leading to pulmonary edema and identification of effective strategies for prevention remain significant clinical concerns. Endothelial barrier function is a key component for maintenance of the integrity of the vascular boundary in the lung, particularly since the gas exchange surface area of the alveolar-capillary membrane is large. This review is focused on new insights in the pulmonary endothelial response to injury and recovery, reversible activation by edemagenic agents, and the biochemical/structural basis for regulation of endothelial barrier function. This information is discussed in the context of fundamental concepts of lung fluid balance and pulmonary function.

  5. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.

    Science.gov (United States)

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua; Wu, Guangyu; Wang, Guansong

    2015-12-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation.

  6. [Vascular endothelial Barrier Function].

    Science.gov (United States)

    Ivanov, A N; Puchinyan, D M; Norkin, I A

    2015-01-01

    Endothelium is an important regulator of selective permeability of the vascular wall for different molecules and cells. This review summarizes current data on endothelial barrier function. Endothelial glycocalyx structure, its function and role in the molecular transport and leukocytes migration across the endothelial barrier are discussed. The mechanisms of transcellular transport of macromolecules and cell migration through endothelial cells are reviewed. Special section of this article addresses the structure and function of tight and adherens endothelial junction, as well as their importance for the regulation of paracellular transport across the endothelial barrier. Particular attention is paid to the signaling mechanism of endothelial barrier function regulation and the factors that influence on the vascular permeability.

  7. The Small GTPase Rap1 Is a Novel Regulator of RPE Cell Barrier Function

    Science.gov (United States)

    Wittchen, Erika S.

    2011-01-01

    Purpose. To determine whether the small GTPase Rap1 regulates the formation and maintenance of the retinal pigment epithelial (RPE) cell junctional barrier. Methods. An in vitro model was used to study RPE barrier properties. To dissect the role of Rap1, two techniques were used to inhibit Rap1 function: overexpression of RapGAP, which acts as a negative regulator of endogenous Rap1 activity, and treatment with engineered, adenovirally-transduced microRNAs to knockdown Rap1 protein expression. Transepithelial electrical resistance (TER) and real-time cellular analysis (RTCA) of impedance were used as readouts for barrier properties. Immunofluorescence microscopy was used to visualize localization of cadherins under steady state conditions and also during junctional reassembly after calcium switch. Finally, choroidal endothelial cell (CEC) migration across RPE monolayers was quantified under conditions of Rap1 inhibition in RPE. Results. Knockdown of Rap1 or inhibition of its activity in RPE reduces TER and electrical impedance of the RPE monolayers. The loss of barrier function is also reflected by the mislocalization of cadherins and formation of gaps within the monolayer. TER measurement and immunofluorescent staining of cadherins after a calcium switch indicate that junctional reassembly kinetics are also impaired. Furthermore, CEC transmigration is significantly higher in Rap1-knockdown RPE monolayers compared with control. Conclusions. Rap1 GTPase is an important regulator of RPE cell junctions, and is required for maintenance of barrier function. This observation that RPE monolayers lacking Rap1 allow greater transmigration of CECs suggests a possible role for potentiating choroidal neovascularization during the pathology of neovascular age-related macular degeneration. PMID:21873678

  8. AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function.

    Science.gov (United States)

    Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M; Cullere, Xavier; Chojnacka, Katarzyna; Cheng, C Yan; Mayadas, Tanya N

    2016-02-01

    The blood-testis barrier (BTB), formed between adjacent Sertoli cells, undergoes extensive remodeling to facilitate the transport of preleptotene spermatocytes across the barrier from the basal to apical compartments of the seminiferous tubules for further development and maturation into spermatozoa. The actin cytoskeleton serves unique structural and supporting roles in this process, but little is known about the role of microtubules and their regulators during BTB restructuring. The large isoform of the cAMP-responsive scaffold protein AKAP9 regulates microtubule dynamics and nucleation at the Golgi. We found that conditional deletion of Akap9 in mice after the initial formation of the BTB at puberty leads to infertility. Akap9 deletion results in marked alterations in the organization of microtubules in Sertoli cells and a loss of barrier integrity despite a relatively intact, albeit more apically localized F-actin and BTB tight junctional proteins. These changes are accompanied by a loss of haploid spermatids due to impeded meiosis. The barrier, however, progressively reseals in older Akap9 null mice, which correlates with a reduction in germ cell apoptosis and a greater incidence of meiosis. However, spermiogenesis remains defective, suggesting additional roles for AKAP9 in this process. Together, our data suggest that AKAP9 and, by inference, the regulation of the microtubule network are critical for BTB function and subsequent germ cell development during spermatogenesis.

  9. Abl family kinases regulate endothelial barrier function in vitro and in mice.

    Directory of Open Access Journals (Sweden)

    Elizabeth M Chislock

    Full Text Available The maintenance of endothelial barrier function is essential for normal physiology, and increased vascular permeability is a feature of a wide variety of pathological conditions, leading to complications including edema and tissue damage. Use of the pharmacological inhibitor imatinib, which targets the Abl family of non-receptor tyrosine kinases (Abl and Arg, as well as other tyrosine kinases including the platelet-derived growth factor receptor (PDGFR, Kit, colony stimulating factor 1 receptor (CSF1R, and discoidin domain receptors, has shown protective effects in animal models of inflammation, sepsis, and other pathologies characterized by enhanced vascular permeability. However, the imatinib targets involved in modulation of vascular permeability have not been well-characterized, as imatinib inhibits multiple tyrosine kinases not only in endothelial cells and pericytes but also immune cells important for disorders associated with pathological inflammation and abnormal vascular permeability. In this work we employ endothelial Abl knockout mice to show for the first time a direct role for Abl in the regulation of vascular permeability in vivo. Using both Abl/Arg-specific pharmacological inhibition and endothelial Abl knockout mice, we demonstrate a requirement for Abl kinase activity in the induction of endothelial permeability by vascular endothelial growth factor both in vitro and in vivo. Notably, Abl kinase inhibition also impaired endothelial permeability in response to the inflammatory mediators thrombin and histamine. Mechanistically, we show that loss of Abl kinase activity was accompanied by activation of the barrier-stabilizing GTPases Rac1 and Rap1, as well as inhibition of agonist-induced Ca(2+ mobilization and generation of acto-myosin contractility. In all, these findings suggest that pharmacological targeting of the Abl kinases may be capable of inhibiting endothelial permeability induced by a broad range of agonists and that use

  10. Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression.

    Directory of Open Access Journals (Sweden)

    Akihiro Watari

    Full Text Available Several stressors are known to influence epithelial tight junction (TJ integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer. Daunorubicin- or rebeccamycin-induced enhancement of the TJ barrier function partly rescued attenuation of the barrier function by the inflammatory cytokines TNF-α and IFN-γ. Daunorubicin and rebeccamycin increased claudin-5 expression and the product was distributed in the actin cytoskeleton fraction, which was enriched with TJ proteins. Caffeine, which is an inhibitor of ataxia telangiectasia mutated protein (ATM and ataxia telangiectasia mutated and Rad3-related protein (ATR, and the Chk1 inhibitor inhibited the TER increases induced by daunorubicin and rebeccamycin, whereas a Chk2 inhibitor did not. Treatment with Chk1 siRNA also significantly inhibited the TER increases. Induction of claudin-5 expression was inhibited by Chk1 inhibitor and by siRNA treatment. Our results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine.

  11. Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression.

    Science.gov (United States)

    Watari, Akihiro; Hasegawa, Maki; Yagi, Kiyohito; Kondoh, Masuo

    2016-01-01

    Several stressors are known to influence epithelial tight junction (TJ) integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER) and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer. Daunorubicin- or rebeccamycin-induced enhancement of the TJ barrier function partly rescued attenuation of the barrier function by the inflammatory cytokines TNF-α and IFN-γ. Daunorubicin and rebeccamycin increased claudin-5 expression and the product was distributed in the actin cytoskeleton fraction, which was enriched with TJ proteins. Caffeine, which is an inhibitor of ataxia telangiectasia mutated protein (ATM) and ataxia telangiectasia mutated and Rad3-related protein (ATR), and the Chk1 inhibitor inhibited the TER increases induced by daunorubicin and rebeccamycin, whereas a Chk2 inhibitor did not. Treatment with Chk1 siRNA also significantly inhibited the TER increases. Induction of claudin-5 expression was inhibited by Chk1 inhibitor and by siRNA treatment. Our results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine.

  12. Skin barrier function

    DEFF Research Database (Denmark)

    2016-01-01

    Renowned experts present the latest knowledge Although a very fragile structure, the skin barrier is probably one of the most important organs of the body. Inward/out it is responsible for body integrity and outward/in for keeping microbes, chemicals, and allergens from penetrating the skin. Since...... the role of barrier integrity in atopic dermatitis and the relationship to filaggrin mutations was discovered a decade ago, research focus has been on the skin barrier, and numerous new publications have become available. This book is an interdisciplinary update offering a wide range of information...... on the subject. It covers new basic research on skin markers, including results on filaggrin and on methods for the assessment of the barrier function. Biological variation and aspects of skin barrier function restoration are discussed as well. Further sections are dedicated to clinical implications of skin...

  13. Glycogen Synthase Kinase 3 (GSK-3) influences epithelial barrier function by regulating Occludin, Claudin-1 and E-cadherin expression

    Energy Technology Data Exchange (ETDEWEB)

    Severson, Eric A.; Kwon, Mike; Hilgarth, Roland S.; Parkos, Charles A. [Epithelial Pathobiology Research Unit, Dept. of Pathology, Emory University, Atlanta, GA 30322 (United States); Nusrat, Asma, E-mail: anusrat@emory.edu [Epithelial Pathobiology Research Unit, Dept. of Pathology, Emory University, Atlanta, GA 30322 (United States)

    2010-07-02

    The Apical Junctional Complex (AJC) encompassing the tight junction (TJ) and adherens junction (AJ) plays a pivotal role in regulating epithelial barrier function and epithelial cell proliferative processes through signaling events that remain poorly characterized. A potential regulator of AJC protein expression is Glycogen Synthase Kinase-3 (GSK-3). GSK-3 is a constitutively active kinase that is repressed during epithelial-mesenchymal transition (EMT). In the present study, we report that GSK-3 activity regulates the structure and function of the AJC in polarized model intestinal (SK-CO15) and kidney (Madin-Darby Canine Kidney (MDCK)) epithelial cells. Reduction of GSK-3 activity, either by small molecule inhibitors or siRNA targeting GSK-3 alpha and beta mRNA, resulted in increased permeability to both ions and bulk solutes. Immunofluorescence labeling and immunoblot analyses revealed that the barrier defects correlated with decreased protein expression of AJC transmembrane proteins Occludin, Claudin-1 and E-cadherin without influencing other TJ proteins, Zonula Occludens-1 (ZO-1) and Junctional Adhesion Molecule A (JAM-A). The decrease in Occludin and E-cadherin protein expression correlated with downregulation of the corresponding mRNA levels for these respective proteins following GSK-3 inhibition. These observations implicate an important role of GSK-3 in the regulation of the structure and function of the AJC that is mediated by differential modulation of mRNA transcription of key AJC proteins, Occludin, Claudin-1 and E-cadherin.

  14. RNase L Interacts with Filamin A To Regulate Actin Dynamics and Barrier Function for Viral Entry

    Science.gov (United States)

    Siddiqui, Mohammad Adnan; Dayal, Shubham; Naji, Merna; Ezelle, Heather J.; Zeng, Chun; Zhou, Aimin; Hassel, Bret A.

    2014-01-01

    ABSTRACT The actin cytoskeleton and its network of associated proteins constitute a physical barrier that viruses must circumvent to gain entry into cells for productive infection. The mechanisms by which the physical signals of infection are sensed by the host to activate an innate immune response are not well understood. The antiviral endoribonuclease RNase L is ubiquitously expressed in a latent form and activated upon binding 2-5A, a unique oligoadenylate produced during viral infections. We provide evidence that RNase L in its inactive form interacts with the actin-binding protein Filamin A to modulate the actin cytoskeleton and inhibit virus entry. Cells lacking either RNase L or Filamin A displayed increased virus entry which was exacerbated in cells lacking both proteins. RNase L deletion mutants that reduced Filamin A interaction displayed a compromised ability to restrict virus entry, supporting the idea of an important role for the RNase L-Filamin A complex in barrier function. Remarkably, both the wild type and a catalytically inactive RNase L mutant were competent to reduce virus entry when transfected into RNase L-deficient cells, indicating that this novel function of RNase L is independent of its enzymatic activity. Virus infection and RNase L activation disrupt its association with Filamin A and release RNase L to mediate its canonical nuclease-dependent antiviral activities. The dual functions of RNase L as a constitutive component of the actin cytoskeleton and as an induced mediator of antiviral signaling and effector functions provide insights into its mechanisms of antiviral activity and opportunities for the development of novel antiviral agents. PMID:25352621

  15. Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.

    Science.gov (United States)

    Burton, Victoria J; Ciuclan, Loredana I; Holmes, Alan M; Rodman, David M; Walker, Christoph; Budd, David C

    2011-01-06

    Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor α or transforming growth factor β1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression.

  16. Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function.

    Science.gov (United States)

    Dohgu, Shinya; Sumi, Noriko; Nishioku, Tsuyoshi; Takata, Fuyuko; Watanabe, Takuya; Naito, Mikihiko; Shuto, Hideki; Yamauchi, Atsushi; Kataoka, Yasufumi

    2010-10-10

    Cyclosporin A, a potent immunosuppressant, can often produce neurotoxicity in patients, although its penetration into the brain is restricted by the blood-brain barrier (BBB). Brain pericytes and astrocytes, which are periendothelial accessory structures of the BBB, can be involved in cyclosporin A-induced BBB disruption. However, the mechanism by which cyclosporin A causes BBB dysfunction remains unknown. Here, we show that in rodent brain endothelial cells, cyclosporin A decreased transendothelial electrical resistance (TEER) by inhibiting intracellular signal transduction downstream of adrenomedullin, an autocrine regulator of BBB function. Cyclosporin A stimulated adrenomedullin release from brain endothelial cells, but did not affect binding of adrenomedullin to its receptors. This cyclosporin A-induced decrease in TEER was attenuated by exogenous addition of adrenomedullin. Cyclosporin A dose-dependently decreased the total cAMP concentration in brain endothelial cells. A combination of cyclosporin A (1microM) with an adenylyl cyclase inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536; 10microM), or a protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89; 1microM), markedly increased sodium fluorescein permeability in brain endothelial cells, whereas each drug alone had no effect. Thus, these data suggest that cyclosporin A inhibits the adenylyl cyclase/cyclic AMP/PKA signaling pathway activated by adrenomedullin, leading to impairment of brain endothelial barrier function. Copyright 2010. Published by Elsevier B.V.

  17. Arhgap17, a RhoGTPase activating protein, regulates mucosal and epithelial barrier function in the mouse colon

    Science.gov (United States)

    Lee, So-young; Kim, Hwain; Kim, Kyoungmi; Lee, Hyunji; Lee, Seungbok; Lee, Daekee

    2016-01-01

    Coordinated regulation of the actin cytoskeleton by the Rho GTPase family is required for the maintenance of polarity in epithelial cells as well as for their proliferation and migration. A RhoGTPase-activating protein 17 (Arhgap17) is known to be involved in multiple cellular processes in vitro, including the maintenance of tight junctions and vesicle trafficking. However, the function of Arhgap17 has not been studied in the physiological context. Here, we generated Arhgap17-deficient mice and examined the effect in the epithelial and mucosal barriers of the intestine. Reporter staining revealed that Arhgap17 expression is limited to the luminal epithelium of intestine. Arhgap17-deficient mice show an increased paracellular permeability and aberrant localization of the apical junction complex in the luminal epithelium, but do not develop spontaneous colitis. The inner mucus layer is impervious to the enteric bacteria irrespective of Tff3 downregulation in the Arhgap17-deficient mice. Interestingly however, treatment with dextran sulfate sodium (DSS) causes an increased accumulation of DSS and TNF production in intraluminal cells and rapid destruction of the inner mucus layer, resulting in increased severity of colitis in mutant mice. Overall, these data reveal that Arhgap17 has a novel function in regulating transcellular transport and maintaining integrity of intestinal barriers. PMID:27229483

  18. Arhgap17, a RhoGTPase activating protein, regulates mucosal and epithelial barrier function in the mouse colon.

    Science.gov (United States)

    Lee, So-Young; Kim, Hwain; Kim, Kyoungmi; Lee, Hyunji; Lee, Seungbok; Lee, Daekee

    2016-01-01

    Coordinated regulation of the actin cytoskeleton by the Rho GTPase family is required for the maintenance of polarity in epithelial cells as well as for their proliferation and migration. A RhoGTPase-activating protein 17 (Arhgap17) is known to be involved in multiple cellular processes in vitro, including the maintenance of tight junctions and vesicle trafficking. However, the function of Arhgap17 has not been studied in the physiological context. Here, we generated Arhgap17-deficient mice and examined the effect in the epithelial and mucosal barriers of the intestine. Reporter staining revealed that Arhgap17 expression is limited to the luminal epithelium of intestine. Arhgap17-deficient mice show an increased paracellular permeability and aberrant localization of the apical junction complex in the luminal epithelium, but do not develop spontaneous colitis. The inner mucus layer is impervious to the enteric bacteria irrespective of Tff3 downregulation in the Arhgap17-deficient mice. Interestingly however, treatment with dextran sulfate sodium (DSS) causes an increased accumulation of DSS and TNF production in intraluminal cells and rapid destruction of the inner mucus layer, resulting in increased severity of colitis in mutant mice. Overall, these data reveal that Arhgap17 has a novel function in regulating transcellular transport and maintaining integrity of intestinal barriers.

  19. Filaggrin and Skin Barrier Function.

    Science.gov (United States)

    Kezic, Sanja; Jakasa, Ivone

    2016-01-01

    The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models

  20. Role of Melatonin, Neuropeptide S and Short Chain Fatty Acids in Regulation of Duodenal Mucosal Barrier Function and Motility

    OpenAIRE

    Wan Saudi, Wan Salman

    2015-01-01

    The duodenal epithelium is regularly exposed to HCl, digestive enzymes, bacteria and toxins, and sometimes also to ethanol and drugs. The imbalance of aggressive factors in the intestinal lumen and mucosal barrier function increases the risk of tissue injury and inflammation. The key components of the duodenal barrier function include mucosal permeability, bicarbonate transport and the secretion or absorption of fluids. This thesis aims to elucidate the role of melatonin, neuropeptide S (NPS)...

  1. On the contribution of mucosal mast cells to the regulation of mouse intestinal barrier function

    NARCIS (Netherlands)

    Rychter, J.

    2010-01-01

    The primary functions of the small intestine are the digestion and transport of luminal content and the absorption of nutrients. During these processes the intestinal mucosa is exposed to various ingested and resident pathogens. The ability of the intestinal wall to prevent transmucosal passage of t

  2. JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.

    Science.gov (United States)

    Monteiro, Ana C; Sumagin, Ronen; Rankin, Carl R; Leoni, Giovanna; Mina, Michael J; Reiter, Dirk M; Stehle, Thilo; Dermody, Terence S; Schaefer, Stacy A; Hall, Randy A; Nusrat, Asma; Parkos, Charles A

    2013-09-01

    Intestinal barrier function is regulated by epithelial tight junctions (TJs), structures that control paracellular permeability. Junctional adhesion molecule-A (JAM-A) is a TJ-associated protein that regulates barrier; however, mechanisms linking JAM-A to epithelial permeability are poorly understood. Here we report that JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex, along with PDZ-GEF1, activates the small GTPase Rap2c. Supporting a functional link, small interfering RNA-mediated down-regulation of the foregoing regulatory proteins results in enhanced permeability similar to that observed after JAM-A loss. JAM-A-deficient mice and cultured epithelial cells demonstrate enhanced paracellular permeability to large molecules, revealing a potential role of JAM-A in controlling perijunctional actin cytoskeleton in addition to its previously reported role in regulating claudin proteins and small-molecule permeability. Further experiments suggest that JAM-A does not regulate actin turnover but modulates activity of RhoA and phosphorylation of nonmuscle myosin, both implicated in actomyosin contraction. These results suggest that JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

  3. Epidermal Growth Factor and Intestinal Barrier Function

    Directory of Open Access Journals (Sweden)

    Xiaopeng Tang

    2016-01-01

    Full Text Available Epidermal growth factor (EGF is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health.

  4. The extracellular matrix protein laminin α2 regulates the maturation and function of the blood-brain barrier.

    Science.gov (United States)

    Menezes, Michael J; McClenahan, Freyja K; Leiton, Cindy V; Aranmolate, Azeez; Shan, Xiwei; Colognato, Holly

    2014-11-12

    Laminins are major constituents of the gliovascular basal lamina of the blood-brain barrier (BBB); however, the role of laminins in BBB development remains unclear. Here we report that Lama2(-/-) mice, lacking expression of the laminin α2 subunit of the laminin-211 heterotrimer expressed by astrocytes and pericytes, have a defective BBB in which systemically circulated tracer leaks into the brain parenchyma. The Lama2(-/-) vascular endothelium had significant abnormalities, including altered integrity and composition of the endothelial basal lamina, inappropriate expression of embryonic vascular endothelial protein MECA32, substantially reduced pericyte coverage, and tight junction abnormalities. Additionally, astrocytic endfeet were hypertrophic and lacked appropriately polarized aquaporin4 channels. Laminin-211 appears to mediate these effects at least in part by dystroglycan receptor interactions, as preventing dystroglycan expression in neural cells led to a similar set of BBB abnormalities and gliovascular disturbances, which additionally included perturbed vascular endothelial glucose transporter-1 localization. These findings provide insight into the cell and molecular changes that occur in congenital muscular dystrophies caused by Lama2 mutations or inappropriate dystroglycan post-translational modifications, which have accompanying brain abnormalities, including seizures. Our results indicate a novel role for laminin-dystroglycan interactions in the cooperative integration of astrocytes, endothelial cells, and pericytes in regulating the BBB.

  5. Skin Barrier Function and Allergens

    DEFF Research Database (Denmark)

    Engebretsen, Kristiane Aasen; Thyssen, Jacob Pontoppidan

    2016-01-01

    The skin is an important barrier protecting us from mechanical insults, microorganisms, chemicals and allergens, but, importantly, also reducing water loss. A common hallmark for many dermatoses is a compromised skin barrier function, and one could suspect an elevated risk of contact sensitization...... and skin barrier status. Psoriasis has traditionally been regarded a Th1-dominated disease, but the discovery of Th17 cells and IL-17 provides new and interesting information regarding the pathogenesis of the disease. Research suggests an inverse relationship between psoriasis and CA, possibly due......) and Th2 (AD) have been proposed as an explanation. Finally, there is convincing evidence that exposure to irritants increases the risk of CS, and patients with ICD are, therefore, at great risk of developing CA. Skin irritation leads to the release of IL-1 and TNF-α, which affects the function of antigen...

  6. Functional barriers: Properties and evaluation

    NARCIS (Netherlands)

    Feigenbaum, A.; Dole, P.; Aucejo, S.; Dainelli, D.; Cruz Garcia, C. de la; Hankemeier, T.; N'Gono, Y.; Papaspyrides, C.D.; Paseiro, P.; Pastorelli, S.; Pavlidou, S.; Pennarun, P.Y.; Saillard, P.; Vidal, L.; Vitrac, O.; Voulzatis, Y.

    2005-01-01

    Functional barriers are multilayer structures deemed to prevent migration of some chemicals released by food-contact materials into food. In the area of plastics packaging, different migration behaviours of mono- and multilayer structures are assessed in terms of lag time and of their influence of t

  7. Wet Work and Barrier Function.

    Science.gov (United States)

    Fartasch, Manigé

    2016-01-01

    Wet work defined as unprotected exposure to humid environments/water; high frequencies of hand washing procedures or prolonged glove occlusion is believed to cause irritant contact dermatitis in a variety of occupations. This review considers the recent studies on wet-work exposure and focuses on its influence on barrier function. There are different methods to study the effect of wet work on barrier function. On the one hand, occupational cohorts at risk can be monitored prospectively by skin bioengineering technology and clinical visual scoring systems; on the other hand, experimental test procedures with defined application of water, occlusion and detergents are performed in healthy volunteers. Both epidemiological studies and the results of experimental procedures are compared and discussed. A variety of epidemiological studies analyze occupational cohorts at risk. The measurement of transepidermal water loss, an indicator of the integrity of the epidermal barrier, and clinical inspection of the skin have shown that especially the frequencies of hand washing and water contact/contact to aqueous mixtures seem to be the main factors for the occurrence of barrier alterations. On the other hand, in a single cross-sectional study, prolonged glove wearing (e.g. occlusion for 6 h per shift in clean-room workers) without exposure to additional hazardous substances seemed not to affect the skin negatively. But regarding the effect of occlusion, there is experimental evidence that previously occluded skin challenged with sodium lauryl sulfate leads to an increased susceptibility to the irritant with an aggravation of the irritant reaction. These findings might have relevance for the real-life situation in so far as after occupational glove wearing, the skin is more susceptible to potential hazards to the skin even during leisure hours.

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

    Science.gov (United States)

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

    2015-09-15

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

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

    Science.gov (United States)

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

    2015-01-01

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h 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. PMID:26080028

  10. Herbal medicines that benefit epidermal permeability barrier function

    Directory of Open Access Journals (Sweden)

    Lizhi Hu

    2015-06-01

    Full Text Available Epidermal permeability barrier function plays a critical role in regulating cutaneous functions. Hence, researchers have been searching for effective and affordable regimens to enhance epidermal permeability barrier function. In addition to topical stratum corneum lipids, peroxisome proliferator-activated receptor, and liver X receptor ligands, herbal medicines have been proven to benefit epidermal permeability barrier function in both normal and diseased skin, including atopic dermatitis, glucocorticoid-induced skin damage, and UVB-damaged skin. The potential mechanisms by which herbal medicines improve the permeability barrier include stimulation of epidermal differentiation, lipid production, antimicrobial peptide expression, and antioxidation. Therefore, utilization of herbal medicines could be a valuable alternative approach to enhance epidermal permeability barrier function in order to prevent and/or treat skin disorders associated with permeability barrier abnormalities.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-09-15

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

  12. Fatty Acid-Binding Protein 5 at the Blood-Brain Barrier Regulates Endogenous Brain Docosahexaenoic Acid Levels and Cognitive Function.

    Science.gov (United States)

    Pan, Yijun; Short, Jennifer L; Choy, Kwok H C; Zeng, Annie X; Marriott, Philip J; Owada, Yuji; Scanlon, Martin J; Porter, Christopher J H; Nicolazzo, Joseph A

    2016-11-16

    Fatty acid-binding protein 5 (FABP5) at the blood-brain barrier contributes to the brain uptake of docosahexaenoic acid (DHA), a blood-derived polyunsaturated fatty acid essential for maintenance of cognitive function. Given the importance of DHA in cognition, the aim of this study was to investigate whether deletion of FABP5 results in cognitive dysfunction and whether this is associated with reduced brain endothelial cell uptake of exogenous DHA and subsequent attenuation in the brain levels of endogenous DHA. Cognitive function was assessed in male and female FABP5(+/+) and FABP5(-/-) mice using a battery of memory paradigms. FABP5(-/-) mice exhibited impaired working memory and short-term memory, and these cognitive deficits were associated with a 14.7 ± 5.7% reduction in endogenous brain DHA levels. The role of FABP5 in the blood-brain barrier transport of DHA was assessed by measuring (14)C-DHA uptake into brain endothelial cells and capillaries isolated from FABP5(+/+) and FABP5(-/-) mice. In line with a crucial role of FABP5 in the brain uptake of DHA, (14)C-DHA uptake into brain endothelial cells and brain capillaries of FABP5(-/-) mice was reduced by 48.4 ± 14.5% and 14.0 ± 4.2%, respectively, relative to those of FABP5(+/+) mice. These results strongly support the hypothesis that FABP5 is essential for maintaining brain endothelial cell uptake of DHA, and that cognitive deficits observed in FABP5(-/-) mice are associated with reduced CNS access of DHA. Genetic deletion of fatty acid-binding protein 5 (FABP5) in mice reduces uptake of exogenous docosahexaenoic acid (DHA) into brain endothelial cells and brain capillaries and reduces brain parenchymal levels of endogenous DHA. Therefore, FABP5 in the brain endothelial cell is a crucial contributor to the brain levels of DHA. Critically, lowered brain DHA levels in FABP5(-/-) mice occurred in tandem with cognitive deficits in a battery of memory paradigms. This study provides evidence of a critical role

  13. Reprint of "The role of cytoskeleton in the regulation of vascular endothelial barrier function" [Microvascular Research 76 (2008) 202-207].

    Science.gov (United States)

    Bogatcheva, Natalia V; Verin, Alexander D

    2009-01-01

    The cytoskeleton is vital to the function of virtually all cell types in the organism as it is required for cell division, cell motility, endo- or exocytosis and the maintenance of cell shape. Endothelial cells, lining the inner surface of the blood vessels, exploit cytoskeletal elements to ensure the integrity of cell monolayer in quiescent endothelium, and to enable the disintegration of the formed barrier in response to various agonists. Vascular permeability is defined by the combination of transcellular and paracellular pathways, with the latter being a major contributor to the inflammation-induced barrier dysfunction. This review will analyze the cytoskeletal elements, which reorganization affects endothelial permeability, and emphasize signaling mechanisms with barrier-protective or barrier-disruptive potential.

  14. Gastric barrier function and toxic damage.

    Science.gov (United States)

    Niv, Yaron; Banić, Marko

    2014-01-01

    Gastric epithelium is the first significant barrier between the inner body and the potentially toxic material in the lumen. Nutrients affect gastric barrier continuously--alcohol, coffee, spices, salted food, etc. Also, very potent noxious agents are widely prescribed drugs--nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and selective serotonin reuptake inhibitors. Helicobacter pylori is a well-known and well-investigated pathogen associated with serious gastric damage and gastric carcinoma. For its defense and maintenance of homeostasis and integrity, except acid secretion and maintenance of low luminal pH, gastric mucosa also has a specific structure, and its function is influenced by different control mechanisms. These include control of mucosal blood flow, control of mucus and bicarbonate secretion, constant cell renewal, and neuronal and hormonal control of defense mechanisms. These mechanisms are mediated by prostaglandins, nitric oxide, growth factors, heat-shock proteins and a neuropeptide called calcitonin gene-related protein. Adrenal glucocorticoids and the central nervous system also play an important role in regulating gastro-protection, especially hypothalamus and the dorsal vagal complex. Gastric mucosa is also an important component of the body's immune system and gut-associated lymphoid tissue which serves as the initiation site for antigen-specific humoral and cell-mediated immune response. Treatment options for gastric barrier dysfunction and damage due to aforementioned noxious agents are guided by the nature of damage and our understanding of the pathophysiological mechanisms involved. Currently, management is guideline driven and depends upon eradication treatment in patients infected with H. pylori and treatment or prevention of aspirin or NSAID ulceration. © 2014 S. Karger AG, Basel.

  15. An Update of the Defensive Barrier Function of Skin

    OpenAIRE

    Lee, Seung Hun; Jeong, Se Kyoo; Ahn, Sung Ku

    2006-01-01

    Skin, as the outermost organ in the human body, continuously confronts the external environment and serves as a primary defense system. The protective functions of skin include UV-protection, anti-oxidant and antimicrobial functions. In addition to these protections, skin also acts as a sensory organ and the primary regulator of body temperature. Within these important functions, the epidermal permeability barrier, which controls the transcutaneous movement of water and other electrolytes, is...

  16. Permanent isolation surface barrier: Functional performance

    Energy Technology Data Exchange (ETDEWEB)

    Wing, N.R.

    1993-10-01

    This document presents the functional performance parameters for permanent isolation surface barriers. Permanent isolation surface barriers have been proposed for use at the Hanford Site (and elsewhere) to isolate and dispose of certain types of waste in place. Much of the waste that would be disposed of using in-place isolation techniques is located in subsurface structures, such as solid waste burial grounds, tanks, vaults, and cribs. Unless protected in some way, the wastes could be transported to the accessible environment via transport pathways, such as water infiltration, biointrusion, wind and water erosion, human interference, and/or gaseous release.

  17. The blood-nerve barrier: structure and functional significance.

    Science.gov (United States)

    Weerasuriya, Ananda; Mizisin, Andrew P

    2011-01-01

    The blood-nerve barrier (BNB) defines the physiological space within which the axons, Schwann cells, and other associated cells of a peripheral nerve function. The BNB consists of the endoneurial microvessels within the nerve fascicle and the investing perineurium. The restricted permeability of these two barriers protects the endoneurial microenvironment from drastic concentration changes in the vascular and other extracellular spaces. It is postulated that endoneurial homeostatic mechanisms regulate the milieu intérieur of peripheral axons and associated Schwann cells. These mechanisms are discussed in relation to nerve development, Wallerian degeneration and nerve regeneration, and lead neuropathy. Finally, the putative factors responsible for the cellular and molecular control of BNB permeability are discussed. Given the dynamic nature of the regulation of the permeability of the perineurium and endoneurial capillaries, it is suggested that the term blood-nerve interface (BNI) better reflects the functional significance of these structures in the maintenance of homeostasis within the endoneurial microenvironment.

  18. Ceramides and barrier function in healthy skin

    OpenAIRE

    Jungerstedt, J; Hellgren, Lars; Drachmann, Tue; Høgh, Julie Kaae; Jemec, GBE; Agner, T

    2010-01-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal ...

  19. Ceramides and barrier function in healthy skin

    OpenAIRE

    Jungerstedt, J; Hellgren, Lars; Drachmann, Tue; Høgh, Julie Kaae; Jemec, GBE; Agner, T

    2010-01-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal ...

  20. Intracellular mediators of JAM-A-dependent epithelial barrier function.

    Science.gov (United States)

    Monteiro, Ana C; Parkos, Charles A

    2012-06-01

    Junctional adhesion molecule-A (JAM-A) is a critical signaling component of the apical junctional complex, a structure composed of several transmembrane and scaffold molecules that controls the passage of nutrients and solutes across epithelial surfaces. Observations from JAM-A-deficient epithelial cells and JAM-A knockout animals indicate that JAM-A is an important regulator of epithelial paracellular permeability; however, the mechanism(s) linking JAM-A to barrier function are not understood. This review highlights recent findings relevant to JAM-A-mediated regulation of epithelial permeability, focusing on the role of upstream and downstream signaling candidates. We draw on what is known about proteins reported to associate with JAM-A in other pathways and on known modulators of barrier function to propose candidate effectors that may mediate JAM-A regulation of epithelial paracellular permeability. Further investigation of pathways highlighted in this review may provide ideas for novel therapeutics that target debilitating conditions associated with barrier dysfunction, such as inflammatory bowel disease.

  1. Ceramides and barrier function in healthy skin

    DEFF Research Database (Denmark)

    Jungerstedt, J; Hellgren, Lars; Drachmann, Tue;

    2010-01-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups...... and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal water loss and with information on dry skin from a questionnaire including 16 people. No statistically...

  2. Embryonic Blood-Cerebrospinal Fluid Barrier Formation and Function

    Directory of Open Access Journals (Sweden)

    David eBueno

    2014-10-01

    Full Text Available During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF. CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS. The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood–brain barrier (BBB systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood–CSF barrier in the context of the crucial roles played by the molecules in eCSF.

  3. Can probiotics modulate human disease by impacting intestinal barrier function?

    NARCIS (Netherlands)

    Bron, Peter A.; Kleerebezem, Michiel; Brummer, Robert Jan; Cani, Patrice D.; Mercenier, Annick; MacDonald, Thomas T.; Garcia-Ródenas, Clara L.; Wells, Jerry M.

    2017-01-01

    Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is

  4. Impaired water barrier function in acne vulgaris.

    Science.gov (United States)

    Yamamoto, A; Takenouchi, K; Ito, M

    1995-01-01

    In acne vulgaris, abnormal follicular keratinization is important for comedo formation, yet the precise mechanisms of comedogenesis are not known. The present study examined the interrelationship between sebum secretion rate (SSR), lipid content and water barrier function (WBF) of the stratum corneum (SC) in 36 acne patients and 29 control subjects. All major SC lipid classes were separated and quantified by thin-layer chromatography/photodensitometry. WBF was evaluated by measuring transepidermal water loss (TEWL), and the hygroscopic properties and waterholding capacity of the SC. The SSR over a period of 3 h was significantly higher in patients with moderate acne than in control subjects, but no significant difference was noticed between patients with mild acne and control subjects. Significant differences between patients with both moderate and mild acne and control subjects were noted in the amount of sphingolipids (ceramides and free sphingosine), but not for any other lipid classes. Furthermore in acne patients, lower amounts of sphingolipids were observed corresponding with a diminished WBF. These results suggest that an impaired WBF caused by decreased amounts of ceramides may be responsible for comedo formation, since barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.

  5. Epithelial Barrier Regulation by Hypoxia-Inducible Factor.

    Science.gov (United States)

    Glover, Louise E; Colgan, Sean P

    2017-09-01

    Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po2 determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.

  6. Ceramides and barrier function in healthy skin.

    Science.gov (United States)

    Mutanu Jungersted, Jakob; Hellgren, Lars I; Høgh, Julie K; Drachmann, T; Jemec, Gregor B E; Agner, Tove

    2010-07-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal water loss and with information on dry skin from a questionnaire including 16 people. No statistically significant differences were found between young and old skin for ceramide subgroups or ceramide/cholesterol ratios, and there was no statistically significant correlation between answers about dry skin and ceramide levels. Interestingly, a statistically significant higher ceramide/cholesterol ratio was found for men than for women (p = 0.02).

  7. Ceramides and barrier function in healthy skin

    DEFF Research Database (Denmark)

    Mutanu Jungersted, Jakob; Hellgren, Lars; Høgh, Julie Kaae

    2010-01-01

    Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups...... and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal water loss and with information on dry skin from a questionnaire including 16 people. No statistically...... significant differences were found between young and old skin for ceramide subgroups or ceramide/cholesterol ratios, and there was no statistically significant correlation between answers about dry skin and ceramide levels. Interestingly, a statistically significant higher ceramide/cholesterol ratio was found...

  8. Government regulation of business in a changing institutional barrier

    Directory of Open Access Journals (Sweden)

    Novikova I.

    2013-02-01

    Full Text Available The article examines the domestic experience in government regulation of business in a changing institutional barrier.Compared the degree of economic freedom in Ukraine. The emphasis is on the need to develop a national strategy of institutional development of domestic entrepreneurship.

  9. Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors.

    Science.gov (United States)

    Wiltshire, Rachael; Nelson, Vicky; Kho, Dan Ting; Angel, Catherine E; O'Carroll, Simon J; Graham, E Scott

    2016-01-27

    Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1β. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors.

  10. Relationship between functional regulation of enteric epithelial barrier and autoimmunity disease%肠上皮屏障功能的调节与自身免疫性疾病的关系

    Institute of Scientific and Technical Information of China (English)

    李兰

    2011-01-01

    Ever increasing research find many autoimmune diseases have close relation to intestinal epithelium barrier. This review will provide a progress on the barrier structure, regulation and relation to autoimmune disease.%近年来研究发现很多自身免疫性疾病与肠上皮屏障的功能密切相关,本文着重对肠上皮屏障的基本结构、调控及与自身免疫性疾病的关系作一综述.

  11. High glucose induces dysfunction of airway epithelial barrier through down-regulation of connexin 43.

    Science.gov (United States)

    Yu, Hongmei; Yang, Juan; Zhou, Xiangdong; Xiao, Qian; Lü, Yang; Xia, Li

    2016-03-01

    The airway epithelium is a barrier to the inhaled antigens and pathogens. Connexin 43 (Cx43) has been found to play critical role in maintaining the function of airway epithelial barrier and be involved in the pathogenesis of the diabetic retinal vasculature, diabetes nephropathy and diabetes skin. Hyperglycemia has been shown to be an independent risk factor for respiratory infections. We hypothesize that the down-regulation of Cx43 induced by HG alters the expression of tight junctions (zonula occludens-1 (ZO-1) and occludin) and contributes to dysfunction of airway epithelial barrier, and Cx43 plays a critical role in the process in human airway epithelial cells (16 HBE). We show that high glucose (HG) decreased the expression of ZO-1 and occludin, disassociated interaction between Cx43 and tight junctions, and then increased airway epithelial transepithelial electrical resistance (TER) and permeability by down-regulation of Cx43 in human airway epithelial cells. These observations demonstrate an important role for Cx43 in regulating HG-induced dysfunction of airway epithelial barrier. These findings may bring new insights into the molecular pathogenesis of pulmonary infection related to diabetes mellitus and lead to novel therapeutic intervention for the dysfunction of airway epithelial barrier in chronic inflammatory airway diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Outer Membrane Vesicles and Soluble Factors Released by Probiotic Escherichia coli Nissle 1917 and Commensal ECOR63 Enhance Barrier Function by Regulating Expression of Tight Junction Proteins in Intestinal Epithelial Cells

    Science.gov (United States)

    Alvarez, Carina-Shianya; Badia, Josefa; Bosch, Manel; Giménez, Rosa; Baldomà, Laura

    2016-01-01

    The gastrointestinal epithelial layer forms a physical and biochemical barrier that maintains the segregation between host and intestinal microbiota. The integrity of this barrier is critical in maintaining homeostasis in the body and its dysfunction is linked to a variety of illnesses, especially inflammatory bowel disease. Gut microbes, and particularly probiotic bacteria, modulate the barrier integrity by reducing gut permeability and reinforcing tight junctions. Probiotic Escherichia coli Nissle 1917 (EcN) is a good colonizer of the human gut with proven therapeutic efficacy in the remission of ulcerative colitis in humans. EcN positively modulates the intestinal epithelial barrier through upregulation and redistribution of the tight junction proteins ZO-1, ZO-2 and claudin-14. Upregulation of claudin-14 has been attributed to the secreted protein TcpC. Whether regulation of ZO-1 and ZO-2 is mediated by EcN secreted factors remains unknown. The aim of this study was to explore whether outer membrane vesicles (OMVs) released by EcN strengthen the epithelial barrier. This study includes other E. coli strains of human intestinal origin that contain the tcpC gene, such as ECOR63. Cell-free supernatants collected from the wild-type strains and from the derived tcpC mutants were fractionated into isolated OMVs and soluble secreted factors. The impact of these extracellular fractions on the epithelial barrier was evaluated by measuring transepithelial resistance and expression of several tight junction proteins in T-84 and Caco-2 polarized monolayers. Our results show that the strengthening activity of EcN and ECOR63 does not exclusively depend on TcpC. Both OMVs and soluble factors secreted by these strains promote upregulation of ZO-1 and claudin-14, and down-regulation of claudin-2. The OMVs-mediated effects are TcpC-independent. Soluble secreted TcpC contributes to the upregulation of ZO-1 and claudin-14, but this protein has no effect on the transcriptional

  13. Barrier function in the peripheral and central nervous system-a review.

    Science.gov (United States)

    Reinhold, A K; Rittner, H L

    2017-01-01

    The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.

  14. Structure and function of the epidermis related to barrier properties.

    Science.gov (United States)

    Baroni, Adone; Buommino, Elisabetta; De Gregorio, Vincenza; Ruocco, Eleonora; Ruocco, Vincenzo; Wolf, Ronni

    2012-01-01

    The most important function of the skin is the formation of a barrier between the "inside" and the "outside" of the organism, which prevents invasion of pathogens and fends off chemical assaults as well as the unregulated loss of water and solutes. The physical barrier is mainly localized in the stratum corneum, which consists of protein-enriched cells and lipid-enriched intercellular domains. Any modifications in epidermal differentiation and lipid composition results in altered barrier function, a central event in various skin alterations and diseases. This contribution presents a brief description of the structure of the skin, paying attention to the most important components responsible for skin barrier function. Copyright © 2012. Published by Elsevier Inc.

  15. Barrier stabilizing mediators in regulation of microvascular endothelial permeability

    Institute of Scientific and Technical Information of China (English)

    HUANG Qiao-bing

    2012-01-01

    Increase of microvascular permeability is one of the most important pathological events in the pathogenesis of trauma and bum injury.Massive leakage of fluid from vascular space leads to lose of blood plasma and decrease of effective circulatory blood volume,resulting in formation of severe tissue edema,hypotension or even shock,especially in severe bum injury.Fluid resuscitation has been the only valid approach to sustain patient's blood volume for a long time,due to the lack of overall and profound understanding of the mechanisms of vascular hyperpenneability response.There is an emerging concept in recent years that some so-called barrier stabilizing mediators play a positive role in preventing the increase of vascular permeability.These mediators may be released in response to proinflammatory mediators and serve to restore endothelial barrier function.Some of these stabilizing mediators are important even in quiescent state because they preserve basal vascular permeability at low levels.This review introduces some of these mediators and reveals their underlying signaling mechanisms during endothelial barrier enhancing process.

  16. The Flux-Flux Correlation Function for Anharmonic Barriers

    CERN Document Server

    Goussev, Arseni; Waalkens, Holger; Wiggins, Stephen

    2010-01-01

    The flux-flux correlation function formalism is a standard and widely used approach for the computation of reaction rates. In this paper we introduce a method to compute the classical and quantum flux-flux correlation functions for anharmonic barriers essentially analytically through the use of the classical and quantum normal forms. In the quantum case we show that the quantum normal form reduces the computation of the flux-flux correlation function to that of an effective one dimensional anharmonic barrier. The example of the computation of the quantum flux-flux correlation function for a fourth order anharmonic barrier is worked out in detail, and we present an analytical expression for the quantum mechanical microcanonical flux-flux correlation function. We then give a discussion of the short-time and harmonic limits.

  17. Guidance document on fat reduction factor, functional barrier concept, phthalates and primary aromatic amines

    DEFF Research Database (Denmark)

    Hoekstra, Eddo J.; Petersen, Jens Højslev; Bustos, Juana

    and the functional barrier, and the restrictions for certain phthalates and primary aromatic amines. The Regulation applies from 1 May 2011. The network of the European Union Reference Laboratory and the National Reference Laboratories for food contact materials created a Task Force in order to give guidance...

  18. Guidance document on fat reduction factor, functional barrier concept, phthalates and primary aromatic amines

    DEFF Research Database (Denmark)

    Hoekstra, Eddo J.; Petersen, Jens Højslev; Bustos, Juana

    and the functional barrier, and the restrictions for certain phthalates and primary aromatic amines. The Regulation applies from 1 May 2011. The network of the European Union Reference Laboratory and the National Reference Laboratories for food contact materials created a Task Force in order to give guidance...

  19. A study on the quantitative evaluation of skin barrier function

    Science.gov (United States)

    Maruyama, Tomomi; Kabetani, Yasuhiro; Kido, Michiko; Yamada, Kenji; Oikaze, Hirotoshi; Takechi, Yohei; Furuta, Tomotaka; Ishii, Shoichi; Katayama, Haruna; Jeong, Hieyong; Ohno, Yuko

    2015-03-01

    We propose a quantitative evaluation method of skin barrier function using Optical Coherence Microscopy system (OCM system) with coherency of near-infrared light. There are a lot of skin problems such as itching, irritation and so on. It has been recognized skin problems are caused by impairment of skin barrier function, which prevents damage from various external stimuli and loss of water. To evaluate skin barrier function, it is a common strategy that they observe skin surface and ask patients about their skin condition. The methods are subjective judgements and they are influenced by difference of experience of persons. Furthermore, microscopy has been used to observe inner structure of the skin in detail, and in vitro measurements like microscopy requires tissue sampling. On the other hand, it is necessary to assess objectively skin barrier function by quantitative evaluation method. In addition, non-invasive and nondestructive measuring method and examination changes over time are needed. Therefore, in vivo measurements are crucial for evaluating skin barrier function. In this study, we evaluate changes of stratum corneum structure which is important for evaluating skin barrier function by comparing water-penetrated skin with normal skin using a system with coherency of near-infrared light. Proposed method can obtain in vivo 3D images of inner structure of body tissue, which is non-invasive and non-destructive measuring method. We formulate changes of skin ultrastructure after water penetration. Finally, we evaluate the limit of performance of the OCM system in this work in order to discuss how to improve the OCM system.

  20. Irsogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells.

    Science.gov (United States)

    Miyata, Ryo; Nomura, Kazuaki; Kakuki, Takuya; Takano, Ken-Ichi; Kohno, Takayuki; Konno, Takumi; Sawada, Norimasa; Himi, Tetsuo; Kojima, Takashi

    2015-04-01

    The airway epithelium of the human nasal mucosa acts as the first physical barrier that protects against inhaled substances and pathogens. Irsogladine maleate (IM) is an enhancer of gastric mucosal protective factors via upregulation of gap junctional intercellular communication (GJIC). GJIC is thought to participate in the formation of functional tight junctions. However, the effects of IM on GJIC and the epithelial barrier in human nasal epithelial cells (HNECs) remain unknown. To investigate the effects of IM on GJIC and the tight junctional barrier in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were treated with IM and the GJIC inhibitors oleamide and 18β-GA. Some cells were pretreated with IM before treatment with TLR3 ligand poly(I:C) to examine whether IM prevented the changes via TLR3-mediated signal pathways. In hTERT-HNECs, GJIC blockers reduced the expression of tight junction molecules claudin-1, -4, -7, occludin, tricellulin, and JAM-A. IM induced GJIC activity and enhanced the expression of claudin-1, -4, and JAM-A at the protein and mRNA levels with an increase of barrier function. GJIC blockers prevented the increase of the tight junction proteins induced by IM. Furthermore, IM prevented the reduction of JAM-A but not induction of IL-8 and TNF-α induced by poly(I:C). In conclusion, IM can maintain the GJIC-dependent tight junctional barrier via regulation of GJIC in upper airway nasal epithelium. Therefore, it is possible that IM may be useful as a nasal spray to prevent the disruption of the epithelial barrier by viral infections and exposure to allergens in human nasal mucosa.

  1. The mass and temperature functions in a moving barrier model

    CERN Document Server

    Popolo, A D

    2002-01-01

    In this paper, I use the extension of the excursion set model of Sheth & Tormen (2002) and the barrier shape obtained in Del Popolo & Gambera (1998) to calculate the unconditional halo mass function, and the conditional mass function in several cosmological models. I show that the barrier obtained in Del Popolo & Gambera (1998), which takes account of tidal interaction between proto-haloes, is a better description of the mass functions than the spherical collapse and is in good agreement with numerical simulations (Tozzi & Governato 1998, and Governato et al. 1999). The results are also in good agreement with those obtained by Sheth & Tormen (2002), only slight differences are observed expecially at the low mass end. I moreover calculate, and compare with simulations, the temperature function obtained by means of the mass functions previously calculated and also using an improved version of the M-T relation, which accounts for the fact that massive clusters accrete matter quasi-continuousl...

  2. Typical diffusion behaviour in packaging polymers - Application to functional barriers

    NARCIS (Netherlands)

    Dole, P.; Feigenbaum, A.E.; Cruz, C. de la; Pastorelli, S.; Paseiro, P.; Hankemeier, T.; Voulzatis, Y.; Aucejo, S.; Saillard, P.; Papaspyrides, C.

    2006-01-01

    When plastics are collected for recycling, possibly contaminated articles might be recycled into food packaging, and thus the contaminants might subsequently migrate into the food. Multilayer functional barriers may be used to delay and to reduce such migration. The contribution of the work reported

  3. Disruption of barrier function in dermatophytosis and pityriasis versicolor.

    Science.gov (United States)

    Lee, Weon Ju; Kim, Jun Young; Song, Chang Hyun; Jung, Hong Dae; Lee, Su Hyun; Lee, Seok-Jong; Kim, Do Won

    2011-11-01

    Dermatophytes have the ability to form molecular attachments to keratin and use it as a source of nutrients, colonizing keratinized tissues, including the stratum corneum of the skin. Malassezia species also affect the stratum corneum of the skin. Therefore, dermatophytosis and pityriasis versicolor of the skin are thought to be important factors of profound changes in skin barrier structure and function. We aimed to describe the changes in transepidermal water loss (TEWL), stratum corneum hydration, and skin pH in the lesions of the dermatophytosis and pityriasis versicolor. Thirty-six patients with dermatophytosis (14 with tinea cruris, 13 with tinea corporis and nine with tinea pedis or tinea manus) and 11 patients with pityriasis versicolor were included in this study. TEWL, stratum corneum conductance and skin pH were determined by biophysical methods to examine whether our patients exhibited changes in barrier function. Dermatophytosis and pityriasis versicolor except tinea pedis and tinea manus showed highly significant increase in TEWL compared with adjacent infection-free skin. Hydration was significantly reduced in lesional skin compared with adjacent infection-free skin. From this study, infections with dermatophytes and Malassezia species on the body can alter biophysical properties of the skin, especially the function of stratum corneum as a barrier to water loss. On the contrary, infections with dermatophytes on the palms and soles little affect the barrier function of the skin. © 2011 Japanese Dermatological Association.

  4. The Functional Requirements and Design Basis for Information Barriers

    Energy Technology Data Exchange (ETDEWEB)

    Fuller, James L.

    2012-05-01

    This report summarizes the results of the Information Barrier Working Group workshop held at Sandia National Laboratory in Albuquerque, NM, February 2-4, 1999. This workshop was convened to establish the functional requirements associated with warhead radiation signature information barriers, to identify the major design elements of any such system or approach, and to identify a design basis for each of these major elements. Such information forms the general design basis to be used in designing, fabricating, and evaluating the complete integrated systems developed for specific purposes.

  5. Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

    OpenAIRE

    2011-01-01

    Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute—(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which c...

  6. Intestinal barrier function and the brain-gut axis.

    Science.gov (United States)

    Alonso, Carmen; Vicario, María; Pigrau, Marc; Lobo, Beatriz; Santos, Javier

    2014-01-01

    The luminal-mucosal interface of the intestinal tract is the first relevant location where microorganism-derived antigens and all other potentially immunogenic particles face the scrutiny of the powerful mammalian immune system. Upon regular functioning conditions, the intestinal barrier is able to effectively prevent most environmental and external antigens to interact openly with the numerous and versatile elements that compose the mucosal-associated immune system. This evolutionary super system is capable of processing an astonishing amount of antigens and non-immunogenic particles, approximately 100 tons in one individual lifetime, only considering food-derived components. Most important, to develop oral tolerance and proper active immune responses needed to prevent disease and inflammation, this giant immunogenic load has to be managed in a way that physiological inflammatory balance is constantly preserved. Adequate functioning of the intestinal barrier involves local and distant regulatory networks integrating the so-called brain-gut axis. Along this complex axis both brain and gut structures participate in the processing and execution of response signals to external and internal changes coming from the digestive tract, using multidirectional pathways to communicate. Dysfunction of brain-gut axis facilitates malfunctioning of the intestinal barrier, and vice versa, increasing the risk of uncontrolled immunological reactions that may trigger mucosal and brain low-grade inflammation, a putative first step to the initiation of more permanent gut disorders. In this chapter, we describe the structure, function and interactions of intestinal barrier, microbiota and brain-gut axis in both healthy and pathological conditions.

  7. Acyl-CoA binding protein and epidermal barrier function

    DEFF Research Database (Denmark)

    Bloksgaard, Maria; Neess, Ditte; Færgeman, Nils J

    2014-01-01

    enzymatic systems; however, the precise function remains unknown. ACBP is expressed at relatively high levels in the epidermis, particularly in the suprabasal layers, which are highly active in lipid synthesis. Targeted disruption of the ACBP gene in mice leads to a pronounced skin and fur phenotype, which...... levels of non-esterified very long chain fatty acids in the stratum corneum of ACBP(-/-) mice. Here we review the current knowledge of ACBP with special focus on the function of ACBP in the epidermal barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis...

  8. Exogenous sphingomyelinase causes impaired intestinal epithelial barrier function

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To test the hypothesis that hydrolysis of sphingomyelin to ceramide changes the composition of tight junctions (TJs) with increasing permeability of the intestinal epithelium.METHODS: Monolayers of Caco-2 cells were used as an in vitro model for the intestinal barrier. Permeability was determined by quantification of transepithelial flux and transepithelial resistance. Sphingolipid-rich membrane microdomains were isolated by a discontinuous sucrose gradient and characterized by Western-blot. Lipid content of microdomains was analysed by tandem mass spectrometry. Ceramide was subcellularly localized by immunofluorescent staining.RESULTS: Exogenous sphingomyelinase increased transepithelial permeability and decreased transepithelial resistance at concentrations as low as 0.01 U/mL.Lipid analysis showed rapid accumulation of ceramide in the membrane fractions containing occludin and claudin-4, representing TJs. In these fractions we observed a concomitant decrease of sphingomyelin and cholesterol with increasing concentrations of ceramide.Immunofluorescent staining confirmed clustering of ceramide at the sites of cell-cell contacts. Neutralization of surface ceramide prevented the permeability-increase induced by platelet activating factor.CONCLUSION: Our findings indicate that changes in lipid composition of TJs impair epithelial barrier functions. Generation of ceramide by sphingomyelinases might contribute to disturbed barrier function seen in diseases such as inflammatory, infectious, toxic or radiogenic bowel disease.

  9. Lipids and skin barrier function - a clinical perspective

    DEFF Research Database (Denmark)

    Jungersted, J.M.; Hellgren, Lars; Jemec, G.B.E.

    2008-01-01

    and in particular, the role of barrier function in the pathogenesis of skin disease and its subsequent treatment protocols. The 3 major lipids in the SC of importance are ceramides, free fatty acids, and cholesterol. Human studies comparing levels of the major SC lipids in patients with atopic dermatitis...... and healthy controls have suggested a possible role for ceramide 1 and to some extent ceramide 3 in the pathogenesis of the disease. Therapies used in diseases involving barrier disruption have been sparely investigated from a lipid perspective. It has been suggested that ultraviolet light as a treatment......The stratum corneum (SC) protects us from dehydration and external dangers. Much is known about the morphology of the SC and penetration of drugs through it, but the data are mainly derived from in vitro and animal experiments. In contrast, only a few studies have the human SC lipids as their focus...

  10. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function.

    Science.gov (United States)

    Yue, Yuan; Wu, Shuangchan; Li, Zhike; Li, Jian; Li, Xiaofei; Xiang, Jin; Ding, Hong

    2015-08-01

    Dietary polysaccharides provide various beneficial effects for our health. We investigated the protective effects of wild jujube (Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou) sarcocarp polysaccharides (WJPs) against experimental inflammatory bowel disease (IBD) by enabling enhanced intestinal barrier function. Colitis was induced in rats by the intrarectal administration of TNBS. We found that WJPs markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage in colitis rats. Moreover, WJPs suppressed the inflammatory response via attenuation of TNF-α, IL-1β, IL-6 and MPO activity in colitis rats. And then, to determine the effect of WJPs on the intestinal barrier, we measured the effect of WJPs on the transepithelial electrical resistance (TER) and FITC-conjugated dextran permeability in Caco-2 cell stimulation with TNF-α. We further demonstrated that the alleviation of WJPs to colon injury was associated with barrier function by assembly of tight junction proteins. Moreover, the effect of WJPs on TER was eliminated by the specific inhibitor of AMPK. AMPK activity was also up-regulated by WJPs in Caco-2 cell stimulation with TNF-α and in colitis rats. This study demonstrates that WJPs protect against IBD by enabling enhanced intestinal barrier function involving the activation of AMPK.

  11. Translational Medicine Study on Cardiac Microvascular Endothelial Barrier Function and Myocardial Ischemia/Re-perfusion Injury

    Institute of Scientific and Technical Information of China (English)

    Yeong Yeh Lee

    2015-01-01

    Vascular endothelial barrier is defined as the ability of endothelial cells and their components that make up the microvascular wall structure in controlling the cellular components and marco-molecular substances in blood from penetrating vascular walls. It is the place for the selective exchange of oxygen, nutrients and metabolites, and has kernel effect in maintaining myocardial micro-environmental homeostasis. In clinic, microvascular permeability is commonly used as the index for evaluating endothelial barrier function. Myocardial microvascular endothelial cells, inter-endothelial connexin and basilar membrane (BM) interact synergically to constitute the basis for barrier function, which has a selective permeability effect on interaction between nutrient substances and other myocardial cell molecules. Increase of microvascular permeability is closely associated with cardiovascular events like coronary heart disease (CHD) and myocardial ischemia, and is the risk factor for CHD attack. And deep exploration of the mechanism of endothelial permeability and positive selection of new-type re-perfusion complementary drugs for alleviating endothelial permeability can be beneifcial in improving the prognosis of patients with acute myocardial infarction (AMI). Therefore, from the view of translational medicine, this study mainly summarized the increase of microvascular permeability and its pathological signiifcance after AMI, physiological and pathological mechanisms of regulating microvascular permeability and complementary therapies for AMI re-perfusion as well as microvascular endothelial barrier function, hoping to provide a basis for improving the prognosis of patients with AMI.

  12. Translational Medicine Study on Cardiac Microvascular Endothelial Barrier Function and Myocardial Ischemia/Re-perfusion Injury

    Directory of Open Access Journals (Sweden)

    Yeong Yeh Lee

    2015-09-01

    Full Text Available Vascular endothelial barrier is defined as the ability of endothelial cells and their components that make up the microvascular wall structure in controlling the cellular components and marco-molecular substances in blood from penetrating vascular walls. It is the place for the selective exchange of oxygen, nutrients and metabolites, and has kernel effect in maintaining myocardial micro-environmental homeostasis. In clinic, microvascular permeability is commonly used as the index for evaluating endothelial barrier function. Myocardial microvascular endothelial cells, inter-endothelial connexin and basilar membrane (BM interact synergically to constitute the basis for barrier function, which has a selective permeability effect on interaction between nutrient substances and other myocardial cell molecules. Increase of microvascular permeability is closely associated with cardiovascular events like coronary heart disease (CHD and myocardial ischemia, and is the risk factor for CHD attack. And deep exploration of the mechanism of endothelial permeability and positive selection of new-type re-perfusion complementary drugs for alleviating endothelial permeability can be beneficial in improving the prognosis of patients with acute myocardial infarction (AMI. Therefore, from the view of translational medicine, this study mainly summarized the increase of microvascular permeability and its pathological significance after AMI, physiological and pathological mechanisms of regulating microvascular permeability and complementary therapies for AMI re-perfusion as well as microvascular endothelial barrier function, hoping to provide a basis for improving the prognosis of patients with AMI.

  13. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function

    Science.gov (United States)

    Reunanen, Justus; Meijerink, Marjolein; Pietilä, Taija E.; Kainulainen, Veera; Klievink, Judith; Huuskonen, Laura; Aalvink, Steven; Skurnik, Mikael; Boeren, Sjef; Satokari, Reetta; Mercenier, Annick; Palva, Airi; Smidt, Hauke; de Vos, Willem M.; Belzer, Clara

    2017-01-01

    Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc_1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc_1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function. PMID:28249045

  14. Crossing the entropy barrier of dynamical zeta functions

    Energy Technology Data Exchange (ETDEWEB)

    Aurich, R.; Bolte, J.; Matthies, C.; Sieber, M.; Steiner, F. (Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik)

    1992-01-01

    Dynamical zeta functions are an important tool to quantize chaotic dynamical systems. The basic quantization rules require the computation of the zeta functions on the real energy axis, where the Euler product representations running over the classical periodic orbits usually do not converge due to the existence of the so-called entropy barrier determined by the topological entropy of the classical system. We shown that the convergence properties of the dynamical zeta functions rewritten as Dirichlet series are governed not only by the well-known topological and metric entropy, but depend crucially on subtle statistical properties of the Maslow indices and of the multiplicities of the periodic orbits that are measured by a new parameter for which we introduce the notion of a third entropy. If and only if the third entropy is nonvanishing, one can cross the entropy barrier; if it exceeds a certain value, one can even compute the zeta function in the physical region by means of a convergent Dirichlet series. A simple statistical model is presented which allows to compute the third entropy. Four examples of chaotic systems are studied in detail to test the model numerically. (orig.).

  15. Protelytic Regulation of the Intestinal Epithelial Barrier: Mechanisms and Interventions

    Science.gov (United States)

    2015-09-01

    molecular mechanisms that mediate matriptase protection during DSS-induced experimental inflammatory colitis, 2) define molecular mechanisms by which...and protein levels by cytokines produced during inflammatory colitis. Further, matriptase acts downstream of prostasin to mediate barrier formation...6 TASK 2 To determine the molecular mechanisms that mediate matriptase protection during mucosal inflammation in experimental

  16. TALE homeodomain proteins regulate site-specific terminal differentiation, LCE genes and epidermal barrier.

    Science.gov (United States)

    Jackson, Ben; Brown, Stuart J; Avilion, Ariel A; O'Shaughnessy, Ryan F L; Sully, Katherine; Akinduro, Olufolake; Murphy, Mark; Cleary, Michael L; Byrne, Carolyn

    2011-05-15

    The epidermal barrier varies over the body surface to accommodate regional environmental stresses. Regional skin barrier variation is produced by site-dependent epidermal differentiation from common keratinocyte precursors and often manifests as site-specific skin disease or irritation. There is strong evidence for body-site-dependent dermal programming of epidermal differentiation in which the epidermis responds by altering expression of key barrier proteins, but the underlying mechanisms have not been defined. The LCE multigene cluster encodes barrier proteins that are differentially expressed over the body surface, and perturbation of LCE cluster expression is linked to the common regional skin disease psoriasis. LCE subclusters comprise genes expressed variably in either external barrier-forming epithelia (e.g. skin) or in internal epithelia with less stringent barriers (e.g. tongue). We demonstrate here that a complex of TALE homeobox transcription factors PBX1, PBX2 and Pknox (homologues of Drosophila Extradenticle and Homothorax) preferentially regulate external rather than internal LCE gene expression, competitively binding with SP1 and SP3. Perturbation of TALE protein expression in stratified squamous epithelia in mice produces external but not internal barrier abnormalities. We conclude that epidermal barrier genes, such as the LCE multigene cluster, are regulated by TALE homeodomain transcription factors to produce regional epidermal barriers.

  17. Barrier function test: Laboratory evaluation of the protective function of some barrier creams against cashewnut shell oil

    Directory of Open Access Journals (Sweden)

    Pasricha J

    1991-01-01

    Full Text Available A barrier function test has been designed to screen the protective capacity of a cream against the cauterizing effect of cashew nut shell oil (CNSO on the skin. The test consists of applying the barrier cream on a 5 cm circular area of skin on the back of a human volunteer and then at its centre applying a 1 cm sq Whatman no. 3 paper disc soaked in the CNSO for 15 minutes and looking for the evidence of cauterization reaction after 48 hours. Of the various creams containing a variety of paraffins, bees wax, polyethylene glycols, methyl cellulose gel, and petrolatum, only polyethylene glycol (PEG cream was found to afford adequate protection against cashew nut shell oil. Addition of 10% zinc oxide or 10% kaolin to the PEG cream did not seem to afford any additional protection. Castor oil already being used by the workers was found to be inferior to the PEG cream.

  18. Regulation of Copper Transport Crossing Brain Barrier Systems by Cu-ATPases: Effect of Manganese Exposure

    OpenAIRE

    Fu, Xue; Zhang, Yanshu; Jiang, Wendy; Monnot, Andrew Donald; Bates, Christopher Alexander; Zheng, Wei

    2014-01-01

    Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered ...

  19. The potential benefits of herbicide regulation: a cautionary note for the Great Barrier Reef catchment area.

    Science.gov (United States)

    Davis, A M; Lewis, S E; Brodie, J E; Benson, Ash

    2014-08-15

    Industry transitions away from traditional photosystem II inhibiting (PSII) herbicides towards an 'alternative' herbicide suite are now widely advocated as a key component of improved environmental outcomes for Australia's Great Barrier Reef and improved environmental stewardship on the part of the Queensland sugar industry. A systematic desktop risk analysis found that based on current farming practices, traditional PSII herbicides can pose significant environmental risks. Several of the 'alternatives' that can directly fill a specific pre-emergent ('soil residual') weed control function similar to regulated PSII herbicides also, however, presented a similar environmental risk profile, regardless of farming systems and bio-climatic zones being considered. Several alternatives with a pre-emergent residual function as well as alternative post-emergent (contact or 'knockdown') herbicides were, predicted to pose lower environmental risks than the regulated PSII herbicides to most trophic levels, although environmental risks could still be present. While several herbicides may well be viable alternatives in terms of weed control, they can still present equal or possibly higher risks to the environment. Imposing additional regulations (or even de-registrations) on particular herbicides could result in marginal, and possibly perverse environmental impacts in the long term, if usage shifts to alternative herbicides with similar risk profiles. Regardless of any regulatory efforts, improved environmental sustainability outcomes in pesticide practices within the Great Barrier Reef catchment area will hinge primarily on the continuing adoption of integrated, strategic pest management systems and technologies applied to both traditional and 'alternative' herbicides. One of the emerging policy challenges is ensuring the requisite technical and extension support for cane growers to ensure effective adoption of rapidly evolving farming system technologies, in a very dynamic and

  20. Regulation of Copper Transport Crossing Brain Barrier Systems by Cu-ATPases: Effect of Manganese Exposure

    Science.gov (United States)

    Fu, Xue; Zhang, Yanshu; Jiang, Wendy; Monnot, Andrew Donald; Bates, Christopher Alexander; Zheng, Wei

    2014-01-01

    Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury. PMID:24614235

  1. Vibration control for a rigid-flexible manipulator with full state constraints via Barrier Lyapunov Function

    Science.gov (United States)

    Cao, Fangfei; Liu, Jinkun

    2017-10-01

    Considering full state constraints, this paper designs a boundary controller for a two-link rigid-flexible manipulator via Barrier Lyapunov Function. The dynamic model of the two-link rigid-flexible manipulator is described by coupled ordinary differential equations- partial differential equations (ODEs-PDEs). Based on the original model without neglecting the high-frequency modes, boundary controller is proposed to regulate the joint positions and eliminate the elastic vibration simultaneously. To ensure that the full state constraints which include position, speed and vibration constraints are not transgressed, a Barrier Lyapunov Function is employed in the proposed controller. The asymptotic stability of the closed-loop system is rigorously proved by the LaSalle's Invariance Principle. Simulations are given to verify the effectiveness of the proposed controller with state constraints.

  2. New Trends in Quantitative Assessment of the Corneal Barrier Function

    Directory of Open Access Journals (Sweden)

    Anton Guimerà

    2014-05-01

    Full Text Available The cornea is a very particular tissue due to its transparency and its barrier function as it has to resist against the daily insults of the external environment. In addition, maintenance of this barrier function is of crucial importance to ensure a correct corneal homeostasis. Here, the corneal epithelial permeability has been assessed in vivo by means of non-invasive tetrapolar impedance measurements, taking advantage of the huge impact of the ion fluxes in the passive electrical properties of living tissues. This has been possible by using a flexible sensor based in SU-8 photoresist. In this work, a further analysis focused on the validation of the presented sensor is performed by monitoring the healing process of corneas that were previously wounded. The obtained impedance measurements have been compared with the damaged area observed in corneal fluorescein staining images. The successful results confirm the feasibility of this novel method, as it represents a more sensitive in vivo and non-invasive test to assess low alterations of the epithelial permeability. Then, it could be used as an excellent complement to the fluorescein staining image evaluation.

  3. Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.

    Science.gov (United States)

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin; Metcalf, Jordan Patrick

    2012-12-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.

  4. Acupuncture and regulation of gastrointestinal function

    Science.gov (United States)

    Li, Hui; He, Tian; Xu, Qian; Li, Zhe; Liu, Yan; Li, Fang; Yang, Bo-Feng; Liu, Cun-Zhi

    2015-01-01

    In China, acupuncture has been considered an effective method for treating gastrointestinal (GI) dysfunction diseases for thousands of years. In fact, acupuncture has gained progressive acceptance from both practitioners and patients worldwide. However, the therapeutic effects and underlying mechanisms in treating GI dysfunction have not yet been established due to a lack of systematic and comprehensive review articles. Therefore, the aim of this review is to discuss the efficacy of acupuncture as a treatment for GI dysfunction and the associated underlying mechanisms. A search of PubMed was conducted for articles that were published over the past 10 years using the terms “acupuncture”, “gastrointestine”, and other relevant keywords. In the following review, we describe the effect and underlying mechanisms of acupuncture on GI function from the perspectives of GI motility, visceral sensitivity, the GI barrier, and the brain-gut axis. The dual regulatory effects of acupuncture may manifest by promoting gastric peristalsis in subjects with low initial gastric motility, and suppressing peristalsis in subjects with active initial motility. In addition, the regulation of acupuncture on gastric motility may be intensity-dependent. Our findings suggest that further studies are needed to investigate the effects and more systematic mechanisms in treating GI dysfunction, and to promote the application of acupuncture for the treatment of GI diseases. PMID:26217082

  5. Barrier Functionality of Porcine and Bovine Brain Capillary Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Ailar Nakhlband

    2011-09-01

    Full Text Available Introduction: To date, isolated cell based blood-brain barrier (BBB models have been widely used for brain drug delivery and targeting, due to their relatively proper bioelectrical and permeability properties. However, primary cultures of brain capillary endothelial cells (BCECs isolated from different species vary in terms of bioelectrical and permeability properties. Methods: To pursue this, in the current investigation, primary porcine and bovine BCECs (PBCECs and BBCECs, respectively were isolated and used as an in vitro BBB model. The bioelectrical and permeability properties were assessed in BCECs co-cultured with C6 cells with/without hydrocortisone (550 nM. The bioelectrical properties were further validated by means of the permeability coefficients of transcellular and paracellular markers. Results: The primary PBCECs displayed significantly higher trans-endothelial electrical resistance (~900 W.cm2 than BBCECs (~700 W.cm2 - both co-cultured with C6 cells in presence of hydrocortisone. Permeability coefficients of propranolol/diazepam and mannitol/sucrose in PBCECs were ~21 and ~2 (×10-6 cm.sec-1, where these values for BBCECs were ~25 and ~5 (×10-6 cm.sec-1. Conclusion: Upon our bioelectrical and permeability findings, both models display discriminative barrier functionality but porcine BCECs seem to provide a better platform than bovine BCECs for drug screening and brain targeting.

  6. Alterations of blood brain barrier function in hyperammonemia: an overview.

    Science.gov (United States)

    Skowrońska, Marta; Albrecht, Jan

    2012-02-01

    Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute--(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which couple adjacent cerebral capillary endothelial cells to each other to form the barrier. Ammonia modulates the transcellular passage of low-to medium-size molecules, by affecting their carriers located at the BBB. Ammonia induces interrelated aberrations of the transport of the large neutral amino acids and aromatic amino acids (AAA), whose influx is augmented by exchange with glutamine produced in the course of ammonia detoxification, and maybe also modulated by the extracellularly acting gamma-glutamyl moiety transferring enzyme, gamma-glutamyl-transpeptidase. Impaired AAA transport affects neurotransmission by altering intracerebral synthesis of catecholamines (serotonin and dopamine), and producing "false neurotransmitters" (octopamine and phenylethylamine). Ammonia also modulates BBB transport of the cationic amino acids: the nitric oxide precursor, arginine, and ornithine, which is an ammonia trap, and affects the transport of energy metabolites glucose and creatine. Moreover, ammonia acting either directly or in synergy with liver injury-derived inflammatory cytokines also evokes subtle increases of the transcellular passage of molecules of different size (BBB "leakage"), which appears to be responsible for the vasogenic component of cerebral edema associated with ALF.

  7. Kinetin Improves Barrier Function of the Skin by Modulating Keratinocyte Differentiation Markers

    Science.gov (United States)

    An, Sungkwan; Cha, Hwa Jun; Ko, Jung-Min; Han, Hyunjoo; Kim, Su Young; Kim, Kyung-Suk; Lee, Song Jeong; An, In-Sook; Kim, Sangwon; Youn, Hae Jeong

    2017-01-01

    Background Kinetin is a plant hormone that regulates growth and differentiation. Keratinocytes, the basic building blocks of the epidermis, function in maintaining the skin barrier. Objective We examined whether kinetin induces skin barrier functions in vitro and in vivo. Methods To evaluate the efficacy of kinetin at the cellular level, expression of keratinocyte differentiation markers was assessed. Moreover, we examined the clinical efficacy of kinetin by evaluating skin moisture, transepidermal water loss (TEWL), and skin surface roughness in patients who used kinetin-containing cream. We performed quantitative real-time polymerase chain reaction to measure the expression of keratinocyte differentiation markers in HaCaT cells following treatment. A clinical trial was performed to assess skin moisture, TEWL, and evenness of skin texture in subjects who used kinetin-containing cream for 4 weeks. Results Kinetin increased involucrin, and keratin 1 mRNA in HaCaT cells. Moreover, use of a kinetin-containing cream improved skin moisture and TEWL while decreasing roughness of skin texture. Conclusion Kinetin induced the expression of keratinocyte differentiation markers, suggesting that it may affect differentiation to improve skin moisture content, TEWL, and other signs of skin aging. Therefore, kinetin is a potential new component for use in cosmetics as an anti-aging agent that improves the barrier function of skin. PMID:28223740

  8. Regulation of TRPML1 function.

    Science.gov (United States)

    Waller-Evans, Helen; Lloyd-Evans, Emyr

    2015-06-01

    TRPML1 is a ubiquitously expressed cation channel found on lysosomes and late endosomes. Mutations in TRPML1 cause mucolipidosis type IV and it has been implicated in Alzheimer's disease and HIV. However, the mechanisms by which TRPML1 activity is regulated are not well understood. This review summarizes the current understanding of TRPML1 activation and regulation.

  9. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of a health claim related to flaxseed oil and vitamin E and maintenance of the skin permeability barrier function pursuant to Article 13(5) of Regulation (EC) No 1924/2006

    DEFF Research Database (Denmark)

    Tetens, Inge

    Following an application from Nutrilinks Sarl, submitted pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Belgium, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim....... The applicant identified two published human intervention studies as being pertinent to the health claim. Owing to the very limited information provided regarding key methodological aspects, and to the important limitations of the statistical analysis performed, the Panel considers that no conclusions can...... be drawn from these studies for the scientific substantiation of the claim. The Panel concludes that a cause and effect relationship has not been established between the consumption of a combination of flaxseed oil and vitamin E and maintenance of the skin permeability barrier function...

  10. Functional Food Market Development in Serbia: Motivations and Barriers

    Directory of Open Access Journals (Sweden)

    Žaklina Stojanović

    2013-11-01

    Full Text Available The aim of this paper is to present main findings obtained from the empirical analysis of the functional food market in Serbia. The analysis is based on the in-depth interviews with relevant processors and retailers present on the market. The following set of topics are considered: (1 motivations (driving forces and barriers to offer products with nutrition and health (N&H claim and (2 perception of consumer demand toward N&H claimed products. Differences between Serbia and other Western Balkan Countries (WBC are explored by using nonparametric techniques based on the independent samples. Results support overall conclusion that this market segment in Serbia is underdeveloped and rather producer than consumer driven compared to more developed WBC markets.

  11. How hormones influence composition and physiological function of the brain-blood barrier.

    Science.gov (United States)

    Hampl, R; Bičíková, M; Sosvorová, L

    2015-01-01

    Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

  12. Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice.

    Science.gov (United States)

    Xue, Yansong; Zhang, Hanying; Sun, Xiaofei; Zhu, Mei-Jun

    2016-01-01

    The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. Metformin supplementation promotes secretory cell lineage differentiation, suppresses

  13. Some methods to regulate low-bias negative differential resistance in σ barrier separating nanoscale molecular transport systems

    Science.gov (United States)

    Shen, Ji-Mei; Liu, Jing; Min, Yi; Zhou, Li-Ping

    2016-12-01

    Using the first-principles method which combines the nonequilibrium Green’s function (NEGF) with density functional theory (DFT), the role of defect, dopant, barrier length and geometric deformation for low-bias negative differential resistance (NDR) in two capped armchair carbon nanotubes (CNTs) sandwiching σ barrier are systematically analyzed. We found that this method can regulate the negative differential resistance (NDR) effects such as current peak and peak position. The adjusting mechanism may originate from orbital interaction and orbital reconstruction. Our calculations try to manipulate the transport characteristics in energy space by simply manipulating the structure in real space, which may promise the potential applications in nanomolecular-electronics in the future.

  14. Sleep Restriction Impairs Blood–Brain Barrier Function

    Science.gov (United States)

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J.; Wang, Yuping

    2014-01-01

    The blood–brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. PMID:25355222

  15. Sleep restriction impairs blood-brain barrier function.

    Science.gov (United States)

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J; Wang, Yuping; Pan, Weihong

    2014-10-29

    The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. Copyright © 2014 the authors 0270-6474/14/3414697-10$15.00/0.

  16. Food Derived Bioactive Peptides and Intestinal Barrier Function

    Directory of Open Access Journals (Sweden)

    Olga Martínez-Augustin

    2014-12-01

    Full Text Available A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action.

  17. Skin Barrier Function and Its Importance at the Start of the Atopic March

    Science.gov (United States)

    Hogan, Mary Beth; Peele, Kathy; Wilson, Nevin W.

    2012-01-01

    Atopic dermatitis can be due to a variety of causes from nonatopic triggers to food allergy. Control of egress of water and protection from ingress of irritants and allergens are key components of cutaneous barrier function. Current research suggests that a degraded barrier function of the skin allows the immune system inappropriate access to environmental allergens. Epidermal aeroallergen exposure may allow sensitization to allergen possibly initiating the atopic march. Further research into connections between epidermal barrier function and possible allergen sensitization will be important to undertake. Future clinical trials focused on skin barrier protection may be of value as a possible intervention in prevention of the initiation of the atopic march. PMID:22619686

  18. Genetic mouse models to study blood–brain barrier development and function

    OpenAIRE

    Sohet, Fabien; Daneman, Richard

    2013-01-01

    The blood–brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health, and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study th...

  19. [Central regulation of adenohypophyseal function].

    Science.gov (United States)

    Vigas, M

    1989-03-01

    The secretion of adenohypophyseal hormones is controlled by hypothalamic hypophysotropic hormones with stimulating (hormone releasing factors) or inhibitory (hormone release inhibiting factors) actions. The release of hypothalamic hormones is regulated by hierarchically higher nerve centres via neurons which liberate neurotransmitters at their endings. The secretion of growth hormone is controlled by hypothalamic hormones, somatotropin releasing factor and somatotropin release-inhibiting factor; of the neurotransmitters, the strongest effects have noradrenaline and dopamine. The release of ACTH is controlled by two stimulating hormones, the ACTH releasing factor and vasopressin, the effects of neurotransmitters are less marked, with the involvement of noradrenaline, serotonin, acetylcholine, gamma aminobutyric acid and other agents. Prolactin release is under the main inhibitory control of hypothalamic dopamine, no release-stimulating hypothalamic factor could be unequivocally demonstrated as yet; likely, several peptides are involved in this mechanism. The release of thyrotropic hormone is stimulated by thyrotropin releasing factor, whereas somatotropin release-inhibiting factor has an inhibitory action. Of the neurotransmitters, the inhibitory effect of dopamine is important; this agent however acts also at the hypophyseal level. External hypothalamic hormones and regulatory neurotransmitters are used in the diagnosis and treatment of neuroendocrine disorders.

  20. The impact of ultraviolet therapy on stratum corneum ceramides and barrier function

    DEFF Research Database (Denmark)

    Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

    2011-01-01

    The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified.The aim of this study was to examine the effect of U...... therapy in dermatological patients on ceramides and skin barrier function.We found that UV light treatment does not change the ratio of important stratum corneum lipids, but we confirm earlier findings of decreased susceptibility to irritants after UV- therapy.......The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified.The aim of this study was to examine the effect of UV...

  1. The impact of ultraviolet therapy on stratum corneum ceramides and barrier function

    DEFF Research Database (Denmark)

    Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

    2011-01-01

    The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified. The aim of this study was to examine the effect of ...... therapy in dermatological patients on ceramides and skin barrier function. We found that UV light treatment does not change the ratio of important stratum corneum lipids, but we confirm earlier findings of decreased susceptibility to irritants after UV- therapy.......The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified. The aim of this study was to examine the effect of UV...

  2. Two essential peritrophic matrix proteins mediate matrix barrier functions in the insect midgut.

    Science.gov (United States)

    Agrawal, Sinu; Kelkenberg, Marco; Begum, Khurshida; Steinfeld, Lea; Williams, Clay E; Kramer, Karl J; Beeman, Richard W; Park, Yoonseong; Muthukrishnan, Subbaratnam; Merzendorfer, Hans

    2014-06-01

    The peritrophic matrix (PM) in the midgut of insects consists primarily of chitin and proteins and is thought to support digestion and provide protection from abrasive food particles and enteric pathogens. We examined the physiological roles of 11 putative peritrophic matrix protein (PMP) genes of the red flour beetle, Tribolium castaneum (TcPMPs). TcPMP genes are differentially expressed along the length of the midgut epithelium of feeding larvae. RNAi of individual PMP genes revealed no abnormal developmental phenotypes for 9 of the 11 TcPMPs. However, RNAi for two PMP genes, TcPMP3 and TcPMP5-B, resulted in depletion of the fat body, growth arrest, molting defects and mortality. In situ permeability assays after oral administration of different-sized FITC-dextran beads demonstrated that the exclusion size of the larval peritrophic matrix (PM) decreases progressively from >2 MDa to RNAi for TcPMP3 and TcPMP5-B, these dextrans penetrated the epithelium of the median midgut, indicating loss of structural integrity and barrier function of the larval PM. In contrast, RNAi for TcPMP5-B, but not RNAi for TcPMP3, resulted in breakdown of impermeability to 4 and 40 kDa dextrans in the PM of the posterior midgut. These results suggest that specific PMPs are involved in the regulation of PM permeability, and that a gradient of barrier function is essential for survival and fat body maintenance.

  3. Regulation of Vascular Function on Posttranscriptional Level

    Directory of Open Access Journals (Sweden)

    Andreas Eisenreich

    2013-01-01

    Full Text Available Posttranscriptional control of gene expression is crucial for regulating plurality of proteins and functional plasticity of the proteome under (pathophysiologic conditions. Alternative splicing as well as micro (miRNA-mediated mechanisms play an important role for the regulation of protein expression on posttranscriptional level. Both alternative splicing and miRNAs were shown to influence cardiovascular functions, such as endothelial thrombogenicity and the vascular tone, by regulating the expression of several vascular proteins and their isoforms, such as Tissue Factor (TF or the endothelial nitric oxide synthase (eNOS. This review will summarize and discuss the latest findings on the (pathophysiologic role of alternative splicing processes as well as of miRNAs on modulation of vascular functions, such as coagulation, thrombosis, and regulation of the vascular tone.

  4. Human intestinal barrier function in health and disease

    NARCIS (Netherlands)

    König, Julia; Wells, Jerry; Cani, Patrice D.; García-Ródenas, Clara L.; MacDonald, Tom; Mercenier, Annick; Whyte, Jacqueline; Troost, Freddy J.; Brummer, Robert-Jan

    2016-01-01

    The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent

  5. Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

    NARCIS (Netherlands)

    Nowarski, Roni; Jackson, Ruaidhrí; Gagliani, Nicola; de Zoete, Marcel R; Palm, Noah W; Bailis, Will; Low, Jun Siong; Harman, Christian C D; Graham, Morven; Elinav, Eran; Flavell, Richard A

    2015-01-01

    The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of

  6. Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

    NARCIS (Netherlands)

    Nowarski, Roni; Jackson, Ruaidhrí; Gagliani, Nicola; de Zoete, Marcel R|info:eu-repo/dai/nl/30483419X; Palm, Noah W; Bailis, Will; Low, Jun Siong; Harman, Christian C D; Graham, Morven; Elinav, Eran; Flavell, Richard A

    2015-01-01

    The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of

  7. Interferon-gamma increased epithelial barrier function via upregulating claudin-7 expression in human submandibular gland duct epithelium.

    Science.gov (United States)

    Abe, Ayumi; Takano, Kenichi; Kojima, Takashi; Nomura, Kazuaki; Kakuki, Takuya; Kaneko, Yakuto; Yamamoto, Motohisa; Takahashi, Hiroki; Himi, Tetsuo

    2016-06-01

    Tight junctions (TJs) are necessary for salivary gland function and may serve as indicators of salivary gland epithelial dysfunction. IgG4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition which disrupts the TJ associated epithelial barrier. The salivary glands are one of the most frequently involved organs in IgG4-RD, however, changes of the TJ associated epithelial barrier in salivary gland duct epithelium is poorly understood. Here, we investigated the regulation and function of TJs in human submandibular gland ductal epithelial cells (HSDECs) in normal and IgG4-RD. We examined submandibular gland (SMG) tissue from eight control individuals and 22 patients with IgG4-RD and established an HSDEC culture system. Immunohistochemistry, immunocytochemistry, western blotting, and measurement of transepithelial electrical resistance (TER) were performed. Claudin-4, claudin-7, occludin, and JAM-A were expressed at the apical side of the duct epithelium in submandibular gland (SMG) tissue and at the cell borders in HSDECs of normal and IgG4-RD. The expression and distribution of TJs in SMG tissue were not different in control individuals and patients with IgG4-RD in vivo and in vitro. Although interferon-gamma (IFNγ) generally disrupts the integrity and function of TJs, as manifested by decreased epithelial barrier function, IFNγ markedly increased the epithelial barrier function of HSDECs via upregulation of claudin-7 expression in HSDECs from patients with IgG4-RD. This is the first report showing an IFNγ-dependent increase in epithelial barrier function in the salivary gland duct epithelium. Our results provide insights into the functional significance of TJs in salivary gland duct epithelium in physiological and pathological conditions, including IgG4-RD.

  8. Accident Analysis and Barrier Function (AEB) Method. Manual for Incident Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Svenson, Ola [Stockholm Univ. (Sweden). Dept. of Psychology

    2000-02-01

    The Accident Analysis and Barrier Function (AEB) Method models an accident or incident as a series of interactions between human and technical systems. In the sequence of human and technical errors leading to an accident there is, in principle, a possibility to arrest the development between each two successive errors. This can be done by a barrier function which, for example, can stop an operator from making an error. A barrier function can be performed by one or several barrier function systems. To illustrate, a mechanical system, a computer system or another operator can all perform a given barrier function to stop an operator from making an error. The barrier function analysis consists of analysis of suggested improvements, the effectiveness of the improvements, the costs of implementation, probability of implementation, the cost of maintaining the barrier function, the probability that maintenance will be kept up to standards and the generalizability of the suggested improvement. The AEB method is similar to the US method called HPES, but differs from that method in different ways. To exemplify, the AEB method has more emphasis on technical errors than HPES. In contrast to HPES that describes a series of events, the AEB method models only errors. This gives a more focused analysis making it well suited for checking other HPES-type accident analyses. However, the AEB method is a generic and stand-alone method that has been applied in other fields than nuclear power, such as, in traffic accident analyses.

  9. New advances in the pathophysiology of intestinal ion transport and barrier function in diarrhea and the impact on therapy.

    Science.gov (United States)

    Hoque, Kazi Mirajul; Chakraborty, Subhra; Sheikh, Irshad Ali; Woodward, Owen M

    2012-06-01

    Diarrhea remains a continuous threat to human health worldwide. Scaling up the best practices for diarrhea prevention requires improved therapies. Diarrhea results from dysregulation of normal intestinal ion transport functions. Host-microbe contact is a key determinant of this response. Underlying mechanisms in the disease state are regulated by intracellular signals that modulate the activity of individual transport proteins responsible for ion transport and barrier function. Similarly, virulence factors of pathogens and their complex interaction with the host has shed light on the mechanism of enteric infection. Great advances in our understanding of the pathophysiologic mechanisms of epithelial transport, and host-microbe interaction have been made in recent years. Application of these new advances may represent strategies to decrease pathogen attachment, enhance intestinal cation absorption, decrease anion secretion and repair barrier function. This review highlights the new advances and better understanding in the pathophysiology of diarrheal diseases and their impact on therapy.

  10. Barrier function in reconstructed epidermis and its resemblance to native human skin

    NARCIS (Netherlands)

    Ponec, M.; Gibbs, S.; Pilgram, G.; Boelsma, E.; Koerten, H.; Bouwstra, J.; Mommaas, M.

    2001-01-01

    One of the prerequisites for the use of human skin equivalents for scientific and screening purposes is that their barrier function is similar to that of native skin. Using human epidermis reconstructed on de-epidermized dermis we demonstrated that the formation of the stratum corneum (SC) barrier i

  11. Barrier function in reconstructed epidermis and its resemblance to native human skin

    NARCIS (Netherlands)

    Ponec, M.; Gibbs, S.; Pilgram, G.; Boelsma, E.; Koerten, H.; Bouwstra, J.; Mommaas, M.

    2001-01-01

    One of the prerequisites for the use of human skin equivalents for scientific and screening purposes is that their barrier function is similar to that of native skin. Using human epidermis reconstructed on de-epidermized dermis we demonstrated that the formation of the stratum corneum (SC) barrier

  12. Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function.

    Science.gov (United States)

    Boer, Magdalena; Duchnik, Ewa; Maleszka, Romuald; Marchlewicz, Mariola

    2016-02-01

    The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part - stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transepidermal water loss and sebum excretion. The knowledge of biophysical skin processes may be useful for the implementation of prophylactic actions whose aim is to restore the barrier function.

  13. Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function

    Directory of Open Access Journals (Sweden)

    Magdalena Boer

    2016-02-01

    Full Text Available The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part – stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transepidermal water loss and sebum excretion. The knowledge of biophysical skin processes may be useful for the implementation of prophylactic actions whose aim is to restore the barrier function.

  14. Optimization Design Model of Functional Gradient Thermal Barrier Coating Material by Using Parallel Computation

    Directory of Open Access Journals (Sweden)

    Chen Zhao

    2016-01-01

    Full Text Available It is important for huge ship to find the ceramic/metal functional gradient thermal barrier coating materials. A parallel computation model is built for optimization design of three-dimensional ceramic/metal functionally gradient thermal barrier coating material. According to the control equation and initial-boundary conditions, the heat transfer problem is considered, and numerical algorithms of optimization design is constructed by adapting difference method. The numerical results shows that gradient thermal barrier coating material can improve the function of material.

  15. The impact of ultraviolet therapy on stratum corneum ceramides and barrier function

    DEFF Research Database (Denmark)

    Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

    2011-01-01

    The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified.The aim of this study was to examine the effect of U...... therapy in dermatological patients on ceramides and skin barrier function.We found that UV light treatment does not change the ratio of important stratum corneum lipids, but we confirm earlier findings of decreased susceptibility to irritants after UV- therapy....

  16. Connexins in endothelial barrier function - novel therapeutic targets countering vascular hyperpermeability.

    Science.gov (United States)

    Soon, Allyson Shook Ching; Chua, Jia Wang; Becker, David Laurence

    2016-10-28

    Prolonged vascular hyperpermeability is a common feature of many diseases. Vascular hyperpermeability is typically associated with changes in the expression patterns of adherens and tight junction proteins. Here, we focus on the less-appreciated contribution of gap junction proteins (connexins) to basal vascular permeability and endothelial dysfunction. First, we assess the association of connexins with endothelial barrier integrity by introducing tools used in connexin biology and relating the findings to customary readouts in vascular biology. Second, we explore potential mechanistic ties between connexins and junction regulation. Third, we review the role of connexins in microvascular organisation and development, focusing on interactions of the endothelium with mural cells and tissue-specific perivascular cells. Last, we see how connexins contribute to the interactions between the endothelium and components of the immune system, by using neutrophils as an example. Mounting evidence of crosstalk between connexins and other junction proteins suggests that we rethink the way in which different junction components contribute to endothelial barrier function. Given the multiple points of connexin-mediated communication arising from the endothelium, there is great potential for synergism between connexin-targeted inhibitors and existing immune-targeted therapeutics. As more drugs targeting connexins progress through clinical trials, it is hoped that some might prove effective at countering vascular hyperpermeability.

  17. Regulation of psychic functions in combat sport

    Directory of Open Access Journals (Sweden)

    Klymenko A.I.

    2010-06-01

    Full Text Available The problems of adjusting of psychical functions are considered in sport. The methods of self-regulation are rotined in sport. The groups of emotional reactions of combat sportsmen are certain. It is set that sporting psychologists and trainers are mainly addressed to training of psychical functions. Also - the system of psychical self-regulation must be complex. It contains affecting physiological reactions and on psychical processes. Five groups of emotional reactions of combat sportsmen are marked. They are directed on development of ability without superfluous emotions to overcome extreme situations in the process of competition activity.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lishi Xie

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

  20. FUNCTIONAL PERFORMANCE, PARTICIPATION AND AUTONOMY AFTER DISCHARGE FROM PROSTHETIC REHABILITATION : BARRIERS, FACILITATORS AND OUTCOMES

    NARCIS (Netherlands)

    van Twillert, Sacha; Stuive, Ilse; Geertzen, Jan H. B.; Postema, Klaas; Lettinga, Ant T.

    2014-01-01

    Objective: To examine functional performance, participation and autonomy after discharge from prosthetic rehabilitation and to identify the barriers and facilitators affecting these outcomes. Design: Concurrent mixed-methods design. Quantitative and qualitative data were collected at discharge from

  1. Impaired skin barrier function in mice with colon carcinoma induced by azoxymethane and dextran sodium sulfate.

    Science.gov (United States)

    Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

    2015-01-01

    We have previously reported that impaired skin barrier function was induced by small intestinal injury in mice. Therefore, we postulated that other intestinal diseases might also influence skin barrier function. In this study, we evaluated the skin barrier function of hairless mice with colon carcinoma that was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). In mice treated with these drugs, we observed elevated transepidermal water loss and reduced skin hydration levels, compared to those in the control mice. In addition, plasma nitrogen di/trioxide (NO2(-)/NO3(-)) levels were significantly elevated, and expression of type I collagen was significantly reduced in the treated mice, compared to those in control. These results suggest that impaired skin barrier function occurs in mice when colon carcinoma is present.

  2. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

    National Research Council Canada - National Science Library

    Jungersted, J. M; Scheer, H; Mempel, M; Baurecht, H; Cifuentes, L; Hogh, J. K; Hellgren, L. I; Jemec, G. B. E; Agner, T; Weidinger, S

    2010-01-01

    ..., Høgh JK, Hellgren LI, Jemec GBE, Agner T, Weidinger S. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010; 65: 911-918. Background...

  3. The repair of impaired epidermal barrier function in rats by the cutaneous application of linoleic acid.

    Science.gov (United States)

    Prottey, C; Hartop, P J; Black, J G; McCormack, J I

    1976-01-01

    Epidermal barrier function in rats was experimentally impaired by two separate means, namely, by rendering the animals deficient in essential fatty acids and by evoking a primary cutaneous irritant response by treating with a solution of sodium laurate. Impaired barrier function was manifested by a greatly increased rate of transepidermal water loss. Application to the skin of sunflower seed oil, which is rich in linoleic acid, rapidly restored to normal the abnormally high rates of transepidermal water loss in both experimental cases, and it was shown with the essential fatty acid-deficient rats that there was a concomitant incorporation of linoleic acid of the sunflower seed oil into epidermal lipids. Cutaneous application of olive oil, which is low in linoleic acid but rich in the non-essential oleic acid, did not influence epidermal barrier function. A close relationship of barrier function and essential fatty acids is indicated.

  4. Interleukin-13 promotes expression of Alix to compromise renal tubular epithelial barrier function.

    Science.gov (United States)

    Xu, Chen; Sun, Guangdong; Yang, Jie; Sun, Qianmei; Tong, Zhaohui

    2015-05-01

    The epithelial barrier dysfunction plays a critical role in a number of kidney diseases. The mechanism is unclear. Alix is a protein involving in protein degradation in epithelial cells. This study aims to investigate that interleukin (IL)-13 inhibits Alix to compromise the kidney epithelial barrier function. In this study, the murine collecting duct cell line (M-1) was cultured in Transwell inserts to investigate the significance of Alix in compromising the epithelial barrier functions. T cell (Teff cells) proliferation assay was employed to assess the antigenicity of ovalbumin (OVA) that was transported across the M-1 monolayer barrier. The results showed that M-1 cells express Alix. Exposure to interleukin (IL)-13 markedly decreased the expression of Alix in M-1 cells, which compromised the M-1 monolayer barrier functions by showing the increases in the permeability to OVA. Over-expression of Alix abolished the IL-13-induced M-1 monolayer barrier dysfunction. Knockdown of Alix significantly increased M-1 monolayer permeability. The OVA collected from the Transwell basal chambers induced the OVA-specific T cell proliferation. We conclude that IL-13 compromises M-1 epithelial barrier functions via inhibiting Alix expression.

  5. Clinical characteristics and epidermal barrier function of papulopustular rosacea: A comparison study with acne vulgaris

    OpenAIRE

    Zhou, Maosong; Xie, Hongfu; Cheng, Lin; Li, Ji

    2016-01-01

    Objective: To evaluate the clinical characteristics and epidermal barrier function of papulopustular rosacea by comparing with acne vulgaris. Methods: Four hundred and sixty-three papulopustular rosacea patients and four hundred and twelve acne vulgaris patients were selected for the study in Xiangya Hospital of Central South University from March 2015 to May 2016. They were analyzed for major facial lesions, self-conscious symptoms and epidermal barrier function. Results: Erythema, burning, ...

  6. Microtubule affinity-regulating kinase 4: structure, function, and regulation.

    Science.gov (United States)

    Naz, Farha; Anjum, Farah; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2013-11-01

    MAP/Microtubule affinity-regulating kinase 4 (MARK4) belongs to the family of serine/threonine kinases that phosphorylate the microtubule-associated proteins (MAP) causing their detachment from the microtubules thereby increasing microtubule dynamics and facilitating cell division, cell cycle control, cell polarity determination, cell shape alterations, etc. The MARK4 gene encodes two alternatively spliced isoforms, L and S that differ in their C-terminal region. These isoforms are differentially regulated in human tissues including central nervous system. MARK4L is a 752-residue-long polypeptide that is divided into three distinct domains: (1) protein kinase domain (59-314), (2) ubiquitin-associated domain (322-369), and (3) kinase-associated domain (703-752) plus 54 residues (649-703) involved in the proper folding and function of the enzyme. In addition, residues 65-73 are considered to be the ATP-binding domain and Lys88 is considered as ATP-binding site. Asp181 has been proposed to be the active site of MARK4 that is activated by phosphorylation of Thr214 side chain. The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation. On the other hand, the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas suggesting its involvement in cell cycle. Several biological functions are also associated with MARK4 including microtubule bundle formation, nervous system development, and positive regulation of programmed cell death. Therefore, MARK4 is considered as the most suitable target for structure-based rational drug design. Our sequence, structure- and function-based analysis should be helpful for better understanding of mechanisms of regulation of microtubule dynamics and MARK4 associated diseases.

  7. Inhibition of Murine Pulmonary Microvascular Endothelial Cell Apoptosis Promotes Recovery of Barrier Function under Septic Conditions

    Directory of Open Access Journals (Sweden)

    Lefeng Wang

    2017-01-01

    Full Text Available Sepsis is characterized by injury of the pulmonary microvasculature and the pulmonary microvascular endothelial cells (PMVEC, leading to barrier dysfunction and acute respiratory distress syndrome (ARDS. Our recent work identified a strong correlation between PMVEC apoptosis and microvascular leak in septic mice in vivo, but the specific role of apoptosis in septic PMVEC barrier dysfunction remains unclear. Thus, we hypothesize that PMVEC apoptosis is likely required for PMVEC barrier dysfunction under septic conditions in vitro. Septic stimulation (mixture of tumour necrosis factor α, interleukin 1β, and interferon γ [cytomix] of isolated murine PMVEC resulted in a significant loss of barrier function as early as 4 h after stimulation, which persisted until 24 h. PMVEC apoptosis, as reflected by caspase activation, DNA fragmentation, and loss of membrane polarity, was first apparent at 8 h after cytomix. Pretreatment of PMVEC with the pan-caspase inhibitor Q-VD significantly decreased septic PMVEC apoptosis and was associated with reestablishment of PMVEC barrier function at 16 and 24 h after stimulation but had no effect on septic PMVEC barrier dysfunction over the first 8 h. Collectively, our data suggest that early septic murine PMVEC barrier dysfunction driven by proinflammatory cytokines is not mediated through apoptosis, but PMVEC apoptosis contributes to late septic PMVEC barrier dysfunction.

  8. Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function.

    Science.gov (United States)

    Xu, Bin; Li, Yan-Li; Xu, Ming; Yu, Chang-Chun; Lian, Meng-Qiao; Tang, Ze-Yao; Li, Chuan-Xun; Lin, Yuan

    2017-03-06

    Geniposide is an iridoid glycosides purified from the fruit of Gardenia jasminoides Ellis, which is known to have antiinflammatory, anti-oxidative and anti-tumor activities. The present study aimed to investigate the effects of geniposide on experimental rat colitis and to reveal the related mechanisms. Experimental rat colitis was induced by rectal administration of a TNBS solution. The rats were treated with geniposide (25, 50 mg·kg(-1)·d(-1), ig) or with sulfasalazine (SASP, 100 mg·kg(-1)·d(-1), ig) as positive control for 14 consecutive days. A Caco-2 cell monolayer exposed to lipopolysaccharides (LPS) was used as an epithelial barrier dysfunction model. Transepithelial electrical resistance (TER) was measured to evaluate intestinal barrier function. In rats with TNBS-induced colitis, administration of geniposide or SASP significantly increased the TNBS-decreased body weight and ameliorated TNBS-induced experimental colitis and related symptoms. Geniposide or SASP suppressed inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and neutrophil infiltration (myeloperoxidase activity) in the colon. In Caco-2 cells, geniposide (25-100 μmol/L) ameliorated LPS-induced endothelial barrier dysfunction via dose-dependently increasing transepithelial electrical resistance (TER). The results from both in vivo and in vitro studies revealed that geniposide down-regulated NF-κB, COX-2, iNOS and MLCK protein expression, up-regulated the expression of tight junction proteins (occludin and ZO-1), and facilitated AMPK phosphorylation. Both AMPK siRNA transfection and AMPK overexpression abrogated the geniposide-reduced MLCK protein expression, suggesting that geniposide ameliorated barrier dysfunction via AMPK-mediated inhibition of the MLCK pathway. In conclusion, geniposide ameliorated TNBS-induced experimental rat colitis by both reducing inflammation and modulating the disrupted epithelial barrier function via activating the AMPK signaling pathway..

  9. Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function

    DEFF Research Database (Denmark)

    Bailey, D M; Evans, K A; James, P E

    2008-01-01

    (2)) and following 6 h passive exposure to hypoxia (12% O(2)). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects......We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood-brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O...

  10. Skin Barrier Function and Its Importance at the Start of the Atopic March

    Directory of Open Access Journals (Sweden)

    Mary Beth Hogan

    2012-01-01

    Full Text Available Atopic dermatitis can be due to a variety of causes from nonatopic triggers to food allergy. Control of egress of water and protection from ingress of irritants and allergens are key components of cutaneous barrier function. Current research suggests that a degraded barrier function of the skin allows the immune system inappropriate access to environmental allergens. Epidermal aeroallergen exposure may allow sensitization to allergen possibly initiating the atopic march. Further research into connections between epidermal barrier function and possible allergen sensitization will be important to undertake. Future clinical trials focused on skin barrier protection may be of value as a possible intervention in prevention of the initiation of the atopic march.

  11. A new all-round density functional based on spin states and SN2 barriers

    Science.gov (United States)

    Swart, Marcel; Solà, Miquel; Bickelhaupt, F. Matthias

    2009-09-01

    We report here a new empirical density functional that is constructed based on the performance of OPBE and PBE for spin states and SN2 reaction barriers and how these are affected by different regions of the reduced gradient expansion. In a previous study [Swart, Solà, and Bickelhaupt, J. Comput. Methods Sci. Eng. 9, 69 (2009)] we already reported how, by switching between OPBE and PBE, one could obtain both the good performance of OPBE for spin states and reaction barriers and that of PBE for weak interactions within one and the same (SSB-sw) functional. Here we fine tuned this functional and include a portion of the KT functional and Grimme's dispersion correction to account for π-π stacking. Our new SSB-D functional is found to be a clear improvement and functions very well for biological applications (hydrogen bonding, π-π stacking, spin-state splittings, accuracy of geometries, reaction barriers).

  12. Executive Functioning, Barriers to Adherence, and Nonadherence in Adolescent and Young Adult Transplant Recipients.

    Science.gov (United States)

    Gutiérrez-Colina, Ana M; Eaton, Cyd K; Lee, Jennifer L; Reed-Knight, Bonney; Loiselle, Kristin; Mee, Laura L; LaMotte, Julia; Liverman, Rochelle; Blount, Ronald L

    2016-08-01

    OBJECTIVE : To evaluate levels of executive functioning in a sample of adolescent and young adult (AYA) transplant recipients, and to examine executive functioning in association with barriers to adherence and medication nonadherence.  METHOD : In all, 41 caregivers and 39 AYAs were administered self- and proxy-report measures.  RESULTS : AYA transplant recipients have significant impairments in executive functioning abilities. Greater dysfunction in specific domains of executive functioning was significantly associated with more barriers to adherence and greater medication nonadherence.  CONCLUSION : AYA transplant recipients are at increased risk for executive dysfunction. The assessment of executive functioning abilities may guide intervention efforts designed to decrease barriers to adherence and promote developmentally appropriate levels of treatment responsibility.

  13. Regulation of brain function by exercise.

    Science.gov (United States)

    Sutoo, Den'etsu; Akiyama, Kayo

    2003-06-01

    The effect of excercise on brain function was investigated through animal experiments. Exercise leads to increased serum calcium levels, and the calcium is transported to the brain. This in turn enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions. There are abnormally low levels of dopamine in the neostriatum and nucleus accumbens of epileptic mice (El mice strain) and spontaneously hypertensive rats (SHR). The low dopamine levels in those animals were improved following intracerebroventricular administration of calcium chloride. Dopamine levels and blood pressure in SHR were also normalized by exercise. In epileptic El mice, convulsions normalized dopamine levels and physiologic function. These findings suggest that exercise or convulsions affect brain function through calcium/calmodulin-dependent dopamine synthesis. This leads to the possibility that some symptoms of Parkinson's disease or senile dementia might be improved by exercise.

  14. Arctigenin from Fructus Arctii (Seed of Burdock Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

    Directory of Open Access Journals (Sweden)

    Hee Soon Shin

    2015-01-01

    Full Text Available Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER value (as an index of barrier function and ovalbumin (OVA permeation (as an index of permeability to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function.

  15. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers.

    Science.gov (United States)

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function.

  16. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

    Science.gov (United States)

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function. PMID:26550018

  17. Intestinal epithelial barrier function and tight junction proteins with heat and exercise

    DEFF Research Database (Denmark)

    Dokladny, Karol; Zuhl, Micah N; Moseley, Pope L

    2016-01-01

    (passive hyperthermia) heat stress on tight junction barrier function in in vitro and in vivo (animals and humans) models. Our secondary focus is to review changes in tight junction proteins in response to exercise or hyperthermic conditions. Finally, we discuss some pharmacological or nutritional...... interventions that may affect the cellular mechanisms involved in maintaining homeostasis of the intestinal epithelial tight junction barrier during heat stress or exercise....

  18. The important role of stratum corneum lipids for the cutaneous barrier function.

    Science.gov (United States)

    van Smeden, J; Janssens, M; Gooris, G S; Bouwstra, J A

    2014-03-01

    The skin protects the body from unwanted influences from the environment as well as excessive water loss. The barrier function of the skin is located in the stratum corneum (SC). The SC consists of corneocytes embedded in a lipid matrix. This lipid matrix is crucial for the lipid skin barrier function. This paper provides an overview of the reported SC lipid composition and organization mainly focusing on healthy and diseased human skin. In addition, an overview is provided on the data describing the relation between lipid modulations and the impaired skin barrier function. Finally, the use of in vitro lipid models for a better understanding of the relation between the lipid composition, lipid organization and skin lipid barrier is discussed. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

  19. The functions of grainy head-like proteins in animals and fungi and the evolution of apical extracellular barriers.

    Directory of Open Access Journals (Sweden)

    Adam Paré

    Full Text Available The Grainy head (GRH family of transcription factors are crucial for the development and repair of epidermal barriers in all animals in which they have been studied. This is a high-level functional conservation, as the known structural and enzymatic genes regulated by GRH proteins differ between species depending on the type of epidermal barrier being formed. Interestingly, members of the CP2 superfamily of transcription factors, which encompasses the GRH and LSF families in animals, are also found in fungi--organisms that lack epidermal tissues. To shed light on CP2 protein function in fungi, we characterized a Neurospora crassa mutant lacking the CP2 member we refer to as grainy head-like (grhl. We show that Neurospora GRHL has a DNA-binding specificity similar to that of animal GRH proteins and dissimilar to that of animal LSF proteins. Neurospora grhl mutants are defective in conidial-spore dispersal due to an inability to remodel the cell wall, and we show that grhl mutants and the long-known conidial separation-2 (csp-2 mutants are allelic. We then characterized the transcriptomes of both Neurospora grhl mutants and Drosophila grh mutant embryos to look for similarities in the affected genes. Neurospora grhl appears to play a role in the development and remodeling of the cell wall, as well as in the activation of genes involved in defense and virulence. Drosophila GRH is required to activate the expression of many genes involved in cuticular/epidermal-barrier formation. We also present evidence that GRH plays a role in adult antimicrobial defense. These results, along with previous studies of animal GRH proteins, suggest the fascinating possibility that the apical extracellular barriers of some animals and fungi might share an evolutionary connection, and that the formation of physical barriers in the last common ancestor was under the control of a transcriptional code that included GRH-like proteins.

  20. The functions of grainy head-like proteins in animals and fungi and the evolution of apical extracellular barriers.

    Science.gov (United States)

    Paré, Adam; Kim, Myungjin; Juarez, Michelle T; Brody, Stuart; McGinnis, William

    2012-01-01

    The Grainy head (GRH) family of transcription factors are crucial for the development and repair of epidermal barriers in all animals in which they have been studied. This is a high-level functional conservation, as the known structural and enzymatic genes regulated by GRH proteins differ between species depending on the type of epidermal barrier being formed. Interestingly, members of the CP2 superfamily of transcription factors, which encompasses the GRH and LSF families in animals, are also found in fungi--organisms that lack epidermal tissues. To shed light on CP2 protein function in fungi, we characterized a Neurospora crassa mutant lacking the CP2 member we refer to as grainy head-like (grhl). We show that Neurospora GRHL has a DNA-binding specificity similar to that of animal GRH proteins and dissimilar to that of animal LSF proteins. Neurospora grhl mutants are defective in conidial-spore dispersal due to an inability to remodel the cell wall, and we show that grhl mutants and the long-known conidial separation-2 (csp-2) mutants are allelic. We then characterized the transcriptomes of both Neurospora grhl mutants and Drosophila grh mutant embryos to look for similarities in the affected genes. Neurospora grhl appears to play a role in the development and remodeling of the cell wall, as well as in the activation of genes involved in defense and virulence. Drosophila GRH is required to activate the expression of many genes involved in cuticular/epidermal-barrier formation. We also present evidence that GRH plays a role in adult antimicrobial defense. These results, along with previous studies of animal GRH proteins, suggest the fascinating possibility that the apical extracellular barriers of some animals and fungi might share an evolutionary connection, and that the formation of physical barriers in the last common ancestor was under the control of a transcriptional code that included GRH-like proteins.

  1. Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery

    NARCIS (Netherlands)

    Heijink, I H; Brandenburg, S M; Postma, D S; van Oosterhout, A J M

    2012-01-01

    Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far. We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in

  2. Clinical implications of the sugar absorption test : Intestinal permeability test to assess mucosal barrier function

    NARCIS (Netherlands)

    Uil, JJ; VanElburg, RM; VanOverbeek, FM; Mulder, CJJ; VanbergeHenegouwen, GP; Heymans, HSA

    1997-01-01

    Background: Functional integrity as an aspect of the mucosal barrier function of the small bowel can be estimated by the intestinal permeability for macromolecules. In the first part of this paper, an overview of intestinal permeability and its measurement is given. Methods: In the second part of th

  3. A novel porcine in vitro model of the blood-cerebrospinal fluid barrier with strong barrier function.

    Directory of Open Access Journals (Sweden)

    Mira Schroten

    Full Text Available Epithelial cells of the plexus choroideus form the structural basis of the blood-cerebrospinal fluid barrier (BCSFB. In vitro models of the BCSFB presenting characteristics of a functional barrier are of significant scientific interest as tools for examination of BCSFB function. Due to a lack of suitable cell lines as in vitro models, primary porcine plexus epithelial cells were subjected to a series of selective cultivation steps until a stable continuous subcultivatable epithelial cell line (PCP-R was established. PCP-R cells grow in a regular polygonal pattern with a doubling time of 28-36 h. At a cell number of 1.5×10(5 in a 24-well plate confluence is reached in 56-72 h. Cells are cytokeratin positive and chromosomal analysis revealed 56 chromosomes at peak (84th subculture. Employing reverse transcription PCR mRNA expression of several transporters and components of cell junctions could be detected. The latter includes tight junction components like Claudin-1 and -3, ZO-1, and Occludin, and the adherens junction protein E-cadherin. Cellular localization studies of ZO-1, Occludin and Claudin-1 by immunofluorescence and morphological analysis by electron microscopy demonstrated formation of a dense tight junction structure. Importantly, when grown on cell culture inserts PCP-R developed typical characteristics of a functional BCSFB including high transepithelial electrical resistance above 600 Ω×cm(2 as well as low permeability for macromolecules. In summary, our data suggest the PCP-R cell line as a suitable in vitro model of the porcine BCSFB.

  4. Cellular zinc is required for intestinal epithelial barrier maintenance via the regulation of claudin-3 and occludin expression.

    Science.gov (United States)

    Miyoshi, Yuka; Tanabe, Soichi; Suzuki, Takuya

    2016-07-01

    Intracellular zinc is required for a variety of cell functions, but its precise roles in the maintenance of the intestinal tight junction (TJ) barrier remain unclear. The present study investigated the essential roles of intracellular zinc in the preservation of intestinal TJ integrity and the underlying molecular mechanisms. Depletion of intracellular zinc in both intestinal Caco-2 cells and mouse colons through the application of a cell-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induced a disruption of the TJ barrier, as indicated by increased FITC-labeled dextran flux and decreased transepithelial electrical resistance. The TPEN-induced TJ disruption is associated with downregulation of two TJ proteins, occludin and claudin-3. Biotinylation of cell surface proteins revealed that the zinc depletion induced the proteolysis of occludin but not claudin-3. Occludin proteolysis was sensitive to the inhibition of calpain activity, and increased calpain activity was observed in the zinc-depleted cells. Although quantitative PCR analysis and promoter reporter assay have demonstrated that the zinc depletion-induced claudin-3 downregulation occurred at transcriptional levels, a site-directed mutation in the egr1 binding site in the claudin-3 promoter sequence induced loss of both the basal promoter activity and the TPEN-induced decreases. Reduced egr1 expression by a specific siRNA also inhibited claudin-3 expression and transepithelial electrical resistance maintenance in cells. This study shows that intracellular zinc has an essential role in the maintenance of the intestinal epithelial TJ barrier through regulation of occludin proteolysis and claudin-3 transcription.

  5. Fusion excitation function measurement for 6Li+64Ni at near-barrier energies

    Directory of Open Access Journals (Sweden)

    Shaikh Md. Moin

    2015-01-01

    Full Text Available Total fusion excitation function has been measured for the reaction of weakly bound 6Li projectile on medium mass 64Ni target at energies near the Coulomb barrier of the system. Online characteristic γ-ray detection method has been used to identify and determine the cross sections of the residues. No suppression of total fusion cross section (σTF is observed at above barrier energies. But enhancement of measured cross section with respect to the one-dimensional barrier penetration model (1-DBPM calculation is observed at below barrier energies. The enhancement can not be explained by coupled channels calculation with dominant projectile and target excitations as well as one-neutron stripping reaction.

  6. A search for parameters of universal sub-barrier fusion excitation function

    Science.gov (United States)

    Qu, W. W.; Zhang, G. L.; Wolski, R.

    2016-11-01

    Many fusion experimental data have been analyzed in terms of a simple universal function which could be used for predictions of fusion cross section below the barrier for arbitrary systems. Sub-barrier fusions based on the concept of Q -fusion value dependence were studied. It is attempted to parameterize the energy-reduced fusion excitation functions around the Coulomb barriers by an analytical phenomenological function. It was found that the speed of driving nuclei towards fusion is faster with the increase of mass asymmetry of colliding systems and those systems with a large difference of the ratio of neutrons to protons. However, a general trend with respect to total mass has not been observed. An exposition of more qualitative conclusions is hindered by apparent inconsistencies of measured fusion cross sections.

  7. Regulation and function of histone acetyltransferase MOF.

    Science.gov (United States)

    Yang, Yang; Han, Xiaofei; Guan, Jingyun; Li, Xiangzhi

    2014-03-01

    The mammalian MOF (male absent on the first), a member of the MYST (MOZ, YBF2, SAS2, and Tip60) family of histone acetyltransferases (HATs), is the major enzyme that catalyzes the acetylation of histone H4 on lysine 16. Acetylation of K16 is a prevalent mark associated with chromatin decondensation. MOF has recently been shown to play an essential role in maintaining normal cell functions. In this study, we discuss the important roles of MOF in DNA damage repair, apoptosis, and tumorigenesis. We also analyze the role of MOF as a key regulator of the core transcriptional network of embryonic stem cells.

  8. Examination of the restoration of epithelial barrier function following superficial keratectomy.

    Science.gov (United States)

    Hutcheon, Audrey E K; Sippel, Kimberly C; Zieske, James D

    2007-01-01

    The goal of the present study was to determine the rate of restoration of the corneal epithelial barrier following a superficial keratectomy using a functional assay of tight junction integrity. Adult Sprague-Dawley rats were anesthetized and a 3-mm superficial keratectomy was performed. The eyes were allowed to heal from 4 h to 8 weeks and the rate of epithelial wound closure was determined. To examine the restoration of the barrier function, EZ-Link Sulfo-NHS-LC-Biotin (LC-Biotin) was applied to all eyes, experimental and control, for 15 min at the time of sacrifice. This compound does not penetrate through intact tight junctions. Indirect immunofluorescence was performed with anti-laminin, a marker of basement membrane; fluorescein-conjugated streptavidin to detect the biotinylated marker; and anti-occludin and anti-ZO-1, markers of tight junctions. Epithelial wound closure was observed at 36-42 h after wounding. LC-Biotin did not penetrate the intact epithelium. Upon wounding, LC-Biotin penetrated into the stroma subjacent and slightly peripheral to the wound area. This pattern was present from 4-48 h post-wounding. The area of LC-Biotin localization decreased with time and the functional barrier was restored by 72 h. Occludin and ZO-1 were present at all time points. The number of cell layers expressing these proteins appeared to increase at 48 and 72 h. Continuous laminin localization was not observed until at least 7 days after wounding. Barrier function is restored within 1-1.5 days after epithelial wound closure. The loss of barrier function does not extend beyond the edge of the original wound. The restoration of barrier function does not appear to correlate with reassembly of the basement membrane in this model.

  9. Regulation of satellite cell function in sarcopenia

    Directory of Open Access Journals (Sweden)

    Stephen E Alway

    2014-09-01

    Full Text Available The mechanisms contributing to sarcopenia include reduced satellite cell (myogenic stem cell function that is impacted by the environment (niche of these cells. Satellite cell function is affected by oxidative stress, which is elevated in aged muscles, and this along with changes in largely unknown systemic factors, likely contribute to the manner in which satellite cells respond to stressors such as exercise, disuse or rehabilitation in sarcopenic muscles. Nutritional intervention provides one therapeutic strategy to improve the satellite cell niche and systemic factors, with the goal of improving satellite cell function in aging muscles. Although many elderly persons consume various nutraceuticals with the hope of improving health, most of these compounds have not been thoroughly tested, and the impacts that they might have on sarcopenia, and satellite cell function are not clear. This review discusses data pertaining to the satellite cell responses and function in aging skeletal muscle, and the impact that three compounds: resveratrol, green tea catechins and β-Hydroxy-β-methylbutyrate have on regulating satellite cell function and therefore contributing to reducing sarcopenia or improving muscle mass after disuse in aging. The data suggest that these nutraceutical compounds improve satellite cell function during rehabilitative loading in animal models of aging after disuse (i.e., muscle regeneration. While these compounds have not been rigorously tested in humans, the data from animal models of aging provide a strong basis for conducting additional focused work to determine if these or other nutraceuticals can offset the muscle losses, or improve regeneration in sarcopenic muscles of older humans via improving satellite cell function.

  10. Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood Brain Barrier in Response to Iron Starvation.

    Science.gov (United States)

    Beydoun, Rami; Hamood, Mohamed A; Gomez Zubeita, Daniela M; Kondapalli, Kalyan C

    2017-01-27

    Iron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain-iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is upregulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced upregulation of the transferrin receptor (TfR) and downregulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and independent iron uptake. We propose NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.

  11. Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients

    NARCIS (Netherlands)

    M. Janssens (Michelle); J. van Smeden (Jeroen); G.S. Gooris (Gert); W. Bras (Wim); G. Portale (Guiseppe); P.J. Caspers (Peter); R. Vreeken (Rob); T. Hankemeier (Thomas); S. Kezic (Sanja); R. Wolterbeek (Ron); A.P.M. Lavrijsen (Adriana); J.A. Bouwstra (Joke)

    2012-01-01

    textabstractA hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a

  12. Relative importance of energy dependent diffuseness parameter and barrier position in the analysis of fusion excitation function data

    Directory of Open Access Journals (Sweden)

    Kharab Rajesh

    2014-03-01

    Full Text Available We have investigated the relative importance of the energy dependence of diffuseness parameter and barrier position in the description of the fusion excitation function data of some heavy ion systems in near barrier energy region. The effects of the energy dependent diffuseness parameter are found to be much more prominent in comparison to those of barrier position.

  13. Examination of the Restoration of Epithelial Barrier Function Following Superficial Keratectomy

    OpenAIRE

    Hutcheon, Audrey E. K.; Sippel, Kimberly C.; Zieske, James D.

    2006-01-01

    The goal of the present study was to determine the rate of restoration of the corneal epithelial barrier following a superficial keratectomy using a functional assay of tight junction integrity. Adult Sprague-Dawley rats were anesthetized and a 3-mm superficial keratectomy was performed. The eyes were allowed to heal from 4 hours to 8 weeks and the rate of epithelial wound closure was determined. To examine the restoration of the barrier function, EZ-Link Sulfo-NHS-LC-Biotin (LC-Biotin) was a...

  14. Functional barrier in two-layer recycled PP films for food packaging applications

    Science.gov (United States)

    Scarfato, P.; Di Maio, L.; Milana, M. R.; Feliciani, R.; Denaro, M.; Incarnato, L.

    2014-05-01

    A preliminary study on bi-layer virgin/contaminated polypropylene co-extruded films was performed in order to evaluate the possibility to realize an effective functional barrier in PP-based multi-layer systems. In particular, the specific migration in 10% v/v aqueous ethanol of two surrogate contaminants (phenyl-cyclohexane and benzophenone) contained in the contaminated layer across the PP functional barrier was measured at different times and the results were compared with those obtained from a contaminated mono-layer polypropylene film. Moreover, the thermal and mechanical performances of the produced films were investigated.

  15. The dividend function in the jump-diffusion dual model with barrier dividend strategy

    Institute of Scientific and Technical Information of China (English)

    LI Bo; WU Rong

    2008-01-01

    A dual model of the perturbed classical compound Poisson risk model is considered under a constant dividend barrier.A new method is used in deriving the boundary condition of the equation for the expectation function by studying the local time of a related process.We obtain the expression for the expected discount dividend function in terms of those in the corresponding perturbed compound Poisson risk model without barriers.A special case in which the gain size is phase-type distributed is illustrated.We also consider the existence of the optimal dividend level.

  16. Etk/Bmx activation modulates barrier function in epithelial cells.

    Science.gov (United States)

    Hamm-Alvarez, S F; Chang, A; Wang, Y; Jerdeva, G; Lin, H H; Kim, K J; Ann, D K

    2001-06-01

    Etk/Bmx is a member of the Tec family of cytoplasmic non-receptor tyrosine kinases known to express in epithelial cells. We demonstrate herein that Etk activation in stably Etk-transfected epithelial Pa-4 cells resulted in a consistently increased transepithelial resistance (TER). After 24 h of hypoxic (1% O(2)) exposure, the TER and equivalent active ion transport rate (I(eq)) were reduced to <5% of the normoxia control in Pa-4 cells, whereas both TER and I(eq) were maintained at comparable and 60% levels, respectively, relative to their normoxic controls in cells with Etk activation. Moreover, Pa-4 cells exhibited an abundant actin stress fiber network with a diffuse distribution of beta-catenin at the cell periphery. By contrast, Etk-activated cells displayed a redistribution of actin to an exclusively peripheral network, with a discrete band of beta-catenin also concentrated at the cell periphery, and an altered occludin distribution profile. On the basis of these findings, we propose that Etk may be a novel regulator of epithelial junctions during physiological and pathophysiological conditions.

  17. Barrier role of actin filaments in regulated mucin secretion from airway goblet cells.

    Science.gov (United States)

    Ehre, Camille; Rossi, Andrea H; Abdullah, Lubna H; De Pestel, Kathleen; Hill, Sandra; Olsen, John C; Davis, C William

    2005-01-01

    Airway goblet cells secrete mucin onto mucosal surfaces under the regulation of an apical, phospholipase C/G(q)-coupled P2Y(2) receptor. We tested whether cortical actin filaments negatively regulate exocytosis in goblet cells by forming a barrier between secretory granules and plasma membrane docking sites as postulated for other secretory cells. Immunostaining of human lung tissues and SPOC1 cells (an epithelial, mucin-secreting cell line) revealed an apical distribution of beta- and gamma-actin in ciliated and goblet cells. In goblet cells, actin appeared as a prominent subplasmalemmal sheet lying between granules and the apical membrane, and it disappeared from SPOC1 cells activated by purinergic agonist. Disruption of actin filaments with latrunculin A stimulated SPOC1 cell mucin secretion under basal and agonist-activated conditions, whereas stabilization with jasplakinolide or overexpression of beta- or gamma-actin conjugated to yellow fluorescent protein (YFP) inhibited secretion. Myristoylated alanine-rich C kinase substrate, a PKC-activated actin-plasma membrane tethering protein, was phosphorylated after agonist stimulation, suggesting a translocation to the cytosol. Scinderin (or adseverin), a Ca(2+)-activated actin filament severing and capping protein was cloned from human airway and SPOC1 cells, and synthetic peptides corresponding to its actin-binding domains inhibited mucin secretion. We conclude that actin filaments negatively regulate mucin secretion basally in airway goblet cells and are dynamically remodeled in agonist-stimulated cells to promote exocytosis.

  18. Prophylactic treatment with growth hormone improves intestinal barrier function and alleviates bacterial translocation in stressed rats

    Institute of Scientific and Technical Information of China (English)

    丁连安; 黎介寿; 李幼生; 刘放南; 谭力

    2004-01-01

    Background Damage to the gut barrier often occurs during critical illnesses. In such cases, it is very important to alleviate impairment of the intestinal barrier and protect intestinal barrier function. This study investigated the protective effect of growth hormone on intestinal barrier function in rats under stress.Methods This study consisted of prospective, randomized, and controlled animal experiments. Twenty-five Sprague-Dawley rats served as total parenteral nutrition (TPN) models and were divided into three groups: TPN group, sepsis (Sep) group, and growth hormone (GH) group. Another 8 rats served as normal controls. Each group received different stress stimuli. Rats were fed for 7 days, and samples were taken for examination 24 hours after garaging with dual saccharides. Results The architecture of the small intestinal mucosa in the Sep group showed the most severe damage among all groups. Nitric oxide levels in blood plasma and immunoglobulin A levels in the intestinal mucosa of the GH group were significantly lower than in the Sep group (P<0.02). There were no significant changes in CD3 counts and in the CD4/CD8 ratio between the four groups. Dual sugar tests and bacteriological examinations revealed that intestinal permeability and rate of bacterial translocation in the GH group were lower than in the Sep group (P<0.01, respectively).Conclusion Prophylactic treatment with growth hormone can alleviate damage to intestinal barrier function caused by trauma and endotoxemia in rats under stress.

  19. A functional mechanistic study of the effect of emollients on the structure and function of the skin barrier.

    Science.gov (United States)

    Danby, S G; Chalmers, J; Brown, K; Williams, H C; Cork, M J

    2016-11-01

    Preventing relapses of atopic dermatitis (AD) through the regular use of topical products to repair the skin barrier defect is an emerging concept. It is still unclear if some commonly used emollients exert a positive effect on the skin barrier. To determine the skin barrier effects of emollients commonly prescribed in the U.K. Two cohorts of volunteers with quiescent AD undertook observer-blind forearm-controlled studies. The first cohort (18 volunteers) treated the volar side of one forearm with two fingertip units of Doublebase(™) gel twice daily for 4 weeks. The second cohort (19 volunteers) undertook the same regimen using Diprobase(®) cream. Transepidermal water loss (TEWL), stratum corneum integrity and hydration, skin surface pH and redness were determined at the test sites before and after treatment. Neither Diprobase(®) cream nor Doublebase(™) gel significantly affected the underlying skin barrier function. Both emollients were associated with significantly increased skin surface pH immediately after application (by 0·8 ± 0·19 and 1·0 ± 0·18 units, respectively), and no erythema. Diprobase(®) cream artificially and transiently (6 h) improved permeability barrier function by 2·9-3·1 g m(-2)  h(-1) TEWL and increased skin hydration by 6·0-6·2 units. Doublebase(™) gel, containing humectants, was associated with a greater (between 10·1 and 13·0 units during the first 6 h) and more sustained increase in hydration, lasting more than 12 h following repeated use. Diprobase(®) cream and Doublebase(™) gel are not associated with skin barrier harm and appear to be appropriate for AD treatment. While displaying emollient properties, neither formulation displayed an ability to actively improve sustained skin barrier function. © 2016 British Association of Dermatologists.

  20. Identification and functional analysis of healing regulators in Drosophila.

    Science.gov (United States)

    Álvarez-Fernández, Carmen; Tamirisa, Srividya; Prada, Federico; Chernomoretz, Ariel; Podhajcer, Osvaldo; Blanco, Enrique; Martín-Blanco, Enrique

    2015-01-01

    Wound healing is an essential homeostatic mechanism that maintains the epithelial barrier integrity after tissue damage. Although we know the overall steps in wound healing, many of the underlying molecular mechanisms remain unclear. Genetically amenable systems, such as wound healing in Drosophila imaginal discs, do not model all aspects of the repair process. However, they do allow the less understood aspects of the healing response to be explored, e.g., which signal(s) are responsible for initiating tissue remodeling? How is sealing of the epithelia achieved? Or, what inhibitory cues cancel the healing machinery upon completion? Answering these and other questions first requires the identification and functional analysis of wound specific genes. A variety of different microarray analyses of murine and humans have identified characteristic profiles of gene expression at the wound site, however, very few functional studies in healing regulation have been carried out. We developed an experimentally controlled method that is healing-permissive and that allows live imaging and biochemical analysis of cultured imaginal discs. We performed comparative genome-wide profiling between Drosophila imaginal cells actively involved in healing versus their non-engaged siblings. Sets of potential wound-specific genes were subsequently identified. Importantly, besides identifying and categorizing new genes, we functionally tested many of their gene products by genetic interference and overexpression in healing assays. This non-saturated analysis defines a relevant set of genes whose changes in expression level are functionally significant for proper tissue repair. Amongst these we identified the TCP1 chaperonin complex as a key regulator of the actin cytoskeleton essential for the wound healing response. There is promise that our newly identified wound-healing genes will guide future work in the more complex mammalian wound healing response.

  1. Identification and functional analysis of healing regulators in Drosophila.

    Directory of Open Access Journals (Sweden)

    Carmen Álvarez-Fernández

    Full Text Available Wound healing is an essential homeostatic mechanism that maintains the epithelial barrier integrity after tissue damage. Although we know the overall steps in wound healing, many of the underlying molecular mechanisms remain unclear. Genetically amenable systems, such as wound healing in Drosophila imaginal discs, do not model all aspects of the repair process. However, they do allow the less understood aspects of the healing response to be explored, e.g., which signal(s are responsible for initiating tissue remodeling? How is sealing of the epithelia achieved? Or, what inhibitory cues cancel the healing machinery upon completion? Answering these and other questions first requires the identification and functional analysis of wound specific genes. A variety of different microarray analyses of murine and humans have identified characteristic profiles of gene expression at the wound site, however, very few functional studies in healing regulation have been carried out. We developed an experimentally controlled method that is healing-permissive and that allows live imaging and biochemical analysis of cultured imaginal discs. We performed comparative genome-wide profiling between Drosophila imaginal cells actively involved in healing versus their non-engaged siblings. Sets of potential wound-specific genes were subsequently identified. Importantly, besides identifying and categorizing new genes, we functionally tested many of their gene products by genetic interference and overexpression in healing assays. This non-saturated analysis defines a relevant set of genes whose changes in expression level are functionally significant for proper tissue repair. Amongst these we identified the TCP1 chaperonin complex as a key regulator of the actin cytoskeleton essential for the wound healing response. There is promise that our newly identified wound-healing genes will guide future work in the more complex mammalian wound healing response.

  2. Phenylalanine hydroxylase: function, structure, and regulation.

    Science.gov (United States)

    Flydal, Marte I; Martinez, Aurora

    2013-04-01

    Mammalian phenylalanine hydroxylase (PAH) catalyzes the rate-limiting step in the phenylalanine catabolism, consuming about 75% of the phenylalanine input from the diet and protein catabolism under physiological conditions. In humans, mutations in the PAH gene lead to phenylketonuria (PKU), and most mutations are mainly associated with PAH misfolding and instability. The established treatment for PKU is a phenylalanine-restricted diet and, recently, supplementation with preparations of the natural tetrahydrobiopterin cofactor also shows effectiveness for some patients. Since 1997 there has been a significant increase in the understanding of the structure, catalytic mechanism, and regulation of PAH by its substrate and cofactor, in addition to improved correlations between genotype and phenotype in PKU. Importantly, there has also been an increased number of studies on the structure and function of PAH from bacteria and lower eukaryote organisms, revealing an additional anabolic role of the enzyme in the synthesis of melanin-like pigments. In this review, we discuss these recent studies, which contribute to define the evolutionary adaptation of the PAH structure and function leading to sophisticated regulation for effective catabolic processing of phenylalanine in mammalian organisms.

  3. Effects of Fe particle irradiation on human endothelial barrier structure and function

    Science.gov (United States)

    Sharma, Preety; Guida, Peter; Grabham, Peter

    2014-07-01

    Space travel involves exposure to biologically effective heavy ion radiation and there is consequently a concern for possible degenerative disorders in humans. A significant target for radiation effects is the microvascular system, which is crucial to healthy functioning of the tissues. Its pathology is linked to disrupted endothelial barrier function and is not only a primary event in a range of degenerative diseases but also an important influencing factor in many others. Thus, an assessment of the effects of heavy ion radiation on endothelial barrier function would be useful for estimating the risks of space travel. This study was aimed at understanding the effects of high LET Fe particles (1 GeV/n) and is the first investigation of the effects of charged particles on the function of the human endothelial barrier. We used a set of established and novel endpoints to assess barrier function after exposure. These include, trans-endothelial electrical resistance (TEER), morphological effects, localization of adhesion and cell junction proteins (in 2D monolayers and in 3D tissue models), and permeability of molecules through the endothelial barrier. A dose of 0.50 Gy was sufficient to cause a progressive reduction in TEER measurements that were significant 48 hours after exposure. Concurrently, there were morphological changes and a 14% loss of cells from monolayers. Gaps also appeared in the normally continuous cell-border localization of the tight junction protein - ZO-1 but not the Platelet endothelial cell adhesion molecule (PECAM-1) in both monolayers and in 3D vessel models. Disruption of barrier function was confirmed by increased permeability to 3 kDa and 10 kDa dextran molecules. A dose of 0.25 Gy caused no detectible change in cell number, morphology, or TEER, but did cause barrier disruption since there were gaps in the cell border localization of ZO-1 and an increased permeability to 3 kDa dextran. These results indicate that Fe particles potently have

  4. Rictor/mTORC2 regulates blood-testis barrier dynamics via its effects on gap junction communications and actin filament network.

    Science.gov (United States)

    Mok, Ka-Wai; Mruk, Dolores D; Lee, Will M; Cheng, C Yan

    2013-03-01

    In the mammalian testis, coexisting tight junctions (TJs), basal ectoplasmic specializations, and gap junctions (GJs), together with desmosomes near the basement membrane, constitute the blood-testis barrier (BTB). The most notable feature of the BTB, however, is the extensive network of actin filament bundles, which makes it one of the tightest blood-tissue barriers. The BTB undergoes restructuring to facilitate the transit of preleptotene spermatocytes at stage VIII-IX of the epithelial cycle. Thus, the F-actin network at the BTB undergoes cyclic reorganization via a yet-to-be explored mechanism. Rictor, the key component of mTORC2 that is known to regulate actin cytoskeleton, was shown to express stage-specifically at the BTB in the seminiferous epithelium. Its expression was down-regulated at the BTB in stage VIII-IX tubules, coinciding with BTB restructuring at these stages. Using an in vivo model, a down-regulation of rictor at the BTB was also detected during adjudin-induced BTB disruption, illustrating rictor expression is positively correlated with the status of the BTB integrity. Indeed, the knockdown of rictor by RNAi was found to perturb the Sertoli cell TJ-barrier function in vitro and the BTB integrity in vivo. This loss of barrier function was accompanied by changes in F-actin organization at the Sertoli cell BTB in vitro and in vivo, associated with a loss of interaction between actin and α-catenin or ZO-1. Rictor knockdown by RNAi was also found to impede Sertoli cell-cell GJ communication, disrupting protein distribution (e.g., occludin, ZO-1) at the BTB, illustrating that rictor is a crucial BTB regulator.

  5. The parametrization of Coulomb barrier heights and positions using a new universal function in the proximity potential

    Science.gov (United States)

    Zhang, G. L.; Pan, M.

    2016-10-01

    The Coulomb barrier heights are calculated by using the proximity potential with a new universal function in comparison with the results of proximity potentials Prox77, AW95, Bass73, BW91, CW76, DP and Ng80. It is found that the new results of Coulomb barrier heights are better than those of most proximity potentials. Then this proximity potential with the new universal function was used to calculate the Coulomb barrier positions and heights from light fusion systems to heavy fusion systems. The parametrized formulas are obtained for Coulomb barrier height and position, and can reproduce most of calculated barrier heights and positions within the accuracy of ± 1%.

  6. Functions of an engineered barrier system for a nuclear waste repository in basalt

    Energy Technology Data Exchange (ETDEWEB)

    Coons, W.E.; Moore, E.L.; Smith, M.J.; Kaser, J.D.

    1980-01-01

    Defined in this document are the functions of components selected for an engineered barrier system for a nuclear waste repository in basalt. The definitions provide a focal point for barrier material research and development by delineating the purpose and operative lifetime of each component of the engineered system. A five-component system (comprised of waste form, canister, buffer, overpack, and tailored backfill) is discussed in terms of effective operation throughout the course of repository history, recognizing that the emplacement environment changes with time. While components of the system are mutually supporting, redundancy is provided by subsystems of physical and chemical barriers which act in concert with the geology to provide a formidable barrier to transport of hazardous materials to the biosphere. The operating philosophy of the conceptual engineered barrier system is clarified by examples pertinent to storage in basalt, and a technical approach to barrier design and material selection is proposed. A method for system validation and qualification is also included which considers performance criteria proposed by external agencies in conjunction with site-specific models and risk assessment to define acceptable levels of system performance.

  7. Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery.

    Science.gov (United States)

    Heijink, I H; Brandenburg, S M; Postma, D S; van Oosterhout, A J M

    2012-02-01

    Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far. We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) from COPD patients, nonsmokers and healthy smokers. We demonstrate that CSE rapidly and transiently impairs 16HBE barrier function, largely due to disruption of cell-cell contacts. CSE induced a similar, but stronger and more sustained, defect in PBECs. Application of the specific epidermal growth factor receptor (EGFR) inhibitor AG1478 showed that EGFR activation contributes to the CSE-induced defects in both 16HBE cells and PBECs. Furthermore, our data indicate that the endogenous protease calpain mediates these defects through tight junction protein degradation. CSE also delayed the reconstitution of 16HBE intercellular contacts during wound healing and attenuated PBEC barrier function upon wound regeneration. These findings were comparable between PBECs from smokers, healthy smokers and COPD patients. In conclusion, we demonstrate for the first time that CSE reduces epithelial integrity, probably by EGFR and calpain-dependent disruption of intercellular contacts. This may increase susceptibility to environmental insults, e.g. inhaled pathogens. Thus, EGFR may be a promising target for therapeutic strategies to improve mucosal barrier function in cigarette smoking-related disease.

  8. Adiponectin in Fresh Frozen Plasma Contributes to Restoration of Vascular Barrier Function After Hemorrhagic Shock.

    Science.gov (United States)

    Deng, Xiyun; Cao, Yanna; Huby, Maria P; Duan, Chaojun; Baer, Lisa; Peng, Zhanglong; Kozar, Rosemary A; Doursout, Marie-Francoise; Holcomb, John B; Wade, Charles E; Ko, Tien C

    2016-01-01

    Hemorrhagic shock is the leading cause of preventable deaths in civilian and military trauma. Use of fresh frozen plasma (FFP) in patients requiring massive transfusion is associated with improved outcomes. FFP contains significant amounts of adiponectin, which is known to have vascular protective function. We hypothesize that FFP improves vascular barrier function largely via adiponectin. Plasma adiponectin levels were measured in 19 severely injured patients in hemorrhagic shock (HS). Compared with normal individuals, plasma adiponectin levels decreased to 49% in HS patients before resuscitation (P < 0.05) and increased to 64% post-resuscitation (but not significant). In a HS mouse model, we demonstrated a similar decrease in plasma adiponectin to 54% but a significant increase to 79% by FFP resuscitation compared with baseline (P < 0.05). HS disrupted lung vascular barrier function, leading to an increase in permeability. FFP resuscitation reversed these HS-induced effects. Immunodepletion of adiponectin from FFP abolished FFP's effects on blocking endothelial hyperpermeability in vitro, and on improving lung vascular barrier function in HS mice. Replenishment with adiponectin rescued FFP's effects. These findings suggest that adiponectin is an important component in FFP resuscitation contributing to the beneficial effects on vascular barrier function after HS.

  9. Microbial products induce claudin-2 to compromise gut epithelial barrier function.

    Directory of Open Access Journals (Sweden)

    Xiaoyu Liu

    Full Text Available The epithelial barrier dysfunction is an important pathogenic feature in a number of diseases. The underlying mechanism is to be further investigated. The present study aims to investigate the role of tight junction protein claudin-2 (Cldn2 in the compromising epithelial barrier function. In this study, the expression of Cldn2 in the epithelial layer of mice and patients with food allergy was observed by immunohistochemistry. The induction of Cldn2 was carried out with a cell culture model. The Cldn2-facilitated antigen internalization was observed by confocal microscopy. The epithelial barrier function in the gut epithelial monolayer was assessed by recording the transepithelial resistance and assessing the permeability to a macromolecular tracer. The results showed that the positive immune staining of Cldn2 was observed in the epithelial layer of the small intestine that was weakly stained in naïve control mice, and strongly stained in sensitized mice as well as patients with food allergy. Exposure to cholera toxin or Staphylococcal enterotoxin B induced the expression of Cldn2 in HT-29 or T84 cells. Cldn2 could bind protein antigen to form complexes to facilitate the antigen transport across the epithelial barrier. Blocking Cldn2 prevented the allergen-related hypersensitivity the intestine. We conclude that the tight junction protein Cldn2 is involved in the epithelial barrier dysfunction.

  10. Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia.

    Science.gov (United States)

    Chen, Tao; Dai, Shu-Hui; Li, Xia; Luo, Peng; Zhu, Jie; Wang, Yu-Hai; Fei, Zhou; Jiang, Xiao-Fan

    2017-09-22

    Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are two well-characterized members of the silent information regulator 2 (Sir2) family of proteins. Both Sirt1 and Sirt3 have been shown to play vital roles in resistance to cellular stress, but the interaction between these two sirtuins has not been fully determined. In this study, we investigated the role of Sirt1-Sirt3 axis in blood-brain barrier (BBB) permeability after ischemia in vitro. Human brain microvascular endothelial cells and astrocytes were co-cultured to model the BBB in vitro and oxygen and glucose deprivation (OGD) was performed to mimic ischemia. The results of transepithelial electrical resistance (TEER) showed that suppression of Sirt1 via siRNA or salermide significantly decreased BBB permeability, whereas Sirt3 knockdown increased BBB permeability. In addition, Sirt1 was shown to regulate Sirt3 expression after OGD through inhibiting the AMPK-PGC1 pathway. Application of the AMPK inhibitor compound C partially prevented the effects of Sirt1-Sirt3 axis on BBB permeability after OGD. The results of flow cytometry and cytochrome c release demonstrated that Sirt1 and Sirt3 exert opposite effects on OGD-induced apoptosis. Furthermore, suppression of Sirt1 was shown to attenuate mitochondrial reactive oxygen species (ROS) generation, which contribute to the Sirt1-Sirt3 axis-induced regulation of BBB permeability and cell damage. In summary, these findings demonstrate that the Sirt1-Sirt3 axis might act as an important modulator in BBB physiology, and could be a therapeutic target for ischemic stroke via regulating mitochondrial ROS generation. Copyright © 2017. Published by Elsevier B.V.

  11. Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease

    NARCIS (Netherlands)

    Bartels, A. L.; van Berckel, B. N. M.; Lubberink, M.; Luurtsema, G.; Lammertsma, A. A.; Leenders, K. L.

    2008-01-01

    The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure an

  12. Blood-Brain Barrier P-Glycoprotein Function in Neurodegenerative Disease

    NARCIS (Netherlands)

    Bartels, A. L.

    2011-01-01

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protectio

  13. Lactulose as a marker of intestinal barrier function in pigs after weaning

    NARCIS (Netherlands)

    Wijtten, P.J.A.; Verstijnen, J.J.; Kempen, van T.A.T.G.; Perdok, H.B.; Gort, G.; Verstegen, M.W.A.

    2011-01-01

    Intestinal barrier function in pigs after weaning is almost exclusively determined in terminal experiments with Ussing chambers. Alternatively, the recovery in urine of orally administered lactulose can be used to assess intestinal permeability in living animals. This experiment was designed to

  14. Knockdown of Filaggrin Impairs Diffusion Barrier Function and Increases UV Sensitivity in a Human Skin Model

    NARCIS (Netherlands)

    M. Mildner; J. Jin; L. Eckhart; S. Kezic; F. Gruber; C. Barresi; C. Stremnitzer; M. Buchberger; V. Mlitz; C. Ballaun; B. Sterniczky; D. Födinger; E. Tschachler

    2010-01-01

    Loss-of-function mutations in the filaggrin gene are associated with ichthyosis vulgaris and atopic dermatitis. To investigate the impact of filaggrin deficiency on the skin barrier, filaggrin expression was knocked down by small interfering RNA (siRNA) technology in an organotypic skin model in vit

  15. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    NARCIS (Netherlands)

    Griep, L.M.; Wolbers, F.; de Wagenaar, B.; ter Braak, Paulus Martinus; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; van der Meer, Andries Dirk; van den Berg, Albert

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely

  16. Lactulose as a marker of intestinal barrier function in pigs after weaning

    NARCIS (Netherlands)

    Wijtten, P.J.A.; Verstijnen, J.J.; Kempen, van T.A.T.G.; Perdok, H.B.; Gort, G.; Verstegen, M.W.A.

    2011-01-01

    Intestinal barrier function in pigs after weaning is almost exclusively determined in terminal experiments with Ussing chambers. Alternatively, the recovery in urine of orally administered lactulose can be used to assess intestinal permeability in living animals. This experiment was designed to stud

  17. Cichorium intybus root extract: A "vitamin D-like" active ingredient to improve skin barrier function.

    Science.gov (United States)

    Maia Campos, P M B G; G Mercurio, D; O Melo, M; Closs-Gonthier, B

    2017-02-01

    During the aging process, the human skin suffers many alterations including dryness, skin barrier function damage. The skin barrier function is important to the prevention of skin alterations and maintenance of homeostasis. So, the objective of this study was to assess the clinical efficacy on skin barrier function of Cichorium intybus root extract in cosmetic formulations with or without UV filters. Fifty women, aged between 45 and 60 years, were divided into two groups. One group received vehicle formulations containing UV filters, and the other group received formulations without UV filters. Both groups received a formulation containing the extract and the vehicle. The formulations were applied twice daily to the upper arms after washing with sodium lauryl sulphate. Transepidermal water loss (TEWL) and skin microrelief were evaluated before and after a 14- and 28-day period of treatment. The control regions and regions where the vehicles were applied showed an increase in the TEWL. For the formulations containing the extract, decreased TEWL and improved microrelief were observed when compared to the vehicle and control areas after a 28-day period. In conclusion, Cichorium intybus root extract showed protective and restructuring effects on the skin and stands out as an innovative ingredient to improve skin barrier function.

  18. Stratum corneum model membranes : molecular organization in relation to skin barrier function

    NARCIS (Netherlands)

    Groen, Daniël

    2011-01-01

    The stratum corneum (SC), the thin uppermost layer of the skin, consists of dead flattened skin cells (corneocytes) embedded in a lipid matrix. The lipid matrix is considered to play a crucial role in the skin barrier function. It consists of ceramides (CER), cholesterol (CHOL) and free fatty acids

  19. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    NARCIS (Netherlands)

    Griep, L.M.; Wolbers, F.; Wagenaar, de B.; Braak, ter P.M.; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; Meer, van der A.D.; Berg, van den A.

    2013-01-01

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understo

  20. Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.

    Science.gov (United States)

    Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis; Park, Kyungho; Roelandt, Truus; Oda, Yuko; Hupe, Melanie; Crumrine, Debra; Lee, Hae-Jin; Gschwandtner, Maria; Thyssen, Jacob P; Trullas, Carles; Tschachler, Erwin; Feingold, Kenneth R; Elias, Peter M

    2013-02-01

    Systemic antagonists of the histamine type 1 and 2 receptors (H1/2r) are widely used as anti-pruritics and central sedatives, but demonstrate only modest anti-inflammatory activity. Because many inflammatory dermatoses result from defects in cutaneous barrier function, and because keratinocytes express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. These results could shift current paradigms of antihistamine utilization from a predominantly systemic to a topical approach.

  1. Dietary Milk Sphingomyelin Prevents Disruption of Skin Barrier Function in Hairless Mice after UV-B Irradiation.

    Directory of Open Access Journals (Sweden)

    Chisato Oba

    Full Text Available Exposure to ultraviolet-B (UV-B irradiation causes skin barrier defects. Based on earlier findings that milk phospholipids containing high amounts of sphingomyelin (SM improved the water content of the stratum corneum (SC in normal mice, here we investigated the effects of dietary milk SM on skin barrier defects induced by a single dose of UV-B irradiation in hairless mice. Nine week old hairless mice were orally administrated SM (146 mg/kg BW/day for a total of ten days. After seven days of SM administration, the dorsal skin was exposed to a single dose of UV-B (20 mJ/cm2. Administration of SM significantly suppressed an increase in transepidermal water loss and a decrease in SC water content induced by UV-B irradiation. SM supplementation significantly maintained covalently-bound ω-hydroxy ceramide levels and down-regulated mRNA levels of acute inflammation-associated genes, including thymic stromal lymphopoietin, interleukin-1 beta, and interleukin-6. Furthermore, significantly higher levels of loricrin and transglutaminase-3 mRNA were observed in the SM group. Our study shows for the first time that dietary SM modulates epidermal structures, and can help prevent disruption of skin barrier function after UV-B irradiation.

  2. Polyphenol-Rich Propolis Extracts Strengthen Intestinal Barrier Function by Activating AMPK and ERK Signaling

    OpenAIRE

    Kai Wang; Xiaolu Jin; Yifan Chen; Zehe Song; Xiasen Jiang; Fuliang Hu; Conlon, Michael A.; Topping, David L.

    2016-01-01

    Propolis has abundant polyphenolic constituents and is used widely as a health/functional food. Here, we investigated the effects of polyphenol-rich propolis extracts (PPE) on intestinal barrier function in human intestinal epithelial Caco-2 cells, as well as in rats. In Caco-2 cells, PPE increased transepithelial electrical resistance and decreased lucifer yellow flux. PPE-treated cells showed increased expression of the tight junction (TJ) loci occludin and zona occludens (ZO)-1. Confocal m...

  3. Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress

    Directory of Open Access Journals (Sweden)

    David eArredondo Zamarripa

    2014-10-01

    Full Text Available Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK production contributes to the increased transport through the blood-retina barrier (BRB in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC, blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19 cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies.

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

    Science.gov (United States)

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

    2016-08-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  6. YB-1 protein: functions and regulation.

    Science.gov (United States)

    Lyabin, Dmitry N; Eliseeva, Irina A; Ovchinnikov, Lev P

    2014-01-01

    The Y-box binding protein 1 (YB-1, YBX1) is a member of the family of DNA- and RNA-binding proteins with an evolutionarily ancient and conserved cold shock domain. It falls into a group of intrinsically disordered proteins that do not follow the classical rule 'one protein-one function' but introduce a novel principle stating that a disordered structure suggests many functions. YB-1 participates in a wide variety of DNA/RNA-dependent events, including DNA reparation, pre-mRNA transcription and splicing, mRNA packaging, and regulation of mRNA stability and translation. At the cell level, the multiple activities of YB-1 are manifested as its involvement in cell proliferation and differentiation, stress response, and malignant cell transformation. WIREs RNA 2014, 5:95-110. doi: 10.1002/wrna.1200 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.

  7. A synthetic C16 omega-hydroxyphytoceramide improves skin barrier functions from diversely perturbed epidermal conditions.

    Science.gov (United States)

    Oh, Myoung Jin; Nam, Jin Ju; Lee, Eun Ok; Kim, Jin Wook; Park, Chang Seo

    2016-10-01

    Omega-hydroxyceramides (ω-OH-Cer) play a crucial role in maintaining the integrity of skin barrier. ω-OH-Cer are the primary lipid constituents of the corneocyte lipid envelope (CLE) covalently attached to the outer surface of the cornified envelope linked to involucrin to become bound form lipids in stratum corneum (SC). CLE becomes a hydrophobic impermeable layer of matured corneocyte preventing loss of natural moisturizing factor inside the corneocytes. More importantly, CLE may also play an important role in the formation of proper orientation of intercellular lipid lamellar structure by interdigitating with the intercellular lipids in a comb-like fashion. Abnormal barrier conditions associated with atopic dermatitis but also UVB-irradiated skins are known to have lowered level of bound lipids, especially ω-OH-Cer, which indicate that ω-OH-Cer play an important role in maintaining the integrity of skin barrier. In this study, protective effects of a novel synthetic C16 omega-hydroxyphytoceramides (ω-OH-phytoceramide) on skin barrier function were investigated. Epidermal barrier disruption was induced by UVB irradiation, tape-stripping in hairless mouse and human skin. Protective effect of damaged epidermis was evaluated using the measurement of transepidermal water loss and cohesion of SC. Increased keratinocyte differentiation was verified using cultured keratinocyte through western blot. Results clearly demonstrated that a synthetic C16 ω-OH-phytoceramide enhanced the integrity of SC and accelerated the recovery of damaged skin barrier function by stimulating differentiation process. In a conclusion, a synthetic C16 ω-OH-phytoceramide treatment improved epidermal homeostasis in several disrupted conditions.

  8. Signaling pathways induced by serine proteases to increase intestinal epithelial barrier function.

    Science.gov (United States)

    Lahey, Kelcie A; Ronaghan, Natalie J; Shang, Judie; Dion, Sébastien P; Désilets, Antoine; Leduc, Richard; MacNaughton, Wallace K

    2017-01-01

    Changes in barrier function of the gastrointestinal tract are thought to contribute to the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Previous work in our lab demonstrated that apical exposure of intestinal epithelial cell lines to serine proteases results in an increase in transepithelial electrical resistance (TER). However, the underlying mechanisms governing this response are unclear. We aimed to determine the requirement for proteolytic activity, epidermal growth factor receptor (EGFR) activation, and downstream intracellular signaling in initiating and maintaining enhanced barrier function following protease treatment using a canine intestinal epithelial cell line (SCBN). We also examined the role of phosphorylation of myosin regulatory light chain on the serine protease-induced increase in TER through. It was found that proteolytic activity of the serine proteases trypsin and matriptase is required to initiate and maintain the protease-mediated increase in TER. We also show that MMP-independent EGFR activation is essential to the sustained phase of the protease response, and that Src kinases may mediate EGFR transactivation. PI3-K and ERK1/2 signaling were important in reaching a maximal increase in TER following protease stimulation; however, their upstream activators are yet to be determined. CK2 inhibition prevented the increase in TER induced by serine proteases. The bradykinin B(2) receptor was not involved in the change in TER in response to serine proteases, and no change in phosphorylation of MLC was observed after trypsin or matriptase treatment. Taken together, our data show a requirement for ongoing proteolytic activity, EGFR transactivation, as well as downstream PI3-K, ERK1/2, and CK2 signaling in protease-mediated barrier enhancement of intestinal epithelial cells. The pathways mediating enhanced barrier function by proteases may be novel therapeutic targets for intestinal disorders characterized by disrupted epithelial

  9. Barrier Lyapunov function-based model-free constraint position control for mechanical systems

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seong Ik; Ha, Hyun Uk; Lee, Jang Myung [Pusan National University, Busan (Korea, Republic of)

    2016-07-15

    In this article, a motion constraint control scheme is presented for mechanical systems without a modeling process by introducing a barrier Lyapunov function technique and adaptive estimation laws. The transformed error and filtered error surfaces are defined to constrain the motion tracking error in the prescribed boundary layers. Unknown parameters of mechanical systems are estimated using adaptive laws derived from the Lyapunov function. Then, robust control used the conventional sliding mode control, which give rise to excessive chattering, is changed to finite time-based control to alleviate undesirable chattering in the control action and to ensure finite-time error convergence. Finally, the constraint controller from the barrier Lyapunov function is designed and applied to the constraint of the position tracking error of the mechanical system. Two experimental examples for the XY table and articulated manipulator are shown to evaluate the proposed control scheme.

  10. Internal resistor of multi-functional tunnel barrier for selectivity and switching uniformity in resistive random access memory.

    Science.gov (United States)

    Lee, Sangheon; Woo, Jiyong; Lee, Daeseok; Cha, Euijun; Hwang, Hyunsang

    2014-01-01

    In this research, we analyzed the multi-functional role of a tunnel barrier that can be integrated in devices. This tunnel barrier, acting as an internal resistor, changes its resistance with applied bias. Therefore, the current flow in the devices can be controlled by a tunneling mechanism that modifies the tunnel barrier thickness for non-linearity and switching uniformity of devices. When a device is in a low-resistance state, the tunnel barrier controls the current behavior of the device because most of the bias is applied to the tunnel barrier owing to its higher resistance. Furthermore, the tunnel barrier induces uniform filament formation during set operation with the tunnel barrier controlling the current flow.

  11. Hydrophobicity of mucosal surface and its relationship to gut barrier function.

    Science.gov (United States)

    Qin, Xiaofa; Caputo, Francis J; Xu, Da-Zhong; Deitch, Edwin A

    2008-03-01

    Loss of the gut barrier has been implicated in the pathogenesis of the multiple organ dysfunction syndrome, and, thus, understanding the intestinal barrier is of potential clinical importance. An important, but relatively neglected, component of the gut barrier is the unstirred mucus layer, which through its hydrophobic and other properties serves as an important barrier to bacterial and other factors within the gut lumen. Thus, the goal of this study was to establish a reproducible method of measuring mucosal hydrophobicity and test the hypothesis that conditions that decrease mucosal hydrophobicity are associated with increased gut permeability. Hydrophobicity was measured in various segments of normal gut by measuring the contact angle of an aqueous droplet placed on the mucosal surface using a commercial goniometer. Second, the effect of the mucolytic agent N-acetyl cysteine on mucosal hydrophobicity and gut permeability was measured, as was the effects of increasing periods of in vivo gut ischemia on these parameters. Gut ischemia was induced by superior mesenteric artery occlusion, and gut permeability was measured by the mucosal-to-serosal passage of fluoresceine isothiocyanate-dextran (4.3 kDa) (FD4) across the everted sacs of ileum. Intestinal mucosal hydrophobicity showed a gradual increase from the duodenum to the end of the ileum and remained at high level in the cecum, colon, and rectum. Both N-acetyl cysteine treatment and ischemia caused a dose-dependent decrease in mucosal hydrophobicity, which significantly correlated increased gut permeability. Mucosal hydrophobicity of the intestine can be reproducibly measured, and decreases in mucosal hydrophobicity closely correlate with increased gut permeability. These results suggest that mucosal hydrophobicity can be a reliable method of measuring the barrier function of the unstirred mucus layer and a useful parameter in evaluating the pathogenesis of gut barrier dysfunction.

  12. Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.

    Science.gov (United States)

    Liu, Wenjing; Wang, Ping; Shang, Chao; Chen, Lin; Cai, Heng; Ma, Jun; Yao, Yilong; Shang, Xiuli; Xue, Yixue

    2014-07-21

    The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. Brain endothelial cells (BECs), held together by tight junctions (TJs), have a primary role in restricting the permeability of the BBB. Endophilin-1 is a multifunctional protein that influences epithelial growth factor receptor (EGFR) endocytosis and degradation and plays an important role in regulating the glomerular filtration barrier in the kidney. Endophilin-1 likely plays a similar role in controlling BBB permeability. In this study, we therefore analyzed the expression and function of endophilin-1 in the human BEC line hCMEC/D3. Our results show that endophilin-1 over-expression reduced the expression of the TJ-associated proteins ZO-1 and occludin and increased the paracellular permeability of hCMEC/D3 cells, whereas silencing of endogenous endophilin-1 yielded the opposite results. Over-expression of ZO-1 and occludin prevented the increase in permeability induced by endophilin-1 over-expression, whereas down-regulation of ZO-1 and occludin prevented the reduction in permeability induced by endophilin-1 silencing. Co-localization and co-immunoprecipitation experiments suggested that endophilin-1 interacts with the EGFR. The levels of EGFR and its downstream effector phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) are significantly decreased when endophilin-1 is over-expressed. Conversely, endophilin-1 down-regulation led to markedly increased levels of these proteins. In addition, the reduced permeability induced by endophilin-1 down-regulation was blocked by AG1478 and PD98059, inhibitors of EGFR and ERK1/2, respectively. Up-regulation of ZO-1 and occludin was blocked by the EGFR and ERK1/2 inhibitors. These results suggest that endophilin-1 regulates BBB permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway in BECs.

  13. Limited English proficient HMO enrollees remain vulnerable to communication barriers despite language assistance regulations.

    Science.gov (United States)

    Hadler, Max W; Chen, Xiao; Gonzalez, Erik; Roby, Dylan H

    2013-02-01

    HMO enrollees with limited English proficiency, and particularly those in poorer health, face communication barriers despite language assistance regulations. More than 1.3 million California HMO enrollees ages 18 to 64 do not speak English well enough to communicate with medical providers and may experience reduced access to high-quality health care if they do not receive appropriate language assistance services. Based on analysis of the 2007 and 2009 California Health Interview Surveys (CHIS), commercial HMO enrollees with limited English proficiency (LEP) in poorer health are more likely to have difficulty understanding their doctors, placing this already vulnerable population at even greater risk. The analysis also uses CHIS to examine the potential impact of health plan monitoring starting in 2009 (due to a 2003 amendment to the Knox-Keene Health Care Services Act) requiring health plans to provide free qualified interpretation and translation services to HMO enrollees. The authors recommend that California's health plans continue to incorporate trained interpreters into their contracted networks and delivery systems, paying special attention to enrollees in poorer health. The results may serve as a planning tool for health plans, providing a detailed snapshot of enrollee characteristics that will help design effective programs now and prepare for a likely increase in insured LEP populations in the future, as full implementation of the Affordable Care Act takes place over the next decade.

  14. 神经酰胺与皮肤屏障%Ceramide and Skin Barrier Function

    Institute of Scientific and Technical Information of China (English)

    吴金燕; 蒋献

    2011-01-01

    Ceramide is one of the lipids in human stratum corneum. The alteration of the ceramide will lead to the change of the lipids, and then the destruction of skin barrier function happens. It plays an important role in the proliferation, differentiation and apoptosis of keratinocytes. Many dermatogic diseases can destroy skin barrier function, and the destruction of barrier function will also result in skin diseases or aggravate the diseases. In a word, increasing attentions are paid to the ceramide's function in the skin.%神经酰胺是人体角质层脂质的主要成分,在皮肤的合成和分布有一定的规律.其质和量的变化可以导致脂质结构的改变,从而影响皮肤屏障功能.不同亚型神经酰胺作用不同,在角质形成细胞增殖、分化及凋亡中起重要作用,是皮肤屏障损伤修复后期重要的效应物质.许多皮肤病可导致角质层屏障功能的破坏,而屏障功能的破坏又是一些皮肤病的病因或加重因素.故神经酰胺在皮肤中的作用越来越受重视.

  15. Polyphenol-Rich Propolis Extracts Strengthen Intestinal Barrier Function by Activating AMPK and ERK Signaling

    Directory of Open Access Journals (Sweden)

    Kai Wang

    2016-05-01

    Full Text Available Propolis has abundant polyphenolic constituents and is used widely as a health/functional food. Here, we investigated the effects of polyphenol-rich propolis extracts (PPE on intestinal barrier function in human intestinal epithelial Caco-2 cells, as well as in rats. In Caco-2 cells, PPE increased transepithelial electrical resistance and decreased lucifer yellow flux. PPE-treated cells showed increased expression of the tight junction (TJ loci occludin and zona occludens (ZO-1. Confocal microscopy showed organized expressions in proteins related to TJ assembly, i.e., occludin and ZO-1, in response to PPE. Furthermore, PPE led to the activation of AMPK, ERK1/2, p38, and Akt. Using selective inhibitors, we found that the positive effects of PPE on barrier function were abolished in cells in which AMPK and ERK1/2 signaling were inhibited. Moreover, rats fed a diet supplemented with PPE (0.3% in the diet exhibited increased colonic epithelium ZO-1 expression. Overall, these data suggest that PPE strengthens intestinal barrier function by activating AMPK and ERK signaling and provide novel insights into the potential application of propolis for human gut health.

  16. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats.

    Science.gov (United States)

    Lauffer, Adriana; Vanuytsel, Tim; Vanormelingen, Christophe; Vanheel, Hanne; Salim Rasoel, Shadea; Tóth, Joran; Tack, Jan; Fornari, Fernando; Farré, Ricard

    2016-01-01

    Psychological stress increases intestinal permeability, potentially leading to low-grade inflammation and symptoms in functional gastrointestinal disorders. We assessed the effect of subacute, chronic and combined stress on intestinal barrier function and mast cell density. Male Wistar rats were allocated to four experimental groups (n = 8/group): 1/sham; 2/subacute stress (isolation and limited movement for 24 h); 3/chronic crowding stress for 14 days and 4/combined subacute and chronic stress. Jejunum and colon were collected to measure: transepithelial electrical resistance (TEER; a measure of epithelial barrier function); gene expression of tight junction molecules; mast cell density. Plasma corticosterone concentration was increased in all three stress conditions versus sham, with highest concentrations in the combined stress condition. TEER in the jejunum was decreased in all stress conditions, but was significantly lower in the combined stress condition than in the other groups. TEER in the jejunum correlated negatively with corticosterone concentration. Increased expression of claudin 1, 5 and 8, occludin and zonula occludens 1 mRNAs was detected after subacute stress in the jejunum. In contrast, colonic TEER was decreased only after combined stress, and the expression of tight junction molecules was unaltered. Increased mast cell density was observed in the chronic and combined stress condition in the colon only. In conclusion, our data show that chronic stress sensitizes the gastrointestinal tract to the effects of subacute stress on intestinal barrier function; different underlying cellular and molecular alterations are indicated in the small intestine versus the colon.

  17. Polyphenol-Rich Propolis Extracts Strengthen Intestinal Barrier Function by Activating AMPK and ERK Signaling.

    Science.gov (United States)

    Wang, Kai; Jin, Xiaolu; Chen, Yifan; Song, Zehe; Jiang, Xiasen; Hu, Fuliang; Conlon, Michael A; Topping, David L

    2016-05-07

    Propolis has abundant polyphenolic constituents and is used widely as a health/functional food. Here, we investigated the effects of polyphenol-rich propolis extracts (PPE) on intestinal barrier function in human intestinal epithelial Caco-2 cells, as well as in rats. In Caco-2 cells, PPE increased transepithelial electrical resistance and decreased lucifer yellow flux. PPE-treated cells showed increased expression of the tight junction (TJ) loci occludin and zona occludens (ZO)-1. Confocal microscopy showed organized expressions in proteins related to TJ assembly, i.e., occludin and ZO-1, in response to PPE. Furthermore, PPE led to the activation of AMPK, ERK1/2, p38, and Akt. Using selective inhibitors, we found that the positive effects of PPE on barrier function were abolished in cells in which AMPK and ERK1/2 signaling were inhibited. Moreover, rats fed a diet supplemented with PPE (0.3% in the diet) exhibited increased colonic epithelium ZO-1 expression. Overall, these data suggest that PPE strengthens intestinal barrier function by activating AMPK and ERK signaling and provide novel insights into the potential application of propolis for human gut health.

  18. GPHR-dependent functions of the Golgi apparatus are essential for the formation of lamellar granules and the skin barrier.

    Science.gov (United States)

    Tarutani, Masahito; Nakajima, Kimiko; Uchida, Yoshikazu; Takaishi, Mikiro; Goto-Inoue, Naoko; Ikawa, Masahito; Setou, Mitsutoshi; Kinoshita, Taroh; Elias, Peter M; Sano, Shigetoshi; Maeda, Yusuke

    2012-08-01

    The lumen of the Golgi apparatus is regulated to be weakly acidic, which is critical for its functions. The Golgi pH regulator (GPHR) is an anion channel essential for normal acidification of the Golgi apparatus, and is therefore required for its functions. The Golgi apparatus has been thought to be the origin of lamellar granules in the skin. To study the functional role(s) of GPHR in the skin, we established keratinocyte-specific GPHR-knockout mice using the Cre-loxP system. These mutant mice exhibited hypopigmented skin, hair loss, and scaliness. Histological examination of GPHR-knockout mice showed ballooning of the basal cells and follicular dysplasia. In addition, inflammatory cells were seen in the dermis. The expression of trans-Golgi network 46, a marker for lamellar bodies, and kallikrein 7, a protein within lamellar bodies, is diminished in GPHR-knockout mouse skin. Examination by electron microscopy revealed that keratinocytes produced aberrant lamellar bodies. The transepidermal water loss of these knockout mice was increased compared with wild-type mice. Moreover, expression of cathelicidin-related antimicrobial peptide (CRAMP) in the skin was diminished. These results suggest that GPHR is essential for the homeostasis of the epidermis including the formation of lamellar bodies and for the barrier function.

  19. The Balance Between Metalloproteinases and TIMPs: Critical Regulator of Microvascular Endothelial Cell Function in Health and Disease.

    Science.gov (United States)

    Masciantonio, Marcello G; Lee, Christopher K S; Arpino, Valerie; Mehta, Sanjay; Gill, Sean E

    2017-01-01

    Endothelial cells (EC), especially the microvascular EC (MVEC), have critical functions in health and disease. For example, healthy MVEC provide a barrier between the fluid and protein found within the blood, and the surrounding tissue. Following tissue injury or infection, the microvascular barrier is often disrupted due to activation and dysfunction of the MVEC. Multiple mechanisms promote MVEC activation and dysfunction, including stimulation by cytokines, mechanical interaction with activated leukocytes, and exposure to harmful leukocyte-derived molecules, which collectively result in a loss of MVEC barrier function. However, MVEC activation is also critical to facilitate recruitment of inflammatory cells, such as neutrophils (PMNs) and monocytes, into the injured or infected tissue. Metalloproteinases, including the matrix metalloproteinases (MMPs) and the closely related, a disintegrin and metalloproteinases (ADAMs), have been implicated in regulating both MVEC barrier function, through cleavage of adherens and tight junctions proteins between adjacent MVEC and through degradation of the extracellular matrix, as well as PMN-MVEC interaction, through shedding of cell surface PMN receptors. Moreover, the tissue inhibitors of metalloproteinases (TIMPs), which collectively inhibit most MMPs and ADAMs, are critical regulators of MVEC activation and dysfunction through their ability to inhibit metalloproteinases and thereby promote MVEC stability. However, TIMPs have been also found to modulate MVEC function through metalloproteinase-independent mechanisms, such as regulation of vascular endothelial growth factor signaling. This chapter is focused on examining the role of the metalloproteinases and TIMPs in regulation of MVEC function in both health and disease. © 2017 Elsevier Inc. All rights reserved.

  20. Promoting effect of lactoferrin on barrier function and epithelial differentiation of human keratinocytes.

    Science.gov (United States)

    Uchida, Ryo; Aoki, Reiji; Aoki-Yoshida, Ayako; Tajima, Atsushi; Takayama, Yoshiharu

    2017-02-01

    The purpose of this study was to elucidate the effects of bovine lactoferrin on keratinocyte differentiation and barrier function. Addition of bovine lactoferrin to differentiating HaCaT human keratinocytes led to increased transepithelial electrical resistance (TER), a marker of epithelial barrier function. This elevation was followed by upregulation of two differentiation markers, involucrin and filaggrin. The expression level of sterol regulatory element-binding protein-1 was also enhanced by bovine lactoferrin. The lactoferrin-induced upregulation of involucrin and filaggrin expression were confirmed in normal human epidermal keratinocytes (NHEK). Treatment with SB203580, a p38 mitogen-activated protein kinase (MAPK) α inhibitor, impaired the upregulation of involucrin and filaggrin expression in response to lactoferrin. The elevation of p38 MAPK phosphorylation was further enhanced by lactoferrin in the initial stage of differentiation of HaCaT keratinocytes. The findings suggest that bovine lactoferrin promotes epithelial differentiation by a p38-MAPK-dependent mechanism.

  1. Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins.

    Science.gov (United States)

    Chen, Xin; Oshima, Tadayuki; Tomita, Toshihiko; Fukui, Hirokazu; Watari, Jiro; Matsumoto, Takayuki; Miwa, Hiroto

    2011-08-01

    Experimental models for esophageal epithelium in vitro either suffer from poor differentiation or complicated culture systems. An air-liquid interface system with normal human bronchial epithelial cells can serve as a model of esophageal-like squamous epithelial cell layers. Here, we explore the influence of bile acids on barrier function and tight junction (TJ) proteins. The cells were treated with taurocholic acid (TCA), glycocholic acid (GCA), or deoxycholic acid (DCA) at different pH values, or with pepsin. Barrier function was measured by transepithelial electrical resistance (TEER) and the diffusion of paracellular tracers (permeability). The expression of TJ proteins, including claudin-1 and claudin-4, was examined by Western blotting of 1% Nonidet P-40-soluble and -insoluble fractions. TCA and GCA dose-dependently decreased TEER and increased paracellular permeability at pH 3 after 1 h. TCA (4 mM) or GCA (4 mM) did not change TEER and permeability at pH 7.4 or pH 4. The combination of TCA and GCA at pH 3 significantly decreased TEER and increased permeability at lower concentrations (2 mM). Pepsin (4 mg/ml, pH 3) did not have any effect on barrier function. DCA significantly decreased the TEER and increased permeability at pH 6, a weakly acidic condition. TCA (4 mM) and GCA (4 mM) significantly decreased the insoluble fractions of claudin-1 and claudin-4 at pH 3. In conclusion, acidic bile salts disrupted the squamous epithelial barrier function partly by modulating the amounts of claudin-1 and claudin-4. These results provide new insights for understanding the role of TJ proteins in esophagitis.

  2. Wigner function studies of spin transport in dilute magnetic semiconductor barrier structures

    Science.gov (United States)

    Grubin, Harold L.

    2004-12-01

    The spin dependent Wigner function is implemented to obtain the IV characteristics of a double barrier resonant tunneling diode with DMS layers. The structure distinguishes between spin-up and spin-down carriers, each of which experiences resonance at different magnetic field dependent bias levels. The results demonstrate the magnetic field dependence of the IV characteristics and illustrate the magnetic field dependence of relative spin-up and spin-down carriers.

  3. [Barriers and challenges of the functional healthcare risk management units in hospitals of Madrid health service].

    Science.gov (United States)

    Pardo-Hernández, A; Navarro-Royo, C; Arguedas-Sanz, R; Albeniz-Lizarraga, C; Morón-Merchante, J

    2014-01-01

    To identify the barriers and challenges for the effective development of risk management units in hospitals of the Madrid Health Service. Descriptive cross-sectional study aimed at the management teams and members of the functional units of 31 hospitals in the Madrid Health Service. A self-administered questionnaire requesting answers in free text was used, identifying up to five barriers and challenges, and their prioritization by awarding from 1-5 points according to their importance. A discourse analysis was then conducted, grouping common themes and sorting them according to their score. The overall response rate was 94%. The most frequently identified barriers were lack of time (21%), inadequate safety culture (13%), lack of publication of their activities (10%), and lack of training (10%). The most important challenge was developing the training (18%), followed by improving the culture (17%), communication of safety activities (11%), and achieve leadership from the managers of the services (11%). According to the study conditions, the main identified barrier identified was the lack of available time, and the principal challenge found was promoting a proactive learning culture. Copyright © 2013 SECA. Published by Elsevier Espana. All rights reserved.

  4. Psychological Stress-Derived Prolactin Modulates Occludin Expression in Vaginal Epithelial Cells to Compromise Barrier Function

    Directory of Open Access Journals (Sweden)

    Xueyan Li

    2015-08-01

    Full Text Available Background/Aims: The causative factors of the vaginitis are not fully understood yet. Epithelial barrier dysfunction plays a critical role in the pathogenesis of vaginitis. This study aims to investigate the role of prolactin (PRL in the causing the vaginal epithelial barrier dysfunction. Methods: Adult rats were treated with water-avoid-stress. The serum levels of PRL were determined by ELISA. T84 cell (T84 cells; a vaginal epithelial cell line monolayers were prepared to be used assessing the epithelial barrier functions. The expression of occludin in T84 cells was assessed by Chromatin immunoprecipitation assay, methylation specifIc PCR, real time quantitative RT-PCR and Western blotting. Results: The results showed that psychological stress markedly increased the serum levels of PRL in the rat vaginal epithelia. Exposure of T84 cells to PRL in the culture markedly increased the phosphorylation of STAT3 and suppressed the expression of occludin in the cells; the transepithelial electric resistance was decreased and the permeability to a macromolecular tracer was increased in the T84 monolayers, which was mimicked by blocking STAT3, or abolished by over expression of occludin in the epithelial cells. Conclusions: Psychological stress-derived PRL induces vaginal epithelial barrier dysfunction by inhibiting the expression of occludin.

  5. Investigating the barrier function of skin lipid models with varying compositions.

    Science.gov (United States)

    Groen, Daniël; Poole, Dana S; Gooris, Gert S; Bouwstra, Joke A

    2011-10-01

    The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the barrier function. The main lipid classes in stratum corneum are ceramides, cholesterol, and free fatty acids. In previous publications, a lipid model was presented, referred to as the stratum corneum substitute (SCS), that closely mimics the SC lipid organization and SC barrier function. In the present study, we use the SCS to study the effect of changes in lipid organization on the lipid barrier function using benzoic acid as permeation compound. First, in the SCS, we increased the level of one of the three major lipid classes keeping the ratio between the other lipid classes constant. An increased cholesterol level resulted in an increase in phase-separated cholesterol and a reduction in the permeability. An increase in ceramide or free fatty acid level resulted in the formation of additional phases, but had no significant influence on the permeability. We also examined models that mimic selected changes in lipid composition reported for dry or diseased skin. The SCS that mimics the composition in recessive X-linked ichthyosis skin displayed a twofold increase in permeability. This increase is possibly related to the formation of an additional, less ordered phase in this model. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Increased intestinal barrier function in the small intestine of formula-fed neonatal piglets.

    Science.gov (United States)

    Huygelen, V; De Vos, M; Willemen, S; Tambuyzer, B; Casteleyn, C; Knapen, D; Van Cruchten, S; Van Ginneken, C

    2012-12-01

    Within-litter birth weight variation is adversely correlated to piglet survival and postnatal growth. A less efficient epithelial barrier function in light piglets may partly explain this inverse relationship between birth weight and zootechnical performance. A compromised epithelial barrier increases paracellular permeability; consequently, toxins, allergenic compounds, or bacteria may enter systemic circulation and induce inflammatory responses. Dietary effects on function of gut epithelium of piglet are largely unknown. This study investigated epithelial barrier function of the small intestine of normal birth weight (NBW) piglets (1.46 ± 0.10 kg) and low birth weight (LBW) piglets (excretion was measured using enzymatic spectrophotometry. Irrespective of birth weight, lactulose levels of FOR10 (4.4 ± 2.3 mmol/L) tended to be lower (P = 0.07) than SOW10 (26.4 ± 10.2 mmol/L) indicating a reduced paracellular intestinal permeability in FOR10. This reduction was associated with a 6-fold elevated (P < 0.01) protein expression of occludin, an important tight junction protein, in FOR10 compared to SOW10. Mannitol levels in FOR10 (31.0 ± 18.2 mmol/L) did not differ (P = 0.28) from SOW10 (61.1 ± 10.2 mmol/L). However, shorter villi (P < 0.01) in FOR10 indicated a reduced absorptive capacity. In conclusion, formula feeding caused minor symptoms of gastrointestinal dysfunction compared to sow-fed piglets irrespective of their birth weight.

  7. Pro-inflammatory cytokine regulation of P-glycoprotein in the developing blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Majid Iqbal

    Full Text Available Placental P-glycoprotein (P-gp acts to protect the developing fetus from exogenous compounds. This protection declines with advancing gestation leaving the fetus and fetal brain vulnerable to these compounds and potential teratogens in maternal circulation. This vulnerability may be more pronounced in pregnancies complicated by infection, which is common during pregnancy. Pro-inflammatory cytokines (released during infection have been shown to be potent inhibitors of P-gp, but nothing is known regarding their effects at the developing blood-brain barrier (BBB. We hypothesized that P-gp function and expression in endothelial cells of the developing BBB will be inhibited by pro-inflammatory cytokines. We have derived brain endothelial cell (BEC cultures from various stages of development of the guinea pig: gestational day (GD 50, 65 (term ~68 days and postnatal day (PND 14. Once these cultures reached confluence, BECs were treated with various doses (10(0-10(4 pg/mL of pro-inflammatory cytokines: interleukin-1β (IL-1β, interleukin-6 (IL-6 or tumor necrosis factor- α (TNF-α. P-gp function or abcb1 mRNA (encodes P-gp expression was assessed following treatment. Incubation of GD50 BECs with IL-1β, IL-6 or TNF-α resulted in no change in P-gp function. GD65 BECs displayed a dose-dependent decrease in function with all cytokines tested; maximal effects at 42%, 65% and 34% with IL-1β, IL-6 and TNF-α treatment, respectively (P<0.01. Inhibition of P-gp function by IL-1β, IL-6 and TNF-α was even greater in PND14 BECs; maximal effects at 36% (P<0.01, 84% (P<0.05 and 55% (P<0.01, respectively. Cytokine-induced reductions in P-gp function were associated with decreased abcb1 mRNA expression. These data suggest that BBB P-gp function is increasingly responsive to the inhibitory effects of pro-inflammatory cytokines, with increasing developmental age. Thus, women who experience infection and take prescription medication during pregnancy may expose the

  8. Assessment of skin barrier function and biochemical changes of ex vivo human skin in response to physical and chemical barrier disruption.

    Science.gov (United States)

    Döge, Nadine; Avetisyan, Araks; Hadam, Sabrina; Pfannes, Eva Katharina Barbosa; Rancan, Fiorenza; Blume-Peytavi, Ulrike; Vogt, Annika

    2016-12-21

    Topical dermatotherapy is intended to be used on diseased skin. Novel drug delivery systems even address differences between intact and diseased skin underlining the need for pre-clinical assessment of different states of barrier disruption. Herein, we studied how short-term incubation in culture media compared to incubation in humidified chambers affects human skin barrier function and viability. On both models we assessed different types and intensities of physical and chemical barrier disruption methods with regard to structural integrity, biophysical parameters and cytokine levels. Tissue degeneration and proliferative activity limited the use of tissue cultures to 48h. Viability is better preserved in cultured tissue. Tape-stripping (50×TS) and 4h sodium lauryl sulfate (SLS) pre-treatment were identified as highly reproducible and effective procedures for barrier disruption. Transepidermal water loss (TEWL) values reproducibly increased with the intensity of disruption while sebum content and skin surface pH were of limited value. Interleukin (IL)-6/8 and various chemokines and proteases were increased in tape-stripped skin which was more pronounced in SLS-treated skin tissue extracts. Thus, albeit limited to 48h, cultured full-thickness skin maintained several barrier characteristics and responded to different intensities of barrier disruption. Potentially, these models can be used to assess pre-clinically the efficacy and penetration of anti-inflammatory compounds.

  9. Cell cycle phase regulates glucocorticoid receptor function.

    Directory of Open Access Journals (Sweden)

    Laura Matthews

    Full Text Available The glucocorticoid receptor (GR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1. Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G(1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle-driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity.

  10. Kisspeptin: a novel regulator of reproductive function.

    Science.gov (United States)

    Dhillo, W S

    2008-08-01

    The UK and international neuroendocrine community was deeply shocked and saddened the unbelievably premature death of Michael Harbuz in Bristol in 2006. Mick was a superb friend and colleague, and played a huge part in the development and activities of the British Neuroendocrine Group/British Society for Neuroendocrinology (BSN), serving as both Membership Secretary and Treasurer between 1999 and 2004. Mick was a leader in the field of neuroendocrine-immune interactions, and brought a great deal of charisma, humour and ability to meetings and conferences. He was also a passionate and committed supporter of the progress of young researchers and of their participation in neuroendocrine events. He recognised that today's postgraduate students and postdoctoral research fellows are tomorrow's neuroendocrine researchers, be it in academia, the health services or industry. To recognise Mick's great commitment to and enthusiasm for postgraduate education both in the University of Bristol and in the BSN, we decided to honour and remember him by instituting the 'Michael Harbuz Young Investigator Prize Lecture' to be delivered annually. Dr Waljit Dhillo from Imperial College London was the inaugural recipient of this award, and presented his lecture at the Annual Meeting of the BSN in Nottingham in September 2007, upon which this review is based. Recent evidence demonstrates that the neuropeptide kisspeptin and its receptor, GPR54, have a fundamental role in initiating the onset of puberty and are important in regulating reproductive function. This review discusses the evidence available from animals and humans demonstrating that kisspeptin potently stimulates the release of gonadotrophins by stimulating the release of gonadotrophin-releasing hormone and that a lack of kisspeptin or GPR54 results in reproductive failure.

  11. Nuclear factor erythroid 2-related factor 2 (Nrf2 regulates airway epithelial barrier integrity

    Directory of Open Access Journals (Sweden)

    Yoshitaka Shintani

    2015-09-01

    Conclusions: Our results indicated that the Nrf2/AOX1 pathway was important for enhancing airway epithelial barrier integrity. Because the airway epithelium of asthmatics is susceptible to reduced barrier integrity, this pathway might be a new therapeutic target for asthma.

  12. Suitability of polystyrene as a functional barrier layer in coloured food contact materials.

    Science.gov (United States)

    Genualdi, Susan; Addo Ntim, Susana; Begley, Timothy

    2015-01-01

    Functional barriers in food contact materials (FCMs) are used to prevent or reduce migration from inner layers in multilayer structures to food. The effectiveness of functional barrier layers was investigated in coloured polystyrene (PS) bowls due to their intended condition of use with hot liquids such as soups or stew. Migration experiments were performed over a 10-day period using USFDA-recommended food simulants (10% ethanol, 50% ethanol, corn oil and Miglyol) along with several other food oils. At the end of the 10 days, solvent dyes had migrated from the PS bowls at 12, 1 and 31,000 ng cm(-)(2) into coconut oil, palm kernel oil and Miglyol respectively, and in coconut oil and Miglyol the colour change was visible to the human eye. Scanning electron microscope (SEM) images revealed that the functional barrier was no longer intact for the bowls exposed to coconut oil, palm kernel oil, Miglyol, 10% ethanol, 50% ethanol and goat's milk. Additional tests showed that 1-dodecanol, a lauryl alcohol derived from palm kernel oil and coconut oil, was present in the PS bowls at an average concentration of 11 mg kg(-1). This compound is likely to have been used as a dispersing agent for the solvent dye and aided the migration of the solvent dye from the PS bowl into the food simulant. The solvent dye was not found in the 10% ethanol, 50% ethanol and goat's milk food simulants above their respective limits of detection, which is likely to be due to its insolubility in aqueous solutions. A disrupted barrier layer is of concern because if there are unregulated materials in the inner layers of the laminate, they may migrate to food, and therefore be considered unapproved food additives resulting in the food being deemed adulterated under the Federal Food Drug and Cosmetic Act.

  13. Polynomial-time interior-point algorithm based on a local self-concordant finite barrier function

    Institute of Scientific and Technical Information of China (English)

    JIN Zheng-jing; BAI Yan-qin

    2009-01-01

    The choice of self-concordant functions is the key to efficient algorithms for linear and quadratic convex optimizations,which provide a method with polynomial-time iterations to solve linear and quadratic convex optimization problems.The parameters of a self-concordant barrier function can be used to compute the complexity bound of the proposed algorithm.In this paper,it is proved that the finite barrier function is a local self-concordant barrier function.By deriving the local values of parameters of this barrier function,the desired complexity bound of an interior-point algorithm based on this local serf-concordant function for linear optimization problem is obtained.The bound matches the best known bound for smallupdate methods.

  14. Executive Function and Emotion Regulation Strategy Use in Adolescents.

    Science.gov (United States)

    Lantrip, Crystal; Isquith, Peter K; Koven, Nancy S; Welsh, Kathleen; Roth, Robert M

    2016-01-01

    Development of emotion regulation strategy use involves a transition from reliance on suppression during childhood to greater use of reappraisal in adolescence and adulthood-a transition that parallels developmental changes in executive functions. We evaluated the relationship between emotion regulation strategy use and executive functioning in the everyday life of 70 typically developing adolescents who completed the Emotion Regulation Questionnaire for Youth and the Behavior Rating Inventory of Executive Function-Self-Report. Results indicated that greater reliance on reappraisal was associated with better executive functions, while reliance on suppression was related to poorer executive functions. Findings suggest that adolescents who rely on reappraisal may have more cognitive resources to help them remain attentive and well regulated in their daily lives. On the other hand, if better executive functions facilitate the use of reappraisal, adolescents' ability to regulate their emotions could potentially be enhanced via supports for executive functions.

  15. Density-Functional-Based Determination of the CH3-CH4 Hydrogen Exchange Reaction Barrier

    CERN Document Server

    Pederson, M R

    1994-01-01

    Due to the overbinding that is inherent in existing {\\em local} approximations to the density-functional formalism, certain reaction energies have not been accessible. Since the generalized gradient approximation significantly decreases the overbinding, prospects for density-functional-based reaction dynamics are promising. Results on the generalized-gradient based determination of the CH3-CH4 hydrogen exchange reaction are presented. Including all Born-Oppenheimer effects an energy barrier of 9.5 kcal/Mole is found which is a very significant improvement over the local-density approximation.

  16. Fabrication of pseudo-ceramide-based lipid microparticles for recovery of skin barrier function.

    Science.gov (United States)

    Kim, Do-Hoon; Park, Woo Ram; Kim, Jeong Hwan; Cho, Eun Chul; An, Eun Jung; Kim, Jin-Woong; Oh, Seong-Geun

    2012-06-01

    The recovery of skin barrier functions was investigated with pseudo-ceramide-based lipid microparticles. The microparticles were prepared by using a fluid bed technique where lipid components (a pseudo-ceramide, cholesterol and a fatty acid) were coated on a sugar seed, and a polymer was subsequently coated on the lipid microparticles. The microparticles contained large amount of pseudo-ceramide, and the pseudo-ceramide was in the form of lamellar structures mixed with other lipid components. In addition, the microparticles were stably dispersed in aqueous media or emulsion systems without any disruption of the microparticles' structures, thereby supplying sufficient amount of the pseudo-ceramide to skins for improving skin barrier functions such as preventing water loss. Such a role of the microparticles was proven by evaluating in vivo the efficacy of the lipid microparticles in reducing a trans-epidermal water loss (TEWL) of impaired murine skins. As a result, the novel pseudo-ceramide-based lipid microparticles for barrier recovery may potentially be applied in the field of dermatology, cosmetics and pharmaceuticals. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function.

    Science.gov (United States)

    Gonzalez-Andrades, Miguel; Alonso-Pastor, Luis; Mauris, Jérôme; Cruzat, Andrea; Dohlman, Claes H; Argüeso, Pablo

    2016-01-13

    The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro. However, these assays are mostly based on monolayer systems that fail to reproduce the differentiation processes associated to multilayered systems. Here, we describe a straightforward in vitro wound assay to evaluate the healing and restoration of barrier function in stratified human corneal epithelial cells. In this assay, circular punch injuries lead to the collective migration of the epithelium as coherent sheets. The closure of the wound was associated with the restoration of the transcellular barrier and the re-establishment of apical intercellular junctions. Altogether, this new model of wound healing provides an important research tool to study the mechanisms leading to barrier function in stratified epithelia and may facilitate the development of future therapeutic applications.

  18. Topical Formulation Containing Beeswax-Based Nanoparticles Improved In Vivo Skin Barrier Function.

    Science.gov (United States)

    Souza, Carla; de Freitas, Luis Alexandre Pedro; Maia Campos, Patrícia Maria Berardo Gonçalves

    2017-02-17

    Lipid nanoparticles have shown many advantages for treatment/prevention of skin disorders with damaged skin barrier function. Beeswax is a favorable candidate for the development of nanosystems in the cosmetic and dermatological fields because of its advantages for the development of products for topical application. In the present study, beeswax-based nanoparticles (BNs) were prepared using the hot melt microemulsion technique and incorporated to a gel-cream formulation. The formulation was subsequently evaluated for its rheological stability and effect on stratum corneum water content (SCWC) and transepidermal water loss (TEWL) using in vivo biophysical techniques. BNs resulted in mean particle size of 95.72 ± 9.63 nm and zeta potential of -9.85 ± 0.57 mV. BN-loaded formulation showed shear thinning behavior, well adjusted by the Herschel-Bulkley model, and a small thixotropy index that were stable for 28 days at different temperatures. BN-loaded formulation was also able to simultaneously decrease the TEWL and increase the SCWC values 28 days after treatment. In conclusion, the novel beeswax-based nanoparticles showed potential for barrier recovery and open the perspective for its commercial use as a novel natural active as yet unexplored in the field of dermatology and cosmetics for treatment of skin diseases with damaged skin barrier function.

  19. Caspase-14 Expression Impairs Retinal Pigment Epithelium Barrier Function: Potential Role in Diabetic Macular Edema

    Directory of Open Access Journals (Sweden)

    Selina Beasley

    2014-01-01

    Full Text Available We recently showed that caspase-14 is a novel molecule in retina with potential role in accelerated vascular cell death during diabetic retinopathy (DR. Here, we evaluated whether caspase-14 is implicated in retinal pigment epithelial cells (RPE dysfunction under hyperglycemia. The impact of high glucose (HG, 30 mM D-glucose on caspase-14 expression in human RPE (ARPE-19 cells was tested, which showed significant increase in caspase-14 expression compared with normal glucose (5 mM D-glucose + 25 mM L-glucose. We also evaluated the impact of modulating caspase-14 expression on RPE cells barrier function, phagocytosis, and activation of other caspases using ARPE-19 cells transfected with caspase-14 plasmid or caspase-14 siRNA. We used FITC-dextran flux assay and electric cell substrate impedance sensing (ECIS to test the changes in RPE cell barrier function. Similar to HG, caspase-14 expression in ARPE-19 cells increased FITC-dextran leakage through the confluent monolayer and decreased the transcellular electrical resistance (TER. These effects of HG were prevented by caspase-14 knockdown. Furthermore, caspase-14 knockdown prevented the HG-induced activation of caspase-1 and caspase-9, the only activated caspases by HG. Phagocytic activity was unaffected by caspase-14 expression. Our results suggest that caspase-14 contributes to RPE cell barrier disruption under hyperglycemic conditions and thus plays a role in the development of diabetic macular edema.

  20. Legal barriers to effective ecosystem management: exploring linkages between liability, regulations, and prescribed fire.

    Science.gov (United States)

    Wonkka, Carissa L; Rogers, William E; Kreuter, Urs P

    2015-12-01

    should consider the benefits of lower legal liability standards in conjunction with regulatory requirements that promote safety for those managing forests and rangelands with fire. Moreover, ecologists and land managers might be better prepared and motivated to educate stakeholder groups who influence prescribed fire policies if they are cognizant of the manner in which policy regulations and liability concerns create legal barriers that inhibit the implementation of effective ecosystem management strategies.

  1. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA.

    Science.gov (United States)

    Bartels, A L; Willemsen, A T M; Kortekaas, R; de Jong, B M; de Vries, R; de Klerk, O; van Oostrom, J C H; Portman, A; Leenders, K L

    2008-07-01

    Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

  2. Possible relationship between intestinal barrier function and formation of pigment gallstones in hamsters

    Institute of Scientific and Technical Information of China (English)

    Ying Fan; Shuo-Dong Wu; Lei Sun; Bei-Bei Fu; Yang Su

    2008-01-01

    BACKGROUND: The presence of bacteria in bile is an important factor in the formation of pigment gallstones. The bile of healthy people is sterile and bacteria in the biliary system come from endogenous infection from the gut. Yet, the route of bacterial translocation into the bile duct is still unclear. Theoretically, two routes exist:one is through the intestinal barrier and the other is by direct relfux from the sphincter of Oddi. This study was undertaken to explore the relationship between the effectiveness of intestinal barrier and the formation of pigment gallstones in hamsters. METHODS: Thirty-two hamsters were divided into an experimental and a control group, with 16 hamsters in each group. A low protein and high cellulose diet was given for 6 weeks to induce the formation of pigment gallstones in the experimental group (PS) and a normal diet was given to the control group (CON). Morphological changes, changes in the levels of serum endotoxin and diamine oxidase, and changes in the numbers of B lymphocytes, plasma cells and secretory immunoglobin A (sIgA) in the intestinal mucosa were assessed after 6 weeks. RESULTS:Four hamsters died during lithogenesis and body weight decreased in the PS group. Pigment gallstones were found in 11 hamsters at the end of the experiment, giving a lithogenesis rate of 91.67%. The serum endotoxin level before and after gallstone formation in the PS group was 0.2960±0.1734 U/ml and 8.2964±4.6268 U/ml, respectively (P CONCLUSIONS:A low protein and high cellulose diet can markedly reduce intestinal barrier function and facilitate the formation of pigment gallstones. The decrease of intestinal barrier function may take part in the formation of pigment gallstones.

  3. Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Leilei Yu

    2016-12-01

    Full Text Available Aluminum (Al is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

  4. Regulation of antimicrobial resistance by extracytoplasmic function (ECF) sigma factors.

    Science.gov (United States)

    Woods, Emily C; McBride, Shonna M

    2017-01-30

    Extracytoplasmic function (ECF) sigma factors are a subfamily of σ(70) sigma factors that activate genes involved in stress-response functions. In many bacteria, ECF sigma factors regulate resistance to antimicrobial compounds. This review will summarize the ECF sigma factors that regulate antimicrobial resistance in model organisms and clinically relevant pathogens.

  5. Longitudinal Associations among Child Maltreatment, Social Functioning, and Cortisol Regulation

    Science.gov (United States)

    Alink, Lenneke R. A.; Cicchetti, Dante; Kim, Jungmeen; Rogosch, Fred A.

    2012-01-01

    Child maltreatment increases the risk for impaired social functioning and cortisol regulation. However, the longitudinal interplay among these factors is still unclear. This study aimed to shed light on the effect of maltreatment on social functioning and cortisol regulation over time. The sample consisted of 236 children (mean age 7.64 years, SD…

  6. Longitudinal Associations among Child Maltreatment, Social Functioning, and Cortisol Regulation

    Science.gov (United States)

    Alink, Lenneke R. A.; Cicchetti, Dante; Kim, Jungmeen; Rogosch, Fred A.

    2012-01-01

    Child maltreatment increases the risk for impaired social functioning and cortisol regulation. However, the longitudinal interplay among these factors is still unclear. This study aimed to shed light on the effect of maltreatment on social functioning and cortisol regulation over time. The sample consisted of 236 children (mean age 7.64 years, SD…

  7. Adenosine Receptors: Expression, Function and Regulation

    Directory of Open Access Journals (Sweden)

    Sandeep Sheth

    2014-01-01

    Full Text Available Adenosine receptors (ARs comprise a group of G protein-coupled receptors (GPCR which mediate the physiological actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochemical characteristics and signaling cascade associated with each receptor and provide insight into how these receptors are regulated in response to agonists. A key property of some of these receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as nuclear factor (NF-κB, to regulate the expression of ARs. Recent observations of oligomerization of these receptors into homo- and heterodimers will be discussed. In addition, the importance of these receptors in the regulation of normal and pathological processes such as sleep, the development of cancers and in protection against hearing loss will be examined.

  8. Functional and structural alterations of epithelial barrier properties of rat ileum following X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Dublineau, I. [Inst. de Radioprotection et de Surete Nucleaire (IRSN), Direction de la RadioProtection de l' Homme, Service de Radiobiologie et d' Epidemiologie, Fontenay-aux-Roses, CEDEX (France)]. E-mail: isabelle.dublineau@irsn.fr; Lebrun, F. [Commissariat a l' Energie Atomique (CEA), Dept. de Radiopathologie et de Radiobiologie, Fontenay-aux-Roses, CEDEX (France); Grison, S.; Griffiths, N.M. [Inst. de Radioprotection et de Surete Nucleaire (IRSN), Direction de la RadioProtection de l' Homme, Service de Radiobiologie et d' Epidemiologie, Fontenay-aux-Roses, CEDEX (France)

    2004-02-01

    Irradiation of the digestive system leads to alterations of the small intestine. We have characterized the disruption of the barrier integrity in rat ileum from 1 to 14 days following irradiation ranging from 6 to 12 Gy. The intestinal permeability to {sup 14}C-mannitol and {sup 3}H-dextran 70,000 was measured in vitro in Ussing chambers. In parallel to these functional studies, immunohistochemical analyses of junctional proteins (ZO-1 and {beta}-catenin) of ileal epithelium were performed by confocal microscopy. Irradiation with 10 Gy induced a marked decrease in epithelial tissue resistance at three days and a fivefold increase in mannitol permeability, without modifications of dextran permeability. A disorganization of the localization for ZO-1 and {beta}-catenin was also observed. At 7 days after irradiation, we observed a recovery of the organization of junctional proteins in parallel to a return of intestinal permeability to control value. In addition to these time-dependent effects, a gradual effect on epithelial integrity of the radiation doses was observed 3 days after irradiation. This study shows a disruption of the integrity of the intestinal barrier in rat ileum following abdominal X-irradiation, depending on the time postirradiation and on the delivered dose. The loss of barrier integrity was characterized by a disorganization of proteins of tight and adherent junctions, leading to increased intestinal permeability to mannitol. (author)

  9. Flow directionality, mountain barriers and functional traits determine diatom metacommunity structuring of high mountain streams.

    Science.gov (United States)

    Dong, Xiaoyu; Li, Bin; He, Fengzhi; Gu, Yuan; Sun, Meiqin; Zhang, Haomiao; Tan, Lu; Xiao, Wen; Liu, Shuoran; Cai, Qinghua

    2016-04-19

    Stream metacommunities are structured by a combination of local (environmental filtering) and regional (dispersal) processes. The unique characters of high mountain streams could potentially determine metacommunity structuring, which is currently poorly understood. Aiming at understanding how these characters influenced metacommunity structuring, we explored the relative importance of local environmental conditions and various dispersal processes, including through geographical (overland), topographical (across mountain barriers) and network (along flow direction) pathways in shaping benthic diatom communities. From a trait perspective, diatoms were categorized into high-profile, low-profile and motile guild to examine the roles of functional traits. Our results indicated that both environmental filtering and dispersal processes influenced metacommunity structuring, with dispersal contributing more than environmental processes. Among the three pathways, stream corridors were primary pathway. Deconstructive analysis suggested different responses to environmental and spatial factors for each of three ecological guilds. However, regardless of traits, dispersal among streams was limited by mountain barriers, while dispersal along stream was promoted by rushing flow in high mountain stream. Our results highlighted that directional processes had prevailing effects on metacommunity structuring in high mountain streams. Flow directionality, mountain barriers and ecological guilds contributed to a better understanding of the roles that mountains played in structuring metacommunity.

  10. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

    Science.gov (United States)

    Nighot, Prashant K; Hu, Chien-An Andy; Ma, Thomas Y

    2015-03-13

    Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.

  11. Enhanced barrier functions and anti-inflammatory effect of cultured coconut extract on human skin.

    Science.gov (United States)

    Kim, Soomin; Jang, Ji Eun; Kim, Jihee; Lee, Young In; Lee, Dong Won; Song, Seung Yong; Lee, Ju Hee

    2017-08-01

    Natural plant oils have been used as a translational alternative to modern medicine. Particularly, virgin coconut oil (VCO) has gained popularity because of its potential benefits in pharmaceutical, nutritional, and cosmetic applications. Cultured coconut extract (CCE) is an alternative end product of VCO, which undergoes a further bacterial fermentation process. This study aimed to investigate the effects of CCE on human skin. We analyzed the expression of skin barrier molecules and collagens after applying CCE on human explanted skin. To evaluate the anti-inflammatory properties of CCE, the expression of inflammatory markers was analyzed after ultraviolet B (UVB) irradiation. The CCE-treated group showed increased expression of cornified cell envelope components, which contribute to protective barrier functions of the stratum corneum. Further, the expression of inflammatory markers was lower in the CCE-treated group after exposure to UVB radiation. These results suggest an anti-inflammatory effect of CCE against UVB irradiation-induced inflammation. Additionally, the CCE-treated group showed increased collagen and hyaluronan synthase-3 expression. In our study, CCE showed a barrier-enhancing effect and anti-inflammatory properties against ex vivo UVB irradiation-induced inflammation. The promising effect of CCE may be attributed to its high levels of polyphenols and fatty acid components. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. An O(√nL) Iteration Large-Step Logarithmic Barrier Function Algorithm for Linear Programming

    OpenAIRE

    TONE, Kaoru

    1989-01-01

    As a natural extension of Roos and Vial's "Long steps with logarithmic penalty barrier function in llnear programming" (1989) and Ye's "An O(n³L) potential reduction algorithm for linear programming" (1989), it will be shown that the classical logarithmic barrier function method can be adjusted so that it generates the optimal solution in O(√nL) iterations, where n is the number of variables and L is the data length.

  13. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis.

    Science.gov (United States)

    Carlsson, Anders H; Yakymenko, Olena; Olivier, Isabelle; Håkansson, Fathima; Postma, Emily; Keita, Asa V; Söderholm, Johan D

    2013-10-01

    OBJECTIVE. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. MATERIAL AND METHODS. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with (51)Cr-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. RESULTS. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in (51)Cr-EDTA-passage compared to controls. (51)Cr-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. CONCLUSIONS. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.

  14. Conformational regulation of urokinase receptor function

    DEFF Research Database (Denmark)

    Gårdsvoll, Henrik; Jacobsen, Benedikte; Kriegbaum, Mette C

    2011-01-01

    PA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized...

  15. Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

    Science.gov (United States)

    van Assema, Daniëlle M E; Lubberink, Mark; Bauer, Martin; van der Flier, Wiesje M; Schuit, Robert C; Windhorst, Albert D; Comans, Emile F I; Hoetjes, Nikie J; Tolboom, Nelleke; Langer, Oliver; Müller, Markus; Scheltens, Philip; Lammertsma, Adriaan A; van Berckel, Bart N M

    2012-01-01

    A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic

  16. Regulation of pituitary cell function by adiponectin.

    Science.gov (United States)

    Rodriguez-Pacheco, Francisca; Martinez-Fuentes, Antonio J; Tovar, Sulay; Pinilla, Leonor; Tena-Sempere, Manuel; Dieguez, Carlos; Castaño, Justo P; Malagon, María M

    2007-01-01

    Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.

  17. Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O”s: functionalization, rotational barriers and non-covalent interactions

    Directory of Open Access Journals (Sweden)

    Golo Storch

    2016-07-01

    Full Text Available Stereodynamic ligands offer intriguing possibilities in enantioselective catalysis. “NU-BIPHEPs” are a class of stereodynamic diphosphine ligands which are easily accessible via rhodium-catalyzed double [2 + 2 + 2] cycloadditions. This study explores the preparation of differently functionalized “NU-BIPHEP(O” compounds, the characterization of non-covalent adduct formation and the quantification of enantiomerization barriers. In order to explore the possibilities of functionalization, we studied modifications of the ligand backbone, e.g., with 3,5-dichlorobenzoyl chloride. Diastereomeric adducts with Okamoto-type cellulose derivatives and on-column deracemization were realized on the basis of non-covalent interactions. Enantioselective dynamic HPLC (DHPLC allowed for the determination of rotational barriers of ΔG‡298K = 92.2 ± 0.3 kJ mol−1 and 99.5 ± 0.1 kJ mol−1 underlining the stereodynamic properties of “NU-BIPHEPs” and “NU-BIPHEP(Os”, respectively. These results make the preparation of tailor-made functionalized stereodynamic ligands possible and give an outline for possible applications in enantioselective catalysis.

  18. Blood-brain barrier P-glycoprotein function in neurodegenerative disease.

    Science.gov (United States)

    Bartels, A L

    2011-01-01

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.

  19. Isolation gowns in health care settings: Laboratory studies, regulations and standards, and potential barriers of gown selection and use

    Science.gov (United States)

    Kilinc Balci, F. Selcen

    2016-01-01

    Although they play an important role in infection prevention and control, textile materials and personal protective equipment (PPE) used in health care settings are known to be one of the sources of cross-infection. Gowns are recommended to prevent transmission of infectious diseases in certain settings; however, laboratory and field studies have produced mixed results of their efficacy. PPE used in health care is regulated as either class I (low risk) or class II (intermediate risk) devices in the United States. Many organizations have published guidelines for the use of PPE, including isolation gowns, in health care settings. In addition, the Association for the Advancement of Medical Instrumentation published a guidance document on the selection of gowns and a classification standard on liquid barrier performance for both surgical and isolation gowns. However, there is currently no existing standard specific to isolation gowns that considers not only the barrier resistance but also a wide array of end user desired attributes. As a result, infection preventionists and purchasing agents face several difficulties in the selection process, and end users have limited or no information on the levels of protection provided by isolation gowns. Lack of knowledge about the performance of protective clothing used in health care became more apparent during the 2014 Ebola epidemic. This article reviews laboratory studies, regulations, guidelines and standards pertaining to isolation gowns, characterization problems, and other potential barriers of isolation gown selection and use. PMID:26391468

  20. War experiences, general functioning and barriers to care among former child soldiers in Northern Uganda: the WAYS study.

    Science.gov (United States)

    Amone-P'Olak, Kennedy; Jones, Peter; Meiser-Stedman, Richard; Abbott, Rosemary; Ayella-Ataro, Paul Stephen; Amone, Jackson; Ovuga, Emilio

    2014-12-01

    Exposure to war is associated with considerable risks for long-term mental health problems (MHP) and poor functioning. Yet little is known about functioning and mental health service (MHS) use among former child soldiers (FCS). We assessed whether different categories of war experiences predict functioning and perceived need for, sources of and barriers to MHS among FCS. Data were drawn from an on-going War-affected Youths (WAYS) cohort study of FCS in Uganda. Participants completed questionnaires about war experiences, functioning and perceived need for, sources of and barriers to MHS. Regression analyses and parametric tests were used to assess between-group differences. Deaths, material losses, threat to loved ones and sexual abuse significantly predicted poor functioning. FCS who received MHS function better than those who did not. Females reported more emotional and behavioural problems and needed MHS more than males. FCS who function poorly indicated more barriers to MHS than those who function well. Stigma, fear of family break-up and lack of health workers were identified as barriers to MHS. Various war experiences affect functioning differently. A significant need for MHS exists amidst barriers to MHS. Nevertheless, FCS are interested in receiving MHS and believe it would benefit them. © The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Constipation-Predominant Irritable Bowel Syndrome Females Have Normal Colonic Barrier and Secretory Function.

    Science.gov (United States)

    Peters, Stephanie A; Edogawa, Shoko; Sundt, Wendy J; Dyer, Roy B; Dalenberg, Daniel A; Mazzone, Amelia; Singh, Ravinder J; Moses, Natalie; Smyrk, Thomas C; Weber, Christopher; Linden, David R; MacNaughton, Wallace K; Turner, Jerrold R; Camilleri, Michael; Katzka, David A; Farrugia, Gianrico; Grover, Madhusudan

    2017-06-01

    The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g (13)C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression. There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of (13)C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm(2) vs. healthy: 29.8 (1.9) Ω cm(2)) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm(2) vs. healthy: 17.6 (1.7) Ω cm(2)); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm(-2)) vs. healthy (56.9 (4.9) μA cm(-2)), P=0.05. Ach-evoked ΔIsc was similar. Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.

  2. Functional characterisation of the maturation of the blood-brain barrier in larval zebrafish.

    Directory of Open Access Journals (Sweden)

    Angeleen Fleming

    Full Text Available Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f. onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals.

  3. Multiconfiguration pair-density functional theory: barrier heights and main group and transition metal energetics.

    Science.gov (United States)

    Carlson, Rebecca K; Li Manni, Giovanni; Sonnenberger, Andrew L; Truhlar, Donald G; Gagliardi, Laura

    2015-01-13

    Kohn-Sham density functional theory, resting on the representation of the electronic density and kinetic energy by a single Slater determinant, has revolutionized chemistry, but for open-shell systems, the Kohn-Sham Slater determinant has the wrong symmetry properties as compared to an accurate wave function. We have recently proposed a theory, called multiconfiguration pair-density functional theory (MC-PDFT), in which the electronic kinetic energy and classical Coulomb energy are calculated from a multiconfiguration wave function with the correct symmetry properties, and the rest of the energy is calculated from a density functional, called the on-top density functional, that depends on the density and the on-top pair density calculated from this wave function. We also proposed a simple way to approximate the on-top density functional by translation of Kohn-Sham exchange-correlation functionals. The method is much less expensive than other post-SCF methods for calculating the dynamical correlation energy starting with a multiconfiguration self-consistent-field wave function as the reference wave function, and initial tests of the theory were quite encouraging. Here, we provide a broader test of the theory by applying it to bond energies of main-group molecules and transition metal complexes, barrier heights and reaction energies for diverse chemical reactions, proton affinities, and the water dimerization energy. Averaged over 56 data points, the mean unsigned error is 3.2 kcal/mol for MC-PDFT, as compared to 6.9 kcal/mol for Kohn-Sham theory with a comparable density functional. MC-PDFT is more accurate on average than complete active space second-order perturbation theory (CASPT2) for main-group small-molecule bond energies, alkyl bond dissociation energies, transition-metal-ligand bond energies, proton affinities, and the water dimerization energy.

  4. G Proteins and Regulation of Effector Function

    Directory of Open Access Journals (Sweden)

    A.R. Dehpour

    1991-07-01

    Full Text Available Cell surface receptors use a variety of membrane signalling mechanisms to translate information encoded in neurotransmitters, hormones, and growth factors into cellular responses.Collectively these mechanisms are refered to as transmembrane signalling or signal transduction. In the simplest example,the process involves a receptor protein-encompassed ion channel whose conductance is regulated by receptor activation.A second type of transmembrane signalling system involves the coupling of at least three separate components, a receptor protein, a guanine nucleotide binding protein (G protein , and an effector mechanism. In some receptor" effector systems the signal transduction pathways is entirely confined to the membrane, in which no intracellular messenger is involved.Alternatively, the activity of an enzyme may be changed to generate a specific intracellular signal molecule or second messenger. Receptors in this latter category may regulate the activity of adenylyl cyclase in a positive manner through a stimulatory G protein( G or in a negative manner through an inhibitory G protein( G. thereby controlling the intracellular level of cAMP. Another membrane- associated enzyme, similar to adenylate cyclase, is phospholipase C which catalizes the hydrolysis of PIP2into IP3and DAG. Phospholipase C coupled receptors are physiologically very important because both products of the reaction act as a second messenger; diacylglycerol activates protein kinase C and IP3 stimulates calcium release from Intracellular stores.

  5. The acoustical Klein-Gordon equation: the wave-mechanical step and barrier potential functions.

    Science.gov (United States)

    Forbes, Barbara J; Pike, E Roy; Sharp, David B

    2003-09-01

    The transformed form of the Webster equation is investigated. Usually described as analogous to the Schrödinger equation of quantum mechanics, it is noted that the second-order time dependency defines a Klein-Gordon problem. This "acoustical Klein-Gordon equation" is analyzed with particular reference to the acoustical properties of wave-mechanical potential functions, U(x), that give rise to geometry-dependent dispersions at rapid variations in tract cross section. Such dispersions are not elucidated by other one-dimensional--cylindrical or conical--duct models. Since Sturm-Liouville analysis is not appropriate for inhomogeneous boundary conditions, the exact solution of the Klein-Gordon equation is achieved through a Green's-function methodology referring to the transfer matrix of an arbitrary string of square potential functions, including a square barrier equivalent to a radiation impedance. The general conclusion of the paper is that, in the absence of precise knowledge of initial conditions on the area function, any given potential function will map to a multiplicity of area functions of identical relative resonance characteristics. Since the potential function maps uniquely to the acoustical output, it is suggested that the one-dimensional wave physics is both most accurately and most compactly described within the Klein-Gordon framework.

  6. Intellectual property and regulation of functional foods

    Directory of Open Access Journals (Sweden)

    Petrović Slobodan D.

    2012-06-01

    Full Text Available Today, there exist scientific evidences that functional foods have favorable physiological and psychological effects as well as additional functions in relation to health, apart from the basic nutritional effects, thus offering the potential of enhance health or reduced the risk of diseases. Since interest in this category of foods has increased, new products have appeared as well as the need to introduce and set up standards and guidelines for the development and promotion of such foods. Technological development in this area and involvement of great multinationals in research investment and development of new products have reinforced the importance of the intellectual property rights, especially of patent protections and trademarks.

  7. Structural plasticity upon learning: regulation and functions.

    Science.gov (United States)

    Caroni, Pico; Donato, Flavio; Muller, Dominique

    2012-07-01

    Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity.

  8. Effect of probiotics in combined with alanyl glutamine on gut barrier function in severely ill patients

    Institute of Scientific and Technical Information of China (English)

    Wei-Peng Song; Li Liu

    2015-01-01

    Objective:To study the protectve effect of probiotics in combined with alanyl glutamine (Gln) on gut barrier function in severely ill patients.Methods:A total of 108 critically ill patients with gastrointestinal diseases were included in the study and randomized into the normal PN group (n=36), the probiotics group (n=36), and the combination group (n=36), which were treated by the conventional parenteral nutrition (PN), PN+probiotics, PN+probiotics+Gln, respectively. The actulose/mannitol (L/M) ratio, and serum endotoxin, lactobacillus and gram-negative bacterium concentrations before operation, the 3rd day and the 8th day after operation in the three groups were determined.Results:The L/M ratio and the serum endotoxin concentration the 8th day after operation in the probiotics group were significantly lower than those in the PN group, while those in the combination group were also significantly lower than those in the probiotics group. The lactobacillus concentration in the probiotics was significantly higher than that in the PN group, while that in the combination group were also significantly higher than that in the probiotics group. The comparison of the gram-negative bacterium concentration among the three groups was not statistically significant.Conclusions:The combination of probiotics in combined with Gln in protecting the gut barrier function has a better effect.

  9. Down-regulation of pigment epithelium-derived factor in uveitic lesion associates with focal vascular endothelial growth factor expression and breakdown of the blood-retinal barrier.

    Science.gov (United States)

    Deeg, Cornelia A; Altmann, Frank; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius

    2007-05-01

    Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Identifying biological markers or pathways associated with this disease may allow the understanding of its pathogenesis at a molecular level. The vitreous is the body fluid closest to the disease-affected tissue and possibly also an effector of pathological processes relevant for ERU. Surgical removal of vitreous leads to cessation of relapses in spontaneous uveitis of both man and horse, therefore vitreous composites are likely to contribute to disease progression. Uveitic vitreous is likely to contain potential biomarkers in relatively undiluted quantities. With the goal to identify these markers, we systematically compared vitreous from healthy and disease-affected eyes by proteomic profiling. Nine differentially expressed proteins were identified, that are functionally related to immune response, inflammation, and maintenance of the blood-retinal barrier. One of these, pigment epithelium-derived factor, a protein involved in maintaining a proper blood-retina barrier as well as protecting from neoangiogenesis was additionally found to be down-regulated within uveitic retinal lesions whereas, conversely, vascular endothelial growth factor was found to be up-regulated at these sites. Together, these changes point to as of yet undiscovered biological pathways involved in the pathogenesis of this autoimmune disease.

  10. 抗氧化剂对表皮通透屏障功能的影响%Influences of Antioxidants on Epidermal Permeability Barrier Function

    Institute of Scientific and Technical Information of China (English)

    蔄茂强; Peter M.Elias

    2013-01-01

    Epidermal permeability barrier function is crucial in regulating cutaneous function.Enhancing epidermal permeability barrier function has become an important preventive and therapeutic approach for some skin disorders and skin aging.Studies have demonstrated that antioxidants stimulate keratinocyte differentiation and epidermal lipid production,which result in improvement of epidermal permeability barrier function.Thus,antioxidants could be useful in preventing and treating some skin disorders and skin aging.%表皮通透屏障功能对皮肤功能具有重要调节作用.增强表皮通透屏障功能已成为防治某些皮肤病和延缓皮肤老化的手段之一.研究显示,抗氧化剂可通过促进表皮细胞分化及其脂的合成而增强表皮透屏障功能.由此提示,抗氧化剂可用于防治某些皮肤病和延缓皮肤老化.

  11. Regulation of immunoproteasome function in the lung

    NARCIS (Netherlands)

    Keller, I.E.; Vosyka, O.; Takenaka, S.; Kloss, A.; Dahlmann, B.; Willems, L.I.; Verdoes, M.; Overkleeft, H.S.; Marcos, E.; Adnot, S.; Hauck, S.M.; Ruppert, C.; Gunther, A.; Herold, S.; Ohno, S.; Adler, H.; Eickelberg, O.; Meiners, S.

    2015-01-01

    Impaired immune function contributes to the development of chronic obstructive pulmonary disease (COPD). Disease progression is further exacerbated by pathogen infections due to impaired immune responses. Elimination of infected cells is achieved by cytotoxic CD8(+) T cells that are activated by MHC

  12. Integration and regulation of cardiovascular function.

    Science.gov (United States)

    Hall, J E

    1999-12-01

    New methods in molecular biology and genetics have made possible many of the dramatic advances in physiological research that have occurred in recent years. For those of us who spend most of our time in the research laboratory, it si sometimes difficult to avoid a research-oriented, reductionist mind-set when discussing physiology with students. This article illustrates, with a few examples, the importance of conveying a "big picture" conceptual framework before discussing the details of cardiovascular physiology. Also, I have chosen examples from cardiac output and blood pressure regulation that show the importance of discussing cardiovascular physiology in terms of feedback control systems and integrating information from other areas, such as renal and endocrine physiology. Finally, I have highlighted the importance of two principles that I believe are often underemphasized in teaching physiology: mass balance and time dependence of physiological control systems.

  13. Hsp70 Structure, Function, Regulation and Influence on Yeast Prions

    OpenAIRE

    D. Sharma; Masison, D. C.

    2009-01-01

    Heat shock proteins protect cells from various conditions of stress. Hsp70, the most ubiquitous and highly conserved Hsp, helps proteins adopt native conformation or regain function after misfolding. Various co-chaperones specify Hsp70 function and broaden its substrate range. We discuss Hsp70 structure and function, regulation by co-factors and influence on propagation of yeast prions.

  14. The Effects of Fire on the Function of the 200-BP-1 Engineered Surface Barrier

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Anderson L.; Link, Steven O.; Hasan, Nazmul; Draper, Kathryn E.

    2009-09-01

    A critical unknown in use of barrier technology for long-term waste isolation is performance after a major disturbance especially when institutional controls are intact, but there are no resources to implement corrective actions. The objective of this study was to quantify the effects of wild fire on alterations the function of an engineered barrier. A controlled burn September 26, 2008 was used to remove all the vegetation from the north side of the barrier. Flame heights exceeded 9 m and temperatures ranged from 250 oC at 1.5 cm below the surface to over 700 oC at 1 m above the surface. Post-fire analysis of soil properties show significant decreases in wettability, hydraulic conductivity, air entry pressure, organic matter, and porosity relative to pre-fire conditions whereas dry bulk density increased. Decreases in hydraulic conductivity and wettabilty immediately after the fire are implicated in a surface runoff event that occurred in January 2009, the first in 13 years. There was a significant increase in macro-nutrients, pH, and electrical conductivity. After one year, hydrophobicity has returned to pre-burn levels with only 16% of samples still showing signs of decreased wettability. Over the same period, hydraulic conductivity and air entry pressure returned to pre-burn levels at one third of the locations but remained identical to values recorded immediately after the fire at the other two thirds. Soil nutrients, pH, and electrical conductivity remain elevated after 1 year. Species composition on the burned surface changed markedly from prior years and relative to the unburned surface and two analog sites. An increase in the proportion of annuals and biennials is characteristic of burned surfaces that have become dominated by ruderal species. Greenhouse seedling emergence tests conducted to assess the seed bank of pre- and post-burn soils and of two analog sites at the McGee Ranch show no difference in the number of species emerging from soils collected

  15. Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.

    Science.gov (United States)

    Janssens, Michelle; van Smeden, Jeroen; Gooris, Gert S; Bras, Wim; Portale, Guiseppe; Caspers, Peter J; Vreeken, Rob J; Hankemeier, Thomas; Kezic, Sanja; Wolterbeek, Ron; Lavrijsen, Adriana P; Bouwstra, Joke A

    2012-12-01

    A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE.

  16. Phosphorylation of Astrin Regulates Its Kinetochore Function.

    Science.gov (United States)

    Chung, Hee Jin; Park, Ji Eun; Lee, Nam Soo; Kim, Hongtae; Jang, Chang-Young

    2016-08-19

    The error-free segregation of chromosomes, which requires the precisely timed search and capture of chromosomes by spindles during early mitotic and meiotic cell division, is responsible for genomic stability and is achieved by the spindle assembly checkpoint in the metaphase-anaphase transition. Mitotic kinases orchestrate M phase events, such as the reorganization of cell architecture and kinetochore (KT) composition with the exquisite phosphorylation of mitotic regulators, to ensure timely and temporal progression. However, the molecular mechanisms underlying the changes of KT composition for stable spindle attachment during mitosis are poorly understood. Here, we show that the sequential action of the kinase Cdk1 and the phosphatase Cdc14A control spindle attachment to KTs. During prophase, the mitotic spindle protein Spag5/Astrin is transported into centrosomes by Kinastrin and phosphorylated at Ser-135 and Ser-249 by Cdk1, which, in prometaphase, is loaded onto the spindle and targeted to KTs. We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment. Mechanistically, Plk1 acts as an upstream kinase for Astrin phosphorylation by Cdk1 and targeting phospho-Astrin to KTs, leading to the recruitment of outer KT components, such as Cenp-E, and the stable attachment of spindles to KTs. These comprehensive findings reveal a regulatory circuit for protein targeting to KTs that controls the KT composition change of stable spindle attachment and chromosome integrity.

  17. Molecular regulation of pancreatic stellate cell function

    Directory of Open Access Journals (Sweden)

    Jaster Robert

    2004-10-01

    Full Text Available Abstract Until now, no specific therapies are available to inhibit pancreatic fibrosis, a constant pathological feature of chronic pancreatitis and pancreatic cancer. One major reason is the incomplete knowledge of the molecular principles underlying fibrogenesis in the pancreas. In the past few years, evidence has been accumulated that activated pancreatic stellate cells (PSCs are the predominant source of extracellular matrix (ECM proteins in the diseased organ. PSCs are vitamin A-storing, fibroblast-like cells with close morphological and biochemical similarities to hepatic stellate cells (also known as Ito-cells. In response to profibrogenic mediators such as various cytokines, PSCs undergo an activation process that involves proliferation, exhibition of a myofibroblastic phenotype and enhanced production of ECM proteins. The intracellular mediators of activation signals, and their antagonists, are only partially known so far. Recent data suggest an important role of enzymes of the mitogen-activated protein kinase family in PSC activation. On the other hand, ligands of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor γ stimulate maintenance of a quiescent PSC phenotype. In the future, targeting regulators of the PSC activation process might become a promising approach for the treatment of pancreatic fibrosis.

  18. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

    Full Text Available Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte-derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus.

  19. Advances in PET imaging of P-glycoprotein function at the blood-brain barrier.

    Science.gov (United States)

    Syvänen, Stina; Eriksson, Jonas

    2013-02-20

    Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders.

  20. Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease.

    Science.gov (United States)

    Bartels, A L; van Berckel, B N M; Lubberink, M; Luurtsema, G; Lammertsma, A A; Leenders, K L

    2008-08-01

    The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration. In the present study BBB P-gp function was investigated in vivo in 10 early stage PD patients and 8 healthy control subjects using (R)-[(11)C]-verapamil and PET. Cerebral volume of distribution (V(d)) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed. In the present study, a larger variation in V(d) of (R)-[(11)C]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed.

  1. Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats

    Directory of Open Access Journals (Sweden)

    Vink Carolien

    2009-04-01

    Full Text Available Abstract Background Glutathione, the main antioxidant of intestinal epithelial cells, is suggested to play an important role in gut barrier function and prevention of inflammation-related oxidative damage as induced by acute bacterial infection. Most studies on intestinal glutathione focus on oxidative stress reduction without considering functional disease outcome. Our aim was to determine whether depletion or maintenance of intestinal glutathione changes susceptibility of rats to Salmonella infection and associated inflammation. Rats were fed a control diet or the same diet supplemented with buthionine sulfoximine (BSO; glutathione depletion or cystine (glutathione maintenance. Inert chromium ethylenediamine-tetraacetic acid (CrEDTA was added to the diets to quantify intestinal permeability. At day 4 after oral gavage with Salmonella enteritidis (or saline for non-infected controls, Salmonella translocation was determined by culturing extra-intestinal organs. Liver and ileal mucosa were collected for analyses of glutathione, inflammation markers and oxidative damage. Faeces was collected to quantify diarrhoea. Results Glutathione depletion aggravated ileal inflammation after infection as indicated by increased levels of mucosal myeloperoxidase and interleukin-1β. Remarkably, intestinal permeability and Salmonella translocation were not increased. Cystine supplementation maintained glutathione in the intestinal mucosa but inflammation and oxidative damage were not diminished. Nevertheless, cystine reduced intestinal permeability and Salmonella translocation. Conclusion Despite increased infection-induced mucosal inflammation upon glutathione depletion, this tripeptide does not play a role in intestinal permeability, bacterial translocation and diarrhoea. On the other hand, cystine enhances gut barrier function by a mechanism unlikely to be related to glutathione.

  2. Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon.

    Directory of Open Access Journals (Sweden)

    Yosuke Shimada

    Full Text Available Microbiota have been shown to have a great influence on functions of intestinal epithelial cells (ECs. The role of indole as a quorum-sensing (QS molecule mediating intercellular signals in bacteria has been well appreciated. However, it remains unknown whether indole has beneficial effects on maintaining intestinal barriers in vivo. In this study, we analyzed the effect of indole on ECs using a germ free (GF mouse model. GF mice showed decreased expression of junctional complex molecules in colonic ECs. The feces of specific pathogen-free (SPF mice contained a high amount of indole; however the amount was significantly decreased in the feces of GF mice by 27-fold. Oral administration of indole-containing capsules resulted in increased expression of both tight junction (TJ- and adherens junction (AJ-associated molecules in colonic ECs in GF mice. In accordance with the increased expression of these junctional complex molecules, GF mice given indole-containing capsules showed higher resistance to dextran sodium sulfate (DSS-induced colitis. A similar protective effect of indole on DSS-induced epithelial damage was also observed in mice bred in SPF conditions. These findings highlight the beneficial role of indole in establishing an epithelial barrier in vivo.

  3. Alteration of intestinal barrier function during activity-based anorexia in mice.

    Science.gov (United States)

    Jésus, Pierre; Ouelaa, Wassila; François, Marie; Riachy, Lina; Guérin, Charlène; Aziz, Moutaz; Do Rego, Jean-Claude; Déchelotte, Pierre; Fetissov, Sergueï O; Coëffier, Moïse

    2014-12-01

    Anorexia nervosa is a severe eating disorder often leading to malnutrition and cachexia, but its pathophysiology is still poorly defined. Chronic food restriction during anorexia nervosa may induce gut barrier dysfunction, which may contribute to disease development and its complications. Here we have characterized intestinal barrier function in mice with activity-based anorexia (ABA), an animal model of anorexia nervosa. Male C57Bl/6 ABA or limited food access (LFA) mice were placed respectively in cages with or without activity wheel. After 5 days of acclimatization, both ABA and LFA mice had progressively limited access to food from 6 h/d at day 6 to 3 h/d at day 9 and until the end of experiment at day 17. A group of pair-fed mice (PF) was also compared to ABA. On day 17, food intake was lower in ABA than LFA mice (2.0 ± 0.18 g vs. 3.0 ± 0.14 g, p anorexia nervosa. The role of these alterations in the pathophysiology of anorexia nervosa should be further evaluated. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  4. N-acetyl glucosamine improves intestinal mucosal barrier function in rat

    Directory of Open Access Journals (Sweden)

    Yanxia Liu

    2012-12-01

    Full Text Available Our study investigated the effect of N-acetylglucosamine (GlcNAc on the intestinal mucosal barrier function in rats. Rats were randomly assigned into normal control group, diarrhea-predominant irritable bowel syndrome (IBS-D group and GlcNAc group. IBS-D was introduced into the IBS-D group without any treatment. The GlcNAc group were treated with GlcNAc. Microvilli and tight junctions of intestinal epithelial cells were detected. The D-lactic acid level and diamine oxidase (DAO activity in the serum were determined. Compared with normal rats, microvilli were sparsely distributed on the intestinal epithelial cells, the tight junction gap also widened, and D-lactic acid level and DAO activity were significantly higher in the IBS-D group. After GlcNAc treatment, the microscopic structure of the intestinal mucosa became largely normal, and the level of D-lactic acid and the DAO activity were lowered. In conclusion, GlcNAc can effectively improve the intestinal mucosal barrier dysfunction, perhaps through enhancing the cellular metabolism.

  5. Change of intestinal mucosa barrier function in the progress of non-alcoholic steatohepatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Sheng Li; Wan-Chun Wu; Chi-Yi He; Zhen Han; Dao-You Jin; Lin Wang

    2008-01-01

    AIM:To explore the change of intestinal mucosa barrier function in the progress of non-alcoholic steatohepatitis (NASH) in rats.METHODS:Thirty-two Sprague-Dawley (SD) rats were randomly divided into control group and model group.Rats in the control group were given normal diet,and rats in the model group were given fat-rich diet.Eight rats in each group were killed at end of the 8th and 12th wk,respectively.The levels of endotoxin,D-xylose,TG,TC,ALl" and AST,intestinal tissue SOD and MDA as well as intestinal mucus secretory IgA (sIgA) were measured.The pathology of liver was observed by HE staining.RESULTS:At end of the 8th wk,there was no marked difference in the levels of endotoxin,D-xylose and sTgA between the two groups.At end of the 12th wk,rats in the model group developed steatohepatitis and had a higher serum level of endotoxin (P = 0.01) and D-xylose (P = 0.00) and a lower serum level of sIgA (P = 0.007).CONCLUSION:Intestinal mucosa barrier malfunction may exist in NASH rats and may be an important promoter of NASH in rats.

  6. Improvement of barrier function and stimulation of colonic epithelial anion secretion by Menoease Pills

    Institute of Scientific and Technical Information of China (English)

    Jin-Xia Zhu; Ning Yang; Gui-Hong Zhang; Lai-Ling Tsang; Yu-Lin Gou; Hau-Yan Connie Wong; Yiu-Wa Chung; Hsiao-Chang Chan

    2004-01-01

    AIM: Menoease Pills (MP), a Chinese medicine-based new formula for postmenopausal women, has been shown to modulate the endocrine and immune systems[1]. The present study investigated the effects of MP and one of its active ingredients, ligustrazine, on epithelial barrier and ion transport function in a human colonic cell line, T84.METHODS: Colonic transepithelial electrophysiological characteristics and colonic anion secretion were studied using the short circuit current (ISC) technique. RT-PCR was used to examine the expression of cytoplasmic proteins associated with the tight junctions, ZO-1(zonula occludens-1) and ZO-2 (zonula occludens-2).RESULTS: Pretreatment of T84 cells with MP (15 μg/mL) for 72 h significantly increased basal potential difference,transepithelial resistance and basal ISC. RT-PCR results showed that the expressions of ZO-1 and ZO-2 were significantly increased after MP treatment, consistent with improved epithelial barrier function. Results of acute stimulation showed that apical addition of MP produced a concentrationdependent (10-5 000 μg/mL, EC50 = 293.9 μg/mL) increase in ISC. MP-induced ISC was inhibited by basolateral treatment with bumetanide (100 μmol/L), an inhibitor of the Na+-K+-2Cl- cotransporter, apical addition of Cl-channel blockers, diphenylamine-2, 2'-dicarboxylic acid (1 mmol/L) or glibenclamide (1 mmol/L), but not 4, 4'-diisothiocyanostilbene2, 2'-disulfonic acid or epithelial Na+ channel blocker,amiloride. The effect of MP on ZO-1 and ZO-2 was mimicked by Ligustrazine and the ligustrazine-induced ISC was also blocked by basolateral application of bumetanide and apical addition of diphenylamine-2, 2'-dicarboxylic acid or glibenclamide, and reduced by a removal of extracellular Cl-.CONCLUSION: The results of the present study suggest that MP and lligustrazine may improve epithelial barrier function and exert a stimulatory effect on colonic anion secretion, indicating the potential use of MP and its active ingredients

  7. [The role of calpains in the regulation of synaptic function].

    Science.gov (United States)

    Karpenko, M N; Tikhomirova, M S

    2014-04-01

    Calpains are calcium-activated neutral cysteine proteases, involved in the regulation of a number of physiological functions. Substrates of calpains include receptors, kinases, phosphatases, cytoskeleton and synaptosomal proteins. Some of them undergo complete degradation, though most of the substrates are subjected to limited proteolysis, which results in proteins having new properties. In the following review, we discuss involvement of calpains in the regulation of synapse structure and function. Namely, calpains participate in the regulation of synthesis, release and reuptake of neurotransmitters, modulation of receptors, stabilization or destabilization of the neuronal cytoskeleton. However, uncontrolled hyperactivation of calpains leads to dysregulation of these processes causing neuronal death.

  8. The functional modulation of epigenetic regulators by alternative splicing

    Directory of Open Access Journals (Sweden)

    Martínez-Balbás Marian

    2007-07-01

    Full Text Available Abstract Background Epigenetic regulators (histone acetyltransferases, methyltransferases, chromatin-remodelling enzymes, etc play a fundamental role in the control of gene expression by modifying the local state of chromatin. However, due to their recent discovery, little is yet known about their own regulation. This paper addresses this point, focusing on alternative splicing regulation, a mechanism already known to play an important role in other protein families, e.g. transcription factors, membrane receptors, etc. Results To this end, we compiled the data available on the presence/absence of alternative splicing for a set of 160 different epigenetic regulators, taking advantage of the relatively large amount of unexplored data on alternative splicing available in public databases. We found that 49 % (70 % in human of these genes express more than one transcript. We then studied their alternative splicing patterns, focusing on those changes affecting the enzyme's domain composition. In general, we found that these sequence changes correspond to different mechanisms, either repressing the enzyme's function (e.g. by creating dominant-negative inhibitors of the functional isoform or creating isoforms with new functions. Conclusion We conclude that alternative splicing of epigenetic regulators can be an important tool for the function modulation of these enzymes. Considering that the latter control the transcriptional state of large sets of genes, we propose that epigenetic regulation of gene expression is itself strongly regulated by alternative splicing.

  9. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA

    NARCIS (Netherlands)

    Bartels, A. L.; Willemsen, A. T. M.; Kortekaas, R.; de Jong, B. M.; de Vries, R.; de Klerk, O.; van Oostrom, J. C. H.; Portman, A.; Leenders, K. L.

    2008-01-01

    Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function

  10. Effects of Ambient Air Particulate Exposure on Blood-Gas Barrier Permeability and Lung Function

    DEFF Research Database (Denmark)

    Bräuner, Elvira Vaclavik; Mortensen, Jann; Møller, Peter

    2009-01-01

    Particulate air pollution is associated with increased risk of pulmonary diseases and detrimental outcomes related to the cardiovascular system, including altered vessel functions. This study's objective was too evaluate the effects of ambient particle exposure on the blood-gas permeability, lung.......5-15.8 microg/m(3) PM(10-2.5)) or filtered (91-542 particles/cm(3)) air collected above a busy street. The clearance rate of aerosolized (99m)Tc-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) was measured as an index for the alveolar epithelial membrane integrity and permeability of the lung blood...... on the concentration of CC16 in plasma and urine or on the static and dynamic volumes or ventilation distribution of the lungs. The study thus demonstrates increased permeability of the alveolar blood-gas barrier following moderate exercise, whereas exposure to ambient levels of urban air particles has no detectable...

  11. Changes in blood-brain barrier function modify the neuroendocrine response to circulating substances.

    Science.gov (United States)

    Jezová, D; Johansson, B B; Oprsalová, Z; Vigas, M

    1989-04-01

    It is known that various experimental, pathological and even physiological situations may be accompanied by transient increases in blood-brain barrier (BBB) permeability. The hypothesis that under such conditions the blood-borne substances can reach the active sites in the brain in concentrations high enough to influence central control of hormone release was verified in these studies. A suitable experimental model of BBB opening by protamine sulfate administration in conscious rats was introduced. Using this model it was shown that the dopaminergic blocker domperidone inhibited apomorphine-induced ACTH release if permeability of the BBB was increased, but not under normal conditions. It is suggested that the changes in BBB function can modify the neuroendocrine response also to other circulating substances and this may be an important, until now unconsidered phenomenon in neuroendocrine research.

  12. Adaptive Neural Network Control of a Marine Vessel With Constraints Using the Asymmetric Barrier Lyapunov Function.

    Science.gov (United States)

    He, Wei; Yin, Zhao; Sun, Changyin

    2016-05-11

    In this paper, we consider the trajectory tracking of a marine surface vessel in the presence of output constraints and uncertainties. An asymmetric barrier Lyapunov function is employed to cope with the output constraints. To handle the system uncertainties, we apply adaptive neural networks to approximate the unknown model parameters of a vessel. Both full state feedback control and output feedback control are proposed in this paper. The state feedback control law is designed by using the Moore-Penrose pseudoinverse in case that all states are known, and the output feedback control is designed using a high-gain observer. Under the proposed method the controller is able to achieve the constrained output. Meanwhile, the signals of the closed loop system are semiglobally uniformly bounded. Finally, numerical simulations are carried out to verify the feasibility of the proposed controller.

  13. Electron energy distribution functions for modelling the plasma kinetics in dielectric barrier discharges

    Energy Technology Data Exchange (ETDEWEB)

    Carman, R.J. [Department of Physics, Division of Information and Communications Sciences, Macquarie University, Sydney, NSW (Australia)). E-mail: rcarman@physics.mq.edu.au; Mildren, R.P. [Centre for Lasers and Applications, Division of Information and Communications Sciences, Macquarie University, Sydney, NSW (Australia)

    2000-10-07

    In modelling the plasma kinetics in dielectric barrier discharges (DBDs), the electron energy conservation equation is often included in the rate equation analysis (rather than utilizing the local-field approximation) with the assumption that the electron energy distribution function (EEDF) has a Maxwellian profile. We show that adopting a Maxwellian EEDF leads to a serious overestimate of the calculated ionization/excitation rate coefficients and the electron mobility for typical plasma conditions in a xenon DBD. Alternative EEDF profiles are trialed (Druyvesteyn, bi-Maxwellian and bi-Druyvesteyn) and benchmarked against EEDFs obtained from solving the steady-state Boltzmann equation. A bi-Druyvesteyn EEDF is shown to be more inherently accurate for modelling simulations of xenon DBDs. (author)

  14. Effect of Alemtuzumab on Intestinal Intraepithelial Lymphocytes and Intestinal Barrier Function in Cynomolgus Model

    Institute of Scientific and Technical Information of China (English)

    Lin-Lin Qu; Ya-Qing Lyu; Hai-Tao Jiang; Ting Shan; Jing-Bin Zhang; Qiu-Rong Li; Jie-Shou Li

    2015-01-01

    Background:Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia).However,serious infectious complications frequently occur after treatment.The reason for increased infections postalemtuzumab treatment is unknown at this stage.We explore the effect ofalemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.Methods:Twelve male cynomolguses were randomly assigned to either a treatment or control group.The treatment group received alemtuzumab (3 mg/kg,intravenous injection) while the control group received the same volume of physiological saline.Intestinal IELs were isolated from the control group and the treatment group (on day 9,35,and 70 after treatment) for counting and flow cytometric analysis.Moreover,intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.Results:The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 x 108 and 1.35 ± 0.09 × 108,respectively; P < 0.05) and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.In addition,the proportion ofapoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42,respectively; P < 0.05).Moreover,the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.Conclusions:Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model.The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment.Notably,intestinal barrier function may be disrupted after alemtuzumab treatment.

  15. Effect of Alemtuzumab on Intestinal Intraepithelial Lymphocytes and Intestinal Barrier Function in Cynomolgus Model

    Directory of Open Access Journals (Sweden)

    Lin-Lin Qu

    2015-01-01

    Full Text Available Background: Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia. However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment. Methods: Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay. Results: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05 and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05. Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment. Conclusions: Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after

  16. Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice

    Institute of Scientific and Technical Information of China (English)

    Yu-Kun Zhou; Huan-Long Qin; Ming Zhang; Tong-Yi Shen; Hong-Qi Chen; Yan-Lei Ma; Zhao-Xin Chu

    2012-01-01

    AIM:To investigate the mechanisms of Lactobacillus plantarum (L.plantarum) action on gut barrier in preoperative and postoperative experimental obstructive jaundice in rats.METHODS:Forty rats were randomly divided into groups of sham-operation,bile duct ligation (BDL),BDL + L.plantarum,BDL + internal biliary drainage (IBD),and BDL + IBD + L.plantarum.Ten days after L,plantarum administration,blood and ileal samples were collected from the rats for morphological examination,and intestinal barrier function,liver function,intestinal oxidative stress and protein kinase C (PKC) activity measurement.The distribution and expression of the PKC and tight junction (TJ) proteins,such as occludin,zonula occludens-1,claudin-1,claudin-4,junction adhesion molecule-A and F-actin,were examined by confocal laser scanning microscopy,immunohistochemistry,Western blotting,real-time fluorescent quantitative polymerase chain reaction assay.RESULTS:L.plantarum administration substantially restored gut barrier,decreased enterocyte apoptosis,improved intestinal oxidative stress,promoted the activity and expression of protein kinase (BDL vs BDL + L.plantarum,0.295 ± 0.007 vs 0.349 ± 0.003,P < 0.05;BDL + IBD vs BDL + IBD + L.plantarum,0.407 ± 0.046 vs 0.465 ± 0.135,P < 0.05),and particularly enhanced the expression and phosphorylation of TJ proteins in the experimental obstructive jaundice (BDL vs BDL + L.plantarum,0.266 ± 0.118 vs 0.326 ± 0.009,P < 0.05).The protective effect of L.plantarum was more prominent after internal biliary drainage (BDL + IBD vs BDL + IBD + L.plantarum,0.415 ± 0.105 vS 0.494 ± 0.145,P < 0.05).CONCLUSION:L.plantarum can decrease intestinal epithelial cell apoptosis,reduce oxidative stress,and prevent TJ disruption in biliary obstruction by activating the PKC pathway.

  17. Beating oscillation and Fano resonance in the laser assisted electron transmission through graphene δ-function magnetic barriers

    Science.gov (United States)

    Biswas, R.; Maity, S.; Sinha, C.

    2016-10-01

    We investigate theoretically the transmission of electrons through a pair of δ-function magnetic barriers in graphene in presence of external monochromatic, linearly polarized and CW laser field. The transmission coefficients are calculated in the framework of non-perturbative Floquet theory using the transfer matrix method. It is noted that the usual Fabry-Perot oscillations in transmission through the graphene magnetic barriers with larger inter barrier separation takes the shape of beating oscillations in presence of the external laser field. The laser assisted transmission spectra are also found to exhibit the characteristic Fano resonances (FR) for smaller values of the inter barrier separation. The appearance of the perfect node in the beating oscillation and the asymmetric Fano line shape can be controlled by varying the intensity of the laser field. The above features could provide some useful and potential information about the light - matter interactions and may be utilized in the graphene based optoelectronic device applications.

  18. Peroxiredoxins in Regulation of MAPK Signalling Pathways; Sensors and Barriers to Signal Transduction

    Science.gov (United States)

    Latimer, Heather R.; Veal, Elizabeth A.

    2016-01-01

    Peroxiredoxins are highly conserved and abundant peroxidases. Although the thioredoxin peroxidase activity of peroxiredoxin (Prx) is important to maintain low levels of endogenous hydrogen peroxide, Prx have also been shown to promote hydrogen peroxide-mediated signalling. Mitogen activated protein kinase (MAPK) signalling pathways mediate cellular responses to a variety of stimuli, including reactive oxygen species (ROS). Here we review the evidence that Prx can act as both sensors and barriers to the activation of MAPK and discuss the underlying mechanisms involved, focusing in particular on the relationship with thioredoxin. PMID:26813660

  19. Alterations of intestinal mucosa structure and barrier function following traumatic brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    Chun-Hua Hang; Ji-Xin Shi; Jie-Shou Li; Wei Wu; Hong-Xia Yin

    2003-01-01

    AIM: Gastrointestinal dysfunction is a common complication in patients with traumatic brain injury (TBI). However, the effect of traumatic brain injury on intestinal mucosa has not been studied previously. The aim of the current study was to explore the alterations of intestinal mucosa morphology and barrier function, and to determine how rapidly the impairment of gut barrier function occurs and how long it persists following traumatic brain injury.METHODS: Male Wistar rats were randomly divided into six groups (6 rats each group) including controls without brain injury and traumatic brain injury groups at hours 3,12, 24, and 72, and on day 7. The intestinal mucosa structure was detected by histopathological examination and electron microscopy. Gut barrier dysfunction was evaluated by detecting serum endotoxin and intestinal permeability. The level of serum endotoxin and intestinal permeability was measured by using chromogenic limulus amebocyte lysate and lactulose/mannitol (L/M) ratio, respectively.RESULTS: After traumatic brain injury, the histopathological alterations of gut mucosa occurred rapidly as early as 3 hours and progressed to a serious state, including shedding of epithelial cells, fracture of villi, focal ulcer, fusion of adjacent villi, dilation of central chyle duct, mucosal atrophy,and vascular dilation, congestion and edema in the villous interstitium and lamina propria. Apoptosis of epithelial cells,fracture and sparseness of microvilli, loss of tight junction between enterocytes, damage of mitochondria and endoplasm, were found by electron microscopy. The villous height, crypt depth and surface area in jejunum decreased progressively with the time of brain injury. As compared with that of control group (183.7±41.8 EU/L), serum endotoxin level was signnificantly increased at 3, 12, and 24 hours following TBI (434.8±54.9 EU/L, 324.2±61.7 EU/L and 303.3±60.2 EU/L, respectively), and peaked at 72 hours (560.5±76.2 EU/L), then declined on day 7

  20. The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression.

    Science.gov (United States)

    de Bruin, Ruben G; van der Veer, Eric P; Prins, Jurriën; Lee, Dae Hyun; Dane, Martijn J C; Zhang, Huayu; Roeten, Marko K; Bijkerk, Roel; de Boer, Hetty C; Rabelink, Ton J; van Zonneveld, Anton Jan; van Gils, Janine M

    2016-02-24

    Proper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis, and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells, and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3'UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity.

  1. Serum response factor controls transcriptional network regulating epidermal function and hair follicle morphogenesis.

    Science.gov (United States)

    Lin, Congxing; Hindes, Anna; Burns, Carole J; Koppel, Aaron C; Kiss, Alexi; Yin, Yan; Ma, Liang; Blumenberg, Miroslav; Khnykin, Denis; Jahnsen, Frode L; Crosby, Seth D; Ramanan, Narendrakumar; Efimova, Tatiana

    2013-03-01

    Serum response factor (SRF) is a transcription factor that regulates the expression of growth-related immediate-early, cytoskeletal, and muscle-specific genes to control growth, differentiation, and cytoskeletal integrity in different cell types. To investigate the role for SRF in epidermal development and homeostasis, we conditionally knocked out SRF in epidermal keratinocytes. We report that SRF deletion disrupted epidermal barrier function leading to early postnatal lethality. Mice lacking SRF in epidermis displayed morphogenetic defects, including an eye-open-at-birth phenotype and lack of whiskers. SRF-null skin exhibited abnormal morphology, hyperplasia, aberrant expression of differentiation markers and transcriptional regulators, anomalous actin organization, enhanced inflammation, and retarded hair follicle (HF) development. Transcriptional profiling experiments uncovered profound molecular changes in SRF-null E17.5 epidermis and revealed that many previously identified SRF target CArG box-containing genes were markedly upregulated in SRF-null epidermis, indicating that SRF may function to repress transcription of a subset of its target genes in epidermis. Remarkably, when transplanted onto nude mice, engrafted SRF-null skin lacked hair but displayed normal epidermal architecture with proper expression of differentiation markers, suggesting that although keratinocyte SRF is essential for HF development, a cross-talk between SRF-null keratinocytes and the surrounding microenvironment is likely responsible for the barrier-deficient mutant epidermal phenotype.

  2. Cost benefit theory and optimal design of gene regulation functions

    Science.gov (United States)

    Kalisky, Tomer; Dekel, Erez; Alon, Uri

    2007-12-01

    Cells respond to the environment by regulating the expression of genes according to environmental signals. The relation between the input signal level and the expression of the gene is called the gene regulation function. It is of interest to understand the shape of a gene regulation function in terms of the environment in which it has evolved and the basic constraints of biological systems. Here we address this by presenting a cost-benefit theory for gene regulation functions that takes into account temporally varying inputs in the environment and stochastic noise in the biological components. We apply this theory to the well-studied lac operon of E. coli. The present theory explains the shape of this regulation function in terms of temporal variation of the input signals, and of minimizing the deleterious effect of cell-cell variability in regulatory protein levels. We also apply the theory to understand the evolutionary tradeoffs in setting the number of regulatory proteins and for selection of feed-forward loops in genetic circuits. The present cost-benefit theory can be used to understand the shape of other gene regulatory functions in terms of environment and noise constraints.

  3. Regulation, Signaling, and Physiological Functions of G-Proteins.

    Science.gov (United States)

    Syrovatkina, Viktoriya; Alegre, Kamela O; Dey, Raja; Huang, Xin-Yun

    2016-09-25

    Heterotrimeric guanine-nucleotide-binding regulatory proteins (G-proteins) mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review, we briefly summarize what is known about the regulation, signaling, and physiological functions of G-proteins. We then focus on a few less explored areas such as the regulation of G-proteins by non-GPCRs and the physiological functions of G-proteins that cannot be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated and of the specificity of G-protein interactions with their regulators.

  4. Hydration effects on the barrier function of stratum corneum lipids: Raman analysis of ceramides 2, III and 5.

    Science.gov (United States)

    Tfayli, Ali; Jamal, Dima; Vyumvuhore, Raoul; Manfait, Michel; Baillet-Guffroy, Arlette

    2013-11-07

    The stratum corneum is the outermost layer of the skin; its barrier function is highly dependent on the composition and the structure as well as the organization of lipids in its extracellular matrix. Ceramides, free fatty acids and cholesterol represent the major lipid classes present in this matrix. They play an important role in maintaining the normal hydration levels required for the normal physiological function. Despite the advancement in the understanding of the structure, composition and the function of the stratum corneum (SC), the concern of "dry skin" remains important in dermatology and care research. Most studies focus on the quantification of water in the skin using different techniques including Raman spectroscopy, while the studies that investigate the effect of hydration on the quality of the barrier function of the skin are limited. Raman spectroscopy provides structural, conformational and organizational information that could help elucidate the effect of hydration on the barrier function of the skin. In order to assess the effect of relative humidity on the lipid barrier function; we used Raman spectroscopy to follow-up the evolution of the conformation and the organization of three synthetic ceramides (CER) differing from each other by the nature of their polar heads (sphingosine, phytosphingosine and α hydroxyl sphingosine), CER 2, III and 5 respectively. CER III and 5 showed a more compact and ordered organization with stronger polar interactions at intermediate relative humidity values, while CER 2 showed opposite tendencies to those observed with CER III and 5.

  5. Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

    OpenAIRE

    2014-01-01

    “Fetal programming” is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal develo...

  6. Administration of sesamol improved blood-brain barrier function in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    VanGilder, R L; Kelly, K A; Chua, M D; Ptachcinski, R L; Huber, Jason D

    2009-07-01

    Uncontrolled or poorly controlled blood glucose during diabetes is an important factor in worsened vascular function. While evidence suggests that hyperglycemia-induced oxidative stress plays a prominent role in development of microangiopathy of the retina, kidney, and nerves, the role oxidative stress plays on blood-brain barrier (BBB) function and structure has lagged behind. In this study, a natural antioxidant, sesamol, was administered to streptozotocin (STZ)-induced diabetic rats to examine the role that oxidative stress plays on BBB structure and function. Experiments were conducted at 56 days after STZ injection. Male Sprague-Dawley rats randomly were divided into four treatment groups CON--control; STZ--STZ-induced diabetes; CON + S--control + sesamol; STZ + S--STZ-induced diabetes + sesamol. Functional and structural changes to the BBB were measured by in situ brain perfusion and western blot analysis of changes in tight junction protein expression. Oxidative stress markers were visualized by fluorescent confocal microscopy and assayed by spectrophotometric analysis. Results demonstrated that the increased BBB permeability observed in STZ-induced diabetic rats was attenuated in STZ + S rats to levels observed in CON. Sesamol treatment reduced the negative impact of STZ-induced diabetes on tight junction protein expression in isolated cerebral microvessels. Oxidative stress markers were elevated in STZ as compared to CON. STZ + S displayed an improved antioxidant capacity which led to a reduced expression of superoxide and peroxynitrite and reduced lipid peroxidation. In conclusion, this study showed that sesamol treatment enhanced antioxidant capacity of the diabetic brain and led to decreased perturbation of hyperglycemia-induced changes in BBB structure and function.

  7. The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling

    Directory of Open Access Journals (Sweden)

    Hiroshi Tanaka

    2017-02-01

    Full Text Available Cellular senescence is an irreversible growth arrest that contributes to development, tumor suppression, and age-related conditions. Senescent cells show active metabolism compared with proliferating cells, but the underlying mechanisms remain unclear. Here we show that the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1, suppresses nucleolar and mitochondrial activities to prevent cellular senescence. SETD8 protein was selectively downregulated in both oncogene-induced and replicative senescence. Inhibition of SETD8 alone was sufficient to trigger senescence. Under these states, the expression of genes encoding ribosomal proteins (RPs and ribosomal RNAs as well as the cyclin-dependent kinase (CDK inhibitor p16INK4A was increased, with a corresponding reduction of H4K20me1 at each locus. As a result, the loss of SETD8 concurrently stimulated nucleolar function and retinoblastoma protein-mediated mitochondrial metabolism. In conclusion, our data demonstrate that SETD8 acts as a barrier to prevent cellular senescence through chromatin-mediated regulation of senescence-associated metabolic remodeling.

  8. Basic and clinical research on the regulation of the intestinal barrier by Lactobacillus and its active protein components: a review with experience of one center.

    Science.gov (United States)

    Liu, Zhi-Hua; Kang, Liang; Wang, Jian-Ping

    2014-12-01

    Probiotics got protective effects on the intestinal barrier. Our present study is to review the basic and clinical progress on the regulation of the intestinal barrier by Lactobacillus and its active protein components, combing the study of our center. Our study have isolated the active component of micro integral membrane protein (MIMP) within the media place of the integral membrane protein of Lactobacillus plantarum, which was verified about the protective effects against the intestinal epithelial dysfunction. On the other hand, we also found the effects of perioperative use of probiotics in the prevention and treatment of postoperative intestinal barrier dysfunction, and reduction of the postoperative infective complications. In this review, we would like to report the founding of our center, involving in the basic and clinical research progress of regulation of intestinal barrier by Lactobacillus and its active protein component MIMP. Furthermore, we may also promote our following studies about the MIMP and its clinical verification.

  9. Salvianolic Acid B Restored Impaired Barrier Function via Downregulation of MLCK by microRNA-1 in Rat Colitis Model.

    Science.gov (United States)

    Xiong, Yongjian; Wang, Jingyu; Chu, Hongwei; Chen, Dapeng; Guo, Huishu

    2016-01-01

    Salvianolic acid B (Sal B) is isolated from the traditional Chinese medical herb Salvia miltiorrhiza and is reported to have a wide range of therapeutic benefits. The aim of this study was to investigate the effects of Sal B on epithelial barrier dysfunction in rat colitis and to uncover related mechanisms. Rat colitis model was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The intestinal barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in vitro respectively. The protein expression related to intestinal barrier function was studied using western blotting. The effects of Sal B on inflammatory responses, oxidative damage and colitis recurrence were also studied in this study. The intestinal barrier dysfunction in colitis was reversed by Sal B, accompanied with the decrease of tight junction proteins, and the effect could be blocked by microRNA-1(miR-1) inhibition. The inflammatory responses, oxidative damage and colitis recurrence were also decreased by Sal B. The colitis symptoms and recurrences were ameliorated by Sal B, and restoration of impaired barrier function via downregulation of MLCK by miR-1 maybe involved in this effect. This study provides some novel insights into both of the pathological mechanisms and treatment alternatives of inflammatory bowel disease.

  10. Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.

    Science.gov (United States)

    Keszthelyi, D; Troost, F J; Jonkers, D M; van Eijk, H M; Lindsey, P J; Dekker, J; Buurman, W A; Masclee, A A M

    2014-08-01

    Alterations in serotonergic (5-HT) metabolism and/or intestinal integrity have been associated with irritable bowel syndrome (IBS). To assess the effects of the precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on mucosal 5-HT availability and intestinal integrity, and to assess potential differences between healthy controls and IBS patients. Fifteen IBS patients and 15 healthy volunteers participated in this randomised double-blind placebo-controlled study. Intestinal integrity was assessed by dual-sugar test and by determining the mucosal expression of tight junction proteins after ingestion of an oral bolus of 100 mg 5-HTP or placebo. Mucosal serotonergic metabolism was assessed in duodenal biopsy samples. 5-HTP administration significantly increased mucosal levels of 5-HIAA, the main metabolite of 5-HT, in both healthy controls (7.1 ± 1.7 vs. 2.5 ± 0.7 pmol/mg, 5-HTP vs. placebo, P = 0.02) and IBS patients (20.0 ± 4.8 vs. 8.1 ± 1.3 pmol/mg, 5-HTP vs. placebo, P = 0.02), with the latter group showing a significantly larger increase. Lactulose/L-rhamnose ratios were significantly lower after administration of 5-HTP (P HTP resulted in a further decrease in occludin expression. Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients. © 2014 John Wiley & Sons Ltd.

  11. Novel Functionally Graded Thermal Barrier Coatings in Coal-Fired Power Plant Turbines

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jing [Indiana Univ., Indianapolis, IN (United States)

    2016-11-01

    This project presents a detailed investigation of a novel functionally graded coating material, pyrochlore oxide, for thermal barrier coating (TBC) in gas turbines used in coal-fired power plants. Thermal barrier coatings are refractory materials deposited on gas turbine components, which provide thermal protection for metallic components at operating conditions. The ultimate goal of this research is to develop a manufacturing process to produce the novel low thermal conductivity and high thermal stability pyrochlore oxide based coatings with improved high-temperature durability. The current standard TBC, yttria stabilized zirconia (YSZ), has service temperatures limited to <1200°C, due to sintering and phase transition at higher temperatures. In contrast, pyrochlore oxide, e.g., lanthanum zirconate (La2Zr2O7, LZ), has demonstrated lower thermal conductivity and better thermal stability, which are crucial to high temperature applications, such as gas turbines used in coal-fired power plants. Indiana University – Purdue University Indianapolis (IUPUI) has collaborated with Praxair Surface Technologies (PST), and Changwon National University in South Korea to perform the proposed research. The research findings are critical to the extension of current TBCs to a broader range of high-temperature materials and applications. Several tasks were originally proposed and accomplished, with additional new opportunities identified during the course of the project. In this report, a description of the project tasks, the main findings and conclusions are given. A list of publications and presentations resulted from this research is listed in the Appendix at the end of the report.

  12. Regulated competition in health care: Switching and barriers to switching in the Dutch health insurance system

    Directory of Open Access Journals (Sweden)

    Rijken Mieke

    2011-05-01

    Full Text Available Abstract Background In 2006, a number of changes in the Dutch health insurance system came into effect. In this new system mobility of insured is important. The idea is that insured switch insurers because they are not satisfied with quality of care and the premium of their insurance. As a result, insurers will in theory strive for a better balance between price and quality. The Dutch changes have caught the attention, internationally, of both policy makers and researchers. In our study we examined switching behaviour over three years (2007-2009. We tested if there are differences in the numbers of switchers between groups defined by socio-demographic and health characteristics and between the general population and people with chronic illness or disability. We also looked at reasons for (not-switching and at perceived barriers to switching. Methods Switching behaviour and reasons for (not-switching were measured over three years (2007-2009 by sending postal questionnaires to members of the Dutch Health Care Consumer Panel and of the National Panel of people with Chronic illness or Disability. Data were available for each year and for each panel for at least 1896 respondents - a response of between 71% and 88%. Results The percentages of switchers are low; 6% in 2007, 4% in 2008 and 3% in 2009. Younger and higher educated people switch more often than older and lower educated people and women switch more often than men. There is no difference in the percentage of switchers between the general population and people with chronic illness or disability. People with a bad self-perceived health, and chronically ill and disabled, perceive more barriers to switching than others. Conclusion The percentages of switchers are comparable to the old system. Switching is not based on quality of care and thus it can be questioned whether it will lead to a better balance between price and quality. Although there is no difference in the frequency of switching

  13. Is peripheral immunity regulated by blood-brain barrier permeability changes?

    Directory of Open Access Journals (Sweden)

    Erin Bargerstock

    Full Text Available S100B is a reporter of blood-brain barrier (BBB integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD. Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient. After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc. and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.

  14. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease.

    Science.gov (United States)

    Williams, Benjamin B; Tebbutt, Niall C; Buchert, Michael; Putoczki, Tracy L; Doggett, Karen; Bao, Shisan; Johnstone, Cameron N; Masson, Frederick; Hollande, Frederic; Burgess, Antony W; Scott, Andrew M; Ernst, Matthias; Heath, Joan K

    2015-08-01

    The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33(-/-) mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33(-/-) mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33(-/-) mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33(-/-) mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33(-/-) mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33(-/-) mice provide a valuable model to study the mechanisms linking intestinal

  15. Protection of human corneal epithelial cells from TNF-α-induced disruption of barrier function by rebamipide.

    Science.gov (United States)

    Kimura, Kazuhiro; Morita, Yukiko; Orita, Tomoko; Haruta, Junpei; Takeji, Yasuhiro; Sonoda, Koh-Hei

    2013-04-17

    TNF-α disrupts the barrier function of cultured human corneal epithelial (HCE) cells. We investigated the effects of the cytoprotective drug rebamipide on this barrier disruption by TNF-α as well as on corneal epithelial damage in a rat model of dry eye. The barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance. The distribution of tight-junction (ZO-1, occludin) and adherens-junction (E-cadherin, β-catenin) proteins, and the p65 subunit of nuclear factor-κB (NF-κB) was determined by immunofluorescence microscopy. Expression of junctional proteins as well as phosphorylation of the NF-κB inhibitor IκB-α and myosin light chain (MLC) were examined by immunoblot analysis. A rat model of dry eye was developed by surgical removal of exorbital lacrimal glands. Rebamipide inhibited the disruption of barrier function as well as the downregulation of ZO-1 expression, and the disappearance of ZO-1 from the interfaces of neighboring HCE cells induced by TNF-α. It also inhibited the phosphorylation and downregulation of IκB-α, the translocation of p65 to the nucleus, the formation of actin stress fibers, and the phosphorylation of MLC induced by TNF-α in HCE cells. Treatment with rebamipide eyedrops promoted the healing of corneal epithelial defects as well as attenuated the loss of ZO-1 from the surface of corneal epithelial cells in rats. Rebamipide protects corneal epithelial cells from the TNF-α-induced disruption of barrier function by maintaining the distribution and expression of ZO-1 as well as the organization of the actin cytoskeleton. Rebamipide is, thus, a potential drug for preventing or ameliorating the loss of corneal epithelial barrier function associated with ocular inflammation.

  16. Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function

    OpenAIRE

    Boer, Magdalena; Duchnik, Ewa; Maleszka, Romuald; Marchlewicz, Mariola

    2016-01-01

    The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part – stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transep...

  17. Filaggrin in the frontline: role in skin barrier function and disease.

    Science.gov (United States)

    Sandilands, Aileen; Sutherland, Calum; Irvine, Alan D; McLean, W H Irwin

    2009-05-01

    Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the approximately 400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.

  18. Oxygen functionalization of MWCNTs in RF-dielectric barrier discharge Ar/O2 plasma

    Science.gov (United States)

    Abdel-Fattah, E.; Ogawa, D.; Nakamura, K.

    2017-07-01

    The oxygenation of multi-wall carbon nanotubes (MWCNTs) was performed via a radio frequency dielectric barrier discharge (RF-DBD) in an Ar/{{\\text{H}}2}\\text{O} plasma mixture. The relative intensity of the Ar/{{\\text{O}}2} plasma species was characterized by optical emission spectroscopy (OES). The effects of treatment time, RF power and oxygen gas percentage on the chemical composition and surface morphology of MWCNTs were investigated by means of x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and field emission scanning electron microscopy (FE-SEM). The results of FTIR and XPS revealed the presence of oxygen-containing functional groups on the MWCNTs treated in an Ar/{{\\text{O}}2} plasma at an RF power of 50 W and pressure of 400 Pa. The amount of oxygen functional groups (C=O, C-O, and O-COO) also increased by increasing treatment time up to 6 min, but slightly decreased when treatment time was increased by 10 min. The increase of oxygen gas percentage in the plasma mixture does not affect the oxygen content in the treated MWCNTs. Meanwhile, MWCNTs treated at high power (80 W) showed a reduction in oxygen functional groups in comparison with low RF power conditions. The Raman analysis was consistent with the XPS and FTIR results. The integrity of the nanotube patterns also remained damaged as observed by FE-SEM images. The MWCNTs treated in RF-DBD using the Ar/{{\\text{O}}2} plasma mixture showed improved dispersibility in deionized water. A correlation between the OES data and the observed surface characterization for an improved understanding of the functionalization of MWCNTs in Ar/{{\\text{O}}2} plasma was presented.

  19. Anesthesia and Surgery Impair Blood–Brain Barrier and Cognitive Function in Mice

    Directory of Open Access Journals (Sweden)

    Siming Yang

    2017-08-01

    Full Text Available Blood–brain barrier (BBB dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy under 1.4% isoflurane anesthesia (anesthesia/surgery for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification, and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of β-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age-associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium.

  20. The distinctive role of executive functions in implicit emotion regulation.

    Science.gov (United States)

    Sperduti, Marco; Makowski, Dominique; Arcangeli, Margherita; Wantzen, Prany; Zalla, Tiziana; Lemaire, Stéphane; Dokic, Jérôme; Pelletier, Jérôme; Piolino, Pascale

    2017-02-01

    Several theoretical models stress the role of executive functions in emotion regulation (ER). However, most of the previous studies on ER employed explicit regulatory strategies that could have engaged executive functions, beyond regulatory processes per se. Recently, there has been renewed interest in implicit forms of ER, believed to be closer to daily-life requirements. While various studies have shown that implicit and explicit ER engage partially overlapping neurocognitive processes, the contribution of different executive functions in implicit ER has not been investigated. In the present study, we presented participants with negatively valenced pictures of varying emotional intensity preceded by short texts describing them as either fictional or real. This manipulation was meant to induce a spontaneous emotional down-regulation. We recorded electrodermal activity (EDA) and subjective reports of emotion arousal. Executive functions (updating, switching, and inhibition) were also assessed. No difference was found between the fictional and real condition on EDA. A diminished self-reported arousal was observed, however, when pictures were described as fictional for high- and mild-intensity material, but not for neutral material. The amount of down-regulation in the fictional condition was found to be predicted by interindividual variability in updating performances, but not by the other measures of executive functions, suggesting its implication even in implicit forms of ER. The relationship between down-regulation and updating was significant only for high-intensity material. We discuss the role of updating in relation to the consciousness of one's emotional state.

  1. Claudin-5 regulates blood-brain barrier permeability by modifying brain microvascular endothelial cell proliferation, migration, and adhesion to prevent lung cancer metastasis.

    Science.gov (United States)

    Ma, Shun-Chang; Li, Qi; Peng, Jia-Yi; Zhouwen, Jian-Long; Diao, Jin-Fu; Niu, Jian-Xing; Wang, Xi; Guan, Xiu-Dong; Jia, Wang; Jiang, Wen-Guo

    2017-09-29

    To investigate the roles of Claudin-5 (CLDN5) in regulating the permeability of the blood-brain barrier (BBB) during lung cancer brain metastasis. By silencing and overexpressing the CLDN5 gene in human brain vascular endothelial (hCMEC/D3) cells, we demonstrated the attenuation of cell migration ability and CLDN5's significant positive role in cell proliferation in CLDN5-overexpressing hCMEC/D3 cells and observed the opposite result in the CLDN5 knockdown group. The reinforced CLDN5 expression reduced the paracellular permeability of hCMEC/D3 cells and decreased the invasion of lung adenocarcinoma A549 cells. Overall, 1685 genes were found to be differentially expressed between the CLDN5-overexpressing cells and the control cells using the Affymetrix Human Transcriptome Array 2.0 (HTA 2.0), and the function of these genes was determined by Gene Ontology and pathway analyses. The possible biological functions of the 1685 genes include cell proliferation, adhesion molecules, and the Jak-STAT, PI3K-Akt, Wnt, and Notch signaling pathways. The identified sets of mRNAs that were specific to CLDN5-overexpressing hCMEC/D3 cells were verified by a qRT-PCR experiment. CLDN5 regulates the permeability of BBB by regulating the proliferation, migration, and permeability of hCMEC/D3 cells, especially through the cell adhesion molecule signaling pathway, to enhance the function of the tight junctions, which was involved in reducing the formation of lung cancer brain metastasis. © 2017 John Wiley & Sons Ltd.

  2. Modulating the skin barrier function by DMSO: molecular dynamics simulations of hydrophilic and hydrophobic transmembrane pores

    NARCIS (Netherlands)

    den Otter, Wouter K.; Notman, R.; Anwar, J.; Noro, M.G.; Briels, Willem J.

    2008-01-01

    The dense lipid bilayers at the outer surface of the skin represent the primary barrier to molecules penetrating the human skin. One approach to overcome this barrier, with promising applications in administering medicinal drugs to the body, is to employ chemical permeability enhancers. How these

  3. Modulating the skin barrier function by DMSO: molecular dynamics simulations of hydrophilic and hydrophobic transmembrane pores

    NARCIS (Netherlands)

    Otter, den W.K.; Notman, R.; Anwar, J.; Noro, M.G.; Briels, W.J.

    2008-01-01

    The dense lipid bilayers at the outer surface of the skin represent the primary barrier to molecules penetrating the human skin. One approach to overcome this barrier, with promising applications in administering medicinal drugs to the body, is to employ chemical permeability enhancers. How these en

  4. Modulating the skin barrier function by DMSO: molecular dynamics simulations of hydrophilic and hydrophobic transmembrane pores

    NARCIS (Netherlands)

    den Otter, Wouter K.; Notman, R.; Anwar, J.; Noro, M.G.; Briels, Willem J.

    2008-01-01

    The dense lipid bilayers at the outer surface of the skin represent the primary barrier to molecules penetrating the human skin. One approach to overcome this barrier, with promising applications in administering medicinal drugs to the body, is to employ chemical permeability enhancers. How these en

  5. Effect of adjuvant lactulose enema therapy on outcome and intestinal mucosal barrier function in patients with acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Ling Gao; Ming-Quan Li

    2016-01-01

    Objective:To analyze the effect of adjuvant lactulose enema therapy on outcome and intestinal mucosal barrier function in patients with acute pancreatitis.Methods: A total of 98 patients with acute pancreatitis were randomly divided into observation group and control group, control group received conventional symptomatic treatment, observation group received symptomatic treatment + adjuvant lactulose enema therapy, and differences in levels of inflammatory cytokines, RAAS system-related molecules and mucosal barrier function-related indexes in serum as well as intestinal flora quantity in stool samples were compared between two groups after treatment.Results:Serum inflammatory cytokines IL-1β, IL-6, IL-8, PCT and TNF-α levels of enema group were significantly lower than those of control group; serum RAAS system molecules R, AngI, AngII and ALD levels were significantly lower than those of control group; serum mucosal barrier function indexes D-lactate, LPS, I-FABP and DAO levels were significantly lower than those of control group; the quantity of bifidobacterium and lactobacillus in stool samples were significantly more than those of control group while the quantity of enterobacterium, enterococcus and E. coli were significantly lower than those of control group.Conclusion:Adjuvant lactulose enema therapy can promote the improvement of acute pancreatitis, and restore patients’ intestinal mucosal barrier function.

  6. Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro

    NARCIS (Netherlands)

    Buist, H.E.; Sandt, J.J.M. van de; Burgsteden, J.A. van; Heer, C. de

    2005-01-01

    The dermal route of exposure is important in worker exposure to biocidal products. Many biocidal active substances which are used on a daily basis may decrease the barrier function of the skin to a larger extent than current risk assessment practice addresses, due to possible skin effects of repeate

  7. Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro

    NARCIS (Netherlands)

    Buist, H.E.; Sandt, J.J.M. van de; Burgsteden, J.A. van; Heer, C. de

    2005-01-01

    The dermal route of exposure is important in worker exposure to biocidal products. Many biocidal active substances which are used on a daily basis may decrease the barrier function of the skin to a larger extent than current risk assessment practice addresses, due to possible skin effects of repeate

  8. New insights into transduction pathways that regulate boar sperm function.

    Science.gov (United States)

    Hurtado de Llera, A; Martin-Hidalgo, D; Gil, M C; Garcia-Marin, L J; Bragado, M J

    2016-01-01

    Detailed molecular mechanisms mediating signal transduction cascades that regulate boar sperm function involving Ser/Thr and tyrosine phosphorylation of proteins have been reviewed previously. Therefore, this review will focus in those kinase pathways identified recently (boar spermatozoa that regulate different functional spermatozoa processes. AMP-activated protein kinase (AMPK) is a cell energy sensor kinase that was first identified in mammalian spermatozoa in 2012, and since then it has emerged as an essential regulator of boar sperm function. Signaling pathways leading to AMPK activation in boar sperm are highlighted in this review (PKA, CaMKKα/β, and PKC as well as Ca(2+) and cAMP messengers as upstream regulators). Interestingly, stimuli considered as cell stress (hyperosmotic stress, inhibition of mitochondrial activity, absence of intracellular Ca(2+)) markedly activate AMPK in boar spermatozoa. Moreover, AMPK plays a remarkable and necessary regulatory role in mammalian sperm function, controlling essential boar sperm functional processes such as motility, viability, mitochondrial membrane potential, organization and fluidity of plasma membrane, and outer acrosome membrane integrity. These mentioned processes are all required under fluctuating environment of spermatozoa when transiting through the female reproductive tract to achieve fertilization. An applied role of AMPK in artificial insemination techniques is also suggested as during boar seminal doses preservation at 17 °C, physiological levels of AMPK activity markedly increase (maximum on Day 7) and result essential to maintain the aforementioned fundamental sperm processes. Moreover, regulation of sperm function exerted by the glycogen synthase kinase 3 and Src family kinase pathways is summarized.

  9. Maintaining the balance. Novel molecular mechanisms regulating Foxp3 function

    NARCIS (Netherlands)

    Fleskens, V.

    2014-01-01

    A balanced immune response requires tight control of immune activation at various levels, which crucially involves the establishment of specific gene expression programs by key transcriptional regulators including the transcription factor Foxp3. As the driving factor of both development and function

  10. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

    NARCIS (Netherlands)

    Mittag, J.; Lyons, D.J.; Sällström, J.; Vujoviv, M.; Dudazy-Gralla, S.; Warner, A.; Wallis, K.; Alkemade, A.; Nordström, K.; Monyer, H.; Broberger, C.; Arner, A.; Vennström, B.

    2013-01-01

    Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone’s

  11. Tropomyosin - master regulator of actin filament function in the cytoskeleton.

    Science.gov (United States)

    Gunning, Peter W; Hardeman, Edna C; Lappalainen, Pekka; Mulvihill, Daniel P

    2015-08-15

    Tropomyosin (Tpm) isoforms are the master regulators of the functions of individual actin filaments in fungi and metazoans. Tpms are coiled-coil parallel dimers that form a head-to-tail polymer along the length of actin filaments. Yeast only has two Tpm isoforms, whereas mammals have over 40. Each cytoskeletal actin filament contains a homopolymer of Tpm homodimers, resulting in a filament of uniform Tpm composition along its length. Evidence for this 'master regulator' role is based on four core sets of observation. First, spatially and functionally distinct actin filaments contain different Tpm isoforms, and recent data suggest that members of the formin family of actin filament nucleators can specify which Tpm isoform is added to the growing actin filament. Second, Tpms regulate whole-organism physiology in terms of morphogenesis, cell proliferation, vesicle trafficking, biomechanics, glucose metabolism and organ size in an isoform-specific manner. Third, Tpms achieve these functional outputs by regulating the interaction of actin filaments with myosin motors and actin-binding proteins in an isoform-specific manner. Last, the assembly of complex structures, such as stress fibers and podosomes involves the collaboration of multiple types of actin filament specified by their Tpm composition. This allows the cell to specify actin filament function in time and space by simply specifying their Tpm isoform composition.

  12. The effects of heat on skin barrier function and in vivo dermal absorption.

    Science.gov (United States)

    Oliveira, Gabriela; Leverett, Jesse C; Emamzadeh, Mandana; Lane, Majella E

    2014-04-10

    Enhanced delivery of ingredients across the stratum corneum (SC) is of great interest for improving the efficacy of topically applied formulations. Various methods for improving dermal penetration have been reported including galvanic devices and micro-needles. From a safety perspective it is important that such approaches do not compromise SC barrier function. This study investigates the influence of topically applied heat in vivo on the dermal uptake and penetration of a model active, allantoin from gel and lotion formulations. A custom designed device was used to deliver 42°C for 30s daily to human subjects after application of two formulations containing allantoin. The results were compared with sites treated with formulations containing no active and no heat, and a control site. In addition to penetration of allantoin, the integrity of the SC was monitored using trans-epidermal water loss (TEWL) measurements. The results showed that just 30s of 42°C topically applied heat was enough to cause significantly more penetration of allantoin from the lotion formulation compared with no application of heat. TEWL data indicated that the integrity of the skin was not compromised by the treatment. However, the application of heat did not promote enhanced penetration of the active from the gel formulation. Vehicle composition is therefore an important factor when considering thermal enhancement strategies for targeting actives to the skin.

  13. Entamoeba histolytica contains an occludin-like protein that can alter colonic epithelial barrier function.

    Science.gov (United States)

    Goplen, Michael; Lejeune, Manigandan; Cornick, Steve; Moreau, France; Chadee, Kris

    2013-01-01

    The exact mechanism by which Entamoeba histolytica disrupts the human colonic epithelium and invades the mucosa has yet to be clearly elucidated. E. histolytica produces a diverse array of putative virulent factors such as glycosidase, cysteine proteinases and amebapore that can modulate and/or disrupt epithelial barrier functions. However, it is currently thought that E. histolytica produces numerous other molecules and strategies to disrupt colonic mucosal defenses. In this study, we document a putative mechanism whereby the parasite alters the integrity of human epithelium by expressing a cognate tight junction protein of the host. We detected this protein as "occludin-like" as revealed by immunoblotting and immunoprecipitation studies and visualization by confocal microscopy using antibodies highly specific for human occludin. We propose that E. histolytica occludin-like protein might displace mucosal epithelial occludin-occludin tight junction interactions resulting in epithelial disruption analogous to sub mucosal human dendritic cells sampling luminal contents. These results indicate that E. histolytica occludin is a putative virulent component that can play a role in the pathogenesis of intestinal amebiasis.

  14. Entamoeba histolytica contains an occludin-like protein that can alter colonic epithelial barrier function.

    Directory of Open Access Journals (Sweden)

    Michael Goplen

    Full Text Available The exact mechanism by which Entamoeba histolytica disrupts the human colonic epithelium and invades the mucosa has yet to be clearly elucidated. E. histolytica produces a diverse array of putative virulent factors such as glycosidase, cysteine proteinases and amebapore that can modulate and/or disrupt epithelial barrier functions. However, it is currently thought that E. histolytica produces numerous other molecules and strategies to disrupt colonic mucosal defenses. In this study, we document a putative mechanism whereby the parasite alters the integrity of human epithelium by expressing a cognate tight junction protein of the host. We detected this protein as "occludin-like" as revealed by immunoblotting and immunoprecipitation studies and visualization by confocal microscopy using antibodies highly specific for human occludin. We propose that E. histolytica occludin-like protein might displace mucosal epithelial occludin-occludin tight junction interactions resulting in epithelial disruption analogous to sub mucosal human dendritic cells sampling luminal contents. These results indicate that E. histolytica occludin is a putative virulent component that can play a role in the pathogenesis of intestinal amebiasis.

  15. Adaptive NN Control Using Integral Barrier Lyapunov Functionals for Uncertain Nonlinear Block-Triangular Constraint Systems.

    Science.gov (United States)

    Liu, Yan-Jun; Tong, Shaocheng; Chen, C L Philip; Li, Dong-Juan

    2016-09-19

    A neural network (NN) adaptive control design problem is addressed for a class of uncertain multi-input-multi-output (MIMO) nonlinear systems in block-triangular form. The considered systems contain uncertainty dynamics and their states are enforced to subject to bounded constraints as well as the couplings among various inputs and outputs are inserted in each subsystem. To stabilize this class of systems, a novel adaptive control strategy is constructively framed by using the backstepping design technique and NNs. The novel integral barrier Lyapunov functionals (BLFs) are employed to overcome the violation of the full state constraints. The proposed strategy can not only guarantee the boundedness of the closed-loop system and the outputs are driven to follow the reference signals, but also can ensure all the states to remain in the predefined compact sets. Moreover, the transformed constraints on the errors are used in the previous BLF, and accordingly it is required to determine clearly the bounds of the virtual controllers. Thus, it can relax the conservative limitations in the traditional BLF-based controls for the full state constraints. This conservatism can be solved in this paper and it is for the first time to control this class of MIMO systems with the full state constraints. The performance of the proposed control strategy can be verified through a simulation example.

  16. Phytoplankton, bacterioplankton and virioplankton structure and function across the southern Great Barrier Reef shelf

    Science.gov (United States)

    Alongi, Daniel M.; Patten, Nicole L.; McKinnon, David; Köstner, Nicole; Bourne, David G.; Brinkman, Richard

    2015-02-01

    Bacterioplankton and phytoplankton dynamics, pelagic respiration, virioplankton abundance, and the diversity of pelagic diazotrophs and other bacteria were examined in relation to water-column nutrients and vertical mixing across the southern Great Barrier Reef (GBR) shelf where sharp inshore to offshore gradients in water chemistry and hydrology prevail. A principal component analysis (PCA) revealed station groups clustered geographically, suggesting across-shelf differences in plankton function and structure driven by changes in mixing intensity, sediment resuspension, and the relative contributions of terrestrial, reef and oceanic nutrients. At most stations and sampling periods, microbial abundance and activities peaked both inshore and at channels between outer shelf reefs of the Pompey Reef complex. PCA also revealed that virioplankton numbers and biomass correlated with bacterioplankton numbers and production, and that bacterial growth and respiration correlated with net primary production, suggesting close virus-bacteria-phytoplankton interactions; all plankton groups correlated with particulate C, N, and P. Strong vertical mixing facilitates tight coupling of pelagic and benthic shelf processes as, on average, 37% and 56% of N and P demands of phytoplankton are derived from benthic nutrient regeneration and resuspension. These across-shelf planktonic trends mirror those of the benthic microbial community.

  17. Effect of lactobacillus on the gut microfiora and barrier function of the rats with abdominal infection

    Institute of Scientific and Technical Information of China (English)

    Huan-Long Qin; Tong-Yi Shen; Zhi-Guang Gao; Xiao-Bing Fan; Xiao-Min Hang; Yan-Qun Jiang; Hui-Zhen Zhang

    2005-01-01

    AIM: To investigate the effect of probiotics supplemented by gut on the tight junctions of epithelial cells, barrier function and the microflora of rats with abdominal infection. METHODS: After the model of cecal ligation and perforation established, SD rats were divided into two groups: parenteral nutrition (PN) group and PN+probiotics (probiotics) group, PN solution was supplemented by neck vein and probiotics was delivered via the jejunostomy tube for five days. Vena cava blood and the homogenated tissue of liver, lung and mesenteric lymph nodes were cultured to determine the bacterial translocation rate (BTR). The ultrastructure of epithelial tight junctions and microvilli of the gut were observed by electron microscopy; occluding expression was measured by indirect-immune fluorescence method; anaerobic bacterial growth by anaerobic culture and DNA fingerprint of bacterial colonies of the feces by PCR. RESULTS: The quantity of lactobacteria and bifydobacteria in probiotics group was higher than that of PN group. The profiles of DNA fingerprint expression in probiotics group were similar to that in the normal group, a new 16S rDNA sequence appeared in the profile in PN group. The occludin expression, the integrality of the gut epithelial tight junctionand microvilli in probiotics group were improved as compared with PN group. The BTR and endotoxin in blood were reduced more significantly in probiotics group as compared with PN group.CONCLUSION: The probiotics could improve the gut microflora disturbance, increase occludin expression, maintain the gut epithelial tight junction and decrease the bacterial translocations rate.

  18. Dietary inulin alters the intestinal absorptive and barrier function of piglet intestine after weaning.

    Science.gov (United States)

    Awad, Wageha A; Ghareeb, Khaled; Paßlack, Nadine; Zentek, Jürgen

    2013-08-01

    An experiment was conducted to study the effects of dietary inulin supplementation on the electrophysiological properties of small intestine of suckling and weaned piglets as indicators for glucose absorption and barrier function. Ten sows were divided into two groups, receiving either a control diet, or a diet with 3% inulin. The diets were fed from 3 weeks ante partum to 6 weeks post partum. In the first 2 weeks of life, piglets received only sow's milk. Irrespective to sex and without castration of males, four piglets (one piglet of each litter) from each group were selected and sacrificed on day 10 of age. The gastrointestinal tract of each piglet was removed and segments were immediately taken from the mid-jejunum and mounted in Ussing chambers. Furthermore, at weaning (6 weeks old) 8 piglets were randomly selected irrespective to sex and males were un-castrated (4 animals from sows received control diet and 4 animals from sows received 3% inulin supplemented diet) and fed for 2 weeks either control weaning diet or inulin supplemented diet. Thereafter segments of the mid-jejunum were used to investigate the effect of inulin on the gut electrophysiology of weaned piglets. The increase in short-circuit current (Isc) after the addition of glucose is an indicator of higher glucose absorption and the higher tissue conductance (Gt) of the epithelium suggested a higher intestinal permeability to paracellular Na(+). In suckling piglets, the addition of d-glucose on the luminal side of the isolated jejunal mucosa increased (P<0.001) the Isc in the inulin-supplemented and control groups compared to basal values. Electrogenic glucose transport (ΔIsc) was similar in suckling piglets from sows fed inulin or control diet, suggesting that feeding of inulin to the mother sows had no effect on glucose absorption across the jejunal mucosa of suckling piglets. However, the dietary inulin supplementation after weaning increased the ΔIsc (P<0.001) compared with the controls

  19. DHA protects against experimental colitis in IL-10-deficient mice associated with the modulation of intestinal epithelial barrier function.

    Science.gov (United States)

    Zhao, Jie; Shi, Peiliang; Sun, Ye; Sun, Jing; Dong, Jian-Ning; Wang, Hong-Gang; Zuo, Lu-Gen; Gong, Jian-Feng; Li, Yi; Gu, Li-Li; Li, Ning; Li, Jie-Shou; Zhu, Wei-Ming

    2015-07-01

    A defect in the intestinal barrier is one of the characteristics of Crohn's disease (CD). The tight junction (TJ) changes and death of epithelial cells caused by intestinal inflammation play an important role in the development of CD. DHA, a long-chain PUFA, has been shown to be helpful in treating inflammatory bowel disease in experimental models by inhibiting the NF-κB pathway. The present study aimed at investigating the specific effect of DHA on the intestinal barrier function in IL-10-deficient mice. IL-10-deficient mice (IL-10(-/-)) at 16 weeks of age with established colitis were treated with DHA (i.g. 35.5 mg/kg per d) for 2 weeks. The severity of their colitis, levels of pro-inflammatory cytokines, epithelial gene expression, the distributions of TJ proteins (occludin and zona occludens (ZO)-1), and epithelial apoptosis in the proximal colon were measured at the end of the experiment. DHA treatment attenuated the established colitis and was associated with reduced infiltration of inflammatory cells in the colonic mucosa, lower mean histological scores and decreased levels of pro-inflammatory cytokines (IL-17, TNF-α and interferon-γ). Moreover, enhanced barrier function was observed in the DHA-treated mice that resulted from attenuated colonic permeability, rescued expression and corrected distributions of occludin and ZO-1. The results of the present study indicate that DHA therapy may ameliorate experimental colitis in IL-10(-/-) mice by improving the intestinal epithelial barrier function.

  20. Effect of Topical Iloprost and Nitroglycerin on Gastric Microcirculation and Barrier Function during Hemorrhagic Shock in Dogs.

    Science.gov (United States)

    Truse, Richard; Hinterberg, Jonas; Schulz, Jan; Herminghaus, Anna; Weber, Andreas; Mettler-Altmann, Tabea; Bauer, Inge; Picker, Olaf; Vollmer, Christian

    2017-01-01

    Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions. In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro- and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood. During hemorrhage, gastric mucosal oxygenation decreased from 77 ± 4 to 37 ± 7%. This effect was attenuated by nitroglycerin (78 ± 6 to 47 ± 13%) and iloprost (82 ± 4 to 54 ± 9%). Sucrose plasma levels increased during hemorrhage from 7 ± 4 to 55 ± 15 relative amounts. This was alleviated by nitroglycerin (5 ± 8 to 29 ± 38 relative amounts). These effects were independent of systemic hemodynamic variables. During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function. © 2017 S. Karger AG, Basel.

  1. MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function.

    Science.gov (United States)

    McKenna, Lindsay B; Schug, Jonathan; Vourekas, Anastassios; McKenna, Jaime B; Bramswig, Nuria C; Friedman, Joshua R; Kaestner, Klaus H

    2010-11-01

    Whereas the importance of microRNA (miRNA) for the development of several tissues is well established, its role in the intestine is unknown. We aimed to quantify the complete miRNA expression profile of the mammalian intestinal mucosa and to determine the contribution of miRNAs to intestinal homeostasis using genetic means. We determined the miRNA transcriptome of the mouse intestinal mucosa using ultrahigh throughput sequencing. Using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP), we identified miRNA-messenger RNA target relationships in the jejunum. We employed gene ablation of the obligatory miRNA-processing enzyme Dicer1 to derive mice deficient for all miRNAs in intestinal epithelia. miRNA abundance varies dramatically in the intestinal mucosa, from 1 read per million to 250,000. Of the 453 miRNA families identified, mmu-miR-192 is the most highly expressed in both the small and large intestinal mucosa, and there is a 53% overlap in the top 15 expressed miRNAs between the 2 tissues. The intestinal epithelium of Dicer1(loxP/loxP);Villin-Cre mutant mice is disorganized, with a decrease in goblet cells, a dramatic increase in apoptosis in crypts of both jejunum and colon, and accelerated jejunal cell migration. Furthermore, intestinal barrier function is impaired in Dicer1-deficient mice, resulting in intestinal inflammation with lymphocyte and neutrophil infiltration. Our list of miRNA-messenger RNA targeting relationships in the small intestinal mucosa provides insight into the molecular mechanisms behind the phenotype of Dicer1 mutant mice. We have identified all intestinal miRNAs and shown using gene ablation of Dicer1 that miRNAs play a vital role in the differentiation and function of the intestinal epithelium. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  2. I. Fission Probabilities, Fission Barriers, and Shell Effects. II. Particle Structure Functions

    Energy Technology Data Exchange (ETDEWEB)

    Jing, Kexing [Univ. of California, Berkeley, CA (United States)

    1999-05-01

    In Part I, fission excitation functions of osmium isotopes 185,186, 187, 189 Os produced in 3He +182,183, 184, 186W reactions, and of polonium isotopes 209,210, 211, 212Po produced in 3He/4He + 206, 207, 208Pb reactions, were measured with high precision. These excitation functions have been analyzed in detail based upon the transition state formalism. The fission barriers, and shell effects for the corresponding nuclei are extracted from the detailed analyses. A novel approach has been developed to determine upper limits of the transient time of the fission process. The upper limits are constrained by the fission probabilities of neighboring isotopes. The upper limits for the transient time set with this new method are 15x 10–21 sec and 25x 10–21 sec for 0s and Po compound nuclei, respectively. In Part II, we report on a search for evidence of the optical modulations in the energy spectra of alpha particles emitted from hot compound nuclei. The optical modulations are expected to arise from the ~-particle interaction with the rest of the nucleus as the particle prepares to exit. Some evidence for the modulations has been observed in the alpha spectra measured in the 3He-induced reactions, 3He + natAg in particular. The identification of the modulations involves a technique that subtracts the bulk statistical background from the measured alpha spectra, in order for the modulations to become visible in the residuals. Due to insufficient knowledge of the background spectra, however, the presented evidence should only be regarded as preliminary and tentative.

  3. Functional and morphological changes of the gut barrier during the restitution process after hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    Jian-Xing Chang; Zi-Tong Huang; Shuang Chen; Li-Ping Ma; Long-Yuan Jiang; Jian-Wen Chen; Rui-Ming Chang; Li-Qiang Wen; Wei Wu; Zhi-Peng Jiang

    2005-01-01

    AIM: To investigate the functional, morphological changes of the gut barrier during the restitution process after hemorrhagic shock, and the regional differences of the large intestine and small intestine in response to ischemia/reperfusion injury.METHODS: Forty-seven Sprague-Dawley rats with body weight of 250-300 g were divided into two groups: control group (sham shock n = 5) and experimental group (n = 42).Experimental group was further divided into six groups (n = 7 each) according to different time points after the hemorrhagic shock, including 0th h group, 1st h group, 3rd h group, 6th h group, 12th h group and 24th h group. All the rats were gavaged with 2 mL of suspension of lactulose (L) (100 mg/2 mL) and mannitol (M) (50 mg/each) at the beginning and then an experimental rat model of hemorrhagic shock was set up. The specimens from jejunum, ileum and colon tissues and the blood samples from the portal vein were taken at 0, 1, 3, 6, 12 and 24 h after shock resuscitation, respectively. The morphological changes of the intestinal mucosa, including the histology of intestinal mucosa, the thickness of mucosa, the height of villi, the index of mucosal damage and the numbers of goblet cells, were determined by light microscope and/or electron microscope. The concentrations of the bacterial endotoxin lipopolysaccharides (LPS) from the portal vein blood, which reflected the gut barrier function, were examined by using Limulus test. At the same time point,to evaluate intestinal permeability, all urine was collected and the concentrations of the metabolically inactive markers such as L and M in urine were measured by using GC-9A gas chromatographic instrument.RESULTS: After the hemorrhagic shock, the mucosal epithelial injury was obvious in small intestine even at the 0th h, and it became more serious at the 1st and the 3rd h. The tissue restitution was also found after 3 h,though the injury was still serious. Most of the injured mucosal restitution was established

  4. The Serbian functional food market: Does regulation make a difference?

    Directory of Open Access Journals (Sweden)

    Stojanović Žaklina

    2012-01-01

    Full Text Available This paper focuses on empirical analysis of the Serbian functional food market and its comparison with those in other Western Balkan countries (WBC. The purpose is to examine whether the existence of regulation, as an institutional precondition, makes a difference on the operating of the functional food market. This market is a new, fast developing segment, based on health claims made for food. Consumers in Serbia cannot verify health claims either before or after the purchase/consumption, since the property rights on information are extremely weak. Additionally, with successful innovation the free-rider problem usually occurs. Thus, strong institutional support is necessary to ensure regular market functioning. In order to identify the effects of regulation and some other factors with crucial influence on the differences between Serbian and other WBC functional food markets, pooled cross sectional analysis is conducted. The fixed-group effects model is estimated based on data of product categories observed across WBC. Differences in the current level of WBC market development could be explained by the existence of legal regulation, competition, and other factors. All results implicate the necessity of regulatory supervision as well as closer cooperation between government, the private sector, consumer groups, academics, and the research community in further functional food market development in Serbia.

  5. Cellular regulation of the structure and function of aortic valves

    Directory of Open Access Journals (Sweden)

    Ismail El-Hamamsy

    2010-01-01

    Full Text Available The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.

  6. Comparative study of fusion barriers using Skyrme interactions and the energy density functional

    Science.gov (United States)

    Ghodsi, O. N.; Torabi, F.

    2015-12-01

    Using different Skyrme interactions, we have carried out a comparative analysis of fusion barriers for a wide range of interacting nuclei in the framework of semiclassical Skyrme energy density formalism. The results of our calculations reveal that SVI, SII, and SIII Skyrme forces are able to reproduce the empirical values of barrier heights with higher accuracy than the other considered forces in this formalism. It is also shown that the calculated nucleus-nucleus potentials derived from such Skyrme interactions are able to explain the fusion cross sections at energies near and above the barrier.

  7. Comparative study of fusion barriers using Skyrme interactions and the energy density functional

    CERN Document Server

    Ghodsi, O N

    2015-01-01

    Using different Skyrme interactions, we have carried out a comparative analysis of fusion barriers for a wide range of interacting nuclei in the framework of semiclassical Skyrme energy density formalism. The results of our calculations reveal that SVI, SII, and SIII Skyrme forces are able to reproduce the empirical values of barrier heights with higher accuracy than the other considered forces in this formalism. It is also shown that the calculated nucleus-nucleus potentials derived from such Skyrme interactions are able to explain the fusion cross sections at energies near and above the barrier.

  8. Plastid sigma factors: Their individual functions and regulation in transcription.

    Science.gov (United States)

    Chi, Wei; He, Baoye; Mao, Juan; Jiang, Jingjing; Zhang, Lixin

    2015-09-01

    Sigma factors are the predominant factors involved in transcription regulation in bacteria. These factors can recruit the core RNA polymerase to promoters with specific DNA sequences and initiate gene transcription. The plastids of higher plants originating from an ancestral cyanobacterial endosymbiont also contain sigma factors that are encoded by a small family of nuclear genes. Although all plastid sigma factors contain sequences conserved in bacterial sigma factors, a considerable number of distinct traits have been acquired during evolution. The present review summarises recent advances concerning the regulation of the structure, function and activity of plastid sigma factors since their discovery nearly 40 years ago. We highlight the specialised roles and overlapping redundant functions of plastid sigma factors according to their promoter selectivity. We also focus on the mechanisms that modulate the activity of sigma factors to optimise plastid function in response to developmental cues and environmental signals. This article is part of a Special Issue entitled: Chloroplast Biogenesis.

  9. The functional role of platelets in the regulation of angiogenesis.

    Science.gov (United States)

    Walsh, Tony G; Metharom, Pat; Berndt, Michael C

    2015-01-01

    Functionally, platelets are primarily recognized as key regulators of thrombosis and hemostasis. Upon vessel injury, the typically quiescent platelet interacts with subendothelial matrix to regulate platelet adhesion, activation and aggregation, with subsequent induction of the coagulation cascade forming a thrombus. Recently, however, newly described roles for platelets in the regulation of angiogenesis have emerged. Platelets possess an armory of pro- and anti-angiogenic proteins, which are actively sequestered and highly organized in α-granule populations. Platelet activation facilitates their release, eliciting potent angiogenic responses through mechanisms that appear to be tightly regulated. In conjunction, the release of platelet-derived phospholipids and microparticles has also earned merit as synergistic regulators of angiogenesis. Consequently, platelets have been functionally implicated in a range of angiogenesis-dependent processes, including physiological roles in wound healing, vascular development and blood/lymphatic vessel separation, whilst facilitating aberrant angiogenesis in a range of diseases including cancer, atherosclerosis and diabetic retinopathy. Whilst the underlying mechanisms are only starting to be elucidated, significant insights have been established, suggesting that platelets represent a promising therapeutic strategy in diseases requiring angiogenic modulation. Moreover, anti-platelet therapies targeting thrombotic complications also exert protective effects in disorders characterized by persistent angiogenesis.

  10. Molecular interactions of plant oil components with stratum corneum lipids correlate with clinical measures of skin barrier function.

    Science.gov (United States)

    Mack Correa, Mary Catherine; Mao, Guangru; Saad, Peter; Flach, Carol R; Mendelsohn, Richard; Walters, Russel M

    2014-01-01

    Plant-derived oils consisting of triglycerides and small amounts of free fatty acids (FFAs) are commonly used in skincare regimens. FFAs are known to disrupt skin barrier function. The objective of this study was to mechanistically study the effects of FFAs, triglycerides and their mixtures on skin barrier function. The effects of oleic acid (OA), glyceryl trioleate (GT) and OA/GT mixtures on skin barrier were assessed in vivo through measurement of transepidermal water loss (TEWL) and fluorescein dye penetration before and after a single application. OA's effects on stratum corneum (SC) lipid order in vivo were measured with infrared spectroscopy through application of perdeuterated OA (OA-d34 ). Studies of the interaction of OA and GT with skin lipids included imaging the distribution of OA-d34 and GT ex vivo with IR microspectroscopy and thermodynamic analysis of mixtures in aqueous monolayers. The oil mixtures increased both TEWL and fluorescein penetration 24 h after a single application in an OA dose-dependent manner, with the highest increase from treatment with pure OA. OA-d34 penetrated into skin and disordered SC lipids. Furthermore, the ex vivo IR imaging studies showed that OA-d34 permeated to the dermal/epidermal junction while GT remained in the SC. The monolayer experiments showed preferential interspecies interactions between OA and SC lipids, while the mixing between GT and SC lipids was not thermodynamically preferred. The FFA component of plant oils may disrupt skin barrier function. The affinity between plant oil components and SC lipids likely determines the extent of their penetration and clinically measurable effects on skin barrier functions. © 2013. Johnson & Johnson Consumer Companies Inc.. Experimental Dermatology published by John Wiley & Sons Ltd.

  11. Regulator Loss Functions and Hierarchical Modeling for Safety Decision Making.

    Science.gov (United States)

    Hatfield, Laura A; Baugh, Christine M; Azzone, Vanessa; Normand, Sharon-Lise T

    2017-07-01

    Regulators must act to protect the public when evidence indicates safety problems with medical devices. This requires complex tradeoffs among risks and benefits, which conventional safety surveillance methods do not incorporate. To combine explicit regulator loss functions with statistical evidence on medical device safety signals to improve decision making. In the Hospital Cost and Utilization Project National Inpatient Sample, we select pediatric inpatient admissions and identify adverse medical device events (AMDEs). We fit hierarchical Bayesian models to the annual hospital-level AMDE rates, accounting for patient and hospital characteristics. These models produce expected AMDE rates (a safety target), against which we compare the observed rates in a test year to compute a safety signal. We specify a set of loss functions that quantify the costs and benefits of each action as a function of the safety signal. We integrate the loss functions over the posterior distribution of the safety signal to obtain the posterior (Bayes) risk; the preferred action has the smallest Bayes risk. Using simulation and an analysis of AMDE data, we compare our minimum-risk decisions to a conventional Z score approach for classifying safety signals. The 2 rules produced different actions for nearly half of hospitals (45%). In the simulation, decisions that minimize Bayes risk outperform Z score-based decisions, even when the loss functions or hierarchical models are misspecified. Our method is sensitive to the choice of loss functions; eliciting quantitative inputs to the loss functions from regulators is challenging. A decision-theoretic approach to acting on safety signals is potentially promising but requires careful specification of loss functions in consultation with subject matter experts.

  12. Regulation of taurine transport at the blood-placental barrier by calcium ion, PKC activator and oxidative stress conditions

    Science.gov (United States)

    2010-01-01

    Background In the present study, we investigated the changes of uptake and efflux transport of taurine under various stress conditions using rat conditionally immortalized syncytiotrophoblast cell line (TR-TBT cells), as in vitro blood-placental barrier (BPB) model. Methods The transport of taurine in TR-TBT cells were characterized by cellular uptake study using radiolabeled taurine. The efflux of taurine was measured from the amount of radiolabeled taurine remaining in the cells after the uptake of radiolabeled taurine for 60 min. Results Taurine uptake was significantly decreased by phosphorylation of protein kinase C (PKC) activator in TR-TBT cells. Also, calcium ion (Ca2+) was involved in taurine transport in TR-TBT cells. Taurine uptake was inhibited and efflux was enhanced under calcium free conditions in the cells. In addition, oxidative stress induced the change of taurine transport in TR-TBT cells, but the changes were different depending on the types of oxidative stress inducing agents. Tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS) and diethyl maleate (DEM) significantly increased taurine uptake, but H2O2 and nitric oxide (NO) donor decreased taurine uptake in the cells. Taurine efflux was down-regulated by TNF-α in TR-TBT cells. Conclusion Taurine transport in TR-TBT cells were regulated diversely at extracellular Ca2+ level, PKC activator and oxidative stress conditions. It suggested that variable stresses affected the taurine supplies from maternal blood to fetus and taurine level of fetus. PMID:20804613

  13. Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair.

    NARCIS (Netherlands)

    Koning, H.D. de; Bogaard, E.H.J. van den; Bergboer, J.G.M.; Kamsteeg, M.; Vlijmen-Willems, I.M.J.J. van; Hitomi, K.; Henry, J.; Simon, M.; Takashita, N.; Ishida-Yamamoto, A.; Schalkwijk, J.; Zeeuwen, P.L.J.M.

    2012-01-01

    BACKGROUND: Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope

  14. Stress plays provoking role in hypertension-related stroke: injuries of blood-brain barrier function

    Science.gov (United States)

    Semyachkina-Glushkovskaya, O.; Shirokov, A.; Gekalyuk, A.; Abakumov, M.; Navolokin, N.; Abdurashitov, A.; Pavlov, A.; Ulanova, M.; Fedorova, V.; Razubaeva, V.; Saranceva, E.; Li, P.; Huang, Q.; Zhu, D.; Luo, Q.; Tuchin, V.; Kurths, J.

    2017-02-01

    Chronic hypertension itself does not cause stroke but significantly decreases the resistant to stroke induced by stress due to exhausting of adaptive capacity of cerebral endothelium and decrease resistance of blood-brain barrier to stress.

  15. Addressing barriers to eco-innovation: Exploring the finance mobilisation functions of institutional innovation intermediaries

    NARCIS (Netherlands)

    Polzin, Friedemann; Flotow, von Paschen; Klerkx, L.W.A.

    2016-01-01

    This research article explores the role of institutional innovation intermediaries in accelerating the commercialisation of (clean) technologies. Drawing on the finance and innovation intermediaries literatures, we show that financial barriers to eco-innovation can be partly overcome by particular

  16. Molecular mechanisms regulating expression and function of transcription regulator "inhibitor of differentiation 3"

    Institute of Scientific and Technical Information of China (English)

    Robert Wai-sui LIM; Jin-mei WU

    2005-01-01

    The transcription factor antagonist inhibitor of differentiation 3 (Id3) has been implicated in many diverse developmental, physiological and pathophysiological processes. Its expression and function is subjected to many levels of complex regulation. This review summarizes the current understanding of these mechanisms and describes how they might be related to the diverse functions that have been attributed to the Id3 protein. Detailed understanding of these mechanisms should provide insights towards the development of therapeutic approaches to various diseases, including cancer and atherogenesis.

  17. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

    DEFF Research Database (Denmark)

    Jungersted, J M; Scheer, H; Mempel, M

    2010-01-01

    Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies...... have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype....

  18. Metabolic regulation of regulatory T cell development and function

    Directory of Open Access Journals (Sweden)

    David John Coe

    2014-11-01

    Full Text Available It is now well established that the effector T cell (Teff response is regulated by a series of metabolic switches. Quiescent T cells predominantly require ATP-generating processes, whereas proliferating Teff require high metabolic flux through growth-promoting pathways, such as glycolysis. Pathways that control metabolism and immune cell function are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell effector functions. Furthermore, functionally distinct T cell subsets have been shown to require distinct energetic and biosynthetic pathways to support their specific functional needs. In particular, naturally occurring regulatory T cells (Treg are characterized by a unique metabolic signature distinct to that of conventional Teff cells. We here briefly review the signaling pathways that control Treg metabolism and how this metabolic phenotype integrates their differentiation and function. Ultimately, these metabolic features may provide new opportunities for the therapeutic modulation of unwanted immune responses.

  19. Trypanosome infection establishment in the tsetse fly gut is influenced by microbiome-regulated host immune barriers.

    Directory of Open Access Journals (Sweden)

    Brian L Weiss

    Full Text Available Tsetse flies (Glossina spp. vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb and epithelial (inducible nitric oxide synthase and dual oxidase immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm(Apo present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm(Apo adults present a structurally compromised peritrophic matrix (PM, which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm(Apo flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results

  20. Regulation and function of AMPK in physiology and diseases.

    Science.gov (United States)

    Jeon, Sang-Min

    2016-07-15

    5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse molecular mechanisms and physiological conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiological processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its critical roles in physiology and pathology, AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the molecular and physiological regulation of AMPK and its metabolic and physiological functions. In addition, we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.

  1. Regulation of sodium channel function by bilayer elasticity

    DEFF Research Database (Denmark)

    Lundbaek, Jens A; Birn, Pia; Hansen, Anker J

    2004-01-01

    be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta-octyl-glucoside, Genapol X-100......, Triton X-100, and reduced Triton X-100) that make lipid bilayers less "stiff", as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change...... in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer-protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein...

  2. IL-17A potentiates TNFα-induced secretion from human endothelial cells and alters barrier functions controlling neutrophils rights of passage.

    Science.gov (United States)

    Bosteen, Markus H; Tritsaris, Katerina; Hansen, Anker J; Dissing, Steen

    2014-05-01

    Interleukin-17A (IL-17A) is an important pro-inflammatory cytokine that regulates leukocyte mobilization and recruitment. To better understand how IL-17A controls leukocyte trafficking across capillaries in the peripheral blood circulation, we used primary human dermal microvascular endothelial cells (HDMEC) to investigate their secretory potential and barrier function when activated with IL-17A and TNFα. Activation by TNFα and IL-17A causes phosphorylation of p38 as well as IκBα whereby NFκB subsequently becomes phosphorylated, a mechanism that initiates transcription of adhesion molecules such as E-selectin. Members of the neutrophil-specific GRO-family chemokines were significantly up-regulated upon IL-17A stimulation on the mRNA and protein level, whereas all tested non-neutrophil-specific chemokines remained unchanged in comparison. Moreover, a striking synergistic effect in the induction of granulocyte colony-stimulating factors (G-CSF) was elicited when IL-17A was used in combination with TNFα, and IL-17A was able to significantly augment the levels of TNFα-induced E-selectin and ICAM-1. In accordance with this observation, IL-17A was able to markedly increase TNFα-induced neutrophil adherence to HDMEC monolayers in an in vitro adhesion assay. Using a trans-well migration assay with an HDMEC monolayer as a barrier, we here show that pre-stimulating the endothelial cells with TNFα and IL-17A together enhances the rate of neutrophil transmigration compared to TNFα or IL-17A alone. These results show that IL-17A and TNFα act in cooperation to facilitate neutrophil migration across the endothelial cell barrier. In addition, the synergistic actions of IL-17A with TNFα to secrete G-CSF appear to be important for mobilizing neutrophils from the bone marrow to the blood stream.

  3. Emotion regulation in Asperger's syndrome and high-functioning autism.

    Science.gov (United States)

    Samson, Andrea C; Huber, Oswald; Gross, James J

    2012-08-01

    It is generally thought that individuals with Asperger's syndrome and high-functioning autism (AS/HFA) have deficits in theory of mind. These deficits have been previously linked to problems with social cognition. However, we reasoned that AS/HFA individuals' Theory of Mind deficits also might lead to problems with emotion regulation. To assess emotional functioning in AS/HFA, 27 AS/HFA adults (16 women) and 27 age-, gender-, and education-matched typically developing (TD) participants completed a battery of measures of emotion experience, labeling, and regulation. With respect to emotion experience, individuals with AS/HFA reported higher levels of negative emotions, but similar levels of positive emotions, compared with TD individuals. With respect to emotion labeling, individuals with AS/HFA had greater difficulties identifying and describing their emotions, with approximately two-thirds exceeding the cutoff for alexithymia. With respect to emotion regulation, individuals with AS/HFA used reappraisal less frequently than TD individuals and reported lower levels of reappraisal self-efficacy. Although AS/HFA individuals used suppression more frequently than TD individuals, no difference in suppression self-efficacy was found. It is important to note that these differences in emotion regulation were evident even when controlling for emotion experience and labeling. Implications of these deficits are discussed, and future research directions are proposed.

  4. Systemic regulation of photosynthetic function in field-grown sorghum.

    Science.gov (United States)

    Li, Tao; Liu, Yujun; Shi, Lei; Jiang, Chuangdao

    2015-09-01

    The photosynthetic characteristics of developing leaves of plants grown under artificial conditions are, to some extent, regulated systemically by mature leaves; however, whether systemic regulation of photosynthesis occurs in field-grown crops is unclear. To explore this question, we investigated the effects of planting density on growth characteristics, gas exchange, leaf nitrogen concentration and chlorophyll a fluorescence in field-grown sorghum (Sorghum bicolor L.). Our results showed that close planting resulted in a marked decline in light intensity in lower canopy. Sorghum plants grown at a high planting density had lower net photosynthetic rate (Pn), stomatal conductance (Gs), and transpiration rate (E) than plants grown at a low planting density. Moreover, in the absence of mineral deficiency, close planting induced a slight increase in leaf nitrogen concentration. The decreased photosynthesis in leaves of the lower canopy at high planting density was caused mainly by the low light. However, newly developed leaves exposed to high light in the upper canopy of plants grown at high planting density also exhibited a distinct decline in photosynthesis relative to plants grown at low planting density. Based on these results, the photosynthetic function of the newly developed leaves in the upper canopy was not determined fully by their own high light environment. Accordingly, we suggest that the photosynthetic function of newly developed leaves in the upper canopy of field-grown sorghum plants is regulated systemically by the lower canopy leaves. The differences in systemic regulation of photosynthesis were also discussed between field conditions and artificial conditions.

  5. Dynamic Regulation and Function of Histone Monoubiquitination in Plants

    Directory of Open Access Journals (Sweden)

    Jing eFeng

    2014-03-01

    Full Text Available Polyubiquitin chain deposition on a target protein frequently leads to proteasome-mediated degradation whereas monoubiquitination modifies target protein property and function independent of proteolysis. Histone monoubiquitination occurs in chromatin and is in nowadays recognized as one critical type of epigenetic marks in eukaryotes. While H2A monoubiquitination (H2Aub1 is generally associated with transcription repression mediated by the Polycomb pathway, H2Bub1 is involved in transcription activation. H2Aub1 and H2Bub1 levels are dynamically regulated via deposition and removal by specific enzymes. We review knows and unknowns of dynamic regulation of H2Aub1 and H2Bub1 deposition and removal in plants and highlight the underlying crucial functions in gene transcription, cell proliferation/differentiation, and plant growth and development. We also discuss crosstalks existing between H2Aub1 or H2Bub1 and different histone methylations for an ample mechanistic understanding.

  6. Ubiquitination-dependent mechanisms regulate synaptic growth and function.

    Science.gov (United States)

    DiAntonio, A; Haghighi, A P; Portman, S L; Lee, J D; Amaranto, A M; Goodman, C S

    2001-07-26

    The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

  7. Neural progenitor cells regulate microglia functions and activity.

    Science.gov (United States)

    Mosher, Kira I; Andres, Robert H; Fukuhara, Takeshi; Bieri, Gregor; Hasegawa-Moriyama, Maiko; He, Yingbo; Guzman, Raphael; Wyss-Coray, Tony

    2012-11-01

    We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity.

  8. Na+ channel function, regulation, structure, trafficking and sequestration

    Science.gov (United States)

    Chen-Izu, Ye; Shaw, Robin M; Pitt, Geoffrey S; Yarov-Yarovoy, Vladimir; Sack, Jon T; Abriel, Hugues; Aldrich, Richard W; Belardinelli, Luiz; Cannell, Mark B; Catterall, William A; Chazin, Walter J; Chiamvimonvat, Nipavan; Deschenes, Isabelle; Grandi, Eleonora; Hund, Thomas J; Izu, Leighton T; Maier, Lars S; Maltsev, Victor A; Marionneau, Celine; Mohler, Peter J; Rajamani, Sridharan; Rasmusson, Randall L; Sobie, Eric A; Clancy, Colleen E; Bers, Donald M

    2015-01-01

    This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias: Na+ channel and Na+ transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na+ channel function and regulation, Na+ channel structure and function, and Na+ channel trafficking, sequestration and complexing. PMID:25772290

  9. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease

    Directory of Open Access Journals (Sweden)

    Benjamin B. Williams

    2015-08-01

    Full Text Available The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD and colitis-associated cancer (CAC. Glycoprotein A33 (GPA33 is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33−/− mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33−/− mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS to injure the intestinal epithelium. Gpa33−/− mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM followed by two cycles of DSS. In contrast, Gpa33−/− mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33−/− mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33−/− mice provide a valuable model to study the mechanisms

  10. The plasma membrane: Penultimate regulator of ADAM sheddase function.

    Science.gov (United States)

    Reiss, Karina; Bhakdi, Sucharit

    2017-11-01

    ADAM10 and ADAM17 are the best characterized members of the ADAM (A Disintegrin and Metalloproteinase) - family of transmembrane proteases. Both are involved diverse physiological and pathophysiological processes. ADAMs are known to be regulated by posttranslational mechanisms. However, emerging evidence indicates that the plasma membrane with its unique dynamic properties may additionally play an important role in controlling sheddase function. Membrane events that could contribute to regulation of ADAM-function are summarized. Surface expression of peptidolytic activity should be differentiated from ADAM-sheddase function since the latter additionally requires that the protease finds its substrate in the lipid bilayer. We propose that this is achieved through horizontal and vertical reorganization of membrane nanoarchitecture coordinately occurring at the sites of sheddase activation. Reshuffling of nanodomains thereby guides traffic of enzyme and substrate to each other. For ADAM17 phosphatidylserine exposure is required to then induce its shedding function. The novel concept that physicochemical properties of the lipid bilayer govern the action of ADAM-proteases may be extendable to other functional proteins that act at the cell surface. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. Copyright © 2017. Published by Elsevier B.V.

  11. Metabolic influences that regulate DC function in tumors

    Directory of Open Access Journals (Sweden)

    Timothy Nicholas James Bullock

    2014-01-01

    Full Text Available Dendritic cells (DC are critical regulators of both activation and tolerance in the adaptive immune response. The dual nature of DC immunoregulatory function depends on their differentiation and activation status. DC found within the tumor microenvironment (TME and tumor draining lymph node often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. The major determinants of DC activation and the functional alterations in DC that result from integrating exogenous stimuli have been well investigated. Extensive efforts have been made to elucidate how the TME contributes to the inactivated/dysfunctional phenotype of tumor-associated DC (TADC. Although performed predominantly on in vitro DC cultures, recent evidence indicates that DC undergo required, coordinated alterations in their metabolism upon activation, and dysregulated metabolism in TADC is associated with their reduced immunostimulatory capacity. In this review, we will focus on the role of glycolysis and fatty acid metabolism in DC activation and function and discuss how these metabolic pathways may be regulated in TADC. Further, we consider the need for developing novel experimental approaches to assess metabolic choices in vivo, and the necessity for integrating metabolic regulation into the optimized development of DC for tumor vaccines and immunotherapy for cancer.

  12. Glutamine and recombinant human growth hormone protect intestinal barrier function following portal hypertension surgery

    Institute of Scientific and Technical Information of China (English)

    Zhao-Feng Tang; Yun-Biao Ling; Nan Lin; Zheng Hao; Rui-Yun Xu

    2007-01-01

    AIM: To evaluate the effects of combined treatment of glutamine (Gln) and recombinant human growth hormone(rhGH) on intestinal barrier function following portal hypertension surgery.METHODS: This study was designed as a prospective,randomized and controlled clinical trial. Forty two patients after portal hypertension surgery were randomly assigned into 2 groups: control group (n = 20) and supplemental group (adding Gin and rhGH, n = 22). Every patient received isocaloric and isonitrogenous standard total parenteral nutrition (TPN) starting 3 d after surgery for 7 d. Blood samples were obtained before surgery and at the 3rd and 10th day postoperatively. Host immunity was evaluated by measuring levels of CD4, CD8, CD4/CD8, IgG, IgM and IgA, and the inflammatory responses were determined by assessing IL-2, TNF-α and C-reactive protein (CRP) levels. Intestinal permeability and integrity was evaluated by L/M test and histological examination, respectively.RESULTS: On postoperative d 10, CD4, CD4/CD8, IgG and IL-2 levels in supplemental group were significantly higher than those in control group (33.7 ± 5.5 vs 31.0± 5.4, P < 0.05, (1.17 ± 0.32 vs 1.05 ± 0.15, P < 0.05,13.94 ± 1.09 vs 12.33±1.33, P < 0.05, and 368.12± 59.25 vs 318.12 ± 45.65, P < 0.05, respectively),whereas the increase in serum TNF-α concentration was significantly reduced (41.02 ± 27.56 vs 160.09 ± 35.17,P < 0.05). The increase in L/M ratio was significantly lower in the supplemental group than in the control group (0.0166 ± 0.0017 vs 0.0339 ± 0.0028, P < 0.05).Moreover, mucosal integrity in the supplemental group was better than in the control group.CONCLUSION: Postoperative administration of TPN supplemented with Gin and rhGH in patients after portal hypertension surgery improves immune function,modulates inflammatory response, prevents the intestinal mucous membrane from atrophy and preserves intestinal integrity.

  13. Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function

    DEFF Research Database (Denmark)

    Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis

    2013-01-01

    express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation...... of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r...... antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic...

  14. Functionally gradient materials for thermal barrier coatings in advanced gas turbine systems

    Energy Technology Data Exchange (ETDEWEB)

    Banovic, S.W.; Barmak, K.; Chan, H.M. [Lehigh Univ., Bethlehem, PA (United States)] [and others

    1995-10-01

    New designs for advanced gas turbine engines for power production are required to have higher operating temperatures in order to increase efficiency. However, elevated temperatures will increase the magnitude and severity of environmental degradation of critical turbine components (e.g. combustor parts, turbine blades, etc{hor_ellipsis}). To offset this problem, the usage of thermal barrier coatings (TBCs) has become popular by allowing an increase in maximum inlet temperatures for an operating engine. Although thermal barrier technology is over thirty years old, the principle failure mechanism is the spallation of the ceramic coating at or near the ceramic/bond coat interface. Therefore, it is desirable to develop a coating that combines the thermal barrier qualities of the ceramic layer and the corrosion protection by the metallic bond coat without the detrimental effects associated with the localization of the ceramic/metal interface to a single plane.

  15. Excitation Functions of Fusion and Fission for 32S+170Er at Energies Near and Below Coulomb Barrier

    Institute of Scientific and Technical Information of China (English)

    BAO; Peng-fei; LIN; Cheng-jian; YANG; Feng; JIA; Hui-ming; XU; Xin-xing; YANG; Lei; SUN; Li-jie; MA; Nan-ru; ZHANG; Huan-qiao; LIU; Zu-hua

    2013-01-01

    Excitation functions of fusion evaporation residue(ER)and fission for 32S+170Er system at near barrier energy region were measured,respectively.With the comparison to the calculations of coupledchannels effects,it is accessible to investigate the impacts on the fusion and fission processes of target deformation and the dependence on the entrance-channel.The experiment was performed at Beijing HI-13 Tandem Accelerator.Fission and fusion evaporation

  16. Probabilistic migration modelling focused on functional barrier efficiency and low migration concepts in support of risk assessment.

    Science.gov (United States)

    Brandsch, Rainer

    2017-10-01

    Migration modelling provides reliable migration estimates from food-contact materials (FCM) to food or food simulants based on mass-transfer parameters like diffusion and partition coefficients related to individual materials. In most cases, mass-transfer parameters are not readily available from the literature and for this reason are estimated with a given uncertainty. Historically, uncertainty was accounted for by introducing upper limit concepts first, turning out to be of limited applicability due to highly overestimated migration results. Probabilistic migration modelling gives the possibility to consider uncertainty of the mass-transfer parameters as well as other model inputs. With respect to a functional barrier, the most important parameters among others are the diffusion properties of the functional barrier and its thickness. A software tool that accepts distribution as inputs and is capable of applying Monte Carlo methods, i.e., random sampling from the input distributions of the relevant parameters (i.e., diffusion coefficient and layer thickness), predicts migration results with related uncertainty and confidence intervals. The capabilities of probabilistic migration modelling are presented in the view of three case studies (1) sensitivity analysis, (2) functional barrier efficiency and (3) validation by experimental testing. Based on the predicted migration by probabilistic migration modelling and related exposure estimates, safety evaluation of new materials in the context of existing or new packaging concepts is possible. Identifying associated migration risk and potential safety concerns in the early stage of packaging development is possible. Furthermore, dedicated material selection exhibiting required functional barrier efficiency under application conditions becomes feasible. Validation of the migration risk assessment by probabilistic migration modelling through a minimum of dedicated experimental testing is strongly recommended.

  17. The light responsive transcriptome of the zebrafish: function and regulation.

    Directory of Open Access Journals (Sweden)

    Benjamin D Weger

    Full Text Available Most organisms possess circadian clocks that are able to anticipate the day/night cycle and are reset or "entrained" by the ambient light. In the zebrafish, many organs and even cultured cell lines are directly light responsive, allowing for direct entrainment of the clock by light. Here, we have characterized light induced gene transcription in the zebrafish at several organizational levels. Larvae, heart organ cultures and cell cultures were exposed to 1- or 3-hour light pulses, and changes in gene expression were compared with controls kept in the dark. We identified 117 light regulated genes, with the majority being induced and some repressed by light. Cluster analysis groups the genes into five major classes that show regulation at all levels of organization or in different subset combinations. The regulated genes cover a variety of functions, and the analysis of gene ontology categories reveals an enrichment of genes involved in circadian rhythms, stress response and DNA repair, consistent with the exposure to visible wavelengths of light priming cells for UV-induced damage repair. Promoter analysis of the induced genes shows an enrichment of various short sequence motifs, including E- and D-box enhancers that have previously been implicated in light regulation of the zebrafish period2 gene. Heterologous reporter constructs with sequences matching these motifs reveal light regulation of D-box elements in both cells and larvae. Morpholino-mediated knock-down studies of two homologues of the D-box binding factor Tef indicate that these are differentially involved in the cell autonomous light induction in a gene-specific manner. These findings suggest that the mechanisms involved in period2 regulation might represent a more general pathway leading to light induced gene expression.

  18. Charge regulation and local dielectric function in planar polyelectrolyte brushes.

    Science.gov (United States)

    Kumar, Rajeev; Sumpter, Bobby G; Kilbey, S Michael

    2012-06-21

    Understanding the effect of inhomogeneity on the charge regulation and dielectric properties, and how it depends on the conformational characteristics of the macromolecules is a long-standing problem. In order to address this problem, we have developed a field-theory to study charge regulation and local dielectric function in planar polyelectrolyte brushes. The theory is used to study a polyacid brush, which is comprised of chains end-grafted at the solid-fluid interface, in equilibrium with a bulk solution containing monovalent salt ions, solvent molecules, and pH controlling acid. In particular, we focus on the effects of the concentration of added salt and pH of the bulk in determining the local charge and dielectric function. Our theoretical investigations reveal that the dipole moment of the ion-pairs formed as a result of counterion adsorption on the chain backbones play a key role in affecting the local dielectric function. For polyelectrolytes made of monomers having dipole moments lower than the solvent molecules, dielectric decrement is predicted inside the brush region. However, the formation of ion-pairs (due to adsorption of counterions coming from the dissociation of added salt) more polar than the solvent molecules is shown to increase the magnitude of the dielectric function with respect to its bulk value. Furthermore, an increase in the bulk salt concentration is shown to increase the local charge inside the brush region.

  19. Regulation of REGγ cellular distribution and function by SUMO modification

    Institute of Scientific and Technical Information of China (English)

    Yan Wu; Honglin Luo; Xiaotao Li; Lu Wang; Ping Zhou; Guangqiang Wang; Yu Zeng; Ying Wang; Jian Liu; Bianhong Zhang; Shuang Liu

    2011-01-01

    Discovery of emerging REGy-regulated proteins has accentuated the RECry-proteasome as an important pathway in multiple biological processes, including cell growth, cell cycle regulation, and apoptosis. However, little is known about the regulation of the REGy-proteasome pathway. Here we demonstrate that REGγ can be SUMOylated in vitro and in vivo by SUMO-1, SUMO-2, and SUMO-3. The SUMO-E3 protein inhibitor of activated STAT(PIAS)1physically associates with REGy and promotes SUMOylation of REGy. SUMOylation of RECry was found to occur at multiple sites, including K6, K14, and K12. Mutation analysis indicated that these SUMO sites simultaneously contributed to the SUMOylation status of REGy in cells. Posttranslational modification of REGγ by SUMO conjugation was revealed to mediate cytosolic translocation of REGγ and to cause increased stability of this proteasome activator.SUMOylation-deficient REGγ displayed attenuated ability to degrade p21waf//Cipl due to reduced affinity of the REGγ SUMOylation-defective mutant for p21. Taken together, we report a previously unrecognized mechanism regulating the activity of the proteasome activator REGy. This regulatory mechanism may enable REGy to function as a more potent factor in protein degradation with a broader substrate spectrum.

  20. Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function.

    Science.gov (United States)

    Haines, Ricci J; Corbin, Karen D; Pendleton, Laura C; Meininger, Cynthia J; Eichler, Duane C

    2012-04-27

    Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regulates AS and eNOS transcription to support NO production. Moreover, we show that insulin enhances NO production in response to physiological cues such as bradykinin. To translate these results to an in vivo model, we show that AS transcription is diminished in coronary endothelial cells isolated from rats with streptozotocin (STZ)-induced diabetes. Importantly, we demonstrate restoration of AS and eNOS transcription by insulin treatment in STZ-diabetic rats, and show that this restoration was accompanied by improved endothelial function as measured by endothelium-dependent vasorelaxation. Overall, this report demonstrates, both in cell culture and whole animal studies, that insulin maintains vascular function, in part, through the maintenance of AS transcription, thus ensuring an adequate supply of arginine to maintain vascular endothelial response to physiological cues. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Kif5 regulates mitochondrial movement, morphology, function and neuronal survival.

    Science.gov (United States)

    Iworima, Diepiriye G; Pasqualotto, Bryce A; Rintoul, Gordon L

    2016-04-01

    Due to the unique architecture of neurons, trafficking of mitochondria throughout processes to regions of high energetic demand is critical to sustain neuronal health. It has been suggested that compromised mitochondrial trafficking may play a role in neurodegenerative diseases. We evaluated the consequences of disrupted kif5c-mediated mitochondrial trafficking on mitochondrial form and function in primary rat cortical neurons. Morphological changes in mitochondria appeared to be due to remodelling, a phenomenon distinct from mitochondrial fission, which resulted in punctate-shaped mitochondria. We also demonstrated that neurons displaying punctate mitochondria exhibited relatively decreased ROS and increased cellular ATP levels using ROS-sensitive GFP and ATP FRET probes, respectively. Somewhat unexpectedly, neurons overexpressing the dominant negative form of kif5c exhibited enhanced survival following excitotoxicity, suggesting that the impairment of mitochondrial trafficking conferred some form of neuroprotection. However, when neurons were exposed to H2O2, disruption of kif5c exacerbated cell death indicating that the effect on cell viability was dependent on the mode of toxicity. Our results suggest a novel role of kif5c. In addition to mediating mitochondrial transport, kif5c plays a role in the mechanism of regulating mitochondrial morphology. Our results also suggest that kif5c mediated mitochondrial dynamics may play an important role in regulating mitochondrial function and in turn cellular health. Moreover, our studies demonstrate an interesting interplay between the regulation of mitochondrial motility and morphology.

  2. Regulation of immunological and inflammatory functions by biotin.

    Science.gov (United States)

    Kuroishi, Toshinobu

    2015-12-01

    Biotin is a water-soluble B-complex vitamin and is well-known as a co-factor for 5 indispensable carboxylases. Holocarboxylase synthetase (HLCS) catalyzes the biotinylation of carboxylases and other proteins, whereas biotinidase catalyzes the release of biotin from biotinylated peptides. Previous studies have reported that nutritional biotin deficiency and genetic defects in either HLCS or biotinidase induces cutaneous inflammation and immunological disorders. Since biotin-dependent carboxylases involve various cellular metabolic pathways including gluconeogenesis, fatty acid synthesis, and the metabolism of branched-chain amino acids and odd-chain fatty acids, metabolic abnormalities may play important roles in immunological and inflammatory disorders caused by biotin deficiency. Transcriptional factors, including NF-κB and Sp1/3, are also affected by the status of biotin, indicating that biotin regulates immunological and inflammatory functions independently of biotin-dependent carboxylases. An in-vivo analysis with a murine model revealed the therapeutic effects of biotin supplementation on metal allergies. The novel roles of biotinylated proteins and their related enzymes have recently been reported. Non-carboxylase biotinylated proteins induce chemokine production. HLCS is a nuclear protein involved in epigenetic and chromatin regulation. In this review, comprehensive knowledge on the regulation of immunological and inflammatory functions by biotin and its potential as a therapeutic agent is discussed.

  3. Structure and function of the cystic fibrosis transmembrane conductance regulator

    Directory of Open Access Journals (Sweden)

    M.M. Morales

    1999-08-01

    Full Text Available Cystic fibrosis (CF is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR. Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs, and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs.

  4. Regulation of ROS Production and Vascular Function by Carbon Monoxide

    Directory of Open Access Journals (Sweden)

    Yoon Kyung Choi

    2012-01-01

    Full Text Available Carbon monoxide (CO is a gaseous molecule produced from heme by heme oxygenase (HO. CO interacts with reduced iron of heme-containing proteins, leading to its involvement in various cellular events via its production of mitochondrial reactive oxygen species (ROS. CO-mediated ROS production initiates intracellular signal events, which regulate the expression of adaptive genes implicated in oxidative stress and functions as signaling molecule for promoting vascular functions, including angiogenesis and mitochondrial biogenesis. Therefore, CO generated either by exogenous delivery or by HO activity can be fundamentally involved in regulating mitochondria-mediated redox cascades for adaptive gene expression and improving blood circulation (i.e., O2 delivery via neovascularization, leading to the regulation of mitochondrial energy metabolism. This paper will highlight the biological effects of CO on ROS generation and cellular redox changes involved in mitochondrial metabolism and angiogenesis. Moreover, cellular mechanisms by which CO is exploited for disease prevention and therapeutic applications will also be discussed.

  5. Human Prostatic Acid Phosphatase: Structure, Function and Regulation

    Directory of Open Access Journals (Sweden)

    William G. Chaney

    2013-05-01

    Full Text Available Human prostatic acid phosphatase (PAcP is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa cells, which results in reduced tumorigenicity. Further, the interaction of cPAcP and ErbB-2 regulates androgen sensitivity of PCa cells. Knockdown of cPAcP expression allows androgen-sensitive PCa cells to develop the castration-resistant phenotype, where cells proliferate under an androgen-reduced condition. Thus, cPAcP has a significant influence on PCa cell growth. Interestingly, promoter analysis suggests that PAcP expression can be regulated by NF-κB, via a novel binding sequence in an androgen-independent manner. Further understanding of PAcP function and regulation of expression will have a significant impact on understanding PCa progression and therapy.

  6. Functional Enhancers As Master Regulators of Tissue-Specific Gene Regulation and Cancer Development

    Science.gov (United States)

    Ko, Je Yeong; Oh, Sumin; Yoo, Kyung Hyun

    2017-01-01

    Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells. In addition, noncoding RNAs, named eRNAs, are synthesized at super-enhancer regions before their target genes are transcribed. Many functional studies revealed that super-enhancers and eRNAs are essential for the regulation of tissue-specific gene expression. In this review, we summarize recent findings concerning enhancer function in tissue-specific gene regulation and cancer development. PMID:28359147

  7. Effect of heat stress on intestinal barrier function of human intestinal epithelial Caco-2 cells

    Directory of Open Access Journals (Sweden)

    Gui-zhen XIAO

    2013-07-01

    Full Text Available Objective To investigate the heat stress-induced dysfunction of intestinal barrier including intestinal tight junction and apoptosis of epithelial cells. Methods Human intestinal epithelial Caco-2 cell monolayers, serving as the intestinal barrier model, were exposed to different temperature (37-43℃ for designated time. Transepithelial electrical resistance (TEER and horseradish peroxidase (HRP flux permeability were measured to evaluate barrier integrity. Level of tight junction (TJ protein occludin was analyzed by Western blotting. Cell apoptosis rate was determined using Annexin V-FITC/PI kit by flow cytometry. Results Compared with the 37℃ group, TEER lowered and the permeability for HRP increased significantly after heat exposure (P<0.01 in 39℃, 41℃ and 43℃ groups. The expression of occludin increased when the temperature was elevated from 37℃ to 41℃, and it reached the maximal level at 41℃. However, its expression gradually decreased with passage of time at 43℃. Cell apoptosis was enhanced with elevation of the temperature (P<0.05 or P<0.01. Conclusion Heat stress can induce damage to tight junction and enhance apoptosis of epithelial cells, thus causing dysfunction of intestinal epithelial barrier.

  8. Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

    NARCIS (Netherlands)

    Ravenstijn, Paulien Gerarda Maria

    2009-01-01

    Parkinson’s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences

  9. PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

    Science.gov (United States)

    Hirabayashi, Tetsuya; Anjo, Tatsuki; Kaneko, Arisa; Senoo, Yuuya; Shibata, Akitaka; Takama, Hiroyuki; Yokoyama, Kohei; Nishito, Yasumasa; Ono, Tomio; Taya, Choji; Muramatsu, Kazuaki; Fukami, Kiyoko; Muñoz-Garcia, Agustí; Brash, Alan R.; Ikeda, Kazutaka; Arita, Makoto; Akiyama, Masashi; Murakami, Makoto

    2017-01-01

    Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1−/− epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1−/− keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects. PMID:28248300

  10. Addressing barriers to eco-innovation: Exploring the finance mobilisation functions of institutional innovation intermediaries

    NARCIS (Netherlands)

    Polzin, Friedemann; Flotow, von Paschen; Klerkx, L.W.A.

    2016-01-01

    This research article explores the role of institutional innovation intermediaries in accelerating the commercialisation of (clean) technologies. Drawing on the finance and innovation intermediaries literatures, we show that financial barriers to eco-innovation can be partly overcome by particular f

  11. Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

    NARCIS (Netherlands)

    Ravenstijn, Paulien Gerarda Maria

    2009-01-01

    Parkinson’s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences

  12. Addressing barriers to eco-innovation: Exploring the finance mobilisation functions of institutional innovation intermediaries

    NARCIS (Netherlands)

    Polzin, Friedemann; Flotow, von Paschen; Klerkx, L.W.A.

    2016-01-01

    This research article explores the role of institutional innovation intermediaries in accelerating the commercialisation of (clean) technologies. Drawing on the finance and innovation intermediaries literatures, we show that financial barriers to eco-innovation can be partly overcome by particular f

  13. A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease.

    Science.gov (United States)

    Rodríguez-Feo, Juan Antonio; Puerto, Marta; Fernández-Mena, Carolina; Verdejo, Cristina; Lara, José Manuel; Díaz-Sánchez, María; Álvarez, Emilio; Vaquero, Javier; Marín-Jiménez, Ignacio; Bañares, Rafael; Menchén, Luis

    2015-06-15

    Inflammatory bowel disease (IBD) is characterized by an impaired intestinal barrier function. We aimed to investigate the role of reticulon-4B (RTN-4B/NOGO-B), a structural protein of the endoplasmic reticulum, in intestinal barrier function and IBD. We used immunohistochemistry, confocal microscopy, real-time PCR, and Western blotting to study tissue distribution and expression levels of RTN-4B/NOGO-B in control and IBD samples from mouse and humans. We also targeted RTN-4B/NOGO-B using siRNAs in cultured human intestinal epithelial cell (IECs). Epithelial barrier permeability was assessed by transepithelial electrical resistance (TEER) measurement. RTN-4B/NOGO-B is expressed in the intestine mainly by IECs. Confocal microscopy revealed a colocalization of RTN-4B, E-cadherin, and polymerized actin fibers in tissue and cultured IECs. RTN-4B mRNA and protein expression were lower in the colon of IL-10(-/-) compared with wild-type mice. Colocalization of RTN-4B/E-cadherin/actin was reduced in the colon of IL-10(-/-) mice. Analysis of endoscopic biopsies from IBD patients showed a significant reduction of RTN-4B/NOGO-B expression in inflamed mucosa compared with control. Treatment of IECs with H2O2 reduced TEER values and triggered phosphorylation of RTN-4B in serine 107 residues as well as downregulation of RTN-4B expression. Acute RTN-4B/NOGO-B knockdown by siRNAs resulted in a decreased TEER values and reduction of E-cadherin and α-catenin expression and in the amount of F-actin-rich filaments in IECs. Epithelial RTN-4B/NOGO-B was downregulated in human and experimental IBD. RTN-4B participates in the intestinal epithelial barrier function, most likely via its involvement in E-cadherin, α-catenin expression, and actin cytoskeleton organization at sites of cell-to-cell contacts.

  14. Stratum Corneum Lipids: Their Role for the Skin Barrier Function in Healthy Subjects and Atopic Dermatitis Patients.

    Science.gov (United States)

    van Smeden, Jeroen; Bouwstra, Joke A

    2016-01-01

    Human skin acts as a primary barrier between the body and its environment. Crucial for this skin barrier function is the lipid matrix in the outermost layer of the skin, the stratum corneum (SC). Two of its functions are (1) to prevent excessive water loss through the epidermis and (2) to avoid that compounds from the environment permeate into the viable epidermal and dermal layers and thereby provoke an immune response. The composition of the SC lipid matrix is dominated by three lipid classes: cholesterol, free fatty acids and ceramides. These lipids adopt a highly ordered, 3-dimensional structure of stacked densely packed lipid layers (lipid lamellae): the lateral and lamellar lipid organization. The way in which these lipids are ordered depends on the composition of the lipids. One very common skin disease in which the SC lipid barrier is affected is atopic dermatitis (AD). This review addresses the SC lipid composition and organization in healthy skin, and elaborates on how these parameters are changed in lesional and nonlesional skin of AD patients. Concerning the lipid composition, the changes in the three main lipid classes and the importance of the carbon chain lengths of the lipids are discussed. In addition, this review addresses how these changes in lipid composition induce changes in lipid organization and subsequently correlate with an impaired skin barrier function in both lesional and nonlesional skin of these patients. Furthermore, the effect of filaggrin and mutations in the filaggrin gene on the SC lipid composition is critically discussed. Also, the breakdown products of filaggrin, the natural moisturizing factor molecules and its relation to SC-pH is described. Finally, the paper discusses some major changes in epidermal lipid biosynthesis in patients with AD and other related skin diseases, and how inflammation has a deteriorating effect on the SC lipids and SC biosynthesis. The review ends with perspectives on future studies in relation to

  15. The cortical acto-myosin network: from diffusion barrier to functional gateway in the transport of neurosecretory vesicles to the plasma membrane

    Directory of Open Access Journals (Sweden)

    Andreas ePapadopulos

    2013-10-01

    Full Text Available Dysregulation of regulated exocytosis is linked to an array of pathological conditions, including neurodegenerative disorders, asthma and diabetes. Understanding the molecular mechanisms underpinning neuroexocytosis including the processes that allow neurosecretory vesicles to access and fuse with the plasma membrane and to recycle post-fusion, is therefore critical to the design of future therapeutic drugs that will efficiently tackle these diseases. Despite considerable efforts to determine the principles of vesicular fusion, the mechanisms controlling the approach of vesicles to the plasma membrane in order to undergo tethering, docking, priming, and fusion remain poorly understood. All these steps involve the cortical actin network, a dense mesh of actin filaments localized beneath the plasma membrane. Recent work overturned the long-held belief that the cortical actin network only plays a passive constraining role in neuroexocytosis functioning as a physical barrier that partly breaks down upon entry of Ca2+ to allow secretory vesicles to reach the plasma membrane. A multitude of new roles for the cortical actin network in regulated exocytosis have now emerged and point to highly dynamic novel functions of key myosin molecular motors. Myosins are not only believed to help bring about dynamic changes in the actin cytoskeleton, tethering and guiding vesicles to their fusion sites, but they also regulate the size and duration of the fusion pore, thereby directly contributing to the release of neurotransmitters and hormones.Here we discuss the functions of the cortical actin network, myosins and their effectors in controlling the processes that lead to tethering, directed transport, docking, and fusion of exocytotic vesicles in regulated exocytosis.

  16. Regulation of Natural Killer Cell Function by STAT3

    Directory of Open Access Journals (Sweden)

    Nicholas eCacalano

    2016-04-01

    Full Text Available Natural killer (NK cells, key members of a distinct hempatopoietic lineage, innate lymphoid cells (ILCs, are critical effectors that mediate cytotoxicity toward tumor and virally-infected cells but also regulate inflammation, antigen presentation and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell-cell contact and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The Signal Transducer and Activator of Transcription (STAT-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of immune surveillance. Even after tumors become established, NK cells are critical components of anti-cancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients and the lack of NK cells in the tumor microenvironment often correlates with poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells which determine the outcome of cancer immunity are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of natural killer cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.

  17. Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

    Science.gov (United States)

    Savetsky, Ira L; Albano, Nicholas J; Cuzzone, Daniel A; Gardenier, Jason C; Torrisi, Jeremy S; García Nores, Gabriela D; Nitti, Matthew D; Hespe, Geoffrey E; Nelson, Tyler S; Kataru, Raghu P; Dixon, J Brandon; Mehrara, Babak J

    2015-11-01

    Obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. In addition, recent studies have shown that obesity impairs lymphatic function. As the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice. We found that obese mice have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant vascular endothelial growth factor-C remarkably increased lymphangiogenesis, lymphatic function, and lymphatic endothelial cell expression of chemokine (C-C motif) ligand 21, while decreasing inflammation and expression of inducible nitrous oxide synthase. These changes resulted in considerably decreased dermatitis responses in both lean and obese mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and a prolonged inflammatory response.

  18. Structural interaction and functional regulation of polycystin-2 by filamin.

    Directory of Open Access Journals (Sweden)

    Qian Wang

    Full Text Available Filamins are important actin cross-linking proteins implicated in scaffolding, membrane stabilization and signal transduction, through interaction with ion channels, receptors and signaling proteins. Here we report the physical and functional interaction between filamins and polycystin-2, a TRP-type cation channel mutated in 10-15% patients with autosomal dominant polycystic kidney disease. Yeast two-hybrid and GST pull-down experiments demonstrated that the C-termini of filamin isoforms A, B and C directly bind to both the intracellular N- and C-termini of polycystin-2. Reciprocal co-immunoprecipitation experiments showed that endogenous polycystin-2 and filamins are in the same complexes in renal epithelial cells and human melanoma A7 cells. We then examined the effect of filamin on polycystin-2 channel function by electrophysiology studies with a lipid bilayer reconstitution system and found that filamin-A substantially inhibits polycystin-2 channel activity. Our study indicates that filamins are important regulators of polycystin-2 channel function, and further links actin cytoskeletal dynamics to the regulation of this channel protein.

  19. Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat

    NARCIS (Netherlands)

    Visser, J. T. J.; Lammers, K.; Hoogendijk, A.; Boer, M. W.; Brugman, S.; Beijer-Liefers, S.; Zandvoort, A.; Harmsen, H.; Welling, G.; Stellaard, F.; Bos, N. A.; Fasano, A.; Rozing, J.

    2010-01-01

    Aims/hypothesis Impaired intestinal barrier function is observed in type I diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading

  20. Test Plan to Assess Fire Effects on the Function of an Engineered Surface Barrier

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Anderson L.; Berlin, Gregory T.; Cammann, Jerry W.; Leary, Kevin D.; Link, Steven O.

    2008-09-29

    Wildfire is a frequent perturbation in shrub steppe ecosystems, altering the flora, fauna, atmosphere, and soil of these systems. Research on the fire effects has focused mostly on natural ecosystems with essentially no attention on engineered systems like surface barriers. The scope of the project is to use a simulated wildfire to induce changes in an engineered surface barrier and document the effects on barrier performance. The main objective is to quantify the effects of burning and the resulting post-fire conditions on alterations in soil physical properties; hydrologic response, particularly the water balance; geochemical properties; and biological properties. A secondary objective is to use the lessons learned to maximize fire protection in the design of long-term monitoring systems based on electronic sensors. A simulated wildfire will be initiated, controlled and monitored at the 200-BP-1 barrier in collaboration with the Hanford Fire Department during the fall of 2008. The north half of the barrier will be divided into nine 12 x 12 m plots, each of which will be randomly assigned a fuel load of 2 kg m-2 or 4 kg m-2. Each plot will be ignited around the perimeter and flames allowed to carry to the centre. Any remaining unburned vegetation will be manually burned off using a drip torch. Progress of the fire and its effects will be monitored using point measurements of thermal, hydrologic, and biotic variables. Three measures of fire intensity will be used to characterize fire behavior: (1) flame height, (2) the maximum temperature at three vertical profile levels, and (3) total duration of elevated temperature at these levels. Pre-burn plant information, including species diversity, plant height, and canopy diameter will be measured on shrubs from the plots to be burned and from control plots at the McGee ranch. General assessments of shrub survival, recovery, and recruitment will be made after the fire. Near-surface soil samples will be collected pre- and

  1. miRNA-mediated functional changes through co-regulating function related genes.

    Directory of Open Access Journals (Sweden)

    Jie He

    Full Text Available BACKGROUND: MicroRNAs play important roles in various biological processes involving fairly complex mechanism. Analysis of genome-wide miRNA microarray demonstrate that a single miRNA can regulate hundreds of genes, but the regulative extent on most individual genes is surprisingly mild so that it is difficult to understand how a miRNA provokes detectable functional changes with such mild regulation. RESULTS: To explore the internal mechanism of miRNA-mediated regulation, we re-analyzed the data collected from genome-wide miRNA microarray with bioinformatics assay, and found that the transfection of miR-181b and miR-34a in Hela and HCT-116 tumor cells regulated large numbers of genes, among which, the genes related to cell growth and cell death demonstrated high Enrichment scores, suggesting that these miRNAs may be important in cell growth and cell death. MiR-181b induced changes in protein expression of most genes that were seemingly related to enhancing cell growth and decreasing cell death, while miR-34a mediated contrary changes of gene expression. Cell growth assays further confirmed this finding. In further study on miR-20b-mediated osteogenesis in hMSCs, miR-20b was found to enhance osteogenesis by activating BMPs/Runx2 signaling pathway in several stages by co-repressing of PPARγ, Bambi and Crim1. CONCLUSIONS: With its multi-target characteristics, miR-181b, miR-34a and miR-20b provoked detectable functional changes by co-regulating functionally-related gene groups or several genes in the same signaling pathway, and thus mild regulation from individual miRNA targeting genes could have contributed to an additive effect. This might also be one of the modes of miRNA-mediated gene regulation.

  2. Exosome Biogenesis, Regulation, and Function in Viral Infection.

    Science.gov (United States)

    Alenquer, Marta; Amorim, Maria João

    2015-09-17

    Exosomes are extracellular vesicles released upon fusion of multivesicular bodies(MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) during the process of MVB formation. Exosomes were shown to contain selectively sorted functional proteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in the physiology of the healthy and diseased organism. Challenges in the field include the identification of mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles and the understanding of the underlying processes directing MVBs for degradation or fusion with the plasma membrane. The investigation into the formation and roles of exosomes in viral infection is in its early years. Although still controversial, exosomes can, in principle, incorporate any functional factor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation.This review initially focuses on the composition and biogenesis of exosomes. It then explores the regulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system,which is tightly regulated and able to respond to several stimuli that lead to alterations in the composition of its sub-compartments. We discuss the current knowledge of how these changes affect exosomal release. We then summarize how different viruses exploit specific proteins of endocytic sub-compartments and speculate that it could interfere with exosome function, although no direct link between viral usage of the endocytic system and exosome release has yet been reported. Many recent reports have ascribed functions to exosomes released from cells infected with a variety of animal viruses, including viral spread, host immunity, and manipulation of the microenvironment, which are discussed. Given the ever-growing roles and importance of exosomes in viral infections, understanding what regulates their composition and levels, and

  3. Structure, Function and Regulation of the Clostridium cellulovorans Cellulosome

    Energy Technology Data Exchange (ETDEWEB)

    Doi, Roy H

    2008-06-01

    Our major goal for this project (2004-2008) was to obtain an understanding ofthe structure, function, and regulation of the Clostridium cellulovorans cellulosomes. Our specific goals were to select genes for cellulosomal and non-cellulosomal enzymes and characterize their products, to study the synergistic action between cellulosomal and non-cellulosomal enzymes, to study the composition of cellulosomes when cells were grown with different carbon sources, continue our studies on the scaffolding protein and examine heterologous expression of cellulosomal genes in Bacillus subtilis. We fulfilled the specific goals of our proposal.

  4. Fission excitation function for 19F + 194,196,198Pt at near and above barrier energies

    Directory of Open Access Journals (Sweden)

    Singh Varinderjit

    2015-01-01

    Full Text Available Fission excitation functions for 19F + 194,196,198Pt reactions populating 213,215,217Fr compound nuclei are reported. Out of these three compound nuclei, 213Fr is a shell closed (N=126 compound nucleus and the other two are away from the shell closure. From a comparison of the experimental fission cross-sections with the statistical model predictions, it is observed that the fission cross-sections are underestimated by the statistical model predictions using shell corrected finite range rotating liquid drop model (FRLDM fission barriers. Further the FRLDM fission barriers are reduced to fit the fission cross-sections over the entire measured energy range.

  5. Novel mechanisms that regulate clot structure/function.

    Science.gov (United States)

    Ariëns, Robert A S

    2016-05-01

    The structure and function of the blood clot has been associated with altered risk of thrombosis. Dense fibrin structures with small pores increase the risk of thrombosis, and have major functional consequences by increasing the resistance to fibrinolysis and altering the visco-elastic properties of the clot. However, while the structural changes to the overall fibrin network have been extensively characterised, little is known regarding the intrafibrillar structure of fibrin, the way protofibrils are arranged inside the fibrin fibers and the functional consequences of this. This brief paper aims to review recent findings regarding novel mechanisms that regulate fibrin intrafibrillar structure, including the degree of protofibril packing, their functional consequences, and the effects of FXIII activation on clot structure and thrombosis. It is concluded that fibrin intrafibrillar structure represents a major novel mechanism that influences clot structure and stability. Future studies are required to investigate the role of fibrin intrafibrillar structure in the functional characteristics of the blood clot, and in diseases of bleeding and thrombosis.

  6. Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability.

    Science.gov (United States)

    Kürti, Levente; Veszelka, Szilvia; Bocsik, Alexandra; Ozsvári, Béla; Puskás, László G; Kittel, Agnes; Szabó-Révész, Piroska; Deli, Mária A

    2013-05-01

    The nasal pathway represents an alternative route for non-invasive systemic administration of drugs. The main advantages of nasal drug delivery are the rapid onset of action, the avoidance of the first-pass metabolism in the liver and the easy applicability. In vitro cell culture systems offer an opportunity to model biological barriers. Our aim was to develop and characterize an in vitro model based on confluent layers of the human RPMI 2650 cell line. Retinoic acid, hydrocortisone and cyclic adenosine monophosphate, which influence cell attachment, growth and differentiation have been investigated on the barrier formation and function of the nasal epithelial cell layers. Real-time cell microelectronic sensing, a novel label-free technique was used for dynamic monitoring of cell growth and barrier properties of RPMI 2650 cells. Treatments enhanced the formation of adherens and tight intercellular junctions visualized by electron microscopy, the presence and localization of junctional proteins ZO-1 and β-catenin demonstrated by fluorescent immunohistochemistry, and the barrier function of nasal epithelial cell layers. The transepithelial resistance of the RPMI 2650 cell model reached 50 to 200 Ω × cm(2), the permeability coefficient for 4.4 kDa FITC-dextran was 9.3 to 17 × 10(-6) cm/s, in agreement with values measured on nasal mucosa from in vivo and ex vivo experiments. Based on these results human RPMI 2650 cells seem to be a suitable nasal epithelial model to test different pharmaceutical excipients and various novel formulations, such as nanoparticles for toxicity and permeability.

  7. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

    DEFF Research Database (Denmark)

    Høgh, Julie Kaae; Hellgren, Lars; Jungersted, JM

    2010-01-01

    Background: Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now......, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. Methods: A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer...... differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Conclusion: Our results...

  8. The Role of ATP in the Regulation of NCAM Function

    DEFF Research Database (Denmark)

    Hübschmann, Martin; Skladchikova, Galina

    2008-01-01

    Extracellular ATP is an abundant signaling molecule that has a number of functions in the nervous system. It is released by both neurons and glial cells, activates purinergic receptors and acts as a trophic factor as well as a neurotransmitter. In this review, we summarize the evidence for a direct...... ATP-NCAM interaction and discuss its functional implications. The ectodomain of NCAM contains the ATP binding Walker motif A and has intrinsic ATPase activity, which could modulate NCAM-dependent signaling processes. NCAM interacts directly with and signals through FGFR. The NCAM binding site to ATP...... overlaps with the site of NCAM-FGFR interaction, and ATP is capable of disrupting NCAM-FGFR binding. This implies that NCAM signaling through FGFR can be regulated by ATP, which is supported by the observation that ATP can abrogate NCAM-induced neurite outgrowth. Finally, ATP can induce NCAM ectodomain...

  9. Structure, regulation and function of gap junctions in liver

    Science.gov (United States)

    Maes, Michaël; Decrock, Elke; Wang, Nan; Leybaert, Luc; da Silva, Tereza Cristina; Veloso Alves Pereira, Isabel; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2016-01-01

    Gap junctions are a specialized group of cell-to-cell junctions that mediate direct intercellular communication between cells. They arise from the interaction of 2 hemichannels of adjacent cells, which in turn are composed of 6 connexin proteins. In liver, gap junctions are predominantly found in hepatocytes and play critical roles in virtually all phases of the hepatic life cycle, including cell growth, differentiation, liver-specific functionality and cell death. Liver gap junctions are directed through a broad variety of mechanisms ranging from epigenetic control of connexin expression to posttranslational regulation of gap junction activity. This paper reviews established and novel aspects regarding the architecture, control and functional relevance of liver gap junctions. PMID:27001459

  10. Role of Estrogen in Thyroid Function and Growth Regulation

    Directory of Open Access Journals (Sweden)

    Ana Paula Santin

    2011-01-01

    Full Text Available Thyroid diseases are more prevalent in women, particularly between puberty and menopause. It is wellknown that estrogen (E has indirect effects on the thyroid economy. Direct effects of this steroid hormone on thyroid cells have been described more recently; so, the aim of the present paper was to review the evidences of these effects on thyroid function and growth regulation, and its mechanisms. The expression and ratios of the two E receptors, α and β, that mediate the genomic effects of E on normal and abnormal thyroid tissue were also reviewed, as well as nongenomic, distinct molecular pathways. Several evidences support the hypothesis that E has a direct role in thyroid follicular cells; understanding its influence on the growth and function of the thyroid in normal and abnormal conditions can potentially provide new targets for the treatment of thyroid diseases.

  11. Function and regulation of lipid biology in Caenorhabditis elegans aging

    Directory of Open Access Journals (Sweden)

    Nicole Shangming Hou

    2012-05-01

    Full Text Available Rapidly expanding aging populations and a concomitant increase in the prevalence of age-related diseases are global health problems today. Over the past three decades, a large body of work has led to the identification of genes and regulatory networks that affect longevity and health span, often benefitting from the tremendous power of genetics in vertebrate and invertebrate model organisms. Interestingly, many of these factors appear linked to lipids, important molecules that participate in cellular signaling, energy metabolism, and structural compartmentalization. Despite the putative link between lipids and longevity, the role of lipids in aging remains poorly understood. Emerging data from the model organism Caenorhabditis elegans suggest that lipid composition may change during aging, as several pathways that influence aging also regulate lipid metabolism enzymes; moreover, some of these enzymes apparently play key roles in the pathways that affect the rate of aging. By understanding how lipid biology is regulated during C. elegans aging, and how it impacts molecular, cellular and organismal function, we may gain insight into novel ways to delay aging using genetic or pharmacological interventions. In the present review we discuss recent insights into the roles of lipids in C. elegans aging, including regulatory roles played by lipids themselves, the regulation of lipid metabolic enzymes, and the roles of lipid metabolism genes in the pathways that affect aging.

  12. TonB-dependent transporters: regulation, structure, and function.

    Science.gov (United States)

    Noinaj, Nicholas; Guillier, Maude; Barnard, Travis J; Buchanan, Susan K

    2010-01-01

    TonB-dependent transporters (TBDTs) are bacterial outer membrane proteins that bind and transport ferric chelates, called siderophores, as well as vitamin B(12), nickel complexes, and carbohydrates. The transport process requires energy in the form of proton motive force and a complex of three inner membrane proteins, TonB-ExbB-ExbD, to transduce this energy to the outer membrane. The siderophore substrates range in complexity from simple small molecules such as citrate to large proteins such as serum transferrin and hemoglobin. Because iron uptake is vital for almost all bacteria, expression of TBDTs is regulated in a number of ways that include metal-dependent regulators, σ/anti-σ factor systems, small RNAs, and even a riboswitch. In recent years, many new structures of TBDTs have been solved in various states, resulting in a more complete understanding of siderophore selectivity and binding, signal transduction across the outer membrane, and interaction with the TonB-ExbB-ExbD complex. However, the transport mechanism is still unclear. In this review, we summarize recent progress in understanding regulation, structure, and function in TBDTs and questions remaining to be answered.

  13. Function and Regulation of Lipid Biology in Caenorhabditis elegans Aging

    Science.gov (United States)

    Hou, Nicole Shangming; Taubert, Stefan

    2012-01-01

    Rapidly expanding aging populations and a concomitant increase in the prevalence of age-related diseases are global health problems today. Over the past three decades, a large body of work has led to the identification of genes and regulatory networks that affect longevity and health span, often benefiting from the tremendous power of genetics in vertebrate and invertebrate model organisms. Interestingly, many of these factors appear linked to lipids, important molecules that participate in cellular signaling, energy metabolism, and structural compartmentalization. Despite the putative link between lipids and longevity, the role of lipids in aging remains poorly understood. Emerging data from the model organism Caenorhabditis elegans suggest that lipid composition may change during aging, as several pathways that influence aging also regulate lipid metabolism enzymes; moreover, some of these enzymes apparently play key roles in the pathways that affect the rate of aging. By understanding how lipid biology is regulated during C. elegans aging, and how it impacts molecular, cellular, and organismal function, we may gain insight into novel ways to delay aging using genetic or pharmacological interventions. In the present review we discuss recent insights into the roles of lipids in C. elegans aging, including regulatory roles played by lipids themselves, the regulation of lipid metabolic enzymes, and the roles of lipid metabolism genes in the pathways that affect aging. PMID:22629250

  14. Iloprost improves endothelial barrier function in LPS-induced lung injury

    Science.gov (United States)

    Birukova, Anna A.; Wu, Tinghuai; Tian, Yufeng; Meliton, Angelo; Sarich, Nicolene; Tian, Xinyong; Leff, Alan; Birukov, Konstantin G.

    2013-01-01

    RATIONALE Protective effects of prostacyclin and its stable analog Iloprost are mediated by elevation of intracellular cAMP leading to enhancement of peripheral actin cytoskeleton and cell-cell adhesive structures. This study tested hypothesis that iloprost may exhibit protective effects against lung injury and endothelial barrier dysfunction induced by bacterial wall lypopolysacharide (LPS). METHODS Endothelial barrier dysfunction was assessed by measurements of transendothelial permeability, morphologically, and analysis of LPS-activated inflammatory signaling. In vivo, C57BL/6J mice were challenged with LPS with or without iloprost or 8-bromoadenosine-3′,5′-cyclic monophosphate (Br-cAMP) treatment. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, and Evans blue extravasation. RESULTS Iloprost and Br-cAMP attenuated disruption of endothelial monolayer and suppressed activation of p38 mitogen activated protein (MAP) kinase, NFκB pathway, Rho signaling, ICAM1 expression, and neutrophil migration after LPS challenge. In vivo, iloprost was effective against LPS-induced protein and neutrophil accumulation in bronchoalveolar lavage fluid and reduced myeloperoxidase activation, ICAM-1 expression, and Evans blue extravasation in the lungs. Inhibition of Rac activity abolished barrier protective and anti-inflammatory effects of iloprost and Br-cAMP. CONCLUSION Iloprost-induced elevation of intracellular cAMP triggers Rac signaling, which attenuates LPS-induced NFκB and p38 MAPK inflammatory pathways and Rho-dependent mechanism of endothelial permeability. PMID:22790920

  15. Regulative Function of Telomerase and Extracelluar Regulated Protein Kinases to Leukemic Cell Apoptosis

    Institute of Scientific and Technical Information of China (English)

    李登举; 张瑶珍; 曹文静; 孙岚; 徐慧珍; 路武

    2002-01-01

    Summary: In order to investigate the regulative function of telomerase and phosphorylated (acti-vated) extracelluar regulated protein kinase (ERK) i and 2 in the leukemic cell lines HL-60 andK562 proliferation inhibition and apoptosis, three chemotherapeutic drugs Harringtonine (HRT),Vincristine(VCR)and Etoposide(Vp16)were selected as inducers. The proliferation inhibition ratewas detected by MTT method, the cell cycle and cell apoptosis was analyzed by flow cytometryand the telomerase activity was detected by the telomeric repeat amplification protocol (TRAP)assay and bioluminescence analysis method. The phosphorylated ERK1/2 protein expression wasdetected by western blot method. The results showed that HRT, VCR and Vp16 could inhibit cellproliferation, induce apoptosis, inhibit telomerase activity and down-regulate the protein expres-sion of phosphorylated ERK. It was suggested that ERK signal transduction pathway was involvedin the down-regulation of telomerase activity and the onset of apoptosis in the leukemic cells treat-ed by HRT, VCR and Vp16.

  16. Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function.

    Science.gov (United States)

    Sahakian, Eva; Powers, John J; Chen, Jie; Deng, Susan L; Cheng, Fengdong; Distler, Allison; Woods, David M; Rock-Klotz, Jennifer; Sodre, Andressa L; Youn, Je-In; Woan, Karrune V; Villagra, Alejandro; Gabrilovich, Dmitry; Sotomayor, Eduardo M; Pinilla-Ibarz, Javier

    2015-02-01

    Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.

  17. Regulation of thrombosis and vascular function by protein methionine oxidation

    Science.gov (United States)

    Gu, Sean X.; Stevens, Jeff W.

    2015-01-01

    Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

  18. Cellular Functions Regulated by Phosphorylation of EGFR on Tyr845

    Directory of Open Access Journals (Sweden)

    Ken-ichi Sato

    2013-05-01

    Full Text Available The Src gene product (Src and the epidermal growth factor receptor (EGFR are prototypes of oncogene products and function primarily as a cytoplasmic non-receptor tyrosine kinase and a transmembrane receptor tyrosine kinase, respectively. The identification of Src and EGFR, and the subsequent extensive investigations of these proteins have long provided cutting edge research in cancer and other molecular and cellular biological studies. In 1995, we reported that the human epidermoid carcinoma cells, A431, contain a small fraction of Src and EGFR in which these two kinase were in physical association with each other, and that Src phosphorylates EGFR on tyrosine 845 (Y845 in the Src-EGFR complex. Y845 of EGFR is located in the activation segment of the kinase domain, where many protein kinases contain kinase-activating autophosphorylation sites (e.g., cAMP-dependent protein kinase, Src family kinases, transmembrane receptor type tyrosine kinases or trans-phosphorylation sites (e.g., cyclin-dependent protein kinase, mitogen-activated protein kinase, Akt protein kinase. A number of studies have demonstrated that Y845 phosphorylation serves an important role in cancer as well as normal cells. Here we compile the experimental facts involving Src phosphorylation of EGFR on Y845, by which cell proliferation, cell cycle control, mitochondrial regulation of cell metabolism, gamete activation and other cellular functions are regulated. We also discuss the physiological relevance, as well as structural insights of the Y845 phosphorylation.

  19. Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune regulation and brain-gut interactions.

    Science.gov (United States)

    Hyland, Niall P; Quigley, Eamonn M M; Brint, Elizabeth

    2014-07-21

    Irritable bowel syndrome (IBS) is a common, sometimes debilitating, gastrointestinal disorder worldwide. While altered gut motility and sensation, as well as aberrant brain perception of visceral events, are thought to contribute to the genesis of symptoms in IBS, a search for an underlying aetiology has, to date, proven unsuccessful. Recently, attention has been focused on the microbiota as a possible factor in the pathogenesis of IBS. Prompted by a number of clinical observations, such as the recognition of the de novo development of IBS following enteric infections, as well as descriptions of changes in colonic bacterial populations in IBS and supported by clinical responses to interventions, such as antibiotics and probiotics, that modify the microbiota, various approaches have been taken to investigating the microbiota-host response in IBS, as well as in animal models thereof. From such studies a considerable body of evidence has accumulated to indicate the activation or upregulation of both factors involved in bacterial engagement with the host as well host defence mechanisms against bacteria. Alterations in gut barrier function, occurring in response, or in parallel, to changes in the microbiota, have also been widely described and can be seen to play a pivotal role in generating and sustaining host immune responses both within and beyond the gut. In this manner a plausible hypothesis, based on an altered microbiota and/or an aberrant host response, for the pathogenesis, of at least some instances of IBS, can be generated.

  20. Validation of a questionnaire measuring the regulation of autonomic function

    Directory of Open Access Journals (Sweden)

    Matthes H

    2008-06-01

    Full Text Available Abstract Background To broaden the range of outcomes that we can measure for patients undergoing treatment for oncological and other chronic conditions, we aimed to validate a questionnaire measuring self-reported autonomic regulation (aR, i.e. to characterise a subject's autonomic functioning by questions on sleeping and waking, vertigo, morningness-eveningness, thermoregulation, perspiration, bowel movements and digestion. Methods We administered the questionnaire to 440 participants (♀: N = 316, ♂: N = 124: 95 patients with breast cancer, 49 with colorectal cancer, 60 with diabetes mellitus, 39 with coronary heart disease, 28 with rheumatological conditions, 32 with Hashimoto's disease, 22 with multiple morbidities and 115 healthy people. We administered the questionnaire a second time to 50.2% of the participants. External convergence criteria included the German version of the Hospital Anxiety and Depression Scale (HADS-D, a short questionnaire on morningness-eveningness, the Herdecke Quality of Life Questionnaire (HLQ and a short version questionnaire on self-regulation. Results A principal component analysis yielded a three dimensional 18-item inventory of aR. The subscales orthostatic-circulatory, rest/activity and digestive regulation had internal consistency (Cronbach-α: rα = 0.65 – 0.75 and test-retest reliability (rrt = 0.70 – 85. AR was negatively associated with anxiety, depression, and dysmenorrhoea but positively correlated to HLQ, self-regulation and in part to morningness (except digestive aR (0.49 – 0.13, all p Conclusion An internal validation of the long-version scale of aR yielded consistent relationships with health versus illness, quality of life and personality. Further studies are required to clarify the issues of external validity, clinical and physiological relevance.

  1. Influence of puerarin, paeoniflorin, and menthol on structure and barrier function of tight junctions in MDCK and MDCK-MDR1 Cells

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    2015-04-01

    Conclusion: Menthol but not puerarin and paeoniflorin may enhance paracellular transport and improve drug penetration of the BBB by disrupting the structure and, thereby, weakening the barrier function of TJs.

  2. A look at epidermal barrier function in atopic dermatitis: physiologic lipid replacement and the role of ceramides.

    Science.gov (United States)

    Sajić, D; Asiniwasis, R; Skotnicki-Grant, S

    2012-07-01

    This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD.

  3. Circumventricular organs: definition and role in the regulation of endocrine and autonomic function.

    Science.gov (United States)

    Ganong, W F

    2000-01-01

    1. The circumventricular organs (CVO) are structures that permit polypeptide hypothalamic hormones to leave the brain without disrupting the blood-brain barrier (BBB) and permit substances that do not cross the BBB to trigger changes in brain function. 2. In mammals, CVO include only the median eminence and adjacent neurohypophysis, organum vasculosum lamina terminalis, subfornical organ and the area postrema. 3. The CVO are characterized by their small size, high permeability and fenestrated capillaries. The subcommissural organ is not highly permeable and does not have fenestrated capillaries, but new evidence indicates that it may be involved in the hypertension produced by aldosterone acting on the brain. 4. Feedback control of corticotropin-releasing hormone (CRH) secretion is exerted by free steroids diffusing into the brain, but substances such as cytokines and angiotensin II act on CVO to produce increases in CRH secretion. Gonadal steroids also diffuse into the brain to regulate gonadotrophin-releasing hormone secretion. Thyrotropin-releasing hormone secretion is regulated by thyroid hormones transported across cerebral capillaries. However, CVO may be involved in the negative feedback control of growth hormone and prolactin secretion.

  4. Male gonadal function in coeliac disease: III. Pituitary regulation.

    Science.gov (United States)

    Farthing, M J; Rees, L H; Dawson, A M

    1983-12-01

    Pituitary regulation of gonadal function was investigated in 39 consecutive men with treated and untreated coeliac disease and in an intestinal disease control group of 19 men with Crohn's disease of similar age and general nutritional status. Basal serum FSH concentration was increased in 10 of the coeliacs (26%) compared to only two of 19 men with Crohn's disease (11%). This abnormality was observed with equal frequency in both treated and untreated coeliacs, and was not associated with oligospermia. Serum LH concentration was increased in eight of 15 untreated coeliacs (53%) with sub-total villous atrophy, an abnormality which unlike the elevation of serum FSH, appears to return towards normal after gluten withdrawal. Serum LH was high in coeliacs despite marked elevation of the free testosterone index. Exaggerated responses of FSH and LH to LHRH were found in 89% and 45% respectively, of coeliacs with sub-total villous atrophy. However, exaggerated responses of LH alone were found more frequently in coeliacs than in men with Crohn's disease (P less than 0.02) and unlike the exaggerated FSH responses, LH responses were closely related to jejunal morphology. Exaggerated responses of FSH and LH in coeliacs were commonly found when basal gonadotrophin concentrations were normal. The occurrence of exaggerated gonadotrophin responses could not be related to plasma concentration of testosterone, dihydrotestosterone, oestradiol or the free testosterone index. Serum prolactin was modestly raised in 25% of untreated and partially treated coeliacs and in the same proportion of men with Crohn's disease. Elevated serum prolactin concentrations never exceeded 809 mU/l and were not associated with impotence or infertility. This study provides further evidence that in men with coeliac disease there is a derangement of pituitary regulation of gonadal function. This would seem to be part of a wider disturbance of central regulatory mechanisms of endocrine function in coeliac

  5. Iloprost improves endothelial barrier function in lipopolysaccharide-induced lung injury.

    Science.gov (United States)

    Birukova, Anna A; Wu, Tinghuai; Tian, Yufeng; Meliton, Angelo; Sarich, Nicolene; Tian, Xinyong; Leff, Alan; Birukov, Konstantin G

    2013-01-01

    The protective effects of prostacyclin and its stable analogue iloprost are mediated by elevation of intracellular cyclic AMP (cAMP) leading to enhancement of the peripheral actin cytoskeleton and cell-cell adhesive structures. This study tested the hypothesis that iloprost may exhibit protective effects against lung injury and endothelial barrier dysfunction induced by bacterial wall lipopolysaccharide (LPS). Endothelial barrier dysfunction was assessed by measurements of transendothelial permeability, morphologically and by analysis of LPS-activated inflammatory signalling. In vivo, C57BL/6J mice were challenged with LPS with or without iloprost or 8-bromoadenosine-3',5'-cyclic monophosphate (Br-cAMP) treatment. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count and Evans blue extravasation. Iloprost and Br-cAMP attenuated the disruption of the endothelial monolayer, and suppressed the activation of p38 mitogen-activated protein kinase (MAPK), the nuclear factor (NF)-κB pathway, Rho signalling, intercellular adhesion molecular (ICAM)-1 expression and neutrophil migration after LPS challenge. In vivo, iloprost was effective against LPS-induced protein and neutrophil accumulation in bronchoalveolar lavage fluid, and reduced myeloperoxidase activation, ICAM-1 expression and Evans blue extravasation in the lungs. Inhibition of Rac activity abolished the barrier-protective and anti-inflammatory effects of iloprost and Br-cAMP. Iloprost-induced elevation of intracellular cAMP triggers Rac signalling, which attenuates LPS-induced NF-κB and p38 MAPK inflammatory pathways and the Rho-dependent mechanism of endothelial permeability.

  6. Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.

    Science.gov (United States)

    Vaziri, Nosratola D; Zhao, Ying-Yong; Pahl, Madeleine V

    2016-05-01

    Chronic kidney disease (CKD) results in systemic inflammation and oxidative stress which play a central role in CKD progression and its adverse consequences. Although many of the causes and consequences of oxidative stress and inflammation in CKD have been extensively explored, little attention had been paid to the intestine and its microbial flora as a potential source of these problems. Our recent studies have revealed significant disruption of the colonic, ileal, jejunal and gastric epithelial tight junction in different models of CKD in rats. Moreover, the disruption of the epithelial barrier structure and function found in uremic animals was replicated in cultured human colonocytes exposed to uremic human plasma in vitro We have further found significant changes in the composition and function of colonic bacterial flora in humans and animals with advanced CKD. Together, uremia-induced impairment of the intestinal epithelial barrier structure and function and changes in composition of the gut microbiome contribute to the systemic inflammation and uremic toxicity by accommodating the translocation of endotoxin, microbial fragments and other noxious luminal products in the circulation. In addition, colonic bacteria are the main source of several well-known pro-inflammatory uremic toxins such as indoxyl sulfate, p-cresol sulfate, trimethylamine-N-oxide and many as-yet unidentified retained compounds in end-stage renal disease patients. This review is intended to provide an overview of the effects of CKD on the gut microbiome and intestinal epithelial barrier structure and their role in the pathogenesis of systemic inflammation and uremic toxicity. In addition, potential interventions aimed at mitigating these abnormalities are briefly discussed.

  7. Balancing spatially regulated β-actin translation and dynamin-mediated endocytosis is required to assemble functional epithelial monolayers.

    Science.gov (United States)

    Cruz, Lissette A; Vedula, Pavan; Gutierrez, Natasha; Shah, Neel; Rodriguez, Steven; Ayee, Brian; Davis, Justin; Rodriguez, Alexis J

    2015-12-01

    -mediated endocytosis regulates epithelial monolayer structure and barrier function.

  8. Functional Imaging of Autonomic Regulation: Methods and Key Findings

    Directory of Open Access Journals (Sweden)

    Paul M Macey

    2016-01-01

    Full Text Available Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI. The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: 1 describe the fMRI neuroimaging methodology for assessment of autonomic neural control, 2 outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, 3 illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and 4 highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with

  9. Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions

    Science.gov (United States)

    Storch, Golo; Pallmann, Sebastian; Rominger, Frank

    2016-01-01

    Summary Stereodynamic ligands offer intriguing possibilities in enantioselective catalysis. “NU-BIPHEPs” are a class of stereodynamic diphosphine ligands which are easily accessible via rhodium-catalyzed double [2 + 2 + 2] cycloadditions. This study explores the preparation of differently functionalized “NU-BIPHEP(O)” compounds, the characterization of non-covalent adduct formation and the quantification of enantiomerization barriers. In order to explore the possibilities of functionalization, we studied modifications of the ligand backbone, e.g., with 3,5-dichlorobenzoyl chloride. Diastereomeric adducts with Okamoto-type cellulose derivatives and on-column deracemization were realized on the basis of non-covalent interactions. Enantioselective dynamic HPLC (DHPLC) allowed for the determination of rotational barriers of ΔG ‡ 298K = 92.2 ± 0.3 kJ mol−1 and 99.5 ± 0.1 kJ mol−1 underlining the stereodynamic properties of “NU-BIPHEPs” and “NU-BIPHEP(O)s”, respectively. These results make the preparation of tailor-made functionalized stereodynamic ligands possible and give an outline for possible applications in enantioselective catalysis. PMID:27559397

  10. Serotonin regulates osteoblast proliferation and function in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Dai, S.Q.; Yu, L.P. [Department of Orthopedic Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu (China); Shi, X. [Department of Obstetrics and Gynecology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu (China); Wu, H. [Emergency Department, The First Affiliated Hospital, Soochow University, Suzhou (China); Shao, P.; Yin, G.Y.; Wei, Y.Z. [Department of Orthopedic Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu (China)

    2014-08-01

    The monoamine serotonin (5-hydroxytryptamine, 5-HT), a well-known neurotransmitter, also has important functions outside the central nervous system. The objective of this study was to investigate the role of 5-HT in the proliferation, differentiation, and function of osteoblasts in vitro. We treated rat primary calvarial osteoblasts with various concentrations of 5-HT (1 nM to 10 µM) and assessed the rate of osteoblast proliferation, expression levels of osteoblast-specific proteins and genes, and the ability to form mineralized nodules. Next, we detected which 5-HT receptor subtypes were expressed in rat osteoblasts at different stages of osteoblast differentiation. We found that 5-HT could inhibit osteoblast proliferation, differentiation, and mineralization at low concentrations, but this inhibitory effect was mitigated at relatively high concentrations. Six of the 5-HT receptor subtypes (5-HT{sub 1A}, 5-HT{sub 1B}, 5-HT{sub 1D}, 5-HT{sub 2A}, 5-HT{sub 2B}, and 5-HT{sub 2C}) were found to exist in rat osteoblasts. Of these, 5-HT{sub 2A} and 5-HT{sub 1B} receptors had the highest expression levels, at both early and late stages of differentiation. Our results indicated that 5-HT can regulate osteoblast proliferation and function in vitro.

  11. MEIS1 functions as a potential AR negative regulator

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Liang [Department of Urology, Chinese PLA Medical School/Chinese PLA General Hospital, Beijing 100853 (China); Department of Urology, Civil Aviation General Hospital/Civil Aviation Medical College of Peking University, Beijing 100123 (China); Li, Mingyang [Department of Gastroenterology, Nan Lou Division, Chinese PLA Medical School/Chinese PLA General Hospital, Beijing 100853 (China); Feng, Fan [Department of Pharmacy, General Hospital of Shenyang Military Command, Shenyang 110016 (China); Yang, Yutao [Beijing Institute for Neuroscience, Capital Medical University, Beijing 100069 (China); Hang, Xingyi [National Scientific Data Sharing Platform for Population and Health, Beijing 100730 (China); Cui, Jiajun, E-mail: cuijn@ucmail.uc.edu [Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 (United States); Gao, Jiangping, E-mail: jpgao@163.com [Department of Urology, Chinese PLA Medical School/Chinese PLA General Hospital, Beijing 100853 (China)

    2014-10-15

    The androgen receptor (AR) plays critical roles in human prostate carcinoma progression and transformation. However, the activation of AR is regulated by co-regulators. MEIS1 protein, the homeodomain transcription factor, exhibited a decreased level in poor-prognosis prostate tumors. In this study, we investigated a potential interaction between MEIS1 and AR. We found that overexpression of MEIS1 inhibited the AR transcriptional activity and reduced the expression of AR target gene. A potential protein–protein interaction between AR and MEIS1 was identified by the immunoprecipitation and GST pull-down assays. Furthermore, MEIS1 modulated AR cytoplasm/nucleus translocation and the recruitment to androgen response element in prostate specific antigen (PSA) gene promoter sequences. In addition, MEIS1 promoted the recruitment of NCoR and SMRT in the presence of R1881. Finally, MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells. Taken together, our data suggests that MEIS1 functions as a novel AR co-repressor. - Highlights: • A potential interaction was identified between MEIS1 and AR signaling. • Overexpression of MEIS1 reduced the expression of AR target gene. • MEIS1 modulated AR cytoplasm/nucleus translocation. • MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells.

  12. Regulation of Vascular and Renal Function by Metabolite Receptors*

    Science.gov (United States)

    Peti-Peterdi, János; Kishore, Bellamkonda K.; Pluznick, Jennifer L.

    2016-01-01

    To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis—from salt and water balance to metabolism—by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families—(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and (c) short-chain fatty acid receptors—we emphasize the unique and important roles that these receptors play in renal and vascular physiology and pathophysiology. PMID:26667077

  13. Regulation of Vascular and Renal Function by Metabolite Receptors.

    Science.gov (United States)

    Peti-Peterdi, János; Kishore, Bellamkonda K; Pluznick, Jennifer L

    2016-01-01

    To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis-from salt and water balance to metabolism-by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families-(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and

  14. RNA-Mediated Regulation of HMGA1 Function

    Directory of Open Access Journals (Sweden)

    Arndt G. Benecke

    2015-05-01

    Full Text Available The high mobility group protein A1 (HMGA1 is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

  15. Regulation of ovarian function by the matrix metalloproteinase system

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    @@ In most organs of mammals, cyclic remodelling of tissues after morphogenesis is minimal; however, repro-ductive tissues of female animals including endometrium, mammary gland, ovarian follicle and corpus luteum un-dergo growth, maturation and involution at various stages in the reproductive cycle or lifespan of the animal. Recon-struction of the extracellular matrix (ECM) is required for the dynamic tissue reorganization characteristic of these tissues. The ECM consists of proteinaceous and nonpro-teinaceous molecules that provide the tissue-specific, ex-tracellular architecture to which cells attach. Furthermore, interaction of cellular receptors with proteins of the ECM can regulate cellular structure, second messenger genera-tion and gene expression. Maintenance of ECM homeo-stasis depends largely on coordinated action of matrix metalloproteinases (MMPs) and tissue inhibitors of met-alloproteinases (TIMPs)-- an important proteinase sys-tem responsible for degradating and remodelling of ECM[1]. MMPs/TIMPs have been recognized as the cru-cial role players in regulating follicular and luteal function for their extensive involvements in the cyclic changes of dynamic ovarian tissues. In recent years, literature that MMP system has important roles in ovary is accumulating. The focus of this review is on the effects of MMPs and their inhibitors, TIMPs on follicular growth, atresia, ovu-lation, luteal development, and luteolysis. Emphasis has been given to the recent progress in the new field when-ever possible.

  16. Regulation and function of DNA methylation in plants and animals

    KAUST Repository

    He, Xinjian

    2011-02-15

    DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review. © 2011 IBCB, SIBS, CAS All rights reserved.

  17. Polyamines Function in Stress Tolerance: From Synthesis to Regulation

    Directory of Open Access Journals (Sweden)

    Ji-Hong eLiu

    2015-10-01

    Full Text Available Plants are challenged by a variety of biotic or abiotic stresses, which can affect their growth and development, productivity and geographic distribution. In order to survive adverse environmental conditions, plants have evolved various adaptive strategies, among which is the accumulation of metabolites that play protective roles. A well-established example of the metabolites that are involved in stress responses, or stress tolerance, is the low-molecular-weight aliphatic polyamines, including putrescine,spermidine and spermine. The critical role of polyamines in stress tolerance is suggested by several lines of evidence: firstly, the transcript levels of polyamine biosynthetic genes, as well as the activities of the corresponding enzymes, are induced by stresses; secondly, elevation of endogenous polyamine levels by exogenous supply of polyamines, or overexpression of polyamine biosynthetic genes, results in enhanced stress tolerance; and thirdly, a reduction of endogenous polyamines is accompanied by compromised stress tolerance. A number of studies have demonstrated that polyamines function in stress tolerance largely by modulating the homeostasis of reactive oxygen species (ROS due to their direct, or indirect, roles in regulating antioxidant systems or suppressing ROS production. The transcriptional regulation of polyamine synthesis by transcription factors is also reviewed here. Meanwhile, future perspectives on polyamine research are also suggested.

  18. Regulation and Function of Lactate Oxidation in Streptococcus faecium

    Science.gov (United States)

    London, Jack

    1968-01-01

    Regulation of the synthesis and function of an l(+)-specific lactate-oxidizing enzyme system found in a homofermentative Streptococcus was investigated. With the exception of fructose, aerobic growth at the expense of a variety of substrates resulted in the formation of a lactate oxidation system; anaerobic growth resulted in a marked reduction or complete loss of lactate-oxidizing activity. Growth on fructose, under aerobic and anaerobic conditions, invariably produced a decrease in the activity of the lactate oxidation system. A negative control, activated by an early intermediate product of glycolysis, appeared to be responsible for repression of the lactate-oxidizing enzyme(s). The enzyme system confers upon the organism the ability to grow aerobically at the expense of l(+)-lactic acid. PMID:5646625

  19. Exosome Biogenesis, Regulation, and Function in Viral Infection

    Directory of Open Access Journals (Sweden)

    Marta Alenquer

    2015-09-01

    Full Text Available Exosomes are extracellular vesicles released upon fusion of multivesicular bodies(MVBs with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs duringthe process of MVB formation. Exosomes were shown to contain selectively sorted functionalproteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in thephysiology of the healthy and diseased organism. Challenges in the field include the identificationof mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles andthe understanding of the underlying processes directing MVBs for degradation or fusion with theplasma membrane. The investigation into the formation and roles of exosomes in viral infection is inits early years. Although still controversial, exosomes can, in principle, incorporate any functionalfactor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation.This review initially focuses on the composition and biogenesis of exosomes. It then explores theregulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system,which is tightly regulated and able to respond to several stimuli that lead to alterations in thecomposition of its sub-compartments. We discuss the current knowledge of how these changesaffect exosomal release. We then summarize how different viruses exploit specific proteins ofendocytic sub-compartments and speculate that it could interfere with exosome function, althoughno direct link between viral usage of the endocytic system and exosome release has yet beenreported. Many recent reports have ascribed functions to exosomes released from cells infectedwith a variety of animal viruses, including viral spread, host immunity, and manipulation of themicroenvironment, which are discussed. Given the ever-growing roles and importance of exosomesin viral infections, understanding what regulates their composition and levels, and

  20. c-Yes regulates cell adhesion at the blood-testis barrier and the apical ectoplasmic specialization in the seminiferous epithelium of rat testes.

    Science.gov (United States)

    Xiao, Xiang; Mruk, Dolores D; Lee, Will M; Cheng, C Yan

    2011-04-01

    During spermatogenesis, extensive junction restructuring takes place at the blood-testis barrier (BTB) and the Sertoli cell-spermatid interface known as the apical ectoplasmic specialization (apical ES, a testis-specific adherens junction) in the seminiferous epithelium. However, the mechanism(s) that regulates these critical events in the testis remains unknown. Based on the current concept in the field, changes in the phosphorylation status of integral membrane proteins at these sites can induce alterations in protein endocytosis and recycling, causing junction restructuring. Herein, c-Yes, a non-receptor protein tyrosine kinase, was found to express abundantly at the BTB and apical ES stage-specifically, coinciding with junction restructuring events at these sites during the seminiferous epithelial cycle of spermatogenesis. c-Yes also structurally associated with adhesion proteins at the BTB (e.g., occludin and N-cadherin) and the apical ES (e.g., β1-integrin, laminins β3 and γ3), possibly to regulate phosphorylation status of proteins at these sites. SU6656, a selective c-Yes inhibitor, was shown to perturb the Sertoli cell tight junction-permeability barrier in vitro, which is mediated by changes in the distribution of occludin and N-cadherin at the cell-cell interface, moving from cell surface to cytosol, thereby destabilizing the tight junction-barrier. However, this disruptive effect of SU6656 on the barrier was blocked by testosterone. Furthermore, c-Yes is crucial to maintain the actin filament network in Sertoli cells since a blockade of c-Yes by SU6656 induced actin filament disorganization. In summary, c-Yes regulates BTB and apical ES integrity by maintaining proper distribution of integral membrane proteins and actin filament organization at these sites.

  1. Borneol Depresses P-Glycoprotein Function by a NF-κB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model.

    Science.gov (United States)

    Fan, Xiang; Chai, Lijuan; Zhang, Han; Wang, Yuefei; Zhang, Boli; Gao, Xiumei

    2015-11-18

    P-glycoprotein (P-gp) on brain microvascular endothelial cells (BMECs) that form the blood brain barrier (BBB), influences transportation of substances between blood and brain. The objective of this study was to characterize the effects of borneol on P-gp efflux function on BBB and explore the potential mechanisms. We established an in vitro BBB model comprised of rat BMECs and astrocytes to measure the effects of borneol on the known P-gp substrates transport across BBB, and examined the function and expression of P-gp in BMECs and the signaling pathways regulating P-gp expression. Borneol increased intracellular accumulation of Rhodamine 123, enhanced verapamil and digoxin across the BBB in vitro model, and depressed mdr1a mRNA and P-gp expression. Borneol could activate nuclear factor-κB (NF-κB) and inhibition of NF-κB with MG132 (carbobenzoxy-Leu-Leu-leucinal) and SN50 (an inhibitory peptide) obscuring the P-gp decreases induced by borneol. These data suggested that borneol depresses P-gp function in BMECs by a NF-κB signaling medicated mechanism in a BBB in vitro model.

  2. Are there any different effects of Bifidobacterium, Lactobacillus and Streptococcus on intestinal sensation, barrier function and intestinal immunity in PI-IBS mouse model?

    Directory of Open Access Journals (Sweden)

    Huan Wang

    Full Text Available BACKGROUND AND AIMS: Research has increasingly suggested that gut flora plays an important role in the development of post-infectious irritable bowel syndrome (PI-IBS. Studies of the curative effect of probiotics for IBS have usually been positive but not always. However, the differences of treatment effects and mechanisms among probiotic stains, or mixture of them, are not clear. In this study, we compared the effects of different probiotics (Befidobacterium, Lactobacillus, Streptococcus or mixture of the three on intestinal sensation, barrier function and intestinal immunity in PI-IBS mouse model. METHODS: PI-IBS model was induced by Trichinella spiralis infection in mice. Different probiotics were administered to mice after 8 weeks infection. Visceral sensitivity was measured by scores of abdominal withdrawal reflex (AWR and the threshold intensity of colorectal distention. Colonic smooth muscle contractile response was assessed by contraction of the longitudinal muscle strips. Plasma diamine oxidase (DAO and d-lactate were determined by an enzymatic spectrophotometry. Expression of tight junction proteins and cytokines in ileum were measured by Western blotting. RESULTS: Compared to control mice, PI-IBS mice treated either alone with Befidobacterium or Lactobacillus (but not Streptococcus, or the mixture of the three exhibited not only decreased AWR score and contractile response, but also reduced plasma DAO and D-lactate. These probiotic treatments also suppressed the expression of proinflammatory cytokine IL-6 and IL-17 and promoted the expression of major tight junction proteins claudin-1 and occludin. The mixture of the three probiotic strains performed better than the individual in up-regulating these tight junction proteins and suppressing IL-17 expression. CONCLUSIONS: Bifidobacterium and Lactobacillus, but not Streptococcus, alleviated visceral hypersensitivity and recovered intestinal barrier function as well as inflammation in PI

  3. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema.

    Science.gov (United States)

    Jungersted, J M; Scheer, H; Mempel, M; Baurecht, H; Cifuentes, L; Høgh, J K; Hellgren, L I; Jemec, G B E; Agner, T; Weidinger, S

    2010-07-01

    Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations.

  4. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions.

    Science.gov (United States)

    Mittag, Jens; Lyons, David J; Sällström, Johan; Vujovic, Milica; Dudazy-Gralla, Susi; Warner, Amy; Wallis, Karin; Alkemade, Anneke; Nordström, Kristina; Monyer, Hannah; Broberger, Christian; Arner, Anders; Vennström, Björn

    2013-01-01

    Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone's central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1.

  5. Regulation of Multidrug Resistance P-Glycoprotein in the Developing Blood-Brain Barrier: Interplay between Glucocorticoids and Cytokines.

    Science.gov (United States)

    Iqbal, M; Baello, S; Javam, M; Audette, M C; Gibb, W; Matthews, S G

    2016-03-01

    P-glycoprotein (P-gp) encoded by Abcb1 provides protection to the developing brain from xenobiotics. P-gp in brain endothelial cells (BECs) derived from the developing brain microvasculature is up-regulated by glucocorticoids and inhibited by pro-inflammatory cytokines in vitro. However, little is known about how prenatal maternal glucocorticoid treatment can affect Abcb1/P-gp function and subsequent cytokine regulation in foetal BECs. We hypothesised that glucocorticoid exposure increases Abcb1/P-gp in the foetal brain microvasculature and enhances the sensitivity of Abcb1/P-gp in BECs to the inhibitory effects of cytokines. BECs isolated from dexamethasone- or vehicle-exposed foetal guinea pigs were cultured and treated with interleukin-1β, interleukin-6 or tumour necrosis factor-α, and Abcb1/P-gp expression and function were assessed. Prenatal dexamethasone exposure significantly increased Abcb1/P-gp expression/activity and cytokine receptor levels in BECs of the foetal brain microvasculature. Foetal dexamethasone exposure in vivo also increased the subsequent responsiveness of BECs to pro-inflammatory cytokines in vitro. In conclusion, maternal treatment with synthetic glucocorticoids appears to prematurely mature P-gp mediated drug resistance at the foetal BBB in vivo and profoundly impact the subsequent responsiveness of P-gp to pro-inflammatory cytokines in the foetal BEC. The significance of these findings to foetal brain protection against xenobiotics and other P-gp substrates in vivo requires further elaboration. However, the results of the present study may have implications for human pregnancy and foetal brain protection, particularly in cases of preterm birth combined with infection.

  6. Effects of Mycotoxins on Intestinal Mucosal Barrier Function%霉菌毒素影响肠道黏膜屏障功能

    Institute of Scientific and Technical Information of China (English)

    高亚男; 王加启; 李松励; 张养东; 郑楠

    2016-01-01

    Mycotoxins widely exist in feed ingredients and human food, posing a serious threat to animals and human health.As the first barrier between the body and external contaminants, intestinal barriers mucosal main-ly constitute four interrelated functional barriers which are mechanical barrier, chemical barrier, immune barrier as well as biological barrier.This review summarized the effects of mycotoxins on intestinal mucosal barrier and its mechanisms based on the previous study.%霉菌毒素是一类广泛存在于饲料原料和人类食品中,对动物和人类健康造成严重威胁的危害因子。作为机体抵御外来污染物的第1道屏障,肠道黏膜屏障主要由相互联系的机械屏障、化学屏障、免疫屏障和生物屏障构成。本文在国内外已有的研究基础上,对霉菌毒素对肠道黏膜屏障功能的影响及其作用机制进行综述。

  7. Oxymatrine improves intestinal epithelial barrier function involving NF-κB-mediated signaling pathway in CCl4-induced cirrhotic rats.

    Directory of Open Access Journals (Sweden)

    Jian-Bo Wen

    Full Text Available Accumulating evidence suggests that intestinal epithelial barrier dysfunction plays an important role in the pathogenesis of hepatic cirrhosis and its complications such as gastrointestinal injury and hepatic encephalopathy. To date, there is no cure for cirrhosis-associated intestinal mucosal lesion and ulcer. This study aimed to investigate the effect of oxymatrine on intestinal epithelial barrier function and the underlying mechanism in carbon tetrachloride (CCl4-induced cirrhotic rats. Thirty CCl4-induced cirrhotic rats were randomly divided into treatment group, which received oxymatrine treatment (63 mg/kg, and non-treatment group, which received the same dose of 5% glucose solution (vehicle. The blank group (n = 10 healthy rats received no treatment. Terminal ileal samples were collected for histopathological examination. The expression level of nuclear factor-κB (NF-κB p65 in ileal tissue was evaluated by immunohistochemistry. The gene and protein expression levels of tumor necrosis factor-α (TNF-α and interleukin 6 (IL-6 in ileal tissues were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR and enzyme-linked immunosorbent assay (ELISA, respectively. Additionally, plasma endotoxin level was determined. In comparison to the blank group, a significant alteration in the morphology of intestinal mucosal villi in the non-treatment group was observed. The intestinal mucosal villi were atrophic, shorter, and fractured, and inflammatory cells were infiltrated into the lamina propria and muscular layer. Besides, serious swell of villi and loose structure of mucous membrane were observed. Oxymatrine reversed the CCl4-induced histological changes and restored intestinal barrier integrity. Moreover, oxymatrine reduced the protein expression level of NF-κB p65, TNF-α, and IL-6, which were elevated in the vehicle-treated group. In addition, the serum endotoxin level was significantly decreased after oxymatrine treatment in

  8. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature.

    Directory of Open Access Journals (Sweden)

    Tony E Walshe

    Full Text Available Pericyte-endothelial cell (EC interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-beta signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-beta signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-beta signaling was inhibited by systemic expression of soluble endoglin (sEng and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-beta signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG. Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-beta signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-beta signaling. These results implicate constitutive TGF-beta signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-beta signaling in vasoproliferative and vascular degenerative retinal diseases.

  9. Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients[S

    Science.gov (United States)

    Janssens, Michelle; van Smeden, Jeroen; Gooris, Gert S.; Bras, Wim; Portale, Guiseppe; Caspers, Peter J.; Vreeken, Rob J.; Hankemeier, Thomas; Kezic, Sanja; Wolterbeek, Ron; Lavrijsen, Adriana P.; Bouwstra, Joke A.

    2012-01-01

    A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE. PMID:23024286

  10. Xylem cell death: emerging understanding of regulation and function.

    Science.gov (United States)

    Bollhöner, Benjamin; Prestele, Jakob; Tuominen, Hannele

    2012-02-01

    Evolutionary, as well as genetic, evidence suggests that vascular development evolved originally as a cell death programme that allowed enhanced movement of water in the extinct protracheophytes, and that secondary wall formation in the water-conducting cells evolved afterwards, providing mechanical support for effective long-distance transport of water. The extant vascular plants possess a common regulatory network to coordinate the different phases of xylem maturation, including secondary wall formation, cell death, and finally autolysis of the cell contents, by the action of recently identified NAC domain transcription factors. Consequently, xylem cell death is an inseparable part of the xylem maturation programme, making it difficult to uncouple cell death mechanistically from secondary wall formation, and thus identify the key factors specifically involved in regulation of cell death. Current knowledge suggests that the necessary components for xylem cell death are produced early during xylem differentiation, and cell death is prevented through the action of inhibitors and storage of hydrolytic enzymes in inactive forms in compartments such as the vacuole. Bursting of the central vacuole triggers autolytic hydrolysis of the cell contents, which ultimately leads to cell death. This cascade of events varies between the different xylem cell types. The water-transporting tracheary elements rely on a rapid cell death programme, with hydrolysis of cell contents taking place for the most part, if not entirely, after vacuolar bursting, while the xylem fibres disintegrate cellular contents at a slower pace, well before cell death. This review includes a detailed description of cell morphology, function of plant growth regulators, such as ethylene and thermospermine, and the action of hydrolytic nucleases and proteases during cell death of the different xylem cell types.

  11. Adrenomedullin and endothelial barrier function%肾上腺髓质素和内皮屏障功能

    Institute of Scientific and Technical Information of China (English)

    张玮珏; 王新华; 周荣斌

    2011-01-01

    研究表明,内皮屏障功能丧失是急性炎症的标志,并且在严重感染中促成器官功能衰竭,但是目前还没有关于内皮屏障功能稳定性治疗方面的研究.内源性肽肾上腺髓质素(Adrenomedullin,AM)血清水平显示其在严重感染包括脓毒症和脓毒性休克时升高,在体内和体外脓毒症模型中用作有效的内皮屏障功能的稳定剂.AM还具有心血管保护作用,包括在炎症状态保护微循环.总之,AM可能作为一个有效的保护因素,通过保护内皮屏障功能防治严重感染中的心血管功能障碍.%Although loss of endothelial barrier function is a hall mark of every acute inflammation and contributes to fatal loss of organ function during severe infections,there is no sufficient therapy for stabilization of endothelial barrier function. Endogenous peptide adrenomedullin (AM) serum levels were shown to be increased during severe infection including sepsis and septic shock. In different in vitro and in vivo models AM acted as a potent therapeutic endothelial barrier function-stabilizing agent. Activation of specific receptors by AM results in elevation of second messenger cAMP. AM inhibits actin-myosin based endothelial cell contraction and junctional disassembly,thereby preventing paracellular permeability and oedema formation. The peptide furthermore possesses several protective cardiovascular qualities,including protection of the microcirculation during inflammation,and proven to be as an efficient counter-regulatory molecule in various models of sepsis and scptic shock. Overall, AM may be an attractive molecule to combat against cardiovascular malfunction during severe infection.

  12. Dietary glutamine and oral antibiotics each improve indexes of gut barrier function in rat short bowel syndrome.

    Science.gov (United States)

    Tian, Junqiang; Hao, Li; Chandra, Prakash; Jones, Dean P; Willams, Ifor R; Gewirtz, Andrew T; Ziegler, Thomas R

    2009-02-01

    Short bowel syndrome (SBS) is associated with gut barrier dysfunction. We examined effects of dietary glutamine (GLN) or oral antibiotics (ABX) on indexes of gut barrier function in a rat model of SBS. Adult rats underwent a 60% distal small bowel + proximal colonic resection (RX) or bowel transection (TX; control). Rats were pair fed diets with or without l-GLN for 20 days after operation. Oral ABX (neomycin, metronidazole, and polymyxin B) were given in some RX rats fed control diet. Stool secretory immunoglobulin A (sIgA) was measured serially. On day 21, mesenteric lymph nodes (MLN) were cultured for gram-negative bacteria. IgA-positive plasma cells in jejunum, stool levels of flagellin- and lipopolysaccharide (LPS)-specific sIgA, and serum total, anti-flagellin- and anti-LPS IgG levels were determined. RX caused gram-negative bacterial translocation to MLN, increased serum total and anti-LPS IgG and increased stool total sIgA. After RX, dietary GLN tended to blunt bacterial translocation to MLN (-29%, P = NS) and significantly decreased anti-LPS IgG levels in serum, increased both stool and jejunal mucosal sIgA and increased stool anti-LPS-specific IgA. Oral ABX eliminated RX-induced bacterial translocation, significantly decreased total and anti-LPS IgG levels in serum, significantly decreased stool total IgA and increased stool LPS-specific IgA. Partial small bowel-colonic resection in rats is associated with gram-negative bacterial translocation from the gut and a concomitant adaptive immune response to LPS. These indexes of gut barrier dysfunction are ameliorated or blunted by administration of dietary GLN or oral ABX, respectively. Dietary GLN upregulates small bowel sIgA in this model.

  13. An analysis of potential barriers and enablers to regulating the television marketing of unhealthy foods to children at the state government level in Australia

    Directory of Open Access Journals (Sweden)

    Chung Alexandra

    2012-12-01

    Full Text Available Abstract Background In Australia there have been many calls for government action to halt the effects of unhealthy food marketing on children's health, yet implementation has not occurred. The attitudes of those involved in the policy-making process towards regulatory intervention governing unhealthy food marketing are not well understood. The objective of this research was to understand the perceptions of senior representatives from Australian state and territory governments, statutory authorities and non-government organisations regarding the feasibility of state-level government regulation of television marketing of unhealthy food to children in Australia. Method Data from in-depth semi-structured interviews with senior representatives from state and territory government departments, statutory authorities and non-government organisations (n=22 were analysed to determine participants' views about regulation of television marketing of unhealthy food to children at the state government level. Data were analysed using content and thematic analyses. Results Regulation of television marketing of unhealthy food to children was supported as a strategy for obesity prevention. Barriers to implementing regulation at the state level were: the perception that regulation of television advertising is a Commonwealth, not state/territory, responsibility; the power of the food industry and; the need for clear evidence that demonstrates the effectiveness of regulation. Evidence of community support for regulation was also cited as an important factor in determining feasibility. Conclusions The regulation of unhealthy food marketing to children is perceived to be a feasible strategy for obesity prevention however barriers to implementation at the state level exist. Those involved in state-level policy making generally indicated a preference for Commonwealth-led regulation. This research suggests that implementation of regulation of the television marketing of

  14. An analysis of potential barriers and enablers to regulating the television marketing of unhealthy foods to children at the state government level in Australia.

    Science.gov (United States)

    Chung, Alexandra; Shill, Jane; Swinburn, Boyd; Mavoa, Helen; Lawrence, Mark; Loff, Bebe; Crammond, Bradley; Sacks, Gary; Allender, Steven; Peeters, Anna

    2012-12-28

    In Australia there have been many calls for government action to halt the effects of unhealthy food marketing on children's health, yet implementation has not occurred. The attitudes of those involved in the policy-making process towards regulatory intervention governing unhealthy food marketing are not well understood. The objective of this research was to understand the perceptions of senior representatives from Australian state and territory governments, statutory authorities and non-government organisations regarding the feasibility of state-level government regulation of television marketing of unhealthy food to children in Australia. Data from in-depth semi-structured interviews with senior representatives from state and territory government departments, statutory authorities and non-government organisations (n=22) were analysed to determine participants' views about regulation of television marketing of unhealthy food to children at the state government level. Data were analysed using content and thematic analyses. Regulation of television marketing of unhealthy food to children was supported as a strategy for obesity prevention. Barriers to implementing regulation at the state level were: the perception that regulation of television advertising is a Commonwealth, not state/territory, responsibility; the power of the food industry and; the need for clear evidence that demonstrates the effectiveness of regulation. Evidence of community support for regulation was also cited as an important factor in determining feasibility. The regulation of unhealthy food marketing to children is perceived to be a feasible strategy for obesity prevention however barriers to implementation at the state level exist. Those involved in state-level policy making generally indicated a preference for Commonwealth-led regulation. This research suggests that implementation of regulation of the television marketing of unhealthy food to children should ideally occur under the direction

  15. The Development of Self-Regulation and Executive Function in Young Children

    Science.gov (United States)

    McClelland, Megan M.; Tominey, Shauna L.

    2014-01-01

    Self-regulation lays the foundation for positive social relationships and academic success. In this article, we provide an overview of self-regulation and the key terms related to selfregulation, such as executive function. We discuss research on how self-regulation develops and connections between self-regulation and social and academic outcomes.…

  16. Using Synthetic Biology to Distinguish and Overcome Regulatory and Functional Barriers Related to Nitrogen Fixation

    OpenAIRE

    Xia Wang; Jian-Guo Yang; Li Chen; Ji-Long Wang; Qi Cheng; Ray Dixon; Yi-Ping Wang

    2013-01-01

    Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ~100% activity of native K. pneumoniae syste...

  17. The mediating role of metacognition in the relationship between executive function and self-regulated learning.

    Science.gov (United States)

    Follmer, D Jake; Sperling, Rayne A

    2016-12-01

    Researchers have demonstrated significant relations among executive function, metacognition, and self-regulated learning. However, prior research emphasized the use of indirect measures of executive function and did not evaluate how specific executive functions are related to participants' self-regulated learning. The primary goals of the current study were to examine and test the relations among executive function, metacognition, and self-regulated learning as well as to examine how self-regulated learning is informed by executive function. The sample comprised 117 undergraduate students attending a large, Mid-Atlantic research university in the United States. Participants were individually administered direct and indirect measures of executive function, metacognition, and self-regulated learning. A mediation model specifying the relations among the regulatory constructs was proposed. In multiple linear regression analyses, executive function predicted metacognition and self-regulated learning. Direct measures of inhibition and shifting accounted for a significant amount of the variance in metacognition and self-regulated learning beyond an indirect measure of executive functioning. Separate mediation analyses indicated that metacognition mediated the relationship between executive functioning and self-regulated learning as well as between specific executive functions and self-regulated learning. The findings of this study are supported by previous research documenting the relations between executive function and self-regulated learning, and extend prior research by examining the manner in which executive function and self-regulated learning are linked. The findings provide initial support for executive functions as key processes, mediated by metacognition, that predict self-regulated learning. Implications for the contribution of executive functions to self-regulated learning are discussed. © 2016 The British Psychological Society.

  18. Moderate dietary protein restriction alters the composition of gut microbiota and improves ileal barrier function in adult pig model

    Science.gov (United States)

    Fan, Peixin; Liu, Ping; Song, Peixia; Chen, Xiyue; Ma, Xi

    2017-01-01

    This study was conducted to investigate impacts of dietary protein levels on gut bacterial community and gut barrier. The intestinal microbiota of finishing pigs, fed with 16%, 13% and 10% crude protein (CP) in diets, respectively, were investigated using Illumina MiSeq sequencing. The ileal bacterial richness tended to decrease when the dietary protein concentration reduced from 16% to 10%. The proportion of Clostridium_sensu_stricto_1 in ileum significantly decreased, whereas Escherichia-Shigella increased with reduction of protein concentration. In colon, the proportion of Clostridium_sensu_stricto_1 and Turicibacter increased, while the proportion of RC9_gut_group significantly decreased with the dietary protein reduction. Notably, the proportion of Peptostreptococcaceae was higher in both ileum and colon of 13% CP group. As for metabolites, the intestinal concentrations of SCFAs and biogenic amines decreased with the dietary protein reduction. The 10% CP dietary treatment damaged ileal mucosal morphology, and decreased the expression of biomarks of intestinal cells (Lgr5 and Bmi1), whereas the expression of tight junction proteins (occludin and claudin) in 13% CP group were higher than the other two groups. In conclusion, moderate dietary protein restriction (13% CP) could alter the bacterial community and metabolites, promote colonization of beneficial bacteria in both ileum and colon, and improve gut barrier function. PMID:28252026

  19. Structure, Function and Regulation of the Hsp90 Machinery

    Directory of Open Access Journals (Sweden)

    Jing Li

    2013-06-01

    Full Text Available Heat shock protein 90 (Hsp90 is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

  20. Wntless functions in mature osteoblasts to regulate bone mass.

    Science.gov (United States)

    Zhong, Zhendong; Zylstra-Diegel, Cassandra R; Schumacher, Cassie A; Baker, Jacob J; Carpenter, April C; Rao, Sujata; Yao, Wei; Guan, Min; Helms, Jill A; Lane, Nancy E; Lang, Richard A; Williams, Bart O

    2012-08-14

    Recent genome-wide association studies of individuals of Asian and European descent have found that SNPs located within the genomic region (1p31.3) encoding the Wntless (Wls)/Gpr177 protein are associated significantly with reduced bone mineral density. Wls/Gpr177 is a newly identified chaperone protein that specifically escorts Wnt ligands for secretion. Given the strong functional association between the Wnt signaling pathways and bone development and homeostasis, we generated osteoblast-specific Wls-deficient (Ocn-Cre;Wls-flox) mice. Homozygous conditional knockout animals were born at a normal Mendelian frequency. Whole-body dual-energy X-ray absorptiometry scanning revealed that bone-mass accrual was significantly inhibited in homozygotes as early as 20 d of age. These homozygotes had spontaneous fractures and a high frequency of premature lethality at around 2 mo of age. Microcomputed tomography analysis and histomorphometric data revealed a dramatic reduction of both trabecular and cortical bone mass in homozygous mutants. Bone formation in homozygotes was severely impaired, but no obvious phenotypic change was observed in mice heterozygous for the conditional deletion. In vitro studies showed that Wls-deficient osteoblasts had a defect in differentiation and mineralization, with significant reductions in the expression of key osteoblast differentiation regulators. In summary, these results reveal a surprising and crucial role of osteoblast-secreted Wnt ligands in bone-mass accrual.

  1. Silibinin regulates lipid metabolism and differentiation in functional human adipocytes

    Directory of Open Access Journals (Sweden)

    Ignazio eBarbagallo

    2016-01-01

    Full Text Available Silibinin, a natural plant flavonoid, is the main active constituent found in milk thistle (Silybum marianum. It is known to have hepatoprotective, anti-neoplastic effect and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodelling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.

  2. ISG15 regulates peritoneal macrophages functionality against viral infection.

    Directory of Open Access Journals (Sweden)

    Emilio Yángüez

    Full Text Available Upon viral infection, the production of type I interferon (IFN and the subsequent upregulation of IFN stimulated genes (ISGs generate an antiviral state with an important role in the activation of innate and adaptive host immune responses. The ubiquitin-like protein (UBL ISG15 is a critical IFN-induced antiviral molecule that protects against several viral infections, but the mechanism by which ISG15 exerts its antiviral function is not completely understood. Here, we report that ISG15 plays an important role in the regulation of macrophage responses. ISG15-/- macrophages display reduced activation, phagocytic capacity and programmed cell death activation in response to vaccinia virus (VACV infection. Moreover, peritoneal macrophages from mice lacking ISG15 are neither able to phagocyte infected cells nor to block viral infection in co-culture experiments with VACV-infected murine embryonic fibroblast (MEFs. This phenotype is independent of cytokine production and secretion, but clearly correlates with impaired activation of the protein kinase AKT in ISG15 knock-out (KO macrophages. Altogether, these results indicate an essential role of ISG15 in the cellular immune antiviral response and point out that a better understanding of the antiviral responses triggered by ISG15 may lead to the development of therapies against important human pathogens.

  3. Functions of vasopressin and oxytocin in bone mass regulation

    Science.gov (United States)

    Sun, Li; Tamma, Roberto; Yuen, Tony; Colaianni, Graziana; Ji, Yaoting; Cuscito, Concetta; Bailey, Jack; Dhawan, Samarth; Lu, Ping; Calvano, Cosima D.; Zhu, Ling-Ling; Zambonin, Carlo G.; Di Benedetto, Adriana; Stachnik, Agnes; Liu, Peng; Grano, Maria; Colucci, Silvia; Davies, Terry F.; New, Maria I.; Zallone, Alberta; Zaidi, Mone

    2016-01-01

    Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr−/− mice have osteopenia, and Avpr1α−/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr−/−:Avpr1α−/− double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α−/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling. PMID:26699482

  4. Function and regulation of plant major intrinsic proteins

    DEFF Research Database (Denmark)

    Popovic, Milan

    Arsenic is a metalloid that is toxic to living organisms. The use of arsenic-contaminated ground water for drinking and for irrigation in agriculture presents serious health problems for millions of people in many parts of the world. Arsenate (As(V)) and arsenite (As(III)), the two most widespread...... inorganic forms of arsenic in the environment, can be taken up by plants and thus enter the food chain. Once inside the root cells, As(V) is reduced to As(III) which is then extruded to the soil solution or bound to phytochelatins (PCs) and transported to the vacuole in an effort to accomplish...... vacuoles. In this study using Arabidopsis, the role of TIP subfamily in arsenic transport was examined together with the role of N-terminus in regulation of AtNIP5;1, which has previously been shown to transport As(III) in a yeast expression system. The results showed that AtTIP4;1 functions...

  5. Influence of Traditional Chinese Medicine on Intestinal Floras and Intestinal Mucosal Barrier Function%中药对肠道菌群及肠黏膜屏障功能的影响

    Institute of Scientific and Technical Information of China (English)

    段智璇; 田维毅

    2016-01-01

    Intestinal not only has the digestion ,absorption ,it also plays a very important barrier func-tion of prevent harmful material such as bacteria and toxins invades the body ,regulating the body’s stress re-sponse and produce inflammation medium .Studies have found that the effective components of Chinese medicine has a certain influence and protection on the intestinal flora and intestinal mucosal barrier function .Based on re-searches in recent years ,we summarized the influence of traditional Chinese medicine on intestinal flora and in-testinal mucous membrane barrier function .%肠道不仅具有消化、吸收作用,在阻止肠腔内细菌、毒素等有害物质侵入人体、调控机体应激反应、生成炎症介质方面同样发挥着重要的屏障功能。有研究显示,中药有效成分对肠道菌群和肠道黏膜屏障功能有一定的影响及保护作用。文章结合近年来有关中药对肠道菌群以及肠道黏膜屏障功能的相关研究进行综述。

  6. To enhance nursing research on skin barrier function of preterm infants%提高早产儿皮肤屏障功能护理研究

    Institute of Scientific and Technical Information of China (English)

    王蓓珺; 胡晓静

    2011-01-01

    It reviewed nursing research progress on skin barrier function of preterm infants from aspects of structural and functional characteristics of newborns, skin nursing, and enhancing skin barrier function of preterm infants.%从新生儿皮肤结构与功能特点、皮肤护理、提高早产儿皮肤屏障功能的方法方面对提高早产儿皮肤屏障功能护理研究进展进行了综述.

  7. UPEC biomimickry at the urothelial barrier: lectin-functionalized PLGA microparticles for improved intravesical chemotherapy.

    Science.gov (United States)

    Neutsch, Lukas; Wambacher, Michael; Wirth, Eva-Maria; Spijker, Sylvia; Kählig, Hanspeter; Wirth, Michael; Gabor, Franz

    2013-06-25

    The urgent demand for more potent treatment schedules in bladder cancer (BCa) therapy calls for a refinement of the intravesical administration modalities. However, progress on drug delivery systems tailored to the penetration-hostile urothelial barrier lags behind the advancements in comparable fields. This study reports on a multimodal, carrier-based delivery concept that combines biorecognitive targeting with modified release strategies for improved intravesical chemotherapy. The plant lectin wheat germ agglutinin (WGA) was immobilized on poly(lactide-co-glycolide) (PLGA) microparticles (MP) to induce stable cytoadhesion via cellular carbohydrate chains, similar to the specific attachment mechanism utilized by uropathogenic bacteria. A panel of DNA-selective chemotherapeutics with established track record in uro-oncology was screened for physicochemical compatibility with the polymeric carrier formulation. Critical limitations in encapsulation efficiency were found for mitomycin C (MMC), doxorubicin (DOX), and gemcitabine hydrochloride (GEM), despite multiparametric optimization of the preparation conditions. In contrast, the amphiphilic 4-(N)-stearoyl prodrug of gemcitabine (GEM-C18) exhibited excellent processability with PLGA. In vitro bioassays on 5637 human BCa cells showed that the enhanced cytoadhesion of WGA-GEM-C18-PGLA-MP traces back to the specific lectin/carbohydrate interaction, and is not easily disrupted by adverse environmental factors. Owing to several synergistic effects, the combined prodrug/targeting approach resulted in strong cytostatic response even when adjusting the exposure scheme to the confined temporal conditions of instillative treatment. Our results highlight the importance of fine-tuning both pharmacokinetic and pharmacologic parameters to gain adequate impact on urothelial cancer cells, and assign promising potential to glycan-targeted delivery concepts for the intravesical route.

  8. Role of Microbiota in Strengthening Ocular Mucosal Barrier Function Through Secretory IgA.

    Science.gov (United States)

    Kugadas, Abirami; Wright, Quentin; Geddes-McAlister, Jennifer; Gadjeva, Mihaela

    2017-09-01

    The purpose of this study was to evaluate mechanisms controlling secretory IgA (SIgA) production, thereby ensuring maintenance of ocular surface health. To determine whether the presence of specific gut commensal species regulates SIgA levels and IgA transcripts in the eye-associated lymphoid tissues (EALT), specific-pathogen-free (SPF) Swiss Webster (SW) mice were treated with antibiotic cocktails, germ-free (GF) SW mice were reconstituted with diverse commensal gut microbiota, or monocolonized with gut-specific commensals. Proteomic profiling and quantitative real-time polymerase chain reaction (qRT-PCR) were used to quantify SIgA and IgA levels. 16S rDNA sequencing was carried out to characterize commensal microbiota. Commensal presence regulated ocular surface SIgA levels and mRNA IgA transcripts in EALT. Oral antibiotic cocktail intake significantly reduced gut commensal presence, while maintaining ocular surface commensal levels reduced SIgA and IgA transcripts in EALT. Analysis of gut microbial communities revealed that SPF SW mice carried abundant Bacteroides organisms when compared to SPF C57BL6/N mice, with B. acidifaciens being the most prominent species in SPF SW mice. Monocolonization of GF SW mice with B. acidifaciens, a strict gut anaerobe, resulted in significant increase of IgA transcripts in the EALT, implying generation of B-cell memory. These data illustrated a "gut-eye" axis of immune regulation. Exposure of the host to gut commensal species may serve as a priming signal to generate B-cell repertoires at sites different from the gut, such as EALT, thereby ensuring broad protection.

  9. REGULATION OF PPARγ FUNCTION BY TNF-α

    OpenAIRE

    Ye, Jianping

    2008-01-01

    The nuclear receptor PPARγ is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPARγ activity by TNF-α is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPARγ activity is regulated by TNF-α at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK and p38 may be involved in the TNF-regulation of PPARγ. Of the four kinases, IKK is a dominant signaling mole...

  10. Host Epithelial Interactions with Helicobacter Pylori: A Role for Disrupted Gastric Barrier Function in the Clinical Outcome of Infection?

    Directory of Open Access Journals (Sweden)

    Andre G Buret

    2005-01-01

    Full Text Available Infection of the human stomach with Helicobacter pylori may develop into gastritis, ulceration, adenocarcinoma and mucosal lymphomas. The pathogenic mechanisms that determine the clinical outcome from this microbial-epithelial interaction remain poorly understood. An increasing number of reports suggests that disruptions of epithelial barrier function may contribute to pathology and postinfectious complications in a variety of gastrointestinal infections. The aim of this review is to critically discuss the implications of H pylori persistence on gastric disease, with emphasis on the role of myosin light chain kinase, claudins and matrix metalloproteinases in gastric permeability defects, and their contribution to the development of cancer. These mechanisms and the associated signalling events may represent novel therapeutic targets to control disease processes induced by H pylori, a microbial pathogen that colonizes the stomach of over 50% of the human population.

  11. Effects of Locally Applied Glycerol and Xylitol on the Hydration, Barrier Function and Morphological Parameters of the Skin.

    Science.gov (United States)

    Korponyai, Csilla; Szél, Edit; Behány, Zoltán; Varga, Erika; Mohos, Gábor; Dura, Ágnes; Dikstein, Shabtay; Kemény, Lajos; Erős, Gábor

    2017-02-08

    Glycerol and xylitol hydrate the skin and improve its barrier function over a short period. We studied the effects of glycerol and xylitol on the physiological properties and morphology of the skin after longer-term application. Twelve volunteers with dry skin were examined. Three areas on the arms were determined. Area 1 served as untreated control. The vehicle was applied to area 2, while area 3 was treated twice daily with a formulation containing glycerol (5%) and xylitol (5%) for 14 days. Transepidermal water loss (TEWL), hydration and biomechanical properties of the skin were monitored. Biopsies were taken for routine histology and immunohistochemistry for filaggrin and matrix metalloproteinase-1 (MMP-1). The polyols increased the skin hydration and protein quantity of filaggrin, elevated the interdigitation index, decreased the TEWL and improved the biomechanical properties of the skin, but did not change the protein expression of MMP-1. A combination of glycerol and xylitol can be useful additional therapy for dry skin.

  12. Clinical effectiveness of low-power laser radiation and functioning of hemosalivatory barrier in patients with rheumatic diseases

    Science.gov (United States)

    Gladkova, Natalia D.; Karachistov, Alexander B.; Komarova, Lia G.; Alekseeva, Olga P.; Grunina, Elena A.

    1996-11-01

    We have estimated the clinical effectiveness of several regimes and ways of low power laser therapy (LT) on the basis of a double 'blind', placebo-controlling randomizing comparative test in 454 patients with rheumatic diseases (RD). LT for RD has a well-expressed placebo effect. The level of clinical effect of LT for RD is not so high. We couldn't achieve 'a considerable improvement' in any cases, 'an improvement' was secured in only 18 percent. LT should be viewed as a symptomatic means, with a primary anesthetic and feebly expressed anti-inflammatory effect, which can not influence the course of the rheumatoid process. Only in 15 percent of patients with RD, a sufficient functioning of hemo-salivary barrier was observed, the latter providing a reserve for adaption mechanism, which leads under the influence of stressor agents of medium strength not only to anesthetic, but also to moderately expressed anti- inflammatory effect.

  13. Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate.

    Science.gov (United States)

    Shityakov, Sergey; Salvador, Ellaine; Pastorin, Giorgia; Förster, Carola

    2015-01-01

    In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell(®) system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCNT-FITC rapid dissociation as an intermediate phase.

  14. Evolution of cement based materials in a repository for radioactive waste and their chemical barrier function

    Energy Technology Data Exchange (ETDEWEB)

    Kienzler, Bernhard; Metz, Volker; Schlieker, Martina; Bohnert, Elke [Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen (Germany). Inst. fuer Nukleare Entsorgung (INE)

    2015-07-01

    The use of cementitious materials in nuclear waste management is quite widespread. It covers the solidification of low/intermediate-level liquid as well as solid wastes (e.g. laboratory wastes) and serves as shielding. For both high-level and intermediate-low level activity repositories, cement/concrete likewise plays an important role. It is used as construction material for underground and surface disposals, but more importantly it serves as barrier or sealing material. For the requirements of waste conditioning, special cement mixtures have been developed. These include special mixtures for the solidification of evaporator concentrates, borate binding additives and for spilling solid wastes. In recent years, low-pH cements were strongly discussed especially for repository applications, e.g. (Celine CAU DIT COUMES 2008; Garcia-Sineriz, et al. 2008). Examples for relevant systems are Calcium Silicate Cements (ordinary Portland cement (OPC) based) or Calcium Aluminates Cements (CAC). Low-pH pore solutions are achieved by reduction of the portlandite content by partial substitution of OPC by mineral admixtures with high silica content. The blends follow the pozzolanic reaction consuming Ca(OH){sub 2}. Potential admixtures are silica fume (SF) and fly ashes (FA). In these mixtures, super plasticizers are required, consisting of polycarboxilate or naphthalene formaldehyde as well as various accelerating admixtures (Garcia-Sineriz, et al. 2008). The pH regime of concrete/cement materials may stabilize radionuclides in solution. Newly formed alteration products retain or release radionuclides. An important degradation product of celluloses in cement is iso-saccharin acid. According to Glaus 2004 (Glaus and van Loon 2004), it reacts with radionuclides forming dissolved complexes. Apart from potentially impacting radionuclide solubility limitations, concrete additives, radionuclides or other strong complexants compete for surface sites for sorbing onto cement phases. In

  15. Barriers to Functional and Qualitative Technology Education In Developing Countries: Nigeria as a Case Study.

    Science.gov (United States)

    Ojo, David A.

    Science and Technology have been widely recognized as the most important potent tools for socio-economic development. This paper begins with a brief critical and evaluative review of the status of science and technology education in developing countries in Africa. The conceptual framework and the major features of a functional and qualitative…

  16. Development of a vernix caseosa substitute : a novel strategy to improve skin barrier function and repair

    NARCIS (Netherlands)

    Rißmann, Robert

    2009-01-01

    Vernix caseosa (VC) is the cheesy, white cream that covers the skin of the human fetus and the newborn. VC is a protective cream, which consists of water containing dead cells that are embedded in lipids. This natural cream is suggested to feature multiple biological functions such as facilitating t

  17. Bridges or Barriers? Public Policy and the Community College Transfer Function

    Science.gov (United States)

    Boswell, Katherine

    2004-01-01

    Opportunity in this country is more and more a function of education. Education matters. Headlines tell the story. On average, the individual with an associate's degree will earn 20-to-30 percent more than the worker who only has a high school diploma. The worker with a bachelor's degree will earn 40 percent more than the high school graduate. The…

  18. Role of epidermis-type lipoxygenases for skin barrier function and adipocyte differentiation

    DEFF Research Database (Denmark)

    Fürstenberger, Gerhard; Epp, Nikolas; Eckl, Katja-Martina

    2007-01-01

    12R-lipoxygenase (12R-LOX) and epidermis-type LOX-3 (eLOX-3) are novel members of the multigene family of mammalian LOX. A considerable gap exists between the identification of these enzymes and their biologic function. Here, we present evidence that 12R-LOX and eLOX-3, acting in sequence, and e...

  19. Functional foods: regulation and innovations in the EU

    NARCIS (Netherlands)

    Moors, E.H.M.

    2012-01-01

    Worldwide consumers are becoming more interested in the relation between food and health. In order to harmonize regulation on foods throughout the EU, the Regulation EC1924/2006 on nutrition and health claims came into force, as a first specific set of EU legal rules dealing with nutrition and

  20. Defining the Functional Network of Epigenetic Regulators in Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    Chongyuan Luo; Brittany G.Durgin; Naohide Watanabe; Eric Lam

    2009-01-01

    Development of ChiP-chip and ChlP-seq technologies has allowed genome-wide high-resolution profiling of chromatin-associated marks and binding sites for epigenetic regulators.However,signals for directing epigenetic modi fiers to their target sites are not understood.In this paper,we tested the hypothesis that genome location can affect the involvement of epigenetic regulators using Chromatin Charting (CC) Lines,which have an identical transgene construct inserted at different locations in the Arabidopsis genome.Four CC lines that showed evidence for epigenetic silencing of the luciferase reporter gene were transformed with RNAi vectors individually targeting epigenetic regulators LHP1,MOM1,CMT3,DRD1,DRM2,SUVH2,CLF,and HD1.Involvement of a particular epigenetic regulator in silencing the transgene locus in a CC line was determined by significant alterations in luciferase expression after suppression of the regulator's expression.Our results suggest that the targeting of epigenetic regulators can be influenced by genome location as well as sequence context.In addition,the relative importance of an epigenetic regulator can be influenced by tissue identity.We also report a novel approach to predict interactions between epigenetic regulators through clustering analysis of the regulators using alterations in gene expression of putative downstream targets,including endogenous loci and transgenes,in epigenetic mutants or RNAi lines.Our data support the existence of a complex and dynamic network of epigenetic regulators that serves to coordinate and control global gene expression in higher plants.

  1. Modulation of ocular surface glycocalyx barrier function by a galectin-3 N-terminal deletion mutant and membrane-anchored synthetic glycopolymers.

    Directory of Open Access Journals (Sweden)

    Jerome Mauris

    Full Text Available BACKGROUND: Interaction of transmembrane mucins with the multivalent carbohydrate-binding protein galectin-3 is critical to maintaining the integrity of the ocular surface epithelial glycocalyx. This study aimed to determine whether disruption of galectin-3 multimerization and insertion of synthetic glycopolymers in the plasma membrane could be used to modulate glycocalyx barrier function in corneal epithelial cells. METHODOLOGY/PRINCIPAL FINDINGS: Abrogation of galectin-3 biosynthesis in multilayered cultures of human corneal epithelial cells using siRNA, and in galectin-3 null mice, resulted in significant loss of corneal barrier function, as indicated by increased permeability to the rose bengal diagnostic dye. Addition of β-lactose, a competitive carbohydrate inhibitor of galectin-3 binding activity, to the cell culture system, transiently disrupted barrier function. In these experiments, treatment with a dominant negative inhibitor of galectin-3 polymerization lacking the N-terminal domain, but not full-length galectin-3, prevented the recovery of barrier function to basal levels. As determined by fluorescence microscopy, both cellobiose- and lactose-containing glycopolymers incorporated into apical membranes of corneal epithelial cells, independently of the chain length distribution of the densely glycosylated, polymeric backbones. Membrane incorporation of cellobiose glycopolymers impaired barrier function in corneal epithelial cells, contrary to their lactose-containing counterparts, which bound to galectin-3 in pull-down assays. CONCLUSIONS/SIGNIFICANCE: These results indicate that galectin-3 multimerization and surface recognition of lactosyl residues is required to maintain glycocalyx barrier function at the ocular surface. Transient modification of galectin-3 binding could be therapeutically used to enhance the efficiency of topical drug delivery.

  2. Activated protein C: A regulator of human skin epidermal keratinocyte function.

    Science.gov (United States)

    McKelvey, Kelly; Jackson, Christopher John; Xue, Meilang

    2014-05-26

    Activated protein C (APC) is a physiological anticoagulant, derived from its precursor protein C (PC). Independent of its anticoagulation, APC possesses strong anti-inflammatory, anti-apoptotic and barrier protective properties which appear to be protective in a number of disorders including chronic wound healing. The epidermis is the outermost skin layer and provides the first line of defence against the external environment. Keratinocytes are the most predominant cells in the epidermis and play a critical role in maintaining epidermal barrier function. PC/APC and its receptor, endothelial protein C receptor (EPCR), once thought to be restricted to the endothelium, are abundantly expressed by skin epidermal keratinocytes. These cells respond to APC by upregulating proliferation, migration and matrix metalloproteinase-2 activity and inhibiting apoptosis/inflammation leading to a wound healing phenotype. APC also increases barrier function of keratinocyte monolayers by promoting the expression of tight junction proteins and re-distributing them to cell-cell contacts. These cytoprotective properties of APC are mediated through EPCR, protease-activated receptors, epidermal growth factor receptor or Tie2. Future preventive and therapeutic uses of APC in skin disorders associated with disruption of barrier function and inflammation look promising. This review will focus on APC's function in skin epidermis/keratinocytes and its therapeutical potential in skin inflammatory conditions.

  3. Regulation of small intestinal transport function by fatty acids and the role of PPAR alpha

    NARCIS (Netherlands)

    Bosch, van den H.M.

    2008-01-01

    A key function of the small intestine is to form a selective barrier between the body and the environment. Potentially dangerous compounds and organisms have to be kept in the lumen, while simultaneously nutrients have to be taken up efficiently. Furthermore, the enterocyte is the first place where

  4. Activated protein C: A regulator of human skin epidermal keratinocyte function

    Institute of Scientific and Technical Information of China (English)

    Kelly; McKelvey; Christopher; John; Jackson; Meilang; Xue

    2014-01-01

    Activated protein C(APC) is a physiological anticoagulant, derived from its precursor protein C(PC). Independent of its anticoagulation, APC possesses strong anti-inflammatory, anti-apoptotic and barrier protective properties which appear to be protective in a number of disorders including chronic wound healing. The epidermis is the outermost skin layer and provides the first line of defence against the external environment. Keratinocytes are the most predominant cells in the epidermis and play a critical role in maintaining epidermal barrier function. PC/APC and its receptor, endothelial protein C receptor(EPCR), once thought to be restricted to the endothelium, are abundantly expressed by skin epidermal keratinocytes. These cells respond to APC by upregulating proliferation, migration and matrix metalloproteinase-2 activity and inhibiting apoptosis/inflammation leading to a wound healing phenotype. APC also increases barrier function of keratinocyte monolayers by promoting the expression of tight junction proteins and re-distributing them to cell-cell contacts. These cytoprotective properties of APC are mediated through EPCR, protease-activated receptors, epidermal growth factor receptor or Tie2. Future preventive and therapeutic uses of APC in skin disorders associated with disruption of barrier function and inflammation look promising. This review will focus on APC’s function in skin epidermis/keratinocytes and its therapeutical potential in skin inflammatory conditions.

  5. Using synthetic biology to distinguish and overcome regulatory and functional barriers related to nitrogen fixation.

    Science.gov (United States)

    Wang, Xia; Yang, Jian-Guo; Chen, Li; Wang, Ji-Long; Cheng, Qi; Dixon, Ray; Wang, Yi-Ping

    2013-01-01

    Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ~100% activity of native K. pneumoniae system. Based on the expression levels of these BioBrick parts, a T7 RNA polymerase-LacI expression system was used to replace the σ(54)-dependent promoters located upstream of nif operons. Expression patterns of nif operons were critical for the maximum activity of the recombinant system. By mimicking these expression levels with variable-strength T7-dependent promoters, ~42% of the nitrogenase activity of the σ(54)-dependent nif system was achieved in E. coli. When the newly constructed T7-dependent nif system was challenged with different genetic and physiological conditions, it bypassed the original complex regulatory circuits, with minor physiological limitations. Therefore, we have successfully replaced the nif regulatory elements with a simple expression system that may provide the first step for further research of introducing nif genes into eukaryotic organelles, which has considerable potentials in agro-biotechnology.

  6. Using synthetic biology to distinguish and overcome regulatory and functional barriers related to nitrogen fixation.

    Directory of Open Access Journals (Sweden)

    Xia Wang

    Full Text Available Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ~100% activity of native K. pneumoniae system. Based on the expression levels of these BioBrick parts, a T7 RNA polymerase-LacI expression system was used to replace the σ(54-dependent promoters located upstream of nif operons. Expression patterns of nif operons were critical for the maximum activity of the recombinant system. By mimicking these expression levels with variable-strength T7-dependent promoters, ~42% of the nitrogenase activity of the σ(54-dependent nif system was achieved in E. coli. When the newly constructed T7-dependent nif system was challenged with different genetic and physiological conditions, it bypassed the original complex regulatory circuits, with minor physiological limitations. Therefore, we have successfully replaced the nif regulatory elements with a simple expression system that may provide the first step for further research of introducing nif genes into eukaryotic organelles, which has considerable potentials in agro-biotechnology.

  7. Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.

    Science.gov (United States)

    Jantsch, Jonathan; Schatz, Valentin; Friedrich, Diana; Schröder, Agnes; Kopp, Christoph; Siegert, Isabel; Maronna, Andreas; Wendelborn, David; Linz, Peter; Binger, Katrina J; Gebhardt, Matthias; Heinig, Matthias; Neubert, Patrick; Fischer, Fabian; Teufel, Stefan; David, Jean-Pierre; Neufert, Clemens; Cavallaro, Alexander; Rakova, Natalia; Küper, Christoph; Beck, Franz-Xaver; Neuhofer, Wolfgang; Muller, Dominik N; Schuler, Gerold; Uder, Michael; Bogdan, Christian; Luft, Friedrich C; Titze, Jens

    2015-03-03

    Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection.

  8. Salvianolic acid B restored impaired barrier function via downregulation of MLCK by microRNA-1 in rat inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Yongjian eXiong

    2016-05-01

    Full Text Available Salvianolic acid B (Sal B is isolated from the traditional Chinese medical herb Salvia miltiorrhiza and is reported to have a wide range of therapeutic benefits. The aim of this study was to investigate the effects of Sal B on epithelial barrier dysfunction in rat inflammatory bowel disease (IBD and to uncover related mechanisms. Rat IBD model was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS. The intestinal barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in vitro respectively. The protein expression related to intestinal barrier function was studied using western blotting. Besides, the effects of Sal B on inflammatory responses, oxidative damage and IBD recurrence were also studied in this study. The intestinal barrier dysfunction in IBD was reversed by Sal B, accompanied with the decrease of tight junction proteins, and the effect could be blocked by microRNA-1(miR-1 inhibition. The inflammatory responses, oxidative damage and IBD recurrence were also decreased by Sal B. The IBD symptoms and recurrences were ameliorated by Sal B, and restoration of impaired barrier function via dowunregulation of MLCK by miR-1 maybe involved in this effect. This study provides some novel insights into the both of the pathological mechanisms and treatment alternatives of IBD.

  9. Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Enrrico Bloise

    2017-02-01

    Full Text Available Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB. As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C, increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5 were injected (i.p. with PolyI:C (5 mg/kg or 10 mg/kg or vehicle (saline. [3H]digoxin (P-gp substrate was injected (i.v. 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus, and fetal brains were collected. Results: PolyI:C exposure (4h significantly elevated maternal plasma IL-6 (P<0.001 and increased [3H]digoxin accumulation in the fetal brain (P<0.05. In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

  10. Impaired barrier function by dietary fructo-oligosaccharides (FOS in rats is accompanied by increased colonic mitochondrial gene expression

    Directory of Open Access Journals (Sweden)

    Kramer Evelien

    2008-03-01

    well as three other peptide hormone genes; peptide YY, pancreatic polypeptide and cholecystokinin. Conclusion We conclude that altered energy metabolism may underly colonic barrier function disruption due to FOS feeding in rats.

  11. Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function

    OpenAIRE

    Haines, Ricci J.; Corbin, Karen D.; Pendleton, Laura C; Meininger, Cynthia J; Eichler, Duane C.

    2012-01-01

    Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regu...

  12. Xenobiotic, bile acid, and cholesterol transporters: function and regulation.

    Science.gov (United States)

    Klaassen, Curtis D; Aleksunes, Lauren M

    2010-03-01

    regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

  13. FHL2 regulates hematopoietic stem cell functions under stress conditions

    Science.gov (United States)

    Hou, Yu; Wang, Xiaoqin; Li, LiPing; Fan, Rong; Chen, Ju; Zhu, Tongyu; Li, Wen; Jiang, Yanwen; Mittal, Nupur; Wu, Wenshu; Peace, David; Qian, Zhijian

    2014-01-01

    FHL2, a member of the four and one half LIM domain protein family, is a critical transcriptional modulator. Here, we identify FHL2 as a critical regulator of hematopoietic stem cells (HSCs) that is essential for maintaining HSC self-renewal under regenerative stress. We find that Fhl2 loss has limited effects on hematopoiesis under homeostatic conditions. In contrast, Fhl2-null chimeric mice reconstituted with Fhl2-null bone marrow cells developed abnormal hematopoiesis with significantly reduced numbers of HSCs, hematopoietic progenitor cells (HPCs), red blood cells and platelets as well as hemoglobin levels. In addition, HSCs displayed a significantly reduced self-renewal capacity and were skewed toward myeloid lineage differentiation. We find that Fhl2 loss reduces both HSC quiescence and survival in response to regenerative stress, probably as a consequence of Fhl2-loss-mediated down-regulation of cyclin dependent kinase (CDK)-inhibitors, including p21(Cip) and p27(Kip1). Interestingly, FHL2 is regulated under control of a tissue specific promoter in hematopoietic cells and it is down-regulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells. Furthermore, we find that down-regulation of FHL2 frequently occurs in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, raising a possibility that FHL2 down-regulation plays a role in the pathogenesis of myeloid malignancies. PMID:25179730

  14. The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease.

    Science.gov (United States)

    Wesemann, Duane R; Nagler, Cathryn R

    2016-04-19

    Allergic disease affects millions. Despite many advances in our understanding of the immune system in the past century, the physiologic underpinning for the existence of allergy remains largely mysterious. Food allergies, in particular, have increased dramatically in recent years, adding a new sense of urgency to unraveling this mystery. The concurrence of significant lifestyle changes in Western societies with increasing disease prevalence implies a causal link. Demographic variables that influence the composition and function of the commensal microbiota early in life seem to be most important. Identifying the evolutionary and physiologic foundations of allergic disease and defining what about our modern environment is responsible for its increased incidence will provide insights critical to the development of new approaches to prevention and treatment.

  15. Functionalized low defect graphene nanoribbons and polyurethane composite film for improved gas barrier and mechanical performances.

    Science.gov (United States)

    Xiang, Changsheng; Cox, Paris J; Kukovecz, Akos; Genorio, Bostjan; Hashim, Daniel P; Yan, Zheng; Peng, Zhiwei; Hwang, Chih-Chau; Ruan, Gedeng; Samuel, Errol L G; Sudeep, Parambath M; Konya, Zoltan; Vajtai, Robert; Ajayan, Pulickel M; Tour, James M

    2013-11-26

    A thermoplastic polyurethane (TPU) composite film containing hexadecyl-functionalized low-defect graphene nanoribbons (HD-GNRs) was produced by solution casting. The HD-GNRs were well distributed within the polyurethane matrix, leading to phase separation of the TPU. Nitrogen gas effective diffusivity of TPU was decreased by 3 orders of magnitude with only 0.5 wt % HD-GNRs. The incorporation of HD-GNRs also improved the mechanical properties of the composite films, as predicted by the phase separation and indicated by tensile tests and dynamic mechanical analyses. The improved properties of the composite film could lead to potential applications in food packaging and lightweight mobile gas storage containers.

  16. Function, kinetic properties, crystallization, and regulation of microbial malate dehydrogenase

    Institute of Scientific and Technical Information of China (English)

    Tóshiko TAKAHASHI-ÍÑIGUEZ; Nelly ABURTO-RODRÍGUEZ; Ana Laura VILCHIS-GONZÁLEZ; María Elena FLORES

    2016-01-01

    of the enzymatic reaction. Furthermore, due to the importance of its function, the transcription and activity of this enzyme are rigorously regulated. Crystal structures of MDH from different bacterial sources led to the identification of the regions involved in substrate and cofactor binding and the residues important for the dimer-dimer interface. This structural information alows one to make direct modifications to improve the enzyme catalysis by increasing its activity, cofactor binding capacity, substrate specificity, and thermostability. A comparative analysis of the phylogenetic reconstruction of MDH reveals interesting facts about its evolutionary history, dividing this superfamily of proteins into two principle clades and establishing relationships between MDHs from different celular compartments from archaea, bacteria, and eukaryotes.

  17. DIRECTIONS AND MECHANISMS OF STATE REGULATION OF THE PRODUCTION OF FUNCTIONAL BAKERY PRODUCTS

    Directory of Open Access Journals (Sweden)

    I. P. Bogomolova

    2014-01-01

    Full Text Available Summary. In the article the basic socio-economic problems associated with micronutrient deficiency in the diet of the population and their possible solutions through production of a functional purpose, summed up the experience of foreign countries, as well as the possible mechanisms of state regulation and support enterprises of the baking industry in socially significant programs. The rapid pace of development of the economies of most countries of the world have led to negative social consequences, the main one of which is a violation of the power structure in the general population, lack of nutritional vitamins and trace elements , jetlag and diet , eating dangerous and harmful products . Way out of this situation is the creation and distribution of food functionality, including the baking of products. Currently, the production of functional food - one of the fastest growing areas of activity of subjects of the food industry. In enterprises of our region there is a great potential for the development of this segment. By the State in support of this direction are implemented targeted programs aimed at the development of the baking industry for the production of enriched bakery products. The paper presents the principles that can contribute to the effective interaction with state actors bakery business needed to overcome the lag in the development of socially significant sectors of the Russian economy from foreign counterparts, such as the development of competition and the creation of favorable conditions for the realization of entrepreneurial initiatives; increasing the investment attractiveness, social and economic efficiency of production and sale of bread and bakery in the Delhi - regions; reducing administrative barriers to accelerate the development of the market of bread and bakery products functional and specialized purpose . Bakery products needs competent positioning, because the development of the market and changing consumer

  18. Functionalization of Hydrogen-free Diamond-like Carbon Films using Open-air Dielectric Barrier Discharge Atmospheric Plasma Treatments

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Instituto de Materiales de Madrid, C.S.I.C., Cantoblanco, 28049 Madrid, Spain; Instituto de Quimica-Fisica" Rocasolano" C.S.I.C., 28006 Madrid, Spain; Mahasarakham University, Mahasarakham 44150, Thailand; CASTI, CNR-INFM Regional Laboratory, L' Aquila 67100, Italy; SUNY Upstate Medical University, Syracuse, NY 13210, USA; Endrino, Jose; Endrino, J. L.; Marco, J. F.; Poolcharuansin, P.; Phani, A.R.; Allen, M.; Albella, J. M.; Anders, A.

    2007-12-28

    A dielectric barrier discharge (DBD) technique has been employed to produce uniform atmospheric plasmas of He and N2 gas mixtures in open air in order to functionalize the surface of filtered-arc deposited hydrogen-free diamond-like carbon (DLC) films. XPS measurements were carried out on both untreated and He/N2 DBD plasma treated DLC surfaces. Chemical states of the C 1s and N 1s peaks were collected and used to characterize the surface bonds. Contact angle measurements were also used to record the short- and long-term variations in wettability of treated and untreated DLC. In addition, cell viability tests were performed to determine the influence of various He/N2 atmospheric plasma treatments on the attachment of osteoblast MC3T3 cells. Current evidence shows the feasibility of atmospheric plasmas in producing long-lasting variations in the surface bonding and surface energy of hydrogen-free DLC and consequently the potential for this technique in the functionalization of DLC coated devices.

  19. Asymmetric Barrier Lyapunov Function-Based Wheel Slip Control for Antilock Braking System

    Directory of Open Access Journals (Sweden)

    Xiaolei Chen

    2015-01-01

    Full Text Available As an important device of the aircraft landing system, the antilock braking system (ABS has a function to avoid aircraft wheels self-locking. To deal with the strong nonlinear characteristics, complex nonlinear control schemes are applied in ABS. However, none of existing control schemes focus on the braking operating status, which directly reflects wheels self-locking degree. In this paper, the braking operating status region is divided into three regions: the healthy region, the light slip region, and the deep slip region. An ABLF-based wheel slip controller is proposed for ABS to constrain the braking system operating status in the healthy region and the light slip region. Therefore the ABS will be prevented from operating in the deep slip region. Under the proposed control scheme, self-locking is avoided completely and zero steady state error tracking of the wheel optimal slip ratio is implemented. The Hardware-In-Loop (HIL experiments have validated the effectiveness of the proposed controller.

  20. The Effect of an Emollient Containing Urea, Ceramide NP, and Lactate on Skin Barrier Structure and Function in Older People with Dry Skin.

    Science.gov (United States)

    Danby, Simon G; Brown, Kirsty; Higgs-Bayliss, Tim; Chittock, John; Albenali, Lujain; Cork, Michael J

    2016-01-01

    Xerosis affects up to 75% of older people and develops as a result of a skin barrier defect. Emollients are widely used to treat xerosis; however, there is limited understanding of the differences between them and their effects on the skin barrier in older people. This study aimed to compare the effect of a commercially available emollient containing 5% urea, ceramide NP and lactate (test emollient) to an alternative emollient without these additives (control emollient) on the properties of the skin barrier in older people. Two cohorts of 21 volunteers aged >60 years with dry skin were recruited. The first applied the test emollient to one forearm and no treatment to the other for 28 days. The second compared the test emollient to the control emollient observing the same parameters. Effects on the skin barrier were determined by measuring skin barrier function, hydration, skin surface pH and by analysing Fourier transform infrared spectra before and after treatment. A third cohort of 6 young adults was recruited to investigate the effect of a single treatment with the test emollient on the molecular structure of the skin barrier at greater depths by employing the tape-stripping technique. The test emollient hydrated the skin to a significantly greater extent and for a longer period of time compared to the control emollient, an effect associated with a significant elevation of carboxylate groups (a marker of natural moisturizing factor content) within the stratum corneum. Furthermore, the test emollient imparted additional benefits to the structure and function of the skin barrier not exhibited by the control emollient. In conclusion, the test emollient addressed the pathological features of xerotic aged skin, supporting its use as first-line therapy for xerotic skin conditions in this population. © 2016 The Author(s) Published by S. Karger AG, Basel.

  1. Chondrocytic Atf4 regulates osteoblast differentiation and function via Ihh

    OpenAIRE

    Wang, Weiguang; Lian, Na; Ma, Yun; Li, Lingzhen; Gallant, Richard C.; Elefteriou, Florent; Yang, Xiangli

    2012-01-01

    Atf4 is a leucine zipper-containing transcription factor that activates osteocalcin (Ocn) in osteoblasts and indian hedgehog (Ihh) in chondrocytes. The relative contribution of Atf4 in chondrocytes and osteoblasts to the regulation of skeletal development and bone formation is poorly understood. Investigations of the Atf4–/–;Col2a1-Atf4 mouse model, in which Atf4 is selectively overexpressed in chondrocytes in an Atf4-null background, demonstrate that chondrocyte-derived Atf4 regulates osteog...

  2. IL-10 Function, Regulation, and in Bacterial Keratitis

    OpenAIRE

    Hazlett, Linda D.; Jiang, Xiaoyu; McClellan, Sharon A.

    2014-01-01

    The immune system protects the host from pathogenic microbes, but tight regulation of the evoked response is requisite to limit bystander damage. The interleukin (IL)-10 family of cytokines, composed of 9 members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and 3 distantly related members, IL-28A, IL-28B, and IL-29, plays a central role in this regulation. IL-10 family cytokines emerged before the adaptive immune response and elicit diverse host defense mechanisms, especially from epithelial ce...

  3. Dietary Lactobacillus rhamnosus GG Supplementation Improves the Mucosal Barrier Function in the Intestine of Weaned Piglets Challenged by Porcine Rotavirus.

    Directory of Open Access Journals (Sweden)

    Xiangbing Mao

    Full Text Available Lactobacillus rhamnosus GG (LGG has been regarded as a safe probiotic strain. The aim of this study was to investigate whether dietary LGG supplementation could alleviate diarrhea via improving jejunal mucosal barrier function in the weaned piglets challenged by RV, and further analyze the potential roles for apoptosis of jejunal mucosal cells and intestinal microbiota. A total of 24 crossbred barrows weaned at 21 d of age were assigned randomly to 1 of 2 diets: the basal diet and LGG supplementing diet. On day 11, all pigs were orally infused RV or the sterile essential medium. RV infusion increased the diarrhea rate, increased the RV-Ab, NSP4 and IL-2 concentrations and the Bax mRNA levels of jejunal mucosa (P<0.05, decreased the villus height, villus height: crypt depth, the sIgA, IL-4 and mucin 1 concentrations and the ZO-1, occludin and Bcl-2 mRNA levels of jejunal mucosa (P<0.05, and affected the microbiota of ileum and cecum (P<0.05 in the weaned pigs. Dietary LGG supplementation increased the villus height and villus height: crypt depth, the sIgA, IL-4, mucin 1 and mucin 2 concentrations, and the ZO-1, occludin and Bcl-2 mRNA levels of the jejunal mucosa (P<0.05 reduced the Bax mRNA levels of the jejunal mucosa (P<0.05 in weaned pigs. Furthermore, dietary LGG supplementation alleviated the increase of diarrhea rate in the weaned pigs challenged by RV (P<0.05, and relieve the effect of RV infection on the villus height, crypt depth and the villus height: crypt depth of the jejunal mucosa (P<0.05, the NSP4, sIgA, IL-2, IL-4, mucin 1 and mucin 2 concentrations of jejunal mucosa (P<0.05, the ZO-1, occludin, Bax and Bcl-2 mRNA levels of the jejunal mucosa (P<0.05, and the microbiota of ileum and cecum (P<0.05 in the weaned pigs challenged by RV. These results suggest that supplementing LGG in diets alleviated the diarrhea of weaned piglets challenged by RV via inhibiting the virus multiplication and improving the jejunal mucosal barrier

  4. Dietary Lactobacillus rhamnosus GG Supplementation Improves the Mucosal Barrier Function in the Intestine of Weaned Piglets Challenged by Porcine Rotavirus.

    Science.gov (United States)

    Mao, Xiangbing; Gu, Changsong; Hu, Haiyan; Tang, Jun; Chen, Daiwen; Yu, Bing; He, Jun; Yu, Jie; Luo, Junqiu; Tian, Gang

    2016-01-01

    Lactobacillus rhamnosus GG (LGG) has been regarded as a safe probiotic strain. The aim of this study was to investigate whether dietary LGG supplementation could alleviate diarrhea via improving jejunal mucosal barrier function in the weaned piglets challenged by RV, and further analyze the potential roles for apoptosis of jejunal mucosal cells and intestinal microbiota. A total of 24 crossbred barrows weaned at 21 d of age were assigned randomly to 1 of 2 diets: the basal diet and LGG supplementing diet. On day 11, all pigs were orally infused RV or the sterile essential medium. RV infusion increased the diarrhea rate, increased the RV-Ab, NSP4 and IL-