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Sample records for immunization reduces damage

  1. Reducing Radiation Damage

    SciTech Connect

    Blankenbecler, Richard

    2006-06-05

    This talk describes the use of a modified treatment sequence, i.e., radiation dose, geometry, dwell time, etc., to mitigate some of the deleterious effects of cancer radiotherapy by utilizing natural cell repair processes. If bad side effects can be reduced, a more aggressive therapy can be put into place. Cells contain many mechanisms that repair damage of various types. If the damage can not be repaired, cells will undergo apoptosis (cell death). Data will be reviewed that support the fact that a small dose of radiation will activate damage repair genes within a cell. Once the mechanisms are fully active, they will efficiently repair the severe damage from a much larger radiation dose. The data ranges from experiments on specific cell cultures using microarray (gene chip) techniques to experiments on complete organisms. The suggested effect and treatment is consistent with the assumption that all radiation is harmful, no matter how small the dose. Nevertheless, the harm can be reduced. These mechanisms need to be further studied and characterized. In particular, their time dependence needs to be understood before the proposed treatment can be optimized. Under certain situations it is also possible that the deleterious effects of chemotherapy can be mitigated and the damage to radiation workers can be reduced.

  2. Maternal immune stimulation reduces both placental morphologic damage and down-regulated placental growth-factor and cell cycle gene expression caused by urethane: are these events related to reduced teratogenesis?

    PubMed

    Sharova, L V; Sharov, A A; Sura, P; Gogal, R M; Smith, B J; Holladay, S D

    2003-07-01

    Activation of the maternal immune system in mice decreased cleft palate caused by the chemical teratogen, urethane. Direct and indirect mechanisms for this phenomenon have been suggested, including maternal macrophages that cross the placenta to find and eliminate pre-teratogenic cells, or maternal immune proteins (cytokines) that cross placenta to alleviate or partially alleviate toxicant-mediated effects in the developing fetus. A third mechanism to explain improved fetal developmental outcome in teratogen-challenged pregnant mice might involve beneficial effects of immune stimulation on the placenta. In the present experiments, urethane treatment altered placental morphology and impaired placental function, the latter indicated by down-regulated activity of cell cycle genes and of genes encoding cytokines and growth factors. Maternal immune stimulation with either Freund's complete adjuvant (FCA) or interferon-gamma (IFNgamma) reduced morphologic damage to the placenta caused by urethane and normalized expression of several genes that were down-regulated by urethane. Urethane treatment also shifted placental cytokine gene expression toward a T cell helper 1 (Th1) profile, while immunostimulation tended to restore a Th2 profile that may be more beneficial to pregnancy and fetal development. These data suggest that the beneficial effects of maternal immune stimulation on fetal development in teratogen-exposed mice may, in part, result from improved placental structure and function.

  3. Damage signals in the insect immune response

    PubMed Central

    Krautz, Robert; Arefin, Badrul; Theopold, Ulrich

    2014-01-01

    Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have afflicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes. PMID:25071815

  4. DNA Damage Response and Immune Defense: Links and Mechanisms

    PubMed Central

    Nakad, Rania; Schumacher, Björn

    2016-01-01

    DNA damage plays a causal role in numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signaling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signaling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signaling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans. PMID:27555866

  5. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

    PubMed Central

    Grace, Marcy B.; Singh, Vijay K.; Rhee, Juong G.; Jackson, William E.; Kao, Tzu-Cheg; Whitnall, Mark H.

    2012-01-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID:22843381

  6. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.

    PubMed

    Grace, Marcy B; Singh, Vijay K; Rhee, Juong G; Jackson, William E; Kao, Tzu-Cheg; Whitnall, Mark H

    2012-11-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.

  7. Eye damage control by reduced blue illumination.

    PubMed

    Ueda, Toshihiko; Nakanishi-Ueda, Takako; Yasuhara, Hajime; Koide, Ryohei; Dawson, William W

    2009-12-01

    The aim of this study was to demonstrate that a blue light and ultraviolet cut-off filter (blue filter) could reduce short-wavelength retina/RPE damage threshold by a continuous spectrum source. Sixteen normal eyes of two rhesus monkeys and six cynomolgus monkeys were subjected to macular irradiation of 20, 24, 27.4, 30, 35, 45, 50 and 60 J/cm(2) energy densities. The values of energy density were measured before the blue filter. Lesions were measured before and at 2 and 30 days after irradiation of a 2.8 mm diameter region within the macular arcade. Measures were fundoscopy, fluorescein angiography and long wavelength scanning by the Heidelberg Retinal Tomograph (HRT) unit. The lesions, which were produced, were scored and compared to irradiant energy density of the blue LED (NSPB500S, Nichia, Tokushima, Japan). The exposure at the 20 J/cm(2) produced no detectable result at 2 or 30 days. Exposure at 35 J/cm(2) showed definite lesion production without blue filter. With the filter added there was one indication of minor change. At 60 J/cm(2) there was extensive heavy, enduring damage without the filter and with the filter damage was present but was significantly attenuated. These results strongly support the conclusion that the blue filter attenuation reduces the frequency of damage by exposure. This experimental system is a useful model for normal human eye aging and continuous spectrum environment irradiance.

  8. 5-AED Enhances Survival of Irradiated Mice in a G-CSF-Dependent Manner, Stimulates Innate Immune Cell Function, Reduces Radiation-induced DNA Damage and Induces Genes that Modulate Cell Cycle Progression and Apoptosis

    DTIC Science & Technology

    2012-01-01

    pre-irradiation) radio- protectants and (post-irradiation) therapeutics, as recognized by civilian and military government agencies [2– 4 ]. 5-AED is...2012 4 . TITLE AND SUBTITLE 5-AED Enhances Survival of Irradiated Mice in a G-CSF-Dependent Manner, Stimulates Innate Immune Cell Function, Reduces...control after 4 days, but not 8 days. The time course of plasma 5-AED after buccal de- livery (60 mg/kg) was similar, but levels were significantly lower

  9. How damage diversification can reduce systemic risk

    NASA Astrophysics Data System (ADS)

    Burkholz, Rebekka; Garas, Antonios; Schweitzer, Frank

    2016-04-01

    We study the influence of risk diversification on cascading failures in weighted complex networks, where weighted directed links represent exposures between nodes. These weights result from different diversification strategies and their adjustment allows us to reduce systemic risk significantly by topological means. As an example, we contrast a classical exposure diversification (ED) approach with a damage diversification (DD) variant. The latter reduces the loss that the failure of high degree nodes generally inflict to their network neighbors and thus hampers the cascade amplification. To quantify the final cascade size and obtain our results, we develop a branching process approximation taking into account that inflicted losses cannot only depend on properties of the exposed, but also of the failing node. This analytic extension is a natural consequence of the paradigm shift from individual to system safety. To deepen our understanding of the cascade process, we complement this systemic perspective by a mesoscopic one: an analysis of the failure risk of nodes dependent on their degree. Additionally, we ask for the role of these failures in the cascade amplification.

  10. How damage diversification can reduce systemic risk.

    PubMed

    Burkholz, Rebekka; Garas, Antonios; Schweitzer, Frank

    2016-04-01

    We study the influence of risk diversification on cascading failures in weighted complex networks, where weighted directed links represent exposures between nodes. These weights result from different diversification strategies and their adjustment allows us to reduce systemic risk significantly by topological means. As an example, we contrast a classical exposure diversification (ED) approach with a damage diversification (DD) variant. The latter reduces the loss that the failure of high degree nodes generally inflict to their network neighbors and thus hampers the cascade amplification. To quantify the final cascade size and obtain our results, we develop a branching process approximation taking into account that inflicted losses cannot only depend on properties of the exposed, but also of the failing node. This analytic extension is a natural consequence of the paradigm shift from individual to system safety. To deepen our understanding of the cascade process, we complement this systemic perspective by a mesoscopic one: an analysis of the failure risk of nodes dependent on their degree. Additionally, we ask for the role of these failures in the cascade amplification.

  11. Increasing Immunization Compliance by Reducing Provisional Admittance

    ERIC Educational Resources Information Center

    Davis, Wendy S.; Varni, Susan E.; Barry, Sara E.; Frankowski, Barbara L.; Harder, Valerie S.

    2016-01-01

    Students in Vermont with incomplete or undocumented immunization status are provisionally admitted to schools and historically had a calendar year to resolve their immunization status. The process of resolving these students' immunization status was challenging for school nurses. We conducted a school-based quality improvement effort to increase…

  12. Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

    PubMed Central

    Delano, Matthew J.; Ward, Peter A.

    2016-01-01

    Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after “recovery” from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical “recovery,” with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved. PMID:26727230

  13. Method for Reducing Pumping Damage to Blood

    NASA Technical Reports Server (NTRS)

    Bozeman, Richard J., Jr. (Inventor); Akkerman, James W. (Inventor); Aber, Gregory S. (Inventor); VanDamm, George Arthur (Inventor); Bacak, James W. (Inventor); Svejkovsky, Robert J. (Inventor); Benkowski, Robert J. (Inventor)

    1997-01-01

    Methods are provided for minimizing damage to blood in a blood pump wherein the blood pump comprises a plurality of pump components that may affect blood damage such as clearance between pump blades and housing, number of impeller blades, rounded or flat blade edges, variations in entrance angles of blades, impeller length, and the like. The process comprises selecting a plurality of pump components believed to affect blood damage such as those listed herein before. Construction variations for each of the plurality of pump components are then selected. The pump components and variations are preferably listed in a matrix for easy visual comparison of test results. Blood is circulated through a pump configuration to test each variation of each pump component. After each test, total blood damage is determined for the blood pump. Preferably each pump component variation is tested at least three times to provide statistical results and check consistency of results. The least hemolytic variation for each pump component is preferably selected as an optimized component. If no statistical difference as to blood damage is produced for a variation of a pump component, then the variation that provides preferred hydrodynamic performance is selected. To compare the variation of pump components such as impeller and stator blade geometries, the preferred embodiment of the invention uses a stereolithography technique for realizing complex shapes within a short time period.

  14. Method to reduce damage to backing plate

    DOEpatents

    Perry, Michael D.; Banks, Paul S.; Stuart, Brent C.

    2001-01-01

    The present invention is a method for penetrating a workpiece using an ultra-short pulse laser beam without causing damage to subsequent surfaces facing the laser. Several embodiments are shown which place holes in fuel injectors without damaging the back surface of the sack in which the fuel is ejected. In one embodiment, pulses from an ultra short pulse laser remove about 10 nm to 1000 nm of material per pulse. In one embodiment, a plasma source is attached to the fuel injector and initiated by common methods such as microwave energy. In another embodiment of the invention, the sack void is filled with a solid. In one other embodiment, a high viscosity liquid is placed within the sack. In general, high-viscosity liquids preferably used in this invention should have a high damage threshold and have a diffusing property.

  15. Maternal antibodies reduce costs of an immune response during development.

    PubMed

    Grindstaff, Jennifer L

    2008-03-01

    Young vertebrates are dependent primarily on innate immunity and maternally derived antibodies for immune defense. This reliance on innate immunity and the associated inflammatory response often leads to reduced growth rates after antigenic challenge. However, if offspring have maternal antibodies that recognize an antigen, these antibodies should block stimulation of the inflammatory response and reduce growth suppression. To determine whether maternal and/or offspring antigen exposure affect antibody transmission and offspring growth, female Japanese quail (Coturnix japonica) and their newly hatched chicks were immunized. Mothers were immunized with lipopolysaccharide (LPS), killed avian reovirus vaccine (AR), or were given a control, phosphate-buffered saline, injection. Within each family, one-third of offspring were immunized with LPS, one-third were immunized with AR, and one-third were given the control treatment. Maternal immunization significantly affected the specific types of antibodies that were transmitted. In general, immunization depressed offspring growth. However, offspring immunized with the same antigen as their mother exhibited elevated growth in comparison to siblings immunized with a different antigen. This suggests that the growth suppressive effects of antigen exposure during development can be partially ameliorated by the presence of maternal antibodies, but in the absence of specific maternal antibodies, offspring are dependent on more costly innate immune defenses. Together, the results suggest that the local disease environment of mothers prior to reproduction significantly affects maternal antibody transmission and these maternal antibodies may allow offspring to partially maintain growth during infection in addition to providing passive humoral immune defense.

  16. Immune Activation Reduces Sperm Quality in the Great Tit

    PubMed Central

    Losdat, Sylvain; Richner, Heinz; Blount, Jonathan D.; Helfenstein, Fabrice

    2011-01-01

    Mounting an immune response against pathogens incurs costs to organisms by its effects on important life-history traits, such as reproductive investment and survival. As shown recently, immune activation produces large amounts of reactive species and is suggested to induce oxidative stress. Sperm are highly susceptible to oxidative stress, which can negatively impact sperm function and ultimately male fertilizing efficiency. Here we address the question as to whether mounting an immune response affects sperm quality through the damaging effects of oxidative stress. It has been demonstrated recently in birds that carotenoid-based ornaments can be reliable signals of a male's ability to protect sperm from oxidative damage. In a full-factorial design, we immune-challenged great tit males while simultaneously increasing their vitamin E availability, and assessed the effect on sperm quality and oxidative damage. We conducted this experiment in a natural population and tested the males' response to the experimental treatment in relation to their carotenoid-based breast coloration, a condition-dependent trait. Immune activation induced a steeper decline in sperm swimming velocity, thus highlighting the potential costs of an induced immune response on sperm competitive ability and fertilizing efficiency. We found sperm oxidative damage to be negatively correlated with sperm swimming velocity. However, blood resistance to a free-radical attack (a measure of somatic antioxidant capacity) as well as plasma and sperm levels of oxidative damage (lipid peroxidation) remained unaffected, thus suggesting that the observed effect did not arise through oxidative stress. Towards the end of their breeding cycle, swimming velocity of sperm of more intensely colored males was higher, which has important implications for the evolution of mate choice and multiple mating in females because females may accrue both direct and indirect benefits by mating with males having better quality sperm

  17. As we age: Does slippage of quality control in the immune system lead to collateral damage?

    PubMed

    Müller, Ludmila; Pawelec, Graham

    2015-09-01

    The vertebrate adaptive immune system is remarkable for its possession of a very broad range of antigen receptors imbuing the system with exquisite specificity, in addition to the phagocytic and inflammatory cells of the innate system shared with invertebrates. This system requires strict control both at the level of the generation the cells carrying these receptors and at the level of their activation and effector function mediation in order to avoid autoimmunity and mitigate immune pathology. Thus, quality control checkpoints are built into the system at multiple nodes in the response, relying on clonal selection and regulatory networks to maximize pathogen-directed effects and minimize collateral tissue damage. However, these checkpoints are compromised with age, resulting in poorer immune control manifesting as tissue-damaging autoimmune and inflammatory phenomena which can cause widespread systemic disease, paradoxically compounding the problems associated with increased susceptibility to infectious disease and possibly cancer in the elderly. Better understanding the reasons for slippage of immune control will pave the way for developing rational strategies for interventions to maintain appropriate immunity while reducing immunopathology.

  18. Reduced Deuterium Retention in Simultaneously Damaged and Annealed Tungsten

    NASA Astrophysics Data System (ADS)

    Simmonds, Michael; Wang, Yongqiang; Doerner, Russell; Barton, Joseph; Baldwin, Matthew; Tynan, George; CenterEnergy Research, UC San Diego Collaboration; Materials Science; Technology, Los Alamos National Laboratory Collaboration

    2016-10-01

    Fusion relevant displacement damage performed at elevated temperature in tungsten (W) and its influence on deuterium (D) retention is explored. Displacement damage performed in room temperature W allows defects to effectively become frozen-in. In this work, 5 MeV Cu ions produced up to 0.2 dpa damage in W samples at various temperatures up to 1243 K were subsequently exposed to D plasma at 383 K to a fluence of 1024 ions/m2 . Subsequent Nuclear Reaction Analysis (NRA) and Thermal Desorption Spectrometry (TDS) show that increased temperature during damage creation reduces D retention. TDS clearly shows that the Cu ion induced traps are annealed and approach intrinsic concentrations as the simultaneous damage/heating approaches 1243 K. Lastly, analysis of the TDS data is shown to provide an estimate of 0.09 eV for the recovery activation energy, similar to the mobility energy calculated for self-interstitial atoms (SIA).

  19. Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries.

    PubMed

    Glezer, Isaias; Lapointe, Amelie; Rivest, Serge

    2006-04-01

    Regarded as a damaging reaction, innate immune response can either improve or worsen brain outcome after injury. Hence, inflammatory molecules might modulate cell susceptibility or healing events. The remyelination that follows brain lesions is dependent on the recruitment of oligodendrocyte progenitor cells (OPCs) and expression of genes controlling differentiation and myelin production, such as Olig1 and Olig2 bHLH transcription factors. We aimed to determine how innate immunity affects these processes. Here we report that lipopolysaccharide (LPS) infusion triggered OPC reactivity. Acute inflammation changed the distribution of Olig1- and Olig2-expressing cells following chemical demyelination, enhanced reappearance of transcription signals linked to remyelination and rapidly cleared myelin debris. Although cells expressing Olig1, Olig2, and proteolipid protein were attracted to demyelinated sites in the course of chronic inflammation, myelin loss was not associated with the effects of inflammation on OPC reactivity. In addition, the beneficial properties of brain immunity are broadened to an aggressive model of injury, wherein LPS through Toll-like receptor 4 (TLR4) reduced surfactant-mediated damage while anti-inflammatory treatment enlarged the lesion. In conclusion, TLR4 activation in microglia is a powerful mechanism for improving repair at the remyelination level and protecting the cerebral tissue in presence of agents with strong cytolytic properties.

  20. Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse.

    PubMed

    Wang, Xin-Shi; Fang, Hui-Lin; Chen, Yu; Liang, Shan-Shan; Zhu, Zhen-Guo; Zeng, Qing-Yi; Li, Jia; Xu, Hui-Qin; Shao, Bei; He, Jin-Cai; Hou, Sheng-Tao; Zheng, Rong-Yuan

    2014-08-05

    We have previously shown that Idazoxan (IDA), an imidazoline 2 receptor ligand, is neuroprotective against spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE) in mouse, an animal modal of multiple sclerosis (MS). However, the protective mechanism remains unclear. Here, we provided evidence to show that IDA confers neuroprotection through reduction in blood-brain barrier (BBB) damage. EAE was induced by immunizing C57 BL/6 mice with myelin oligodendrocyte glycoprotein35-55 amino acid peptide (MOG35-55). IDA was administrated for 14 days after MOG immunization at 2 mg/kg (i.p., bid). Significant reduction in BBB damage occurred in the IDA-treated group of mice compared with the saline-treated group, as evidenced by the reduction in Evan׳s blue content in the brain tissue and the reduced BBB tight junction damage viewed under a transmission electron microscope. Moreover, EAE-induced reductions in tight junction proteins (JAM-1, Occludin, Claudin-5 and ZO-1) were also significantly ameliorated in IDA-treated mice, all of which supported the notion that IDA reduced BBB damage. Interestingly, the expression levels of extracellular matrix metalloproteinase-9 (MMP-9) and the ratio of MMP-9 against tissue inhibitor of metalloproteinase-1 (TIMP-1), which is known to be associated with MS-induced BBB damage, were significantly reduced in IDA-treated group, lending further support to the hypothesis that IDA confers brain protection through reducing BBB damage. This study raised a possibility that IDA is a promising pro-drug for development against MS.

  1. Reduced cellular immune response in social insect lineages

    PubMed Central

    Sconiers, Warren B.; Frank, Steven D.; Dunn, Robert R.; Tarpy, David R.

    2016-01-01

    Social living poses challenges for individual fitness because of the increased risk of disease transmission among conspecifics. Despite this challenge, sociality is an evolutionarily successful lifestyle, occurring in the most abundant and diverse group of organisms on earth—the social insects. Two contrasting hypotheses predict the evolutionary consequences of sociality on immune systems. The social group hypothesis posits that sociality leads to stronger individual immune systems because of the higher risk of disease transmission in social species. By contrast, the relaxed selection hypothesis proposes that social species have evolved behavioural immune defences that lower disease risk within the group, resulting in lower immunity at the individual level. We tested these hypotheses by measuring the encapsulation response in 11 eusocial and non-eusocial insect lineages. We built phylogenetic mixed linear models to investigate the effect of behaviour, colony size and body size on cellular immune response. We found a significantly negative effect of colony size on encapsulation response (Markov chain Monte Carlo generalized linear mixed model (mcmcGLMM) p < 0.05; phylogenetic generalized least squares (PGLS) p < 0.05). Our findings suggest that insects living in large societies may rely more on behavioural mechanisms, such as hygienic behaviours, than on immune function to reduce the risk of disease transmission among nest-mates. PMID:26961895

  2. Trauma equals danger--damage control by the immune system.

    PubMed

    Stoecklein, Veit M; Osuka, Akinori; Lederer, James A

    2012-09-01

    Traumatic injuries induce a complex host response that disrupts immune system homeostasis and predisposes patients to opportunistic infections and inflammatory complications. The response to injuries varies considerably by type and severity, as well as by individual variables, such as age, sex, and genetics. These variables make studying the impact of trauma on the immune system challenging. Nevertheless, advances have been made in understanding how injuries influence immune system function as well as the immune cells and pathways involved in regulating the response to injuries. This review provides an overview of current knowledge about how traumatic injuries affect immune system phenotype and function. We discuss the current ideas that traumatic injuries induce a unique type of a response that may be triggered by a combination of endogenous danger signals, including alarmins, DAMPs, self-antigens, and cytokines. Additionally, we review and propose strategies for redirecting injury responses to help restore immune system homeostasis.

  3. Immunomodulation by poly-YE reduces organophosphate-induced brain damage.

    PubMed

    Finkelstein, Arseny; Kunis, Gilad; Berkutzki, Tamara; Ronen, Ayal; Krivoy, Amir; Yoles, Eti; Last, David; Mardor, Yael; Van Shura, Kerry; McFarland, Emylee; Capacio, Benedict A; Eisner, Claire; Gonzales, Mary; Gregorowicz, Danise; Eisenkraft, Arik; McDonough, John H; Schwartz, Michal

    2012-01-01

    Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.

  4. Reducing Wildlife Damage with Cost-Effective Management Programmes.

    PubMed

    Krull, Cheryl R; Stanley, Margaret C; Burns, Bruce R; Choquenot, David; Etherington, Thomas R

    2016-01-01

    Limiting the impact of wildlife damage in a cost effective manner requires an understanding of how control inputs change the occurrence of damage through their effect on animal density. Despite this, there are few studies linking wildlife management (control), with changes in animal abundance and prevailing levels of wildlife damage. We use the impact and management of wild pigs as a case study to demonstrate this linkage. Ground disturbance by wild pigs has become a conservation issue of global concern because of its potential effects on successional changes in vegetation structure and composition, habitat for other species, and functional soil properties. In this study, we used a 3-year pig control programme (ground hunting) undertaken in a temperate rainforest area of northern New Zealand to evaluate effects on pig abundance, and patterns and rates of ground disturbance and ground disturbance recovery and the cost effectiveness of differing control strategies. Control reduced pig densities by over a third of the estimated carrying capacity, but more than halved average prevailing ground disturbance. Rates of new ground disturbance accelerated with increasing pig density, while rates of ground disturbance recovery were not related to prevailing pig density. Stochastic simulation models based on the measured relationships between control, pig density and rate of ground disturbance and recovery indicated that control could reduce ground disturbance substantially. However, the rate at which prevailing ground disturbance was reduced diminished rapidly as more intense, and hence expensive, pig control regimes were simulated. The model produced in this study provides a framework that links conservation of indigenous ecological communities to control inputs through the reduction of wildlife damage and suggests that managers should consider carefully the marginal cost of higher investment in wildlife damage control, relative to its marginal conservation return.

  5. Reducing Wildlife Damage with Cost-Effective Management Programmes

    PubMed Central

    Krull, Cheryl R.; Stanley, Margaret C.; Burns, Bruce R.; Choquenot, David; Etherington, Thomas R.

    2016-01-01

    Limiting the impact of wildlife damage in a cost effective manner requires an understanding of how control inputs change the occurrence of damage through their effect on animal density. Despite this, there are few studies linking wildlife management (control), with changes in animal abundance and prevailing levels of wildlife damage. We use the impact and management of wild pigs as a case study to demonstrate this linkage. Ground disturbance by wild pigs has become a conservation issue of global concern because of its potential effects on successional changes in vegetation structure and composition, habitat for other species, and functional soil properties. In this study, we used a 3-year pig control programme (ground hunting) undertaken in a temperate rainforest area of northern New Zealand to evaluate effects on pig abundance, and patterns and rates of ground disturbance and ground disturbance recovery and the cost effectiveness of differing control strategies. Control reduced pig densities by over a third of the estimated carrying capacity, but more than halved average prevailing ground disturbance. Rates of new ground disturbance accelerated with increasing pig density, while rates of ground disturbance recovery were not related to prevailing pig density. Stochastic simulation models based on the measured relationships between control, pig density and rate of ground disturbance and recovery indicated that control could reduce ground disturbance substantially. However, the rate at which prevailing ground disturbance was reduced diminished rapidly as more intense, and hence expensive, pig control regimes were simulated. The model produced in this study provides a framework that links conservation of indigenous ecological communities to control inputs through the reduction of wildlife damage and suggests that managers should consider carefully the marginal cost of higher investment in wildlife damage control, relative to its marginal conservation return. PMID

  6. Drill-in fluid reduces formation damage, increases production rates

    SciTech Connect

    Hands, N.; Kowbel, K.; Nouris, R.

    1998-07-13

    A sodium formate drill-in fluid system reduced formation damage, resulting in better-than-expected production rates for an off-shore Dutch development well. Programmed to optimize production capacity and reservoir drainage from a Rotliegend sandstone gas discovery, the 5-7/8-in. subhorizontal production interval was drilled and completed barefoot with a unique, rheologically engineered sodium formate drill-in fluid system. The new system, consisting of a sodium formate (NaCOOH) brine as the base fluid and properly sized calcium carbonate as the formation-bridging agent, was selected on the basis of its well-documented record in reducing solids impairment and formation damage in similar sandstone structures in Germany. The system was engineered around the low-shear-rate viscosity (LSRV) concept, designed to provide exceptional rheological properties. After describing the drilling program, the paper gives results on the drilling and completion.

  7. Improving the distribution and reducing the magnitude of pavement damage

    NASA Astrophysics Data System (ADS)

    Barker, W. R.; Chou, U. T.

    1980-08-01

    In the analysis of flexible pavement, the layered elastic theory was used to compute the pavement response. For the rigid pavement, finite difference, layered elastic theory, and Westergard procedures were used to compute tensile stresses in concrete that formed the basis for predicting allowable stress repetitions. For flexible pavement, the only effective means to reduce pavement damage was to modify the wheel assembly to reduce stress or strain at the critical locations in the pavement systems. The most effective modification would be to increase the spacing between duals. For rigid pavements, the edge effect was critical, thus suggesting that modifications to shift the loading away from the pavement edge would be effective.

  8. Probiotic Bacillus coagulans GBI-30, 6086 reduces exercise-induced muscle damage and increases recovery

    PubMed Central

    Jäger, Ralf; Shields, Kevin A.; Lowery, Ryan P.; De Souza, Eduardo O.; Partl, Jeremy M.; Hollmer, Chase; Purpura, Martin

    2016-01-01

    Objective. Probiotics have been reported to support healthy digestive and immune function, aid in protein absorption, and decrease inflammation. Further, a trend to increase vertical jump power has been observed following co-administration of protein and probiotics in resistance-trained subjects. However, to date the potential beneficial effect of probiotics on recovery from high intensity resistance exercise have yet to be explored. Therefore, this study examined the effect of co-administration of protein and probiotics on muscle damage, recovery and performance following a damaging exercise bout. Design. Twenty nine (n = 29) recreationally-trained males (mean ± SD; 21.5 ± 2.8 years; 89.7 ± 28.2 kg; 177.4 ± 8.0 cm) were assigned to consume either 20 g of casein (PRO) or 20 g of casein plus probiotic (1 billion CFU Bacillus coagulans GBI-30, 6086, PROBC) in a crossover, diet-controlled design. After two weeks of supplementation, perceptional measures, athletic performance, and muscle damage were analyzed following a damaging exercise bout. Results. The damaging exercise bout significantly increased muscle soreness, and reduced perceived recovery; however, PROBC significantly increased recovery at 24 and 72 h, and decreased soreness at 72 h post exercise in comparison to PRO. Perceptual measures were confirmed by increases in CK (PRO: +266.8%, p = 0.0002; PROBC: +137.7%, p = 0.01), with PROBC showing a trend towards reduced muscle damage (p = 0.08). The muscle-damaging exercise resulted in significantly increased muscle swelling and Blood Urea Nitrogen levels in both conditions with no difference between groups. The strenuous exercise significantly reduced athletic performance in PRO (Wingate Peak Power; PRO: (−39.8 watts, −5.3%, p = 0.03)), whereas PROBC maintained performance (+10.1 watts, +1.7%). Conclusions. The results provide evidence that probiotic supplementation in combination with protein tended to reduce indices of muscle damage, improves recovery

  9. Probiotic Bacillus coagulans GBI-30, 6086 reduces exercise-induced muscle damage and increases recovery.

    PubMed

    Jäger, Ralf; Shields, Kevin A; Lowery, Ryan P; De Souza, Eduardo O; Partl, Jeremy M; Hollmer, Chase; Purpura, Martin; Wilson, Jacob M

    2016-01-01

    Objective. Probiotics have been reported to support healthy digestive and immune function, aid in protein absorption, and decrease inflammation. Further, a trend to increase vertical jump power has been observed following co-administration of protein and probiotics in resistance-trained subjects. However, to date the potential beneficial effect of probiotics on recovery from high intensity resistance exercise have yet to be explored. Therefore, this study examined the effect of co-administration of protein and probiotics on muscle damage, recovery and performance following a damaging exercise bout. Design. Twenty nine (n = 29) recreationally-trained males (mean ± SD; 21.5 ± 2.8 years; 89.7 ± 28.2 kg; 177.4 ± 8.0 cm) were assigned to consume either 20 g of casein (PRO) or 20 g of casein plus probiotic (1 billion CFU Bacillus coagulans GBI-30, 6086, PROBC) in a crossover, diet-controlled design. After two weeks of supplementation, perceptional measures, athletic performance, and muscle damage were analyzed following a damaging exercise bout. Results. The damaging exercise bout significantly increased muscle soreness, and reduced perceived recovery; however, PROBC significantly increased recovery at 24 and 72 h, and decreased soreness at 72 h post exercise in comparison to PRO. Perceptual measures were confirmed by increases in CK (PRO: +266.8%, p = 0.0002; PROBC: +137.7%, p = 0.01), with PROBC showing a trend towards reduced muscle damage (p = 0.08). The muscle-damaging exercise resulted in significantly increased muscle swelling and Blood Urea Nitrogen levels in both conditions with no difference between groups. The strenuous exercise significantly reduced athletic performance in PRO (Wingate Peak Power; PRO: (-39.8 watts, -5.3%, p = 0.03)), whereas PROBC maintained performance (+10.1 watts, +1.7%). Conclusions. The results provide evidence that probiotic supplementation in combination with protein tended to reduce indices of muscle damage, improves recovery

  10. Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage.

    PubMed

    Yu, Chao; Tan, Shanjun; Zhou, Chunyu; Zhu, Cuilin; Kang, Xin; Liu, Shuai; Zhao, Shuang; Fan, Shulin; Yu, Zhen; Peng, Ai; Wang, Zhen

    2016-11-01

    Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.

  11. Improved immunization strategy to reduce energy consumption on nodes traffic

    NASA Astrophysics Data System (ADS)

    Yuan, Jiazheng; Zhao, Dongyan; Long, Keping; Zheng, Yongrong

    2017-04-01

    The increasing requirement of transmission network sizes would result in huge energy consumption with communication traffic. Green communication technologies are expected to help in reducing energy consumption impact to environment. Therefore, it is important to design energy-efficient strategy that can decrease energy consumption. This paper proposes to use the acquaintance and improved targeted immunization strategies from complex systems to resolve energy consumption issues and uses traffic as measure standard to obtain a stable threshold. The simulation results show that the improved control strategy is better and more effective to save as much energy as possible.

  12. Transgenic Mouse Model for Reducing Oxidative Damage in Bone

    NASA Technical Reports Server (NTRS)

    Schreurs, Ann-Sofie; Torres, S.; Truong, T.; Moyer, E. L.; Kumar, A.; Tahimic, Candice C. G.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

    2016-01-01

    Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the

  13. Grounding after moderate eccentric contractions reduces muscle damage

    PubMed Central

    Brown, Richard; Chevalier, Gaétan; Hill, Michael

    2015-01-01

    Grounding a human to the earth has resulted in changes in the physiology of the body. A pilot study on grounding and eccentric contractions demonstrated shortened duration of pain, reduced creatine kinase (CK), and differences in blood parameters. This follow-up study was conducted to investigate the effects of grounding after moderate eccentric contractions on pain, CK, and complete blood counts. Thirty-two healthy young men were randomly divided into grounded (n=16) and sham-grounded (n=16) groups. On days 1 through 4, visual analog scale for pain evaluations and blood draws were accomplished. On day 1, the participants performed eccentric contractions of 200 half-knee bends. They were then grounded or sham-grounded to the earth for 4 hours on days 1 and 2. Both groups experienced pain on all posttest days. On day 2, the sham-grounded group experienced significant CK increase (P<0.01) while the CK of the grounded group did not increase significantly; the between-group difference was significant (P=0.04). There was also an increase in the neutrophils of the grounded group on day 3 (P=0.05) compared to the sham-grounded group. There was a significant increase in platelets in the grounded group on days 2 through 4. Grounding produced changes in CK and complete blood counts that were not shared by the sham-grounded group. Grounding significantly reduced the loss of CK from the injured muscles indicating reduced muscle damage. These results warrant further study on the effects of earthing on delayed onset muscle damage. PMID:26443876

  14. Plant immunity triggered by engineered in vivo release of oligogalacturonides, damage-associated molecular patterns

    PubMed Central

    Benedetti, Manuel; Pontiggia, Daniela; Raggi, Sara; Cheng, Zhenyu; Scaloni, Flavio; Ferrari, Simone; Ausubel, Frederick M.; Cervone, Felice; De Lorenzo, Giulia

    2015-01-01

    Oligogalacturonides (OGs) are fragments of pectin that activate plant innate immunity by functioning as damage-associated molecular patterns (DAMPs). We set out to test the hypothesis that OGs are generated in planta by partial inhibition of pathogen-encoded polygalacturonases (PGs). A gene encoding a fungal PG was fused with a gene encoding a plant polygalacturonase-inhibiting protein (PGIP) and expressed in transgenic Arabidopsis plants. We show that expression of the PGIP–PG chimera results in the in vivo production of OGs that can be detected by mass spectrometric analysis. Transgenic plants expressing the chimera under control of a pathogen-inducible promoter are more resistant to the phytopathogens Botrytis cinerea, Pectobacterium carotovorum, and Pseudomonas syringae. These data provide strong evidence for the hypothesis that OGs released in vivo act as a DAMP signal to trigger plant immunity and suggest that controlled release of these molecules upon infection may be a valuable tool to protect plants against infectious diseases. On the other hand, elevated levels of expression of the chimera cause the accumulation of salicylic acid, reduced growth, and eventually lead to plant death, consistent with the current notion that trade-off occurs between growth and defense. PMID:25870275

  15. Reduced immune cell responses on nano and submicron rough titanium.

    PubMed

    Lu, Jing; Webster, Thomas J

    2015-04-01

    Current bare metal stents can be improved by nanotechnology to support the simultaneous acceleration of endothelialization and consequent reduction of immune cell responses after implantation. In our prior study, electron beam deposition was utilized to create different scales of roughness on titanium stents including flat (F-Ti), a mixture of nanometer and submicron (S-Ti), and nanometer (N-Ti). Enhanced endothelial responses (adhesion, migration, and nitric acid/endothelin-1 secretion) on nanometer to submicron rough titanium were observed compared to flat titanium. The present study aimed to further investigate the influence of nano and submicron titanium surface features on immune cells. Initial monocyte adhesion was found to be reduced on nano and submicron surface features compared to a flat surface. In a model including both endothelial cells and monocytes, it was proven that the submicron surface gave rise to an endothelial cell monolayer which generated the highest amount of NOx and subsequently led to decreased adhesiveness of endothelial cells to monocytes. The analysis of monocyte morphology gave hints to less differentiated monocytes on a submicron surface. Furthermore, the adhesion of and pro-inflammatory cytokine release from macrophages were all reduced on nano and submicron titanium surface features compared to a flat surface. This study, thus, suggests that nano and submicron titanium surfaces should be further studied for improved vascular stent performance.

  16. Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

    PubMed Central

    Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C.; Khadayate, Sanjay; Mas, Valeria R.; Nitsch, Dorothea D.; Wang, Zhen; Norman, Jill T.; Wilcox, Christopher S.; Wheeler, David C.; Leiper, James

    2015-01-01

    Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule–specific Ddah1 knockout (Ddah1PT−/−) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT−/− mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. PMID:25855779

  17. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

    PubMed Central

    Mortensen, Martin B.; Kjolby, Mads; Gunnersen, Stine; Larsen, Jakob V.; Palmfeldt, Johan; Falk, Erling; Nykjaer, Anders; Bentzon, Jacob F.

    2014-01-01

    Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis. PMID:25401472

  18. LOX-1, oxidant stress, mtDNA damage, autophagy, and immune response in atherosclerosis.

    PubMed

    Ding, Zufeng; Liu, Shijie; Wang, Xianwei; Dai, Yao; Khaidakov, Magomed; Romeo, Francesco; Mehta, Jawahar L

    2014-07-01

    As a major receptor for oxidized low density lipoprotein (ox-LDL), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is upregulated in many pathophysiological events, including endothelial cell dysfunction and smooth muscle cell growth, as well as monocyte migration and transformation into foam cells, which are present in atherosclerosis and myocardial ischemia. Excessive production of reactive oxygen species (ROS) increases LOX-1 expression, induces mitochondrial DNA damage, and activates autophagy. Damaged mitochondrial DNA that escapes from autophagy induces an inflammatory response. This paper reviews the potential link between LOX-1, mitochondrial DNA damage, autophagy, and immune response in atherosclerosis.

  19. Ichthyophonus-induced cardiac damage: a mechanism for reduced swimming stamina in salmonids

    USGS Publications Warehouse

    Kocan, R.; LaPatra, S.; Gregg, J.; Winton, J.; Hershberger, P.

    2006-01-01

    Swimming stamina, measured as time-to-fatigue, was reduced by approximately two-thirds in rainbow trout experimentally infected with Ichthyophonus. Intensity of Ichthyophonus infection was most severe in cardiac muscle but multiple organs were infected to a lesser extent. The mean heart weight of infected fish was 40% greater than that of uninfected fish, the result of parasite biomass, infiltration of immune cells and fibrotic (granuloma) tissue surrounding the parasite. Diminished swimming stamina is hypothesized to be due to cardiac failure resulting from the combination of parasite-damaged heart muscle and low myocardial oxygen supply during sustained aerobic exercise. Loss of stamina in Ichthyophonus-infected salmonids could explain the poor performance previously reported for wild Chinook and sockeye salmon stocks during their spawning migration. ?? 2006 Blackwell Publishing Ltd.

  20. Models Of Lower Extremity Damage In Mice: Time Course of Organ Damage & Immune Response

    PubMed Central

    Menzel, Christoph L; Pfeifer, Roman; Darwiche, Sophie S; Kobbe, Philipp; Gill, Roop; Shapiro, Richard A; Loughran, Patricia; Vodovotz, Yoram; Scott, Melanie J; Zenati, Mazen S; Billiar, Timothy R; Pape, Hans-Christoph

    2011-01-01

    Background Posttraumatic inflammatory changes have been identified as major causes of altered organ function and failure. Both hemorrhage and soft tissue damage induce these inflammatory changes. Exposure to heterologous bone in animal models has recently been shown to mimic this inflammatory response in a stable and reproducible fashion. This follow-up study tests the hypothesis that inflammatory responses are comparable between a novel trauma model (“pseudofracture”, PFx) and a bilateral femur fracture (BFF) model. Materials and Methods In C57BL/6 mice, markers for remote organ dysfunction and inflammatory responses were compared in 4 groups (control/sham/BFF/PFx) at the time points 2, 4, and 6 hours. Results Hepatocellular damage in BFF and PFx was highly comparable in extent and evolution, as shown by similar levels of NFκB activation and plasma ALT. Pulmonary inflammatory responses were also comparably elevated in both trauma models as early as 2h after trauma as measured by myeloperoxidase activity (MPO). Muscle damage was provoked in both BFF and PFx mice over the time course, although BFF induced significantly higher AST and CK levels. IL-6 levels were also similar with early and sustained increases over time in both trauma models. Conclusions Both BFF and PFx create similar reproducible inflammatory and remote organ responses. PFx will be a useful model to study longer term inflammatory effects that cannot be studied using BFF. PMID:21276982

  1. Transgenic Mouse Model for Reducing Oxidative Damage in Bone

    NASA Technical Reports Server (NTRS)

    Schreurs, A.-S.; Torres, S.; Truong, T.; Kumar, A.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

    2014-01-01

    Exposure to musculoskeletal disuse and radiation result in bone loss; we hypothesized that these catabolic treatments cause excess reactive oxygen species (ROS), and thereby alter the tight balance between bone resorption by osteoclasts and bone formation by osteoblasts, culminating in bone loss. To test this, we used transgenic mice which over-express the human gene for catalase, targeted to mitochondria (MCAT). Catalase is an anti-oxidant that converts the ROS hydrogen peroxide into water and oxygen. MCAT mice were shown previously to display reduced mitochondrial oxidative stress and radiosensitivity of the CNS compared to wild type controls (WT). As expected, MCAT mice expressed the transgene in skeletal tissue, and in marrow-derived osteoblasts and osteoclast precursors cultured ex vivo, and also showed greater catalase activity compared to wildtype (WT) mice (3-6 fold). Colony expansion in marrow cells cultured under osteoblastogenic conditions was 2-fold greater in the MCAT mice compared to WT mice, while the extent of mineralization was unaffected. MCAT mice had slightly longer tibiae than WT mice (2%, P less than 0.01), although cortical bone area was slightly lower in MCAT mice than WT mice (10%, p=0.09). To challenge the skeletal system, mice were treated by exposure to combined disuse (2 wk Hindlimb Unloading) and total body irradiation Cs(137) (2 Gy, 0.8 Gy/min), then bone parameters were analyzed by 2-factor ANOVA to detect possible interaction effects. Treatment caused a 2-fold increase (p=0.015) in malondialdehyde levels of bone tissue (ELISA) in WT mice, but had no effect in MCAT mice. These findings indicate that the transgene conferred protection from oxidative damage caused by treatment. Unexpected differences between WT and MCAT mice emerged in skeletal responses to treatment.. In WT mice, treatment did not alter osteoblastogenesis, cortical bone area, moment of inertia, or bone perimeter, whereas in MCAT mice, treatment increased these

  2. Reducing Nonstructural Earthquake Damage: A Practical Guide for Schools. [Videotape].

    ERIC Educational Resources Information Center

    Federal Emergency Management Agency, Washington, DC.

    This videotape describes the nonstructural areas within a school that can be damaged and create hazards for students, teachers, and staff during and after an earthquake; and discusses preventive measures to lower the injury potential from these hazards. It confirms that the best procedure to use during an earthquake to protect oneself from…

  3. Methods for globally treating silica optics to reduce optical damage

    DOEpatents

    Miller, Philip Edward; Suratwala, Tayyab Ishaq; Bude, Jeffrey Devin; Shen, Nan; Steele, William Augustus; Laurence, Ted Alfred; Feit, Michael Dennis; Wong, Lana Louie

    2012-11-20

    A method for preventing damage caused by high intensity light sources to optical components includes annealing the optical component for a predetermined period. Another method includes etching the optical component in an etchant including fluoride and bi-fluoride ions. The method also includes ultrasonically agitating the etching solution during the process followed by rinsing of the optical component in a rinse bath.

  4. The role of glutamate and the immune system in organophosphate-induced CNS damage.

    PubMed

    Eisenkraft, Arik; Falk, Avshalom; Finkelstein, Arseny

    2013-08-01

    Organophosphate (OP) poisoning is associated with long-lasting neurological damage, which is attributed mainly to the excessive levels of glutamate caused by the intoxication. Glutamate toxicity, however, is not specific to OP poisoning, and is linked to propagation of damage in both acute and chronic neurodegenerative conditions in the central nervous system (CNS). In addition to acute excitotoxic effects of glutamate, there is now a growing amount of evidence of its intricate immunomodulatory effects in the brain, involving both the innate and the adaptive immune systems. Moreover, it was demonstrated that immunomodulatory treatments, aimed at regulating the interaction between the resident immune cells of the brain (microglia) and the peripheral immune system, can support buffering of excessive levels of glutamate and restoration of the homeostasis. In this review, we will discuss the role of glutamate as an excitotoxic agent in the acute phase of OP poisoning, and the possible functions it may have as both a neuroprotectant and an immunomodulator in the sub-acute and chronic phases of OP poisoning. In addition, we will describe the novel immune-based neuroprotective strategies aimed at counteracting the long-term neurodegenerative effects of glutamate in the CNS.

  5. CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage.

    PubMed

    Chang, Yan; Jia, Xiaoyi; Wei, Fang; Wang, Chun; Sun, Xiaojing; Xu, Shu; Yang, Xuezhi; Zhao, Yingjie; Chen, Jingyu; Wu, Huaxun; Zhang, Lingling; Wei, Wei

    2016-05-17

    Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin (Pae), was evaluated in rats with adjuvant-induced arthritis (AA) to study its potential anti-arthritic activity. AA rats were treated with CP-25 (25, 50, or 100 mg/kg) from days 17 to 29 after immunization. CP-25 effectively reduced clinical and histopathological scores compared with the AA groups. CP-25-treated rats exhibited decreases in pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) coupled with an increase in the anti-inflammatory cytokine TGF-β1 in the serum. CP-25 treatment inhibited M1 macrophage activation and enhanced M2 macrophage activation by influencing cytokine production. Decreases in Th17-IL-17 and the Th17-associated transcription factor RAR-related orphan receptor gamma (ROR-γt) dramatically demonstrated the immunomodulatory effects of CP-25 on abnormal immune dysfunction. In addition, CP-25 suppressed the production of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase (MMP) 9, which supported its anti-osteoclastic effects. The data presented here demonstrated that CP-25 significantly inhibited the progression of rat AA by reducing inflammation, immunity and bone damage. The protective effects of CP-25 in AA highlight its potential as an ideal new anti-arthritic agent for human RA.

  6. Tree diversity reduces pest damage in mature forests across Europe

    PubMed Central

    Castagneyrol, Bastien; Vialatte, Aude; Deconchat, Marc; Jactel, Hervé

    2016-01-01

    Forest pest damage is expected to increase with global change. Tree diversity could mitigate this impact, but unambiguous demonstration of the diversity–resistance relationship is lacking in semi-natural mature forests. We used a network of 208 forest plots sampled along two orthogonal gradients of increasing tree species richness and latitudes to assess total tree defoliation in Europe. We found a positive relationship between tree species richness and resistance to insect herbivores: overall damage to broadleaved species significantly decreased with the number of tree species in mature forests. This pattern of associational resistance was frequently observed across tree species and countries, irrespective of their climate. These findings confirm the greater potential of mixed forests to face future biotic disturbances in a changing world. PMID:27122011

  7. Damage to the ventromedial prefrontal cortex reduces interpersonal disgust

    PubMed Central

    Ciaramelli, Elisa; Sperotto, Rebecca G.; Mattioli, Flavia

    2013-01-01

    Disgust for contaminating objects (core disgust), immoral behaviors (moral disgust) and unsavory others (interpersonal disgust), have been assumed to be closely related. It is not clear, however, whether different forms of disgust are mediated by overlapping or specific neural substrates. We report that 10 patients with damage to the ventromedial prefrontal cortex (vmPFC) avoided behaviors that normally elicit interpersonal disgust (e.g. using the scarf of a busker) less frequently than healthy and brain-damaged controls, whereas they avoided core and moral disgust elicitors at normal rates. These results indicate that different forms of disgust are dissociated neurally. We propose that the vmPFC is causally (and selectively) involved in mediating interpersonal disgust, shaping patterns of social avoidance and approach. PMID:22842816

  8. Investigation of water spray to reduce collateral thermal damage during laser resection of soft tissue

    NASA Astrophysics Data System (ADS)

    Theisen-Kunde, D.; Wolken, H.; Ellebrecht, D.; Danicke, V.; Wurster, L.; Kleemann, M.; Birngruber, R.

    2013-06-01

    To reduce unwanted collateral thermal damage to surrounding tissue and organs during laparoscopic laser dissection (cw, wavelength: 1.9μm) of porcine liver water spray was used. Size and amount of the produced water droplets of the water spray were photographed by short time imaging and analyzed by imaging software. At in vivo measurements on fresh porcine liver the depth of thermal damage was reduced by 85 % with water spray and the lateral size of thermal damage at the tissue surface could be reduced by 67%. This results show that especially for laparoscopic laser surgery water spray application might be a useful tool to avoid unwanted collateral thermal damage.

  9. Tissue Plasminogen Activator Reduces Neurological Damage after Cerebral Embolism

    NASA Astrophysics Data System (ADS)

    Zivin, Justin A.; Fisher, Marc; Degirolami, Umberto; Hemenway, Carl C.; Stashak, Joan A.

    1985-12-01

    Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.

  10. Immune alterations, lipid peroxidation, and muscle damage following a hill race.

    PubMed

    Simpson, Richard J; Wilson, Martin R; Black, James R; Ross, James A; Whyte, Greg P; Guy, Keith; Florida-James, Geraint D

    2005-04-01

    Hill races usually include large downhill running sections, which can induce significant degrees of muscle damage in a field setting. This study examined the link between muscle damage, oxidative stress, and immune perturbations following a 7-km mountainous hill race with 457 m of ascent and 457 m of descent. Venous blood samples were taken from 7 club level runners before, immediately after, and 48 hrs postrace. Samples were analysed for total and differential leukocyte counts, markers of muscle damage (CK), lipid peroxidation (MDA), and acute phase proteins (CRP; fibrinogen; alpha-1-ACT). The total antioxidant status (TEAC) and plasma levels of the proinflammatory cytokines IL-6, IL-8, and TNF-alpha were also determined. Subjective pain reports, and plasma activities of CK, MDA, and circulatory monocytes reached peak values at 48 hrs postrace (p < 0.05). TEAC and the cytokine IL-8 increased immediately after the race (p < 0.05). Plasma TNF-alpha remained unchanged (p > 0.05). Despite the reports of muscle damage and soreness, no evidence of an acute phase response was observed (p > 0.05), which may be explained by the failure of the race to induce a plasma TNF-alpha response. Future studies should examine the link between muscle damage, oxidative stress, and the acute phase response following hill races of longer duration with larger eccentric components.

  11. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance.

    PubMed

    Ermolaeva, Maria A; Segref, Alexandra; Dakhovnik, Alexander; Ou, Hui-Ling; Schneider, Jennifer I; Utermöhlen, Olaf; Hoppe, Thorsten; Schumacher, Björn

    2013-09-19

    DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell divisions, whereas somatic tissues are entirely post-mitotic. Consequently, DNA damage checkpoints function specifically in the germ line, whereas somatic tissues in adult C. elegans are highly radio-resistant. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin-proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.

  12. DNA damage, apoptosis and langerhans cells--Activators of UV-induced immune tolerance.

    PubMed

    Timares, Laura; Katiyar, Santosh K; Elmets, Craig A

    2008-01-01

    Solar UVR is highly mutagenic but is only partially absorbed by the outer stratum corneum of the epidermis. UVR can penetrate into the deeper layers of the epidermis, depending on melanin content, where it induces DNA damage and apoptosis in epidermal cells, including those in the germinative basal layer. The cellular decision to initiate either cellular repair or undergo apoptosis has evolved to balance the acute need to maintain skin barrier function with the long-term risk of retaining precancerous cells. Langerhans cells (LCs) are positioned suprabasally, where they may sense UV damage directly, or indirectly through recognition of apoptotic vesicles and soluble mediators derived from surrounding keratinocytes. Apoptotic vesicles will contain UV-induced altered proteins that may be presented to the immune system as foreign. The observation that UVR induces immune tolerance to skin-associated antigens suggests that this photodamage response has evolved to preserve the skin barrier by protecting it from autoimmune attack. LC involvement in this process is not clear and controversial. We will highlight some basic concepts of photobiology and review recent advances pertaining to UV-induced DNA damage, apoptosis regulation, novel immunomodulatory mechanisms and the role of LCs in generating antigen-specific regulatory T cells.

  13. Characterization of Plant Cell Wall Damage-Associated Molecular Patterns Regulating Immune Responses.

    PubMed

    Bacete, Laura; Mélida, Hugo; Pattathil, Sivakumar; Hahn, Michael G; Molina, Antonio; Miedes, Eva

    2017-01-01

    The plant cell wall is one of the first defensive barriers that pathogens need to overcome to successfully colonize plant tissues. Plant cell wall is considered a dynamic structure that regulates both constitutive and inducible defense mechanisms. The wall is a potential source of a diverse set of Damage-Associated Molecular Patterns (DAMPs), which are signalling molecules that trigger immune responses. However, just a few active wall ligands, such as oligogalacturonic acids (OGs), have been characterized so far. To identify additional wall-derived DAMPs, we obtained different plant wall fractions and tested their capacity to trigger immune responses using a calcium read-out system. To characterize the active DAMPs structures present in these fractions, we applied Glycome Profiling, a technology that uses a large and diverse set of specific monoclonal antibodies against wall carbohydrate ligands. The methods describe here can be used in combination with other biochemical approaches to identify and purify new plant cell wall DAMPs.

  14. Rotary ultrasonic bone drilling: Improved pullout strength and reduced damage.

    PubMed

    Gupta, Vishal; Pandey, Pulak M; Silberschmidt, Vadim V

    2017-03-01

    Bone drilling is one of the most common operations used to repair fractured parts of bones. During a bone drilling process, microcracks are generated on the inner surface of the drilled holes that can detrimentally affect osteosynthesis and healing. This study focuses on the investigation of microcracks and pullout strength of cortical-bone screws in drilled holes. It compares conventional surgical bone drilling (CSBD) with rotary ultrasonic bone drilling (RUBD), a novel approach employing ultrasonic vibration with a diamond-coated hollow tool. Both techniques were used to drill holes in porcine bones in an in-vitro study. Scanning electron microscopy was used to observe microcracks and surface morphology. The results obtained showed a significant decrease in the number and dimensions of microcracks generated on the inner surface of drilled holes with the RUBD process in comparison to CSBD. It was also observed that a higher rotational speed and a lower feed rate resulted in lower damage, i.e. fewer microcracks. Biomechanical axial pullout strength of a cortical bone screw inserted into a hole drilled with RUBD was found to be much higher (55-385%) than that for CSBD.

  15. Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage

    PubMed Central

    Dai, Chao; Deng, Yun; Quinlan, Aaron; Gaskin, Felicia; Tsao, Betty P; Fu, Shu Man

    2014-01-01

    Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to genes that contribute directly to susceptibility to end organ damage. It is concluded that the interactions among these two major pathways will provide further insight into the pathogenesis of SLE. An interactive model of the two major pathways is proposed without emphasis on the importance of breaking tolerance to autoantigens. PMID:25458999

  16. Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

    PubMed

    Moon, Eunjung; Han, Jeong Eun; Jeon, Sejin; Ryu, Jong Hoon; Choi, Ji Woong; Chun, Jerold

    2015-01-01

    Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

  17. Experimental Colitis Is Attenuated by Cardioprotective Diet Supplementation That Reduces Oxidative Stress, Inflammation, and Mucosal Damage

    PubMed Central

    Vargas Robles, Hilda; Citalán Madrid, Alí Francisco; García Ponce, Alexander; Silva Olivares, Angelica; Shibayama, Mineko; Betanzos, Abigail; Del Valle Mondragón, Leonardo; Nava, Porfirio; Schnoor, Michael

    2016-01-01

    Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are multifactorial, relapsing disorders of the gastrointestinal tract. However, the etiology is still poorly understood but involves altered immune responses, epithelial dysfunction, environmental factors, and nutrition. Recently, we have shown that the diet supplement corabion has cardioprotective effects due to reduction of oxidative stress and inflammation. Since oxidative stress and inflammation are also prominent risk factors in IBD, we speculated that corabion also has beneficial effects on experimental colitis. Colitis was induced in male mice by administration of 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 3 or 7 days with or without daily gavage feeding of corabion consisting of vitamin C, vitamin E, L-arginine, and eicosapentaenoic and docosahexaenoic acid. We found that corabion administration attenuated DSS-induced colon shortening, tissue damage, and disease activity index during the onset of colitis. Mechanistically, these effects could be explained by reduced neutrophil recruitment, oxidative stress, production of proinflammatory cytokines, and internalization of the junctional proteins ZO-1 and E-cadherin leading to less edema formation. Thus, corabion may be a useful diet supplement for the management of chronic inflammatory intestinal disorders such as IBD. PMID:26881044

  18. Evaporative cooling with sprinklers to reduce heat-related fruit damage in northern highbush blueberry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hot and sunny weather can cause a considerable amount of fruit damage in blueberries and results in millions of dollars of crop loss each year. The objective of this study was to evaluate the efficacy of using sprinklers to reduce the damage. The study was conducted for 2 years in a mature planting ...

  19. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats.

    PubMed

    Ma, Daqing; Hossain, Mahmuda; Pettet, Garry K J; Luo, Yan; Lim, Ta; Akimov, Stanislav; Sanders, Robert D; Franks, Nicholas P; Maze, Mervyn

    2006-02-01

    Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury.

  20. Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis.

    PubMed

    Zhang, Minjie; Mani, Sriniwasan B; He, Yao; Hall, Amber M; Xu, Lin; Li, Yefu; Zurakowski, David; Jay, Gregory D; Warman, Matthew L

    2016-08-01

    Joints that have degenerated as a result of aging or injury contain dead chondrocytes and damaged cartilage. Some studies have suggested that chondrocyte death precedes cartilage damage, but how the loss of chondrocytes affects cartilage integrity is not clear. In this study, we examined whether chondrocyte death undermines cartilage integrity in aging and injury using a rapid 3D confocal cartilage imaging technique coupled with standard histology. We induced autonomous expression of diphtheria toxin to kill articular surface chondrocytes in mice and determined that chondrocyte death did not lead to cartilage damage. Moreover, cartilage damage after surgical destabilization of the medial meniscus of the knee was increased in mice with intact chondrocytes compared with animals whose chondrocytes had been killed, suggesting that chondrocyte death does not drive cartilage damage in response to injury. These data imply that chondrocyte catabolism, not death, contributes to articular cartilage damage following injury. Therefore, therapies targeted at reducing the catabolic phenotype may protect against degenerative joint disease.

  1. Radiation damage in protein crystals is reduced with a micron-sized X-ray beam.

    PubMed

    Sanishvili, Ruslan; Yoder, Derek W; Pothineni, Sudhir Babu; Rosenbaum, Gerd; Xu, Shenglan; Vogt, Stefan; Stepanov, Sergey; Makarov, Oleg A; Corcoran, Stephen; Benn, Richard; Nagarajan, Venugopalan; Smith, Janet L; Fischetti, Robert F

    2011-04-12

    Radiation damage is a major limitation in crystallography of biological macromolecules, even for cryocooled samples, and is particularly acute in microdiffraction. For the X-ray energies most commonly used for protein crystallography at synchrotron sources, photoelectrons are the predominant source of radiation damage. If the beam size is small relative to the photoelectron path length, then the photoelectron may escape the beam footprint, resulting in less damage in the illuminated volume. Thus, it may be possible to exploit this phenomenon to reduce radiation-induced damage during data measurement for techniques such as diffraction, spectroscopy, and imaging that use X-rays to probe both crystalline and noncrystalline biological samples. In a systematic and direct experimental demonstration of reduced radiation damage in protein crystals with small beams, damage was measured as a function of micron-sized X-ray beams of decreasing dimensions. The damage rate normalized for dose was reduced by a factor of three from the largest (15.6 μm) to the smallest (0.84 μm) X-ray beam used. Radiation-induced damage to protein crystals was also mapped parallel and perpendicular to the polarization direction of an incident 1-μm X-ray beam. Damage was greatest at the beam center and decreased monotonically to zero at a distance of about 4 μm, establishing the range of photoelectrons. The observed damage is less anisotropic than photoelectron emission probability, consistent with photoelectron trajectory simulations. These experimental results provide the basis for data collection protocols to mitigate with micron-sized X-ray beams the effects of radiation damage.

  2. Partially flexible MEMS neural probe composed of polyimide and sucrose gel for reducing brain damage during and after implantation

    NASA Astrophysics Data System (ADS)

    Jeon, Myounggun; Cho, Jeiwon; Kim, Yun Kyung; Jung, Dahee; Yoon, Eui-Sung; Shin, Sehyun; Cho, Il-Joo

    2014-02-01

    This paper presents a flexible microelectromechanical systems (MEMS) neural probe that minimizes neuron damage and immune response, suitable for chronic recording applications. MEMS neural probes with various features such as high electrode densities have been actively investigated for neuron stimulation and recording to study brain functions. However, successful recording of neural signals in chronic application using rigid silicon probes still remains challenging because of cell death and macrophages accumulated around the electrodes over time from continuous brain movement. Thus, in this paper, we propose a new flexible MEMS neural probe that consists of two segments: a polyimide-based, flexible segment for connection and a rigid segment composed of thin silicon for insertion. While the flexible connection segment is designed to reduce the long-term chronic neuron damage, the thin insertion segment is designed to minimize the brain damage during the insertion process. The proposed flexible neural probe was successfully fabricated using the MEMS process on a silicon on insulator wafer. For a successful insertion, a biodegradable sucrose gel is coated on the flexible segment to temporarily increase the probe stiffness to prevent buckling. After the insertion, the sucrose gel dissolves inside the brain exposing the polyimide probe. By performing an insertion test, we confirm that the flexible probe has enough stiffness. In addition, by monitoring immune responses and brain histology, we successfully demonstrate that the proposed flexible neural probe incurs fivefold less neural damage than that incurred by a conventional silicon neural probe. Therefore, the presented flexible neural probe is a promising candidate for recording stable neural signals for long-time chronic applications.

  3. The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion.

    PubMed

    Du, W; Amarachintha, S; Wilson, A; Pang, Q

    2017-02-01

    Fanconi anemia (FA) is an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca(-/-) hematopoietic stem cells to DNA crosslinking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of pre-leukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability, but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients. Furthermore, we identified transcription program underlying dysregulated DDR and cell migration, myeloid proliferation, and immune response in the Fanca(-/-) pre-LSCs. Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca(-/-) pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca(-/-) pre-LSC expansion and leukemia development. Our study implicates diminishing DDR as a root cause of FA leukemogenesis, which subsequently collaborates with other signaling pathways for leukemogenic transformation.

  4. Down-regulation of miR-181a can reduce heat stress damage in PBMCs of Holstein cows.

    PubMed

    Chen, Kun-Lin; Fu, Yuan-Yuan; Shi, Min-Yan; Li, Hui-Xia

    2016-09-01

    Heat stress can weaken the immune system and even increase livestock's susceptibility to disease. MicroRNA (miR) is short non-coding RNA that functions in post-transcriptional regulation of gene expression and some phenotypes. Our recent study found that miR-181a is highly expressed in the serum of heat-stressed Holstein cows, but the potential function of miR-181a is still not clarified. In this study, peripheral blood mononuclear cells (PBMCs), isolated from Holstein cows' peripheral blood, were used to investigate the effects of miR-181a inhibitor on heat stress damage. Our results showed that significant apoptosis and oxidative damage were induced by heat stress in PBMCs. However, with apoptosis, the levels of reactive oxygen species (ROS) and content of malondialdehyde (MDA) were reduced, while the content of glutathione (GSH) and the activity of superoxide dismutase (SOD) were increased even under heat stress conditions after transfecting miR-181a inhibitors to PBMCs. Meanwhile, mRNA expression of bax and caspase-3 was significantly decreased, but mRNA expression of bcl-2 was increased in transfected PBMCs. In conclusion, our results demonstrated that down-regulation of miR-181a can reduce heat stress damage in PBMCs of Holstein cows.

  5. Evaluation of oil shale bitumen as a pavement asphalt additive to reduce moisture damage susceptibility

    SciTech Connect

    Robertson, R.E.; Harnsberger, P.M.; Wolf, J.M.

    1991-01-01

    An unrefined shale bitumen was evaluated as an agent to reduce moisture damage susceptibility of asphalt aggregate mixtures. Some activity was observed but less than might have been expected based on the molecular weight and nitrogen content of the bitumen. The counter effects of free carboxylic acids, which are known to be variable in asphalt and which are also present in the unrefined bitumen, appear to diminish the activity of the bitumen to inhibit moisture damage. 5 refs., 1 tab.

  6. Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage.

    PubMed

    Dao, Vinh; Pandeswara, Srilakshmi; Liu, Yang; Hurez, Vincent; Dodds, Sherry; Callaway, Danielle; Liu, Aijie; Hasty, Paul; Sharp, Zelton D; Curiel, Tyler J

    2015-05-01

    Cancer prevention is a cost-effective alternative to treatment. In mice, the mTOR inhibitor rapamycin prevents distinct spontaneous, noninflammatory cancers, making it a candidate broad-spectrum cancer prevention agent. We now show that oral microencapsulated rapamycin (eRapa) prevents skin cancer in dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogen-induced, inflammation-driven carcinogenesis. eRapa given before DMBA/TPA exposure significantly increased tumor latency, reduced papilloma prevalence and numbers, and completely inhibited malignant degeneration into squamous cell carcinoma. Rapamycin is primarily an mTORC1-specific inhibitor, but eRapa did not reduce mTORC1 signaling in skin or papillomas, and did not reduce important proinflammatory factors in this model, including p-Stat3, IL17A, IL23, IL12, IL1β, IL6, or TNFα. In support of lack of mTORC1 inhibition, eRapa did not reduce numbers or proliferation of CD45(-)CD34(+)CD49f(mid) skin cancer initiating stem cells in vivo and marginally reduced epidermal hyperplasia. Interestingly, eRapa reduced DMBA/TPA-induced skin DNA damage and the hras codon 61 mutation that specifically drives carcinogenesis in this model, suggesting reduction of DNA damage as a cancer prevention mechanism. In support, cancer prevention and DNA damage reduction effects were lost when eRapa was given after DMBA-induced DNA damage in vivo. eRapa afforded picomolar concentrations of rapamycin in skin of DMBA/TPA-exposed mice, concentrations that also reduced DMBA-induced DNA damage in mouse and human fibroblasts in vitro. Thus, we have identified DNA damage reduction as a novel mechanism by which rapamycin can prevent cancer, which could lay the foundation for its use as a cancer prevention agent in selected human populations.

  7. Immunization with Brucella VirB Proteins Reduces Organ Colonization in Mice through a Th1-Type Immune Response and Elicits a Similar Immune Response in Dogs

    PubMed Central

    Pollak, Cora N.; Wanke, María Magdalena; Estein, Silvia M.; Delpino, M. Victoria; Monachesi, Norma E.; Comercio, Elida A.; Fossati, Carlos A.

    2014-01-01

    VirB proteins from Brucella spp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice from Brucella infection and whether this response can be induced in the dog, a natural host for Brucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-γ), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with live Brucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN-γ than cells from control animals upon in vitro stimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane of Brucella organisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis of B. canis was assessed in vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization by Brucella in mice can be also elicited in dogs. PMID:25540276

  8. Immunization with Brucella VirB proteins reduces organ colonization in mice through a Th1-type immune response and elicits a similar immune response in dogs.

    PubMed

    Pollak, Cora N; Wanke, María Magdalena; Estein, Silvia M; Delpino, M Victoria; Monachesi, Norma E; Comercio, Elida A; Fossati, Carlos A; Baldi, Pablo C

    2015-03-01

    VirB proteins from Brucella spp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice from Brucella infection and whether this response can be induced in the dog, a natural host for Brucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-γ), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with live Brucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN-γ than cells from control animals upon in vitro stimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane of Brucella organisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis of B. canis was assessed in vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization by Brucella in mice can be also elicited in dogs.

  9. Simulated climate change causes immune suppression and protein damage in the crustacean Nephrops norvegicus.

    PubMed

    Hernroth, Bodil; Sköld, Helen Nilsson; Wiklander, Kerstin; Jutfelt, Fredrik; Baden, Susanne

    2012-11-01

    Rising atmospheric carbon dioxide concentration is causing global warming, which affects oceans by elevating water temperature and reducing pH. Crustaceans have been considered tolerant to ocean acidification because of their retained capacity to calcify during subnormal pH. However, we report here that significant immune suppression of the Norway lobster, Nephrops norvegicus, occurs after a 4-month exposure to ocean acidification (OA) at a level predicted for the year 2100 (hypercapnic seawater with a pH lowered by 0.4 units). Experiments carried out at different temperatures (5, 10, 12, 14, 16, and 18°C) demonstrated that the temperature within this range alone did not affect lobster immune responses. In the OA-treatment, hemocyte numbers were reduced by almost 50% and the phagocytic capacity of the remaining hemocytes was inhibited by 60%. The reduction in hemocyte numbers was not due to increased apoptosis in hematopoetic tissue. Cellular responses to stress were investigated through evaluating advanced glycation end products (AGE) and lipid oxidation in lobster hepatopancreata, and OA-treatment was shown to significantly increase AGEs', indicating stress-induced protein alterations. Furthermore, the extracellular pH of lobster hemolymph was reduced by approximately 0.2 units in the OA-treatment group, indicating either limited pH compensation or buffering capacity. The negative effects of OA-treatment on the nephropidae immune response and tissue homeostasis were more pronounced at higher temperatures (12-18°C versus 5°C), which may potentially affect disease severity and spread. Our results signify that ocean acidification may have adverse effects on the physiology of lobsters, which previously had been overlooked in studies of basic parameters such as lobster growth or calcification.

  10. Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice

    PubMed Central

    Garofalo, Stefano; D’Alessandro, Giuseppina; Chece, Giuseppina; Brau, Frederic; Maggi, Laura; Rosa, Alessandro; Porzia, Alessandra; Mainiero, Fabrizio; Esposito, Vincenzo; Lauro, Clotilde; Benigni, Giorgia; Bernardini, Giovanni; Santoni, Angela; Limatola, Cristina

    2015-01-01

    Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment. PMID:25818172

  11. Protein-poor diet reduces host-specific immune gene expression in Bombus terrestris

    PubMed Central

    Brunner, Franziska S.; Schmid-Hempel, Paul; Barribeau, Seth M.

    2014-01-01

    Parasites infect hosts non-randomly as genotypes of hosts vary in susceptibility to the same genotypes of parasites, but this specificity may be modulated by environmental factors such as nutrition. Nutrition plays an important role for any physiological investment. As immune responses are costly, resource limitation should negatively affect immunity through trade-offs with other physiological requirements. Consequently, nutritional limitation should diminish immune capacity in general, but does it also dampen differences among hosts? We investigated the effect of short-term pollen deprivation on the immune responses of our model host Bombus terrestris when infected with the highly prevalent natural parasite Crithidia bombi. Bumblebees deprived of pollen, their protein source, show reduced immune responses to infection. They failed to upregulate a number of genes, including antimicrobial peptides, in response to infection. In particular, they also showed less specific immune expression patterns across individuals and colonies. These findings provide evidence for how immune responses on the individual-level vary with important elements of the environment and illustrate how nutrition can functionally alter not only general resistance, but also alter the pattern of specific host–parasite interactions. PMID:24850921

  12. Reduced winter snowfall damages the structure and function of wintergreen ferns.

    PubMed

    Tessier, Jack T

    2014-06-01

    • Premise of the study: The full impact of climate change on ecosystems and the humans that depend on them is uncertain. Anthropogenic climate change is resulting in winters with less snow than is historically typical. This deficit may have an impact on wintergreen ferns whose fronds lie prostrate under the snowpack and are thereby protected from frost.• Methods: Frost damage and ecophysiological traits were quantified for three species of wintergreen fern (Dryopteris intermedia, Dryopteris marginalis, and Polystichum acrostichoides) near Delhi, NY following the winters of 2012 (which had very little snowfall) and 2013 (which had typical snowfall).• Key results: Dryopteris intermedia was the most common species and had the highest percentage of frost-damaged fronds and the highest percentage of its cover damaged in 2012. Frost damage was significantly less in 2013 for all species. Polystichum acrostichoides had the highest vernal photosynthetic rate in undamaged fronds, and all three species had a negative net photosynthetic rate in frost-damaged fronds. The wintergreen fern community lost 36.69 ± 2.80% of its productive surface area to frost damage in 2012. Dryopteris intermedia had the thinnest leaves and this trait may have made it the most susceptible to frost damage.• Conclusions: These results demonstrate that repeated winters of little snow may have a significant impact on the structure and functioning of the wintergreen fern community, and species will respond to a reduced snowpack on an individual basis.

  13. Antecedent glycemic control reduces severe hypoglycemia-induced neuronal damage in diabetic rats.

    PubMed

    Reno, Candace M; Tanoli, Tariq; Bree, Adam; Daphna-Iken, Dorit; Cui, Chen; Maloney, Susan E; Wozniak, David F; Fisher, Simon J

    2013-06-15

    Brain damage due to severe hypoglycemia occurs in insulin-treated people with diabetes. This study tests the hypothesis that chronic insulin therapy that normalizes elevated blood glucose in diabetic rats would be neuroprotective against brain damage induced by an acute episode of severe hypoglycemia. Male Sprague-Dawley rats were split into three groups: 1) control, non-diabetic; 2) STZ-diabetic; and 3) insulin-treated STZ-diabetic. After 3 wk of chronic treatment, unrestrained awake rats underwent acute hyperinsulinemic severe hypoglycemic (10-15 mg/dl) clamps for 1 h. Rats were subsequently analyzed for brain damage and cognitive function. Severe hypoglycemia induced 15-fold more neuronal damage in STZ-diabetic rats compared with nondiabetic rats. Chronic insulin treatment of diabetic rats, which nearly normalized glucose levels, markedly reduced neuronal damage induced by severe hypoglycemia. Fortunately, no cognitive defects associated with the hypoglycemia-induced brain damage were observed in any group. In conclusion, antecedent blood glucose control represents a major modifiable therapeutic intervention that can afford diabetic subjects neuroprotection against severe hypoglycemia-induced brain damage.

  14. Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory

    PubMed Central

    Benoun, Joseph M.; Labuda, Jasmine C.

    2016-01-01

    ABSTRACT Antibiotic intervention is an effective treatment strategy for many bacterial infections and liberates bacterial antigens and stimulatory products that can induce an inflammatory response. Despite the opportunity for bacterial killing to enhance the development of adaptive immunity, patients treated successfully with antibiotics can suffer from reinfection. Studies in mouse models of Salmonella and Chlamydia infection also demonstrate that early antibiotic intervention reduces host protective immunity to subsequent infection. This heightened susceptibility to reinfection correlates with poor development of Th1 and antibody responses in antibiotic-treated mice but can be overcome by delayed antibiotic intervention, thus suggesting a requirement for sustained T cell stimulation for protection. Although the contribution of memory T cell subsets is imperfectly understood in both of these infection models, a protective role for noncirculating memory cells is suggested by recent studies. Together, these data propose a model where antibiotic treatment specifically interrupts tissue-resident memory T cell formation. Greater understanding of the mechanistic basis of this phenomenon might suggest therapeutic interventions to restore a protective memory response in antibiotic-treated patients, thus reducing the incidence of reinfection. PMID:27999159

  15. New techniques for reducing the thermochemical damage in the course of laser surgery.

    PubMed

    Armon, E; Laufer, G

    1987-01-01

    New techniques were proposed for reducing the damage incurred to living tissues owing to temperature rise induced by surgical lasers. Precooling of the tissue and spatial filtering were evaluated numerically and were shown to be most effective in most surgical procedures. Application of pulse trains was also evaluated numerically and optimal operating conditions were identified.

  16. Annotation of the Asian Citrus Psyllid Genome Reveals a Reduced Innate Immune System

    PubMed Central

    Arp, Alex P.; Hunter, Wayne B.; Pelz-Stelinski, Kirsten S.

    2016-01-01

    Citrus production worldwide is currently facing significant losses due to citrus greening disease, also known as Huanglongbing. The citrus greening bacteria, Candidatus Liberibacter asiaticus (CLas), is a persistent propagative pathogen transmitted by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae). Hemipterans characterized to date lack a number of insect immune genes, including those associated with the Imd pathway targeting Gram-negative bacteria. The D. citri draft genome was used to characterize the immune defense genes present in D. citri. Predicted mRNAs identified by screening the published D. citri annotated draft genome were manually searched using a custom database of immune genes from previously annotated insect genomes. Toll and JAK/STAT pathways, general defense genes Dual oxidase, Nitric oxide synthase, prophenoloxidase, and cellular immune defense genes were present in D. citri. In contrast, D. citri lacked genes for the Imd pathway, most antimicrobial peptides, 1,3-β-glucan recognition proteins (GNBPs), and complete peptidoglycan recognition proteins. These data suggest that D. citri has a reduced immune capability similar to that observed in A. pisum, P. humanus, and R. prolixus. The absence of immune system genes from the D. citri genome may facilitate CLas infections, and is possibly compensated for by their relationship with their microbial endosymbionts. PMID:27965582

  17. Annotation of the Asian Citrus Psyllid Genome Reveals a Reduced Innate Immune System.

    PubMed

    Arp, Alex P; Hunter, Wayne B; Pelz-Stelinski, Kirsten S

    2016-01-01

    Citrus production worldwide is currently facing significant losses due to citrus greening disease, also known as Huanglongbing. The citrus greening bacteria, Candidatus Liberibacter asiaticus (CLas), is a persistent propagative pathogen transmitted by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae). Hemipterans characterized to date lack a number of insect immune genes, including those associated with the Imd pathway targeting Gram-negative bacteria. The D. citri draft genome was used to characterize the immune defense genes present in D. citri. Predicted mRNAs identified by screening the published D. citri annotated draft genome were manually searched using a custom database of immune genes from previously annotated insect genomes. Toll and JAK/STAT pathways, general defense genes Dual oxidase, Nitric oxide synthase, prophenoloxidase, and cellular immune defense genes were present in D. citri. In contrast, D. citri lacked genes for the Imd pathway, most antimicrobial peptides, 1,3-β-glucan recognition proteins (GNBPs), and complete peptidoglycan recognition proteins. These data suggest that D. citri has a reduced immune capability similar to that observed in A. pisum, P. humanus, and R. prolixus. The absence of immune system genes from the D. citri genome may facilitate CLas infections, and is possibly compensated for by their relationship with their microbial endosymbionts.

  18. Ascorbic acid and beta-carotene reduce stress-induced oxidative organ damage in rats.

    PubMed

    Esrefoglu, M; Akinci, A; Taslidere, E; Elbe, H; Cetin, A; Ates, B

    2016-10-01

    Antioxidants are potential therapeutic agents for reducing stress-induced organ damage. We investigated the effects of ascorbic acid and β-carotene on oxidative stress-induced cerebral, cerebellar, cardiac and hepatic damage using microscopy and biochemistry. Male Wistar albino rats were divided into five groups: untreated control, stressed, stressed + saline, stressed + ascorbic acid and stressed + β-carotene. The rats in the stressed groups were subjected to starvation, immobilization and cold. The histopathological damage scores for the stressed and stressed + saline groups were higher than those of the control group for all organs examined. The histopathological damage scores and mean tissue malondialdehyde levels for the groups treated with antioxidants were lower than those for the stressed and stressed + saline groups. Mean tissue superoxide dismutase activities for groups that received antioxidants were higher than those for the stressed + saline group for most organs evaluated. Ascorbic acid and β-carotene can reduce stress-induced organ damage by both inhibiting lipid oxidation and supporting the cellular antioxidant defense system.

  19. Constant illumination reduces circulating melatonin and impairs immune function in the cricket Teleogryllus commodus.

    PubMed

    Durrant, Joanna; Michaelides, Ellie B; Rupasinghe, Thusitha; Tull, Dedreia; Green, Mark P; Jones, Therésa M

    2015-01-01

    Exposure to constant light has a range of negative effects on behaviour and physiology, including reduced immune function in both vertebrates and invertebrates. It is proposed that the associated suppression of melatonin (a ubiquitous hormone and powerful antioxidant) in response to the presence of light at night could be an underlying mechanistic link driving the changes to immune function. Here, we investigated the relationship between constant illumination, melatonin and immune function, using a model invertebrate species, the Australian black field cricket, Teleogryllus commodus. Crickets were reared under either a 12 h light: 12 h dark regimen or a constant 24 h light regimen. Circulating melatonin concentration and immune function (haemocyte concentration, lytic activity and phenoloxidase (PO) activity) were assessed in individual adult crickets through the analysis of haemolymph. Constant illumination reduced melatonin and had a negative impact on haemocyte concentrations and lytic activity, but its effect on PO activity was less apparent. Our data provide the first evidence, to our knowledge, of a link between exposure to constant illumination and variation in haemocyte concentration in an invertebrate model, while also highlighting the potential complexity of the immune response following exposure to constant illumination. This study provides insight into the possible negative effect of artificial night-time lighting on the physiology of invertebrates, but whether lower and potentially more ecologically relevant levels of light at night produce comparable results, as has been reported in several vertebrate taxa, remains to be tested.

  20. Constant illumination reduces circulating melatonin and impairs immune function in the cricket Teleogryllus commodus

    PubMed Central

    Michaelides, Ellie B.; Rupasinghe, Thusitha; Tull, Dedreia; Green, Mark P.; Jones, Therésa M.

    2015-01-01

    Exposure to constant light has a range of negative effects on behaviour and physiology, including reduced immune function in both vertebrates and invertebrates. It is proposed that the associated suppression of melatonin (a ubiquitous hormone and powerful antioxidant) in response to the presence of light at night could be an underlying mechanistic link driving the changes to immune function. Here, we investigated the relationship between constant illumination, melatonin and immune function, using a model invertebrate species, the Australian black field cricket, Teleogryllus commodus. Crickets were reared under either a 12 h light: 12 h dark regimen or a constant 24 h light regimen. Circulating melatonin concentration and immune function (haemocyte concentration, lytic activity and phenoloxidase (PO) activity) were assessed in individual adult crickets through the analysis of haemolymph. Constant illumination reduced melatonin and had a negative impact on haemocyte concentrations and lytic activity, but its effect on PO activity was less apparent. Our data provide the first evidence, to our knowledge, of a link between exposure to constant illumination and variation in haemocyte concentration in an invertebrate model, while also highlighting the potential complexity of the immune response following exposure to constant illumination. This study provides insight into the possible negative effect of artificial night-time lighting on the physiology of invertebrates, but whether lower and potentially more ecologically relevant levels of light at night produce comparable results, as has been reported in several vertebrate taxa, remains to be tested. PMID:26339535

  1. Protective immunity and lack of histopathological damage two years after DNA vaccination against infectious hematopoietic necrosis virus in trout

    USGS Publications Warehouse

    Kurath, Gael; Garver, Kyle A.; Corbeil, Serge; Elliott, Diane G.; Anderson, Eric D.; LaPatra, Scott E.

    2006-01-01

    The DNA vaccine pIHNw-G encodes the glycoprotein of the fish rhabdovirus infectious hematopoietic necrosis virus (IHNV). Vaccine performance in rainbow trout was measured 3, 6, 13, 24, and 25 months after vaccination. At three months all fish vaccinated with 0.1 μg pIHNw-G had detectable neutralizing antibody (NAb) and they were completely protected from lethal IHNV challenge with a relative percent survival (RPS) of 100% compared to control fish. Viral challenges at 6, 13, 24, and 25 months post-vaccination showed protection with RPS values of 47–69%, while NAb seroprevalence declined to undetectable levels. Passive transfer experiments with sera from fish after two years post-vaccination were inconsistent but significant protection was observed in some cases. The long-term duration of protection observed here defined a third temporal phase in the immune response to IHNV DNA vaccination, characterized by reduced but significant levels of protection, and decline or absence of detectable NAb titers. Examination of multiple tissues showed an absence of detectable long-term histopathological damage due to DNA vaccination.

  2. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation.

    PubMed

    Saita, Diego; Ferrarese, Roberto; Foglieni, Chiara; Esposito, Antonio; Canu, Tamara; Perani, Laura; Ceresola, Elisa Rita; Visconti, Laura; Burioni, Roberto; Clementi, Massimo; Canducci, Filippo

    2016-07-07

    Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases.

  3. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation

    PubMed Central

    Saita, Diego; Ferrarese, Roberto; Foglieni, Chiara; Esposito, Antonio; Canu, Tamara; Perani, Laura; Ceresola, Elisa Rita; Visconti, Laura; Burioni, Roberto; Clementi, Massimo; Canducci, Filippo

    2016-01-01

    Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases. PMID:27383250

  4. Reducing tuber damage by potato tuberworm (Lepidoptera: Gelechiidae) with cultural practices and insecticides.

    PubMed

    Clough, G H; Rondon, S i; DeBano, S J; David, N; Hamm, P B

    2010-08-01

    Cultural practices and insecticide treatments and combinations were evaluated for effect on tuber damage by potato tuberworm, Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae) in the Columbia basin of eastern Oregon and Washington. A range of intervals between initial application of several insecticides and vine-kill were tested to determine how early to implement a program to control potato tuberworm tuber damage. Esfenvalerate, methamidophos, and methomyl were applied at recommended intervals, with programs beginning from 28 to 5 d before vine-kill. All insecticide treatments significantly reduced tuber damage compared with the untreated control, but there was no apparent advantage to beginning control efforts earlier than later in the season. Esfenvalerate and indoxacarb at two rates and a combination of the two insecticides were applied weekly beginning 4 wk before and at vine-kill, and indoxacarb was applied at and 1 wk postvine-kill as chemigation treatments. Application of insecticides at and after vine-kill also reduced tuberworm infestation. 'Russet Norkotah' and 'Russet Burbank' plants were allowed to naturally senesce or were chemically defoliated. They received either no irrigation or were irrigated by center-pivot with 0.25 cm water daily from vine-kill until harvest 2 wk later. Daily irrigation after vine-kill reduced tuber damage, and chemical vine-kill tended to reduce tuber damage compared with natural senescence. Covering hills with soil provides good protection but must be done by vine-kill. Data from these trials indicate that the most critical time for initiation of control methods is immediately before and at vine-kill.

  5. The Use of Feed Additives to Reduce the Effects of Aflatoxin and Deoxynivalenol on Pig Growth, Organ Health and Immune Status during Chronic Exposure

    PubMed Central

    Weaver, Alexandra C.; See, M. Todd; Hansen, Jeff A.; Kim, Yong B.; De Souza, Anna L. P.; Middleton, Tina F.; Kim, Sung Woo

    2013-01-01

    Three feed additives were tested to improve the growth and health of pigs chronically challenged with aflatoxin (AF) and deoxynivalenol (DON). Gilts (n = 225, 8.8 ± 0.4 kg) were allotted to five treatments: CON (uncontaminated control); MT (contaminated with 150 µg/kg AF and 1100 µg/kg DON); A (MT + a clay additive); B (MT + a clay and dried yeast additive); and C (MT + a clay and yeast culture additive). Average daily gain (ADG) and feed intake (ADFI) were recorded for 42 days, blood collected for immune analysis and tissue samples to measure damage. Feeding mycotoxins tended to decrease ADG and altered the immune system through a tendency to increase monocytes and immunoglobulins. Mycotoxins caused tissue damage in the form of liver bile ductule hyperplasia and karyomegaly. The additives in diets A and B reduced mycotoxin effects on the immune system and the liver and showed some ability to improve growth. The diet C additive played a role in reducing liver damage. Collectively, we conclude that AF and DON can be harmful to the growth and health of pigs consuming mycotoxins chronically. The selected feed additives improved pig health and may play a role in pig growth. PMID:23867763

  6. Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening

    PubMed Central

    Eberson, Lance S.; Secomb, Timothy W.; Larmonier, Nicolas; Larson, Douglas F.

    2014-01-01

    Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4+CD25+Foxp3+ regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Three-month-old male C57BL/6J mice were treated with IL-2/mAbCD25 concomitantly with continuous infusion of angiotensin type 1 receptor agonist, [Val5]angiotensin II. Our results indicate that the IL-2/mAbCD25 complex effectively induced Treg phenotype expansion by 5-fold in the spleens with minimal effects on total CD4+ and CD8+ T-lymphocyte numbers. The IL-2/mAbCD25 complex inhibited angiotensin II-mediated aortic collagen remodeling and the resulting stiffening, analyzed with in vivo pulse wave velocity and effective Young's modulus. Furthermore, the IL-2/mAbCD25 complex suppressed angiotensin II-mediated Th17 responses in the lymphoid organs and reduced gene expression of IL-17 as well as T cell and macrophage infiltrates in the aortic tissue. This study provides data that support the protective roles of Tregs in vascular stiffening and highlights the use of the IL-2/mAbCD25 complex as a new potential therapy in angiotensin II-related vascular diseases. PMID:25258681

  7. Birds and bats reduce insect biomass and leaf damage in tropical forest restoration sites.

    PubMed

    Morrison, Emily B; Lindell, Catherine A

    2012-07-01

    Both birds and bats are important insect predators in tropical systems. However, the relative influence of birds and bats on insect populations and their indirect effects on leaf damage have not previously been investigated in tropical forest restoration sites. Leaf damage by herbivorous insects can negatively affect the growth and survival of tropical plants and thus can influence the success of tropical forest restoration efforts. We used an exclosure experiment to examine the top-down effects of birds and bats on insects and leaf damage in a large-scale forest restoration experiment. Given the potential influence of tree planting design on bird and bat abundances, we also investigated planting design effects on bird and bat insectivory and leaf damage. The experiment included two planting treatment plots: islands, where trees were planted in patches, and plantations, where trees were planted in rows to create continuous cover. In both types of plots, insect biomass was highest on tree branches where both birds and bats were excluded from foraging and lowest on branches without exclosures where both birds and bats were present. In the island plots, birds and bats had approximately equal impacts on insect populations, while in plantations bats appeared to have a slightly stronger effect on insects than did birds. In plantations, the levels of leaf damage were higher on branches where birds and bats were excluded than on branches where both had access. In island plots, no significant differences in leaf damage were found between exclosure treatments although potential patterns were in the same direction as in the plantations. Our results suggest that both birds and bats play important roles as top predators in restoration systems by reducing herbivorous insects and their damage to planted trees. Tropical restoration projects should include efforts to attract and provide suitable habitat for birds and bats, given their demonstrated ecological importance.

  8. Trekking poles reduce downhill walking-induced muscle and cartilage damage in obese women

    PubMed Central

    Cho, Su Youn; Roh, Hee Tae

    2016-01-01

    [Purpose] This study investigated the effect of the use of trekking poles on muscle and cartilage damage and fatigue during downhill walking in obese women. [Subjects and Methods] Subjects included eight obese women who had a body fat percentage greater than 30. Subjects performed downhill walking without a trekking pole (NP) and with a trekking pole (TP) at 50% heart rate reserve for 30 minutes on a treadmill. The treadmill was set at a 15% downhill declination. Blood samples were collected to examine muscle damage (serum creatine kinase [CK] and lactate dehydrogenase [LDH] levels), cartilage damage (serum cartilage oligomeric matrix protein [COMP] levels), and fatigue (plasma lactate levels) at the pre-walking baseline (PWB), immediately after walking (IAW), and 2 hours post-walking (2HPW). [Results] The CK, LDH, COMP, and lactate levels were significantly increased IAW when compared with those at the PWB in both trials. In addition, in the NP trial, the CK, LDH, and COMP levels were significantly increased at 2HPW when compared with those at the PWB. [Conclusion] Downhill walking can cause muscle and cartilage damage, and our results suggest that the use of a trekking pole can reduce temporary muscle and cartilage damage after downhill walking. PMID:27313374

  9. Chemical genoprotection: reducing biological damage to as low as reasonably achievable levels

    PubMed Central

    Alcaraz, M; Armero, D; Martínez-Beneyto, Y; Castillo, J; Benavente-García, O; Fernandez, H; Alcaraz-Saura, M; Canteras, M

    2011-01-01

    Objectives The aim of this study was to evaluate the antioxidant substances present in the human diet with an antimutagenic protective capacity against genotoxic damage induced by exposure to X-rays in an attempt to reduce biological damage to as low a level as reasonably possible. Methods Ten compounds were assessed using the lymphocyte cytokinesis-block micronucleus (MN) cytome test. The compounds studied were added to human blood at 25 μM 5 min before exposure to irradiation by 2 Gy of X-rays. Results The protective capacity of the antioxidant substances assessed was from highest to lowest according to the frequency of the MN generated by X-ray exposure: rosmarinic acid = carnosic acid = δ-tocopherol = l-acid ascorbic = apigenin = amifostine (P < 0.001) > green tea extract = diosmine = rutin = dimetylsulfoxide (P < 0.05) > irradiated control. The reduction in genotoxic damage with the radiation doses administered reached 58%, which represents a significant reduction in X-ray-induced chromosomal damage (P < 0.001). This degree of protection is greater than that obtained with amifostine, a radioprotective compound used in radiotherapy and which is characterised by its high toxicity. Conclusion Several antioxidant substances, common components of the human diet and lacking toxicity, offer protection from the biological harm induced by ionizing radiation. Administering these protective substances to patients before radiological exploration should be considered, even in the case of small radiation doses and regardless of the biological damage expected. PMID:21697157

  10. Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans

    PubMed Central

    Li, Minghui; Liu, Jinfen; Jiang, Chuan; Zhang, Haibo; Ye, Lincai; Zheng, Jinghao

    2017-01-01

    Background Postnatal human cardiomyocyte proliferation declines rapidly with age, which has been suggested to be correlated with increases in oxidative DNA damage in mice and plays an important role in regulating cardiomyocyte proliferation. However, the relationship between oxidative DNA damage and age in humans is unclear. Methods Sixty right ventricular outflow myocardial tissue specimens were obtained from ventricular septal defect infant patients during routine congenital cardiac surgery. These specimens were divided into three groups based on age: group A (age 0–6 months), group B (age, 7–12 months), and group C (>12 months). Each tissue specimen was subjected to DNA extraction, RNA extraction, and immunofluorescence. Results Immunofluorescence and qRT-PCR analysis revealed that DNA damage markers—mitochondrial DNA copy number, oxoguanine 8, and phosphorylated ataxia telangiectasia mutated—were highest in Group B. However immunofluorescence and qRT-PCR demonstrated that two cell proliferation markers, Ki67 and cyclin D2, were decreased with age. In addition, wheat germ agglutinin-staining indicated that the average size of cardiomyocytes increased with age. Conclusions Oxidative DNA damage of cardiomyocytes was not correlated positively with age in human beings. Oxidative DNA damage is unable to fully explain the reduced proliferation of human cardiomyocytes. PMID:28099512

  11. α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage

    PubMed Central

    Bordia, Tanuja; Perez, Xiomara A.; McIntosh, J. Michael; Decker, Michael W.; Quik, Maryka

    2015-01-01

    Background ABT-126 is a novel, safe and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. Here we test the antidyskinetic effect of ABT-126 in MPTP-treated squirrel monkeys with moderate and more severe nigrostriatal damage. Methods Monkeys (n=21, Set 1) were lesioned with MPTP 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n=5), or treated with vehicle (n=6) or ABT-126 (n=10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1-2 times for a total of 3-4 MPTP injections. The antidyskinetic effect of ABT-126, nicotine and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n=23, Set 2) was lesioned with MPTP only 1-2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n=6), ABT-894 (n=6), nicotine (n=5) or vehicle (n=6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. Results With moderate nigrostriatal damage (MPTP 1-2×), ABT-126 dose-dependently decreased dyskinesias (~60%), with similar results with ABT-894 (~60%) or nicotine (~60%). With more severe damage (MPTP 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. Conclusion The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early and later stage Parkinson's disease. PMID:26573698

  12. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

    PubMed Central

    Cereda, Matteo; Gambardella, Gennaro; Benedetti, Lorena; Iannelli, Fabio; Patel, Dominic; Basso, Gianluca; Guerra, Rosalinda F.; Mourikis, Thanos P.; Puccio, Ignazio; Sinha, Shruti; Laghi, Luigi; Spencer, Jo; Rodriguez-Justo, Manuel; Ciccarelli, Francesca D.

    2016-01-01

    Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation. PMID:27377421

  13. Cerium Oxide Nanoparticles Reduce Microglial Activation and Neurodegenerative Events in Light Damaged Retina

    PubMed Central

    Fiorani, Lavinia; Passacantando, Maurizio; Santucci, Sandro; Di Marco, Stefano; Bisti, Silvia; Maccarone, Rita

    2015-01-01

    The first target of any therapy for retinal neurodegeneration is to slow down the progression of the disease and to maintain visual function. Cerium oxide or ceria nanoparticles reduce oxidative stress, which is known to play a pivotal role in neurodegeneration. Our aim was to investigate whether cerium oxide nanoparticles were able to mitigate neurodegeneration including microglial activation and related inflammatory processes induced by exposure to high intensity light. Cerium oxide nanoparticles were injected intravitreally or intraveinously in albino Sprague-Dawley rats three weeks before exposing them to light damage of 1000 lux for 24 h. Electroretinographic recordings were performed a week after light damage. The progression of retinal degeneration was evaluated by measuring outer nuclear layer thickness and TUNEL staining to quantify photoreceptors death. Immunohistochemical analysis was used to evaluate retinal stress, neuroinflammatory cytokines and microglial activation. Only intravitreally injected ceria nanoparticles were detected at the level of photoreceptor outer segments 3 weeks after the light damage and electoretinographic recordings showed that ceria nanoparticles maintained visual response. Moreover, this treatment reduced neuronal death and “hot spot” extension preserving the outer nuclear layer morphology. It is noteworthy that in this work we demonstrated, for the first time, the ability of ceria nanoparticles to reduce microglial activation and their migration toward outer nuclear layer. All these evidences support ceria nanoparticles as a powerful therapeutic agent in retinal neurodegenerative processes. PMID:26469804

  14. Cerium Oxide Nanoparticles Reduce Microglial Activation and Neurodegenerative Events in Light Damaged Retina.

    PubMed

    Fiorani, Lavinia; Passacantando, Maurizio; Santucci, Sandro; Di Marco, Stefano; Bisti, Silvia; Maccarone, Rita

    2015-01-01

    The first target of any therapy for retinal neurodegeneration is to slow down the progression of the disease and to maintain visual function. Cerium oxide or ceria nanoparticles reduce oxidative stress, which is known to play a pivotal role in neurodegeneration. Our aim was to investigate whether cerium oxide nanoparticles were able to mitigate neurodegeneration including microglial activation and related inflammatory processes induced by exposure to high intensity light. Cerium oxide nanoparticles were injected intravitreally or intraveinously in albino Sprague-Dawley rats three weeks before exposing them to light damage of 1000 lux for 24 h. Electroretinographic recordings were performed a week after light damage. The progression of retinal degeneration was evaluated by measuring outer nuclear layer thickness and TUNEL staining to quantify photoreceptors death. Immunohistochemical analysis was used to evaluate retinal stress, neuroinflammatory cytokines and microglial activation. Only intravitreally injected ceria nanoparticles were detected at the level of photoreceptor outer segments 3 weeks after the light damage and electoretinographic recordings showed that ceria nanoparticles maintained visual response. Moreover, this treatment reduced neuronal death and "hot spot" extension preserving the outer nuclear layer morphology. It is noteworthy that in this work we demonstrated, for the first time, the ability of ceria nanoparticles to reduce microglial activation and their migration toward outer nuclear layer. All these evidences support ceria nanoparticles as a powerful therapeutic agent in retinal neurodegenerative processes.

  15. Efficacy of curcumin to reduce hepatic damage induced by alcohol and thermally treated oil in rats.

    PubMed

    El-Deen, Nasr A M N; Eid, Mohamed

    2010-01-01

    The authors investigated the effect of curcumin on markers of oxidative stress and liver damage in rats that chronically ingested alcohol and heated oil. Nine groups of ten Wistar male rats received combinations of curcumin 100 mg/kg body weight daily, ethanol 5 mg/kg, 15% dietary sunflower oil and 15% heated sunflower oil for 12 weeks. Serum and liver tissue were collected. Groups 4-6, which had received compounds causing oxidative stress, showed increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, triglycerides, low density lipoprotein, very low density lipoprotein and reduced high density lipoprotein, protein and albumin, compared with the controls. Reductions were observed in glutathione peroxidase and reductase gene expression, superoxide dismutase activity, glutathione peroxidase activity, glutathione reductase activity, reduced glutathione concentration and catalase enzyme activity. Groups 7, 8 and 9 which received curcumin with heated oil, ethanol or both, showed lower elevations in serum and oxidative damage markers compared with the corresponding non-curcumin treated groups. It can be concluded that curcumin reduces markers of liver damage in rats treated with heated sunflower oil or ethanol.

  16. Immunizations

    MedlinePlus

    ... Get Weight Loss Surgery? A Week of Healthy Breakfasts Shyness Immunizations KidsHealth > For Teens > Immunizations Print A A A What's in this article? Why Are Vaccinations Important? Why Do I Need Shots? Which Vaccinations Do ...

  17. Vitamin D3 Reduces Tissue Damage and Oxidative Stress Caused by Exhaustive Exercise

    PubMed Central

    Ke, Chun-Yen; Yang, Fwu-Lin; Wu, Wen-Tien; Chung, Chen-Han; Lee, Ru-Ping; Yang, Wan-Ting; Subeq, Yi-Maun; Liao, Kuang-Wen

    2016-01-01

    Exhaustive exercise results in inflammation and oxidative stress, which can damage tissue. Previous studies have shown that vitamin D has both anti-inflammatory and antiperoxidative activity. Therefore, we aimed to test if vitamin D could reduce the damage caused by exhaustive exercise. Rats were randomized to one of four groups: control, vitamin D, exercise, and vitamin D+exercise. Exercised rats received an intravenous injection of vitamin D (1 ng/mL) or normal saline after exhaustive exercise. Blood pressure, heart rate, and blood samples were collected for biochemical testing. Histological examination and immunohistochemical (IHC) analyses were performed on lungs and kidneys after the animals were sacrificed. In comparison to the exercise group, blood markers of skeletal muscle damage, creatine kinase and lactate dehydrogenase, were significantly (P < 0.05) lower in the vitamin D+exercise group. The exercise group also had more severe tissue injury scores in the lungs (average of 2.4 ± 0.71) and kidneys (average of 3.3 ± 0.6) than the vitamin D-treated exercise group did (1.08 ± 0.57 and 1.16 ± 0.55). IHC staining showed that vitamin D reduced the oxidative product 4-Hydroxynonenal in exercised animals from 20.6% to 13.8% in the lungs and from 29.4% to 16.7% in the kidneys. In summary, postexercise intravenous injection of vitamin D can reduce the peroxidation induced by exhaustive exercise and ameliorate tissue damage, particularly in the kidneys and lungs. PMID:26941574

  18. Curcumin reduces cold storage-induced damage in human cardiac myoblasts.

    PubMed

    Abuarqoub, Hadil; Green, Colin J; Foresti, Roberta; Motterlini, Roberto

    2007-04-30

    Curcumin is a polyphenolic compound possessing interesting anti-inflammatory and antioxidant properties and has the ability to induce the defensive protein heme oxygenase-1 (HO-1). The objective of this study was to investigate whether curcumin protects against cold storage-mediated damage of human adult atrial myoblast cells (Girardi cells) and to assess the potential involvement of HO-1 in this process. Girardi cells were exposed to either normothermic or hypothermic conditions in Celsior preservation solution in the presence or absence of curcumin. HO-1 protein expression and heme oxygenase activity as well as cellular damage were assessed after cold storage or cold storage followed by re-warming. In additional experiments, an inhibitor of heme oxygenase activity (tin protoporphyrin IX, 10 microM) or siRNA for HO-1 were used to investigate the participation of HO-1 as a mediator of curcumin-induced effects. Treatment with curcumin produced a marked induction of cardiac HO-1 in normothermic condition but cells were less responsive to the polyphenolic compound at low temperature. Cold storage-induced damage was markedly reduced in the presence of curcumin and HO-1 contributed to some extent to this effect. Thus, curcumin added to Celsior preservation solution effectively prevents the damage caused by cold-storage; this effect involves the protective enzyme HO-1 but also other not yet identified mechanisms.

  19. An Intact Reducing Glycan Promotes the Specific Immune Response to Lacto-N-neotetraose-BSA Neoglycoconjugates

    PubMed Central

    Prasanphanich, Nina S.; Song, Xuezheng; Heimburg-Molinaro, Jamie; Luyai, Anthony E.; Lasanajak, Yi; Cutler, Christopher E.; Smith, David F.; Cummings, Richard D.

    2015-01-01

    The mammalian immune system responds to eukaryotic glycan antigens during infections, cancer, and autoimmune disorders, but the immunological bases for such responses are unclear. Conjugate vaccines containing bacterial polysaccharides linked to carrier proteins (neoglycoconjugates) have proven successful, but these often contain repeating epitopes and the reducing end of the glycan is less important, unlike typical glycan determinants in eukaryotes, which are shorter in length and may include the reducing end. Here we have compared the effects of two linkage methods, one that opens the ring at the reducing end of the glycan, and one that leaves the reducing end closed, on the glycan specificity of the vaccine response in rabbits and mice. We immunized rabbits and mice with bovine serum albumin (BSA) conjugates of synthetic open- and closed-ring forms (OR versus CR) of a simple tetrasaccharide lacto-N-neo-tetraose (LNnT, Galβ1-4GlcNAcβ1-3Galβ1-4Glc), and tested reactivity to the immunogens and several related glycans in both OR and CR versions on glycan microarrays. We found that in rabbits the immune response to the CR conjugate was directed toward the glycan, whereas the OR conjugate elicited antibodies to the reducing end of the glycan and linker region but not specifically to the glycan itself. Unexpectedly, mice did not generate a glycan-specific response to the CR conjugate. Our findings indicate that the reducing end of the sugar is crucial for generation of a glycan-specific response to some eukaryotic vaccine epitopes, and that there are species-specific differences in the ability to make a glycan-specific response to some glycoconjugates. These findings warrant further investigation with regard to rational design of glycoconjugate vaccines. PMID:25671348

  20. Platelet-rich plasma reduces the oxidative damage determined by a skeletal muscle contusion in rats.

    PubMed

    Martins, Rodrigo Pereira; Hartmann, Diane Duarte; de Moraes, Jefferson Potiguara; Soares, Felix Alexandre Antunes; Puntel, Gustavo Orione

    2016-12-01

    Platelet-rich plasma (PRP) has received increasing attention and is widely used in clinical practice in order to stimulate human tissue healing. Contusions are very common injuries observed in sports and affect the function of the musculoskeletal system. This study investigated the effects of PRP on the oxidative damage determined by a contusion induced in gastrocnemius muscle of rats. PRP was injected intramuscularly immediately after injury and every 48 h, and the biochemical analysis was performed 1, 3, 5, or 7 days after the contusion onset in order to evaluate the changes characteristics of the healing process. The contusion increased the levels of oxidative stress markers such as thiobarbituric acid reactive substances and oxidized dichlorofluorescein both in skeletal muscle tissue and erythrocytes preparations, and PRP treatment significantly reduced these oxidative damage markers. Furthermore, the contusion decreased the cellular viability in the site of the lesion and PRP was effective in diminishing this effect. Moreover, PRP increased the levels of enzymatic antioxidants superoxide dismutase and catalase activities in the injured muscle, and also the non-protein thiols (-SH) group levels in erythrocytes. In conclusion PRP, in the form that was used in this study, was able to modulate the oxidative damage determined by a classical skeletal muscle injury possibly by reducing the impairment of myocytes mitochondrial function and improving their endogenous antioxidant defense systems.

  1. Chronic Schistosoma japonicum Infection Reduces Immune Response to Vaccine against Hepatitis B in Mice

    PubMed Central

    Chen, Lin; Liu, Wen-qi; Lei, Jia-hui; Guan, Fei; Li, Man-jun; Song, Wen-jian; Li, Yong-long; Wang, Ting

    2012-01-01

    Background Hepatitis B and schistosomiasis are most prevalent in Africa and Asia, and co-infections of both are frequent in these areas. The immunomodulation reported to be induced by schistosome infections might restrict immune control of hepatitis B virus (HBV) leading to more severe viral infection. Vaccination is the most effective measure to control and prevent HBV infection, but there is evidence for a reduced immune response to the vaccine in patients with chronic schistosomiasis japonica. Methodology/Principal Findings In this paper, we demonstrate in a mouse model that a chronic Schistosoma japonicum infection can inhibit the immune response to hepatitis B vaccine (HBV vaccine) and lead to lower production of anti-HBs antibodies, interferon-γ (IFN-γ) and interleukin-2 (IL-2). After deworming with Praziquantel (PZQ), the level of anti-HBs antibodies gradually increased and the Th2-biased profile slowly tapered. At 16 weeks after deworming, the levels of anti-HBs antibodies and Th1/Th2 cytokines returned to the normal levels. Conclusions/Significance The results suggest that the preexisting Th2-dominated immune profile in the host infected with the parasite may down–regulate levels of anti-HBs antibodies and Th1 cytokines. To improve the efficacy of HBV vaccination in schistosome infected humans it may be valuable to treat them with praziquantel (PZQ) some time prior to HBV vaccination. PMID:23272112

  2. Damage-reducing measures to manage flood risks in a changing climate

    NASA Astrophysics Data System (ADS)

    Kreibich, Heidi; Bubeck, Philip; Van Vliet, Mathijs; De Moel, Hans

    2014-05-01

    Damage due to floods has increased during the last few decades, and further increases are expected in several regions due to climate change and a growing vulnerability. To address the projected increase in flood risk, a combination of structural and non-structural flood risk mitigation measures is considered as a promising adaptation strategy. Such a combination takes into account that flood defence systems may fail, and prepare for unexpected crisis situations via land-use planning, building construction, evacuation and disaster response. Non-structural flood risk mitigation measures like shielding with water shutters or sand bags, building fortification or safeguarding of hazardous substances are often voluntary: they demand self-dependent action by the population at risk (Bubeck et al. 2012; 2013). It is believed that these measures are especially effective in areas with frequent flood events and low flood water levels, but some types of measures showed a significant damage-reducing effect also during extreme flood events, such as the Elbe River flood in August 2002 in Germany (Kreibich et al. 2005; 2011). Despite the growing importance of damage-reducing measures, information is still scarce about factors that motivate people to undertake such measures, the state of implementation of various non-structural measures in different countries and their damage reducing effects. Thus, we collected information and undertook an international review about this topic in the framework of the Dutch KfC project "Climate proof flood risk management". The contribution will present an overview about the available information on damage-reducing measures and draw conclusions for practical flood risk management in a changing climate. References: Bubeck, P., Botzen, W. J. W., Suu, L. T. T., Aerts, J. C. J. H. (2012): Do flood risk perceptions provide useful insights for flood risk management? Findings from central Vietnam. Journal of Flood Risk Management, 5, 4, 295-302 Bubeck, P

  3. Soft Perches in an Aviary System Reduce Incidence of Keel Bone Damage in Laying Hens

    PubMed Central

    Stratmann, Ariane; Fröhlich, Ernst K. F.; Harlander-Matauschek, Alexandra; Schrader, Lars; Toscano, Michael J.; Würbel, Hanno; Gebhardt-Henrich, Sabine G.

    2015-01-01

    Keel bone fractures and deviations are one of the major welfare and health issues in commercial laying hens. In non-cage housing systems like aviaries, falls and collisions with perches and other parts of the housing system are assumed to be one of the main causes for the high incidence of keel bone damage. The objectives of this study were to investigate the effectiveness of a soft perch material to reduce keel bone fractures and deviations in white (Dekalb White) and brown laying hens (ISA Brown) kept in an aviary system under commercial conditions. In half of 20 pens, all hard, metal perches were covered with a soft polyurethane material. Palpation of 20 hens per pen was conducted at 18, 21, 23, 30, 38, 44 and 64 weeks of age. Production data including egg laying rate, floor eggs, mortality and feed consumption were collected over the whole laying period. Feather condition and body mass was assessed twice per laying period. The results revealed that pens with soft perches had a reduced number of keel bone fractures and deviations. Also, an interaction between hybrid and age indicated that the ISA hybrid had more fractured keel bones and fewer non-damaged keel bones compared with the DW hybrid at 18 weeks of age, a response that was reversed at the end of the experiment. This is the first study providing evidence for the effectiveness of a soft perch material within a commercial setting. Due to its compressible material soft perches are likely to absorb kinetic energy occurring during collisions and increase the spread of pressure on the keel bone during perching, providing a mechanism to reduce keel bone fractures and deviations, respectively. In combination with genetic selection for more resilient bones and new housing design, perch material is a promising tool to reduce keel bone damage in commercial systems. PMID:25811980

  4. Galectin-3 Blockade Reduces Renal Fibrosis in Two Normotensive Experimental Models of Renal Damage

    PubMed Central

    Martinez-Martinez, Ernesto; Ibarrola, Jaime; Calvier, Laurent; Fernandez-Celis, Amaya; Leroy, Celine; Cachofeiro, Victoria; Rossignol, Patrick; Lopez-Andres, Natalia

    2016-01-01

    Background Galectin-3 (Gal-3), a β-galactoside-binding lectin, is increased in kidney injury and its pharmacological blockade reduces renal damage in acute kidney injury, hyperaldosteronism or hypertensive nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in early renal damage associated with obesity and aortic stenosis (AS). Results Gal-3 was upregulated in kidneys from high fat diet (HFD) rats and in animals with partial occlusion of ascending aorta (AS). Urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) and urinary albumin were enhanced in HFD and AS rats. In kidney from obese rats, fibrotic markers (collagen, TFG-β), epithelial-mesenchymal transition molecules (α-smooth muscle actin, E-cadherin), inflammatory mediator (osteopontin) and kidney injury marker (kidney injury molecule-1) were modified. In kidney from AS rats, fibrotic markers (collagen, CTGF), epithelial-mesenchymal transition molecules (fibronectin, α-smooth muscle actin, β-catenin, E-cadherin) and kidney injury markers (NGAL, kidney injury molecule-1) were altered. Histologic observations of obese and AS rat kidneys revealed tubulointerstitial fibrosis. The pharmacological inhibition of Gal-3 with MCP normalized renal Gal-3 levels as well as functional, histological and molecular alterations in obese and AS rats. Conclusions In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation and damage, while these alterations were prevented by Gal-3 blockade. These data suggest that Gal-3 could be a new player in renal molecular, histological and functional alterations at early stages of kidney damage. PMID:27829066

  5. High level methicillin resistance correlates with reduced Staphylococcus aureus endothelial cell damage.

    PubMed

    Seidl, Kati; Leemann, Michèle; Palheiros Marques, Miguel; Rachmühl, Carole; Leimer, Nadja; Andreoni, Federica; Achermann, Yvonne; Zinkernagel, Annelies S

    2017-01-01

    There has been controversy about the intrinsic virulence of methicillin-resistant Staphylococcus aureus (MRSA) as compared to methicillin-susceptible S. aureus (MSSA). To address this discrepancy, the intrinsic virulence of 42 MRSA and 40 MSSA clinical isolates was assessed by testing endothelial cell (EC) damage, a surrogate marker for virulence in blood stream infections. Since these clinical isolates represent a heterogeneous group, well characterized S. aureus laboratory strains with SCCmec loss- and gain-of-function mutations were used in addition. The clinical MRSA isolates carrying typical hospital acquired SCCmec types (I, II or III) induced significantly less damage (47.8%) as compared to isolates with other SCCmec types (62.3%, p=0.03) and MSSA isolates (64.2%, p<0.01). There was a strong inverse correlation between high-level oxacillin resistance and low EC damage induction (R(2)=0.4464, p<0.001). High-level oxacillin resistant strains (MIC >32μ/ml) grew significantly slower as compared to isolates with low-level resistance (p=0.047). The level of EC damage positively correlated with α- and δ-toxin production (p<0.0001 and p<0.05, respectively) but not with β-toxin production. Invasive MRSA isolates (n=21, 56.3%) were significantly less cytotoxic as compared to invasive MSSA isolates (n=20, 68.0%, p<0.05). There was no difference between EC damage induced by superficial versus invasive isolates in either MRSA or MSSA strains. Our data suggest that the intrinsic virulence of MRSA is similar or even reduced as compared to MSSA strains but is linked to the level of methicillin resistance.

  6. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

    PubMed Central

    Uhde, Melanie; Ajamian, Mary; Caio, Giacomo; De Giorgio, Roberto; Indart, Alyssa; Green, Peter H; Verna, Elizabeth C; Volta, Umberto; Alaedini, Armin

    2016-01-01

    Objective Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. Design Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. Results Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. Conclusions These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease. PMID:27459152

  7. Coupling aging immunity with a sedentary lifestyle: has the damage already been done?--a mini-review.

    PubMed

    Simpson, Richard J; Guy, Keith

    2010-01-01

    The elderly population is at an unprecedented risk of infectious diseases and malignancy due to apparently inevitable age-related declines in immunity. The 'immune risk profile' (IRP) is an array of biomarkers that has been used to predict morbidity and mortality in older adults. As it is generally accepted that middle-aged and elderly individuals who habitually participate in moderate-intensity exercise are less likely to incur an infection than their sedentary counterparts, this review addresses current knowledge on the effects of regular exercise on aspects of adaptive immunity as they relate to the IRP. Findings from cross-sectional studies mostly show enhanced immunity in physically active compared to sedentary older adults. These include greater T-cell responsiveness to mitogens in vitro, a reduced frequency of antigen-experienced and senescent T-cells (i.e. CD45RO+/KLRG1+/CD57+/CD28-), enhanced IL-2 production and T-lymphocyte expression of the IL-2 receptor, longer chromosome telomere lengths in blood leukocytes and in vivo immune responses to vaccines and recall antigens. In contrast, the evidence from the available longitudinal studies that have used an exercise training intervention in previously sedentary elderly to improve similar immune responses is less compelling. Although this might indicate that exercise has limited immune restorative properties in previously sedentary elderly, there are still relatively few studies that have addressed specific IRP criteria and the large variation in experimental design among the longitudinal studies complicates the juxtaposition of these results. It is clear that a more substantial and focused research approach is required before physical exercise can be used in earnest as an effective immune restorative strategy in the elderly. This mini-review summarizes the major findings of these studies and proposes future avenues of research to investigate the effects of regular exercise on aspects of adaptive immunity in

  8. P-Selectin preserves immune tolerance in mice and is reduced in human cutaneous lupus

    PubMed Central

    González-Tajuelo, Rafael; Silván, Javier; Pérez-Frías, Alicia; de la Fuente-Fernández, María; Tejedor, Reyes; Espartero-Santos, Marina; Vicente-Rabaneda, Esther; Juarranz, Ángeles; Muñoz-Calleja, Cecilia; Castañeda, Santos; Gamallo, Carlos; Urzainqui, Ana

    2017-01-01

    Mice deficient in P-Selectin presented altered immunity/tolerance balance. We have observed that the absence of P-Selectin promotes splenomegaly with reduced naïve T cell population, elevated activated/effector T cell subset, increased germinal center B and Tfh populations and high production of autoreactive antibodies. Moreover, 1.5-3-month-old P-selectin KO mice showed reduced IL-10-producing leukocytes in blood and a slightly reduced Treg population in the skin. With aging and, coinciding with disease severity, there is an increase in the IL17+ circulating and dermal T cell subpopulations and reduction of dermal Treg. As a consequence, P-Selectin deficient mice developed a progressive autoimmune syndrome showing skin alterations characteristic of lupus prone mice and elevated circulating autoantibodies, including anti-dsDNA. Similar to human SLE, disease pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli, and a complex pattern of autoantibodies. More important, skin biopsies of cutaneous lupus erythematosus patients did not show increased expression of P-Selectin, as described for other inflammatory diseases, and the number of vessels expressing P-Selectin was reduced. PMID:28150814

  9. P-Selectin preserves immune tolerance in mice and is reduced in human cutaneous lupus.

    PubMed

    González-Tajuelo, Rafael; Silván, Javier; Pérez-Frías, Alicia; de la Fuente-Fernández, María; Tejedor, Reyes; Espartero-Santos, Marina; Vicente-Rabaneda, Esther; Juarranz, Ángeles; Muñoz-Calleja, Cecilia; Castañeda, Santos; Gamallo, Carlos; Urzainqui, Ana

    2017-02-02

    Mice deficient in P-Selectin presented altered immunity/tolerance balance. We have observed that the absence of P-Selectin promotes splenomegaly with reduced naïve T cell population, elevated activated/effector T cell subset, increased germinal center B and Tfh populations and high production of autoreactive antibodies. Moreover, 1.5-3-month-old P-selectin KO mice showed reduced IL-10-producing leukocytes in blood and a slightly reduced Treg population in the skin. With aging and, coinciding with disease severity, there is an increase in the IL17(+) circulating and dermal T cell subpopulations and reduction of dermal Treg. As a consequence, P-Selectin deficient mice developed a progressive autoimmune syndrome showing skin alterations characteristic of lupus prone mice and elevated circulating autoantibodies, including anti-dsDNA. Similar to human SLE, disease pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli, and a complex pattern of autoantibodies. More important, skin biopsies of cutaneous lupus erythematosus patients did not show increased expression of P-Selectin, as described for other inflammatory diseases, and the number of vessels expressing P-Selectin was reduced.

  10. Seamustard (Undaria pinnatifida) Improves Growth, Immunity, Fatty Acid Profile and Reduces Cholesterol in Hanwoo Steers

    PubMed Central

    Hwang, J. A.; Islam, M. M.; Ahmed, S. T.; Mun, H. S.; Kim, G. M.; Kim, Y. J.; Yang, C. J.

    2014-01-01

    The study was designed to evaluate the effect of 2% seamustard (Undaria pinnatifida) by-product (SW) on growth performance, immunity, carcass characteristics, cholesterol content and fatty acid profile in Hanwoo steers. A total of 20 Hanwoo steers (ave. 22 months old; 619 kg body weight) were randomly assigned to control (basal diet) and 2% SW supplemented diet. Dietary SW supplementation significantly (p<0.05) improved average daily gain and gain:feed ratio as well as serum immunoglobulin G concentration. Chemical composition and quality grade of meat and carcass yield grades evaluated at the end of the trial were found to be unaffected by SW supplementation. Dietary SW significantly reduced meat cholesterol concentration (p<0.05). Dietary SW supplementation significantly reduced the myristic acid (C14:0) and palmitoleic acid (C16:ln-7) concentration, while SW increased the concentration of stearic acid (C18:0) and linolenic acid (C18:3n-3) compared to control (p<0.05). Dietary SW supplementation had no effect on saturated fatty acids (SFA), unsaturated fatty acids, poly unsaturated fatty acid (PUFA) or mono unsaturated fatty acid content in muscles. A reduced ratio of PUFA/SFA and n-6/n-3 were found in SW supplemented group (p<0.05). In conclusion, 2% SW supplementation was found to improve growth, immunity and fatty acid profile with significantly reduced cholesterol of beef. PMID:25083105

  11. Seamustard (Undaria pinnatifida) Improves Growth, Immunity, Fatty Acid Profile and Reduces Cholesterol in Hanwoo Steers.

    PubMed

    Hwang, J A; Islam, M M; Ahmed, S T; Mun, H S; Kim, G M; Kim, Y J; Yang, C J

    2014-08-01

    The study was designed to evaluate the effect of 2% seamustard (Undaria pinnatifida) by-product (SW) on growth performance, immunity, carcass characteristics, cholesterol content and fatty acid profile in Hanwoo steers. A total of 20 Hanwoo steers (ave. 22 months old; 619 kg body weight) were randomly assigned to control (basal diet) and 2% SW supplemented diet. Dietary SW supplementation significantly (p<0.05) improved average daily gain and gain:feed ratio as well as serum immunoglobulin G concentration. Chemical composition and quality grade of meat and carcass yield grades evaluated at the end of the trial were found to be unaffected by SW supplementation. Dietary SW significantly reduced meat cholesterol concentration (p<0.05). Dietary SW supplementation significantly reduced the myristic acid (C14:0) and palmitoleic acid (C16:ln-7) concentration, while SW increased the concentration of stearic acid (C18:0) and linolenic acid (C18:3n-3) compared to control (p<0.05). Dietary SW supplementation had no effect on saturated fatty acids (SFA), unsaturated fatty acids, poly unsaturated fatty acid (PUFA) or mono unsaturated fatty acid content in muscles. A reduced ratio of PUFA/SFA and n-6/n-3 were found in SW supplemented group (p<0.05). In conclusion, 2% SW supplementation was found to improve growth, immunity and fatty acid profile with significantly reduced cholesterol of beef.

  12. Ionizing Radiation Selectively Reduces Skin Regulatory T Cells and Alters Immune Function

    PubMed Central

    Zhou, Yu; Ni, Houping; Balint, Klara; Sanzari, Jenine K.; Dentchev, Tzvete; Diffenderfer, Eric S.; Wilson, Jolaine M.; Cengel, Keith A.; Weissman, Drew

    2014-01-01

    The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth’s magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstrate that radiation, both homogeneous and inhomogeneous, induces inflammation with resultant specific loss of regulatory T cells from the skin. This results in a hyper-responsive state with increased delayed type hypersensitivity in vivo and CD4+ T cell proliferation in vitro. The effects of inhomogeneous radiation to the skin of astronauts or as part of a therapeutic approach could result in an unexpected enhancement in skin immune function. The effects of this need to be considered in the design of radiation therapy protocols and in the development of countermeasures for extended space travel. PMID:24959865

  13. Selective ozone concentrations may reduce the ischemic damage after a stroke.

    PubMed

    Frosini, Maria; Contartese, Antonella; Zanardi, Iacopo; Travagli, Valter; Bocci, Velio

    2012-05-01

    Abstract Stroke is one of the most debilitating diseases, and it is unfortunate that only a small percentage of patients can be treated with thrombolytic agents. Consequently, there is an urgent need of finding an alternative procedure for reoxygenating the so-called penumbra at the earliest time as possible for reducing morbidity and disability. A preliminary, preclinical study has been carried out by using rat hippocampal and cortical brain slices subjected to oxygen-glucose deprivation. Oxygen-ozone gaseous mixture appeared to be effective in reverting damage of brain tissues, supporting the evaluation of this approach in well-designed clinical trials in stroke patients.

  14. Elevated oxidative damage is correlated with reduced fitness in interpopulation hybrids of a marine copepod

    PubMed Central

    Barreto, Felipe S.; Burton, Ronald S.

    2013-01-01

    Aerobic energy production occurs via the oxidative phosphorylation pathway (OXPHOS), which is critically dependent on interactions between the 13 mitochondrial DNA (mtDNA)-encoded and approximately 70 nuclear-encoded protein subunits. Disruptive mutations in any component of OXPHOS can result in impaired ATP production and exacerbated oxidative stress; in mammalian systems, such mutations are associated with ageing as well as numerous diseases. Recent studies have suggested that oxidative stress plays a role in fitness trade-offs in life-history evolution and functional ecology. Here, we show that outcrossing between populations with divergent mtDNA can exacerbate cellular oxidative stress in hybrid offspring. In the copepod Tigriopus californicus, we found that hybrids that showed evidence of fitness breakdown (low fecundity) also exhibited elevated levels of oxidative damage to DNA, whereas those with no clear breakdown did not show significantly elevated damage. The extent of oxidative stress in hybrids appears to be dependent on the degree of genetic divergence between their respective parental populations, but this pattern requires further testing using multiple crosses at different levels of divergence. Given previous evidence in T. californicus that hybridization disrupts nuclear/mitochondrial interactions and reduces hybrid fitness, our results suggest that such negative intergenomic epistasis may also increase the production of damaging cellular oxidants; consequently, mtDNA evolution may play a significant role in generating postzygotic isolating barriers among diverging populations. PMID:23902912

  15. Basic fibroblast growth factor reduces functional and structural damage in chronic kidney disease.

    PubMed

    Villanueva, Sandra; Contreras, Felipe; Tapia, Andrés; Carreño, Juan E; Vergara, Cesar; Ewertz, Ernesto; Cespedes, Carlos; Irarrazabal, Carlos; Sandoval, Mauricio; Velarde, Victoria; Vio, Carlos P

    2014-02-15

    Chronic kidney disease (CKD) is characterized by loss of renal function. The pathological processes involved in the progression of this condition are already known, but the molecular mechanisms have not been completely explained. Recent reports have shown the intrinsic capacity of the kidney to undergo repair after acute injury through the reexpression of repairing proteins (Villanueva S, Cespedes C, Vio CP. Am J Physiol Regul Integr Comp Physiol 290: R861-R870, 2006). Stimulation with basic fibroblast growth factor (bFGF) could accelerate this process. However, it is not known whether bFGF can induce this phenomenon in kidney cells affected by CKD. Our aim was to study the evolution of renal damage in animals with CKD treated with bFGF and to relate the amount of repairing proteins with renal damage progression. Male Sprague-Dawley rats were subjected to 5/6 nephrectomy (NPX) and treated with bFGF (30 μg/kg, NPX+bFGF); a control NPX group was treated with saline (NPX+S). Animals were euthanized 35 days after bFGF administration. Functional effects were assessed based on serum creatinine levels; morphological damage was assessed by the presence of macrophages (ED-1), interstitial α-smooth muscle actin (α-SMA), and interstitial collagen through Sirius red staining. The angiogenic factors VEGF and Tie-2 and the epithelial/tubular factors Ncam, bFGF, Pax-2, bone morphogenic protein-7, Noggin, Lim-1, Wnt-4, and Smads were analyzed. Renal stem cells were evaluated by Oct-4. We observed a significant reduction in serum creatinine levels, ED-1, α-SMA, and Sirius red as well as an important induction of Oct-4, angiogenic factors, and repairing proteins in NPX+bFGF animals compared with NPX+S animals. These results open new perspectives toward reducing damage progression in CKD.

  16. Oxidative damage of hepatopancreas induced by pollution depresses humoral immunity response in the freshwater crayfish Procambarus clarkii.

    PubMed

    Wei, Keqiang; Yang, Junxian

    2015-04-01

    Previous studies provide evidences for the possible oxidative damage of toxic environmental pollutants to tissue protein in fish and amphibian, but little information is available about their effects on immunity response in crustacean. In the present study, we evaluated the relationship between oxidative damage and immune response induced by both typical pollutants (viz. copper and beta-cypermethrin), by exposing the freshwater Procambarus clarkii to sub-lethal concentrations (1/40, 1/20, 1/10 and 1/5 of the 96 h LC50) up to 96 h. Five biomarkers of oxidative stress, i.e. reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and protein carbonyl in hepatopancreas, and two immune factors, i.e. phenoloxidase (PO) and hemocyanin in haemolymph were determined. The results indicated that there was a significant increase (P < 0.05) in the contents of ROS, MDA and protein carbonyl accompanied by markedly decreased (P < 0.05) PO and hemocyanin levels in a dose and time dependent manner. The significant and positive correlation (P < 0.01) between protein carbonyls induction and MDA formation was observed in crayfish hepatopancreas at 96 h. The production of these protein carbonyls could significantly depress (P < 0.01) the levels of phenoloxidase and hemocyanin in hemolymph. Higher contents of ROS enhanced the risk of lipid peroxidation, protein carbonylation and immunosuppression of crayfish, and hepatopancreas might play an important role in immune system of crustaceans. Protein oxidation may be one of the main mechanisms for pollution-induced immunotoxicity in P. clarkii.

  17. High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection

    PubMed Central

    Meadows, Danielle N.; Bahous, Renata H.; Best, Ana F.; Rozen, Rima

    2015-01-01

    Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host’s immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents) or folic acid-supplemented diets (FASD, 10x recommended level) for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p<0.01, Cox proportional hazards) and higher parasitemia (p< 0.01, joint model of parasitemia and survival) compared with CD mice. FASD mice had lower numbers of splenocytes, total T cells, and lower numbers of specific T and NK cell sub-populations, compared with CD mice (p<0.05, linear mixed effects). Increased brain TNFα immunoreactive protein (p<0.01, t-test) and increased liver Abca1 mRNA (p<0.01, t-test), a modulator of TNFα, were observed in FASD mice; these variables correlated positively (rs = 0.63, p = 0.01). Bcl-xl/Bak mRNA was increased in liver of FASD mice (p<0.01, t-test), suggesting reduced apoptotic potential. We conclude that high dietary folate increases parasite replication, disturbs the immune response and reduces resistance to malaria in mice. These findings have relevance for malaria-endemic regions, when considering anti-folate anti-malarials, food fortification or vitamin supplementation programs. PMID:26599510

  18. Passive immunization to reduce Campylobacter jejuni colonization and transmission in broiler chickens

    PubMed Central

    2014-01-01

    Campylobacter jejuni is the most common cause of bacterium-mediated diarrheal disease in humans worldwide. Poultry products are considered the most important source of C. jejuni infections in humans but to date no effective strategy exists to eradicate this zoonotic pathogen from poultry production. Here, the potential use of passive immunization to reduce Campylobacter colonization in broiler chicks was examined. For this purpose, laying hens were immunized with either a whole-cell lysate or the hydrophobic protein fraction of C. jejuni and their eggs were collected. In vitro tests validated the induction of specific ImmunoglobulinY (IgY) against C. jejuni in the immunized hens’ egg yolks, in particular. In seeder experiments, preventive administration of hyperimmune egg yolk significantly (P < 0.01) reduced bacterial counts of seeder animals three days after oral inoculation with approximately 104 cfu C. jejuni, compared with control birds. Moreover, transmission to non-seeder birds was dramatically reduced (hydrophobic protein fraction) or even completely prevented (whole-cell lysate). Purified IgY promoted bacterial binding to chicken intestinal mucus, suggesting enhanced mucosal clearance in vivo. Western blot analysis in combination with mass spectrometry after two-dimensional gel-electrophoresis revealed immunodominant antigens of C. jejuni that are involved in a variety of cell functions, including chemotaxis and adhesion. Some of these (AtpA, EF-Tu, GroEL and CtpA) are highly conserved proteins and could be promising targets for the development of subunit vaccines. PMID:24589217

  19. High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection.

    PubMed

    Meadows, Danielle N; Bahous, Renata H; Best, Ana F; Rozen, Rima

    2015-01-01

    Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host's immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents) or folic acid-supplemented diets (FASD, 10x recommended level) for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p<0.01, Cox proportional hazards) and higher parasitemia (p< 0.01, joint model of parasitemia and survival) compared with CD mice. FASD mice had lower numbers of splenocytes, total T cells, and lower numbers of specific T and NK cell sub-populations, compared with CD mice (p<0.05, linear mixed effects). Increased brain TNFα immunoreactive protein (p<0.01, t-test) and increased liver Abca1 mRNA (p<0.01, t-test), a modulator of TNFα, were observed in FASD mice; these variables correlated positively (rs = 0.63, p = 0.01). Bcl-xl/Bak mRNA was increased in liver of FASD mice (p<0.01, t-test), suggesting reduced apoptotic potential. We conclude that high dietary folate increases parasite replication, disturbs the immune response and reduces resistance to malaria in mice. These findings have relevance for malaria-endemic regions, when considering anti-folate anti-malarials, food fortification or vitamin supplementation programs.

  20. Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine.

    PubMed

    DaSilva, Kevin A; Brown, Mary E; McLaurin, JoAnne

    2009-02-25

    Immunization with amyloid-beta (Abeta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Abeta. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Abeta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Abeta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Abeta alone. Moreover, use of Abeta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Abeta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Abeta. These antibodies decreased plaque load by as much as 36+/-8% and insoluble Abeta42 levels by 56+/-3%. Clearance of Abeta was most effective when antibodies were directed against N-terminal epitopes of Abeta. Moreover, immunization reduced CAA by as much as 69+/-12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Abeta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Abeta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.

  1. Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage

    PubMed Central

    Hara, Hideaki; Friedlander, Robert M.; Gagliardini, Valeria; Ayata, Cenk; Fink, Klaus; Huang, Zhihong; Shimizu-Sasamata, Masao; Yuan, Junying; Moskowitz, Michael A.

    1997-01-01

    The interleukin 1β converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1β (IL-1β) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1β levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1β levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-d-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage. PMID:9050895

  2. The KnowRISK project: Tools and strategies to reduce non-structural damage

    NASA Astrophysics Data System (ADS)

    Sousa Oliveira, Carlos; Lopes, Mário; Mota de Sá, Francisco; Amaral Ferreia, Mónica; Candeias, Paulo; Campos Costa, Alfredo; Rupakhety, Rajesh; Meroni, Fabrizio; Azzaro, Raffaele; D'Amico, Salvatore; Langer, Horst; Musacchio, Gemma; Sousa Silva, Delta; Falsaperla, Susanna; Scarfì, Luciano; Tusa, Giuseppina; Tuvé, Tiziana

    2016-04-01

    The project KnowRISK (Know your city, Reduce seISmic risK through non-structural elements) is financed by the European Commission to develop prevention measures that may reduce non-structural damage in urban areas. Pilot areas of the project are within the three European participating countries, namely Portugal, Iceland and Italy. Non-structural components of a building include all those components that are not part of the structural system, more specifically the architectural, mechanical, electrical, and plumbing systems, as well as furniture, fixtures, equipment, and contents. Windows, partitions, granite veneer, piping, ceilings, air conditioning ducts and equipment, elevators, computer and hospital equipment, file cabinets, and retail merchandise are all examples of non-structural components that are vulnerable to earthquake damage. We will use the experience gained during past earthquakes, which struck in particular Iceland, Italy and Portugal (Azores). Securing the non-structural elements improves the safety during an earthquake and saves lives. This paper aims at identifying non-structural seismic protection measures in the pilot areas and to develop a portfolio of good practices for the most common and serious non-structural vulnerabilities. This systematic identification and the portfolio will be achieved through a "cross-knowledge" strategy based on previous researches, evidence of non-structural damage in past earthquakes. Shake table tests of a group of non-structural elements will be performed. These tests will be filmed and, jointly with portfolio, will serve as didactic supporting tools to be used in workshops with building construction stakeholders and in risk communication activities. A Practical Guide for non-structural risk reduction will be specifically prepared for citizens on the basis of the outputs of the project, taking into account the local culture and needs of each participating country.

  3. Ventromedial prefrontal damage reduces mind-wandering and biases its temporal focus.

    PubMed

    Bertossi, Elena; Ciaramelli, Elisa

    2016-11-01

    Mind-wandering, an ubiquitous expression of humans' mental life, reflects a drift of attention away from the current task towards self-generated thoughts, and has been associated with activity in the brain default network. To date, however, little is understood about the contribution of individual nodes of this network to mind-wandering. Here, we investigated whether the ventromedial prefrontal cortex (vmPFC) is critically involved in mind-wandering, by studying the propensity to mind-wander in patients with lesion to the vmPFC (vmPFC patients), control patients with lesions not involving the vmPFC, and healthy individuals. Participants performed three tasks varying in cognitive demands while their thoughts were periodically sampled, and a self-report scale of daydreaming in daily life. vmPFC patients exhibited reduced mind-wandering rates across tasks, and claimed less frequent daydreaming, than both healthy and brain-damaged controls. vmPFC damage reduced off-task thoughts related to the future, while it promoted those about the present. These results indicate that vmPFC critically supports mind-wandering, possibly by helping to construct future-related scenarios and thoughts that have the potential to draw attention inward, away from the ongoing tasks.

  4. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response.

    PubMed

    Brines, M; Cerami, A

    2008-11-01

    In its classic hormonal role, erythropoietin (EPO) is produced by the kidney and regulates the number of erythrocytes within the circulation to provide adequate tissue oxygenation. EPO also mediates other effects directed towards optimizing oxygen delivery to tissues, e.g. modulating regional blood flow and reducing blood loss by promoting thrombosis within damaged vessels. Over the past 15 years, many unexpected nonhaematopoietic functions of EPO have been identified. In these more recently appreciated nonhormonal roles, locally-produced EPO signals through a different receptor isoform and is a major molecular component of the injury response, in which it counteracts the effects of pro-inflammatory cytokines. Acutely, EPO prevents programmed cell death and reduces the development of secondary, pro-inflammatory cytokine-induced injury. Within a longer time frame, EPO provides trophic support to enable regeneration and healing. As the region immediately surrounding damage is typically relatively deficient in endogenous EPO, administration of recombinant EPO can provide increased tissue protection. However, effective use of EPO as therapy for tissue injury requires higher doses than for haematopoiesis, potentially triggering serious adverse effects. The identification of a tissue-protective receptor isoform has facilitated the engineering of nonhaematopoietic, tissue-protective EPO derivatives, e.g. carbamyl EPO, that avoid these complications. Recently, regions within the EPO molecule mediating tissue protection have been identified and this has enabled the development of potent tissue-protective peptides, including some mimicking EPO's tertiary structure but unrelated in primary sequence.

  5. Reduced Sensitivity to Sooner Reward During Intertemporal Decision-Making Following Insula Damage in Humans

    PubMed Central

    Sellitto, Manuela; Ciaramelli, Elisa; Mattioli, Flavia; di Pellegrino, Giuseppe

    2016-01-01

    During intertemporal choice, humans tend to prefer small-sooner rewards over larger-delayed rewards, reflecting temporal discounting (TD) of delayed outcomes. Functional neuroimaging (fMRI) evidence has implicated the insular cortex in time-sensitive decisions, yet it is not clear whether activity in this brain region is crucial for, or merely associated with, TD behavior. Here, patients with damage to the insula (Insular patients), control patients with lesions outside the insula, and healthy individuals chose between smaller-sooner and larger-later monetary rewards. Insular patients were less sensitive to sooner rewards than were the control groups, exhibiting reduced TD. A Voxel-based Lesion-Symptom Mapping (VLSM) analysis confirmed a statistically significant association between insular damage and reduced TD. These results indicate that the insular cortex is crucial for intertemporal choice. We suggest that he insula may be necessary to anticipate the bodily/emotional effects of receiving rewards at different delays, influencing the computation of their incentive value. Devoid of such input, insular patients’ choices would be governed by a heuristic of quantity, allowing patients to wait for larger options. PMID:26793084

  6. Treatment with carnosine reduces hypoxia-ischemia brain damage in a neonatal rat model.

    PubMed

    Zhang, Huizhen; Guo, Shang; Zhang, Linlin; Jia, Liting; Zhang, Zhan; Duan, Hongbao; Zhang, Jingbin; Liu, Jingyan; Zhang, Weidong

    2014-03-15

    Perinatal hypoxia-ischemia brain damage (HIBD) is a major cause of mortality and morbidity in neonates, and there is currently no effective therapy for HIBD. Carnosine plays a neuroprotective role in adult brain damage. We have previously demonstrated that carnosine pretreatment protects against HIBD in a neonatal rat model. Therefore, we hypothesized that treatment with carnosine would also have neuroprotective effects. Hypoxia-ischemia was induced in rats on postnatal days 7-9 (P7-9). Carnosine was administered intraperitoneally at a dose of 250mg/kg at 0h, 24h, and 48h after hypoxia-ischemia was induced. The biochemical markers of oxidative stress and apoptosis were evaluated at 72h after hypoxia-ischemia was induced, Brain learning and memory function performance were observed using the Morris water maze test on postnatal days 28-33 (P28-33). Treatment with carnosine post-HIBD significantly reduced the concentration of 8-iso-prostaglandinF2alpha in brain tissue and decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the hippocampus CA1 region and cortex as well as the mitochondria caspase-3 protein expression. Furthermore, carnosine also improved the cognitive function of P28-33 rats, whose cognitive function decline was due to HIBD. These results demonstrate that carnosine treatment after HIBD can reduce the brain injury, improving brain function. Carnosine could be an attractive candidate for treating HIBD.

  7. Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage

    PubMed Central

    Huang, Wei; Wu, Jiyuan; Yang, Huiqin; Xiong, Yin; Jiang, Rui; Cui, Tianpen; Ye, Duyun

    2017-01-01

    Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage. PMID:27768123

  8. Lonicera caerulea fruits reduce UVA-induced damage in hairless mice.

    PubMed

    Vostálová, Jitka; Galandáková, Adéla; Palíková, Irena; Ulrichová, Jitka; Doležal, Dalibor; Lichnovská, Radka; Vrbková, Jana; Rajnochová Svobodová, Alena

    2013-11-05

    UVA photons are less energetic than UVB photons but they are more abundant in solar radiation. Modern tools have shown that UVA light has serious adverse effects on the skin. We investigated the effect of consuming Lonicera caerulea berries on UVA-induced damage in SKH-1 mice. The mice were fed a diet containing L. caerulea berries (10%, w/w) for 14 days before a single UVA (30 J/cm(2)) treatment. Effects on haematological and antioxidant parameters were evaluated 4 and 24h after irradiation. The bioavailability of L. caerulea phenolics was also assessed. Consuming the L. caerulea berry-enriched diet caused reduced malondialdehyde production and increased catalase activity and glutathione levels were found in skin and erythrocytes. UVA-induced NADPH:quinone oxidoreductase-1 and gamma-L-glutamate-L-cysteine ligase protein in skin were reduced in mice fed L. caerulea berries. Enhanced heme oxygenase-1 level in skin, interleukin-17 in plasma and reduced interleukin-12 levels in plasma were found in the mice on the experimental diet. Histological (pyknotic) changes in the nuclei of basal cells induced by UVA exposure were reduced in L. caerulea berry consuming animals. HLPC-MS analysis showed high concentrations of hippuric acid, one of the main metabolites of aromatic amino acids and phenolic compounds, in skin, liver, urine and faeces of mice consuming the berries. Taken together, consumption of L. caerulea berries affords protection from the adverse effects of a single UVA exposure mainly via modulation of antioxidant parameters.

  9. Altered Biomarkers of Mucosal Immunity and Reduced Vaginal Lactobacillus Concentrations in Sexually Active Female Adolescents

    PubMed Central

    Madan, Rebecca Pellett; Carpenter, Colleen; Fiedler, Tina; Kalyoussef, Sabah; McAndrew, Thomas C.; Viswanathan, Shankar; Kim, Mimi; Keller, Marla J.; Fredricks, David N.; Herold, Betsy C.

    2012-01-01

    Background Genital secretions collected from adult women exhibit in vitro activity against herpes simplex virus (HSV) and Escherichia coli (E. coli), but prior studies have not investigated this endogenous antimicrobial activity or its mediators in adolescent females. Methodology/Principal Findings Anti-HSV and anti-E.coli activity were quantified from cervicovaginal lavage (CVL) specimens collected from 20 sexually active adolescent females (15–18 years). Soluble immune mediators that may influence this activity were measured in CVL, and concentrations of Lactobacillus jensenii and crispatus were quantified by PCR from vaginal swabs. Results for adolescents were compared to those obtained from 54 healthy, premenopausal adult women. Relative to specimens collected from adults, CVL collected from adolescent subjects had significantly reduced activity against E. coli and diminished concentrations of protein, IgG, and IgA but significantly increased anti-HSV activity and concentrations of interleukin (IL)-1α, IL-6 and IL-1 receptor antagonist. Vaginal swabs collected from adolescent subjects had comparable concentrations of L. crispatus but significantly reduced concentrations of L. jensenii, relative to adult swabs. Conclusions/Significance Biomarkers of genital mucosal innate immunity may differ substantially between sexually active adolescents and adult women. These findings warrant further study and may have significant implications for prevention of sexually transmitted infections in adolescent females. PMID:22808157

  10. Reducing the Risk of Damage to Power Transformers of 110 kV and Above Accompanying Internal Short Circuits

    SciTech Connect

    L’vova, M. M.; L’vov, S. Yu.; Komarov, V. B.; Lyut’ko, E. O.; Vdoviko, V. P.; Demchenko, V. V.; Belyaev, S. G.; Savel’ev, V. A.; L’vov, M. Yu. L’vov, Yu. N.

    2015-03-15

    Methods of increasing the operating reliability of power transformers, autotransformers and shunting reactors in order to reduce the risk of damage, which accompany internal short circuits and equipment fires and explosions, are considered.

  11. Vitamin A supplementation reduces the monocyte chemoattractant protein-1 intestinal immune response of Mexican children.

    PubMed

    Long, Kurt Z; Santos, Jose Ignacio; Estrada Garcia, Teresa; Haas, Meredith; Firestone, Mathew; Bhagwat, Jui; Dupont, Herbert L; Hertzmark, Ellen; Rosado, Jorge L; Nanthakumar, Nanda N

    2006-10-01

    The impact of vitamin A supplementation on childhood diarrhea may be determined by the regulatory effect supplementation has on the mucosal immune response in the gut. Previous studies have not addressed the impact of vitamin A supplementation on the production of monocyte chemoattractant protein 1 (MCP-1), an essential chemokine involved in pathogen-specific mucosal immune response. Fecal MCP-1 concentrations, determined by an enzyme-linked immuno absorption assay, were compared among 127 Mexican children 5-15 mo of age randomized to receive a vitamin A supplement (<12 mo of age, 20,000 IU of retinol; > or =12 mo, 45,000 iu) every 2 mo or a placebo as part of a larger vitamin A supplementation trial. Stools collected during the summer months were screened for MCP-1 and gastrointestinal pathogens. Values of MCP-1 were categorized into 3 levels (nondetectable, or =median). Multinomial logistic regression models were used to determine whether vitamin A-supplemented children had different categorical values of MCP-1 compared with children in the placebo group. Differences in categorical values were also analyzed stratified by gastrointestinal pathogen infections and by diarrheal symptoms. Overall, children who received the vitamin A supplement had reduced fecal concentrations of MCP-1 compared with children in the placebo group (median pg/mg protein +/- interquartile range: 284.88 +/- 885.35 vs. 403.39 +/- 913.16; odds ratio 0.64, 95% CI 0.42-97, P = 0.03). Vitamin A supplemented children infected with enteropathogenic Escherichia coli (EPEC) had reduced MCP-1 levels (odds ratio = 0.38, 95% CI 0.18-0.80) compared with children in the placebo group. Among children not infected with Ascaris lumbricoides vitamin A supplemented children had reduced MCP-1 levels (OR = 0.62, 95% CI 0.41-0.94). These findings suggest that vitamin A has an anti-inflammatory effect in the gastrointestinal tract by reducing MCP-1 concentrations.

  12. Immunization

    MedlinePlus

    ... remembers" the germ and can fight it again. Vaccines contain germs that have been killed or weakened. When given to a healthy person, the vaccine triggers the immune system to respond and thus ...

  13. High effectiveness of tailored flower strips in reducing pests and crop plant damage

    PubMed Central

    Tschumi, Matthias; Albrecht, Matthias; Entling, Martin H.; Jacot, Katja

    2015-01-01

    Providing key resources to animals may enhance both their biodiversity and the ecosystem services they provide. We examined the performance of annual flower strips targeted at the promotion of natural pest control in winter wheat. Flower strips were experimentally sown along 10 winter wheat fields across a gradient of landscape complexity (i.e. proportion non-crop area within 750 m around focal fields) and compared with 15 fields with wheat control strips. We found strong reductions in cereal leaf beetle (CLB) density (larvae: 40%; adults of the second generation: 53%) and plant damage caused by CLB (61%) in fields with flower strips compared with control fields. Natural enemies of CLB were strongly increased in flower strips and in part also in adjacent wheat fields. Flower strip effects on natural enemies, pests and crop damage were largely independent of landscape complexity (8–75% non-crop area). Our study demonstrates a high effectiveness of annual flower strips in promoting pest control, reducing CLB pest levels below the economic threshold. Hence, the studied flower strip offers a viable alternative to insecticides. This highlights the high potential of tailored agri-environment schemes to contribute to ecological intensification and may encourage more farmers to adopt such schemes. PMID:26311668

  14. A Modified Catheterization Procedure to Reduce Bladder Damage when Collecting Urine Samples from Holstein Cows

    PubMed Central

    TAMURA, Tetsuo; NAKAMURA, Hiroshi; SATO, Say; SEKI, Makoto; NISHIKI, Hideto

    2014-01-01

    ABSTRACT This study proposed a modified procedure, using a small balloon catheter (SB catheter, 45 ml), for reducing bladder damage in cows. Holstein cows and the following catheters were prepared: smaller balloon catheter (XSB catheter; 30 ml), SB catheter and standard balloon catheter (NB catheter; 70 ml, as the commonly used, standard size). In experiment 1, each cow was catheterized. The occurrence of catheter-associated hematuria (greater than 50 RBC/HPF) was lower in the SB catheter group (0.0%, n=7) than in the NB catheter group (71.4%, n=7; P<0.05). In experiment 2, general veterinary parameters, urine pH, body temperature and blood values in cows were not affected before or after insertion of SB catheters (n=6). The incidence of urinary tract infection (UTI) was 3.0% per catheterized day (n=22). In experiment 3, feeding profiles, daily excretion of urinary nitrogen (P<0.05) and rate from nitrogen intake in urine (P<0.01), were higher with use of the SB catheter (n=13) than with the use of the vulva urine cup (n=18), indicating that using the SB catheter can provide accurate nutritional data. From this study, we concluded that when using an SB catheter, the following results occur; reduction in bladder damage without any veterinary risks and accuracy in regard to feeding parameters, suggesting this modified procedure using an SB catheter is a useful means of daily urine collection. PMID:24561376

  15. High effectiveness of tailored flower strips in reducing pests and crop plant damage.

    PubMed

    Tschumi, Matthias; Albrecht, Matthias; Entling, Martin H; Jacot, Katja

    2015-09-07

    Providing key resources to animals may enhance both their biodiversity and the ecosystem services they provide. We examined the performance of annual flower strips targeted at the promotion of natural pest control in winter wheat. Flower strips were experimentally sown along 10 winter wheat fields across a gradient of landscape complexity (i.e. proportion non-crop area within 750 m around focal fields) and compared with 15 fields with wheat control strips. We found strong reductions in cereal leaf beetle(CLB) density (larvae: 40%; adults of the second generation: 53%) and plant damage caused by CLB (61%) in fields with flower strips compared with control fields. Natural enemies of CLB were strongly increased in flower strips and in part also in adjacent wheat fields. Flower strip effects on natural enemies, pests and crop damage were largely independent of landscape complexity(8-75% non-crop area). Our study demonstrates a high effectiveness of annual flower strips in promoting pest control, reducing CLB pest levels below the economic threshold. Hence, the studied flower strip offers a viable alternative to insecticides. This highlights the high potential of tailored agri-environment schemes to contribute to ecological intensification and may encourage more farmers to adopt such schemes.

  16. Damage Detection in Flexible Plates through Reduced-Order Modeling and Hybrid Particle-Kalman Filtering.

    PubMed

    Capellari, Giovanni; Azam, Saeed Eftekhar; Mariani, Stefano

    2015-12-22

    Health monitoring of lightweight structures, like thin flexible plates, is of interest in several engineering fields. In this paper, a recursive Bayesian procedure is proposed to monitor the health of such structures through data collected by a network of optimally placed inertial sensors. As a main drawback of standard monitoring procedures is linked to the computational costs, two remedies are jointly considered: first, an order-reduction of the numerical model used to track the structural dynamics, enforced with proper orthogonal decomposition; and, second, an improved particle filter, which features an extended Kalman updating of each evolving particle before the resampling stage. The former remedy can reduce the number of effective degrees-of-freedom of the structural model to a few only (depending on the excitation), whereas the latter one allows to track the evolution of damage and to locate it thanks to an intricate formulation. To assess the effectiveness of the proposed procedure, the case of a plate subject to bending is investigated; it is shown that, when the procedure is appropriately fed by measurements, damage is efficiently and accurately estimated.

  17. Damage Detection in Flexible Plates through Reduced-Order Modeling and Hybrid Particle-Kalman Filtering

    PubMed Central

    Capellari, Giovanni; Eftekhar Azam, Saeed; Mariani, Stefano

    2015-01-01

    Health monitoring of lightweight structures, like thin flexible plates, is of interest in several engineering fields. In this paper, a recursive Bayesian procedure is proposed to monitor the health of such structures through data collected by a network of optimally placed inertial sensors. As a main drawback of standard monitoring procedures is linked to the computational costs, two remedies are jointly considered: first, an order-reduction of the numerical model used to track the structural dynamics, enforced with proper orthogonal decomposition; and, second, an improved particle filter, which features an extended Kalman updating of each evolving particle before the resampling stage. The former remedy can reduce the number of effective degrees-of-freedom of the structural model to a few only (depending on the excitation), whereas the latter one allows to track the evolution of damage and to locate it thanks to an intricate formulation. To assess the effectiveness of the proposed procedure, the case of a plate subject to bending is investigated; it is shown that, when the procedure is appropriately fed by measurements, damage is efficiently and accurately estimated. PMID:26703615

  18. FeTPPS Reduces Secondary Damage and Improves Neurobehavioral Functions after Traumatic Brain Injury

    PubMed Central

    Bruschetta, Giuseppe; Impellizzeri, Daniela; Campolo, Michela; Casili, Giovanna; Di Paola, Rosanna; Paterniti, Irene; Esposito, Emanuela; Cuzzocrea, Salvatore

    2017-01-01

    Traumatic brain injury (TBI) determinate a cascade of events that rapidly lead to neuron's damage and death. We already reported that administration of FeTPPS, a 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin iron III chloride peroxynitrite decomposition catalyst, possessed evident neuroprotective effects in a experimental model of spinal cord damage. The present study evaluated the neuroprotective property of FeTPPS in TBI, using a clinically validated model of TBI, the controlled cortical impact injury (CCI). We observe that treatment with FeTPPS (30 mg/kg, i.p.) reduced: the state of brain inflammation and the tissue hurt (histological score), myeloperoxidase activity, nitric oxide production, glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines expression and apoptosis process. Moreover, treatment with FeTPPS re-established motor-cognitive function after CCI and it resulted in a reduction of lesion volumes. Our results established that FeTPPS treatment decreases the growth of inflammatory process and the tissue injury associated with TBI. Thus our study confirmed the neuroprotective role of FeTPPS treatment on TBI. PMID:28223911

  19. The DNA damage response and immune signaling alliance: Is it good or bad? Nature decides when and where.

    PubMed

    Pateras, Ioannis S; Havaki, Sophia; Nikitopoulou, Xenia; Vougas, Konstantinos; Townsend, Paul A; Panayiotidis, Michalis I; Georgakilas, Alexandros G; Gorgoulis, Vassilis G

    2015-10-01

    The characteristic feature of healthy living organisms is the preservation of homeostasis. Compelling evidence highlight that the DNA damage response and repair (DDR/R) and immune response (ImmR) signaling networks work together favoring the harmonized function of (multi)cellular organisms. DNA and RNA viruses activate the DDR/R machinery in the host cells both directly and indirectly. Activation of DDR/R in turn favors the immunogenicity of the incipient cell. Hence, stimulation of DDR/R by exogenous or endogenous insults triggers innate and adaptive ImmR. The immunogenic properties of ionizing radiation, a prototypic DDR/R inducer, serve as suitable examples of how DDR/R stimulation alerts host immunity. Thus, critical cellular danger signals stimulate defense at the systemic level and vice versa. Disruption of DDR/R-ImmR cross talk compromises (multi)cellular integrity, leading to cell-cycle-related and immune defects. The emerging DDR/R-ImmR concept opens up a new avenue of therapeutic options, recalling the Hippocrates quote "everything in excess is opposed by nature."

  20. Photomultiplier circuit including means for rapidly reducing the sensitivity thereof. [and protection from radiation damage

    NASA Technical Reports Server (NTRS)

    Mcclenahan, J. O. (Inventor)

    1974-01-01

    A simple, reliable and inexpensive control circuit is described for rapidly reducing the bias voltage across one or more of the dynode stages of a photomultiplier, to substantially decrease its sensitivity to incoming light at those times where excess light intensity might damage the tube. The control circuit comprises a switching device, such as a silicon controlled rectifier (SCR), coupled between a pair of the electrodes in the tube, preferably the cathode and first dynode, or the first and second dynodes, the switching device operating in response to a trigger pulse applied to its gate to short circuit the two electrodes. To insure the desired reduction in sensitivity, two switching stages, the devices be employed between two of the electrode stages, the devices being operated simultaneously to short circuit both stages.

  1. Iron porphyrinate Fe(TPPS) reduces brain cell damage in rats intrastriatally lesioned by quinolinate.

    PubMed

    González-Cortés, Carolina; Salinas-Lara, Citlaltepetl; Gómez-López, Marcos Artemio; Tena-Suck, Martha Lilia; Pérez-De La Cruz, Verónica; Rembao-Bojórquez, Daniel; Pedraza-Chaverrí, José; Gómez-Ruiz, Celedonio; Galván-Arzate, Sonia; Ali, Syed F; Santamaría, Abel

    2008-01-01

    It has been recently demonstrated that the reactive nitrogen species (RNS) peroxynitrite (ONOO(-)) is involved in the neurotoxic pattern produced by quinolinic acid in the rat brain [V. Pérez-De La Cruz, C. González-Cortés, S. Galván-Arzate, O.N. Medina-Campos, F. Pérez-Severiano, S.F. Ali, J. Pedraza-Chaverrí, A. Santamaría, Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III), Neuroscience 135 (2005) 463-474.]. The aim of this work was to investigate whether ONOO(-) can also be responsible for morphological alterations and inflammatory events in the same paradigm. For this purpose, we evaluated the effect of a pre-treatment with the iron porphyrinate Fe(TPPS), a well-known ONOO(-) decomposition catalyst (10 mg/kg, i.p., 120 min before lesion), on the quinolinate-induced striatal cell damage and immunoreactivities to glial-fibrilar acidic protein (GFAP), interleukin 6 (IL-6) and inducible nitric oxide synthase (iNOS), one and seven days after the intrastriatal infusion of quinolinate (240 nmol/microl) to rats. The striatal tissue from animals lesioned by quinolinate showed a significant degree of damage and enhanced immunoreactivities to GFAP, IL-6 and iNOS, both at 1 and 7 days post-lesion. Pre-treatment of rats with Fe(TPPS) significantly attenuated or prevented all these markers at both post-lesion times tested, except for GFAP immunoreactivity at 7 days post-lesion and iNOS immunoreactivity at 1 day post-lesion. Altogether, our results suggest that ONOO(-) is actively participating in triggering inflammatory events and morphological alterations in the toxic model produced by quinolinate, since the use of agents affecting its formation, such as Fe(TPPS), are effective experimental tools to reduce the brain lesions associated to excitotoxic and oxidative damage.

  2. Deferoxamine reduces intracerebral hemorrhage-induced white matter damage in aged rats.

    PubMed

    Ni, Wei; Okauchi, Masanobu; Hatakeyama, Tetsuhiro; Gu, Yuxiang; Keep, Richard F; Xi, Guohua; Hua, Ya

    2015-10-01

    Iron contributes to c-Jun N-terminal kinases (JNK) activation in young rats and white matter injury in piglets after intracerebral hemorrhage (ICH). In the present study, we examined the effect of deferoxamine on ICH-induced white matter injury and JNK activation and in aged rats. Male Fischer 344 rats (18months old) had either an intracaudate injection of 100μl of autologous blood or a needle insertion (sham). The rats were treated with deferoxamine or vehicle with different regimen (dosage, duration and time window). White matter injury and activation of JNK were examined. We found that a dose of DFX should be at more than 10mg/kg for a therapeutic duration more than 2days with a therapeutic time window of 12h to reduce ICH-induced white matter loss at 2months. ICH-induced white matter injury was associated with JNK activation. The protein levels of phosphorylated-JNK (P-JNK) were upregulated at day-1 after ICH and then gradually decreased. P-JNK immunoreactivity was mostly located in white matter bundles. ICH-induced JNK activation was reduced by DFX treatment. This study demonstrated that DFX can reduce ICH-induced JNK activation and white matter damage.

  3. Pulsed Electromagnetic Field Exposure Reduces Hypoxia and Inflammation Damage in Neuron-Like and Microglial Cells.

    PubMed

    Vincenzi, Fabrizio; Ravani, Annalisa; Pasquini, Silvia; Merighi, Stefania; Gessi, Stefania; Setti, Stefania; Cadossi, Ruggero; Borea, Pier Andrea; Varani, Katia

    2017-05-01

    In the present study, the effect of low-frequency, low-energy pulsed electromagnetic fields (PEMFs) has been investigated by using different cell lines derived from neuron-like cells and microglial cells. In particular, the primary aim was to evaluate the effect of PEMF exposure in inflammation- and hypoxia-induced injury in two different neuronal cell models, the human neuroblastoma-derived SH-SY5Y cells and rat pheochromocytoma PC12 cells and in N9 microglial cells. In neuron-like cells, live/dead and apoptosis assays were performed in hypoxia conditions from 2 to 48 h. Interestingly, PEMF exposure counteracted hypoxia damage significantly reducing cell death and apoptosis. In the same cell lines, PEMFs inhibited the activation of the hypoxia-inducible factor 1α (HIF-1α), the master transcriptional regulator of cellular response to hypoxia. The effect of PEMF exposure on reactive oxygen species (ROS) production in both neuron-like and microglial cells was investigated considering their key role in ischemic injury. PEMFs significantly decreased hypoxia-induced ROS generation in PC12, SH-SY5Y, and N9 cells after 24 or 48 h of incubation. Moreover, PEMFs were able to reduce some of the most well-known pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 release in N9 microglial cells stimulated with different concentrations of LPS for 24 or 48 h of incubation time. These results show a protective effect of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells suggesting that PEMFs could represent a potential therapeutic approach in cerebral ischemic conditions. J. Cell. Physiol. 232: 1200-1208, 2017. © 2016 Wiley Periodicals, Inc.

  4. Immune defense reduces respiratory fitness in Callinectes sapidus, the Atlantic blue crab.

    PubMed

    Burnett, Louis E; Holman, Jeremy D; Jorgensen, Darwin D; Ikerd, Jennifer L; Burnett, Karen G

    2006-08-01

    Crustacean gills function in gas exchange, ion transport, and immune defense against microbial pathogens. Hemocyte aggregates that form in response to microbial pathogens become trapped in the fine vasculature of the gill, leading to the suggestion by others that respiration and ion regulation might by impaired during the course of an immune response. In the present study, injection of the pathogenic bacterium Vibrio campbellii into Callinectes sapidus, the Atlantic blue crab, caused a dramatic decline in oxygen uptake from 4.53 to 2.56 micromol g-1 h-1. This decline in oxygen uptake is associated with a large decrease in postbranchial PO2, from 16.2 (+/-0.46 SEM, n=7) to 13.1 kPa (+/-0.77 SEM, n=9), while prebranchial PO2 remains unchanged. In addition, injection of Vibrio results in the disappearance of a pH change across the gills, an indication of reduced CO2 excretion. The hemolymph hydrostatic pressure change across the gill circulation increases nearly 2-fold in Vibrio-injected crabs compared with a negligible change in pressure across the gill circulation in saline-injected, control crabs. This change, in combination with stability of heart rate and branchial chamber pressure, is indicative of a significant increase in vascular resistance across the gills that is induced by hemocyte nodule formation. A healthy, active blue crab can eliminate most invading bacteria, but the respiratory function of the gills is impaired. Thus, when blue crabs are engaged in the immune response, they are less equipped to engage in oxygen-fueled activities such as predator avoidance, prey capture, and migration. Furthermore, crabs are less fit to invade environments that are hypoxic.

  5. Autoimmune damage to spermatogenesis in rodents immunized with mouse F9 embryonic carcinoma cells.

    PubMed Central

    Vojtiskova, M; Pokorna, Z; Draber, P

    1983-01-01

    Significant inhibition of spermatogenesis and appearance of antibodies against spermatogenic cells identified by cytotoxicity and immunofluorescence reactions were observed in mice of inbred strains 129/Sv and BALB/c and in albino guinea pigs after syngeneic, allogeneic, and xenogeneic immunization with mouse F9 embryonic carcinoma cells and Freund's complete adjuvant. A similar syngeneic immunization with PYS-2 cells was ineffective. Appropriate absorption experiments confirmed the similarity between the antigens of F9 and spermatogenic cells and the absence of such a similarity with antigens of PYS-2 cells. These results support the hypothesis that the oncofetal F9 antigens represent spermatogenic differentiation antigens and thus play an essential role in spermatogenic cell differentiation. PMID:6340100

  6. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.

    PubMed

    Seyhun, Ersin; Malo, Antje; Schäfer, Claus; Moskaluk, Christopher A; Hoffmann, Ralf-Thorsten; Göke, Burkhard; Kubisch, Constanze H

    2011-11-01

    In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

  7. Losartan reduces oxidative damage to renal DNA and conserves plasma antioxidant capacity in diabetic rats.

    PubMed

    Lodovici, Maura; Bigagli, Elisabetta; Tarantini, Francesca; Di Serio, Claudia; Raimondi, Laura

    2015-11-01

    Increased reactive oxygen species (ROS) levels produced by hyperglycemia and angiotensin-II (AT-II) are considered among the pathogenic factors in the malignant transformation of diabetic renal cells. We aimed to investigate the potential role of AT-II in the increased cancer risk seen in diabetes; measuring oxidative damage to renal DNA and protective antioxidant defenses, including adiponectin (Adp) and plasma antioxidant capacity by the Ferric Reducing Ability of Plasma (FRAP) method. In the kidney of streptozotocin (STZ)-induced (55 mg/kg) diabetic rats either treated or not treated for 3 weeks with losartan, an AT-II type 1 receptor antagonist (20 mg/kg/day); we measured 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) levels, as an index of oxidative DNA damage, circulating Adp and FRAP. Diabetic rats showed significantly higher 8-oxodGuo levels in renal DNA (8.48 ± 0.98 × 10(-6) dG, mean ± SEM n = 11) than normoglycemic ones (1.18 ± 0.04 × 10(-6) dG, mean ± SEM, n=7) and lower plasma Adp and FRAP levels in comparison to normoglycemics. The treatment of diabetic rats with losartan significantly (P < 0.01) reduced 8-oxodGuo levels (5.4 ± 0.58 × 10(-6) dG, mean ± SEM n=9) in renal DNA and conserved FRAP values. Moreover, an inverse correlation was found between 8-oxodGuo in kidney DNA and circulating Adp levels in normoglycemic and diabetic rats. Losartan treatment preserves FRAP levels, reduces DNA oxidative injury and thus the carcinogenesis risk. Furthermore, our results indicate that Adp plasma levels are a further marker of oxidative injury to the kidney and confirm that it is an important part of the plasma antioxidant defense.

  8. Reduced-order modeling for mistuned centrifugal impellers with crack damages

    NASA Astrophysics Data System (ADS)

    Wang, Shuai; Zi, Yanyang; Li, Bing; Zhang, Chunlin; He, Zhengjia

    2014-12-01

    An efficient method for nonlinear vibration analysis of mistuned centrifugal impellers with crack damages is presented. The main objective is to investigate the effects of mistuning and cracks on the vibration features of centrifugal impellers and to explore effective techniques for crack detection. Firstly, in order to reduce the input information needed for component mode synthesis (CMS), the whole model of an impeller is obtained by rotation transformation based on the finite element model of a sector model. Then, a hybrid-interface method of CMS is employed to generate a reduced-order model (ROM) for the cracked impeller. The degrees of freedom on the crack surfaces are retained in the ROM to simulate the crack breathing effects. A novel approach for computing the inversion of large sparse matrix is proposed to save memory space during model order reduction by partitioning the matrix into many smaller blocks. Moreover, to investigate the effects of mistuning and cracks on the resonant frequencies, the bilinear frequency approximation is used to estimate the resonant frequencies of the mistuned impeller with a crack. Additionally, statistical analysis is performed using the Monte Carlo simulation to study the statistical characteristics of the resonant frequencies versus crack length at different mistuning levels. The results show that the most significant effect of mistuning and cracks on the vibration response is the shift and split of the two resonant frequencies with the same nodal diameters. Finally, potential quantitative indicators for detection of crack of centrifugal impellers are discussed.

  9. Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis.

    PubMed

    Yu, Changhui; Merza, Mohammed; Luo, Lingtao; Thorlacius, Henrik

    2015-01-05

    Neutrophil recruitment is known to be a rate-limiting step in mediating tissue injury in severe acute pancreatitis (AP). However, the signalling mechanisms controlling inflammation and organ damage in AP remain elusive. Herein, we examined the role of Ras signalling in AP. Male C57BL/6 mice were treated with a Ras inhibitor (farnesylthiosalicylic acid, FTS) before infusion of taurocholate into the pancreatic duct. Pancreatic and lung tissues as well as blood were collected 24 h after pancreatitis induction. Pretreatment with FTS decreased serum amylase levels by 82% and significantly attenuated acinar cell necrosis, tissue haemorrhage and oedema formation in taurocholate-induced pancreatitis. Inhibition of Ras signalling reduced myeloperoxidase (MPO) levels in the inflamed pancreas by 42%. In addition, administration of FTS decreased pancreatic levels of CXC chemokines as well as circulating levels of interleukin-6 and high-mobility group box 1 in animals exposed to taurocholate. Moreover, treatment with FTS reduced taurocholate-induced MPO levels in the lung. Inhibition of Ras signalling had no effect on neutrophil expression of Mac-1 in mice with pancreatitis. Moreover, FTS had no direct impact on trypsin activation in isolated pancreatic acinar cells. These results indicate that Ras signalling controls CXC chemokine formation, neutrophil recruitment and tissue injury in severe AP. Thus, our findings highlight a new signalling mechanism regulating neutrophil recruitment in the pancreas and suggest that inhibition of Ras signalling might be a useful strategy to attenuate local and systemic inflammation in severe AP.

  10. Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage

    PubMed Central

    Neretti, Nicola; Wang, Pei-Yu; Brodsky, Alexander S.; Nyguyen, Hieu H.; White, Kevin P.; Rogina, Blanka; Helfand, Stephen L.

    2009-01-01

    Decreased Indy activity extends lifespan in D. melanogaster without significant reduction in fecundity, metabolic rate, or locomotion. To understand the underlying mechanisms leading to lifespan extension in this mutant strain, we compared the genome-wide gene expression changes in the head and thorax of adult Indy mutant with control flies over the course of their lifespan. A signature enrichment analysis of metabolic and signaling pathways revealed that expression levels of genes in the oxidative phosphorylation pathway are significantly lower in Indy starting at day 20. We confirmed experimentally that complexes I and III of the electron transport chain have lower enzyme activity in Indy long-lived flies by Day 20 and predicted that reactive oxygen species (ROS) production in mitochondria could be reduced. Consistently, we found that both ROS production and protein damage are reduced in Indy with respect to control. However, we did not detect significant differences in total ATP, a phenotype that could be explained by our finding of a higher mitochondrial density in Indy mutants. Thus, one potential mechanism by which Indy mutants extend life span could be through an alteration in mitochondrial physiology leading to an increased efficiency in the ATP/ROS ratio. PMID:19164521

  11. Treatment with selectin blocking antibodies after lengthening contractions of mouse muscle blunts neutrophil accumulation but does not reduce damage.

    PubMed

    Sloboda, Darcée D; Brooks, Susan V

    2016-01-01

    P- and E-selectins are expressed on the surface of endothelial cells and may contribute to neutrophil recruitment following injurious lengthening contractions of skeletal muscle. Blunting neutrophil, but not macrophage, accumulation after lengthening contractions may provide a therapeutic benefit as neutrophils exacerbate damage to muscle fibers, while macrophages promote repair. In this study, we tested the hypothesis that P- and E-selectins contribute to neutrophil, but not macrophage, accumulation in muscles after contraction-induced injury, and that reducing neutrophil accumulation by blocking the selectins would be sufficient to reduce damage to muscle fibers. To test our hypothesis, we treated mice with antibodies to block P- and E-selectin function and assessed leukocyte accumulation and damage in muscles 2 days after lengthening contractions. Treatment with P/E-selectin blocking antibodies reduced neutrophil content by about half in muscles subjected to lengthening contractions. In spite of the reduction in neutrophil accumulation, we did not detect a decrease in damage 2 days after lengthening contractions. We conclude that P- and/or E-selectin contribute to the neutrophil accumulation associated with contraction-induced muscle damage and that only a portion of the neutrophils that typically accumulate following injurious lengthening contractions is sufficient to induce muscle fiber damage and force deficits. Thus, therapeutic interventions based on blocking the selectins or other adhesion proteins will have to reduce neutrophil numbers by more than 50% in order to provide a benefit.

  12. The selective estrogen receptor modulator, bazedoxifene, reduces ischemic brain damage in male rat.

    PubMed

    Castelló-Ruiz, María; Torregrosa, Germán; Burguete, María C; Miranda, Francisco J; Centeno, José M; López-Morales, Mikahela A; Gasull, Teresa; Alborch, Enrique

    2014-07-11

    While the estrogen treatment of stroke is under debate, selective estrogen receptor modulators (SERMs) arise as a promising alternative. We hypothesize that bazedoxifene (acetate, BZA), a third generation SERM approved for the treatment of postmenopausal osteoporosis, reduces ischemic brain damage in a rat model of transient focal cerebral ischemia. For comparative purposes, the neuroprotective effect of 17β-estradiol (E2) has also been assessed. Male Wistar rats underwent 60min middle cerebral artery occlusion (intraluminal thread technique), and grouped according to treatment: vehicle-, E2- and BZA-treated rats. Optimal plasma concentrations of E2 (45.6±7.8pg/ml) and BZA (20.7±2.1ng/ml) were achieved 4h after onset of ischemia, and maintained until the end of the procedure (24h). Neurofunctional score and volume of the damaged brain regions were the main end points. At 24h after ischemia-reperfusion, neurofunctional examination of the animals did not show significant differences among the three experimental groups. By contrast, both E2- and BZA-treated groups showed significantly lower total infarct volumes, BZA acting mainly in the cortical region and E2 acting mainly at the subcortical level. Our results demonstrate that: (1) E2 at physiological plasma levels in female rats is neuroprotective in male rats when given at the acute stage of the ischemic challenge and (2) BZA at clinically relevant plasma levels mimics the neuroprotective action of E2 and could be, therefore, a candidate in stroke treatment.

  13. Petroselinum Crispum is Effective in Reducing Stress-Induced Gastric Oxidative Damage

    PubMed Central

    Akıncı, Ayşin; Eşrefoğlu, Mukaddes; Taşlıdere, Elif; Ateş, Burhan

    2017-01-01

    Background: Oxidative stress has been shown to play a principal role in the pathogenesis of stress-induced gastric injury. Parsley (Petroselinum crispum) contains many antioxidants such as flavanoids, carotenoids and ascorbic acid. Aims: In this study, the histopathological and biochemical results of nutrition with a parsley-rich diet in terms of eliminating stress-induced oxidative gastric injury were evaluated. Study Design: Animal experimentation Methods: Forty male Wistar albino rats were divided into five groups: control, stress, stress + standard diet, stress + parsley-added diet and stress + lansoprazole (LPZ) groups. Subjects were exposed to 72 hours of fasting and later immobilized and exposed to the cold at +4 degrees for 8 hours to create a severe stress condition. Samples from the animals’ stomachs were arranged for microscopic and biochemical examinations. Results: Gastric mucosal injury was obvious in rats exposed to stress. The histopathologic damage score of the stress group (7.00±0.57) was higher than that of the control group (1.50±0.22) (p<0.05). Significant differences in histopathologic damage score were found between the stress and stress + parsley-added diet groups (p<0.05), the stress and stress + standard diet groups (p<0.05), and the stress and stress + LPZ groups (p<0.05). The mean tissue malondialdehyde levels of the stress + parsley-added group and the stress + LPZ group were lower than that of the stress group (p<0.05). Parsley supported the cellular antioxidant system by increasing the mean tissue glutathione level (53.31±9.50) and superoxide dismutase (15.18±1.05) and catalase (16.68±2.29) activities. Conclusion: Oral administration of parsley is effective in reducing stress-induced gastric injury by supporting the cellular antioxidant defence system. PMID:28251024

  14. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  15. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

    PubMed Central

    Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

    2015-01-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  16. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant.

    PubMed

    Monaris, D; Sbrogio-Almeida, M E; Dib, C C; Canhamero, T A; Souza, G O; Vasconcellos, S A; Ferreira, L C S; Abreu, P A E

    2015-08-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigA(C)) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigA(C), either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigA(C) or LigA(C) coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen.

  17. Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain

    PubMed Central

    Xie, Wenrui; Chen, Sisi; Strong, Judith A.; Li, Ai-Ling; Lewkowich, Ian P.

    2016-01-01

    Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro- and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a “microsympathectomy” by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions. SIGNIFICANCE STATEMENT Sympathetic blockade is used for many pain conditions, but preclinical studies show both pro- and anti-nociceptive effects. The sympathetic nervous system also has both pro- and anti-inflammatory effects on immune tissues and cells. We examined effects of a very localized sympathectomy. By cutting the gray rami to the spinal

  18. Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees.

    PubMed

    Steinmann, Nadja; Corona, Miguel; Neumann, Peter; Dainat, Benjamin

    2015-01-01

    The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee's susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions.

  19. Melatonin as a possible antidote to UV radiation induced cutaneous damages and immune-suppression: An overview.

    PubMed

    Goswami, Soumik; Haldar, Chandana

    2015-12-01

    The sun rays brings along the ultraviolet radiations (UVRs) which prove deleterious for living organisms. The UVR is a known mutagen and is the prime cause of skin carcinomas. UVR causes acute oxidative stress and this in turn deteriorates other physiological functions. Inflammatory conditions and elevation of pro-inflammatory molecules are also associated with UVR mediated cellular damages. The inflammatory conditions can secondarily trigger the generation of free radicals and this act cumulatively in further deterioration of tissue homeostasis. Photoimmunologists have also related UVR to the suppression of not only cutaneous but also systemic immunity by different mechanisms. Some researchers have proposed the use of various plant products as antioxidants against UVR induced oxidative imbalances but Melatonin is gaining rapid interest as a product that can be utilized to delineate the pathological effects of UVR since it is an established antioxidant. Besides the antioxidative nature, the capacity of melatonin to attenuate apoptosis and more importantly the efficacy of its metabolites to further aid in the detoxification of free radicals have made it a key player to be utilized against UVR mediated aggravated conditions. However, there is need for further extensive investigation to speculate melatonin as an antidote to UVR. Although too early to prescribe melatonin as a clinical remedy, the hormone can be integrated into dermal formulations or oral supplements to prevent the ever increasing incidences of skin cancers due to the prevalence of the UVR on the surface of the earth. The present review focuses and substantiates the work by different photo-biologists demonstrating the protective effects of melatonin and its metabolites against solar UVR - Melatonin as a possible antidote to UV radiation induced cutaneous damages and immune-suppression: an overview. J Photochem Photobiol B.

  20. Progesterone-based contraceptives reduce adaptive immune responses and protection against sequential influenza A virus infections.

    PubMed

    Hall, Olivia J; Nachbagauer, Raffael; Vermillion, Meghan S; Fink, Ashley L; Phuong, Vanessa; Krammer, Florian; Klein, Sabra L

    2017-02-08

    In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV), are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with mouse adapted (ma) H1N1 virus. Treatment with P4 or LNG reduced morbidity, but had no effect on pulmonary virus titers, during primary H1N1 infection as compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus neutralizing antibody titers, but not hemagglutinin stalk antibody titers, were lower in progestin-treated mice as compared with placebo-treated mice. Females were challenged six weeks later with either a maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. Protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as numbers and activity of H1N1- and H3N2-specific memory CD8+ T cells, including tissue resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased neutralizing and IgG antibody titers against both challenge viruses compared with placebo treatment. While the immunomodulatory properties of progestins protected naïve females against severe outcome from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history.IMPORTANCE The impact of hormone-based contraceptives on the outcome of infectious diseases outside of the reproductive tract is rarely considered. Using a mouse

  1. Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans

    PubMed Central

    Dreschers, Stephan; Saupp, Peter; Hornef, Mathias; Prehn, Andrea; Platen, Christopher; Morschhäuser, Joachim; Orlikowsky, Thorsten W.

    2016-01-01

    Background Invasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C.albicans initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO). Hypothesis Phagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLR-mediated immune responses. Methods The ability to phagocytose C. albicans, expression of TLRs, the induction of apoptosis (assessment of sub-G1 and nick-strand breaks) were analyzed by FACS. TLR signalling was induced by agonists such as lipopolysaccharide (LPS), Pam3Cys, FSL-1 and Zymosan and blocked (neutralizing TLR2 antibodies and MYD88 inhibitor). Results Phagocytic indices of PBMO and CBMO were similar. Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of MAP kinase P38 and expression of TNF-α, which were stronger on PBMO compared to CBMO (p < 0.005). Downstream, TLR2 signalling initiated caspase-3-dependent PICD which was found reduced in CBMO (p < 0.05 vs PBMO). Conclusion Our data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO. PMID:27870876

  2. Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route

    PubMed Central

    Carey, John B.; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V. S.; Draper, Simon J.; Moore, Anne C.

    2014-01-01

    Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP142, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP142 also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP142 using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies. PMID:25142082

  3. Inosine-Containing RNA Is a Novel Innate Immune Recognition Element and Reduces RSV Infection

    PubMed Central

    Liao, Jie-ying; Thakur, Sheetal A.; Zalinger, Zachary B.; Gerrish, Kevin E.; Imani, Farhad

    2011-01-01

    During viral infections, single- and double-stranded RNA (ssRNA and dsRNA) are recognized by the host and induce innate immune responses. The cellular enzyme ADAR-1 (adenosine deaminase acting on RNA-1) activation in virally infected cells leads to presence of inosine-containing RNA (Ino-RNA). Here we report that ss-Ino-RNA is a novel viral recognition element. We synthesized unmodified ssRNA and ssRNA that had 6% to16% inosine residues. The results showed that in primary human cells, or in mice, 10% ss-Ino-RNA rapidly and potently induced a significant increase in inflammatory cytokines, such as interferon (IFN)-β (35 fold), tumor necrosis factor (TNF)-α (9.7 fold), and interleukin (IL)-6 (11.3 fold) (p<0.01). Flow cytometry data revealed a corresponding 4-fold increase in influx of neutrophils into the lungs by ss-Ino-RNA treatment. In our in vitro experiments, treatment of epithelial cells with ss-Ino-RNA reduced replication of respiratory syncytial virus (RSV). Interestingly, RNA structural analysis showed that ss-Ino-RNA had increased formation of secondary structures. Our data further revealed that extracellular ss-Ino-RNA was taken up by scavenger receptor class-A (SR-A) which activated downstream MAP Kinase pathways through Toll-like receptor 3 (TLR3) and dsRNA-activated protein kinase (PKR). Our data suggests that ss-Ino-RNA is an as yet undescribed virus-associated innate immune stimulus. PMID:22028885

  4. Rational application of chemicals in response to oil spills may reduce environmental damage.

    PubMed

    Tamis, Jacqueline E; Jongbloed, Ruud H; Karman, Chris C; Koops, Wierd; Murk, Albertinka J

    2012-04-01

    Oil spills, for example those due to tanker collisions and groundings or platform accidents, can have huge adverse impacts on marine systems. The impact of an oil spill at sea depends on a number of factors, such as spill volume, type of oil spilled, weather conditions, and proximity to environmentally, economically, or socially sensitive areas. Oil spilled at sea threatens marine organisms, whole ecosystems, and economic resources in the immediate vicinity, such as fisheries, aquaculture, recreation, and tourism. Adequate response to any oil spill to minimize damage is therefore of great importance. The common response to an oil spill is to remove all visible oil from the water surface, either mechanically or by using chemicals to disperse the oil into the water column to biodegrade. This is not always the most suitable response to an oil spill, as the chemical application itself may also have adverse effects, or no response may be needed. In this article we discuss advantages and disadvantages of using chemical treatments to reduce the impact of an oil spill in relation to the conditions of the spill. The main characteristics of chemical treatment agents are discussed and presented within the context of a basic decision support scheme.

  5. Reflective Polyethylene Mulch Reduces Mexican Bean Beetle (Coleoptera: Coccinellidae) Densities and Damage in Snap Beans.

    PubMed

    Nottingham, L B; Kuhar, T P

    2016-08-01

    Mexican bean beetle, Epilachna varivestis Mulsant, is a serious pest of snap beans, Phaseolus vulgaris L., in the eastern United States. These beetles are intolerant to direct sunlight, explaining why individuals are typically found on the undersides of leaves and in the lower portion of the plant canopy. We hypothesized that snap beans grown on reflective, agricultural polyethylene (plastic mulch) would have fewer Mexican bean beetles and less injury than those grown on black plastic or bare soil. In 2014 and 2015, beans were seeded into beds of metallized, white, and black plastic, and bare soil, in field plots near Blacksburg, VA. Mexican bean beetle density, feeding injury, predatory arthropods, and snap bean yield were sampled. Reflected light intensity, temperature, and humidity were monitored using data loggers. Pyranometer readings showed that reflected light intensity was highest over metallized plastic and second highest over white plastic; black plastic and bare soil were similarly low. Temperature and humidity were unaffected by treatments. Significant reductions in Mexican bean beetle densities and feeding injury were observed in both metallized and white plastic plots compared to black plastic and bare soil, with metallized plastic having the fewest Mexican bean beetle life stages and injury. Predatory arthropod densities were not reduced by reflective plastic. Metallized plots produced the highest yields, followed by white. The results of this study suggest that growing snap beans on reflective plastic mulch can suppress the incidence and damage of Mexican bean beetle, and increase yield in snap beans.

  6. Low-Power 2-MHz Pulsed-Wave Transcranial Ultrasound Reduces Ischemic Brain Damage in Rats.

    PubMed

    Alexandrov, Andrei V; Barlinn, Kristian; Strong, Roger; Alexandrov, Anne W; Aronowski, Jaroslaw

    2011-09-01

    It is largely unknown whether prolonged insonation with ultrasound impacts the ischemic brain tissue by itself. Our goal was to evaluate safety and the effect of high-frequency ultrasound on infarct volume in rats. Thirty-two Long-Evans rats with permanent middle cerebral and carotid artery occlusions received either 2-MHz ultrasound at two levels of insonation power (128 or 10 mW) or no ultrasound (controls). We measured cerebral hemorrhage, indirect and direct infarct volume as well as edema volume at 24 h. No cerebral hemorrhages were detected in all animals. Exposure to low-power (10 mW) ultrasound resulted in a significantly decreased indirect infarct volume (p = 0.0039), direct infarct volume (p = 0.0031), and brain edema volume (p = 0.01) compared with controls. High-power (128 mW) ultrasound had no significant effects. An additional experiment with India ink showed a greater intravascular penetration of dye into ischemic tissues exposed to low-power ultrasound. Insonation with high-frequency, low-power ultrasound reduces ischemic brain damage in rat. Its effect on edema reduction and possible promotion of microcirculation could be used to facilitate drug and nutrient delivery to ischemic areas.

  7. Myocardial changes in acute Trypanosoma cruzi infection. Ultrastructural evidence of immune damage and the role of microangiopathy.

    PubMed Central

    Andrade, Z. A.; Andrade, S. G.; Correa, R.; Sadigursky, M.; Ferrans, V. J.

    1994-01-01

    Histological and ultrastructural studies of the hearts of dogs sacrificed 18 to 26 days after intraperitoneal inoculation with 4 x 10(5) blood forms of the 12 SF strain of Trypanosoma cruzi/kg of body weight disclosed myocarditis characterized by parasitic invasion of some myocytes, damage and necrosis of nonparasitized myocytes, and interstitial infiltration by mononuclear cells. Nonparasitized myocytes showed alterations ranging from mild edema to severe myocytolysis. These changes often were accompanied by contacts of myocytes with lymphocytes (both granular and agranular) and macrophages. These contacts were characterized by focal loss of the myocyte basement membrane and close approximation of the plasma membranes of the two cells. Contacts between lymphocytes and capillary endothelial cells were also frequent. Platelet aggregates and fibrin microthrombi were observed in some capillaries. Our findings suggest that immune effector cells play a major role in the pathogenesis of the myocyte damage and the microangiopathy in acute Chagas' disease. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:8203476

  8. Reduced Leukocyte Infiltration in Absence of Eosinophils Correlates with Decreased Tissue Damage and Disease Susceptibility in ΔdblGATA Mice during Murine Neurocysticercosis

    PubMed Central

    Mishra, Pramod K.; Li, Qun; Munoz, Luis E.; Mares, Chris A.; Morris, Elizabeth G.; Teale, Judy M.; Cardona, Astrid E.

    2016-01-01

    Neurocysticercosis (NCC) is one of the most common helminth parasitic diseases of the central nervous system (CNS) and the leading cause of acquired epilepsy worldwide. NCC is caused by the presence of the metacestode larvae of the tapeworm Taenia solium within brain tissues. NCC patients exhibit a long asymptomatic phase followed by a phase of symptoms including increased intra-cranial pressure and seizures. While the asymptomatic phase is attributed to the immunosuppressive capabilities of viable T. solium parasites, release of antigens by dying organisms induce strong immune responses and associated symptoms. Previous studies in T. solium-infected pigs have shown that the inflammatory response consists of various leukocyte populations including eosinophils, macrophages, and T cells among others. Because the role of eosinophils within the brain has not been investigated during NCC, we examined parasite burden, disease susceptibility and the composition of the inflammatory reaction in the brains of infected wild type (WT) and eosinophil-deficient mice (ΔdblGATA) using a murine model of NCC in which mice were infected intracranially with Mesocestoides corti, a cestode parasite related to T. solium. In WT mice, we observed a time-dependent induction of eosinophil recruitment in infected mice, contrasting with an overall reduced leukocyte infiltration in ΔdblGATA brains. Although, ΔdblGATA mice exhibited an increased parasite burden, reduced tissue damage and less disease susceptibility was observed when compared to infected WT mice. Cellular infiltrates in infected ΔdblGATA mice were comprised of more mast cells, and αβ T cells, which correlated with an abundant CD8+ T cell response and reduced CD4+ Th1 and Th2 responses. Thus, our data suggest that enhanced inflammatory response in WT mice appears detrimental and associates with increased disease susceptibility, despite the reduced parasite burden in the CNS. Overall reduced leukocyte infiltration due to

  9. Murine Corneal Inflammation and Nerve Damage After Infection With HSV-1 Are Promoted by HVEM and Ameliorated by Immune-Modifying Nanoparticle Therapy

    PubMed Central

    Edwards, Rebecca G.; Kopp, Sarah J.; Ifergan, Igal; Shui, Jr-Wen; Kronenberg, Mitchell; Miller, Stephen D.; Longnecker, Richard

    2017-01-01

    Purpose To determine cellular and temporal expression patterns of herpes virus entry mediator (HVEM, Tnfrsf14) in the murine cornea during the course of herpes simplex virus 1 (HSV-1) infection, the impact of this expression on pathogenesis, and whether alterations in HVEM or downstream HVEM-mediated effects ameliorate corneal disease. Methods Corneal HVEM levels were assessed in C57BL/6 mice after infection with HSV-1(17). Leukocytic infiltrates and corneal sensitivity loss were measured in the presence, global absence (HVEM knockout [KO] mice; Tnfrsf14−/−), or partial absence of HVEM (HVEM conditional KO). Effects of immune-modifying nanoparticles (IMPs) on viral replication, corneal sensitivity, and corneal infiltrates were measured. Results Corneal HVEM+ populations, particularly monocytes/macrophages during acute infection (3 days post infection [dpi]) and polymorphonuclear neutrophils (PMN) during the chronic inflammatory phase (14 dpi), increased after HSV-1 infection. Herpes virus entry mediator increased leukocytes in the cornea and corneal sensitivity loss. Ablation of HVEM from CD45+ cells, or intravenous IMP therapy, reduced infiltrates in the chronic phase and maintained corneal sensitivity. Conclusions Herpes virus entry mediator was expressed on two key populations: corneal monocytes/macrophages and PMNs. Herpes virus entry mediator promoted the recruitment of myeloid cells to the cornea in the chronic phase. Herpes virus entry mediator–associated corneal sensitivity loss preceded leukocytic infiltration, suggesting it may play an active role in recruitment. We propose that HVEM on resident corneal macrophages increases nerve damage and immune cell invasion, and we showed that prevention of late-phase infiltration of PMN and CD4+ T cells by IMP therapy improved clinical symptoms and mortality and reduced corneal sensitivity loss caused by HSV-1. PMID:28114589

  10. Reducing the Risks of Nonstructural Earthquake Damage: A Practical Guide. Earthquake Hazards Reduction Series 1.

    ERIC Educational Resources Information Center

    Reitherman, Robert

    The purpose of this booklet is to provide practical information to owners, operators, and occupants of office and commercial buildings on the vulnerabilities posed by earthquake damage to nonstructural items and the means available to deal with these potential problems. Examples of dangerous nonstructural damages that have occurred in past…

  11. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.

    PubMed

    Thiele, Kristin; Solano, M Emilia; Huber, Samuel; Flavell, Richard A; Kessler, Timo; Barikbin, Roja; Jung, Roman; Karimi, Khalil; Tiegs, Gisa; Arck, Petra C

    2015-10-01

    Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

  12. Hemagglutinin Stalk Immunity Reduces Influenza Virus Replication and Transmission in Ferrets

    PubMed Central

    Nachbagauer, Raffael; Miller, Matthew S.; Hai, Rong; Ryder, Alex B.; Rose, John K.; Palese, Peter; García-Sastre, Adolfo

    2015-01-01

    We assessed whether influenza virus hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 influenza virus infection. Immunization of ferrets by a universal influenza virus vaccine strategy based on viral vectors expressing chimeric hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no virus replication at all following natural exposure to influenza virus. PMID:26719251

  13. Non-immune mechanisms of muscle damage in myositis: Role of the endoplasmic reticulum stress response and autophagy in the disease pathogenesis

    PubMed Central

    Henriques-Pons, Andrea; Nagaraju, Kanneboyina

    2010-01-01

    Purpose of review Recent literature in inflammatory myopathies suggests that both immune (cell-mediated and humoral) and non-immune (endoplasmic reticulum (ER) stress and autophagy) mechanisms play a role in muscle fiber damage and dysfunction. This review describes these findings and discusses their relevance to disease pathogenesis and therapy. Recent findings Recent data highlights the role of ER stress response especially the roles of Hexose-6-phosphate dehydrogenase and ER-anchored RING finger E3 ligase in the activation of unfolded protein response and the formation of vacuoles and inclusions in myopathies. Several studies investigated the link between inflammation and the beta amyloid associated muscle fiber degeneration and loss of muscle function. Likewise, the roles of ER stress and autophagy in skeletal muscle damage have been explored in multiple muscle diseases. Summary Current data indicate that the ER stress, NF-kB pathway and autophagy are active in the skeletal muscle of myositis patients, and the pro-inflammatory NF-kB pathway connects the immune and non-immune pathways of muscle damage. The relative contributions of each of these pathways to muscle fiber damage are presently unclear. Therefore further defining the role of these pathways in disease pathogenesis should help to design effective therapeutic agents for these diseases. PMID:19713850

  14. Modelling the benefits of flood emergency management measures in reducing damages: a case study on Sondrio, Italy

    NASA Astrophysics Data System (ADS)

    Molinari, D.; Ballio, F.; Menoni, S.

    2013-08-01

    The European "Floods Directive" 2007/60/EU has produced an important shift from a traditional approach to flood risk management centred only on hazard analysis and forecast to a newer one which encompasses other aspects relevant to decision-making and which reflect recent research advances in both hydraulic engineering and social studies on disaster risk. This paper accordingly proposes a way of modelling the benefits of flood emergency management interventions calculating the possible damages by taking into account exposure, vulnerability, and expected damage reduction. The results of this model can be used to inform decisions and choices for the implementation of flood emergency management measures. A central role is played by expected damages, which are the direct and indirect consequence of the occurrence of floods in exposed and vulnerable urban systems. How damages should be defined and measured is a key question that this paper tries to address. The Floods Directive suggests that mitigation measures taken to reduce flood impact need to be evaluated also by means of a cost-benefit analysis. The paper presents a methodology for assessing the effectiveness of early warning for flash floods, considering its potential impact in reducing direct physical damage, and it assesses the general benefit in regard to other types of damages and losses compared with the emergency management costs. The methodology is applied to the case study area of the city of Sondrio in the northern Alpine region of Italy. A critical discussion follows the application. Its purpose is to highlight the strengths and weaknesses of available models for quantifying direct physical damage and of the general model proposed, given the current state of the art in damage and loss assessment.

  15. Ascorbic acid extends replicative life span of human embryonic fibroblast by reducing DNA and mitochondrial damages.

    PubMed

    Hwang, Won-Sang; Park, Seong-Hoon; Kim, Hyun-Seok; Kang, Hong-Jun; Kim, Min-Ju; Oh, Soo-Jin; Park, Jae-Bong; Kim, Jaebong; Kim, Sung Chan; Lee, Jae-Yong

    2007-01-01

    Ascorbic acid has been reported to extend replicative life span of human embryonic fibroblast (HEF). Since the detailed molecular mechanism of this phenomenon has not been investigated, we attempted to elucidate. Continuous treatment of HEF cells with ascorbic acid (at 200 microM) from 40 population doubling (PD) increased maximum PD numbers by 18% and lowered SA-beta-gal positive staining, an aging marker, by 2.3 folds, indicating that ascorbic acid extends replicative life span of HEF cells. Ascorbic acid treatment lowered DCFH by about 7 folds and Rho123 by about 70%, suggesting that ascorbic acid dramatically decreased ROS formation. Ascorbic acid also increased aconitase activity, a marker of mitochondrial aging, by 41%, indicating that ascorbic acid treatment restores age-related decline of mitochondrial function. Cell cycle analysis by flow cytometry revealed that ascorbic acid treatment decreased G1 population up to 12%. Further western blot analysis showed that ascorbic acid treatment decreased levels of p53, phospho-p53 at ser 15, and p21, indicating that ascorbic acid relieved senescence-related G1 arrest. Analysis of AP (apurinic/apyrimidinic) sites showed that ascorbic acid treatment decreased AP site formation by 35%. We also tested the effect of hydrogen peroxide treatment, as an additional oxidative stress. Continuous treatment of 20 microM of hydrogen peroxide from PD 40 of HEF cells resulted in premature senescence due to increased ROS level, and increased AP sites. Taken together, the results suggest that ascorbic acid extends replicative life span of HEF cells by reducing mitochondrial and DNA damages through lowering cellular ROS.

  16. Increasing Safety and Reducing Environmental Damage Risk from Aging High-Level Radioactive Waste Tanks

    SciTech Connect

    Steffler, Eric D.; McClintock, Frank A.; Lam, Poh-Sang; Williamson, Richard L.; Lloyd, W. R.; Rashid, Mark M.

    2003-06-01

    There exists a paramount need for improved understanding the behavior of high-level nuclear waste containers and the impact on structural integrity in terms of leak tightness and mechanical stability. The current program aims to develop and verify models of crack growth in high level waste tanks under accidental overloads such as ground settlement, earthquakes and airplane crashes based on extending current fracture mechanics methods. While studies in fracture have advanced, the mechanics have not included extensive crack growth. For problems at the INEEL, Savannah River Site and Hanford there are serious limitations to current theories regarding growth of surface cracks through the thickness and the extension of through-thickness cracks. We propose to further develop and extend slip line fracture mechanics (SLFM, a ductile fracture modeling methodology) and, if need be, other ductile fracture characterizing approaches with the goal of predicting growth of surface cracks to the point o f penetration of the opposing surface. Ultimately we aim to also quantify the stress and displacement fields surrounding a growing crack front (slanted and tunneled) using generalized plane stress and fully plastic, three-dimensional finite element analyses. Finally, we will investigate the fracture processes associated with the previously observed transition of stable ductile crack growth to unstable cleavage fracture to include estimates of event probability. These objectives will build the groundwork for a reliable predictive model of fracture in the HLW storage tanks that will also be applicable to standardized spent nuclear fuel storage canisters. This predictive capability will not only reduce the potential for severe environmental damage, but will also serve to guide safe retrieval of waste. This program was initiated in November of 2001.

  17. Increasing Safety and Reducing Environmental Damage Risk from Aging High-Level Radioactive Waste Tanks

    SciTech Connect

    Steffler, Eric D.; McClintock, Frank A.; Lam, Poh-Sang; Lloyd, W. R.

    2002-06-01

    There exists a paramount need for improved understanding the behavior of high-level nuclear waste containers and the impact on structural integrity in terms of leak tightness and mechanical stability. The current program, which at the time of this writing is in its early stages, aims to develop and verify models of crack growth in high level waste tanks under accidental overloads such as ground settlement, earthquakes and airplane crashes based on extending current fracture mechanics methods. While studies in fracture have advanced, the mechanics have not included extensive crack growth. For problems at the INEEL, Savannah River Site and Hanford there are serious limitations to current theories regarding growth of surface cracks through the thickness and the extension of through-thickness cracks. We propose to further develop and extend slip line fracture mechanics (SLFM, a ductile fracture modeling methodology) and, if need be, other ductile fracture characterizing approaches with the goal of predicting growth of surface cracks to the point of penetration of the opposing surface. We also aim to quantify the stress and displacement fields surrounding a growing crack front (slanted and tunneled) using generalized plane stress and fully plastic, three-dimensional finite element analyses. Finally, we will quantify the fracture processes associated with the previously observed transition of stable ductile crack growth to unstable cleavage fracture to include estimates of event probability. These objectives will build the groundwork for a reliable predictive model of fracture in the HLW storage tanks that will also be applicable to standardized spent nuclear fuel storage canisters. This predictive capability will not only reduce the potential for severe environmental damage, but will also serve to justify life extension through retrieval of waste. This program was initiated in November of 2001.

  18. Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus.

    PubMed

    Di Curzio, Domenico L; Buist, Richard J; Del Bigio, Marc R

    2013-10-01

    Hydrocephalus is a neurological condition characterized by altered cerebrospinal fluid (CSF) flow with enlargement of ventricular cavities in the brain. A reliable model of hydrocephalus in gyrencephalic mammals is necessary to test preclinical hypotheses. Our objective was to characterize the behavioral, structural, and histological changes in juvenile ferrets following induction of hydrocephalus. Fourteen-day old ferrets were given an injection of kaolin (aluminum silicate) into the cisterna magna. Two days later and repeated weekly until 56 days of age, magnetic resonance (MR) imaging was used to assess ventricle size. Behavior was examined thrice weekly. Compared to age-matched saline-injected controls, severely hydrocephalic ferrets weighed significantly less, their postures were impaired, and they were hyperactive prior to extreme debilitation. They developed significant ventriculomegaly and displayed white matter destruction. Reactive astroglia and microglia detected by glial fibrillary acidic protein (GFAP) and Iba-1 immunostaining were apparent in white matter, cortex, and hippocampus. There was a hydrocephalus-related increase in activated caspase 3 labeling of apoptotic cells (7.0 vs. 15.5%) and a reduction in Ki67 labeling of proliferating cells (23.3 vs. 5.9%) in the subventricular zone (SVZ). Reduced Olig2 immunolabeling suggests a depletion of glial precursors. GFAP content was elevated. Myelin basic protein (MBP) quantitation and myelin biochemical enzyme activity showed early maturational increases. Where white matter was not destroyed, the remaining axons developed myelin similar to the controls. In conclusion, the hydrocephalus-induced periventricular disturbances may involve developmental impairments in cell proliferation and glial precursor cell populations. The ferret should prove useful for testing hypotheses about white matter damage and protection in the immature hydrocephalic brain.

  19. Diet enriched with procyanidins enhances antioxidant activity and reduces myocardial post-ischaemic damage in rats.

    PubMed

    Facino, R M; Carini, M; Aldini, G; Berti, F; Rossoni, G; Bombardelli, E; Morazzoni, P

    1999-01-01

    Aim of this work was to study the efficacy of procyanidins from Vitis vinifera seeds, a standardized mixture of polyphenol antioxidants, on cardiac mechanics following ischemia/reperfusion stunning in the rat, after 3 weeks supplementation. Young and aged male rats were fed a diet enriched with procyanidins complexed (1:3 w/w) with soybean lecithin (2.4%); control animals (CTR-young and CTR-aged) received an equal amount of lecithin and 2 additional groups of animals the standard diet. At the end of the treatment, the total plasma antioxidant defense (TRAP), vitamin E, ascorbic acid and uric acid were determined in plasma and the hearts from all groups of animals subjected to moderate ischemia (flow reduction to 1 ml/min for 20 min) and reperfusion (15 ml/min for 30 min). In both young and aged rats supplemented with procyanidins the recovery of left ventricular developed pressure (LVDP) at the end of reperfusion was 93% (p < 0.01) and 74% (p < 0.01) of the preischemic values and the values of coronary perfusion pressure (CPP) were maintained close to those of the preischemic period. Also creatine kinase (CK) outflow was restrained to baseline levels, while a 2-fold increase in prostacyclin (6-keto-PGF1alpha) in the perfusate from hearts of young and aged rats was elicited during both ischemia and reperfusion. In parallel, procyanidins significantly increased the total antioxidant plasma capacity (by 40% in young and by 30% in aged rats) and the plasma levels of ascorbic acid, while tend to reduce vitamin E levels; no significant differences were observed in uric acid levels. The results of this study demonstrate that procyanidins supplementation in the rat (young and aged) makes the heart less susceptible to ischemia/reperfusion damage and that this is positively associated to an increase in plasma antioxidant activity.

  20. Cinnamaldehyde enhances in vitro parameters of immunity and reduces in vivo infection against avian coccidiosis.

    PubMed

    Lee, Sung Hyen; Lillehoj, Hyun S; Jang, Seung I; Lee, Kyung Woo; Park, Myeong Seon; Bravo, David; Lillehoj, Erik P

    2011-09-01

    The effects of cinnamaldehyde (CINN) on in vitro parameters of immunity and in vivo protection against avian coccidiosis were evaluated. In vitro stimulation of chicken spleen lymphocytes with CINN (25-400 ng/ml) induced greater cell proliferation compared with the medium control (P < 0·001). CINN activated cultured macrophages to produce higher levels of NO at 1·2-5·0 μg/ml (P < 0·001), inhibited the growth of chicken tumour cells at 0·6-2·5 μg/ml (P < 0·001) and reduced the viability of Eimeria tenella parasites at 10 and 100 μg/ml (P < 0·05 and P < 0·001, respectively), compared with media controls. In chickens fed a diet supplemented with CINN at 14·4 mg/kg, the levels of IL-1β, IL-6, IL-15 and interferon-γ transcripts in intestinal lymphocytes were 2- to 47-fold higher (P < 0·001) compared with chickens given a non-supplemented diet. To determine the effect of CINN diets on avian coccidiosis, chickens were fed diets supplemented with CINN at 14·4 mg/kg (E. maxima or E. tenella) or 125 mg/kg (E. acervulina) from hatch for 24 d, and orally infected with 2·0 × 10(4) sporulated oocysts at age 14 d. CINN-fed chickens showed 16·5 and 41·6 % increased body-weight gains between 0-9 d post-infection (DPI) with E. acervulina or E. maxima, reduced E. acervulina oocyst shedding between 5-9 DPI and increased E. tenella-stimulated parasite antibody responses at 9 DPI compared with controls.

  1. Increased colostral somatic cell counts reduce pre-weaning calf immunity, health and growth.

    PubMed

    Ferdowsi Nia, E; Nikkhah, A; Rahmani, H R; Alikhani, M; Mohammad Alipour, M; Ghorbani, G R

    2010-10-01

    Our objective was to study the relationships between colostral somatic cell counts (SCC, a criterion for mastitis severity at parturition) and early calf growth, blood indicators of immunity, and pre-weaning faecal and health states. Sixty-nine Holstein cows were assigned to three groups of greater (n = 21, 5051 × 10(3)), medium (n = 38, 2138 × 10(3)) and lower (n = 10, 960 × 10(3)) colostral SCC (per ml) in a completely randomized design. Calves received 2 l of colostrum on day 1, and jugular blood was sampled at birth, at 3 h after the first colostrum feeding and at 42 days of age for immunoglobulin G (IgG) measurements. Calves were fed transition milk from their dams until 3 days of age and whole milk from 4 to 60 days of age twice daily at 10% of body weight. Health status and faecal physical scores were recorded daily for 42 days. Increased colostral SCC was associated with increased serum IgG at parturition. Colostral pH increased and fat percentage decreased linearly with the rising SCC. Feeding colostrum with greater SCC was associated with reduced serum IgG concentrations at 3 h after first colostrum feeding, greater incidences of diarrhoea and compromised health status during the first 42 days of age, and reduced weaning weight gain, but had no effects on calf body length and withers height. Colostral volume and percentages of protein, lactose, solids-non-fat, total solids and IgG were comparable among groups. Results suggest a role for SCC, as an indicator of mastitis and colostral health quality, in affecting calf health. As a result of the novelty of calf health dependence on colostral SCC found, future studies to further characterize such relationships and to uncover or rule out possible mediators are required before colostral SCC could be recommended for routine on-farm use in managing dry cow and calf production.

  2. Effect of β-carotene on catechol-induced genotoxicity in vitro: evidence of both enhanced and reduced DNA damage.

    PubMed

    Åsgård, R; Hellman, B

    2013-09-01

    Intake of antioxidants from the diet has been recognized to have beneficial health effects, but the potential benefit of taking antioxidants such as β-carotene as supplements is controversial. The aim of the present study was to evaluate the potential protective effects of a physiologically relevant concentration (2 μM) of β-carotene on the DNA damaging effects of catechol in mouse lymphoma L5178Y cells. Two different exposure protocols were used: simultaneous exposure to β-carotene and catechol for 3 h; and exposure to catechol for 3 h after 18 h pre-treatment with the vitamin. DNA damage was evaluated using the comet assay (employing one procedure for general damage, and another procedure, which also included oxidative DNA damage). Independent of exposure protocol and procedure for comet assay, β-carotene did not increase the basal level of DNA damage. However, at the highest concentration of catechol (1 mM), β-carotene was found to clearly increase the level of catechol-induced DNA damage, especially in the pre-treated cells. Interestingly, an opposite effect was observed at lower concentrations of catechol, but the β-carotene related reduction of catechol-induced genotoxicity was significant (P < 0.05) only for the procedure including oxidative damage induced by 0.5 mM catechol. Taken together our results indicate that β- carotene can both reduce and enhance the DNA damaging effects of a genotoxic agent such as catechol. This indicates that it is the level of catechol-induced DNA damage that seems to determine whether β-carotene should be regarded as a beneficial or detrimental agent when it comes to its use as a dietary supplement.

  3. Dynamics of animal movement in an ecological context: dragonfly wing damage reduces flight performance and predation success

    PubMed Central

    Combes, S. A.; Crall, J. D.; Mukherjee, S.

    2010-01-01

    Much of our understanding of the control and dynamics of animal movement derives from controlled laboratory experiments. While many aspects of animal movement can be probed only in these settings, a more complete understanding of animal locomotion may be gained by linking experiments on relatively simple motions in the laboratory to studies of more complex behaviours in natural settings. To demonstrate the utility of this approach, we examined the effects of wing damage on dragonfly flight performance in both a laboratory drop–escape response and the more natural context of aerial predation. The laboratory experiment shows that hindwing area loss reduces vertical acceleration and average flight velocity, and the predation experiment demonstrates that this type of wing damage results in a significant decline in capture success. Taken together, these results suggest that wing damage may take a serious toll on wild dragonflies, potentially reducing both reproductive success and survival. PMID:20236968

  4. Dynamics of animal movement in an ecological context: dragonfly wing damage reduces flight performance and predation success.

    PubMed

    Combes, S A; Crall, J D; Mukherjee, S

    2010-06-23

    Much of our understanding of the control and dynamics of animal movement derives from controlled laboratory experiments. While many aspects of animal movement can be probed only in these settings, a more complete understanding of animal locomotion may be gained by linking experiments on relatively simple motions in the laboratory to studies of more complex behaviours in natural settings. To demonstrate the utility of this approach, we examined the effects of wing damage on dragonfly flight performance in both a laboratory drop-escape response and the more natural context of aerial predation. The laboratory experiment shows that hindwing area loss reduces vertical acceleration and average flight velocity, and the predation experiment demonstrates that this type of wing damage results in a significant decline in capture success. Taken together, these results suggest that wing damage may take a serious toll on wild dragonflies, potentially reducing both reproductive success and survival.

  5. Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage

    PubMed Central

    Quispe Calla, Nirk E.; Pavelko, Stephen D.; Cherpes, Thomas L.

    2016-01-01

    While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response. PMID:27606424

  6. Reducing Mechanical Formation Damage by Minimizing Interfacial Tension and Capillary Pressure in Tight Gas

    NASA Astrophysics Data System (ADS)

    Ahmed, Arshad; Talib Shuker, Muhannad; Rehman, Khalil; Bahrami, Hassan; Memon, Muhammad Khan

    2013-12-01

    Tight gas reservoirs incur problems and significant damage caused by low permeability during drilling, completion, stimulation and production. They require advanced improvement techniques to achieve flow gas at optimum rates. Water blocking damage (phase Trapping/retention of fluids) is a form of mechanical formation damage mechanism, which is caused by filtrate invasion in drilling operations mostly in fracturing. Water blocking has a noticeable impact on formation damage in gas reservoirs which tends to decrease relative permeability near the wellbore. Proper evaluation of damage and the factors which influence its severity is essential to optimize well productivity. Reliable data regarding interfacial tension between gas and water is required in order to minimize mechanical formation damage potential and to optimize gas production. This study was based on the laboratory experiments of interfacial tension by rising drop method between gas-brine, gas-condensate and gas-brine. The results showed gas condensate has low interfacial tension value 6 - 11 dynes/cm when compared to gas-brine and gas- diesel which were 44 - 58 dynes/cm and 14 - 19 dynes/cm respectively. In this way, the capillary pressure of brine-gas system was estimated as 0.488 psi, therefore diesel-gas system was noticed about 0.164 psi and 0.098 psi for condensate-gas system. A forecast model was used by using IFT values to predict the phase trapping which shows less severe phase trapping damage in case of condensate than diesel and brine. A reservoir simulation study was also carried out in order to better understand the effect of hysteresis on well productivity and flow efficiency affected due to water blocking damage in tight gas reservoirs.

  7. Protective effects of melatonin against the damages of neuroendocrine-immune induced by lipopolysaccharide in diabetic rats.

    PubMed

    Zhong, L-Y; Yang, Z-H; Li, X-R; Wang, H; Li, L

    2009-10-01

    The present study was to determine the protective effects of melatonin (MLT) against the damages of neuroendocrine-immune induced by lipopolysaccharide (LPS) in streptozotocin (STZ)-induced diabetic rats, and to analyze the parameters related to diabetes and oxidative stress. A total of 70 male Sprague-Dawley rats were assigned to this experiment. 10 of rats received STZ intraperitoneally (i.p.) alone as diabetic control; 40 of rats as the Diabetes+LPS received STZ plus LPS i.p. after induction of diabetes with STZ, then assigned to sub-groups as MLT (0.1) (mg), MLT (1) (mg), and Vehicle group, received two doses MLT and vehicle, i.p., respectively, q6 h for 12 h after LPS administration; and the remaining served as normal and LPS control. LPS significantly increased the serum levels of TNF-alpha and IL-6 in normal and diabetic rats; LPS also dramatically increased the plasma concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone. Both 0.1 and 1 mg/kg MLT doses significantly decreased the serum levels of TNF-alpha and IL-6. Significant inhibitory effects of MLT (1 mg/kg) were observed on the plasma concentrations of CRH, ACTH, and corticosterone of the HPA axis. The beneficial effects of MLT, such as the antioxidant activity and maintaining glucose homoeostasis, were also observed in this study, this resulted in a protective effect against the damages caused by LPS in STZ-induced diabetic rats. This finding probably provides a new approach for preventing the undesirable effects of the vicious cycle of hyperglycemia and stress factors such as severe infection in diabetic patients.

  8. Platelet Apoptosis in Adult Immune Thrombocytopenia: Insights into the Mechanism of Damage Triggered by Auto-Antibodies

    PubMed Central

    Goette, Nora P.; Glembotsky, Ana C.; Lev, Paola R.; Grodzielski, Matías; Contrufo, Geraldine; Pierdominici, Marta S.; Espasandin, Yesica R.; Riveros, Dardo; García, Alejandro J.; Molinas, Felisa C.; Heller, Paula G.

    2016-01-01

    Mechanisms leading to decreased platelet count in immune thrombocytopenia (ITP) are heterogeneous. This study describes increased platelet apoptosis involving loss of mitochondrial membrane potential (ΔΨm), caspase 3 activation (aCasp3) and phosphatidylserine (PS) externalization in a cohort of adult ITP patients. Apoptosis was not related to platelet activation, as PAC-1 binding, P-selectin exposure and GPIb-IX internalization were not increased. Besides, ITP platelets were more sensitive to apoptotic stimulus in terms of aCasp3. Incubation of normal platelets with ITP plasma induced loss of ΔΨm, while PS exposure and aCasp3 remained unaltered. The increase in PS exposure observed in ITP platelets could be reproduced in normal platelets incubated with ITP plasma by adding normal CD3+ lymphocytes to the system as effector cells. Addition of leupeptin -a cathepsin B inhibitor- to this system protected platelets from apoptosis. Increased PS exposure was also observed when normal platelets and CD3+ lymphocytes were incubated with purified IgG from ITP patients and was absent when ITP plasma was depleted of auto-antibodies, pointing to the latter as responsible for platelet damage. Apoptosis was present in platelets from all patients carrying anti-GPIIb-IIIa and anti-GPIb auto-antibodies but was absent in the patient with anti-GPIa-IIa auto-antibodies. Platelet damage inversely correlated with platelet count and decreased during treatment with a thrombopoietin receptor agonist. These results point to a key role for auto-antibodies in platelet apoptosis and suggest that antibody-dependent cell cytotoxicity is the mechanism underlying this phenomenon. PMID:27494140

  9. Experimentally activated immune defence in female pied flycatchers results in reduced breeding success.

    PubMed

    Ilmonen, P; Taarna, T; Hasselquist, D

    2000-04-07

    Traditional explanations for the negative fitness consequences of parasitism have focused on the direct pathogenic effects of infectious agents. However, because of the high selection pressure by the parasites, immune defences are likely to be costly and trade off with other fitness-related traits, such as reproductive effort. In a field experiment, we immunized breeding female flycatchers with non-pathogenic antigens (diphtheria-tetanus vaccine), which excluded the direct negative effects of parasites, in order to test the consequences of activated immune defence on hosts' investment in reproduction and self-maintenance. Immunized females decreased their feeding effort and investment in self-maintenance (rectrix regrowth) and had lower reproductive output (fledgling quality and number) than control females injected with saline. Our results reveal the phenotypic cost of immune defence by showing that an activated immune system per se can lower the host's breeding success. This may be caused by an energetic or nutritional trade-off between immune function and physical workload when feeding young or be an adaptive response to 'infection' to avoid physiological disorders such as oxidative stress and immunopathology.

  10. Reproductive state, but not testosterone, reduces immune function in male house sparrows (Passer domesticus).

    PubMed

    Greenman, Chris G; Martin, Lynn B; Hau, Michaela

    2005-01-01

    The immune system requires energetic and nutritional resources to optimally defend organisms against pathogens and parasites. Because resources are typically limited, immune function may require a trade-off with other physiologically demanding activities. Here, we examined whether photoperiodically induced seasonal states (breeding, molting, or nonbreeding) affected the cutaneous immune response of captive male house sparrows (Passer domesticus). To assess immune function in these birds, we injected the mitogen phytohemagglutinin (PHA) into the patagium and measured the resulting wing web swelling. Molting and nonbreeding birds had similar immune responses to PHA injection. However, males in a breeding state showed lower immune responses than both molting and nonbreeding birds even though they did not actually breed. We tested whether this decrease in the PHA swelling response in birds in a breeding state was due to elevated plasma concentrations of testosterone (T) by administering T to birds in a nonbreeding state. Contrary to some evidence in the literature, T did not suppress the response to PHA in house sparrows. Our data show that passerine birds show seasonal modulation in immune function, even in benign environmental conditions. However, even though T is often cited as a strong immunosuppressant, it is not fully responsible for this seasonal modulation.

  11. Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees

    PubMed Central

    Steinmann, Nadja; Corona, Miguel; Neumann, Peter; Dainat, Benjamin

    2015-01-01

    The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee’s susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions. PMID:26121358

  12. Can radiation damage to protein crystals be reduced using small-molecule compounds?

    PubMed Central

    Kmetko, Jan; Warkentin, Matthew; Englich, Ulrich; Thorne, Robert E.

    2011-01-01

    Recent studies have defined a data-collection protocol and a metric that provide a robust measure of global radiation damage to protein crystals. Using this protocol and metric, 19 small-molecule compounds (introduced either by cocrystalliz­ation or soaking) were evaluated for their ability to protect lysozyme crystals from radiation damage. The compounds were selected based upon their ability to interact with radiolytic products (e.g. hydrated electrons, hydrogen, hydroxyl and perhydroxyl radicals) and/or their efficacy in protecting biological molecules from radiation damage in dilute aqueous solutions. At room temperature, 12 compounds had no effect and six had a sensitizing effect on global damage. Only one compound, sodium nitrate, appeared to extend crystal lifetimes, but not in all proteins and only by a factor of two or less. No compound provided protection at T = 100 K. Scavengers are ineffective in protecting protein crystals from global damage because a large fraction of primary X-ray-induced excitations are generated in and/or directly attack the protein and because the ratio of scavenger molecules to protein molecules is too small to provide appreciable competitive protection. The same reactivity that makes some scavengers effective radioprotectors in protein solutions may explain their sensitizing effect in the protein-dense environment of a crystal. A more productive focus for future efforts may be to identify and eliminate sensitizing compounds from crystallization solutions. PMID:21931220

  13. Vitamin E-coated dialysis membranes reduce the levels of oxidative genetic damage in hemodialysis patients.

    PubMed

    Rodríguez-Ribera, Lara; Corredor, Zuray; Silva, Irene; Díaz, Juan Manuel; Ballarín, José; Marcos, Ricard; Pastor, Susana; Coll, Elisabet

    2017-03-01

    End-stage renal disease patients present oxidative stress status that increases when they are submitted to hemodialysis (HD). This increase in oxidative stress can affect their genetic material, among other targets. The objective of this study was to evaluate the effect of using polysulfone membranes coated with vitamin E, during the HD sessions, on the levels of genetic damage of HD patients. Forty-six patients were followed for 6 months, of whom 29 changed from conventional HD to the use of membranes coated with vitamin E. The level of genetic damage was measured using the micronucleus and the comet assays, both before and after the follow-up period. Serum vitamin E concentration was also checked. The obtained results showed that 24% of our patients presented vitamin E deficiency, and this was normalized in those patients treated with vitamin E-coated membranes. Patients with vitamin E deficiency showed higher levels of oxidative DNA damage. After the use of vitamin E-coated membranes we detected a significant decrease in the levels of oxidative damage. Additionally, hemoglobin values increased significantly with the use of vitamin E-coated membranes. In conclusion, the use of vitamin E-coated membranes supposes a decrease on the levels of oxidative DNA damage, and improves the uremic anemia status. Furthermore, the use of this type of membrane was also effective in correcting vitamin E deficiency.

  14. Camel milk lactoferrin reduces the proliferation of colorectal cancer cells and exerts antioxidant and DNA damage inhibitory activities.

    PubMed

    Habib, Hosam M; Ibrahim, Wissam H; Schneider-Stock, Regine; Hassan, Hassan M

    2013-11-01

    Lactoferrin (Lf), the main iron-binding protein of milk, has biological activities. We have evaluated the potential of camel milk lactoferrin for its ability to inhibit the proliferation of the colon cancer cell line, HCT-116, in vitro, DNA damage and its antioxidant activities for the first time. The antioxidant capacity of Lf was evaluated by different assays, including ferric-reducing/antioxidant power assay (FRAP), free radical-scavenging activity (DPPH), nitric oxide (NO) radical-scavenging assay, total antioxidant activity and DNA damage, compared with vitamin C and rutin.

  15. A novel small-molecule enantiomeric analogue of traditional (-)-morphinans has specific TLR9 antagonist properties and reduces sterile inflammation-induced organ damage.

    PubMed

    Hoque, Rafaz; Farooq, Ahmad; Malik, Ahsan; Trawick, Bobby N; Berberich, David W; McClurg, Joseph P; Galen, Karen P; Mehal, Wajahat

    2013-04-15

    TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (-)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small-molecule antagonist of TLR9 with greater specificity for TLR9 than oligo-based antagonists. COV08-0064 has wide bioavailability, including the s.c. and oral routes. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9-mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan-based novel small-molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury.

  16. A Novel Small Molecule Enantiomeric Analogue of Traditional (−)-morphinans has Specific TLR9 Antagonist Properties and Reduces Sterile Inflammation Induced Organ Damage

    PubMed Central

    Hoque, Rafaz; Farooq, Ahmad; Malik, Ahsan; Trawick, Bobby N.; Berberich, David W.; McClurg, Joseph P.; Galen, Karen P.; Mehal, Wajahat

    2013-01-01

    TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (−)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small molecule antagonist of TLR9 with greater specificity for TLR9 than oligo based antagonists. COV08-0064 has wide bioavailability, including the subcutaneous and per oral route. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9 mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan based novel small molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury. PMID:23509352

  17. Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

    PubMed Central

    Miska, Jason; Abdulreda, Midhat H.; Devarajan, Priyadharshini; Lui, Jen Bon; Suzuki, Jun; Pileggi, Antonello; Berggren, Per-Olof

    2014-01-01

    Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell–mediated damage and protection of pancreatic islet grafts. Both CD4+ and CD8+ effector T (Teff) lymphocytes directly engaged target cells. Strikingly, juxtaposed β cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3+ regulatory T (Treg) cells persistently contacted Teff cells with or without involvement of CD11c+ dendritic cells, an observation conciliating with the in vitro “trademark” of Treg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings. PMID:24567447

  18. Damage Characterization Method for Structural Health Management Using Reduced Number of Sensor Inputs

    NASA Technical Reports Server (NTRS)

    Krishnamurthy, T.; Hochhalter, Jacob D.; Gallegos, Adam M.

    2012-01-01

    The development of validated multidisciplinary Integrated Vehicle Health Management (IVHM) tools, technologies, and techniques to enable detection, diagnosis, prognosis, and mitigation in the presence of adverse conditions during flight will provide effective solutions to deal with safety related challenges facing next generation aircraft. The adverse conditions include loss of control caused by environmental factors, actuator and sensor faults or failures, and damage conditions. A major concern in these structures is the growth of undetected damage (cracks) due to fatigue and low velocity foreign impacts that can reach a critical size during flight, resulting in loss of control of the aircraft. Hence, development of efficient methodologies to determine the presence, location, and severity of damage in critical structural components is highly important in developing efficient structural health management systems.

  19. A padding method to reduce edge effects for enhanced damage identification using wavelet analysis

    NASA Astrophysics Data System (ADS)

    Montanari, Lorenzo; Basu, Biswajit; Spagnoli, Andrea; Broderick, Brian M.

    2015-02-01

    Vibration response based structural damage identification by spatial wavelet analysis is widely considered a powerful tool in Structural Health Monitoring (SHM). This work deals with the issue of border distortions in wavelet transform that can mask tiny damages close to the boundary of a structure. Since traditional padding methods (e.g., zero-padding, symmetric padding, linear padding) are often not satisfactory, a simple and computationally inexpensive signal extension method, based on fitting polynomial functions and continuity conditions at the extrema, is proposed. The method is applied to analyze noisy mode shapes and static deflection of cracked cantilever and simply supported beams. The effectiveness and the versatility of the method in localizing tiny damages close to clamped, free or hinged beam boundaries is demonstrated. Furthermore, an extensive comparison with the linear padding method and Messina's isomorphism methods is carried out.

  20. Can radiation damage to protein crystals be reduced using small-molecule compounds?

    SciTech Connect

    Kmetko, Jan; Warkentin, Matthew; Englich, Ulrich; Thorne, Robert E.

    2011-10-01

    Free-radical scavengers that are known to be effective protectors of proteins in solution are found to increase global radiation damage to protein crystals. Protective mechanisms may become deleterious in the protein-dense environment of a crystal. Recent studies have defined a data-collection protocol and a metric that provide a robust measure of global radiation damage to protein crystals. Using this protocol and metric, 19 small-molecule compounds (introduced either by cocrystallization or soaking) were evaluated for their ability to protect lysozyme crystals from radiation damage. The compounds were selected based upon their ability to interact with radiolytic products (e.g. hydrated electrons, hydrogen, hydroxyl and perhydroxyl radicals) and/or their efficacy in protecting biological molecules from radiation damage in dilute aqueous solutions. At room temperature, 12 compounds had no effect and six had a sensitizing effect on global damage. Only one compound, sodium nitrate, appeared to extend crystal lifetimes, but not in all proteins and only by a factor of two or less. No compound provided protection at T = 100 K. Scavengers are ineffective in protecting protein crystals from global damage because a large fraction of primary X-ray-induced excitations are generated in and/or directly attack the protein and because the ratio of scavenger molecules to protein molecules is too small to provide appreciable competitive protection. The same reactivity that makes some scavengers effective radioprotectors in protein solutions may explain their sensitizing effect in the protein-dense environment of a crystal. A more productive focus for future efforts may be to identify and eliminate sensitizing compounds from crystallization solutions.

  1. Pest tradeoffs in technology: Reduced damage by caterpillars in Bt cotton benefits aphids.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A number of studies have now reported increased levels of non Bt-targeted secondary pests in Bt crops. We carried out a series of greenhouse and field experiments comparing aphid populations on Bt-and non Bt-cotton that were damaged by the Bt-targeted caterpillar, Heliothis virescens. We found in bo...

  2. Oral tungstate (Na2WO4) exposure reduces adaptive immune responses in mice after challenge.

    PubMed

    Osterburg, Andrew R; Robinson, Chad T; Mokashi, Vishwesh; Stockelman, Michael; Schwemberger, Sandy J; Chapman, Gail; Babcock, George F

    2014-01-01

    Tungstate (WO²⁻₄) has been identified as a ground water contaminant at military firing ranges and can be absorbed by ingestion. In this study, C57BL6 mice were exposed to sodium tungstate (Na2WO4·2H2O) (0, 2, 62.5, 125, and 200 mg/kg/day) in their drinking water for an initial 28-day screen and in a one-generation (one-gen) model. Twenty-four hours prior to euthanasia, mice were intraperitoneally injected with Staphylococcal enterotoxin B (SEB) (20 μg/mouse) or saline as controls. After euthanasia, splenocytes and blood were collected and stained with lymphocyte and/or myeloid immunophenotyping panels and analyzed by flow cytometry. In the 28-day and one-gen exposure, statistically significant reductions were observed in the quantities of activated cytotoxic T-cells (TCTL; CD3(+)CD8(+)CD71(+)) and helper T-cells (TH; CD3(+)CD4(+)CD71(+)) from spleens of SEB-treated mice. In the 28-day exposures, CD71(+) TCTL cells were 12.87 ± 2.05% (SE) in the 0 tungstate (control) group compared to 4.44 ± 1.42% in the 200 mg/kg/day (p < 0.001) group. TH cells were 4.85 ± 1.23% in controls and 2.76 ± 0.51% in the 200 mg/kg/day (p < 0.003) group. In the one-gen exposures, TCTL cells were 7.98 ± 0.49% and 6.33 ± 0.49% for P and F1 mice after 0 mg/kg/day tungstate vs 1.58 ± 0.23% and 2.52 ± 0.25% after 200 mg/kg/day of tungstate (p < 0.001). Similarly, TH cells were reduced to 6.21 ± 0.39% and 7.20 ± 0.76%, respectively, for the 0 mg/kg/day P and F1 mice, and 2.28 ± 0.41% and 2.85 ± 0.53%, respectively, for the 200 mg/kg/day tungstate P and F1 groups (p < 0.001). In delayed-type hypersensitivity Type IV experiments, tungstate exposure prior to primary and secondary antigen challenge significantly reduced footpad swelling at 20 and 200 mg/kg/day. These data indicate that exposure to tungstate can result in immune suppression that may, in turn, reduce host defense against

  3. Dietary oils modify the host immune response and colonic tissue damage following Citrobacter rodentium infection in mice.

    PubMed

    Hekmatdoost, Azita; Wu, Xiujuan; Morampudi, Vijay; Innis, Sheila M; Jacobson, Kevan

    2013-05-15

    Inflammatory bowel disease is an intestinal inflammatory disorder of multifactorial origin, in which diets that favor high n-6 and low n-3 fatty acids have been implicated. The present study addressed whether dietary n-6 and n-3 fatty acids alter colonic mucosal response to Citrobacter rodentium (C. rodentium) infection. Mice were fed diets identical except for fatty acids, with an energy percentage of 15% 18:2n-6 and <0.06% 18:3n-3, 4.2% 18:2n-6 and 1.9% 18:3n-3, or 1.44% 20:5n-3, 4.9% 22:6n-3, 0.32% 18:2n-6, and 0.12% 18:3n-3 from safflower, canola, or fish oil, respectively for 3 wk before infection. Dietary oils had no effect on colonic C. rodentium growth but altered colon 20:4n-6/(20:5n-3+22:6n-3) with 9.40 ± 0.06, 1.94 ± 0.08, and 0.32 ± 0.03% in colon phosphatidylcholine and 3.82 ± 0.18, 1.14 ± 0.02, and 0.30 ± 0.02% in phosphatidylethanolamine of mice fed safflower, canola, or fish oil, respectively. At 10 days postinfection, histological damage, F4/80-positive macrophages, and myeloperoxidase-positive neutrophils in colonic mucosa were higher in infected mice fed safflower than fish oil. Colon gene transcripts for macrophage inflammatory protein 2, keratinocyte cytokine, and monocyte chemoattractant protein 1 expression were significantly higher in infected mice fed safflower than canola or fish oil; IFN-γ, IL-6, and IL-17A expression were significantly elevated in mice fed safflower rather than fish oil; and IL-10 was significantly higher in mice fed fish oil rather than canola or safflower oil. This study demonstrates that oils high in 18:2n-6 with minimal n-3 fatty acids exacerbate mucosal immune response, whereas oils high in n-3 fatty acids attenuate mucosal immune response to C. rodentium. These studies implicate dietary oils as environmental modifiers of intestinal inflammation in response to infection.

  4. L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.

    PubMed

    Shao, Lan; Li, Qing-Huan; Tan, Zheng

    2004-11-12

    Telomere is the repetitive DNA sequence at the end of chromosomes, which shortens progressively with cell division and limits the replicative potential of normal human somatic cells. L-carnosine, a naturally occurring dipeptide, has been reported to delay the replicative senescence, and extend the lifespan of cultured human diploid fibroblasts. In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine.

  5. A flexure-based steerable needle: high curvature with reduced tissue damage.

    PubMed

    Swaney, Philip J; Burgner, Jessica; Gilbert, Hunter B; Webster, Robert J

    2013-04-01

    In the quest to design higher curvature bevel-steered needles, kinked bevel-tips have been one of the most successful approaches yet proposed. However, the price to be paid for enhancing steerability in this way has been increased tissue damage, since the prebent tip cuts a local helical path into tissue when axially rotated. This is problematic when closed-loop control is desired, because the controller will typically require the needle to rotate rapidly, and it is particularly problematic when duty cycling (i.e., continual needle spinning) is used to adjust curvature. In this paper, we propose a new flexure-based needle tip design that provides the enhanced steerability of kinked bevel-tip needles, while simultaneously minimizing tissue damage.

  6. A Flexure-Based Steerable Needle: High Curvature With Reduced Tissue Damage

    PubMed Central

    Burgner, Jessica; Gilbert, Hunter B.; Webster, Robert J.

    2013-01-01

    In the quest to design higher curvature bevel-steered needles, kinked bevel-tips have been one of the most successful approaches yet proposed. However, the price to be paid for enhancing steerability in this way has been increased tissue damage, since the prebent tip cuts a local helical path into tissue when axially rotated. This is problematic when closed-loop control is desired, because the controller will typically require the needle to rotate rapidly, and it is particularly problematic when duty cycling (i.e., continual needle spinning) is used to adjust curvature. In this paper, we propose a new flexure-based needle tip design that provides the enhanced steerability of kinked bevel-tip needles, while simultaneously minimizing tissue damage. PMID:23204267

  7. Acrolein scavengers, cysteamine and N-benzylhydroxylamine, reduces the mouse liver damage after acetaminophen overdose

    PubMed Central

    KOYAMA, Ryo; MIZUTA, Ryushin

    2016-01-01

    Our previous study suggested that the highly toxic α,β-unsaturated aldehyde acrolein, a byproduct of oxidative stress, plays a major role in acetaminophen-induced liver injury. In this study, to determine the involvement of acrolein in the liver injury and to identify novel therapeutic options for the liver damage, we examined two putative acrolein scavengers, a thiol compound cysteamine and a hydroxylamine N-benzylhydroxylamine, in cell culture and in mice. Our results showed that cysteamine and N-benzylhydroxylamine effectively prevented the cell toxicity of acrolein in vitro and acetaminophen-induced liver injury in vivo, which suggested that acrolein is involved in the liver damage, and these two drugs can be potential therapeutic options for this condition. PMID:27594275

  8. Chinese green tea consumption reduces oxidative stress, inflammation and tissues damage in smoke exposed rats

    PubMed Central

    Al-Awaida, Wajdy; Akash, Muhanad; Aburubaiha, Zaid; Talib, Wamidh H.; Shehadeh, Hayel

    2014-01-01

    Objective(s): One cause of cigarette smoking is oxidative stress that may alter the cellular antioxidant defense system, induce apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. It has been shown that Chinese green tea (CGT) (Lung Chen Tea) has higher antioxidant property than black tea. In this paper, we will explore the preventive effect of CGT on cigarette smoke-induced oxidative damage, apoptosis and tissues inflammation in albino rat model. Materials and Methods: Albino rats were randomly divided into four groups, i.e. sham air (SA), cigarette smoke (CS), CGT 2% plus SA or plus CS. The exposure to smoking was carried out as a single daily dose (1 cigarette/rat) for a period of 90 days using an electronically controlled smoking machine. Sham control albino rats were exposed to air instead of cigarette smoke. Tissues were collected 24 hr after last CS exposure for histology and all enzyme assays. Apoptosis was evidenced by the fragmentation of DNA using TUNEL assay. Results: Long-term administration of cigarette smoke altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. All these pathophysiological and biochemical events were significantly improved when the cigarette smoke-exposed albino rats were given CGT infusion as a drink instead of water. Conclusion: Exposure of albino rat model to cigarette smoke caused oxidative stress, altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and tissues damage, which could be prevented by supplementation of CGT. PMID:25729541

  9. Tertiary nitrogen heterocyclic material to reduce moisture-induced damage in asphalt-aggregate mixtures

    DOEpatents

    Plancher, Henry; Petersen, Joseph C.

    1982-01-01

    Asphalt-aggregate roads crack when subjected to freezing and thawing cycles. Herein, the useful life of asphalts are substantially improved by a minor amount of a moisture damage inhibiting agent selected from compounds having a pyridine moiety, including acid salts of such compounds. A shale oil fraction may serve as the source of the improving agent and may simply be blended with conventional petroleum asphalts.

  10. Evaluating the Thermal Damage Resistance of Reduced Graphene Oxide/Carbon Nanotube Hybrid Coatings

    NASA Astrophysics Data System (ADS)

    David, Lamuel; Feldman, Ari; Mansfield, Elisabeth; Lehman, John; Singh, Gurpreet; National Institute of Standards and Technology Collaboration

    2014-03-01

    Carbon nanotubes and graphene are known to exhibit some exceptional thermal (K ~ 2000 to 4400 W.m-1K-1 at 300K) and optical properties. Here, we demonstrate preparation and testing of multiwalled carbon nanotubes and chemically modified graphene-composite spray coatings for use on thermal detectors for high-power lasers. The synthesized nanocomposite material was tested by preparing spray coatings on aluminum test coupons used as a representation of the thermal detector's surface. These coatings were then exposed to increasing laser powers and extended exposure times to quantify their damage threshold and optical absorbance. The graphene/carbon nanotube (prepared at varying mass% of graphene in CNTs) coatings demonstrated significantly higher damage threshold values at 2.5 kW laser power (10.6 μm wavelength) than carbon paint or MWCNTs alone. Electron microscopy and Raman spectroscopy of irradiated specimens showed that the composite coating endured high laser-power densities (up to 2 kW.cm-2) without significant visual damage. This research is based on work supported by the National Science Foundation (Chemical, Bioengineering, Environmental, and Transport Systems Division), under grant no. 1335862 to G. Singh.

  11. Antioxidant and micronutrient-rich milk formula reduces lead poisoning and related oxidative damage in lead-exposed mice.

    PubMed

    Zhang, Yu; Li, Qingqing; Liu, Xiaojie; Zhu, Hui; Song, Aihua; Jiao, Jingjing

    2013-07-01

    Lead poisoning is a global environmental disease that induces lifelong adverse health effects. The effect of a milk formula consisting of antioxidant of bamboo leaves (AOB), vitamin C (Vc), calcium lactate (CaLac), ferrous sulfate (FeSO₄) and zinc sulfate (ZnSO₄) on the reduction of lead and lead-induced oxidative damage in lead-exposed mice was studied. The lead-reducing effect of milk formula was investigated via a 7-week toxicokinetics study and a tissue distribution level examination. The ameliorating effect of milk formula on lead-induced oxidative damage was investigated. Results demonstrated current milk formula could effectively reduce blood lead levels (BLLs) and lead distribution levels of liver, kidneys, thighbones and brain in mice based on metal ion-mediated antagonism and chelation mechanisms. This milk formula could not only protect lead-susceptible tissues against lead poisoning, but also maintain normal absorption and distribution of essential elements in vivo. Meanwhile, current milk formula could prevent the reduction of δ-aminolevulinic acid dehydratase (δ-ALAD) activity and enhancement of free erythrocyte protoporphyrins (FEP) levels in blood erythrocytes of mice. Also, this formula could indirectly protect blood cell membranes against lead-induced lipid peroxidation. We conclude that current optimized milk formula effectively reduces lead poisoning and lead-induced in vivo oxidative damage in lead-exposed mice.

  12. Ebola Virus Makona Shows Reduced Lethality in an Immune-deficient Mouse Model.

    PubMed

    Smither, Sophie J; Eastaugh, Lin; Ngugi, Sarah; O'Brien, Lyn; Phelps, Amanda; Steward, Jackie; Lever, Mark Stephen

    2016-10-15

    Ebola virus Makona (EBOV-Makona; from the 2013-2016 West Africa outbreak) shows decreased virulence in an immune-deficient mouse model, compared with a strain from 1976. Unlike other filoviruses tested, EBOV-Makona may be slightly more virulent by the aerosol route than by the injected route, as 2 mice died following aerosol exposure, compared with no mortality among mice that received intraperitoneal injection of equivalent or higher doses. Although most mice did not succumb to infection, the detection of an immunoglobulin G antibody response along with observed clinical signs suggest that the mice were infected but able to clear the infection and recover. We hypothesize that this may be due to the growth rates and kinetics of the virus, which appear slower than that for other filoviruses and consequently give more time for an immune response that results in clearance of the virus. In this instance, the immune-deficient mouse model is unlikely to be appropriate for testing medical countermeasures against this EBOV-Makona stock but may provide insight into pathogenesis and the immune response to virus.

  13. Selection of broilers with improved innate immune responsiveness to reduce on-farm infection by foodborne pathogens.

    PubMed

    Swaggerty, Christina L; Pevzner, Igal Y; He, Haiqi; Genovese, Kenneth J; Nisbet, David J; Kaiser, Pete; Kogut, Michael H

    2009-09-01

    Economic pressure on the modern poultry industry has directed the selection process towards fast-growing broilers that have a reduced feed conversion ratio. Selection based heavily on growth characteristics could adversely affect immune competence leaving chickens more susceptible to disease. Since the innate immune response directs the acquired immune response, efforts to select poultry with an efficient innate immune response would be beneficial. Our laboratories have been evaluating the innate immune system of two parental broiler lines to assess their capacity to protect against multiple infections. We have shown increased in vitro heterophil function corresponds with increased in vivo resistance to Gram-positive and Gram-negative bacterial infections. Additionally, there are increased mRNA expression levels of pro-inflammatory cytokines/chemokines in heterophils isolated from resistant lines compared to susceptible lines. Collectively, all data indicate there are measurable differences in innate responsiveness under genetic control. Recently, a small-scale selection trial was begun. We identified sires within a broiler population with higher and/or lower-than-average pro-inflammatory cytokine/chemokine mRNA expression levels and subsequently utilized small numbers of high-expressing and low-expressing sires to produce progeny with increased or decreased, respectively, pro-inflammatory cytokine/chemokine profiles. This novel approach should allow us to improve breeding stock by improving the overall immunological responsiveness. This will produce a line of chickens with an effective pro-inflammatory innate immune response that should improve resistance against diverse pathogens, improve responses to vaccines, and increase livability. Ongoing work from this project is providing fundamental information for the development of poultry lines that will be inherently resistant to colonization by pathogenic and food-poisoning microorganisms. Utilization of pathogen

  14. The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus.

    PubMed

    Valle-Dorado, María Guadalupe; Santana-Gómez, César Emmanuel; Orozco-Suárez, Sandra Adela; Rocha, Luisa

    2015-05-01

    Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p < 0.001) and neuronal damage in dentate gyrus, CA1 and CA3. In contrast to SS-SE group, rats from the CG-SE group showed increased latency to the establishment of the status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment.

  15. Managing population immunity to reduce or eliminate the risks of circulation following the importation of polioviruses.

    PubMed

    Thompson, Kimberly M; Kalkowska, Dominika A; Duintjer Tebbens, Radboud J

    2015-03-24

    Poliovirus importations into polio-free countries represent a major concern during the final phases of global eradication of wild polioviruses (WPVs). We extend dynamic transmission models to demonstrate the dynamics of population immunity out through 2020 for three countries that only used inactivated poliovirus vaccine (IPV) for routine immunization: the US, Israel, and The Netherlands. For each country, we explore the vulnerability to re-established transmission following an importation for each poliovirus serotype, including the impact of immunization choices following the serotype 1 WPV importation that occurred in 2013 in Israel. As population immunity declines below the threshold required to prevent transmission, countries become at risk for re-established transmission. Although importations represent stochastic events that countries cannot fully control because people cross borders and polioviruses mainly cause asymptomatic infections, countries can ensure that any importations die out. Our results suggest that the general US population will remain above the threshold for transmission through 2020. In contrast, Israel became vulnerable to re-established transmission of importations of live polioviruses by the late 2000s. In Israel, the recent WPV importation and outbreak response use of bivalent oral poliovirus vaccine (bOPV) eliminated the vulnerability to an importation of poliovirus serotypes 1 and 3 for several years, but not serotype 2. The Netherlands experienced a serotype 1 WPV outbreak in 1992-1993 and became vulnerable to re-established transmission in religious communities with low vaccine acceptance around the year 2000, although the general population remains well-protected from widespread transmission. All countries should invest in active management of population immunity to avoid the potential circulation of imported live polioviruses. IPV-using countries may wish to consider prevention opportunities and/or ensure preparedness for response

  16. Prevalence of Plasmodium falciparum transmission reducing immunity among primary school children in a malaria moderate transmission region in Zimbabwe.

    PubMed

    Paul, Noah H; Vengesai, Arthur; Mduluza, Takafira; Chipeta, James; Midzi, Nicholas; Bansal, Geetha P; Kumar, Nirbhay

    2016-11-01

    Malaria continues to cause alarming morbidity and mortality in more than 100 countries worldwide. Antigens in the various life cycle stages of malaria parasites are presented to the immune system during natural infection and it is widely recognized that after repeated malaria exposure, adults develop partially protective immunity. Specific antigens of natural immunity represent among the most important targets for the development of malaria vaccines. Immunity against the transmission stages of the malaria parasite represents an important approach to reduce malaria transmission and is believed to become an important tool for gradual elimination of malaria. Development of immunity against Plasmodium falciparum sexual stages was evaluated in primary school children aged 6-16 years in Makoni district of Zimbabwe, an area of low to modest malaria transmission. Malaria infection was screened by microscopy, rapid diagnostic tests and finally using nested PCR. Plasma samples were tested for antibodies against recombinant Pfs48/45 and Pfs47 by ELISA. Corresponding serum samples were used to test for P. falciparum transmission reducing activity in Anopheles stephensi and An. gambiae mosquitoes using the membrane feeding assay. The prevalence of malaria diagnosed by rapid diagnostic test kit (Paracheck)™ was 1.7%. However, of the randomly tested blood samples, 66% were positive by nested PCR. ELISA revealed prevalence (64% positivity at 1:500 dilution, in randomly selected 66 plasma samples) of antibodies against recombinant Pfs48/45 (mean A 405nm=0.53, CI=0.46-0.60) and Pfs47 (mean A405nm=0.91, CI=0.80-1.02); antigens specific to the sexual stages. The mosquito membrane feeding assay demonstrated measurable transmission reducing ability of the samples that were positive for Pfs48/45 antibodies by ELISA. Interestingly, 3 plasma samples revealed enhancement of infectivity of P. falciparum in An. stephensi mosquitoes. These studies revealed the presence of antibodies with

  17. Method and apparatus for reducing diffraction-induced damage in high power laser amplifier systems

    DOEpatents

    Campillo, Anthony J.; Newnam, Brian E.; Shapiro, Stanley L.; Terrell, Jr., N. James

    1976-01-01

    Self-focusing damage caused by diffraction in laser amplifier systems may be minimized by appropriately tailoring the input optical beam profile by passing the beam through an aperture having a uniform high optical transmission within a particular radius r.sub.o and a transmission which drops gradually to a low value at greater radii. Apertures having the desired transmission characteristics may readily be manufactured by exposing high resolution photographic films and plates to a diffuse, disk-shaped light source and mask arrangement.

  18. Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

    PubMed Central

    West, Ewan; Osborne, Craig; Nolan, William; Bate, Clive

    2015-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2) and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage. PMID:26043272

  19. Adaptive immune response in JAM-C-deficient mice: normal initiation but reduced IgG memory.

    PubMed

    Zimmerli, Claudia; Lee, Boris P L; Palmer, Gaby; Gabay, Cem; Adams, Ralf; Aurrand-Lions, Michel; Imhof, Beat A

    2009-04-15

    We have recently shown that junctional adhesion molecule (JAM)-C-deficient mice have leukocytic pulmonary infiltrates, disturbed neutrophil homeostasis, and increased postnatal mortality. This phenotype was partially rescued when mice were housed in ventilated isolators, suggesting an inability to cope with opportunistic infections. In the present study, we further examined the adaptive immune responses in JAM-C(-/-) mice. We found that murine conventional dendritic cells express in addition to Mac-1 and CD11c also JAM-B as ligand for JAM-C. By in vitro adhesion assay, we show that murine DCs can interact with recombinant JAM-C via Mac-1. However, this interaction does not seem to be necessary for dendritic cell migration and function in vivo, even though JAM-C is highly expressed by lymphatic sinuses of lymph nodes. Nevertheless, upon immunization and boosting with a protein Ag, JAM-C-deficient mice showed decreased persistence of specific circulating Abs although the initial response was normal. Such a phenotype has also been observed in a model of Ag-induced arthritis, showing that specific IgG2a Ab titers are reduced in the serum of JAM-C(-/-) compared with wild-type mice. Taken together, these data suggest that JAM-C deficiency affects the adaptive humoral immune response against pathogens, in addition to the innate immune system.

  20. Fluoride reduced the immune privileged function of mouse Sertoli cells via the regulation of Fas/FasL system.

    PubMed

    Sun, Zilong; Nie, Qingli; Zhang, Lianjie; Niu, Ruiyan; Wang, Jundong; Wang, Shaolin

    2017-02-01

    Previous investigations have demonstrated the adverse impacts of fluoride on Sertoli cells (SCs), such as oxidative stress and apoptosis. SCs are the crucial cellular components that can create the immune privileged environment in testis. However, the effect of fluoride on SCs immune privilege is unknown. In this study, mouse SCs were exposed to sodium fluoride with varying concentrations of 10(-5), 10(-4), and 10(-3) mol/L to establish the model of fluoride-treated SCs (F-SCs) in vitro. After 48 h of incubation, F-SCs were transplanted underneath the kidney capsule of mice for 21 days, or cocultured with spleen lymphocytes for another 48 h. Immunohistochemical analysis of GATA4 in SCs grafts underneath kidney capsule presented less SCs distribution and obvious immune cell infiltration in F-SCs groups. In addition, the levels of FasL protein and mRNA in non-cocultured F-SCs decreased with the increase of fluoride concentration. When cocultured with F-SCs, lymphocytes presented significantly high cell viability and low apoptosis in F-SCs groups. Protein and mRNA expressions of FasL in cocultured F-SCs and Fas in lymphocytes were reduced, and the caspase 8 and caspase 3 mRNA levels were also decreased in fluoride groups in a dose-dependent manner. These findings indicated that fluoride influenced the testicular immune privilege through disturbing the Fas/FasL system.

  1. Functions of innate and acquired immune system are reduced in domestic pigeons (Columba livia domestica) given a low protein diet

    PubMed Central

    Mabuchi, Yuko; Frankel, Theresa L.

    2016-01-01

    Racing pigeons are exposed to and act as carriers of diseases. Dietary protein requirement for their maintenance has not been determined experimentally despite their being domesticated for over 7000 years. A maintenance nitrogen (protein) requirement (MNR) for pigeons was determined in a balance study using diets containing 6, 10 and 14% crude protein (CP). Then, the effects of feeding the diets were investigated to determine whether they were adequate to sustain innate and acquired immune functions. Nitrogen intake from the 6% CP diet was sufficient to maintain nitrogen balance and body weight in pigeons. However, the immune functions of phagocytosis, oxidative burst and lymphocyte proliferation in pigeons fed this diet were reduced compared with those fed 10 and 14% CP diets. Pigeons given the 6 and 10% CP diets had lower antibody titres following inoculation against Newcastle disease (ND) than those on the 14% CP diet. A confounding factor found on autopsy was the presence of intestinal parasites in some of the pigeons given the 6 and 10% CP diets; however, none of the pigeons used to measure MNR or acquired immunity to ND were infested with parasites. In conclusion, neither the 6 nor 10% CP diets adequately sustained acquired immune function of pigeons. PMID:27069640

  2. Weeding volatiles reduce leaf and seed damage to field-grown soybeans and increase seed isoflavones.

    PubMed

    Shiojiri, Kaori; Ozawa, Rika; Yamashita, Ken-Ichi; Uefune, Masayoshi; Matsui, Kenji; Tsukamoto, Chigen; Tokumaru, Susumu; Takabayashi, Junji

    2017-01-30

    Field experiments were conducted over 3 years (2012, 2013, and 2015), in which half of the young stage soybean plants were exposed to volatiles from cut goldenrods three times over 2-3 weeks, while the other half remained unexposed. There was a significant reduction in the level of the total leaf damage on exposed soybean plants compared with unexposed ones. In 2015, the proportion of damage to plants by Spodoptera litura larvae, a dominant herbivore, was significantly less in the exposed field plots than in the unexposed plots. Under laboratory conditions, cut goldenrod volatiles induced the direct defenses of soybean plants against S. litura larvae and at least three major compounds, α-pinene, β-myrcene, and limonene, of cut goldenrod volatiles were involved in the induction. The number of undamaged seeds from the exposed plants was significantly higher than that from unexposed ones. Concentrations of isoflavones in the seeds were significantly higher in seeds from the exposed plants than in those from the unexposed plants. Future research evaluating the utility of weeding volatiles, as a form of plant-plant communications, in pest management programs is necessary.

  3. Weeding volatiles reduce leaf and seed damage to field-grown soybeans and increase seed isoflavones

    PubMed Central

    Shiojiri, Kaori; Ozawa, Rika; Yamashita, Ken-Ichi; Uefune, Masayoshi; Matsui, Kenji; Tsukamoto, Chigen; Tokumaru, Susumu; Takabayashi, Junji

    2017-01-01

    Field experiments were conducted over 3 years (2012, 2013, and 2015), in which half of the young stage soybean plants were exposed to volatiles from cut goldenrods three times over 2–3 weeks, while the other half remained unexposed. There was a significant reduction in the level of the total leaf damage on exposed soybean plants compared with unexposed ones. In 2015, the proportion of damage to plants by Spodoptera litura larvae, a dominant herbivore, was significantly less in the exposed field plots than in the unexposed plots. Under laboratory conditions, cut goldenrod volatiles induced the direct defenses of soybean plants against S. litura larvae and at least three major compounds, α-pinene, β-myrcene, and limonene, of cut goldenrod volatiles were involved in the induction. The number of undamaged seeds from the exposed plants was significantly higher than that from unexposed ones. Concentrations of isoflavones in the seeds were significantly higher in seeds from the exposed plants than in those from the unexposed plants. Future research evaluating the utility of weeding volatiles, as a form of plant–plant communications, in pest management programs is necessary. PMID:28134284

  4. Immune response to Plasmodium vivax has a potential to reduce malaria severity.

    PubMed

    Chuangchaiya, S; Jangpatarapongsa, K; Chootong, P; Sirichaisinthop, J; Sattabongkot, J; Pattanapanyasat, K; Chotivanich, K; Troye-Blomberg, M; Cui, L; Udomsangpetch, R

    2010-05-01

    Plasmodium falciparum infection causes transient immunosuppression during the parasitaemic stage. However, the immune response during simultaneous infections with both P. vivax and P. falciparum has been investigated rarely. In particular, it is not clear whether the host's immune response to malaria will be different when infected with a single or mixed malaria species. Phenotypes of T cells from mixed P. vivax-P. falciparum (PV-PF) infection were characterized by flow cytometry, and anti-malarial antibodies in the plasma were determined by an enzyme-linked immunosorbent assay. We found the percentage of CD3+delta2+-T cell receptor (TCR) T cells in the acute-mixed PV-PF infection and single P. vivax infection three times higher than in the single P. falciparum infection. This implied that P. vivax might lead to the host immune response to the production of effector T killer cells. During the parasitaemic stage, the mixed PV-PF infection had the highest number of plasma antibodies against both P. vivax and P. falciparum. Interestingly, plasma from the group of single P. vivax or P. falciparum malaria infections had both anti-P. vivax and anti-P. falciparum antibodies. In addition, antigenic cross-reactivity of P. vivax or P. falciparum resulting in antibodies against both malaria species was shown in the supernatant of lymphocyte cultures cross-stimulated with either antigen of P. vivax or P. falciparum. The role of delta2 +/- TCR T cells and the antibodies against both species during acute mixed malaria infection could have an impact on the immunity to malaria infection.

  5. Radix Ilicis Pubescentis total flavonoids ameliorates neuronal damage and reduces lesion extent in a mouse model of transient ischemic attack.

    PubMed

    Miao, Ming-San; Guo, Lin; Li, Rui-Qi; Zhang, Xiao-Lei

    2016-03-01

    Flavonoids are a major component in the traditional Chinese medicine Radix Ilicis Pubescentis. Previous studies have shown that the administration of Radix Ilicis Pubescentis total flavonoids is protective in cerebral ischemia. However, to our knowledge, no studies have examined whether the total flavonoids extracted from Radix Ilicis Pubescentis prevent or ameliorate neuronal damage following transient ischemic attacks. Therefore, Radix Ilicis Pubescentis total flavonoids question and the potential underlying mechanisms. Thus, beginning 3 days before the induction of a mouse model of transient ischemic attack using tert-butyl hydroperoxide injections, mice were intragastrically administered 0.3, 0.15, or 0.075 g/kg of Radix Ilicis Pubescentis total flavonoids daily for 10 days. The results of spectrophotometric analyses demonstrated that Radix Ilicis Pubescentis total flavonoids enhanced oxygen free radical scavenging and reduced pathological alterations in the brain. Hematoxylin-eosin staining results showed that Radix Ilicis Pubescentis total flavonoids reduced hippocampal neuronal damage and cerebral vascular injury in this mouse model of transient ischemic attack. These results suggest that the antioxidant effects of Radix Ilicis Pubescentis total flavonoids alleviate the damage to brain tissue caused by transient ischemic attack.

  6. Black Currant Nectar Reduces Muscle Damage and Inflammation Following a Bout of High-Intensity Eccentric Contractions.

    PubMed

    Hutchison, Alexander T; Flieller, Emily B; Dillon, Kimber J; Leverett, Betsy D

    2016-01-01

    This investigation determined the efficacy of black currant nectar (BCN) in reducing symptoms of exercise-induced muscle damage (EIMD). Sixteen college students were randomly assigned to drink either 16 oz of BCN or a placebo (PLA) twice a day for eight consecutive days. A bout of eccentric knee extensions (3 × 10 sets @ 115% of 1RM) was performed on the fourth day. Outcome measures included muscle soreness (subjective scale from 0 to 10) and blood markers of muscle damage (creatine kinase, CK), inflammation (interleukin-6, IL-6), and oxygen radical absorbance capacity (ORAC). Although there were no differences in reported soreness between groups, consumption of BCN reduced CK levels at both 48 (PLA = 82.13% vs. BCN = -6.71%, p = .042) and 96 h post exercise (PLA = 74.96% vs. BCN = -12.11%, p = .030). The change in IL-6 was higher in the PLA group (PLA = 8.84% vs. BCN = -6.54%, p = .023) at 24 h post exercise. The change in ORAC levels was higher in the treatment group (BCN = 2.68% vs. PLA = -6.02%, p = .039) at 48 h post exercise. Our results demonstrate that consumption of BCN prior to and after a bout of eccentric exercise attenuates muscle damage and inflammation.

  7. Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia

    PubMed Central

    Yang, Xiao; Hei, Changhun; Liu, Ping; Song, Yaozu; Thomas, Taylor; Tshimanga, Sylvie; Wang, Feng; Niu, Jianguo; Sun, Tao; Li, P. Andy

    2015-01-01

    The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage. PMID:26681922

  8. Antiparasite treatments reduce humoral immunity and impact oxidative status in raptor nestlings

    PubMed Central

    Hanssen, Sveinn Are; Bustnes, Jan Ove; Schnug, Lisbeth; Bourgeon, Sophie; Johnsen, Trond Vidar; Ballesteros, Manuel; Sonne, Christian; Herzke, Dorte; Eulaers, Igor; Jaspers, Veerle L B; Covaci, Adrian; Eens, Marcel; Halley, Duncan J; Moum, Truls; Ims, Rolf Anker; Erikstad, Kjell Einar

    2013-01-01

    Parasites are natural stressors that may have multiple negative effects on their host as they usurp energy and nutrients and may lead to costly immune responses that may cause oxidative stress. At early stages, animals may be more sensitive to infectious organisms because of their rapid growth and partly immature immune system. The objective of this study was to explore effects of parasites by treating chicks of two raptor species (northern goshawk Accipiter gentilis and white-tailed sea eagle Haliaeetus albicilla) against both endoparasites (internal parasites) and ectoparasites (external parasites). Nests were either treated against ectoparasites by spraying with pyrethrin or left unsprayed as control nests. Within each nest, chicks were randomly orally treated with either an antihelminthic medication (fenbendazole) or sterile water as control treatment. We investigated treatment effects on plasma (1) total antioxidant capacity TAC (an index of nonenzymatic circulating antioxidant defenses), (2) total oxidant status TOS (a measure of plasmatic oxidants), and (3) immunoglobulin levels (a measure of humoral immune function). Treatment against ectoparasites led to a reduction in circulating immunoglobulin plasma levels in male chicks. TOS was higher when not receiving any parasite reduction treatment and when receiving both endo- and ectoparasitic reduction treatment compared with receiving only one treatment. TAC was higher in all treatment groups, when compared to controls. Despite the relatively low sample size, this experimental study suggests complex but similar relationships between treatment groups and oxidative status and immunoglobulin levels in two raptor species. PMID:24455145

  9. Reduced expression of selective immune-related genes in silver catfish (Rhamdia quelen) monocytes exposed to atrazine.

    PubMed

    Kirsten, Karina Schreiner; Canova, Raíssa; Soveral, Lucas de Figueiredo; Friedrich, Maria Tereza; Frandoloso, Rafael; Kreutz, Luiz Carlos

    2017-03-03

    The effect of atrazine (ATZ) and its metabolites on aquatic vertebrate species has been a matter of concern to researchers and environmentalist. In this study we exposed head kidney monocytes to sublethal concentrations of atrazine (1 and 10 μg/ml(-1)), corresponding to 1% and 10% of the LC50-96h, to evaluate the expression of immune-related genes central to immune stimulation. The mRNA levels of TNF-α, Mieloperoxidase and Mx genes were significantly reduced following 24 h exposure to both concentrations of ATZ. The mRNA levels of iRAK4 were reduced only at the higher ATZ concentration and the mRNA levels of IL-1β were not affected. The results reported here support our previous findings on the immunosuppressive effect of ATZ indicating its potential to interfere with the expression of immune-related genes, and strengthen the need to regulate ATZ usage aiming to preserve animal and human health.

  10. Immunization with recombinant Pb27 protein reduces the levels of pulmonary fibrosis caused by the inflammatory response against Paracoccidioides brasiliensis.

    PubMed

    Morais, Elis Araujo; Martins, Estefânia Mara do Nascimento; Boelone, Jankerle Neves; Gomes, Dawidson Assis; Goes, Alfredo Miranda

    2015-02-01

    Paracoccidioidomycosis (PCM) is a systemic mycosis in which the host response to the infectious agent typically consists of a chronic granulomatous inflammatory process. This condition causes lesions that impair lung function and lead to chronic pulmonary insufficiency resulting from fibrosis development, which is a sequel and disabling feature of the disease. The rPb27 protein has been studied for prophylactic and therapeutic treatment against PCM. Previous studies from our laboratory have shown a protective effect of rPb27 against PCM. However, these studies have not determined whether rPb27 immunization prevents lung fibrosis. We therefore conducted this study to investigate fibrosis resulting from infection by Paracoccidioides brasiliensis in the lungs of animals immunized with rPb27. Animals were immunized with rPb27 and subsequently infected with a virulent strain of P. brasiliensis. Fungal load was evaluated by counting colony-forming units, and Masson's trichrome staining was performed to evaluate fibrosis at 30 and 90 days post-infection. The levels of CCR7, active caspase 3, collagen and cytokines were analyzed. At the two time intervals mentioned, the rPb27 group showed lower levels of fibrosis on histology and reduced levels of collagen and the chemokine receptor CCR7 in the lungs. CCR7 was detected at higher levels in the control groups that developed very high levels of pulmonary fibrosis. Additionally, the immunized groups showed high levels of active caspase 3, IFN-γ, TGF-β and IL-10 in the early phase of P. brasiliensis infection. Immunization with Pb27, in addition to its protective effect, was shown to prevent pulmonary fibrosis.

  11. Orthotopic bone transplantation in mice. III. Methods of reducing the immune response and their effect on healing

    SciTech Connect

    Kliman, M.; Halloran, P.F.; Lee, E.; Esses, S.; Fortner, P.; Langer, F.

    1981-01-01

    Various methods of reducing the immune response to allogeneic bone grafts, either by pretreating the graft or by immunosuppressing the recipient, were compared. Tibial grafts from B10.D2 mice, either untreated or pretreated in various ways, were transplanted into B10 recipients. The antibody response was followed and the extent of bone healing at 4 months was assessed. Pretreatment of the graft by X-irradiation, freezing, or by incubation in alloantisera (either anti-H-2 or anti-Ia) reduced or abolished the immunogenicity of the graft. Immunosuppression of the recipient with methotrexate or antilymphocyte serum (ALS) also greatly depressed the antibody response. But when healing was assessed, none of these treatments except ALS improved the delayed healing of the bone allografts. The reason for this failure was probably that X-irradiation, freezing, alloantiserum pretreatment, and methotrexate all interfered with bone healing directly, whereas ALS did not. We conclude that many methods will reduce the immune response to allogeneic bone, but that only ALS will improve the healing of the allogeneic bone. Furthermore, as a corollary to the observation that pretreatment with anti-Ia serum markedly reduced the immunogenicity of bone allografts, we conclude that much of the immunogenicity of bone allografts is attributable to a population of Ia-positive cells.

  12. Reduced immune function predicts disease susceptibility in frogs infected with a deadly fungal pathogen

    PubMed Central

    Savage, Anna E.; Terrell, Kimberly A.; Gratwicke, Brian; Mattheus, Nichole M.; Augustine, Lauren; Fleischer, Robert C.

    2016-01-01

    The relationship between amphibian immune function and disease susceptibility is of primary concern given current worldwide declines linked to the pathogenic fungus Batrachochytrium dendrobatidis (Bd). We experimentally infected lowland leopard frogs (Lithobates yavapaiensis) with Bd to test the hypothesis that infection causes physiological stress and stimulates humoral and cell-mediated immune function in the blood. We measured body mass, the ratio of circulating neutrophils to lymphocytes (a known indicator of physiological stress) and plasma bacterial killing ability (BKA; a measure of innate immune function). In early exposure (1–15 days post-infection), stress was elevated in Bd-positive vs. Bd-negative frogs, whereas other metrics were similar between the groups. At later stages (29–55 days post-infection), stress was increased in Bd-positive frogs with signs of chytridiomycosis compared with both Bd-positive frogs without disease signs and uninfected control frogs, which were similar to each other. Infection decreased growth during the same period, demonstrating that sustained resistance to Bd is energetically costly. Importantly, BKA was lower in Bd-positive frogs with disease than in those without signs of chytridiomycosis. However, neither group differed from Bd-negative control frogs. The low BKA values in dying frogs compared with infected individuals without disease signs suggests that complement activity might signify different immunogenetic backgrounds or gene-by-environment interactions between the host, Bd and abiotic factors. We conclude that protein complement activity might be a useful predictor of Bd susceptibility and might help to explain differential disease outcomes in natural amphibian populations. PMID:27293759

  13. Reduced immune function predicts disease susceptibility in frogs infected with a deadly fungal pathogen.

    PubMed

    Savage, Anna E; Terrell, Kimberly A; Gratwicke, Brian; Mattheus, Nichole M; Augustine, Lauren; Fleischer, Robert C

    2016-01-01

    The relationship between amphibian immune function and disease susceptibility is of primary concern given current worldwide declines linked to the pathogenic fungus Batrachochytrium dendrobatidis (Bd). We experimentally infected lowland leopard frogs (Lithobates yavapaiensis) with Bd to test the hypothesis that infection causes physiological stress and stimulates humoral and cell-mediated immune function in the blood. We measured body mass, the ratio of circulating neutrophils to lymphocytes (a known indicator of physiological stress) and plasma bacterial killing ability (BKA; a measure of innate immune function). In early exposure (1-15 days post-infection), stress was elevated in Bd-positive vs. Bd-negative frogs, whereas other metrics were similar between the groups. At later stages (29-55 days post-infection), stress was increased in Bd-positive frogs with signs of chytridiomycosis compared with both Bd-positive frogs without disease signs and uninfected control frogs, which were similar to each other. Infection decreased growth during the same period, demonstrating that sustained resistance to Bd is energetically costly. Importantly, BKA was lower in Bd-positive frogs with disease than in those without signs of chytridiomycosis. However, neither group differed from Bd-negative control frogs. The low BKA values in dying frogs compared with infected individuals without disease signs suggests that complement activity might signify different immunogenetic backgrounds or gene-by-environment interactions between the host, Bd and abiotic factors. We conclude that protein complement activity might be a useful predictor of Bd susceptibility and might help to explain differential disease outcomes in natural amphibian populations.

  14. Spirulina prevents memory dysfunction, reduces oxidative stress damage and augments antioxidant activity in senescence-accelerated mice.

    PubMed

    Hwang, Juen-Haur; Lee, I-Te; Jeng, Kee-Ching; Wang, Ming-Fu; Hou, Rolis Chien-Wei; Wu, Su-Mei; Chan, Yin-Ching

    2011-01-01

    Spirulina has proven to be effective in treating certain cancers, hyperlipidemia, immunodeficiency, and inflammatory processes. In this study, we aimed to investigate the effects of Spirulina on memory dysfunction, oxidative stress damage and antioxidant enzyme activity. Three-month-old male senescence-accelerated prone-8 (SAMP8) mice were randomly assigned to either a control group or to one of two experimental groups (one receiving daily dietary supplementation with 50 mg/kg BW and one with 200 mg/kg BW of Spirulina platensis water extract). Senescence-accelerated-resistant (SAMR1) mice were used as the external control. Results showed that the Spirulina-treated groups had better passive and avoidance scores than the control group. The amyloid β-protein (Aβ) deposition was significantly reduced at the hippocampus and whole brain in both Spirulina groups. The levels of lipid peroxidation were significantly reduced at the hippocampus, striatum, and cortex in both Spirulina groups, while catalase activity was significantly higher only in the 200 mg/kg BW Spirulina group than in the control group. Glutathione peroxidase activity was significantly higher only in the cortex of the 200 mg/kg group than in that of the SAMP8 control group. However, superoxide dismutase activity in all parts of the brain did not significantly differ among all groups. In conclusion, Spirulina platensis may prevent the loss of memory possibly by lessening Aβ protein accumulation, reducing oxidative damage and mainly augmenting the catalase activity.

  15. Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats

    PubMed Central

    Wang, Xin; Shi, Qiankun; Wang, Xiang; Yuan, Shoutao; Wang, Guozheng; Ji, Zhenling

    2015-01-01

    Objective Damage to intestinal epithelial tight junctions plays an important role in sepsis. Recently we found that Carbon Monoxide-Releasing Molecule-2 (CORM-2) is able to protect LPS-induced intestinal epithelial tight junction damage and in this study we will investigate if CORM-2 could protect intestinal epithelial tight junctions in the rat cecal ligation and puncture (CLP) model. Materials and Methods The CLP model was generated using male Sprague-Dawley (SD) rats according to standard procedure and treated with CORM-2 or inactive CORM-2 (iCORM-2), 8 mg/kg, i.v. immediately after CLP induction and euthanized after 24h or 72h (for mortality rate only). Morphological changes were investigated using both transmission electron and confocal microscopy. The levels of important TJ proteins and phosphorylation of myosin light chain (MLC) were examined using Western blotting. Cytokines, IL-1β and TNF-α were measured using ELISA kits. The overall intestinal epithelial permeability was evaluated using FD-4 as a marker. Results CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release. The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats. Conclusions Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality. PMID:26720630

  16. Efficacy of plastic mesh tubes in reducing herbivory damage by the invasive nutria (Myocastor coypus) in an urban restoration site

    USGS Publications Warehouse

    Sheffels, Trevor R.; Systma, Mark D.; Carter, Jacoby; Taylor, Jimmy D.

    2014-01-01

    The restoration of stream corridors is becoming an increasingly important component of urban landscape planning, and the high cost of these projects necessitates the need to understand and address potential ecological obstacles to project success. The nutria(Myocastor coypus) is an invasive, semi-aquatic rodent native to South America that causes detrimental ecological impacts in riparian and wetland habitats throughout its introduced range, and techniques are needed to reduce nutria herbivory damage to urban stream restoration projects. We assessed the efficacy of standard Vexar® plastic mesh tubes in reducing nutria herbivory damage to newly established woody plants. The study was conducted in winter-spring 2009 at Delta Ponds, a 60-ha urban waterway in Eugene, Oregon. Woody plants protected by Vexar® tubes demonstrated 100% survival over the 3-month initial establishment period, while only 17% of unprotected plantings survived. Nutria demonstrated a preference for black cottonwood (Populus balsamifera ssp trichocarpa) over red osier dogwood (Cornussericea) and willow (Salix spp). Camera surveillance showed that nutria were more active in unprotected rather than protected treatments. Our results suggest that Vexar® plastic mesh tubing can be an effective short-term herbivory mitigation tool when habitat use by nutria is low. Additionally, planting functionally equivalent woody plant species that are less preferred by nutria, and other herbivores, may be another method for reducing herbivory and improving revegetation success. This study highlights the need to address potential wildlife damage conflicts in the planning process for stream restoration in urban landscapes.

  17. Efforts to reduce mortality to hydroelectric turbine-passed fish: locating and quantifying damaging shear stresses.

    PubMed

    Cada, Glenn; Loar, James; Garrison, Laura; Fisher, Richard; Neitzel, Duane

    2006-06-01

    Severe fluid forces are believed to be a source of injury and mortality to fish that pass through hydroelectric turbines. A process is described by which laboratory bioassays, computational fluid dynamics models, and field studies can be integrated to evaluate the significance of fluid shear stresses that occur in a turbine. Areas containing potentially lethal shear stresses were identified near the stay vanes and wicket gates, runner, and in the draft tube of a large Kaplan turbine. However, under typical operating conditions, computational models estimated that these dangerous areas comprise less than 2% of the flow path through the modeled turbine. The predicted volumes of the damaging shear stress zones did not correlate well with observed fish mortality at a field installation of this turbine, which ranged from less than 1% to nearly 12%. Possible reasons for the poor correlation are discussed. Computational modeling is necessary to develop an understanding of the role of particular fish injury mechanisms, to compare their effects with those of other sources of injury, and to minimize the trial and error previously needed to mitigate those effects. The process we describe is being used to modify the design of hydroelectric turbines to improve fish passage survival.

  18. Optimization of phytoplankton preservative concentrations to reduce damage during long-term storage.

    PubMed

    Mukherjee, Abhishek; Das, Subhajit; Bhattacharya, Tanima; De, Minati; Maiti, Tusharkanti; Kumar De, Tarun

    2014-04-01

    A study was performed to establish the optimal concentration of traditional preservatives or fixatives such as formaldehyde and acidic Lugol's iodine, in order to preserve phytoplankton samples for long-term storage without the introduction of artifacts or other physical aberrations. The goal of the study was to avoid any visible morphological changes to the preserved cells, minimizing the errors induced by traditional preservative concentrations, and ensuring better accuracy of ecological analyses. We found that both formaldehyde and acidic Lugol's iodine have adverse effects on the preservation of samples. Trichodesmium erythraeum was found to be most susceptible to the effects of acidic Lugol's iodine, since it displayed the highest degree of chain fragmentation when this preservative was used. However, we found that 2.0% (v/v) formaldehyde, 2.5% (v/v) acidic Lugol's iodine, and 2.0% (v/v) formaldehyde+2.5%(v/v) acidic Lugol's iodine combined were most promising, with the latter the most effective even after 3 weeks of preservation. This study also revealed that, in general, the centric diatom species were more sensitive to long-term preservation than their pennate counterparts. The present study is significant as it sheds light on the damage endured by phytoplankton cells during long-term preservation, which can lead to erroneous and biased results upon analyses. The optimal concentration of preservative established experimentally from a wide variety of concentrations caused comparatively moderate changes to the cell dimensions as well as effectively prevented microbial contamination.

  19. Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice

    PubMed Central

    Pei, Zouwei; Okura, Takafumi; Nagao, Tomoaki; Enomoto, Daijiro; Kukida, Masayoshi; Tanino, Akiko; Miyoshi, Ken-ichi; Kurata, Mie; Higaki, Jitsuo

    2016-01-01

    Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE−/−) and ApoE/OPN knockout (ApoE−/−/OPN−/−) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE−/−HD mice, however, significantly suppressed in ApoE−/−/OPN−/−HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE−/−/OPN−/−HD mice than ApoE−/−HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia. PMID:27353458

  20. A reduced immunization scheme to obtain an experimental anti-Loxosceles laeta ("violinist spider") venom.

    PubMed

    de Roodt, Adolfo Rafael; Litwin, Silvana; Dokmetjian, José Christian; Vidal, Juan Carlos

    2002-08-01

    Bites by Loxosceles (L.) laeta spiders can produce severe envenomation in humans. The only specific treatment is the early administration of antivenom. The production of anti-Loxosceles antivenom is hampered by the extremely low venom yield by these spiders and by the difficulties in maintaining a large breeder of Loxosceles. We developed an experimental equinum L. laeta antivenom, using as immunogen venom glands homogenates from spiders captured in Argentina. Horses immunized with venom gland homogenate (1.0 mg total protein per horse) by the subcutaneous route were bled after completion of the immunization scheme. Plasma was fractionated by ammonium sulfate precipitation and treated with pepsin to obtain F(ab')2 fragments. The protein composition of the experimental antivenom was assessed by SDS-PAGE, and its immunochemical reactivity was compared with those of other anti-Loxosceles antivenoms available for therapeutic use in Argentina by ELISA and Western blot. The experimental, homologous anti-L. laeta antivenom appeared to be more efficient in neutralizing the lethal potency in mice and the necrotizing activity in rabbits than of the heterologous antivenom.

  1. Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells

    PubMed Central

    Onken, Marie Luise; Schütze, Sandra; Redlich, Sandra; Götz, Alexander; Hanisch, Uwe-Karsten; Bertsch, Thomas; Ribes, Sandra; Hanenberg, Andrea; Schneider, Simon; Bollheimer, Cornelius; Sieber, Cornel; Nau, Roland

    2014-01-01

    Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis of E. coli K1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing of E. coli K1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections. PMID:24686054

  2. [Pneumococcal vaccination: conjugated vaccine induces herd immunity and reduces antibiotic resistance].

    PubMed

    Pletz, M W; Maus, U; Hohlfeld, J M; Lode, H; Welte, T

    2008-02-01

    Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers and the elderly. Currently, two pneumococcal vaccines are in clinical use. The older vaccine consists of pure capsular polysaccharides from 23 pneumococcal serotypes and induces only a limited B-cell response because polysaccharides are poor antigens that stimulate mainly B-cells. In 2000, a vaccination program with a novel 7-valent pneumococcal conjugate vaccine was launched in the U.S. The conjugation of capsular polysaccharides with a highly immunogenic diphtheria toxoid protein induces both a T cell and B cell response that results in specific humoral and mucosal immunity. Since children are the main reservoir of pneumococci, the 7-valent conjugate vaccine seems to eradicate the respective pneumococcal serotypes within the population, as demonstrated by recent US data. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates. However, recent data suggest a replacement of vaccine-serotypes by non-vaccine serotypes, which conquer the ecological niche created by the vaccine. In order to encounter this problem a 13-valent conjugated vaccine is currently under development.

  3. Dexamethasone and 1,25-dihydroxyvitamin D3 reduce oxidative stress-related DNA damage in differentiating osteoblasts.

    PubMed

    Pawlowska, Elzbieta; Wysokiński, Daniel; Tokarz, Paulina; Piastowska-Ciesielska, Agnieszka; Szczepanska, Joanna; Blasiak, Janusz

    2014-09-19

    The process of osteoblast differentiation is regulated by several factors, including RUNX2. Recent reports suggest an involvement of RUNX2 in DNA damage response (DDR), which is important due to association of differentiation with oxidative stress. In the present work we explore the influence of two RUNX2 modifiers, dexamethasone (DEX) and 1,25-dihydroxyvitamin D3 (1,25-D3), in DDR in differentiating MC3T3-E1 preosteoblasts challenged by oxidative stress. The process of differentiation was associated with reactive oxygen species (ROS) production and tert-butyl hydroperoxide (TBH) reduced the rate of differentiation. The activity of alkaline phosphatase (ALP), a marker of the process of osteoblasts differentiation, increased in a time-dependent manner and TBH further increased this activity. This may indicate that additional oxidative stress, induced by TBH, may accelerate the differentiation process. The cells displayed changes in the sensitivity to TBH in the course of differentiation. DEX increased ALP activity, but 1,25-D3 had no effect on it. These results suggest that DEX might stimulate the process of preosteoblasts differentiation. Finally, we observed a protective effect of DEX and 1,25-D3 against DNA damage induced by TBH, except the day 24 of differentiation, when DEX increased the extent of TBH-induced DNA damage. We conclude that oxidative stress is associated with osteoblasts differentiation and induce DDR, which may be modulated by RUNX2-modifiers, DEX and 1,25-D3.

  4. Reducing the length of time between slaughter and the secondary gonadotropin-releasing factor immunization improves growth performance and clears boar taint compounds in male finishing pigs.

    PubMed

    Lealiifano, A K; Pluske, J R; Nicholls, R R; Dunshea, F R; Campbell, R G; Hennessy, D P; Miller, D W; Hansen, C F; Mullan, B P

    2011-09-01

    The objective of this study was to evaluate whether altering the timing of the secondary anti-gonadotropin-releasing factor (GnRF) immunization closer to slaughter in male finishing pigs would reduce the increase in P2 fat depth (6.5 cm from the midline over the last rib), while still limiting the incidence of boar taint. Entire male pigs are immunized against GnRF to reduce the concentration of testicular steroids that in turn limits the incidence of boar taint. Additionally, testicle measurements and color measurements were taken to examine whether they could be used to differentiate nonimmunized entire males from immunized male pigs. A total of 175 Large White × Landrace entire male pigs aged 16 wk (59 kg of BW) were used in a completely randomized design with 5 treatment groups based on the time that pigs received the secondary immunization before slaughter. Pigs were housed in groups of 7 and randomly allocated to 1 of 5 treatments with 5 replicates per treatment. The treatment groups were as follows: no secondary immunization before slaughter, and the secondary immunization given at 2, 3, 4, or 6 wk before slaughter. The P2 fat depth levels were reduced (P = 0.054) with the secondary immunization closer to slaughter (11.7, 11.3, 12.8, 12.6, and 13.7 mm for no secondary immunization, secondary immunization at 2, 3, 4, and 6 wk before slaughter, respectively). Androstenone concentration did not exceed the generally accepted industry sensory threshold of 1.0 µg/g of fat, and both androstenone concentration in the adipose tissue and testosterone concentrations in the blood were suppressed (P < 0.001) in all immunized pigs regardless of timing of the secondary immunization compared with pigs that did not receive the secondary immunization. Skatole concentration of all pigs in the experiment did not exceed the generally accepted industry sensory threshold of 0.2 µg/g. Testes weight was reduced (P < 0.001) with increased time between slaughter and the secondary

  5. Repeated edaravone treatment reduces oxidative cell damage in rat brain induced by middle cerebral artery occlusion.

    PubMed

    Yamamoto, Yorihiro; Yanagisawa, Makoto; Tak, Nyou Wei; Watanabe, Kazutoshi; Takahashi, Chizuko; Fujisawa, Akio; Kashiba, Misato; Tanaka, Masahiko

    2009-01-01

    The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) has been used to treat acute brain infarction in Japan since 2001. To obtain direct evidence that edaravone serves as an antioxidant in vivo, four groups of rats were prepared: (i) an ischemia/reperfusion (I/R) group receiving 2 h occlusion-reperfusion of the middle cerebral artery; (ii) a single administration group treated by intravenous infusion of edaravone (3 mg/kg) immediately after I/R; (iii) a repeated treatment group receiving twice daily edaravone administration for 14 days; and (iv) a sham operation group without occlusion. Repeated treatment with edaravone significantly improved the neurological symptoms and impairment of motor function as compared to the I/R group, while single administration demonstrated limited efficacy. No significant differences in plasma antioxidants such as ascorbate, urate, and vitamin E, or in redox status of coenzyme Q(9) were observed among the four groups. In contrast, the plasma content of oleic acid in the total free fatty acids (percentage 18:1) was significantly increased in the I/R group for 7 days as compared to the sham operation group. Oleic acid was produced from stearic acid by the action of stearoyl-CoA desaturase to compensate for the oxidative loss of polyunsaturated fatty acids. The above results suggest that cellular oxidative damage in the rat brain is evident for at least 7 days after I/R. Repeated treatment suppressed the percentage 18:1 increment, while the single administration did not, which is consistent with the limited efficacy of single administration.

  6. Bax inhibiting peptide reduces apoptosis in neonatal rat hypoxic-ischemic brain damage

    PubMed Central

    Sun, Meng-Ya; Cui, Kai-Jie; Yu, Mao-Min; Zhang, Hui; Peng, Xiang-Li; Jiang, Hong

    2015-01-01

    Neonatal hypoxic ischemic encephalopathy (HIE) has been reported to induce apoptosis in neonates. We, therefore, analyzed the ability of Bax-inhibiting peptide (BIP) to provide neuroprotective effects during hypoxic-ischemic brain damage (HIBD). Seven-day-old wistar rat pups (n = 198) were randomly divided into a sham-operated group (Group S, n = 18), saline group (Group C, n = 90) and BIP group (Group B, n = 90). Pathological changes in the cerebral tissues of rat pups were analyzed using hematoxylin and eosin stain, TUNEL and Western blot. The expression of cytochrome c and caspase-3 was determined using western blot technique. Rat pups demonstrated neurobehavioral alteration in Groups C and B. TUNEL-positive cells in the left hippocampus were significantly increased in Group C and Group B after HIBD (P < 0.01) when compared with Group S. There was a marked reduction in TUNEL positive cells in subgroups B1 through B4 when compared with the respective subgroups C1 through C5. Compared with Group S, the expression of caspase-3 and cytochrome c was significantly increased in Groups C and B (P < 0.01). The difference in expression of caspase-3 and cytochrome c between subgroups B1 through B4 and C1 through C4 was significant (P < 0.01). In conclusions, the neuro-protective effect of BIP was due to a reduction of nerve cell apoptosis in our neonatal HIE rat model. We propose that BIP has potential as a neuro-protective drug in neonatal HIE cases. PMID:26823794

  7. The compatible solute ectoine reduces the exacerbating effect of environmental model particles on the immune response of the airways.

    PubMed

    Unfried, Klaus; Kroker, Matthias; Autengruber, Andrea; Gotić, Marijan; Sydlik, Ulrich

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution.

  8. The Compatible Solute Ectoine Reduces the Exacerbating Effect of Environmental Model Particles on the Immune Response of the Airways

    PubMed Central

    Gotić, Marijan

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution. PMID:24822073

  9. Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization.

    PubMed Central

    Nossal, G J; Karvelas, M; Pulendran, B

    1993-01-01

    The splenic B-cell repertoire of unimmunized C57BL/6 mice can be examined for anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) B cells of relatively high affinity by using a dual strategy. First, limiting numbers of splenocytes are polyclonally activated by Escherichia coli lipopolysaccharide and a mixture of interleukins 2, 4, and 5 in the presence of 3T3 filler cells, thus ensuring that many B-cell clones switch to IgG1 antibody production. Second, an enzyme-linked immunosorbent assay is geared to register only higher-affinity antibody by (i) detecting only bivalent IgG1 antibody and ignoring IgM and (ii) using a lowly substituted NP-conjugated protein as the capture layer. Naive spleens contain very few higher-affinity anti-NP B cells thus defined, but thymus (T)-dependent immunization causes the appearance of approximately 10(5) per spleen within 2 weeks. The development of these clonable anti-NP antibody-forming cell precursors can be virtually eliminated by a single injection of 1 mg of soluble, freshly deaggregated NP2-human serum albumin (HSA). This toleragen works not only if injected prior to challenge immunization, but even if given up to 6 days later. Soluble HSA works partially but not nearly as well as NP2-HSA, suggesting the possibility that the toleragen must act on T and B cells. NP conjugated to irrelevant carriers achieved partial tolerance in only one of four experiments. The studies demonstrate the need for continuing T-cell help throughout the process of memory B-cell generation. They also show that those recently activated T cells involved in this process can be silenced in vivo by soluble toleragen. PMID:8464928

  10. Medical malpractice reform: noneconomic damages caps reduced payments 15 percent, with varied effects by specialty.

    PubMed

    Seabury, Seth A; Helland, Eric; Jena, Anupam B

    2014-11-01

    The impact of medical malpractice reforms on the average size of malpractice payments in specific physician specialties is unknown and subject to debate. We analyzed a national sample of malpractice claims for the period 1985-2010, merged with information on state liability reforms, to estimate the impact of state noneconomic damages caps on average malpractice payment size for physicians overall and for ten different specialty categories. We then compared how the effects differed according to the restrictiveness of the cap ($250,000 versus $500,000). We found that, overall, noneconomic damages caps reduced average payments by $42,980 (15 percent), compared to having no cap at all. A more restrictive $250,000 cap reduced average payments by $59,331 (20 percent), and a less restrictive $500,000 cap had no significant effect, compared to no cap at all. The effect of the caps overall varied according to specialty, with the largest impact being on claims involving pediatricians and the smallest on claims involving surgical subspecialties and ophthalmologists.

  11. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes.

    PubMed

    Abdel-Malek, Zalfa A; Ruwe, Andrew; Kavanagh-Starner, Renny; Kadekaro, Ana Luisa; Swope, Viki; Haskell-Luevano, Carrie; Koikov, Leonid; Knittel, James J

    2009-10-01

    One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified alpha-MSH core His(6)-d-Phe(7)-Arg(8), which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked alpha-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.

  12. Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair

    PubMed Central

    Budden, Timothy; Davey, Ryan J.; Vilain, Ricardo E.; Ashton, Katie A.; Braye, Stephen G.; Beveridge, Natalie J.; Bowden, Nikola A.

    2016-01-01

    UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non-transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non-transcribed and silent regions of the genome. This study aimed to examine the relationship between UVB and GGR in melanoma. DNA repair capacity and relative expression of NER in melanocytes and melanoma cell lines before and after treatment with UVB was quantified. Transcript expression from 196 melanomas was compared to clinical parameters including solar elastosis and whole transcriptome data collected. Melanoma cell lines showed significantly reduced DNA repair when compared to melanocytes, most significantly in the S phase of the cell cycle. Expression of GGR components XPC, DDB1 and DDB2 was significantly lower in melanoma after UVB. In the melanoma tumours, XPC expression correlated with age of diagnosis and low XPC conferred significantly poorer survival. The same trend was seen in the TCGA melanoma dataset. Reduced GGR in melanoma may contribute to the UV mutation spectrum of the melanoma genome and adds further to the growing evidence of the link between UV, NER and melanoma. PMID:27487145

  13. Nutrient-Enhanced Diet Reduces Noise-Induced Damage to the Inner Ear and Hearing Loss

    PubMed Central

    Le Prell, C. G.; Gagnon, P. M; Bennett, D. C.; Ohlemiller, K. K.

    2011-01-01

    Oxidative stress has been broadly implicated as a cause of cell death and neural degeneration in multiple disease conditions; however, the evidence for successful intervention with dietary antioxidant manipulations has been mixed. In this study, we investigated the potential for protection of cells in the inner ear using a dietary supplement with multiple antioxidant components, selected for their potential interactive effectiveness. Protection against permanent threshold shift (PTS) was observed in CBA/J mice maintained on a diet supplemented with a combination of β-carotene, vitamins C and E, and magnesium when compared to PTS in control mice maintained on a nutritionally complete control diet. Although hair cell survival was not enhanced, noise-induced loss of Type II fibrocytes in the lateral wall was significantly reduced (p<0.05), and there was a trend towards less noise-induced loss in strial cell density in animals maintained on the supplemented diet. Taken together, our data suggest that pre-noise oral treatment with the high-nutrient diet can protect cells in the inner ear and reduce PTS in mice. Demonstration of functional and morphological preservation of cells in the inner ear with oral administration of this antioxidant supplemented diet supports the possibility of translation to human patients, and suggests an opportunity to evaluate antioxidant protection in mouse models of oxidative stress-related disease and pathology. PMID:21708355

  14. Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity

    PubMed Central

    Deshpande, Mandar; Thandavarayan, Rajarajan A.; Xu, Jiang; Yang, Xiao-Ping; Palaniyandi, Suresh S.

    2016-01-01

    Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7–11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 μm2 Vs 221 ± 10 μm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction. PMID:27736868

  15. Progesterone Reduces Secondary Damage, Preserves White Matter, and Improves Locomotor Outcome after Spinal Cord Contusion

    PubMed Central

    Garcia-Ovejero, Daniel; González, Susana; Paniagua-Torija, Beatriz; Lima, Analía; Molina-Holgado, Eduardo; De Nicola, Alejandro F.

    2014-01-01

    Abstract Progesterone is an anti-inflammatory and promyelinating agent after spinal cord injury, but its effectiveness on functional recovery is still controversial. In the current study, we tested the effects of chronic progesterone administration on tissue preservation and functional recovery in a clinically relevant model of spinal cord lesion (thoracic contusion). Using magnetic resonance imaging, we observed that progesterone reduced both volume and rostrocaudal extension of the lesion at 60 days post-injury. In addition, progesterone increased the number of total mature oligodendrocytes, myelin basic protein immunoreactivity, and the number of axonal profiles at the epicenter of the lesion. Further, progesterone treatment significantly improved motor outcome as assessed using the Basso-Bresnahan-Beattie scale for locomotion and CatWalk gait analysis. These data suggest that progesterone could be considered a promising therapeutical candidate for spinal cord injury. PMID:24460450

  16. Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia.

    PubMed

    Bertuglia, Silvia; Reiter, Russel J

    2009-04-01

    Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) associated with hypertension, insulin resistance and a systemic inflammatory response. We evaluated the effects of melatonin on vasodilation, capillary perfusion in hamster cheek pouch and insulin resistance, hypertension, and reactive oxygen species (ROS) and nitrate/nitrite levels after IH for 4 wk. Syrian hamsters were divided into four groups: control group (CON), IH group, and melatonin (10 mg/kg) intraperitoneally administered daily for 4 wk/30 min before intermittent air (MEL) or IH (IH + MEL) exposure. IH alone caused elevated blood pressure, increased hematocrit, fasting hyperglycemia, elevated ROS and nitrite/nitrate levels, and vasoconstriction and reduced microvascular perfusion. Melatonin treatment of IH-exposed animals decreased blood pressure, blood glucose, and ROS and nitrite/nitrate levels, and increased vasodilation and capillary perfusion. An oral glucose tolerance test was performed after 4 wk of IH. During the last 30 min of the hyperinsulinemic euglycemic clamp, blood glucose, and insulin levels were identically matched between groups, but the glucose infusion rate was significantly reduced in IH (29.9 +/- 1.9 mg/kg/min) versus IH + MEL group (45.4 +/- 1.5 mg/kg/min, P < 0.05) demonstrating a decrease in insulin sensitivity. These results suggest that ROS and nitrite/nitrate levels play important roles in the microvascular dysfunction in IH and that this process is attenuated by melatonin. In conclusion, protection induced by melatonin against functional and metabolic impairment in IH is related to the regulation of ROS and nitrite/nitrate levels in the microcirculation. These observations may have importance to OSA pathological changes.

  17. Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: mechanism for immune evasion?

    PubMed

    Soriano, Cyd; Mukaro, Violet; Hodge, Greg; Ahern, Jessica; Holmes, Mark; Jersmann, Hubertus; Moffat, David; Meredith, David; Jurisevic, Craig; Reynolds, Paul N; Hodge, Sandra

    2012-07-01

    Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.

  18. Sodium dodecyl sulfate reduces bacterial contamination in goat colostrum without negative effects on immune passive transfer in goat kids.

    PubMed

    Morales-delaNuez, A; Moreno-Indias, I; Sánchez-Macías, D; Capote, J; Juste, M C; Castro, N; Hernández-Castellano, L E; Argüello, A

    2011-01-01

    To investigate the use of sodium dodecyl sulfate (SDS) as a biocide on goat colostrum, 2 experiments were performed. In the first, 20 goat colostrum samples were divided into 3 aliquots. A different treatment was performed on each aliquot: pasteurization (56°C, 30 min) or addition of SDS to a final concentration of either 0.1 or 1% (36°C, 10 min). Immunoglobulin G and colony-forming units were evaluated before and after treatment. Both pasteurization and treatment with 1% SDS significantly reduced the colony-forming units in colostrum. Treatment with 0.1% SDS was not effective at reducing the colony-forming units in colostrum. The IgG concentration of pasteurized colostrum was significantly lower than that of untreated colostrum, whereas treatment with 1% SDS did not affect the colostrum IgG concentration. In the second experiment, the effects of SDS colostrum treatment on immune passive transfer were evaluated. Forty goat kids were fed either refrigerated colostrum or colostrum treated with 1% SDS twice daily for 2 d. Blood samples were obtained at birth and every day for 5 d. IgG, IgM, and IgA were measured in blood serum to monitor the passive immune transfer process. Creatinine, glucose, total cholesterol, blood urea nitrogen, bilirubin, and aspartate transaminase were also monitored to evaluate the health of kids. No differences in serum IgG, IgM, IgA, creatinine, glucose, total cholesterol, blood urea nitrogen, bilirubin, or aspartate transaminase levels were observed between groups. Our findings indicate that SDS is an efficient colostrum biocide that, unlike pasteurization, does not affect immune passive transfer or goat kid health.

  19. Ascorbic acid, catalase and chlorpromazine reduce cryopreservation-induced damages to crossbred bull spermatozoa.

    PubMed

    Paudel, K P; Kumar, S; Meur, S K; Kumaresan, A

    2010-04-01

    The present study evaluated the effectiveness of ascorbic acid, catalase, chlorpromazine and their combinations in reducing the cryodamages to crossbred bull (Bos taurus x Bos indicus) spermatozoa. A total of 32 ejaculates (eight each from four bulls) were diluted in Tris-citric acid-fructose-egg yolk-glycerol extender. Each ejaculate was split into six parts (five treatment and one control). Treatment groups included 10 mm ascorbic acid, 0.1 mm chlorpromazine, 200 IU/ml catalase, 10 mm ascorbic acid + 0.1 mm chlorpromazine or 200 IU/ml catalase + 0.1 mm chlorpromazine in the extender. Fluorescent probes (Fluorescein isothiocyanate--Pisum sativum agglutinin + Propidium iodide) were used for the assessment of spermatozoa viability and acrosomal status. The proportion of acrosome intact live (AIL), acrosome intact dead, acrosome reacted live and acrosome reacted dead sperm was assessed in fresh, equilibrated and frozen-thawed semen. The functional status of the sperm was assessed using hypo-osmotic sperm swelling test (HOSST). Activities of acrosin and hyaluronidase enzyme were also determined. Lipid peroxidation level was assayed based on the melonaldehyde (MDA) production. In cryopreserved semen, the values of AIL spermatozoa, HOSST response, hyaluronidase and acrosin activity were reduced by 53%, 47%, 34% and 54%, respectively from their initial values in fresh semen. However, MDA level was threefold higher in the frozen-thawed sperm compared with fresh sperm. Significant (p < 0.05) improvement in motility, viability, HOSST response, retention of hyaluonidase and acrosin and reduction in MDA was recorded in ascorbic acid, catalase, ascorbic acid + chlorpromazine and catalase + chlorpromazine incorporated groups. The percentage of AIL sperm was significantly (p < 0.05) higher in ascorbic acid, catalase and ascorbic acid + chlorpromazine incorporated groups compared with the control. Chlorpromazine alone did not improve the post-thaw semen quality but when combined

  20. 17β-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress.

    PubMed

    Wang, Shaolan; Wang, Baoying; Feng, Yan; Mo, Mingshu; Du, Fangying; Li, Hongbo; Yu, Xiaorui

    2015-01-01

    Oxidative stress is considered as a major cause of light-induced retinal neurodegeneration. The protective role of 17β-estradiol (βE2) in neurodegenerative disorders is well known, but its underlying mechanism remains unclear. Here, we utilized a light-induced retinal damage model to explore the mechanism by which βE2 exerts its neuroprotective effect. Adult male and female ovariectomized (OVX) rats were exposed to 8,000 lx white light for 12 h to induce retinal light damage. Electroretinogram (ERG) assays and hematoxylin and eosin (H&E) staining revealed that exposure to light for 12 h resulted in functional damage to the rat retina, histological changes, and retinal neuron loss. However, intravitreal injection (IVI) of βE2 significantly rescued this impaired retinal function in both female and male rats. Based on the level of malondialdehyde (MDA) production (a biomarker of oxidative stress), an increase in retinal oxidative stress followed light exposure, and βE2 administration reduced this light-induced oxidative stress. Quantitative reverse-transcriptase (qRT)-PCR indicated that the messenger RNA (mRNA) levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were downregulated in female OVX rats but were upregulated in male rats after light exposure, suggesting a gender difference in the regulation of these antioxidant enzyme genes in response to light. However, βE2 administration restored or enhanced the SOD and Gpx expression levels following light exposure. Although the catalase (CAT) expression level was insensitive to light stimulation, βE2 also increased the CAT gene expression level in both female OVX and male rats. Further examination indicated that the antioxidant proteins thioredoxin (Trx) and nuclear factor erythroid 2-related factor 2 (Nrf2) are also involved in βE2-mediated antioxidation and that the cytoprotective protein heme oxygenase-1 (HO-1) plays a key role in the endogenous defense mechanism

  1. Iron (FeII) Chelation, Ferric Reducing Antioxidant Power, and Immune Modulating Potential of Arisaema jacquemontii (Himalayan Cobra Lily)

    PubMed Central

    Sudan, Rasleen; Bhagat, Madhulika; Singh, Jasvinder; Koul, Anupurna

    2014-01-01

    This study explored the antioxidant and immunomodulatory potential of ethnomedicinally valuable species, namely, Arisaema jacquemontii of north-western Himalayan region. The tubers, leaves, and fruits of this plant were subjected to extraction using different solvents. In vitro antioxidant studies were performed in terms of chelation power on ferrous ions and FRAP assay. The crude methanol extract of leaves was found to harbour better chelating capacity (58% at 100 μg/mL) and reducing power (FRAP value 1085.4 ± 0.11 μMFe3+/g dry wt.) than all the other extracts. The crude methanol extract was thus further partitioned with solvents to yield five fractions. Antioxidant study of fractions suggested that the methanol fraction possessed significant chelation capacity (49.7% at 100 μg/mL) and reducing power with FRAP value of 1435.4 μM/g dry wt. The fractions were also studied for immune modulating potential where it was observed that hexane fraction had significant suppressive effect on mitogen induced T-cell and B-cell proliferation and remarkable stimulating effect on humoral response by 141% and on DTH response by 168% in immune suppressed mice as compared to the controls. Therefore, it can be concluded that A. jacquemontii leaves hold considerable antioxidant and immunomodulating potential and they can be explored further for the identification of their chemical composition for a better understanding of their biological activities. PMID:24895548

  2. Feasibility of reducing rabies immunoglobulin dosage for passive immunization against rabies: results of In vitro and In vivo studies.

    PubMed

    Madhusudana, Shampur Narayan; Ashwin, Belludi Yajaman; Sudarshan, Sampada

    2013-09-01

    Passive immunization is a crucial parameter for prevention of human rabies. Presently as World Health Organization (WHO) strongly advocates local infiltration of rabies immunoglobulin in and around the bite wound, we feel that there is no basis for calculating the dose of immunoglobulin based on body weight. Keeping this in view we conducted both in vitro and in vivo studies to know whether the dose of immunoglobulin can be reduced and still obtain complete neutralization of the virus. In vitro neutralization studies were conducted using CVS strain of virus and BHK 21 cells. In vivo experiments were conducted in 4 weeks old Swiss albino mice by initial challenge with CVS followed by infiltration with increasing dilutions of either human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). In vitro studies showed that a dose of 100 FFD 50 of CVS was neutralized by increasing dilution of both HRIG and ERIG and 100% neutralization was observed with HRIG and ERIG in as low quantities as 0.025 IU. In mice studies there was 100% survival of mice infiltrated with 0.025 IU of both HRIG and ERIG compared with 100% mortality in mice infiltrated with normal saline. These results suggest that it is possible to reduce the dose of rabies immunoglobulins by at least 16 times the presently advocated dose. These findings needs to be further evaluated using larger animal models and street viruses prevalent in nature but cannot serve as recommendations for use of RIG for passive immunization in humans.

  3. Cytomegalovirus Infection May Contribute to the Reduced Immune Function, Growth, Development, and Health of HIV-Exposed, Uninfected African Children

    PubMed Central

    Filteau, Suzanne; Rowland-Jones, Sarah

    2016-01-01

    With increasing access to antiretroviral therapy (ART) in Africa, most children born to HIV-infected mothers are not themselves HIV-infected. These HIV-exposed, uninfected (HEU) children are at increased risk of mortality and have immune, growth, development, and health deficits compared to HIV-unexposed children. HEU children are known to be at higher risk than HIV-unexposed children of acquiring cytomegalovirus (CMV) infection in early life. This risk is largely unaffected by ART and is increased by breastfeeding, which itself is critically important for child health and survival. Early CMV infection, namely in utero or during early infancy, may contribute to reduced growth, altered or impaired immune functions, and sensory and cognitive deficits. We review the evidence that CMV may be responsible for the health impairments of HEU children. There are currently no ideal safe and effective interventions to reduce postnatal CMV infection. If a clinical trial showed proof of the principle that decreasing early CMV infection improved health and development of HEU children, this could provide the impetus needed for the development of better interventions to improve the health of this vulnerable population. PMID:27446087

  4. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.

    PubMed

    Härtlova, Anetta; Erttmann, Saskia F; Raffi, Faizal Am; Schmalz, Anja M; Resch, Ulrike; Anugula, Sharath; Lienenklaus, Stefan; Nilsson, Lisa M; Kröger, Andrea; Nilsson, Jonas A; Ek, Torben; Weiss, Siegfried; Gekara, Nelson O

    2015-02-17

    Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

  5. Hyperbaric oxygen reduces delayed immune-mediated neuropathology in experimental carbon monoxide toxicity

    SciTech Connect

    Thom, Stephen R. . E-mail: sthom@mail.med.upenn.edu; Bhopale, Veena M.; Fisher, Donald

    2006-06-01

    The goal of this investigation was to determine whether exposure to hyperbaric oxygen (HBO{sub 2}) would ameliorate biochemical and functional brain abnormalities in an animal model of carbon monoxide (CO) poisoning. In this model, CO-mediated oxidative stress causes chemical alterations in myelin basic protein (MBP), which initiates an adaptive immunological response that leads to a functional deficit. CO-exposed rats do not show improvements in task performance in a radial maze. We found that HBO{sub 2} given after CO poisoning will prevent this deficit, but not eliminate all of the CO-mediated biochemical alterations in MBP. MBP from HBO{sub 2} treated CO-exposed rats is recognized normally by a battery of antibodies, but exhibits an abnormal charge pattern. Lymphocytes from HBO{sub 2}-treated and control rats do not become activated when incubated with MBP, immunohistological evidence of microglial activation is not apparent, and functional deficits did not occur, unlike untreated CO-exposed rats. The results indicate that HBO{sub 2} prevents immune-mediated delayed neurological dysfunction following CO poisoning.

  6. Seeking Energy System Pathways to Reduce Ozone Damage to Ecosystems through Adjoint-based Sensitivity Analysis

    NASA Astrophysics Data System (ADS)

    Capps, S. L.; Pinder, R. W.; Loughlin, D. H.; Bash, J. O.; Turner, M. D.; Henze, D. K.; Percell, P.; Zhao, S.; Russell, M. G.; Hakami, A.

    2014-12-01

    Tropospheric ozone (O3) affects the productivity of ecosystems in addition to degrading human health. Concentrations of this pollutant are significantly influenced by precursor gas emissions, many of which emanate from energy production and use processes. Energy system optimization models could inform policy decisions that are intended to reduce these harmful effects if the contribution of precursor gas emissions to human health and ecosystem degradation could be elucidated. Nevertheless, determining the degree to which precursor gas emissions harm ecosystems and human health is challenging because of the photochemical production of ozone and the distinct mechanisms by which ozone causes harm to different crops, tree species, and humans. Here, the adjoint of a regional chemical transport model is employed to efficiently calculate the relative influences of ozone precursor gas emissions on ecosystem and human health degradation, which informs an energy system optimization. Specifically, for the summer of 2007 the Community Multiscale Air Quality (CMAQ) model adjoint is used to calculate the location- and sector-specific influences of precursor gas emissions on potential productivity losses for the major crops and sensitive tree species as well as human mortality attributable to chronic ozone exposure in the continental U.S. The atmospheric concentrations are evaluated with 12-km horizontal resolution with crop production and timber biomass data gridded similarly. These location-specific factors inform the energy production and use technologies selected in the MARKet ALlocation (MARKAL) model.

  7. Pest trade-offs in technology: reduced damage by caterpillars in Bt cotton benefits aphids.

    PubMed

    Hagenbucher, Steffen; Wäckers, Felix L; Wettstein, Felix E; Olson, Dawn M; Ruberson, John R; Romeis, Jörg

    2013-05-07

    The rapid adoption of genetically engineered (GE) plants that express insecticidal Cry proteins derived from Bacillus thuringiensis (Bt) has raised concerns about their potential impact on non-target organisms. This includes the possibility that non-target herbivores develop into pests. Although studies have now reported increased populations of non-target herbivores in Bt cotton, the underlying mechanisms are not fully understood. We propose that lack of herbivore-induced secondary metabolites in Bt cotton represents a mechanism that benefits non-target herbivores. We show that, because of effective suppression of Bt-sensitive lepidopteran herbivores, Bt cotton contains reduced levels of induced terpenoids. We also show that changes in the overall level of these defensive secondary metabolites are associated with improved performance of a Bt-insensitive herbivore, the cotton aphid, under glasshouse conditions. These effects, however, were not as clearly evident under field conditions as aphid populations were not correlated with the amount of terpenoids measured in the plants. Nevertheless, increased aphid numbers were visible in Bt cotton compared with non-Bt cotton on some sampling dates. Identification of this mechanism increases our understanding of how insect-resistant crops impact herbivore communities and helps underpin the sustainable use of GE varieties.

  8. No Evidence for Retinal Damage Evolving from Reduced Retinal Blood Flow in Carotid Artery Disease

    PubMed Central

    Heßler, Henning; Zimmermann, Hanna; Oberwahrenbrock, Timm; Kadas, Ella Maria; Mikolajczak, Janine; Brandt, Alexander U.; Kauert, Andreas; Paul, Friedemann; Schreiber, Stephan J.

    2015-01-01

    Introduction. Carotid artery disease (CAD) comprising high-grade internal carotid artery stenosis (CAS) or carotid artery occlusion (CAO) may lead to ipsilateral impaired cerebral blood flow and reduced retinal blood supply. Objective. To examine the influence of chronic CAD on retinal blood flow, retinal morphology, and visual function. Methods. Patients with unilateral CAS ≥ 50% (ECST criteria) or CAO were grouped according to the grade of the stenosis and to the flow direction of the ophthalmic artery (OA). Retinal perfusion was measured by transorbital duplex ultrasound, assessing central retinal artery (CRA) blood flow velocities. In addition, optic nerve and optic nerve sheath diameter were measured. Optical coherence tomography (OCT) was performed to study retinal morphology. Visual function was assessed using high- and low-contrast visual paradigms. Results. Twenty-seven patients were enrolled. Eyes with CAS ≥ 80%/CAO and retrograde OA blood flow showed a significant reduction in CRA peak systolic velocity (no-CAD side: 0.130 ± 0.035 m/s, CAS/CAO side: 0.098 ± 0.028; p = 0.005; n = 12). OCT, optic nerve thicknesses, and visual functional parameters did not show a significant difference. Conclusion. Despite assessable hemodynamic effects, chronic high-grade CAD does not lead to gaugeable morphological or functional changes of the retina. PMID:26558275

  9. Cryotherapy reduces skeletal muscle damage after ischemia/reperfusion in rats.

    PubMed

    Puntel, Gustavo O; Carvalho, Nélson R; Dobrachinski, Fernando; Salgueiro, Andréia C F; Puntel, Robson L; Folmer, Vanderlei; Barbosa, Nilda B V; Royes, Luiz F F; Rocha, João Batista T; Soares, Félix A A

    2013-02-01

    The aim of this study was to analyze the effects of cryotherapy on the biochemical and morphological changes in ischemic and reperfused (I/R) gastrocnemius muscle of rats. Forty male Wistar rats were divided into control and I/R groups, and divided based on whether or not the rats were submitted to cryotherapy. Following the reperfusion period, biochemical and morphological analyses were performed. Following cryotherapy, a reduction in thiobarbituric acid-reactive substances and dichlorofluorescein oxidation levels were observed in I/R muscle. Cryotherapy in I/R muscle also minimized effects such as decreased cellular viability, levels of non-protein thiols and calcium ATPase activity as well as increased catalase activity. Cryotherapy also limited mitochondrial dysfunction and decreased the presence of neutrophils in I/R muscle, an effect that was corroborated by reduced myeloperoxidase activity in I/R muscle treated with cryotherapy. The effects of cryotherapy are associated with a reduction in the intensity of the inflammatory response and also with a decrease in mitochondrial dysfunction.

  10. Immunization with DAT fragments is associated with long-term striatal impairment, hyperactivity and reduced cognitive flexibility in mice

    PubMed Central

    2012-01-01

    Background Possible interactions between nervous and immune systems in neuro-psychiatric disorders remain elusive. Levels of brain dopamine transporter (DAT) have been implicated in several impulse-control disorders, like attention deficit / hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Here, we assessed the interplay between DAT auto-immunity and behavioural / neurochemical phenotype. Methods Male CD-1 mice were immunized with DAT peptide fragments (DAT-i), or vehicle alone (VEH), to generate elevated circulating levels of DAT auto-antibodies (aAbs). Using an operant delay-of-reward task (20 min daily sessions; timeout 25 sec), mice had a choice between either an immediate small amount of food (SS), or a larger amount of food after a delay (LL), which increased progressively across sessions (from 0 to 150 sec). Results DAT-i mice exhibited spontaneous hyperactivity (2 h-longer wake-up peak; a wake-up attempt during rest). Two sub-populations differing in behavioural flexibility were identified in the VEH control group: they showed either a clear-cut decision to select LL or clear-cut shifting towards SS, as expected. Compared to VEH controls, choice-behaviour profile of DAT-i mice was markedly disturbed, together with long-lasting alterations of the striatal monoamines. Enhanced levels of DA metabolite HVA in DAT-i mice came along with slower acquisition of basal preferences and with impaired shifting; elevation also in DOPAC levels was associated with incapacity to change a rigid selection strategy. This scarce flexibility of performance is indicative of a poor adaptation to task contingencies. Conclusions Hyperactivity and reduced cognitive flexibility are patterns of behaviour consistent with enduring functional impairment of striatal regions. It is yet unclear how anti-DAT antibodies could enter or otherwise affect these brain areas, and which alterations in DAT activity exactly occurred after immunization. Present neuro

  11. Boric acid reduces axonal and myelin damage in experimental sciatic nerve injury.

    PubMed

    Kızılay, Zahir; Erken, Haydar Ali; Çetin, Nesibe Kahraman; Aktaş, Serdar; Abas, Burçin İrem; Yılmaz, Ali

    2016-10-01

    The aim of this study was to investigate the effects of boric acid in experimental acute sciatic nerve injury. Twenty-eight adult male rats were randomly divided into four equal groups (n = 7): control (C), boric acid (BA), sciatic nerve injury (I), and sciatic nerve injury + boric acid treatment (BAI). Sciatic nerve injury was generated using a Yasargil aneurysm clip in the groups I and BAI. Boric acid was given four times at 100 mg/kg to rats in the groups BA and BAI after injury (by gavage at 0, 24, 48 and 72 hours) but no injury was made in the group BA. In vivo electrophysiological tests were performed at the end of the day 4 and sciatic nerve tissue samples were taken for histopathological examination. The amplitude of compound action potential, the nerve conduction velocity and the number of axons were significantly lower and the myelin structure was found to be broken in group I compared with those in groups C and BA. However, the amplitude of the compound action potential, the nerve conduction velocity and the number of axons were significantly greater in group BAI than in group I. Moreover, myelin injury was significantly milder and the intensity of nuclear factor kappa B immunostaining was significantly weaker in group BAI than in group I. The results of this study show that administration of boric acid at 100 mg/kg after sciatic nerve injury in rats markedly reduces myelin and axonal injury and improves the electrophysiological function of injured sciatic nerve possibly through alleviating oxidative stress reactions.

  12. Boric acid reduces axonal and myelin damage in experimental sciatic nerve injury

    PubMed Central

    Kızılay, Zahir; Erken, Haydar Ali; Çetin, Nesibe Kahraman; Aktaş, Serdar; Abas, Burçin İrem; Yılmaz, Ali

    2016-01-01

    The aim of this study was to investigate the effects of boric acid in experimental acute sciatic nerve injury. Twenty-eight adult male rats were randomly divided into four equal groups (n = 7): control (C), boric acid (BA), sciatic nerve injury (I), and sciatic nerve injury + boric acid treatment (BAI). Sciatic nerve injury was generated using a Yasargil aneurysm clip in the groups I and BAI. Boric acid was given four times at 100 mg/kg to rats in the groups BA and BAI after injury (by gavage at 0, 24, 48 and 72 hours) but no injury was made in the group BA. In vivo electrophysiological tests were performed at the end of the day 4 and sciatic nerve tissue samples were taken for histopathological examination. The amplitude of compound action potential, the nerve conduction velocity and the number of axons were significantly lower and the myelin structure was found to be broken in group I compared with those in groups C and BA. However, the amplitude of the compound action potential, the nerve conduction velocity and the number of axons were significantly greater in group BAI than in group I. Moreover, myelin injury was significantly milder and the intensity of nuclear factor kappa B immunostaining was significantly weaker in group BAI than in group I. The results of this study show that administration of boric acid at 100 mg/kg after sciatic nerve injury in rats markedly reduces myelin and axonal injury and improves the electrophysiological function of injured sciatic nerve possibly through alleviating oxidative stress reactions. PMID:27904499

  13. Immune interventions in stroke

    PubMed Central

    Fu, Ying; Liu, Qiang; Anrather, Josef

    2016-01-01

    Inflammatory and immune responses in the brain can shape the clinical presentation and outcome of stroke. Approaches for effective management of acute stroke are sparse and many measures for brain protection fail, but our ability to modulate the immune system and modify the disease progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In acute stroke, microglia activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions. PMID:26303850

  14. Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats

    PubMed Central

    Eros, Krisztian; Magyar, Klara; Deres, Laszlo; Skazel, Arpad; Riba, Adam; Vamos, Zoltan; Kalai, Tamas; Gallyas, Ferenc; Sumegi, Balazs; Toth, Kalman

    2017-01-01

    Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative

  15. Triphasic multinutrient supplementation during acute resistance exercise improves session volume load and reduces muscle damage in strength-trained athletes.

    PubMed

    Bird, Stephen P; Mabon, Tom; Pryde, Mitchell; Feebrey, Sarah; Cannon, Jack

    2013-05-01

    We hypothesized that triphasic multinutrient supplementation during acute resistance exercise would enhance muscular performance, produce a more favorable anabolic profile, and reduce biochemical markers of muscle damage in strength-trained athletes. Fifteen male strength-trained athletes completed two acute lower-body resistance exercise sessions to fatigue 7 days apart. After a 4-hour fast, participants consumed either a multinutrient supplement (Musashi 1-2-3 Step System, Notting Hill, Australia) (SUPP) or placebo (PLA) beverage preexercise (PRE), during (DUR), and immediately postexercise (IP). Session volume loads were calculated as kilograms × repetitions. Lower-body peak power was measured using unloaded repeated countermovement jumps, and blood samples were collected to assess biochemistry, serum hormones, and muscle damage markers at PRE, DUR, IP, 30 minutes postexercise (P30), and 24 hours postexercise (P24h). The SUPP demonstrated increased glucose concentrations at DUR and IP compared with at PRE (P < .01), whereas PLA demonstrated higher glucose at P30 compared with at PRE (P < .001). Session volume load was higher for SUPP compared with PLA (P < .05). Cortisol increased at DUR, IP, and P30 compared with at PRE in both treatments (P < .05); however, SUPP also displayed lower cortisol at P24h compared with at PRE and PLA (P < .01). The total testosterone response to exercise was higher for PLA compared with SUPP (P < .01); however, total creatine kinase and C-reactive protein responses to exercise were lower for SUPP compared with PLA (P < .05). These data indicate that although triphasic multinutrient supplementation did not produce a more favorable anabolic profile, it improved acute resistance exercise performance while attenuating muscle damage in strength-trained athletes.

  16. Dexamethasone loaded core-shell SF/PEO nanofibers via green electrospinning reduced endothelial cells inflammatory damage.

    PubMed

    Chen, Weiming; Li, Dawei; Ei-Shanshory, Ahmed; El-Newehy, Mohamed; Ei-Hamshary, Hany A; Al-Deyab, Salem S; He, Chuanglong; Mo, Xiumei

    2015-02-01

    Silk fibroin (SF)/PEO nanofibers prepared by green electrospinning is safe, non-toxic and environment friendly, it is a potential drug delivery carrier for tissue engineering. In this study, a core-shell nanofibers named as Dex@SF/PEO were obtained by green electrospinning with SF/PEO as the shell and dexamethasone (Dex) in the core. The nanofiber morphology and core-shell structure were studied by Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM). The Dex release behavior from the nanofibers was tested by High Performance liquid (HPLC) method. The protective effect of drug loaded nanofibers mats on Porcine hip artery endothelial cells (PIECs) against LPS-induced inflammatory damage were determined by MTT assay. TEM result showed the distinct core-shell structure of nanofibers. In vitro drug release studies demonstrated that dexamethasone can sustain release over 192 h and core-shell nanofibers showed more slow release of Dex compared with the blending electrospinning nanofibers. Anti-inflammatory activity in vitro showed that released Dex can reduce the PIECs inflammatory damage and apoptosis which induced by lipopolysaccharide (LPS). Dex@SF/PEO nanofibers are safe and non-toxic because of no harmful organic solvents used in the preparation, it is a promising environment friendly drug carrier for tissue engineering.

  17. TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells

    PubMed Central

    Pedersen, Rune Troelsgaard; Kruse, Thomas; Nilsson, Jakob

    2015-01-01

    Genome integrity is critically dependent on timely DNA replication and accurate chromosome segregation. Replication stress delays replication into G2/M, which in turn impairs proper chromosome segregation and inflicts DNA damage on the daughter cells. Here we show that TopBP1 forms foci upon mitotic entry. In early mitosis, TopBP1 marks sites of and promotes unscheduled DNA synthesis. Moreover, TopBP1 is required for focus formation of the structure-selective nuclease and scaffold protein SLX4 in mitosis. Persistent TopBP1 foci transition into 53BP1 nuclear bodies (NBs) in G1 and precise temporal depletion of TopBP1 just before mitotic entry induced formation of 53BP1 NBs in the next cell cycle, showing that TopBP1 acts to reduce transmission of DNA damage to G1 daughter cells. Based on these results, we propose that TopBP1 maintains genome integrity in mitosis by controlling chromatin recruitment of SLX4 and by facilitating unscheduled DNA synthesis. PMID:26283799

  18. Experimental Evidence Shows Salubrinal, an eIF2α Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage

    PubMed Central

    Matsuoka, Masato; Komoike, Yuta

    2015-01-01

    Accumulating evidence indicates that endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) are involved in the pathogenesis of not only the protein misfolding disorders such as certain neurodegenerative and metabolic diseases, but also in the cytotoxicity of environmental pollutants, industrial chemicals, and drugs. Thus, the modulation of ER stress signaling pathways is an important issue for protection against cellular damage induced by xenotoxicants. The substance salubrinal has been shown to prevent dephosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). The phosphorylation of eIF2α appears to be cytoprotective during ER stress, because inhibition of the translation initiation activity of eIF2α reduces global protein synthesis. In addition, the expression of activating transcription factor 4 (ATF4), a transcription factor that induces the expression of UPR target genes, is up-regulated through alternative translation. This review shows that salubrinal can protect cells from the damage induced by a wide range of xenotoxicants, including environmental pollutants and drugs. The canonical and other possible mechanisms of cytoprotection by salubrinal from xenotoxicant-induced ER stress are also discussed. PMID:26193263

  19. Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats.

    PubMed

    Pires, Paulo W; Rogers, Curt T; McClain, Jonathon L; Garver, Hannah S; Fink, Gregory D; Dorrance, Anne M

    2011-07-01

    Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg(-1)·day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.

  20. Massage Therapy for Reducing Stress Hormones and Enhancing Immune Function in Breast Cancer Survivors

    DTIC Science & Technology

    2003-08-01

    effects suggesting that like many other interventions (e.g., exercise, diet, etc), for therapy effects to persist, continued massage treatments may be...In this study massage and relaxation therapies were examined for women with early stages of breast cancer for 1) reducing anxiety and stress hormone...16). Women in the massage and relaxation therapies received 3-30 minute sessions a week for 5 weeks. On the first and last days of the 5-week study

  1. Dietary resveratrol improves immunity but reduces reproduction of broodstock medaka Oryzias latipes (Temminck & Schlegel).

    PubMed

    Kowalska, Agata; Siwicki, Andrzej K; Kowalski, Radosław K

    2017-02-01

    Here, we investigated the effect of dietary resveratrol (20, 40, and 80 µg/g BW/day) on cell-mediated immunity (activity of spleen phagocytes and proliferative response of lymphocytes) and reproductive parameters (egg and sperm quality, i.e. fecundity-total number of eggs produced by individual fish, fertility, embryo survival, and hatching rate) in medaka. Fish fed feed with resveratrol at 40 and 80 µg/g BW/day had significantly higher metabolic activity and intracellular phagocyte killing activity than control. The proliferative lymphocyte activity of the fish from R80 group was greater by more than 20 % in comparison with the control group (P < 0.05). The percentage of macrophages (MO) and their mean fluorescence intensities (MFI) in R40 and R80 groups were significantly higher compared to C and R20 groups (P < 0.05). The differences in MO and MFI values ranged from 52.5 % (±1.5; R0 group) to 65.8 % (±1.6; R80 group) and from 23.2 (±1.4; R0 group) to 38.2 (±2.4; R80 group), respectively. Moreover, resveratrol at 80 µg/g BW/day decreased liver COX activity, i.e. 5.4 in R80 group and 7.9 in R0 group (P < 0.05). The motility parameters of the sperm obtained from the males fed feed supplemented with resveratrol at 80 µg/g BW/day exhibited the highest values except the linearity, which was lower as compared to the control (P < 0.05). The results indicate that diet supplemented with resveratrol at a dosage of 40 µg/g BW/day improves phagocyte killing ability and lymphocyte proliferation in broodstock and accelerates offspring hatch. Also, the results suggest that COX activity influences sperm and oocyte quality in fish; the presence of a COX inhibitor in the dose of 40 µg/g BW/day decreased the embryo survival.

  2. Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS

    PubMed Central

    Kong, Weimin; Li, Hongbo; Tuma, Ronald F.; Ganea, Doina

    2013-01-01

    CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibit leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models. Here we showed that Gp1a, a highly selective CB2 agonist, with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In addition, the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation. PMID:24342422

  3. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

    PubMed

    Mata, M; Ruíz, A; Cerdá, M; Martinez-Losa, M; Cortijo, J; Santangelo, F; Serrano-Mollar, A; Llombart-Bosch, A; Morcillo, E J

    2003-12-01

    Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.

  4. Intramammary Immunization of Pregnant Mice with Staphylococcal Protein A Reduces the Post-Challenge Mammary Gland Bacterial Load but Not Pathology

    PubMed Central

    Gogoi-Tiwari, Jully; Williams, Vincent; Waryah, Charlene Babra; Mathavan, Sangeetha; Tiwari, Harish Kumar; Costantino, Paul; Mukkur, Trilochan

    2016-01-01

    Protein A, encoded by the spa gene, is one of the major immune evading MSCRAMM of S. aureus, demonstrated to be prevalent in a significant percentage of clinical bovine mastitis isolates in Australia. Given its’ reported significance in biofilm formation and the superior performance of S. aureus biofilm versus planktonic vaccine in the mouse mastitis model, it was of interest to determine the immunogenicity and protective potential of Protein A as a potential vaccine candidate against bovine mastitis using the mouse mastitis model. Pregnant Balb/c mice were immunised with Protein A emulsified in an alum-based adjuvant by subcutaneous (s/c) or intramammary (i/mam) routes. While humoral immune response of mice post-immunization were determined using indirect ELISA, cell-mediated immune response was assessed by estimation of interferon-gamma (IFN-γ) produced by protein A-stimulated splenocyte supernatants. Protective potential of Protein A against experimental mastitis was determined by challenge of immunized versus sham-vaccinated mice by i/mam route, based upon manifestation of clinical symptoms, total bacterial load and histopathological damage to mammary glands. Significantly (p<0.05) higher levels of IgG1 isotype were produced in mice immunized by the s/c route. In contrast, significantly higher levels of the antibody isotype IgG2a were produced in mice immunized by the i/mam route (p<0.05). There was significant reduction (p<0.05) in bacterial loads of the mammary glands of mice immunized by Protein A regardless of the route of immunization, with medium level of clinical symptoms observed up to day 3 post-challenge. However, Protein A vaccine failed to protect immunized mice post-challenge with biofilm producing encapsulated S. aureus via i/mam route, regardless of the route of immunization, as measured by the level of mammary tissue damage. It was concluded that, Protein A in its’ native state was apparently not a suitable candidate for inclusion in a cell

  5. IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.

    PubMed

    Cohen, Idan; Idan, Cohen; Rider, Peleg; Peleg, Rider; Vornov, Elena; Elena, Voronov; Tomas, Martin; Martin, Tomas; Tudor, Cicerone; Cicerone, Tudor; Wegner, Mareike; Mareike, Wegner; Brondani, Lydia; Lydia, Brondani; Freudenberg, Marina; Marina, Freudenberg; Mittler, Gerhard; Gerhard, Mittler; Ferrando-May, Elisa; Elisa, Ferrando-May; Dinarello, Charles A; Apte, Ron N; Ron, Apte N; Schneider, Robert; Robert, Schneider

    2015-10-06

    Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1α acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1α knockout mice and show that IL-1α signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.

  6. A single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy

    PubMed Central

    2012-01-01

    Introduction Recent studies reported that human IgG antibodies are susceptible to specific proteolytic cleavage in their lower hinge region, and the hinge cleavage results in a loss of Fc-mediated effector functions. Trastuzumab is a humanized IgG1 therapeutic monoclonal antibody for the treatment of HER2-overexpressing breast cancers, and its mechanisms of action consist of inhibition of HER2 signaling and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC). The objective of this study is to investigate the potential effect of proteinase hinge cleavage on the efficacy of trastuzumab using both a breast cancer cell culture method and an in vivo mouse xenograft tumor model. Methods Trastuzumab antibody was incubated with a panel of human matrix metalloproteinases, and proteolytic cleavage in the lower hinge region was detected using both western blotting and mass spectrometry. Single hinge cleaved trastuzumab (scIgG-T) was purified and evaluated for its ability to mediate ADCC and inhibition of breast cancer cell proliferation in vitro as well as anti-tumor efficacy in the mouse xenograft tumor model. Infiltrated immune cells were detected in tumor tissues by immunohistochemistry. Results scIgG-T retains HER2 antigen binding activity and inhibits HER2-mediated downstream signaling and cell proliferation in vitro when compared with the intact trastuzumab. However, scIgG-T lost Fc-mediated ADCC activity in vitro, and had significantly reduced anti-tumor efficacy in a mouse xenograft tumor model. Immunohistochemistry showed reduced immune cell infiltration in tumor tissues treated with scIgG-T when compared with those treated with the intact trastuzumab, which is consistent with the decreased ADCC mediated by scIgG-T in vitro. Conclusion Trastuzumab can be cleaved by matrix metalloproteinases within the lower hinge. scIgG-T exhibited a significantly reduced anti-tumor efficacy in vivo due to the weakened immune effector function such as ADCC. The results

  7. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction

    PubMed Central

    Hulsmans, Maarten; Courties, Gabriel; Sun, Yuan; Heidt, Timo; Vinegoni, Claudio; Borodovsky, Anna; Fitzgerald, Kevin; Wojtkiewicz, Gregory R.; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F.; Kauffman, Kevin J.; Xing, Yiping; Shaw, Taylor E.; Libby, Peter; Langer, Robert; Weissleder, Ralph; Swirski, Filip K.

    2016-01-01

    Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE−/− mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)–targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI. PMID:27280687

  8. Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.

    PubMed

    Alvarado, Alvaro G; Thiagarajan, Praveena S; Mulkearns-Hubert, Erin E; Silver, Daniel J; Hale, James S; Alban, Tyler J; Turaga, Soumya M; Jarrar, Awad; Reizes, Ofer; Longworth, Michelle S; Vogelbaum, Michael A; Lathia, Justin D

    2016-12-27

    Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals.

  9. Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise

    PubMed Central

    Golbidi, S; Botta, A; Gottfred, S; Nusrat, A; Laher, I; Ghosh, S

    2014-01-01

    Background and Purpose The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts. Experimental Approach The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro. Key Results During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated ‘switch’ in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2O2, a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibroblasts and cardiomyocytes from necrosis induced by H2O2, but elevated caspase-3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase-3 activity, GCLc overexpression during staurosporine-induced death, which was not characterized by ROS, increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH-mediated cytoprotection. Conclusions and Implications While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T2D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise. PMID:25039894

  10. White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate.

    PubMed

    Monk, Jennifer M; Zhang, Claire P; Wu, Wenqing; Zarepoor, Leila; Lu, Jenifer T; Liu, Ronghua; Pauls, K Peter; Wood, Geoffrey A; Tsao, Rong; Robinson, Lindsay E; Power, Krista A

    2015-07-01

    Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut-health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti-inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmβ) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmβ and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1β, IL-6, interferon (IFN)γ, tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNγ, TNFα, IL-1β and IL-6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial-derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon-function priming effect of bean consumption that mitigates colitis severity.

  11. Immunity-Related Protein Expression and Pathological Lung Damage in Mice Poststimulation with Ambient Particulate Matter from Live Bird Markets.

    PubMed

    Meng, Kai; Wu, Bo; Gao, Jing; Cai, Yumei; Yao, Meiling; Wei, Liangmeng; Chai, Tongjie

    2016-01-01

    The objective of this study was to obtain insight into the adverse health effects of airborne particulate matter (PM) collected from live bird markets and to determine whether biological material in PM accounts for immune-related inflammatory response. Mice were exposed to a single or repeated dose of PM, after which the expression of toll-like receptors (TLRs), cytokines, and chemokines in the lungs of infected mice were examined by enzyme-linked immunosorbent assay and histopathological analysis. Results after single and repeated PM stimulation with [Formula: see text] indicated that TLR2 and TLR4 played a dominant role in the inflammatory responses of the lung. Further analysis demonstrated that the expression levels of IL-1β, TNF-α, IFN-γ, IL-8, IP-10, and MCP-1 increased significantly, which could eventually contribute to lung injury. Moreover, biological components in PM were critical in mediating immune-related inflammatory responses and should therefore not be overlooked.

  12. Saccharomyces cerevisiae UFMG A-905 treatment reduces intestinal damage in a murine model of irinotecan-induced mucositis.

    PubMed

    Bastos, R W; Pedroso, S H S P; Vieira, A T; Moreira, L M C; França, C S; Cartelle, C T; Arantes, R M E; Generoso, S V; Cardoso, V N; Neves, M J; Nicoli, J R; Martins, F S

    2016-09-01

    Indigenous microbiota plays a crucial role in the development of several intestinal diseases, including mucositis. Gastrointestinal mucositis is a major and serious side effect of cancer therapy, and there is no effective therapy for this clinical condition. However, some probiotics have been shown to attenuate such conditions. To evaluate the effects of Saccharomyces cerevisiae UFMG A-905 (Sc-905), a potential probiotic yeast, we investigated whether pre- or post-treatment with viable or inactivated Sc-905 could prevent weight loss and intestinal lesions, and maintain integrity of the mucosal barrier in a mucositis model induced by irinotecan in mice. Only post-treatment with viable Sc-905 was able to protect mice against the damage caused by chemotherapy, reducing the weight loss, increase of intestinal permeability and jejunal lesions (villous shortening). Besides, this treatment reduced oxidative stress, prevented the decrease of goblet cells and stimulated the replication of cells in the intestinal crypts of mice with experimental mucositis. In conclusion, Sc-905 protects animals against irinotecan-induced mucositis when administered as a post-treatment with viable cells, and this effect seems to be related with the reduction of oxidative stress and preservation of intestinal mucosa.

  13. High Parasite Burdens Cause Liver Damage in Mice following Plasmodium berghei ANKA Infection Independently of CD8+ T Cell-Mediated Immune Pathology ▿

    PubMed Central

    Haque, Ashraful; Best, Shannon E.; Amante, Fiona H.; Ammerdorffer, Anne; de Labastida, Fabian; Pereira, Tamara; Ramm, Grant A.; Engwerda, Christian R.

    2011-01-01

    Infection of C57BL/6 mice with Plasmodium berghei ANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8+ T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8+ T cells accumulated in the liver following P. berghei ANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8+ T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs during P. berghei ANKA infection. Therefore, we show that P. berghei ANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8+ T cell-mediated pathology. PMID:21343349

  14. Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity

    PubMed Central

    Sarmiento, Luis; Frisk, Gun; Anagandula, Mahesh; Cabrera-Rode, Eduardo; Roivainen, Merja; Cilio, Corrado M.

    2013-01-01

    Three large-scale Echovirus (E) epidemics (E4,E16,E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets. PMID:24223733

  15. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis.

    PubMed

    Barichello, Tatiana; Ceretta, Renan A; Generoso, Jaqueline S; Moreira, Ana Paula; Simões, Lutiana R; Comim, Clarissa M; Quevedo, João; Vilela, Márcia Carvalho; Zuardi, Antonio Waldo; Crippa, José A; Teixeira, Antônio Lucio

    2012-12-15

    Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10μl of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with cannabidiol (2.5, 5, or 10mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of cannabidiol at different doses reduced the TNF-α level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.

  16. Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat.

    PubMed

    Chen, H; Chopp, M; Zhang, R L; Bodzin, G; Chen, Q; Rusche, J R; Todd, R F

    1994-04-01

    We investigated the effect of an anti-CD11b monoclonal antibody (1B6c) on ischemic cell damage after transient middle cerebral artery occlusion. We divided animals into three groups: MAb 1 group (n = 5)--rats were subjected to 2 hours of transient occlusion and 1B6c (1 mg/kg) was administered intravenously at 0 and 22 hours of reperfusion; MAb 2 group (n = 5)--same experimental protocol as MAb 1 group, except that the initial dose of 1B6c was increased to 2 mg/kg; and control group (n = 5)--same experimental protocol as MAb 2 group, except that an isotype-matched control antibody was administered. Animals were weighed and tested for neurological function before and after occlusion of the middle cerebral artery. Forty-six hours after reperfusion, brain sections were stained with hematoxylin and eosin for histology evaluation. We observed a significant reduction of weight loss and improvement in neurological function after ischemia in the MAb 2 animals compared to MAb 1 and vehicle-treated animals (p < 0.05). The lesion volume was significantly smaller in the MAb 2 group (19.5 +/- 1.9%) compared to MAb 1 (29.9 +/- 2.6%) and vehicle-treated (34.2 +/- 5.4%) groups (p < 0.01). Tissue polymorphonuclear cell numbers were reduced in both 1B6c-administered groups. Our data demonstrate that administration of anti-CD11b antibody results in a dose-dependent, significant functional improvement and reduction of ischemic cell damage after transient focal cerebral ischemia in the rat.

  17. Willed-movement training reduces brain damage and enhances synaptic plasticity related proteins synthesis after focal ischemia.

    PubMed

    Nie, Jingjing; Yang, Xiaosu; Tang, Qingping; Shen, Qin; Li, Simin

    2016-01-01

    It has been wildly accepted that willed movement(WM) training promotes neurological rehabilitation in patients with stroke. However, it was not clear whether the effect of WM is better than other forms of exercise. The purpose of this study is to assess different effects of WM and other forms of exercise on rats with focal ischemia. The subjects are all had right middle cerebral artery occlusion (MCAO) surgery and randomly allocated to three groups of training and one control group with no training. Infarct volume by 2,3,5-triphenyltetrazolium chloride (TTC) dye, expression of PICK1 and synaptophysin in cerebral cortex and striatum of injured side by western blotting and immunofluorescence performed are analyzed. Exercise has done respectively on rats in each group for 15 days and 30 days. Compared with the control group, the brain damage is reduced in other groups after 15 days exercise. The protein expressions levels of synaptophysin and PICK1 are upregulated after exercise. Concentration of PICK1 protein in WM is greater than other exercise groups, and the expression of synaptophysin in WM and SM groups are higher than EM groups. The number of PICK1 positive cells, synaptophysin and PICK1 co-positive cells are increased by exercise. Synaptophysin is widely distributed in cortex surrounding the injury area in WM and EM. It is indicated in our result that willed-movement training is the most effective intervention in enhancing the PICK1-mediated synaptic plasticity in the area adjacent to the damage region of ischemic rats.

  18. Antigenotoxic Studies of Different Substances to Reduce the DNA Damage Induced by Aflatoxin B1 and Ochratoxin A

    PubMed Central

    Madrigal-Santillán, Eduardo; Morales-González, José A.; Vargas-Mendoza, Nancy; Reyes-Ramírez, Patricia; Cruz-Jaime, Sandra; Sumaya-Martínez, Teresa; Pérez-Pastén, Ricardo; Madrigal-Bujaidar, Eduardo

    2010-01-01

    Mycotoxins are produced mainly by the mycelial structure of filamentous fungi, or more specifically, molds. These secondary metabolites are synthesized during the end of the exponential growth phase and appear to have no biochemical significance in fungal growth and development. The contamination of foods and feeds with mycotoxins is a significant problem for the adverse effects on humans, animals, and crops that result in illnesses and economic losses. The toxic effect of the ingestion of mycotoxins in humans and animals depends on a number of factors including intake levels, duration of exposure, toxin species, mechanisms of action, metabolism, and defense mechanisms. In general, the consumption of contaminated food and feed with mycotoxin induces to neurotoxic, immunosuppressive, teratogenic, mutagenic, and carcinogenic effect in humans and/or animals. The most significant mycotoxins in terms of public health and agronomic perspective include the aflatoxins, ochratoxin A (OTA), trichothecenes, fumonisins, patulin, and the ergot alkaloids. Due to the detrimental effects of these mycotoxins, several strategies have been developed in order to reduce the risk of exposure. These include the degradation, destruction, inactivation or removal of mycotoxins through chemical, physical and biological methods. However, the results obtained with these methods have not been optimal, because they may change the organoleptic characteristics and nutritional values of food. Another alternative strategy to prevent or reduce the toxic effects of mycotoxins is by applying antimutagenic agents. These substances act according to several extra- or intracellular mechanisms, their main goal being to avoid the interaction of mycotoxins with DNA; as a consequence of their action, these agents would inhibit mutagenesis and carcinogenesis. This article reviews the main strategies used to control AFB1 and ochratoxin A and contains an analysis of some antigenotoxic substances that reduce the

  19. A 1,4-dihydropyridine derivative reduces DNA damage and stimulates DNA repair in human cells in vitro.

    PubMed

    Ryabokon, Nadezhda I; Goncharova, Rose I; Duburs, Gunars; Rzeszowska-Wolny, Joanna

    2005-11-10

    Compounds of the 1,4-dihydropyridine (1,4-DHP) series have been shown to reduce spontaneous, alkylation- and radiation-induced mutation rates in animal test systems. Here we report studies using AV-153, the 1,4-DHP derivative that showed the highest antimutagenic activity in those tests, to examine if it modulates DNA repair in human peripheral blood lymphocytes and in two human lymphoblastoid cell lines, Raji and HL-60. AV-153 caused a 50% inhibition of growth (IC50) of Raji and HL-60 cells at 14.9+/-1.2 and 10.3+/-0.8mM, respectively, but did not show a cytotoxic effect at concentrations <100 microM. Alkaline single-cell gel electrophoresis (comet) assays showed that AV-153 reduced the number of DNA strand breaks in untreated cells and also in cells exposed to 2 Gy of gamma-radiation, 100 microM ethylmethane sulfonate (EMS), or 100 microM H2O2. DNA damage was reduced by up to 87% at AV-153 concentrations between 1 and 10nM, and a positive dose-effect relationship was seen between 0.01 and 1 nM. Comparison of the kinetics of DNA strand-break rejoining in the presence and absence of AV-153 revealed a considerable influence on the rate of repair. In view of the resemblance of this compound's structure to that of dihydronicotinamide, a substrate for poly(ADP-rybose)polymerase, the modulation of DNA repair by AV-153 could involve an influence on poly(ADP)ribosylation.

  20. HMGB1 siRNA can reduce damage to retinal cells induced by high glucose in vitro and in vivo

    PubMed Central

    Jiang, Shuang; Chen, Xiaolong

    2017-01-01

    <0.05), protected morphological changes in the retina, and improved the function of the retina (P<0.05). In HRECs treated with high glucose, HMGB1 siRNA pretreatment increased cell viability, reduced cell apoptosis, and reduced oxidative damage to cells (all P<0.05). Western blot detection found that HMGB1 siRNA pretreatment can inhibit the expression of cleaved caspase 3 and improve the expression of BCL2 (P<0.05). HMGB1 and NFκB expression increased in a time-dependent manner in the high-glucose environment and IKKβ and NFκB protein expression decreased significantly after HMGB1 silencing. Conclusion As a therapeutic target, HMGB1 siRNA can reduce retinal cell damage induced by high glucose in vitro and in vivo and delay DR progress through the HMGB1–IKKβ–NFκB signaling pathway. PMID:28352154

  1. Encapsulation and Diffraction-Pattern-Correction Methods to Reduce the Effect of Damage in X-Ray Diffraction Imaging of Single Biological Molecules

    SciTech Connect

    Hau-Riege, Stefan P.; London, Richard A.; Chapman, Henry N.; Szoke, Abraham; Timneanu, Nicusor

    2007-05-11

    Short and intense x-ray pulses may be used for atomic-resolution diffraction imaging of single biological molecules. Radiation damage and a low signal-to-noise ratio impose stringent pulse requirements. In this Letter, we describe methods for decreasing the damage and improving the signal by encapsulating the molecule in a sacrificial layer (tamper) that reduces atomic motion and by postprocessing the pulse-averaged diffraction pattern to correct for ionization damage. Simulations show that these methods greatly improve the image quality.

  2. Brugia pahangi: immunization with early L3 ES alters parasite migration, and reduces microfilaremia and lymphatic lesion formation in gerbils (Meriones unguiculatus).

    PubMed

    Zipperer, Ginger R; Arumugam, Sridhar; Chirgwin, Sharon R; Coleman, Sharon U; Shakya, Krishna P; Klei, Thomas R

    2013-10-01

    Previous studies have shown that intradermally (ID) injected Brugia pahangi L3 s migrate through various tissues and into the lymphatics of gerbils in a distinct pattern. Excretory/secretory products (ES) produced at the time of invasion of B. pahangi are likely to be important in this early migration phase of the parasite life cycle in their rodent host. Hence, early L3 ES was collected from 24h in vitro cultures of B. pahangi L3 larvae and used in immunization experiments to investigate the effect of immunity to early L3 ES on worm migration, survival and development of B. pahangi. Immunization of gerbils with ES in RIBI adjuvant produced antibodies to numerous ES proteins eliciting a strong humoral response to ES and indirect fluorescent antibody (IFA) assay using anti-ES serum recognized the ES proteins on the surface of B. pahangi L3 larvae. Following ES immunization, gerbils were challenged either ID or intraperitoneally (IP) with 100 L3 s of B. pahangi and euthanized at 3 or 106 days post inoculation (DPI). Immunization with early ES slowed the migration of ID inoculated L3 at 3 DPI and significantly altered the locations of adult worms at 106 DPI. Immunization did not induce protection in any treatment group. However, immunized animals had significantly fewer microfilariae per female worm suggesting the antigens in ES are important in microfilariae development or survival in the host. The number of lymphatic granulomas was also significantly reduced in ES immunized animals. It is important to note that microfilariae serve as a nidus in these granulomas. Our results shows immunization with early Brugia malayi L3 ES alters the worm migration, affects circulating microfilarial numbers and reduces lymphatic granulomas associated with B. pahangi infection in gerbils.

  3. Acyclovir Therapy Reduces the CD4+ T Cell Response against the Immunodominant pp65 Protein from Cytomegalovirus in Immune Competent Individuals.

    PubMed

    Pachnio, Annette; Begum, Jusnara; Fox, Ashini; Moss, Paul

    2015-01-01

    Cytomegalovirus (CMV) infects the majority of the global population and leads to the development of a strong virus-specific immune response. The CMV-specific CD4+ and CD8+ T cell immune response can comprise between 10 and 50% of the T cell pool within peripheral blood and there is concern that this may impair immunity to other pathogens. Elderly individuals with the highest magnitude of CMV-specific immune response have been demonstrated to be at increased risk of mortality and there is increasing interest in interventions that may serve to moderate this. Acyclovir is an anti-viral drug with activity against a range of herpes viruses and is used as long term treatment to suppress reactivation of herpes simplex virus. We studied the immune response to CMV in patients who were taking acyclovir to assess if therapy could be used to suppress the CMV-specific immune response. The T cell reactivity against the immunodominant late viral protein pp65 was reduced by 53% in people who were taking acyclovir. This effect was seen within one year of therapy and was observed primarily within the CD4+ response. Acyclovir treatment only modestly influenced the immune response to the IE-1 target protein. These data show that low dose acyclovir treatment has the potential to modulate components of the T cell response to CMV antigen proteins and indicate that anti-viral drugs should be further investigated as a means to reduce the magnitude of CMV-specific immune response and potentially improve overall immune function.

  4. Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

    SciTech Connect

    Yoshida, Ryoko; Suzuki, Mayu; Sakaguchi, Ryota; Hasegawa, Eiichi; Kimura, Akihiro; Shichita, Takashi; Sekiya, Takashi; Shiraishi, Hiroshi; Shimoda, Kouji; Yoshimura, Akihiko

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKK{beta}-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-{alpha}, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.

  5. Immunity-Related Protein Expression and Pathological Lung Damage in Mice Poststimulation with Ambient Particulate Matter from Live Bird Markets

    PubMed Central

    Meng, Kai; Wu, Bo; Gao, Jing; Cai, Yumei; Yao, Meiling; Wei, Liangmeng; Chai, Tongjie

    2016-01-01

    The objective of this study was to obtain insight into the adverse health effects of airborne particulate matter (PM) collected from live bird markets and to determine whether biological material in PM accounts for immune-related inflammatory response. Mice were exposed to a single or repeated dose of PM, after which the expression of toll-like receptors (TLRs), cytokines, and chemokines in the lungs of infected mice were examined by enzyme-linked immunosorbent assay and histopathological analysis. Results after single and repeated PM stimulation with PM2.5+,PM2.5−,PM10+, and PM10− indicated that TLR2 and TLR4 played a dominant role in the inflammatory responses of the lung. Further analysis demonstrated that the expression levels of IL-1β, TNF-α, IFN-γ, IL-8, IP-10, and MCP-1 increased significantly, which could eventually contribute to lung injury. Moreover, biological components in PM were critical in mediating immune-related inflammatory responses and should therefore not be overlooked. PMID:27446082

  6. REC-2006-A Fractionated Extract of Podophyllum hexandrum Protects Cellular DNA from Radiation-Induced Damage by Reducing the Initial Damage and Enhancing Its Repair In Vivo.

    PubMed

    Chaudhary, Pankaj; Shukla, Sandeep Kumar; Sharma, Rakesh Kumar

    2011-01-01

    Podophyllum hexandrum, a perennial herb commonly known as the Himalayan May Apple, is well known in Indian and Chinese traditional systems of medicine. P. hexandrum has been widely used for the treatment of venereal warts, skin infections, bacterial and viral infections, and different cancers of the brain, lung and bladder. This study aimed at elucidating the effect of REC-2006, a bioactive fractionated extract from the rhizome of P. hexandrum, on the kinetics of induction and repair of radiation-induced DNA damage in murine thymocytes in vivo. We evaluated its effect on non-specific radiation-induced DNA damage by the alkaline halo assay in terms of relative nuclear spreading factor (RNSF) and gene-specific radiation-induced DNA damage via semi-quantitative polymerase chain reaction. Whole body exposure of animals with gamma rays (10 Gy) caused a significant amount of DNA damage in thymocytes (RNSF values 17.7 ± 0.47, 12.96 ± 1.64 and 3.3 ± 0.014) and a reduction in the amplification of β-globin gene to 0, 28 and 43% at 0, 15 and 60 min, respectively. Administrating REC-2006 at a radioprotective concentration (15 mg kg(-1) body weight) 1 h before irradiation resulted in time-dependent reduction of DNA damage evident as a decrease in RNSF values 6.156 ± 0.576, 1.647 ± 0.534 and 0.496 ± 0.012, and an increase in β-globin gene amplification 36, 95 and 99%, at 0, 15 and 60 min, respectively. REC-2006 scavenged radiation-induced hydroxyl radicals in a dose-dependent manner stabilized DPPH free radicals and also inhibited superoxide anions. Various polyphenols and flavonoides present in REC-2006 might contribute to scavenging of radiation-induced free radicals, thereby preventing DNA damage and stimulating its repair.

  7. Use of EPO as an adjuvant in PDT of brain tumors to reduce damage to normal brain

    NASA Astrophysics Data System (ADS)

    Rendon, Cesar A.; Lilge, Lothar

    2004-10-01

    In order to reduce damage to surrounding normal brain in the treatment of brain tumors with photodynamic therapy (PDT), we have investigated the use of the cytokine erythropoietin (EPO) to exploit its well-established role as a neuroprotective agent. In vitro experiments demonstrated that EPO does not confer protection from PDT to rat glioma cells. In vivo testing of the possibility of EPO protecting normal brain tissue was carried out. The normal brains of Lewis rats were treated with Photofrin mediated PDT (6.25 mg/Kg B.W. 22 hours pre irradiation) and the outcome of the treatment compared between animals that received EPO (5000 U/Kg B.W. 22 hours pre irradiation) and controls. This comparison was made based on the volume of necrosis, as measured with the viability stain 2,3,5- Triphenyl tetrazoium chloride (TTC), and incidence of apoptosis, as measured with in situ end labeling assay (ISEL). Western blotting showed that EPO reaches the normal brain and activates the anti-apoptotic protein PKB/AKT1 within the brain cortex. The comparison based on volume of necrosis showed no statistical significance between the two groups. No clear difference was observed in the ISEL staining between the groups. A possible lack of responsivity in the assays that give rise to these results is discussed and future corrections are described.

  8. Clovamide-rich extract from Trifolium pallidum reduces oxidative stress-induced damage to blood platelets and plasma.

    PubMed

    Kolodziejczyk, Joanna; Olas, Beata; Wachowicz, Barbara; Szajwaj, Barbara; Stochmal, Anna; Oleszek, Wieslaw

    2011-09-01

    Numerous plants (including clovers) have been widely used in folk medicine for the treatment of different disorders. This in vitro study was designed to examine the antioxidative effects of the clovamide-rich fraction, obtained from aerial parts of Trifolium pallidum, in the protection of blood platelets and plasma against the nitrative and oxidative damage, caused by peroxynitrite (ONOO(-)). Carbonyl groups and 3-nitrotyrosine in blood platelet and plasma proteins were determined by ELISA tests. Thiol groups level was estimated by using 5,5'-dithio-bis(2-nitro-benzoic acid, DTNB). Plasma lipid peroxidation was measured spectrophotometrically as the production of thiobarbituric acid reactive substances. The results from our work indicate that clovamide-rich T. pallidum extract may reveal the protective properties in the prevention against oxidative stress. The presence of clovamide-rich T. pallidum extract (12.5-100 μg/ml) partly inhibited ONOO(-)-mediated protein carbonylation and nitration. All the used concentrations of T. pallidum extract reduced lipid peroxidation in plasma. The antioxidative action of the tested extract in the protection of blood platelet lipids was less effective; the extract at the lowest final concentration (12.5 μg/ml) had no protective effect against lipid peroxidation. The present results indicate that the extract from T. pallidum is likely to be a source of compounds with the antioxidative properties, useful in the prevention against the oxidative stress-related diseases.

  9. Nest-building behavior of Monk Parakeets and insights into potential mechanisms for reducing damage to utility poles.

    PubMed

    Burgio, Kevin R; Rubega, Margaret A; Sustaita, Diego

    2014-01-01

    The Monk Parakeet (Myiopsitta monachus) commonly uses utility poles as a substrate for building large, bulky nests. These nests often cause fires and electric power outages, creating public safety risks and increasing liability and maintenance costs for electric companies. Previous research has focused on lethal methods and chemical contraception to prevent nesting on utility poles and electrical substations. However, implementation of lethal methods has led to public protests and lawsuits, while chemical contraception may affect other than the targeted species, and must be continually reapplied for effectiveness. One non-lethal alternative, nest removal, is costly and may not be a sustainable measure if Monk Parakeet populations continue to grow. In order to identify cost-effective non-lethal solutions to problems caused by Monk Parakeet nesting, we studied their behavior as they built nests on utility poles. Monk Parakeets initiate nests by attaching sticks at the intersection of the pole and electric lines. We found that parakeets use the electric lines exclusively to gain access to the intersection of lines and pole during nest initiation, and continue to use the lines intensively throughout construction. Monk Parakeets also have more difficulty attaching sticks during the early stages of nest construction than when the nest is nearing completion. These findings suggest that intervention during the earlier stages of nest building, by excluding Monk Parakeets from electric lines adjacent to poles, may be an effective, non-lethal method of reducing or eliminating parakeets nesting on, and damaging, utility poles.

  10. Docosahexaenoic Acid Reduces Cerebral Damage and Ameliorates Long-Term Cognitive Impairments Caused by Neonatal Hypoxia-Ischemia in Rats.

    PubMed

    Arteaga, Olatz; Revuelta, M; Urigüen, L; Martínez-Millán, L; Hilario, E; Álvarez, A

    2016-10-29

    As the interest in the neuroprotective possibilities of docosahexaenoic acid (DHA) for brain injury has grown in the recent years, we aimed to investigate the long-term effects of this fatty acid in an experimental model of perinatal hypoxia-ischemia in rats. To this end, motor activity, aspects of learning, and memory function and anxiety, as well as corticofugal connections visualized by using tracer injections, were evaluated at adulthood. We found that in the hours immediately following the insult, DHA maintained mitochondrial inner membrane integrity and transmembrane potential, as well as the integrity of synaptic processes. Seven days later, morphological damage at the level of the middle hippocampus was reduced, since neurons and myelin were preserved and the astroglial reactive response and microglial activation were seen to be diminished. At adulthood, the behavioral tests revealed that treated animals presented better long-term working memory and less anxiety than non-treated hypoxic-ischemic animals, while no difference was found in the spontaneous locomotor activity. Interestingly, hypoxic-ischemic injury caused alterations in the anterograde corticofugal neuronal connections which were not so evident in rats treated with DHA. Thus, our results indicate that DHA treatment can lead to long-lasting neuroprotective effects in this experimental model of neonatal hypoxia-ischemic brain injury, not only by mitigating axonal changes but also by enhancing cognitive performance at adulthood.

  11. The combined treatment of praziquantel with osteopontin immunoneutralization reduces liver damage in Schistosoma japonicum-infected mice.

    PubMed

    Chen, Bo-Lin; Zhang, Gui-Ying; Wang, Shi-Ping; Li, Qian; Xu, Mei-Hua; Shen, Yue-Ming; Yan, Lu; Gu, Huan; Li, Jia; Huang, Y L; Mu, Yi-Bing

    2012-04-01

    The aim of this study was to evaluate the therapeutic effects of osteopontin neutralization treatment on schistosome-induced liver injury in BALB/C mice. We randomly divided 100 BALB/C mice into groups A, B, C, D and group E. Mice in all groups except group A were abdominally infected with schistosomal cercariae to induce a schistosomal hepatopathological model. Mice in group C, D and group E were respectively administered with praziquantel, praziquantel plus colchicine and praziquantel plus neutralizing osteopontin antibody. We extracted mouse liver tissues at 3 and 9 weeks after the 'stool-eggs-positive' day, observed liver histopathological changes by haematoxylin-eosin and Masson trichrome staining and detected the expression of osteopontin, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β1) by immunohistochemistry, RT-PCR and Western blot. We found that praziquantel plus neutralizing osteopontin antibody treatment significantly decreased the granuloma dimension, the percentage of collagen and the expression of osteopontin, α-SMA and TGF-β1 compared to praziquantel plus colchicine treatment in both the acute and chronic stage of schistosomal liver damage (P<0·05). So we believe that the combined regimen of osteopontin immunoneutralization and anti-helminthic treatment can reduce the granulomatous response and liver fibrosis during the schistosomal hepatopathologic course.

  12. Increasing global agricultural production by reducing ozone damages via methane emission controls and ozone-resistant cultivar selection.

    PubMed

    Avnery, Shiri; Mauzerall, Denise L; Fiore, Arlene M

    2013-04-01

    Meeting the projected 50% increase in global grain demand by 2030 without further environmental degradation poses a major challenge for agricultural production. Because surface ozone (O3 ) has a significant negative impact on crop yields, one way to increase future production is to reduce O3 -induced agricultural losses. We present two strategies whereby O3 damage to crops may be reduced. We first examine the potential benefits of an O3 mitigation strategy motivated by climate change goals: gradual emission reductions of methane (CH4 ), an important greenhouse gas and tropospheric O3 precursor that has not yet been targeted for O3 pollution abatement. Our second strategy focuses on adapting crops to O3 exposure by selecting cultivars with demonstrated O3 resistance. We find that the CH4 reductions considered would increase global production of soybean, maize, and wheat by 23-102 Mt in 2030 - the equivalent of a ~2-8% increase in year 2000 production worth $3.5-15 billion worldwide (USD2000 ), increasing the cost effectiveness of this CH4 mitigation policy. Choosing crop varieties with O3 resistance (relative to median-sensitivity cultivars) could improve global agricultural production in 2030 by over 140 Mt, the equivalent of a 12% increase in 2000 production worth ~$22 billion. Benefits are dominated by improvements for wheat in South Asia, where O3 -induced crop losses would otherwise be severe. Combining the two strategies generates benefits that are less than fully additive, given the nature of O3 effects on crops. Our results demonstrate the significant potential to sustainably improve global agricultural production by decreasing O3 -induced reductions in crop yields.

  13. Increasing global agricultural production by reducing ozone damages via methane emission controls and ozone-resistant cultivar selection

    PubMed Central

    Avnery, Shiri; Mauzerall, Denise L; Fiore, Arlene M

    2013-01-01

    Meeting the projected 50% increase in global grain demand by 2030 without further environmental degradation poses a major challenge for agricultural production. Because surface ozone (O3) has a significant negative impact on crop yields, one way to increase future production is to reduce O3-induced agricultural losses. We present two strategies whereby O3 damage to crops may be reduced. We first examine the potential benefits of an O3 mitigation strategy motivated by climate change goals: gradual emission reductions of methane (CH4), an important greenhouse gas and tropospheric O3 precursor that has not yet been targeted for O3 pollution abatement. Our second strategy focuses on adapting crops to O3 exposure by selecting cultivars with demonstrated O3 resistance. We find that the CH4 reductions considered would increase global production of soybean, maize, and wheat by 23–102 Mt in 2030 – the equivalent of a ∼2–8% increase in year 2000 production worth $3.5–15 billion worldwide (USD2000), increasing the cost effectiveness of this CH4 mitigation policy. Choosing crop varieties with O3 resistance (relative to median-sensitivity cultivars) could improve global agricultural production in 2030 by over 140 Mt, the equivalent of a 12% increase in 2000 production worth ∼$22 billion. Benefits are dominated by improvements for wheat in South Asia, where O3-induced crop losses would otherwise be severe. Combining the two strategies generates benefits that are less than fully additive, given the nature of O3 effects on crops. Our results demonstrate the significant potential to sustainably improve global agricultural production by decreasing O3-induced reductions in crop yields. PMID:23504903

  14. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation.

    PubMed

    Kim, Janice J; Bridle, Byram W; Ghia, Jean-Eric; Wang, Huaqing; Syed, Shahzad N; Manocha, Marcus M; Rengasamy, Palanivel; Shajib, Mohammad Sharif; Wan, Yonghong; Hedlund, Peter B; Khan, Waliul I

    2013-05-01

    Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

  15. Low-dose calcium antagonists reduce energy demand and cellular damage of isolated hearts during both ischemia and reperfusion.

    PubMed

    Becker, B F; Möbert, J

    1999-09-01

    Calcium antagonists may protect against postischemic reperfusion injury of the heart, but neither the time and mode of action leading to cardioprotection is resolved, nor is the generality of this effect proven. Accordingly, the functional and metabolic influence of four different Ca2+-antagonists (diltiazem, 3x10(-8) M; nifedipine, 3x10(-9) M; amlodipine, 3x 10(-9) M; barnidipine, 3x10(-11) M) was examined in preparations of guinea pig hearts (n=7/group) performing pressure-volume work after being subjected to low-flow ischemia (30 min) and reperfusion (35 min). The drugs were applied throughout the study at concentrations without negative inotropic or chronotropic effect, as would be mandatory for any therapeutic application, and without overt coronary dilatation. All calcium antagonists improved postischemic recovery of external heart work: from 42% in controls (post- vs. preischemic value) to 59% for diltiazem, 61% for nifedipine, 65% for amlodipine, and 73% for barnidipine (all P<0.05). Efficiency of myocardial performance (work in relation to oxygen consumption) was low in postischemic controls (8% of total energy equivalents), but significantly improved in treated hearts, especially by barnidipine (15% efficiency). Release of lactate dehydrogenase in the first 5 min of reperfusion, a sign of cell damage, increased from basal (65 mU/min) to 208 mU/min in controls. This increase was fully suppressed by all drugs tested. Myocardial release of lactate and of purine catabolites of adenine nucleotides (markers of anaerobic metabolism) was markedly reduced by Ca2+-antagonists. Interestingly, these metabolic effects were evident not only in the reperfusion phase, but already in the period of low-flow ischemia. Oxidative consumption of pyruvate was enhanced, whereas coronary flow and heart rate showed no postischemic effect of treatment. These findings on isolated guinea pig hearts suggest that Ca2+-antagonists generally improve postischemic pump function and aerobic

  16. Mercury Accumulation, Structural Damages, and Antioxidant and Immune Status Changes in the Gilthead Seabream (Sparus aurata L.) Exposed to Methylmercury.

    PubMed

    Guardiola, F A; Chaves-Pozo, E; Espinosa, C; Romero, D; Meseguer, J; Cuesta, A; Esteban, M A

    2016-05-01

    In aquatic systems, mercury (Hg) is an environmental contaminant that causes acute and chronic damage to multiple organs. In fish, practically all of the organic Hg found is in the form of methylmercury (MeHg), which has been associated with animal and human health problems. This study evaluates the impact of waterborne-exposure to sublethal concentrations of MeHg (10 μg L(-1)) in gilthead seabream (Sparus aurata). Hg was seen to accumulate in liver and muscle, and histopathological damage to skin and liver was detected. Fish exposed to MeHg showed a decreased biological antioxidant potential and increased levels of the reactive oxygen molecules compared with the values found in control fish (nonexposed). Increased liver antioxidant enzyme activities (superoxide dismutase and catalase) were detected in 2 day-exposed fish with respect to the values of control fish. However, fish exposed to MeHg for 10 days showed liver antioxidant enzyme levels similar to those of the control fish but had increased hepato-somatic index and histopathological alterations in liver and skin. Serum complement levels were higher in fish exposed to MeHg for 30 days than in control fish. Moreover, head-kidney leukocyte activities increased, although only phagocytosis and peroxidase activities showed a significant increase after 10 and 30 days, respectively. The data show that 30 days of exposure to waterborne MeHg provokes more significant changes in fish than a short-term exposure of 2 or 10 days.

  17. World Health Organization perspectives on the contribution of the Global Alliance for Vaccines and Immunization on reducing child mortality.

    PubMed

    Bustreo, F; Okwo-Bele, J-M; Kamara, L

    2015-02-01

    Child mortality has decreased substantially globally-from 12.6 million in 1990 to 6.3 million in 2013-due, in large part to of governments' and organisations' work, to prevent pneumonia, diarrhoea and malaria, the main causes of death in the postneonatal period. In 2012, the World Health Assembly adopted the Decade of Vaccines Global Vaccine Action Plan 2011-2020 as the current framework aimed at preventing millions of deaths through more equitable access to existing vaccines for people in all communities. The Global Alliance for Vaccines and Immunization (GAVI) plays a critical role in this effort by financing and facilitating delivery platforms for vaccines, with focused support for the achievements of improved vaccination coverage and acceleration of the uptake of WHO-recommended lifesaving new vaccines in 73 low-income countries. The GAVI Alliance has contributed substantially towards the progress of Millennium Development Goal 4 and to improving women's lives. By 2013, the GAVI Alliance had immunised 440 million additional children and averted six million future deaths from vaccine-preventable diseases in the world's poorest countries. The GAVI Alliance is on track to reducing child mortality to 68 per 1000 live births by 2015 in supported countries. This paper discusses the GAVI Alliance achievements related to Millennium Development Goal 4 and its broader contribution to improving women's lives and health systems, as well as challenges and obstacles it has faced. Additionally, it looks at challenges for the future and how it will continue its work related to reducing child mortality and improving women's health.

  18. A laboratory-based comparison of a molluscicide and an alternative food source (red clover) as means of reducing slug damage to winter wheat.

    PubMed

    Brooks, Andrew S; Wilcox, Andrew; Cook, Richard T; Crook, Mitchell J

    2005-07-01

    Slugs are major pests of many crops in the UK, including winter wheat, yet current methods of control are often unreliable. This study investigates the potential use of red clover, as an alternative food source, to reduce the amount of damage caused to winter wheat by the field slug, Deroceras reticulatum (Müller). Two laboratory-based studies, each conducted over a 7-day period, investigated the effects of red clover seedlings and commercial metaldehyde pellets on damage to winter wheat seeds and seedlings. The results indicate that metaldehyde applications, in the form of commercially available pellets, resulted in significantly greater protection to wheat seeds compared with red clover, whereas metaldehyde and red clover were equally as effective in reducing damage to wheat seedlings. A further laboratory experiment investigated the effect of two slug population densities (48 and 16 adults m(-2)) and high and low red clover seed rates (125% and 75% of a standard rate) on damage to wheat seeds. Results showed that, at the highest slug population density, red clover sown at 125% of the standard rate gave 99% protection to wheat seeds, compared with the 75% seed rate which gave 55%. At the lower slug population density, both seed rates of red clover resulted in similar levels of protection. Implications for the potential use of red clover as an alternative food source for reducing damage to winter wheat in field conditions are discussed.

  19. Immune stimulatory CpG oligodeoxynucleotides reduces Salmonella enterica subsp. Arizonae organ colonization and mortality in young turkeys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Synthetic oligodeoxynucleotides (ODN) containing CpG dinucleotides (CpG ODN) mimic bacterial DNA and are stimulatory to the innate immune system of most vertebrate species. The immunostimulatory activities of CpG ODN have been studied extensively and are well characterized in human and murine immun...

  20. Two dietary polyphenols, fisetin and luteolin, reduce inflammation but augment DNA damage-induced toxicity in human RPE cells.

    PubMed

    Hytti, Maria; Szabó, Dora; Piippo, Niina; Korhonen, Eveliina; Honkakoski, Paavo; Kaarniranta, Kai; Petrovski, Goran; Kauppinen, Anu

    2017-01-09

    Plant-derived polyphenols are known to possess anti-inflammatory and antioxidant effects. In recent years, several studies have investigated their potential benefits for treating chronic diseases associated with prolonged inflammation and excessive oxidative stress, such as age-related macular degeneration (AMD). Previously, two polyphenols, fisetin and luteolin, have been reported to increase the survival of retinal pigment epithelial (RPE) cells suffering from oxidative stress as well as decreasing inflammation but the benefits of polyphenol therapy seem to depend on the model system used. Our aim was to analyze the effects of fisetin and luteolin on inflammation and cellular viability in a model of nonoxidative DNA damage-induced cell death in human RPE (hRPE) cells. Pretreatment of ARPE-19 or primary hRPE cells with the polyphenols augmented etoposide-induced cell death as measured by the lactate dehydrogenase and 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. However, the treatment was able to reduce the release of two proinflammatory cytokines, IL-6 and IL-8, which were determined by enzyme-linked Immunosorbent assay. Analyses of caspase 3 activity, p53 acetylation and SIRT1 protein levels revealed the apoptotic nature of etoposide-evoked cell death and that fisetin and luteolin augmented the etoposide-induced acetylation of p53 and decreased SIRT1 levels. Taken together, our findings suggest that the cytoprotective effects of fisetin and luteolin depend on the stressor they need to combat, whereas their anti-inflammatory potential is sustained over a variety of model systems. Careful consideration of disease pathways will be necessary before fisetin or luteolin can be recommended as therapeutic agents for inflammatory diseases in general and specifically AMD.

  1. Advanced Glycation End-Products Reduce Collagen Molecular Sliding to Affect Collagen Fibril Damage Mechanisms but Not Stiffness

    PubMed Central

    Fessel, Gion; Li, Yufei; Diederich, Vincent; Guizar-Sicairos, Manuel; Schneider, Philipp; Sell, David R.; Monnier, Vincent M.; Snedeker, Jess G.

    2014-01-01

    Advanced glycation end-products (AGE) contribute to age-related connective tissue damage and functional deficit. The documented association between AGE formation on collagens and the correlated progressive stiffening of tissues has widely been presumed causative, despite the lack of mechanistic understanding. The present study investigates precisely how AGEs affect mechanical function of the collagen fibril – the supramolecular functional load-bearing unit within most tissues. We employed synchrotron small-angle X-ray scattering (SAXS) and carefully controlled mechanical testing after introducing AGEs in explants of rat-tail tendon using the metabolite methylglyoxal (MGO). Mass spectrometry and collagen fluorescence verified substantial formation of AGEs by the treatment. Associated mechanical changes of the tissue (increased stiffness and failure strength, decreased stress relaxation) were consistent with reports from the literature. SAXS analysis revealed clear changes in molecular deformation within MGO treated fibrils. Underlying the associated increase in tissue strength, we infer from the data that MGO modified collagen fibrils supported higher loads to failure by maintaining an intact quarter-staggered conformation to nearly twice the level of fibril strain in controls. This apparent increase in fibril failure resistance was characterized by reduced side-by-side sliding of collagen molecules within fibrils, reflecting lateral molecular interconnectivity by AGEs. Surprisingly, no change in maximum fibril modulus (2.5 GPa) accompanied the changes in fibril failure behavior, strongly contradicting the widespread assumption that tissue stiffening in ageing and diabetes is directly related to AGE increased fibril stiffness. We conclude that AGEs can alter physiologically relevant failure behavior of collagen fibrils, but that tissue level changes in stiffness likely occur at higher levels of tissue architecture. PMID:25364829

  2. Usefulness of colchicine to reduce perioperative myocardial damage in patients who underwent on-pump coronary artery bypass grafting.

    PubMed

    Giannopoulos, Georgios; Angelidis, Christos; Kouritas, Vasileios K; Dedeilias, Panagiotis; Filippatos, Gerasimos; Cleman, Michael W; Panagopoulou, Vasiliki; Siasos, Gerasimos; Tousoulis, Dimitrios; Lekakis, John; Deftereos, Spyridon

    2015-05-15

    The objective of the present study was to test whether a perioperative course of colchicine, in patients who underwent standard coronary artery bypass grafting, would result in reduced postoperative increase of myocardial injury biomarker levels. Patients were prospectively randomized to colchicine or placebo starting 48 hours before scheduled coronary artery bypass grafting and for 8 days thereafter (0.5 mg twice daily). The primary outcome parameter was maximal high-sensitivity troponin T (hsTnT) concentration within 48 hours after surgery. Secondary outcome measures were maximal creatine kinase-myocardial brain fraction (CK-MB) levels and area under the curve (AUC) of hsTnT and CK-MB concentrations; 59 patients were included. Maximal hsTnT was 616 pg/ml (396 to 986) in the colchicine group versus 1,613 pg/ml (732 to 2,587) in controls (p = 0.002). Maximal CK-MB was 44.6 ng/ml (36.6 to 68.8) and 93.0 ng/ml (48.0 to 182.3), respectively (p = 0.002). The median AUC for hsTnT was 40,755 pg h/ml (20,868 to 79,176) in controls versus 20,363 pg h/ml (13,891 to 31,661) in the colchicine group (p = 0.002). AUCs for CK-MB were 2,552 ng h/ml (1,564 to 4,791) in controls and 1,586 ng h/ml (1,159 to 2,073) in the colchicine group (p = 0.003). The main complaints associated with colchicine were, as expected, gastrointestinal, with 5 patients (16.7%) in the colchicine group reporting diarrhea versus 1 control (3.4%) (p = 0.195). In conclusion, a short perioperative course of colchicine was effective in attenuating postoperative increases of hsTnT and CK-MB compared with placebo. This finding, which needs confirmation in a larger clinical trial powered to assess clinical endpoints, suggests a potential role for this agent in reducing cardiac surgery-related myocardial damage.

  3. Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity

    PubMed Central

    Botelho, Danielle J.; Leo, Bey Fen; Massa, Christopher B.; Sarkar, Srijata; Tetley, Terry D.; Chung, Kian Fan; Chen, Shu; Ryan, Mary P.; Porter, Alexandra E.; Zhang, Junfeng; Schwander, Stephan K.; Gow, Andrew J.

    2016-01-01

    Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 µg/g body weight) 20 and 110nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered. PMID:26152688

  4. Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

    PubMed

    Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

    2016-01-01

    Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

  5. Reduced inflammatory cell recruitment and tissue damage in spinal cord injury by acellular spinal cord scaffold seeded with mesenchymal stem cells.

    PubMed

    Wang, Yu-Hai; Chen, Jian; Zhou, Jing; Nong, Feng; Lv, Jin-Han; Liu, Jia

    2017-01-01

    Therapy using acellular spinal cord (ASC) scaffolds seeded with bone marrow stromal cells (BMSCs) has previously been shown to restore function of the damaged spinal cord and improve functional recovery in a rat model of acute hemisected spinal cord injury (SCI). The aim of the present study was to determine whether BMSCs and ASC scaffolds promote the functional recovery of the damaged spinal cord in a rat SCI model through regulation of apoptosis and immune responses. Whether this strategy regulates secondary inflammation, which is characterized by the infiltration of immune cells and inflammatory mediators to the lesion site, in SCI repair was investigated. Basso, Beattie, and Bresnahan scores revealed that treatment with BMSCs seeded into an ASC scaffold led to a significant improvement in motor function recovery compared with treatment with an ASC scaffold alone or untreated controls at 2 and 8 weeks after surgery (P<0.05). Two weeks after transplantation, the BMSCs seeded into an ASC scaffold significantly decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, as compared with the ASC scaffold only and control groups. These results suggested that the use of BMSCs decreased the apoptosis of neural cells and thereby limited tissue damage at the lesion site. Notably, the use of BMSCs with an ASC scaffold also decreased the recruitment of macrophages (microglia; P<0.05) and T lymphocytes (P<0.05) around the SCI site, as indicated by immunofluorescent markers. By contrast, there was no inhibition of the inflammatory response in the control and ASC scaffold only groups. BMSCs regulated inflammatory cell recruitment to promote functional recovery. However, there was no significant difference in IgM-positive expression among the three groups (P>0.05). The results of this study demonstrated that BMSCs seeded into ASC scaffolds for repair of spinal cord hemisection defects promoted functional recovery through the early

  6. Reduced inflammatory cell recruitment and tissue damage in spinal cord injury by acellular spinal cord scaffold seeded with mesenchymal stem cells

    PubMed Central

    Wang, Yu-Hai; Chen, Jian; Zhou, Jing; Nong, Feng; Lv, Jin-Han; Liu, Jia

    2017-01-01

    Therapy using acellular spinal cord (ASC) scaffolds seeded with bone marrow stromal cells (BMSCs) has previously been shown to restore function of the damaged spinal cord and improve functional recovery in a rat model of acute hemisected spinal cord injury (SCI). The aim of the present study was to determine whether BMSCs and ASC scaffolds promote the functional recovery of the damaged spinal cord in a rat SCI model through regulation of apoptosis and immune responses. Whether this strategy regulates secondary inflammation, which is characterized by the infiltration of immune cells and inflammatory mediators to the lesion site, in SCI repair was investigated. Basso, Beattie, and Bresnahan scores revealed that treatment with BMSCs seeded into an ASC scaffold led to a significant improvement in motor function recovery compared with treatment with an ASC scaffold alone or untreated controls at 2 and 8 weeks after surgery (P<0.05). Two weeks after transplantation, the BMSCs seeded into an ASC scaffold significantly decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, as compared with the ASC scaffold only and control groups. These results suggested that the use of BMSCs decreased the apoptosis of neural cells and thereby limited tissue damage at the lesion site. Notably, the use of BMSCs with an ASC scaffold also decreased the recruitment of macrophages (microglia; P<0.05) and T lymphocytes (P<0.05) around the SCI site, as indicated by immunofluorescent markers. By contrast, there was no inhibition of the inflammatory response in the control and ASC scaffold only groups. BMSCs regulated inflammatory cell recruitment to promote functional recovery. However, there was no significant difference in IgM-positive expression among the three groups (P>0.05). The results of this study demonstrated that BMSCs seeded into ASC scaffolds for repair of spinal cord hemisection defects promoted functional recovery through the early

  7. Optical damage in reduced Z-cut LiNbO{sub 3} crystals caused by longitudinal photovoltaic and pyroelectric effects

    SciTech Connect

    Kostritskii, S. M.; Aillerie, M.

    2012-01-01

    The marked optical damage was observed in thin Z-cut plates of the deeply reduced nominally pure LiNbO{sub 3} crystals, when a 514.5-nm-laser beam with ordinary polarization was focused on the {+-}Z face. The longitudinal photovoltaic and pyroelectric effects are shown to be responsible for most of the important peculiarities of the optical damage dynamics. The anisotropy in the behavior between the +Z and -Z faces has been explained by interference of the different kinds of pyroelectric and photovoltaic effects to the space-charge field with an altering relative sign.

  8. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats.

    PubMed

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa; Gupta, Pritha

    2017-02-15

    Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1β, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1β, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS.

  9. Pristimerin, a naturally occurring triterpenoid, protects against autoimmune arthritis by modulating the cellular and soluble immune mediators of inflammation and tissue damage.

    PubMed

    Tong, Li; Nanjundaiah, Siddaraju M; Venkatesha, Shivaprasad H; Astry, Brian; Yu, Hua; Moudgil, Kamal D

    2014-12-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting the synovial joints. The currently available drugs for RA are effective only in a proportion of patients and their prolonged use is associated with severe adverse effects. Thus, new anti-arthritic agents are being sought. We tested Pristimerin, a naturally occurring triterpenoid, for its therapeutic activity against rat adjuvant arthritis. Pristimerin effectively inhibited both arthritic inflammation and cartilage and bone damage in the joints. Pristimerin-treated rats exhibited a reduction in the pro-inflammatory cytokines (IL-6, IL-17, IL-18, and IL-23) and the IL-6/IL-17-associated transcription factors (pSTAT3 and ROR-γt), coupled with an increase in the immunomodulatory cytokine IL-10. Also increased was IFN-γ, which can inhibit IL-17 response. In addition, the Th17/Treg ratio was altered in favor of immune suppression and the RANKL/OPG ratio was skewed towards anti-osteoclastogenesis. This is the first report on testing Pristimerin in arthritis. We suggest further evaluation of Pristimerin in RA patients.

  10. Gene Expression of Mesothelioma in Vinylidene Chloride-Exposed F344/N Rats Reveals Immune Dysfunction, Tissue Damage, and Inflammation Pathways

    PubMed Central

    Blackshear, Pamela E.; Pandiri, Arun R.; Nagai, Hiroaki; Bhusari, Sachin; Hong, Lily; Ton, Thai-Vu T.; Clayton, Natasha P.; Wyde, Michael; Shockley, Keith R.; Peddada, Shyamal D.; Gerrish, Kevin E.; Sills, Robert C.; Hoenerhoff, Mark J.

    2014-01-01

    A majority (~80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, genetic factors) account for up to 30% of cases. A recent two-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and vinylidene chloride-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from vinylidene chloride-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the NF-kB signaling pathway, IL-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and NK and DC signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, proinflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor and cell cycle regulation, resulting in an increased incidence of mesothelioma. PMID:24958746

  11. Wheat peptides reduce oxidative stress and inhibit NO production through modulating μ-opioid receptor in a rat NSAID-induced stomach damage model.

    PubMed

    Yin, Hong; Cai, Hui-Zhen; Wang, Shao-Kang; Yang, Li-Gang; Sun, Gui-Ju

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) induce tissue damage and oxidative stress in animal models of stomach damage. In the present study, the protective effects of wheat peptides were evaluated in a NSAID-induced stomach damage model in rats. Different doses of wheat peptides or distilled water were administered daily by gavage for 30 days before the rat stomach damage model was established by administration of NSAIDs (aspirin and indomethacin) into the digestive tract twice. The treatment of wheat peptides decreased the NSAID-induced gastric epithelial cell degeneration and oxidative stress and NO levels in the rats. Wheat peptides significantly increased the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and decreased iNOS activity in stomach. The mRNA expression level of μ-opioid receptor was significantly decreased in wheat peptides-treated rats than that in in the control rats. The results suggest that NSAID drugs induced stomach damage in rats, wchih can be prevented by wheat peptides. The mechanisms for the protective effects were most likely through reducing NSAID-induced oxidative stress.

  12. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

    SciTech Connect

    Stoop, Jeroen N. . E-mail: j.n.stoop@erasmusmc.nl; Molen, Renate G. van der . E-mail: r.vandermolen@erasmusmc.nl; Kuipers, Ernst J. . E-mail: e.j.kuipers@erasmusmc.nl; Kusters, Johannes G. . E-mail: j.g.kusters@erasmusmc.nl; Janssen, Harry L.A. . E-mail: h.janssen@erasmusmc.nl

    2007-04-25

    Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-{gamma} production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response.

  13. Electrolysed reduced water decreases reactive oxygen species-induced oxidative damage to skeletal muscle and improves performance in broiler chickens exposed to medium-term chronic heat stress.

    PubMed

    Azad, M A K; Kikusato, M; Zulkifli, I; Toyomizu, M

    2013-01-01

    1. The present study was designed to achieve a reduction of reactive oxygen species (ROS)-induced oxidative damage to skeletal muscle and to improve the performance of broiler chickens exposed to chronic heat stress. 2. Chickens were given a control diet with normal drinking water, or diets supplemented with cashew nut shell liquid (CNSL) or grape seed extract (GSE), or a control diet with electrolysed reduced water (ERW) for 19 d after hatch. Thereafter, chickens were exposed to a temperature of either 34°C continuously for a period of 5 d, or maintained at 24°C, on the same diets. 3. The control broilers exposed to 34°C showed decreased weight gain and feed consumption and slightly increased ROS production and malondialdehyde (MDA) concentrations in skeletal muscle. The chickens exposed to 34°C and supplemented with ERW showed significantly improved growth performance and lower ROS production and MDA contents in tissues than control broilers exposed to 34°C. Following heat exposure, CNSL chickens performed better with respect to weight gain and feed consumption, but still showed elevated ROS production and skeletal muscle oxidative damage. GSE chickens did not exhibit improved performance or reduced skeletal muscle oxidative damage. 4. In conclusion, this study suggests that ERW could partially inhibit ROS-induced oxidative damage to skeletal muscle and improve growth performance in broiler chickens under medium-term chronic heat treatment.

  14. Epigenetic Control of Immunity

    PubMed Central

    Busslinger, Meinrad; Tarakhovsky, Alexander

    2014-01-01

    Immunity relies on the heterogeneity of immune cells and their ability to respond to pathogen challenges. In the adaptive immune system, lymphocytes display a highly diverse antigen receptor repertoire that matches the vast diversity of pathogens. In the innate immune system, the cell's heterogeneity and phenotypic plasticity enable flexible responses to changes in tissue homeostasis caused by infection or damage. The immune responses are calibrated by the graded activity of immune cells that can vary from yeast-like proliferation to lifetime dormancy. This article describes key epigenetic processes that contribute to the function of immune cells during health and disease. PMID:24890513

  15. Engineering safer-by-design, transparent, silica-coated ZnO nanorods with reduced DNA damage potential

    PubMed Central

    Sotiriou, Georgios A.; Watson, Christa; Murdaugh, Kimberly M.; Darrah, Thomas H.; Pyrgiotakis, Georgios; Elder, Alison; Brain, Joseph D.; Demokritou, Philip

    2014-01-01

    Zinc oxide (ZnO) nanoparticles absorb UV light efficiently while remaining transparent in the visible light spectrum rendering them attractive in cosmetics and polymer films. Their broad use, however, raises concerns regarding potential environmental health risks and it has been shown that ZnO nanoparticles can induce significant DNA damage and cytotoxicity. Even though research on ZnO nanoparticle synthesis has made great progress, efforts on developing safer ZnO nanoparticles that maintain their inherent optoelectronic properties while exhibiting minimal toxicity are limited. Here, a safer-by-design concept was pursued by hermetically encapsulating ZnO nanorods in a biologically inert, nanothin amorphous SiO2 coating during their gas-phase synthesis. It is demonstrated that the SiO2 nanothin layer hermetically encapsulates the core ZnO nanorods without altering their optoelectronic properties. Furthermore, the effect of SiO2 on the toxicological profile of the core ZnO nanorods was assessed using the Nano-Cometchip assay by monitoring DNA damage at a cellular level using human lymphoblastoid cells (TK6). Results indicate significantly lower DNA damage (>3 times) for the SiO2-coated ZnO nanorods compared to uncoated ones. Such an industry-relevant, scalable, safer-by-design formulation of nanostructured materials can liberate their employment in nano-enabled products and minimize risks to the environment and human health. PMID:24955241

  16. A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both mucosal and systemic compartments with reduced IgE antibodies.

    PubMed

    Kweon, Mi-Na; Yamamoto, Masafumi; Watanabe, Fumiko; Tamura, Shinichi; Van Ginkel, Frederik W; Miyauchi, Akira; Takagi, Hiroaki; Takeda, Yoshifumi; Hamabata, Takashi; Fujihashi, Kohtaro; McGhee, Jerry R; Kiyono, Hiroshi

    2002-11-01

    A novel nontoxic form of chimeric mucosal adjuvant that combines the A subunit of mutant cholera toxin E112K with the pentameric B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli was constructed by use of the Brevibacillus choshinensis expression system (mCTA/LTB). Nasal immunization of mice with tetanus toxoid (TT) plus mCTA/LTB elicited significant TT-specific immunoglobulin A responses in mucosal compartments and induced high serum immunoglobulin G and immunoglobulin A anti-TT antibody responses. Although TT plus native CT induced high total and TT-specific immunoglobulin E responses, use of the chimera molecule as mucosal adjuvant did not. Furthermore, all mice immunized with TT plus mCTA/LTB were protected from lethal systemic challenge with tetanus toxin. Importantly, the mice were completely protected from influenza virus infection after nasal immunization with inactivated influenza vaccine together with mCTA/LTB. These results show that B. choshinensis-derived mCTA/LTB is an effective and safe mucosal adjuvant for the induction of protective immunity against potent bacterial exotoxin and influenza virus infection.

  17. Dietary supplementation with lacto-wolfberry enhances the immune response and reduces pathogenesis to influenza infection in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite the availability of vaccines, influenza is a significant public health problem, emphasizing the need for development of additional strategies to enhance host defense against influenza. Wolfberry or Goji berry, long used as a medicinal food in China, has recently been shown to improve immune ...

  18. Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.

    PubMed

    Smith, Anthony J; Wietgrefe, Stephen W; Shang, Liang; Reilly, Cavan S; Southern, Peter J; Perkey, Katherine E; Duan, Lijie; Kohler, Heinz; Müller, Sybille; Robinson, James; Carlis, John V; Li, Qingsheng; Johnson, R Paul; Haase, Ashley T

    2014-09-15

    Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.

  19. Yeast supplementation reduced the immune and metabolic responses to a combined viral-bacterial respiratory disease challenge in feedlot heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two treatments were evaluated in commercial feedlot heifers to determine the effects of a yeast supplement on immune and metabolic responses to a combined viral-bacterial respiratory disease challenge. Thirty-two beef heifers (324 ± 19.2 kg BW) were selected and randomly assigned to one of two treat...

  20. A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid β peptide toxicity in Caenorhabditis elegans.

    PubMed

    Martorell, Patricia; Llopis, Silvia; Gonzalez, Nuria; Ramón, Daniel; Serrano, Gabriel; Torrens, Ana; Serrano, Juan M; Navarro, Maria; Genovés, Salvador

    2017-03-01

    Lactoferrin is a highly multifunctional glycoprotein involved in many physiological functions, including regulation of iron absorption and immune responses. Moreover, there is increasing evidence for neuroprotective effects of lactoferrin. We used Caenorhabditis elegans as a model to test the protective effects, both on phenotype and transcriptome, of a nutraceutical product based on lactoferrin liposomes. In a dose-dependent manner, the lactoferrin-based product protected against acute oxidative stress and extended lifespan of C. elegans N2. Furthermore, Paralysis of the transgenic C. elegans strain CL4176, caused by Aβ1-42 aggregates, was clearly ameliorated by treatment. Transcriptome analysis in treated nematodes indicated immune system stimulation, together with enhancement of processes involved in the oxidative stress response. The lactoferrin-based product also improved the protein homeostasis processes, cellular adhesion processes, and neurogenesis in the nematode. In summary, the tested product exerts protection against aging and neurodegeneration, modulating processes involved in oxidative stress response, protein homeostasis, synaptic function, and xenobiotic metabolism. This lactoferrin-based product is also able to stimulate the immune system, as well as improving reproductive status and energy metabolism. These findings suggest that oral supplementation with this lactoferrin-based product could improve the immune system and antioxidant capacity. Further studies to understand the molecular mechanisms related with neuronal function would be of interest.

  1. Live SIV vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability

    PubMed Central

    Smith, Anthony J; Wietgrefe, Stephen W.; Shang, Liang; Reilly, Cavan S.; Southern, Peter J.; Perkey, Katherine E.; Duan, Lijie; Kohler, Heinz; Muller, Sybille; Robinson, James; Carlis, John V.; Li, Qingsheng; Johnson, R. Paul; Haase, Ashley T.

    2014-01-01

    Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic’s epicentre in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We have identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer antibody production and neonatal Fc receptor (FcRn)-mediated concentration of these antibodies on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. Here we identify as a second protection correlate, blocking CD4+ T cell recruitment to inhibit local expansion of infected founder populations. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine. PMID:25143442

  2. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse

    PubMed Central

    Zheng, Wei; Talley Watts, Lora; Holstein, Deborah M; Wewer, Jimmy; Lechleiter, James D

    2013-01-01

    Glia-based neuroprotection strategies are emerging as promising new avenues to treat brain damage. We previously reported that activation of the glial-specific purinergic receptor, P2Y1R, reduces both astrocyte swelling and brain infarcts in a photothrombotic mouse model of stroke. These restorative effects were dependent on astrocyte mitochondrial metabolism. Here, we extend these findings and report that P2Y1R stimulation with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2MeSADP) reduces and partially reverses neuronal damage induced by photothrombosis. In vivo neuronal morphology was confocally imaged in transgenic mice expressing yellow fluorescent protein under the control of the Thy1 promoter. Astrocyte mitochondrial membrane potentials, monitored with the potential sensitive dye tetra-methyl rhodamine methyl ester, were depolarized after photothrombosis and subsequently repolarized when P2Y1Rs were stimulated. Mice deficient in the astrocyte-specific type 2 inositol 1,4,5 trisphosphate (IP3) receptor exhibited aggravated ischemic dendritic damage after photothrombosis. Treatment of these mice with 2MeSADP did not invoke an intracellular Ca2+ response, did not repolarize astrocyte mitochondria, and did not reduce or partially reverse neuronal lesions induced by photothrombotic stroke. These results demonstrate that IP3-Ca2+ signaling in astrocytes is not only critical for P2Y1R-enhanced protection, but suggest that IP3-Ca2+ signaling is also a key component of endogenous neuroprotection. PMID:23321785

  3. Genipin crosslinking reduced the immunogenicity of xenogeneic decellularized porcine whole-liver matrices through regulation of immune cell proliferation and polarization

    PubMed Central

    Wang, Yujia; Bao, Ji; Wu, Xiujuan; Wu, Qiong; Li, Yi; Zhou, Yongjie; Li, Li; Bu, Hong

    2016-01-01

    Decellularized xenogeneic whole-liver matrices are plausible biomedical materials for the bioengineering of liver transplantation. A common method to reduce the inflammatory potential of xenogeneic matrices is crosslinking. Nevertheless, a comprehensive analysis of the immunogenic features of cross-linked decellularized tissue is still lacking. We aimed to reduce the immunogenicity of decellularized porcine whole-liver matrix through crosslinking with glutaraldehyde or genipin, a new natural agent, and investigated the mechanism of the immune-mediated responses. The histologic assessment of the host’s immune reaction activated in response to these scaffolds, as well as the M1/M2 phenotypic polarization profile of macrophages, was studied in vivo. The genipin-fixed scaffold elicited a predominantly M2 phenotype response, while the glutaraldehyde-fixed scaffold resulted in disrupted host tissue remodeling and a mixed macrophage polarization profile. The specific subsets of immune cells involved in the responses to the scaffolds were identified in vitro. Crosslinking alleviated the host response by reducing the proliferation of lymphocytes and their subsets, accompanied by a decreased release of both Th1 and Th2 cytokines. Therefore, we conclude that the natural genipin crosslinking could lower the immunogenic potential of xenogeneic decellularized whole-liver scaffolds. PMID:27098308

  4. Genipin crosslinking reduced the immunogenicity of xenogeneic decellularized porcine whole-liver matrices through regulation of immune cell proliferation and polarization

    NASA Astrophysics Data System (ADS)

    Wang, Yujia; Bao, Ji; Wu, Xiujuan; Wu, Qiong; Li, Yi; Zhou, Yongjie; Li, Li; Bu, Hong

    2016-04-01

    Decellularized xenogeneic whole-liver matrices are plausible biomedical materials for the bioengineering of liver transplantation. A common method to reduce the inflammatory potential of xenogeneic matrices is crosslinking. Nevertheless, a comprehensive analysis of the immunogenic features of cross-linked decellularized tissue is still lacking. We aimed to reduce the immunogenicity of decellularized porcine whole-liver matrix through crosslinking with glutaraldehyde or genipin, a new natural agent, and investigated the mechanism of the immune-mediated responses. The histologic assessment of the host’s immune reaction activated in response to these scaffolds, as well as the M1/M2 phenotypic polarization profile of macrophages, was studied in vivo. The genipin-fixed scaffold elicited a predominantly M2 phenotype response, while the glutaraldehyde-fixed scaffold resulted in disrupted host tissue remodeling and a mixed macrophage polarization profile. The specific subsets of immune cells involved in the responses to the scaffolds were identified in vitro. Crosslinking alleviated the host response by reducing the proliferation of lymphocytes and their subsets, accompanied by a decreased release of both Th1 and Th2 cytokines. Therefore, we conclude that the natural genipin crosslinking could lower the immunogenic potential of xenogeneic decellularized whole-liver scaffolds.

  5. Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID.

    PubMed

    Cancrini, Caterina; Ferrua, Francesca; Scarselli, Alessia; Brigida, Immacolata; Romiti, Maria Luisa; Barera, Graziano; Finocchi, Andrea; Roncarolo, Maria Grazia; Caniglia, Maurizio; Aiuti, Alessandro

    2010-10-01

    The treatment of choice for severe combined immunodeficiency is bone marrow transplantation from an HLA-identical donor sibling without conditioning. However, this may result in low donor stem cell chimerism, leading to reduced long-term immune reconstitution. We compared engraftment, metabolic, and T-cell and B-cell immune reconstitution of HLA-identical sibling bone marrow transplantation performed in 2 severe combined immunodeficiency infants with adenosine deaminase deficiency from the same family treated with or without a reduced intensity conditioning regimen (busulfan/fludarabine). Only the patient who received conditioning showed a stable mixed chimerism in all lineages, including bone marrow myeloid and B cells. The use of conditioning resulted in higher thymus-derived naïve T cells and T-cell receptor excision circles, normalization of the T-cell repertoire, and faster and complete B-cell and metabolic reconstitution. These results suggest the utility of exploring the use of reduced intensity conditioning in bone marrow transplantation from HLA-identical donor in severe combined immunodeficiency to improve long-term immune reconstitution.

  6. Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function.

    PubMed

    Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J; He, Wei; Voss, Oliver H; Gonzalez-Mejia, M Elba; Guttridge, Denis C; Grotewold, Erich; Doseff, Andrea I

    2016-03-01

    The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo.

  7. Two years research on efficiency of two intercrops, birdsfoot trefoil and summer savory, to reduce damage caused by onion thrips(Thrips tabaci Lindeman, Thysanoptera, Thripidae) on leek.

    PubMed

    Gombac, P; Trdan, S

    2012-01-01

    In 2009 and 2011, a field experiment was carried out at the Laboratory Field at the Biotechnical Faculty in Ljubljana, Slovenia, with the aim to investigate suitability of two intercrops, birdsfoot trefoil (Lotus corniculatus L) and summer savory (Satureja hortensis L.), for reducing damage caused by onion thrips (Thrips tabaci Lindeman) on leek (Allium porrum L.). Four leek cultivars--'Columbus', 'Forrest', 'Lancelot' and 'Lincoln'--were used in the research (Bejo Zaden B.V., Netherlands). In both years, the mean index of damage caused by feeding of the pest on the leek leaves increased from the first evaluation (13 July 2009 and 18 June 2011) in both treatments with intercrops and in control treatment (without intercrop). Leek grown with birdsfoot trefoil as intercrop was in both years statistically the least damaged from thrips. Also summer savory was efficient in the same context in comparison with control treatment. In year 2009 cultivar 'Lancelot' was the least damaged in all treatments, and in year 2011 'Lancelot' and 'Forrest'. In both years intercrop and cultivar also had a significant influence on the yield of leek. The highest yield was obtained on the control plots, meanwhile birdsfoot trefoil and summer savory were pretty competitive and yield of leek grown with them as intercrops was therefore significantly lower.

  8. SPARC (secreted protein acidic and rich in cysteine) knockdown protects mice from acute liver injury by reducing vascular endothelial cell damage

    PubMed Central

    Peixoto, E; Atorrasagasti, C; Aquino, JB; Militello, R; Bayo, J; Fiore, E; Piccioni, F; Salvatierra, E; Alaniz, L; García, MG; Bataller, R; Corrales, F; Gidekel, M; Podhajcer, O; Colombo, MI; Mazzolini, G

    2015-01-01

    Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC−/−) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC−/− mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC−/− mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC−/− mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC−/− mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury. PMID:25410742

  9. Reduced Innate Immune Response to a Staphylococcus aureus Small Colony Variant Compared to Its Wild-Type Parent Strain

    PubMed Central

    Ou, Judy J. J.; Drilling, Amanda J.; Cooksley, Clare; Bassiouni, Ahmed; Kidd, Stephen P.; Psaltis, Alkis J.; Wormald, Peter J.; Vreugde, Sarah

    2016-01-01

    Background: Staphylococcus aureus (S. aureus) small colony variants (SCVs) can survive within the host intracellular milieu and are associated with chronic relapsing infections. However, it is unknown whether host invasion rates and immune responses differ between SCVs and their wild-type counterparts. This study used a stable S. aureus SCV (WCH-SK2SCV) developed from a clinical isolate (WCH-SK2WT) in inflammation-relevant conditions. Intracellular infection rates as well as host immune responses to WCH-SK2WT and WCH-SK2SCV infections were investigated. Method: NuLi-1 cells were infected with either WCH-SK2WT or WCH-SK2SCV, and the intracellular infection rate was determined over time. mRNA expression of cells infected with each strain intra- and extra-cellularly was analyzed using a microfluidic qPCR array to generate an expression profile of thirty-nine genes involved in the host immune response. Results: No difference was found in the intracellular infection rate between WCH-SK2WT and WCH-SK2SCV. Whereas, extracellular infection induced a robust pro-inflammatory response, intracellular infection elicited a modest response. Intracellular WCH-SK2WT infection induced mRNA expression of TLR2, pro-inflammatory cytokines (IL1B, IL6, and IL12) and tissue remodeling factors (MMP9). In contrast, intracellular WCH-SK2SCV infection induced up regulation of only TLR2. Conclusions: Whereas, host intracellular infection rates of WCH-SK2SCV and WCH-SK2WT were similar, WCH-SK2SCV intracellular infection induced a less widespread up regulation of pro-inflammatory and tissue remodeling factors in comparison to intracellular WCH-SK2WT infection. These findings support the current view that SCVs are able to evade host immune detection to allow their own survival. PMID:28083514

  10. Reduced Innate Immune Response to a Staphylococcus aureus Small Colony Variant Compared to Its Wild-Type Parent Strain.

    PubMed

    Ou, Judy J J; Drilling, Amanda J; Cooksley, Clare; Bassiouni, Ahmed; Kidd, Stephen P; Psaltis, Alkis J; Wormald, Peter J; Vreugde, Sarah

    2016-01-01

    Background:Staphylococcus aureus (S. aureus) small colony variants (SCVs) can survive within the host intracellular milieu and are associated with chronic relapsing infections. However, it is unknown whether host invasion rates and immune responses differ between SCVs and their wild-type counterparts. This study used a stable S. aureus SCV (WCH-SK2(SCV)) developed from a clinical isolate (WCH-SK2(WT)) in inflammation-relevant conditions. Intracellular infection rates as well as host immune responses to WCH-SK2(WT) and WCH-SK2(SCV) infections were investigated. Method: NuLi-1 cells were infected with either WCH-SK2(WT) or WCH-SK2(SCV), and the intracellular infection rate was determined over time. mRNA expression of cells infected with each strain intra- and extra-cellularly was analyzed using a microfluidic qPCR array to generate an expression profile of thirty-nine genes involved in the host immune response. Results: No difference was found in the intracellular infection rate between WCH-SK2(WT) and WCH-SK2(SCV). Whereas, extracellular infection induced a robust pro-inflammatory response, intracellular infection elicited a modest response. Intracellular WCH-SK2(WT) infection induced mRNA expression of TLR2, pro-inflammatory cytokines (IL1B, IL6, and IL12) and tissue remodeling factors (MMP9). In contrast, intracellular WCH-SK2(SCV) infection induced up regulation of only TLR2. Conclusions: Whereas, host intracellular infection rates of WCH-SK2(SCV) and WCH-SK2(WT) were similar, WCH-SK2(SCV) intracellular infection induced a less widespread up regulation of pro-inflammatory and tissue remodeling factors in comparison to intracellular WCH-SK2(WT) infection. These findings support the current view that SCVs are able to evade host immune detection to allow their own survival.

  11. Adipose Tissue-Derived Mesenchymal Stromal Cells Protect Mice Infected with Trypanosoma cruzi from Cardiac Damage through Modulation of Anti-parasite Immunity

    PubMed Central

    Mesquita, Fernanda C. P.; Brasil, Guilherme V.; Rocha, Nazareth N.; Takiya, Christina M.; Lima, Ana Paula C. A.; Campos de Carvalho, Antonio C.; Goldenberg, Regina S.; Carvalho, Adriana B.

    2015-01-01

    Background Chagas disease, caused by the protozoan Trypanosoma cruzi (T.cruzi), is a complex disease endemic in Central and South America. It has been gathering interest due to increases in non-vectorial forms of transmission, especially in developed countries. The objective of this work was to investigate if adipose tissue-derived mesenchymal stromal cells (ASC) can alter the course of the disease and attenuate pathology in a mouse model of chagasic cardiomyopathy. Methodology/Principal Findings ASC were injected intraperitoneally at 3 days post-infection (dpi). Tracking by bioluminescence showed that cells remained in the abdominal cavity for up to 9 days after injection and most of them migrated to the abdominal or subcutaneous fat, an early parasite reservoir. ASC injection resulted in a significant reduction in blood parasitemia, which was followed by a decrease in cardiac tissue inflammation, parasitism and fibrosis at 30 dpi. At the same time point, analyses of cytokine release in cells isolated from the heart and exposed to T. cruzi antigens indicated an anti-inflammatory response in ASC-treated animals. In parallel, splenocytes exposed to the same antigens produced a pro-inflammatory response, which is important for the control of parasite replication, in placebo and ASC-treated groups. However, splenocytes from the ASC group released higher levels of IL-10. At 60 dpi, magnetic resonance imaging revealed that right ventricular (RV) dilation was prevented in ASC-treated mice. Conclusions/Significance In conclusion, the injection of ASC early after T. cruzi infection prevents RV remodeling through the modulation of immune responses. Lymphoid organ response to the parasite promoted the control of parasite burden, while the heart, a target organ of Chagas disease, was protected from damage due to an improved control of inflammation in ASC-treated mice. PMID:26248209

  12. Vaccination prepartum enhances the beneficial effects of melatonin on the immune response and reduces platelet responsiveness in sheep

    PubMed Central

    2012-01-01

    Background Melatonin regulates several physiological processes and its powerful action as antioxidant has been widely reported. Melatonin acts modulating the immune system, showing a protective effect on the cardiovascular system and improving vaccine administration as an adjuvant-like agent. Here, we have investigated the role of melatonin as an adjuvant of the Clostridium perfringens vaccine in prepartum sheep and whether melatonin modulates platelet physiology during peripartum. Results The experiments were carried out in peripartum sheep from a farm located in an area of Mediterranean-type ecosystem. Plasma melatonin levels were determined by ELISA and sheep platelet aggregation was monitored using an aggregometer. Here we demonstrated for the first time that plasma melatonin concentration were higher in pregnant (125 pg/mL) than in non-pregnant sheep (15 pg/mL; P < 0.05). Administration of melatonin prepartum did not significantly modify platelet function but significantly improved the immune response to vaccination against C. perfringens. Conclusion Administration of melatonin as an adjuvant provides a significant improvement in the immune response to vaccine administration prepartum against C. perfringens. PMID:22716226

  13. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury.

    PubMed

    García, Elisa; Silva-García, Raúl; Mestre, Humberto; Flores, Nayeli; Martiñón, Susana; Calderón-Aranda, Emma S; Ibarra, Antonio

    2012-03-01

    Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.

  14. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model.

    PubMed

    Du Four, Stephanie; Maenhout, Sarah K; De Pierre, Kari; Renmans, Dries; Niclou, Simone P; Thielemans, Kris; Neyns, Bart; Aerts, Joeri L

    2015-04-01

    Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3(+)CD8(+) T cells and CD11b(+) cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b(+)Ly6C(high)Ly6G(-)). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

  15. Reduced 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-initiated oxidative DNA damage and neurodegeneration in prostaglandin H synthase-1 knockout mice.

    PubMed

    Jeng, Winnie; Wells, Peter G

    2010-05-19

    The neurodegenerative potential of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and underlying mechanisms are under debate. Here, we show that MDMA is a substrate for CNS prostaglandin H synthase (PHS)-catalyzed bioactivation to a free radical intermediate that causes reactive oxygen species (ROS) formation and neurodegenerative oxidative DNA damage. In vitro PHS-1-catalyzed bioactivation of MDMA stereoselectively produced free radical intermediate formation and oxidative DNA damage that was blocked by the PHS inhibitor eicosatetraynoic acid. In vivo, MDMA stereoselectively caused gender-independent DNA oxidation and dopaminergic nerve terminal degeneration in several brain regions, dependent on regional PHS-1 levels. Conversely, MDMA-initiated striatal DNA oxidation, nerve terminal degeneration, and motor coordination deficits were reduced in PHS-1 +/- and -/- knockout mice in a gene dose-dependent fashion. These results confirm the neurodegenerative potential of MDMA and provide the first direct evidence for a novel molecular mechanism involving PHS-catalyzed formation of a neurotoxic MDMA free radical intermediate.

  16. Haloperidol-loaded lipid-core polymeric nanocapsules reduce DNA damage in blood and oxidative stress in liver and kidneys of rats

    NASA Astrophysics Data System (ADS)

    Roversi, Katiane; Benvegnú, Dalila M.; Roversi, Karine; Trevizol, Fabíola; Vey, Luciana T.; Elias, Fabiana; Fracasso, Rafael; Motta, Mariana H.; Ribeiro, Roseane F.; dos S. Hausen, Bruna; Moresco, Rafael N.; Garcia, Solange C.; da Silva, Cristiane B.; Burger, Marilise E.

    2015-04-01

    Haloperidol (HP) nanoencapsulation improves therapeutic efficacy, prolongs the drug action time, and reduces its motor side effects. However, in a view of HP toxicity in organs like liver and kidneys in addition to the lack of knowledge regarding the toxicity of polymeric nanocapsules, our aim was to verify the influence of HP-nanoformulation on toxicity and oxidative stress markers in the liver and kidneys of rats, also observing the damage caused in the blood. For such, 28 adult male Wistar rats were designated in four experimental groups ( n = 7) and treated with vehicle (C group), free haloperidol suspension (FH group), blank nanocapsules suspension (B-Nc group), and haloperidol-loaded lipid-core nanocapsules suspension (H-Nc group). The nanocapsules formulation presented the size of approximately 250 nm. All suspensions were administered to the animals (0.5 mg/kg/day-i.p.) for a period of 28 days. Our results showed that FH caused damage in the liver, evidenced by increased lipid peroxidation, plasma levels of aspartate aminotransferase, and alanine aminotransferase, as well as decreased cellular integrity and vitamin C levels. In kidneys, FH treatment caused damage to a lesser extent, observed by decreased activity of δ-aminolevulinate dehydratase (ALA-D) and levels of VIT C. In addition, FH treatment was also related to a higher DNA damage index in blood. On the other hand, animals treated with H-Nc and B-Nc did not show damage in liver, kidneys, and DNA. Our study indicates that the nanoencapsulation of haloperidol was able to prevent the sub-chronic toxicity commonly observed in liver, kidneys, and DNA, thus reflecting a pharmacological superiority in relation to free drug.

  17. Unilateral nephrectomy 24 hours after bilateral kidney irradiation reduces damage to the function and structure of the remaining kidney

    SciTech Connect

    Liao, Z.X.; Travis, E.L.

    1994-09-01

    The effect of unilateral nephrectomy 24 h after irradiation on renal function and death with renal insufficiency as well as histopathological changes in the kidney was assessed. Single doses totaling 8-18 Gy were given bilaterally to unanesthetized female and male C3Hf/Kam mice. Renal function damage was assayed by blood urea nitrogen (BUN) and hematocrit (Hct). Histological damage was quantified by two parameters: kidney area and number of surviving tubule cells along the renal capsule. The number of glomeruli was scored as an indication of the number of nephrons. Changes in the two functional parameters did not appear sooner after irradiation in the nephrectomized mice than in the non-nephrectomized mice. Rather, less impairment of function was measured by both parameters in the nephrectomized mice but only after radiation doses greater than 12 Gy. The LD{sub 50} at 424 days after irradiation was also higher in the nephrectomized mice than in the mice receiving only irradiation, 13.98 Gy (95% confidence limits = 12.03, 15.93) and 11.71 Gy (95% confidence limits = 10.4, 13.1), respectively, in agreement with the data on function. Unilateral nephrectomy alone induced a 10% increase in size of the contralateral kidney. The dose-response curve for the kidney area from nephrectomized mice was parallel to and displaced above that for non-nephrectomized mice, indicating that the increase in renal mass occurred independent of and was not compromised by radiation. Unilateral nephrectomy alone induced no increase in the number of proximal tubules in the contralateral kidney. 30 refs., 9 figs., 1 tab.

  18. Plant flavone apigenin binds to nucleic acid bases and reduces oxidative DNA damage in prostate epithelial cells.

    PubMed

    Sharma, Haripaul; Kanwal, Rajnee; Bhaskaran, Natarajan; Gupta, Sanjay

    2014-01-01

    Oxidative stress has been linked to prostate carcinogenesis as human prostate tissue is vulnerable to oxidative DNA damage. Apigenin, a dietary plant flavone, possesses anti-proliferative and anticancer effects; however, its antioxidant properties have not been fully elucidated. We investigated sub-cellular distribution of apigenin, it's binding to DNA and protective effects against H2O2-induced DNA damage using transformed human prostate epithelial RWPE-1 cells and prostate cancer LNCaP, PC-3 and DU145 cells. Exposure of cells to apigenin exhibited higher accumulation in RWPE-1 and LNCaP cells, compared to PC-3 and DU145 cells. The kinetics of apigenin uptake in LNCaP cells was estimated with a Km value of 5 µmole/L and Vmax of 190 pmoles/million cells/h. Sub-cellular fractionation demonstrated that nuclear matrix retains the highest concentration of apigenin (45.3%), followed by cytosol (23.9%), nuclear membranes (17.9%) and microsomes (12.9%), respectively. Spectroscopic analysis of apigenin with calf-thymus DNA exhibited intercalation as the dominant binding mode to DNA duplex. Apigenin exposure resulted in significant genoprotective effects in H2O2-stressed RWPE-1 cells by reduction in reactive oxygen species levels. In addition, apigenin exposure suppressed the formation of 8-hydroxy-2' deoxyguanosine and protected exposed cells from apoptosis. Our studies demonstrate that apigenin is readily taken up by normal prostatic epithelial cells and prostate cancer cells, and is incorporated into their nuclei, where its intercalation with nucleic acid bases may account for its antioxidant and chemopreventive activities.

  19. Inefficient replication reduces RecA-mediated repair of UV-damaged plasmids introduced into competent Escherichia coli.

    PubMed

    Jeiranian, H A; Courcelle, C T; Courcelle, J

    2012-09-01

    Transformation of Escherichia coli with purified plasmids containing DNA damage is frequently used as a tool to characterize repair pathways that operate on chromosomes. In this study, we used an assay that allowed us to quantify plasmid survival and to compare how efficiently various repair pathways operate on plasmid DNA introduced into cells relative to their efficiency on chromosomal DNA. We observed distinct differences between the mechanisms operating on the transforming plasmid DNA and the chromosome. An average of one UV-induced lesion was sufficient to inactivate ColE1-based plasmids introduced into nucleotide excision repair mutants, suggesting an essential role for repair on newly introduced plasmid DNA. By contrast, the absence of RecA, RecF, RecBC, RecG, or RuvAB had a minimal effect on the survival of the transforming plasmid DNA containing UV-induced damage. Neither the presence of an endogenous homologous plasmid nor the induction of the SOS response enhanced the survival of transforming plasmids. Using two-dimensional agarose-gel analysis, both replication- and RecA-dependent structures that were observed on established, endogenous plasmids following UV-irradiation, failed to form on UV-irradiated plasmids introduced into E. coli. We interpret these observations to suggest that the lack of RecA-mediated survival is likely to be due to inefficient replication that occurs when plasmids are initially introduced into cells, rather than to the plasmid's size, the absence of homologous sequences, or levels of recA expression.

  20. NK cells lacking FcεRIγ are associated with reduced liver damage in chronic hepatitis C virus infection.

    PubMed

    Oh, Jun S; Ali, Alaa K; Kim, Sungjin; Corsi, Daniel J; Cooper, Curtis L; Lee, Seung-Hwan

    2016-04-01

    A novel subset of human natural killer (NK) cells, which displays potent and broad antiviral responsiveness in concert with virus-specific antibodies, was recently uncovered in cytomegalovirus (CMV)+ individuals. This NK-cell subset (g-NK) was characterized by a deficiency in the expression of FcεRIγ adaptor protein and the long-lasting memory-like NK-cell phenotype, suggesting a role in chronic infections. This study investigates whether the g-NK-cell subset is associated with the magnitude of liver disease during chronic hepatitis C virus (HCV) infection. Analysis of g-NK-cell proportions and function in the PBMCs of healthy controls and chronic HCV subjects showed that chronic HCV subjects had slightly lower proportions of the g-NK-cell subset having similarly enhanced antibody-dependent cellular cytotoxicity responses compared to conventional NK cells. Notably, among CMV+ chronic HCV patients, lower levels of liver enzymes and fibrosis were found in those possessing g-NK cells. g-NK cells were predominant among the CD56(neg) NK cell population often found in chronic HCV patients, suggesting their involvement in immune response during HCV infection. For the first time, our findings indicate that the presence of the g-NK cells in CMV+ individuals is associated with amelioration of liver disease in chronic HCV infection, suggesting the beneficial roles of g-NK cells during a chronic infection.

  1. Hyperreactive onchocerciasis is characterized by a combination of Th17-Th2 immune responses and reduced regulatory T cells.

    PubMed

    Katawa, Gnatoulma; Layland, Laura E; Debrah, Alex Y; von Horn, Charlotte; Batsa, Linda; Kwarteng, Alexander; Arriens, Sandra; W Taylor, David; Specht, Sabine; Hoerauf, Achim; Adjobimey, Tomabu

    2015-01-01

    Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.

  2. Intermittent Left Cervical Vagal Nerve Stimulation Damages the Stellate Ganglia and Reduces Ventricular Rate During Sustained Atrial Fibrillation in Ambulatory Dogs

    PubMed Central

    Chinda, Kroekkiat; Tsai, Wei-Chung; Chan, Yi-Hsin; Lin, Andrew Y.-T.; Patel, Jheel; Zhao, Ye; Tan, Alex Y; Shen, Mark J; Lin, Hongbo; Shen, Changyu; Chattipakorn, Nipon; Rubart-von der Lohe, Michael; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Chen, Zhenhui; Chen, Peng-Sheng

    2015-01-01

    Background The effects of intermittent open loop vagal nerve stimulation (VNS) on ventricular rate (VR) during atrial fibrillation (AF) remain unclear. Objective To test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. Methods We performed left cervical VNS in ambulatory dogs while simultaneously recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in SG. Results We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 s) and long OFF-time (66 s). The integrated SGNA (iSGNA) and VR during AF were 4.84 mV-s [95% confidence interval, CI, 3.08 to 6.60] and 142 bpm [CI, 116 to 168], respectively. VNS reduced iSGNA and VR, respectively, during AF to 3.74 mV-s [CI, 2.27 to 5.20; p=0.021] and 115 bpm [CI, 96 to 134; p=0.016] during 66-s OFF-time, and to 4.07 mV-s [CI, 2.42 to 5.72; p=0.037] and 114 bpm [CI, 83 to 146; p=0.039] during 3-min OFF-time. VNS increased the frequencies of prolonged (>3 s) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. Conclusions VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF. PMID:26607063

  3. Syzygium cumini (Jamun) reduces the radiation-induced DNA damage in the cultured human peripheral blood lymphocytes: a preliminary study.

    PubMed

    Jagetia, Ganesh Chandra; Baliga, Manjeshwar Shrinath

    2002-06-07

    The effects of various concentrations (0.0, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 microg/ml) of the leaf extract of Syzygium cumini Linn. or Eugenia cumini (SC; black plum, Jamun, family Myrtaceae) was studied on the alteration in the radiation-induced micronuclei formation in the cultured human peripheral blood lymphocytes. Treatment of lymphocytes to various concentrations of SC resulted in a dose dependent increase in the micronuclei-induction, especially after 25-100 microg/ml extract. The exposure of human lymphocytes to various concentrations of SC extract before 3 Gy gamma-irradiation resulted in a significant decline in the micronuclei-induction at all the drug doses when compared with the non-drug treated irradiated cultures. A nadir in MNBNC frequency was observed for 12.5 microg/ml drug concentration, where the MNBNC frequency was approximately fourfold lower than that of the non-drug treated irradiated cultures. Therefore, this dose may be considered as an optimum dose for radiation protection. Our study demonstrates that the leaf extract of S. cumini, a plant traditionally used to treat diabetic disorders protects against the radiation-induced DNA damage.

  4. Composition of Herba Pogostemonis water extract and protection of infected mice against Salmonella Typhimurium-induced liver damage and mortality by stimulation of innate immune cells.

    PubMed

    Kim, Sung Phil; Moon, Eunpyo; Nam, Seok Hyun; Friedman, Mendel

    2012-12-12

    GC-MS analysis of a hot water extract of Herba Pogostemonis (HP) revealed the presence of 131 compounds. HP slightly inhibited Salmonella Typhimurium bacteria in culture and stimulated uptake of the bacteria into RAW 264.7 murine macrophage cells as indicated by both increased fluorescence from internalized FITC-dextran and increased colony-forming unit (CFU) counts of the lysed macrophages. Postinfection, the HP-treated cells showed lower bacterial counts than the control. HP elicited altered morphology, elevated inducible NO synthase (iNOS) mRNA, and reduced pro-inflammatory cytokine expression in macrophage cells. Salmonella induced increased expression of iNOS mRNA, cognate polypeptides, and NO. Histology of mice infected with a sublethal dose (1 × 10(4) CFU) of Salmonella showed that intraperitoneally administered HP protected against necrosis of the liver, a biomarker of in vivo salmonellosis. The lifespan of mice infected with a lethal dose (1 × 10(5) CFU) was significantly extended. These results suggest that the activity of HP against bacterial infection in mice occurs through the activation of innate immune macrophage cells. The relationship of composition of HP to bioactivity is discussed.

  5. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.

    PubMed

    Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong; Montgomery, Stephanie A; Ding, Shengli; Wilson, Justin E; Brickey, W June; Mühlbauer, Marcus; McFadden, Rita-Marie T; Hu, Peizhen; Li, Zengshan; Jobin, Christian; Lund, Pauline Kay; Ting, Jenny P-Y

    2016-03-22

    NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1(-/-) mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6). The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apc(min/+) genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apc(min/+) colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1(-/-)Apc(min/+) mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

  6. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats.

    PubMed

    Darsalia, Vladimer; Mansouri, Shiva; Ortsäter, Henrik; Olverling, Anna; Nozadze, Nino; Kappe, Camilla; Iverfeldt, Kerstin; Tracy, Linda M; Grankvist, Nina; Sjöholm, Åke; Patrone, Cesare

    2012-05-01

    Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

  7. Different forms of adiponectin reduce the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells

    PubMed Central

    Cheng, Meng-Yu; Liu, Hu; Zhang, Tie-Mei; Xu, Jian-Ying

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, in which adiponectin may serve an important role. The present study investigated the role of adiponectin in the apoptotic and damaging effect of cigarette smoke extract (CSE) on human bronchial epithelial cells (16HBECs). An MTT assay showed that CSE significantly inhibited the proliferation of 16HBECs (F=1808.88, P<0.01). The 16HBECs were treated with different concentrations of high molecular weight (HMW) adiponectin and globular domain (gAd) adiponectin and it was observed that HMW and gAd dose-dependently inhibited the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-8, and the generation of 4-hydroxy-nonenal and reactive oxygen species (ROS) in 16HBECs, thereby blocking the upregulating effect of CSE on these factors. However, the inhibitory effect of gAd on TNF-α and IL-8 expression was stronger compared with that of HMW, but the suppressing effect of HMW on ROS production was superior compared with that of gAd. Further testing of apoptosis indicated that CSE and HMW promoted the apoptosis of 16HBECs. However, such effects of HMW declined with an increase in concentration. In contrast, gAd showed an inhibitory effect on apoptosis and inhibited the occurrence of CSE-induced apoptosis in a dose-dependent manner. Therefore, the present study demonstrated that different forms of adiponectin may have different mechanisms of action, suggesting that further exploration of their effects may open a new avenue for the treatment of COPD. PMID:28105143

  8. Carvacrol reduces irinotecan-induced intestinal mucositis through inhibition of inflammation and oxidative damage via TRPA1 receptor activation.

    PubMed

    Alvarenga, Elenice M; Souza, Luan K M; Araújo, Thiago S L; Nogueira, Kerolayne M; Sousa, Francisca Beatriz M; Araújo, Alyne R; Martins, Conceição S; Pacífico, Dvison M; de C Brito, Gerly Anne; Souza, Emmanuel P; Sousa, Damião P; Medeiros, Jand Venes R

    2016-12-25

    Intestinal mucositis is an inflammatory process occurring in the intestinal mucosa and is a common side effect of irinotecan hydrochloride (CPT-11) based anticancer regimens. The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptor is highly expressed in the intestinal mucosa and has the ability to identify cell damage signaling indicates its possible association with intestinal mucositis. Carvacrol is an agonist of the TRPA1 receptor and has anti-inflammatory properties. Thus, the aim of the present study was to verify the supposed anti-inflammatory and protective action of carvacrol via TRPA1 activation against intestinal mucositis induced by CPT-11 in mice. Briefly, mice were treated with either DMSO 2% or CPT-11 (75 mg/kg, per 4 days, i.p.) or the carvacrol (25, 75 or 150 mg/kg, per 8 days, i.p.) before CPT-11. In other group, the animals were pretreated with HC-030031, a TRPA1 antagonist, 30 min before treatment with carvacrol. On day 7, animal survival and bacteremia were assessed, and following euthanasia, samples of the jejunum were obtained for morphometric analysis and measurement of antioxidant and pro-inflammatory markers. Carvacrol was found to exert an anti-inflammatory action against CPT-11-induced intestinal mucositis through strong interactions with TRPA1 receptors; reduction in the production or release or both of pro-inflammatory cytokines (TNF-α, IL-1β, and KC); and decrease in other indicators of inflammation (MPO, NF-κB, COX-2) and oxidative stress (GSH, MDA, and NOx levels). It also contributed to the restoration of the tissue architecture of the villi and crypts in the small intestine, and improved clinical parameters such as survival, body mass variation, leukogram, and blood bacterial count. Thus, TRPA1 could be a target for future therapeutic approaches in the treatment of intestinal mucositis.

  9. Coniferyl Aldehyde Reduces Radiation Damage Through Increased Protein Stability of Heat Shock Transcriptional Factor 1 by Phosphorylation

    SciTech Connect

    Kim, Seo-Young; Lee, Hae-June; Nam, Joo-Won; Seo, Eun-Kyoung; Lee, Yun-Sil

    2015-03-15

    Purpose: We previously screened natural compounds and found that coniferyl aldehyde (CA) was identified as an inducer of HSF1. In this study, we further examined the protective effects of CA against ionizing radiation (IR) in normal cell system. Methods and Materials: Western blotting and reverse transcription-polymerase chain reaction tests were performed to evaluate expression of HSF1, HSP27, and HSP70 in response to CA. Cell death and cleavage of PARP and caspase-3 were analyzed to determine the protective effects of CA in the presence of IR or taxol. The protective effects of CA were also evaluated using animal models. Results: CA increased stability of the HSF1 protein by phosphorylation at Ser326, which was accompanied by increased expression of HSP27 and HSP70. HSF1 phosphorylation at Ser326 by CA was mediated by EKR1/2 activation. Cotreatment of CA with IR or taxol in normal cells induced protective effects with phosphorylation- dependent patterns at Ser326 of HSF1. The decrease in bone marrow (BM) cellularity and increase of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive BM cells by IR were also significantly inhibited by CA in mice (30.6% and 56.0%, respectively). A549 lung orthotopic lung tumor model indicated that CA did not affect the IR-mediated reduction of lung tumor nodules, whereas CA protected normal lung tissues from the therapeutic irradiation. Conclusions: These results suggest that CA may be useful for inducing HSF1 to protect against normal cell damage after IR or chemotherapeutic agents.

  10. Chronic infection and the origin of adaptive immune system.

    PubMed

    Usharauli, David

    2010-08-01

    It has been speculated that the rise of the adaptive immune system in jawed vertebrates some 400 million years ago gave them a superior protection to detect and defend against pathogens that became more elusive and/or virulent to the host that had only innate immune system. First, this line of thought implies that adaptive immune system was a new, more sophisticated layer of host defense that operated independently of the innate immune system. Second, the natural consequence of this scenario would be that pathogens would have exercised so strong an evolutionary pressure that eventually no host could have afforded not to have an adaptive immune system. Neither of these arguments is supported by the facts. First, new experimental evidence has firmly established that operation of adaptive immune system is critically dependent on the ability of the innate immune system to detect invader-pathogens and second, the absolute majority of animal kingdom survives just fine with only an innate immune system. Thus, these data raise the dilemma: If innate immune system was sufficient to detect and protect against pathogens, why then did adaptive immune system develop in the first place? In contrast to the innate immune system, the adaptive immune system has one important advantage, precision. By precision I mean the ability of the defense system to detect and remove the target, for example, infected cells, without causing unwanted bystander damage of surrounding tissue. While the target precision per se is not important for short-term immune response, it becomes a critical factor when the immune response is long-lasting, as during chronic infection. In this paper I would like to propose new, "toxic index" hypothesis where I argue that the need to reduce the collateral damage to the tissue during chronic infection(s) was the evolutionary pressure that led to the development of the adaptive immune system.

  11. Hyperbaric Oxygen Pretreatment Improves Cognition and Reduces Hippocampal Damage Via p38 Mitogen-Activated Protein Kinase in a Rat Model

    PubMed Central

    Zhao, Baisong; Pan, Yongying; Wang, Zixin; Xu, Haiping

    2017-01-01

    Purpose To investigate the effects of hyperbaric oxygen (HBO) pretreatment on cognitive decline and neuronal damage in an Alzheimer’s disease (AD) rat model. Materials and Methods Rats were divided into three groups: normal saline (NS), AD, and HBO+AD. In the AD group, amyloid β peptide (Aβ)1-40 was injected into the hippocampal CA1 region of the brain. NS rats received NS injection. In the HBO+AD group, rats received 5 days of daily HBO therapy following Aβ1-40 injection. Learning and memory capabilities were examined using the Morris water maze task. Neuronal damage and astrocyte activation were evaluated by hematoxylin-eosin staining and immunohistochemistry, respectively. Dendritic spine density was determined by Golgi-Cox staining. Tumor necrosis factor-α, interleukin-1β, and interleukin-10 production was assessed by enzyme-linked immunosorbent assay. Neuron apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Protein expression was examined by western blotting. Results Learning and memory dysfunction was ameliorated in the HBO+AD group, as shown by significantly lower swimming distances and escape latency, compared to the AD group. Lower rates of neuronal damage, astrocyte activation, dendritic spine loss, and hippocampal neuron apoptosis were seen in the HBO+AD than in the AD group. A lower rate of hippocampal p38 mitogen-activated protein kinase (MAPK) phosphorylation was observed in the HBO+AD than in the AD group. Conclusion HBO pretreatment improves cognition and reduces hippocampal damage via p38 MAPK in AD rats. PMID:27873505

  12. Venlafaxine treatment after endothelin-1-induced cortical stroke modulates growth factor expression and reduces tissue damage in rats.

    PubMed

    Zepeda, Rodrigo; Contreras, Valentina; Pissani, Claudia; Stack, Katherine; Vargas, Macarena; Owen, Gareth I; Lazo, Oscar M; Bronfman, Francisca C

    2016-08-01

    Neuromodulators, such as antidepressants, may contribute to neuroprotection by modulating growth factor expression to exert anti-inflammatory effects and to support neuronal plasticity after stroke. Our objective was to study whether early treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor, modulates growth factor expression and positively contributes to reducing the volume of infarcted brain tissue resulting in increased functional recovery. We studied the expression of BDNF, FGF2 and TGF-β1 by examining their mRNA and protein levels and cellular distribution using quantitative confocal microscopy at 5 days after venlafaxine treatment in control and infarcted brains. Venlafaxine treatment did not change the expression of these growth factors in sham rats. In infarcted rats, BDNF mRNA and protein levels were reduced, while the mRNA and protein levels of FGF2 and TGF-β1 were increased. Venlafaxine treatment potentiated all of the changes that were induced by cortical stroke alone. In particular, increased levels of FGF2 and TGF-β1 were observed in astrocytes at 5 days after stroke induction, and these increases were correlated with decreased astrogliosis (measured by GFAP) and increased synaptophysin immunostaining at twenty-one days after stroke in venlafaxine-treated rats. Finally, we show that venlafaxine reduced infarct volume after stroke resulting in increased functional recovery, which was measured using ladder rung motor tests, at 21 days after stroke. Our results indicate that the early oral administration of venlafaxine positively contributes to neuroprotection during the acute and late events that follow stroke.

  13. Reduced early hypoxic/ischemic brain damage is associated with increased GLT-1 levels in mice expressing mutant (P301L) human tau

    PubMed Central

    Liao, Guanghong; Zhou, Miou; Cheung, Simon; Galeano, James; Nguyen, Nam; Baudry, Michel; Bi, Xiaoning

    2009-01-01

    Mutations in tau proteins are associated with a group of neurodegenerative diseases, termed tauopathies. To investigate whether over-expressing human tau with P301L mutation also affects stroke-induced brain damage, we performed hypoxia/ischemia (H/I) in young adult P301L tau transgenic mice. Surprisingly, brain infarct volume was significantly smaller in transgenic mice compared to wild-type mice 24 h after H/I induction. TUNEL staining also revealed less brain apoptosis in transgenic mice following H/I. H/I resulted in a significant increase in tau fragments generated by caspase activation and a marked decrease in tau phosphorylation at residue T231 in cortex of wild-type but not transgenic mice. Activation of calpain and caspase-3 following H/I was also reduced in transgenic compared to wild-type mice, as reflected by lower levels of the specific spectrin breakdown products generated by calpain or caspase-3. Finally, basal levels of the glial glutamate transporter, GLT-1, were higher in brains of transgenic as compared to wild-type mice. These results support the idea that enhanced levels of GLT-1 in transgenic mice are responsible for reducing H/I-induced brain damage by decreasing extracellular glutamate accumulation and subsequent calpain and caspase activation. PMID:18992725

  14. The use of an alternative food source (red clover) as a means of reducing slug pest damage to winter wheat: towards field implementation.

    PubMed

    Brooks, Andrew S; Wilcox, Andrew; Cook, Richard T; James, Katherine L; Crook, Mitchell J

    2006-03-01

    Slugs are major pests of many crops in the UK, including winter wheat, yet current methods of control are often unreliable. The aim of this study was to investigate three issues key to the successful field implementation of a control strategy that uses red clover as an alternative food source to reduce the amount of damage caused to winter wheat by the field slug, Deroceras reticulatum (Müller). A series of three experiments was designed to assess this aim. Firstly, under laboratory conditions, red clover was consumed in greater quantities than wheat, even when wheat was presented as a novel food. Secondly, red clover had no significant effects on the emergence and early growth of wheat in a polytunnel experiment. Both these results are crucial to the successful implementation of a strategy that uses red clover as an alternative food source. Lastly, the results of a field experiment were consistent with the results of the polytunnel experiment, in that red clover did not significantly affect wheat emergence. However, plots in which red clover was left to grow until the time of wheat harvest resulted in significantly lower (43%) wheat yields than plots without red clover. These results suggest that red clover must be removed from the field after the wheat has passed its vulnerable seedling stage. Recommendations for the potential use of red clover as an alternative food source for reducing damage to winter wheat in field conditions are discussed and opportunities for further work are suggested.

  15. Olive oil reduces oxidative damage in a 3-nitropropionic acid-induced Huntington's disease-like rat model.

    PubMed

    Tasset, I; Pontes, A J; Hinojosa, A J; de la Torre, R; Túnez, I

    2011-05-01

    Free radicals contribute to altered neuronal functions in neurodegenerative diseases and brain aging, by producing lipid- and other molecule-dependent modifications. The Mediterranean diet has been associated with a reduced risk of neurodegenerative disease. This study sought to verify whether extra-virgin olive oil (EVOO) exerted a brain antioxidant effect, protecting the brain against the oxidative stress caused by 3-nitropropionic acid (3NP). 3NP was administered intraperitoneally (i.p.) at a dose of 20 mg/kg body weight over four consecutive days. EVOO (representing 10% of calorie intake in the total standard daily diet of rats) and hydroxytyrosol (HT; 2.5 mg/kg body weight) were administered for 14 days. In all studied samples, 3NP caused a rise in lipid peroxides (LPO) and a reduction in glutathione (GSH) content. While the results showed that EVOO and HT reduces lipid peroxidation product levels and blocks the GSH depletion prompted by 3NP in both striatum and rest of the brain in Wistar rats. In addition, EVOO blocks and reverses the effect of 3NP on succinate dehydrogenase activity. In brief, the data obtained indicate that EVOO and HT act as a powerful brain antioxidant.

  16. KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease

    PubMed Central

    Levinson, Ralph D.; Yung, Madeline; Meguro, Akira; Ashouri, Elham; Yu, Fei; Mizuki, Nobuhisa; Ohno, Shigeaki

    2016-01-01

    Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt-Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher’s exact probabilities. The incidence of Bx-KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral

  17. False Recall Is Reduced by Damage to the Ventromedial Prefrontal Cortex: Implications for Understanding the Neural Correlates of Schematic Memory

    PubMed Central

    Jones, Samuel H.; Duff, Melissa C.; Tranel, Daniel

    2014-01-01

    Schematic memory, or contextual knowledge derived from experience (Bartlett, 1932), benefits memory function by enhancing retention and speeding learning of related information (Bransford and Johnson, 1972; Tse et al., 2007). However, schematic memory can also promote memory errors, producing false memories. One demonstration is the “false memory effect” of the Deese–Roediger–McDermott (DRM) paradigm (Roediger and McDermott, 1995): studying words that fit a common schema (e.g., cold, blizzard, winter) often produces memory for a nonstudied word (e.g., snow). We propose that frontal lobe regions that contribute to complex decision-making processes by weighting various alternatives, such as ventromedial prefrontal cortex (vmPFC), may also contribute to memory processes by weighting the influence of schematic knowledge. We investigated the role of human vmPFC in false memory by combining a neuropsychological approach with the DRM task. Patients with vmPFC lesions (n = 7) and healthy comparison participants (n = 14) studied word lists that excluded a common associate (the critical item). Recall and recognition tests revealed expected high levels of false recall and recognition of critical items by healthy participants. In contrast, vmPFC patients showed consistently reduced false recall, with significantly fewer intrusions of critical items. False recognition was also marginally reduced among vmPFC patients. Our findings suggest that vmPFC increases the influence of schematically congruent memories, a contribution that may be related to the role of the vmPFC in decision making. These novel neuropsychological results highlight a role for the vmPFC as part of a memory network including the medial temporal lobes and hippocampus (Andrews-Hanna et al., 2010). PMID:24872571

  18. False recall is reduced by damage to the ventromedial prefrontal cortex: implications for understanding the neural correlates of schematic memory.

    PubMed

    Warren, David E; Jones, Samuel H; Duff, Melissa C; Tranel, Daniel

    2014-05-28

    Schematic memory, or contextual knowledge derived from experience (Bartlett, 1932), benefits memory function by enhancing retention and speeding learning of related information (Bransford and Johnson, 1972; Tse et al., 2007). However, schematic memory can also promote memory errors, producing false memories. One demonstration is the "false memory effect" of the Deese-Roediger-McDermott (DRM) paradigm (Roediger and McDermott, 1995): studying words that fit a common schema (e.g., cold, blizzard, winter) often produces memory for a nonstudied word (e.g., snow). We propose that frontal lobe regions that contribute to complex decision-making processes by weighting various alternatives, such as ventromedial prefrontal cortex (vmPFC), may also contribute to memory processes by weighting the influence of schematic knowledge. We investigated the role of human vmPFC in false memory by combining a neuropsychological approach with the DRM task. Patients with vmPFC lesions (n = 7) and healthy comparison participants (n = 14) studied word lists that excluded a common associate (the critical item). Recall and recognition tests revealed expected high levels of false recall and recognition of critical items by healthy participants. In contrast, vmPFC patients showed consistently reduced false recall, with significantly fewer intrusions of critical items. False recognition was also marginally reduced among vmPFC patients. Our findings suggest that vmPFC increases the influence of schematically congruent memories, a contribution that may be related to the role of the vmPFC in decision making. These novel neuropsychological results highlight a role for the vmPFC as part of a memory network including the medial temporal lobes and hippocampus (Andrews-Hanna et al., 2010).

  19. Effect of reducing milk production using a prolactin-release inhibitor or a glucocorticoid on metabolism and immune functions in cows subjected to acute nutritional stress.

    PubMed

    Ollier, S; Beaudoin, F; Vanacker, N; Lacasse, P

    2016-12-01

    When cows are unable to consume enough feed to support milk production, they often fall into severe negative energy balance. This leads to a weakened immune system and increases their susceptibility to infectious diseases. Reducing the milk production of cows subjected to acute nutritional stress decreases their energy deficit. The aim of this study was to compare the effects on metabolism and immune function of reducing milk production using quinagolide (a prolactin-release inhibitor) or dexamethasone in feed-restricted cows. A total of 23 cows in early/mid-lactation were fed for 5 d at 55.9% of their previous dry matter intake to subject them to acute nutritional stress. After 1 d of feed restriction and for 4 d afterward (d 2 to 5), cows received twice-daily i.m. injections of water (control group; n=8), 2mg of quinagolide (QN group; n=7), or water after a first injection of 20mg of dexamethasone (DEX group; n=8). Feed restriction decreased milk production, but the decrease was greater in the QN and DEX cows than in the control cows on d 2 and 3. As expected, feed restriction reduced the energy balance, but the reduction was lower in the QN cows than in the control cows. Feed restriction decreased plasma glucose concentration and increased plasma nonesterified fatty acid (NEFA) and β-hydroxybutyrate (BHB) concentrations. The QN cows had higher glucose concentration and lower BHB concentration than the control cows. The NEFA concentration was also lower in the QN cows than in the control cows on d 2. Dexamethasone injection induced transient hyperglycemia concomitant with a reduction in milk lactose concentration; it also decreased BHB concentration and decreased NEFA initially but increased it later. Feed restriction and quinagolide injections did not affect the blood concentration or activity of polymorphonuclear leukocytes (PMN), whereas dexamethasone injection increased PMN blood concentration but decreased the proportion of PMN capable of inducing oxidative

  20. Elimination of contaminating cap genes in AAV vector virions reduces immune responses and improves transgene expression in a canine gene therapy model.

    PubMed

    Wang, Z; Halbert, C L; Lee, D; Butts, T; Tapscott, S J; Storb, R; Miller, A D

    2014-04-01

    Animal and human gene therapy studies utilizing AAV vectors have shown that immune responses to AAV capsid proteins can severely limit transgene expression. The main source of capsid antigen is that associated with the AAV vectors, which can be reduced by stringent vector purification. A second source of AAV capsid proteins is that expressed from cap genes aberrantly packaged into AAV virions during vector production. This antigen source can be eliminated by the use of a cap gene that is too large to be incorporated into an AAV capsid, such as a cap gene containing a large intron (captron gene). Here, we investigated the effects of elimination of cap gene transfer and of vector purification by CsCl gradient centrifugation on AAV vector immunogenicity and expression following intramuscular injection in dogs. We found that both approaches reduced vector immunogenicity and that combining the two produced the lowest immune responses and highest transgene expression. This combined approach enabled the use of a relatively mild immunosuppressive regimen to promote robust micro-dystrophin gene expression in Duchenne muscular dystrophy-affected dogs. Our study shows the importance of minimizing AAV cap gene impurities and indicates that this improvement in AAV vector production may benefit human applications.

  1. Co-existence of Echinococcus granulosus infection and cancer metastasis in the liver correlates with reduced Th1 immune responses.

    PubMed

    Turhan, N; Esendagli, G; Ozkayar, O; Tunali, G; Sokmensuer, C; Abbasoglu, O

    2015-01-01

    A possible relationship between cancer and Echinococcus granulosus infection has been postulated. As T cells are critical players in immune responses against both infections and malignancies, in an experimental model of secondary echinococcosis and breast cancer, this study aims to observe the progression of cancer and to determine the characters of T-cell responses. 4T1 breast tumour cells were subcutaneously injected into mammary region, whereas protoscoleces were intraperitoneally inoculated into the mice. Hydatid cysts, tumours and metastases were determined with macroscopic and histopathological evaluation. T cells found in spleen, liver and tumour were characterised by flow cytometric analysis of CD3, CD4, CD8, CD25, CCR5, CCR3, IL-4 and IFN-γ. In the mice inoculated both with protoscoleces and with breast tumour cells, increased frequency of cancer metastasis was observed in the liver. The amount of CD4(+) T cells was increased in the liver and in the spleen of mice infected with E. granulosus. However, co-existence of echinococcosis and metastatic lesions in the liver was associated with significant reduction in the IFN-γ(+) and CCR5(+) Th1 cells and increase in the CD25(+) T cells. Our results may indicate an immunological link between cystic echinococcosis and cancer that allows tumour metastasis to flourish in the liver.

  2. Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise.

    PubMed

    Vetreno, Ryan P; Patel, Yesha; Patel, Urvi; Walter, T Jordan; Crews, Fulton T

    2017-02-01

    Serotonergic neurons of the raphe nucleus regulate sleep, mood, endocrine function, and other processes that mature during adolescence. Alcohol abuse and binge drinking are common during human adolescence. We tested the novel hypothesis that adolescent intermittent ethanol exposure would alter the serotonergic system that would persist into adulthood. Using a Wistar rat model of adolescent intermittent ethanol (AIE; 5.0g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55), we found a loss of dorsal raphe nucleus (DRN) serotonin (5-HT)-immunoreactive (+IR) neurons that persisted from late adolescence (P56) into adulthood (P220). Hypothalamic and amygdalar DRN serotonergic projections were reduced following AIE. Tryptophan hydroxylase 2, the rate-limiting 5-HT synthesizing enzyme, and vesicular monoamine transporter 2, which packages 5-HT into synaptic vesicles, were also reduced in the young adult midbrain following AIE treatment. Adolescent intermittent ethanol treatment increased expression of phosphorylated (activated) NF-κB p65 as well as markers of microglial activation (i.e., Iba-1 and CD11b) in the adult DRN. Administration of lipopolysaccharide to mimic AIE-induced innate immune activation reduced 5-HT+IR and increased phosphorylated NF-κB p65+IR similar to AIE treatment. Voluntary exercise during adolescence through young adulthood blunted microglial marker and phosphorylated NF-κB p65+IR, and prevented the AIE-induced loss of 5-HT+IR neurons in the DRN. Together, these novel data reveal that AIE reduces 5-HT+IR neurons in the adult DRN, possibly through an innate immune mechanism, which might impact adult cognition, arousal, or reward sensitivity. Further, exercise prevents the deleterious effects of AIE on the serotonergic system.

  3. Role of controlled cardiac reoxygenation in reducing nitric oxide production and cardiac oxidant damage in cyanotic infantile hearts.

    PubMed Central

    Morita, K; Ihnken, K; Buckberg, G D; Sherman, M P; Young, H H; Ignarro, L J

    1994-01-01

    Cardiopulmonary bypass (CPB) is used increasingly to correct cyanotic heart defects during early infancy, but myocardial dysfunction is often seen after surgical repair. This study evaluates whether starting CPB at a conventional, hyperoxic pO2 causes an "unintentional" reoxygenation (ReO2) injury. We subjected 2-wk-old piglets to ventilator hypoxemia (FIO2 approximately 0.06, pO2 approximately 25 mmHg) followed by 5 min of ReO2 on CPB before instituting cardioplegia. CPB was begun in hypoxemic piglets by either abrupt ReO2 at a pO2 of 400 mmHg (standard clinical practice) or by maintaining pO2 approximately 25 mmHg on CPB until controlling ReO2 with blood cardioplegic arrest. The effects of abrupt vs. gradual ReO2 without surgical ischemia (blood cardioplegia) were also compared. Myocardial nitric oxide (NO) production (chemiluminescence measurements of NO2- + NO3-) and conjugated diene (CD) generation (spectrophotometric A233 measurements of lipid extracts) using aortic and coronary sinus blood samples were assessed during cardioplegic induction. 30 min after CPB, left ventricular end-systolic elastance (Ees, catheter conductance method) was used to determine cardiac function. CPB and blood cardioplegic arrest caused no functional or biochemical change in normoxic (control) hearts. Abrupt ReO2 caused a depression of myocardial function (Ees = 25 +/- 5% of control). Functional depression was relatively unaffected by gradual ReO2 without blood cardioplegia (34% recovery of Ees), and abrupt ReO2 immediately before blood cardioplegia caused a 10-fold rise in cardiac NO and CD production, with subsequent depression of myocardial function (Ees 21 +/- 2% of control). In contrast, controlled cardiac ReO2 reduced NO production 94%, CD did not rise, and Ees was 83 +/- 8% of normal. We conclude ReO2 injury is related to increased NO production during abrupt ReO2, nullifies the cardioprotective effects of blood cardioplegia, and that controlled cardiac ReO2 when starting CPB

  4. VS411 Reduced Immune Activation and HIV-1 RNA Levels in 28 Days: Randomized Proof-of-Concept Study for AntiViral-HyperActivation Limiting Therapeutics

    PubMed Central

    Lori, Franco; De Forni, Davide; Katabira, Elly; Baev, Denis; Maserati, Renato; Calarota, Sandra A.; Cahn, Pedro; Testori, Marco; Rakhmanova, Aza; Stevens, Michael R.

    2012-01-01

    Background A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4+ T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. Methods Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. Results VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4+ T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: −1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3) and fewest adverse events. Conclusions VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system

  5. Reduced-Order Modeling and Wavelet Analysis of Turbofan Engine Structural Response Due to Foreign Object Damage "FOD" Events

    NASA Technical Reports Server (NTRS)

    Turso, James A.; Lawrence, Charles; Litt, Jonathan S.

    2007-01-01

    The development of a wavelet-based feature extraction technique specifically targeting FOD-event induced vibration signal changes in gas turbine engines is described. The technique performs wavelet analysis of accelerometer signals from specified locations on the engine and is shown to be robust in the presence of significant process and sensor noise. It is envisioned that the technique will be combined with Kalman filter thermal/ health parameter estimation for FOD-event detection via information fusion from these (and perhaps other) sources. Due to the lack of high-frequency FOD-event test data in the open literature, a reduced-order turbofan structural model (ROM) was synthesized from a finite-element model modal analysis to support the investigation. In addition to providing test data for algorithm development, the ROM is used to determine the optimal sensor location for FOD-event detection. In the presence of significant noise, precise location of the FOD event in time was obtained using the developed wavelet-based feature.

  6. Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats.

    PubMed

    Ramos, Denise Barbosa; Muller, Gabriel Cardozo; Rocha, Guilherme Botter Maio; Dellavia, Gustavo Hirata; Almeida, Roberto Farina; Pettenuzzo, Leticia Ferreira; Loureiro, Samanta Oliveira; Hansel, Gisele; Horn, Ângelo Cássio Magalhães; Souza, Diogo Onofre; Ganzella, Marcelo

    2016-03-01

    In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window.

  7. Reduced-Order Modeling and Wavelet Analysis of Turbofan Engine Structural Response Due to Foreign Object Damage (FOD) Events

    NASA Technical Reports Server (NTRS)

    Turso, James; Lawrence, Charles; Litt, Jonathan

    2004-01-01

    The development of a wavelet-based feature extraction technique specifically targeting FOD-event induced vibration signal changes in gas turbine engines is described. The technique performs wavelet analysis of accelerometer signals from specified locations on the engine and is shown to be robust in the presence of significant process and sensor noise. It is envisioned that the technique will be combined with Kalman filter thermal/health parameter estimation for FOD-event detection via information fusion from these (and perhaps other) sources. Due to the lack of high-frequency FOD-event test data in the open literature, a reduced-order turbofan structural model (ROM) was synthesized from a finite element model modal analysis to support the investigation. In addition to providing test data for algorithm development, the ROM is used to determine the optimal sensor location for FOD-event detection. In the presence of significant noise, precise location of the FOD event in time was obtained using the developed wavelet-based feature.

  8. Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats.

    PubMed

    Shiha, Ahmed Anis; de Cristóbal, Javier; Delgado, Mercedes; Fernández de la Rosa, Rubén; Bascuñana, Pablo; Pozo, Miguel A; García-García, Luis

    2015-02-01

    The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of

  9. Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation

    PubMed Central

    Crowell, Trevor A; Fletcher, James LK; Sereti, Irini; Pinyakorn, Suteeraporn; Dewar, Robin; Krebs, Shelly J; Chomchey, Nitiya; Rerknimitr, Rungsun; Schuetz, Alexandra; Michael, Nelson L; Phanuphak, Nittaya; Chomont, Nicolas; Ananworanich, Jintanat

    2016-01-01

    Introduction Colonic infiltration by HIV occurs soon after infection, establishing a persistent viral reservoir and a barrier to cure. We investigated virologic and immunologic correlates of detectable colonic HIV RNA during acute HIV infection (AHI) and their response to antiretroviral treatment (ART). Methods From 49,458 samples screened for HIV, 74 participants were enrolled during AHI and 41 consented to optional sigmoidoscopy, HIV RNA was categorized as detectable (≥50 copies/mg) or undetectable in homogenized colon biopsy specimens. Biomarkers and HIV burden in blood, colon and cerebrospinal fluid were compared between groups and after 24 weeks of ART. Results Colonic HIV RNA was detectable in 31 participants (76%) and was associated with longer duration since HIV exposure (median 16 vs. 11 days, p=0.02), higher median plasma levels of cytokines and inflammatory markers (CXCL10 476 vs. 148 pg/mL, p=0.02; TNF-RII 1036 vs. 649 pg/mL, p<0.01; neopterin 2405 vs. 1368 pg/mL, p=0.01) and higher levels of CD8+ T cell activation in the blood (human leukocyte antigen - antigen D related (HLA-DR)/CD38 expression 14.4% vs. 7.6%, p <0.01) and colon (8.9% vs. 4.5%, p=0.01). After 24 weeks of ART, participants with baseline detectable colonic HIV RNA demonstrated persistent elevations in total HIV DNA in colonic mucosal mononuclear cells (CMMCs) (median 61 vs. 0 copies/106 CMMCs, p=0.03) and a trend towards higher total HIV DNA in peripheral blood mononuclear cells (PBMC) (41 vs. 1.5 copies/106 PBMCs, p=0.06). There were no persistent differences in immune activation and inflammation. Conclusions The presence of detectable colonic HIV RNA at the time of ART initiation during AHI is associated with higher levels of proviral DNA after 24 weeks of treatment. Seeding of HIV in the gut may have long-lasting effects on the size of persistent viral reservoirs and may represent an important therapeutic target in eradication strategies. PMID:27637172

  10. B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension.

    PubMed

    Holditch, Sara J; Schreiber, Claire A; Nini, Ryan; Tonne, Jason M; Peng, Kah-Whye; Geurts, Aron; Jacob, Howard J; Burnett, John C; Cataliotti, Alessandro; Ikeda, Yasuhiro

    2015-07-01

    Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.

  11. Nonclassical export pathway: overexpression of NCE102 reduces protein and DNA damage and prolongs lifespan in an SGS1 deficient Saccharomyces cerevisiae.

    PubMed

    Desmyter, Liesbeth; Verstraelen, Jan; Dewaele, Sylviane; Libert, Claude; Contreras, Roland; Chen, Cuiying

    2007-10-01

    In this study, we used our recently developed screening method, Bud-Scar-based Screening (BSS), to screen a yeast cDNA expression library in an SGS1 deletion BY4742 yeast strain. One gene involved in a nonclassical export pathway, NCE102, was found to extend the life span of Deltasgs1 yeast. Deletion of NCE102 in a wild type yeast strain increased its sensitivity to oxidative stress upon diethylmaleate (DEM) treatment but did not shorten its lifespan, indicating that this gene is not essential in determining yeast lifespan. Transformation of NCE102 into either Deltance102 or Deltasgs1 strains could rescue its tolerance to DEM stress, indicating that NCE102 is protective during oxidative stress. Moreover, overexpression of NCE102 in Deltasgs1 strain leads to reduced protein damage. However, overexpression of NCE102 in wild type yeast strain BY4742 neither protected against oxidative stress due to DEM nor extended yeast lifespan compared to its parental wild type strain, indicating that nonclassical export is redundant and DNA repair is fully sufficient in the wild type strain. We therefore demonstrate that a nonclassical export pathway functions as an alternative clearance/detoxification pathway to eliminate damaged material, when the basic repair pathway is not sufficient.

  12. The Xerophyta viscosa aldose reductase (ALDRXV4) confers enhanced drought and salinity tolerance to transgenic tobacco plants by scavenging methylglyoxal and reducing the membrane damage.

    PubMed

    Kumar, Deepak; Singh, Preeti; Yusuf, Mohd Aslam; Upadhyaya, Chandrama Prakash; Roy, Suchandra Deb; Hohn, Thomas; Sarin, Neera Bhalla

    2013-06-01

    We report the efficacy of an aldose reductase (ALDRXV4) enzyme from Xerophyta viscosa Baker in enhancing the prospects of plant's survival under abiotic stress. Transgenic tobacco plants overexpressing ALDRXV4 cDNA showed alleviation of NaCl and mannitol-induced abiotic stress. The transgenic plants survived longer periods of water deficiency and salinity stress and exhibited improved recovery after rehydration as compared to the wild type plants. The increased synthesis of aldose reductase in transgenic plants correlated with reduced methylglyoxal and malondialdehyde accumulation and an elevated level of sorbitol under stress conditions. In addition, the transgenic lines showed better photosynthetic efficiency, less electrolyte damage, greater water retention, higher proline accumulation, and favorable ionic balance under stress conditions. Together, these findings suggest the potential of engineering aldose reductase levels for better performance of crop plants growing under drought and salt stress conditions.

  13. Striatal damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice.

    PubMed

    Maragos, William F; Young, Kristie L; Altman, Chris S; Pocernich, Chava B; Drake, Jennifer; Butterfield, D Allan; Seif, Isabelle; Holschneider, Daniel P; Chen, Kevin; Shih, Jean C

    2004-04-01

    Intrastriatal administration of the succinate dehydrogenase (SDH) inhibitor malonate produces neuronal injury by a "secondary excitotoxic" mechanism involving the generation of reactive oxygen species (ROS). Recent evidence indicates dopamine may contribute to malonate-induced striatal neurodegeneration; infusion of malonate causes a pronounced increase in extracellular dopamine and dopamine deafferentation attenuates malonate toxicity. Inhibition of the catabolic enzyme monoamine oxidase (MAO) also attenuates striatal lesions induced by malonate. In addition to forming 3,4-dihydroxyphenylacetic acid, metabolism of dopamine by MAO generates H2O2, suggesting that dopamine metabolism may be a source of ROS in malonate toxicity. There are two isoforms of MAO, MAO-A and MAO-B. In this study, we have investigated the role of each isozyme in malonate-induced striatal injury using both pharmacological and genetic approaches. In rats treated with either of the specific MAO-A or -B inhibitors, clorgyline or deprenyl, respectively, malonate lesion volumes were reduced by 30% compared to controls. In knock-out mice lacking the MAO-A isoform, malonate-induced lesions were reduced by 50% and protein carbonyls, an index ROS formation, were reduced by 11%, compared to wild-type animals. In contrast, mice deficient in MAO-B showed highly variable susceptibility to malonate toxicity precluding us from determining the precise role of MAO-B in this form of brain damage. These findings indicate that normal levels of MAO-A participate in expression of malonate toxicity by a mechanism involving oxidative stress.

  14. Immunization of teenagers with a fifth dose of reduced DTaP-IPV induces high levels of pertussis antibodies with a significant increase in opsonophagocytic activity.

    PubMed

    Aase, Audun; Herstad, Tove Karin; Merino, Samuel; Bolstad, Merete; Sandbu, Synne; Bakke, Hilde; Aaberge, Ingeborg S

    2011-08-01

    Waning vaccine-induced immunity against Bordetella pertussis is observed among adolescents and adults. A high incidence of pertussis has been reported in this population, which serves as a reservoir for B. pertussis. A fifth dose of reduced antigen of diphtheria-tetanus-acellular-pertussis and inactivated polio vaccine was given as a booster dose to healthy teenagers. The antibody activity against B. pertussis antigens was measured prior to and 4 to 8 weeks after the booster by different assays: enzyme-linked immunosorbent assays (ELISAs) of IgG and IgA against pertussis toxin (PT) and filamentous hemagglutinin (FHA), IgG against pertactin (PRN), opsonophagocytic activity (OPA), and IgG binding to live B. pertussis. There was a significant increase in the IgG activity against PT, FHA, and PRN following the booster immunization (P < 0.001). The prebooster sera showed a geometric mean OPA titer of 65.1 and IgG binding to live bacteria at a geometric mean concentration of 164.9 arbitrary units (AU)/ml. Following the fifth dose, the OPA increased to a titer of 360.4, and the IgG concentration against live bacteria increased to 833.4 AU/ml (P < 0.001 for both). The correlation analyses between the different assays suggest that antibodies against FHA and PRN contribute the most to the OPA and IgG binding.

  15. Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis.

    PubMed

    Massoud, Raya; Enose-Akahata, Yoshimi; Tagaya, Yutaka; Azimi, Nazli; Basheer, Asjad; Jacobson, Steven

    2015-09-01

    Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive inflammatory myelopathy occurring in a subset of HTLV-1-infected individuals. Despite advances in understanding its immunopathogenesis, an effective treatment remains to be found. IL-2 and IL-15, members of the gamma chain (γc) family of cytokines, are prominently deregulated in HAM/TSP and underlie many of the characteristic immune abnormalities, such as spontaneous lymphocyte proliferation (SP), increased STAT5 phosphorylation in the lymphocytes, and increased frequency and cytotoxicity of virus-specific cytotoxic CD8(+) T lymphocytes (CTLs). In this study, we describe a novel immunomodulatory strategy consisting of selective blockade of certain γc family cytokines, including IL-2 and IL-15, with a γc antagonistic peptide. In vitro, a PEGylated form of the peptide, named BNZ132-1-40, reduced multiple immune activation markers such as SP, STAT5 phosphorylation, spontaneous degranulation of CD8(+) T cells, and the frequency of transactivator protein (Tax)-specific CD8(+) CTLs, thought to be major players in the immunopathogenesis of the disease. This strategy is thus a promising therapeutic approach to HAM/TSP with the potential of being more effective than single monoclonal antibodies targeting either IL-2 or IL-15 receptors and safer than inhibitors of downstream signaling molecules such as JAK1 inhibitors. Finally, selective cytokine blockade with antagonistic peptides might be applicable to multiple other conditions in which cytokines are pathogenic.

  16. Delayed neutralization of interleukin 6 reduces organ injury, selectively suppresses inflammatory mediator, and partially normalizes immune dysfunction following trauma and hemorrhagic shock.

    PubMed

    Zhang, Yong; Zhang, Jinxiang; Korff, Sebastian; Ayoob, Faez; Vodovotz, Yoram; Billiar, Timothy R

    2014-09-01

    An excessive and uncontrolled systemic inflammatory response is associated with organ failure, immunodepression, and increased susceptibility to nosocomial infection following trauma. Interleukin 6 (IL-6) plays a particularly prominent role in the host immune response after trauma with hemorrhage. However, as a result of its pleiotropic functions, the effect of IL-6 in trauma and hemorrhage is still controversial. It remains unclear whether suppression of IL-6 after hemorrhagic shock and trauma will attenuate organ injury and immunosuppression. In this study, C57BL/6 mice were treated with anti-mouse IL-6 monoclonal antibody immediately prior to resuscitation in an experimental model combining hemorrhagic shock and lower-extremity injury. Interleukin 6 levels and signaling were transiently suppressed following administrations of anti-IL-6 monoclonal antibody following hemorrhagic shock and lower-extremity injury. This resulted in reduced lung and liver injury, as well as suppression in the levels of key inflammatory mediators including IL-10, keratinocyte-derived chemokine, monocyte chemoattractant protein 1, and macrophage inhibitory protein 1α at both 6 and 24 h. Furthermore, the shift to TH2 cytokine production and suppressed lymphocyte response were partly prevented. These results demonstrate that IL-6 is not only a biomarker but also an important driver of injury-induced inflammation and immune suppression in mice. Rapid measurement of IL-6 levels in the early phase of postinjury care could be used to guide IL-6-based interventions.

  17. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    PubMed Central

    Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

  18. Bone marrow-derived mesenchymal stem cells reduce immune reaction in a mouse model of allergic rhinitis

    PubMed Central

    Zhao, Ning; Liu, Yanjuan; Liang, Hongfeng; Jiang, Xuejun

    2016-01-01

    Object: To determine the potential of bone marrow-derived mesenchymal stem cells (BMSCs) for immunomodulatory mechanism in mice model of allergic rhinitis (AR). Methods: BMSCs were isolated and the surface markers and stemness were analyzed. The effect of BMSCs was evaluated in BALB/c mice that were randomly divided into three groups (control group, ovalbumin (OVA) group, OVA+BMSCs group). BMSCs were administered intravenously to OVA sensitized mice on days 1, 7, 14 and 21, and subsequent OVA challenge was conducted daily from days 22 to 35. Several parameters of allergic inflammation were assessed. Results: Mesenchymal stem cells can be successfully isolated from bone marrow of mice. Intravenous injection of BMSCs significantly reduced allergic symptoms, eosinophil infiltration, OVA-specific immunoglobulin E (IgE), T-helper 2 (Th2) cytokine profile (interleukin (IL)-4, IL-5 and IL-13) and regulatory cytokines (IL-10). In addition, level of Th1 (IFN-γ) was significantly increased. Conclusion: Administration of BMSCs effectively reduced allergic symptoms and inflammatory parameters in the mice model of AR. BMSCs treatment is potentially an alternative therapeutic modality in AR. PMID:28078033

  19. Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice.

    PubMed

    Imeri, Faik; Fallegger, Daniel; Zivkovic, Aleksandra; Schwalm, Stephanie; Enzmann, Gaby; Blankenbach, Kira; Meyer zu Heringdorf, Dagmar; Homann, Thomas; Kleuser, Burkhard; Pfeilschifter, Josef; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea

    2014-10-01

    The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

  20. Plasmodium vivax gametocyte proteins, Pvs48/45 and Pvs47, induce transmission-reducing antibodies by DNA immunization.

    PubMed

    Tachibana, Mayumi; Suwanabun, Nantavadee; Kaneko, Osamu; Iriko, Hideyuki; Otsuki, Hitoshi; Sattabongkot, Jetsumon; Kaneko, Akira; Herrera, Socrates; Torii, Motomi; Tsuboi, Takafumi

    2015-04-15

    Malaria transmission-blocking vaccines (TBV) aim to interfere with the development of the malaria parasite in the mosquito vector, and thus prevent spread of transmission in a community. To date three TBV candidates have been identified in Plasmodium vivax; namely, the gametocyte/gamete protein Pvs230, and the ookinete surface proteins Pvs25 and Pvs28. The Plasmodium falciparum gametocyte/gamete stage proteins Pfs48/45 and Pfs47 have been studied as TBV candidates, and Pfs48/45 shown to induce transmission-blocking antibodies, but the candidacy of their orthologs in P. vivax, Pvs48/45 (PVX_083235) and Pvs47 (PVX_083240), for vivax TBV have not been tested. Herein we investigated whether targeting Pvs48/45 and Pvs47 can inhibit parasite transmission to mosquitoes, using P. vivax isolates obtained in Thailand. Mouse antisera directed against the products from plasmids expressing Pvs48/45 and Pvs47 detected proteins of approximately 45- and 40-kDa, respectively, in the P. vivax gametocyte lysate, by Western blot analysis under non-reducing conditions. In immunofluorescence assays Pvs48/45 was detected predominantly on the surface and Pvs47 was detected in the cytoplasm of gametocytes. Membrane feeding transmission assays demonstrated that anti-Pvs48/45 and -Pvs47 mouse sera significantly reduced the number of P. vivax oocysts developing in the mosquito midgut. Limited amino acid polymorphism of these proteins was observed among 27 P. vivax isolates obtained from Thailand, Vanuatu, and Colombia; suggesting that polymorphism may not be an impediment for the utilization of Pvs48/45 and Pvs47 as TBV antigens. In one Thai isolate we found that the fourth cysteine residue in the Pvs47 cysteine-rich domain (CRD) III (amino acid position 337) is substituted to phenylalanine. However, antibodies targeting Pvs47 CRDI-III showed a significant transmission-reducing activity against this isolate, suggesting that this substitution in Pvs47 was not critical for recognition by the

  1. Immunization with H7-HCP-tir-intimin significantly reduces colonization and shedding of Escherichia coli O157:H7 in goats.

    PubMed

    Zhang, Xuehan; Yu, Zhengyu; Zhang, Shuping; He, Kongwang

    2014-01-01

    Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is the causative agent of hemorrhagic colitis and hemolytic uremic syndrome in humans. However, the bacterium can colonize the intestines of ruminants without causing clinical signs. EHEC O157:H7 needs flagella (H7) and hemorrhagic coli pili (HCP) to adhere to epithelial cells. Then the bacterium uses the translocated intimin receptor (Tir) and an outer membrane adhesion (Intimin) protein to colonize hosts. This leads to the attachment and effacement of (A/E) lesions. A tetravalent recombinant vaccine (H7-HCP-Tir-Intimin) composed of immunologically important portions of H7, HCP, Tir and Intimin proteins was constructed and its efficacy was evaluated using a caprine model. The results showed that the recombinant vaccine induced strong humoral and mucosal immune responses and protected the subjects from live challenges with EHEC O157:H7 86-24 stain. After a second immunization, the average IgG titer peaked at 7.2 × 10(5). Five days after challenge, E. coli O157:H7 was no longer detectable in the feces of vaccinated goats, but naïve goats shed the bacterium throughout the course of the challenge. Cultures of intestinal tissues showed that vaccination of goats with H7-HCP-Tir-Intimin reduced the amount of intestinal colonization by EHEC O157:H7 effectively. Recombinant H7-HCP-Tir-Intimin protein is an excellent vaccine candidate. Data from the present study warrant further efficacy studies aimed at reducing EHEC O157:H7 load on farms and the contamination of carcasses by this zoonotic pathogen.

  2. Chito-oligosaccharide reduces diarrhea incidence and attenuates the immune response of weaned pigs challenged with Escherichia coli K88.

    PubMed

    Liu, P; Piao, X S; Thacker, P A; Zeng, Z K; Li, P F; Wang, D; Kim, S W

    2010-12-01

    Seventy-two barrows (Landrace × Large White, initial BW of 4.9 ± 0.3 kg and 17 ± 3 d old) were used to determine if dietary chito-oligosaccharides can replace antibiotics as a means to reduce signs associated with infection in weaned pigs challenged with Escherichia coli. Pigs were assigned to 1 of 4 treatments in a randomized complete block design using 6 pens per treatment with 3 pigs per pen. The treatments consisted of pigs fed the unsupplemented corn-soybean meal diet challenged or unchallenged with E. coli K88 and pigs fed the same diet supplemented with 160 mg of chito-oligosaccharides or 100 mg of cyadox/kg and challenged with E. coli K88. On d 7, 1 group of pigs fed the unsupplemented diet, as well as all pigs fed diets containing chito-oligosaccharides or cyadox, were orally dosed with 30 mL of an alkaline broth containing E. coli K88. Another group of pigs fed the unsupplemented diet was orally dosed with 30 mL of sterilized alkaline broth. Fecal consistency was visually assessed each morning from d 7 to 14. Blood samples were collected at 0, 24, 48, and 168 h postinfection. On d 14 postchallenge, all pigs were killed to evaluate intestinal morphology and determine E. coli concentrations in the intestine. During the postchallenge period (wk 2), unsupplemented pigs challenged with E. coli had decreased (P < 0.05) BW gain, feed intake, fecal consistency, villus height, villus height:crypt depth ratio, and plasma IGF-1, and increased (P < 0.05) diarrhea incidence, E. coli counts in the intestine, plasma interleukin-1β, plasma IL-10, and IGA-positive cells in the jejunal and ileal lamina propria, compared with unchallenged pigs. Supplementation with cyadox largely mitigated these effects. Although chito-oligosaccharide reduced the incidence of diarrhea, the growth performance of E. coli-challenged pigs supplemented with chito-oligosaccharide was not better than that of unsupplemented pigs challenged with E. coli. Therefore, chito-oligosaccharide, at the

  3. Reduced in vitro immune responses of purified human Leu-3 (helper/inducer phenotype) cells after total lymphoid irradiation

    SciTech Connect

    Field, E.H.; Engleman, E.G.; Terrell, C.P.; Strober, S.

    1984-02-01

    Patients treated with total lymphoid irradiation (TLI) for intractible rheumatoid arthritis showed marked decreases in the in vitro proliferative responses of peripheral blood mononuclear cells (PBM) to antigens and mitogens. To determine whether an intrinsic deficit in helper/inducer cell proliferation contributed to decreased responses, cells of the helper/inducer phenotype were purified from the PBM of treated patients by using monoclonal anti-Leu-3 antibody and a modified panning procedure. The purified Leu-3 cells obtained after TLI showed a marked reduction in (/sup 3/H)thymidine incorporation in response to allogeneic lymphocytes, PHA, Con A, and several protein antigens, as compared with that of cells from the same patients obtained before TLI. In addition, the quantity of Leu-3 surface antigen on the panned cells was reduced after TLI. The results suggest that TLI induces prolonged qualitative as well as quantitative changes in circulating Leu-3 T cells. These changes may contribute to the clinical effects of TLI.

  4. Protection of mice against Shiga toxin 2 (Stx2)-associated damage by maternal immunization with a Brucella lumazine synthase-Stx2 B subunit chimera.

    PubMed

    Mejias, María Pilar; Cabrera, Gabriel; Fernández-Brando, Romina Jimena; Baschkier, Ariela; Ghersi, Giselle; Abrey-Recalde, Maria Jimena; Miliwebsky, Elizabeth; Meiss, Roberto; Goldbaum, Fernando; Zylberman, Vanesa; Rivas, Marta; Palermo, Marina Sandra

    2014-04-01

    Hemolytic-uremic syndrome (HUS) is defined as the triad of anemia, thrombocytopenia, and acute kidney injury. Enterohemorrhagic Shiga toxin (Stx)-producing Escherichia coli (EHEC), which causes a prodromal hemorrhagic enteritis, remains the most common etiology of the typical or epidemic form of HUS. Because no licensed vaccine or effective therapy is presently available for human use, we recently developed a novel immunogen based on the B subunit of Shiga toxin 2 (Stx2B) and the enzyme lumazine synthase from Brucella spp. (BLS) (BLS-Stx2B). The aim of this study was to analyze maternal immunization with BLS-Stx2B as a possible approach for transferring anti-Stx2 protection to the offspring. BALB/c female mice were immunized with BLS-Stx2B before mating. Both dams and pups presented comparable titers of anti-Stx2B antibodies in sera and fecal extracts. Moreover, pups were totally protected against a lethal dose of systemic Stx2 injection up to 2 to 3 months postpartum. In addition, pups were resistant to an oral challenge with an Stx2-producing EHEC strain at weaning and did not develop any symptomatology associated with Stx2 toxicity. Fostering experiments demonstrated that anti-Stx2B neutralizing IgG antibodies were transmitted through breast-feeding. Pups that survived the EHEC infection due to maternally transferred immunity prolonged an active and specific immune response that protected them against a subsequent challenge with intravenous Stx2. Our study shows that maternal immunization with BLS-Stx2B was very effective at promoting the transfer of specific antibodies, and suggests that preexposure of adult females to this immunogen could protect their offspring during the early phase of life.

  5. Protection of Mice against Shiga Toxin 2 (Stx2)-Associated Damage by Maternal Immunization with a Brucella Lumazine Synthase-Stx2 B Subunit Chimera

    PubMed Central

    Mejias, María Pilar; Cabrera, Gabriel; Fernández-Brando, Romina Jimena; Baschkier, Ariela; Ghersi, Giselle; Abrey-Recalde, Maria Jimena; Miliwebsky, Elizabeth; Meiss, Roberto; Goldbaum, Fernando; Zylberman, Vanesa; Rivas, Marta

    2014-01-01

    Hemolytic-uremic syndrome (HUS) is defined as the triad of anemia, thrombocytopenia, and acute kidney injury. Enterohemorrhagic Shiga toxin (Stx)-producing Escherichia coli (EHEC), which causes a prodromal hemorrhagic enteritis, remains the most common etiology of the typical or epidemic form of HUS. Because no licensed vaccine or effective therapy is presently available for human use, we recently developed a novel immunogen based on the B subunit of Shiga toxin 2 (Stx2B) and the enzyme lumazine synthase from Brucella spp. (BLS) (BLS-Stx2B). The aim of this study was to analyze maternal immunization with BLS-Stx2B as a possible approach for transferring anti-Stx2 protection to the offspring. BALB/c female mice were immunized with BLS-Stx2B before mating. Both dams and pups presented comparable titers of anti-Stx2B antibodies in sera and fecal extracts. Moreover, pups were totally protected against a lethal dose of systemic Stx2 injection up to 2 to 3 months postpartum. In addition, pups were resistant to an oral challenge with an Stx2-producing EHEC strain at weaning and did not develop any symptomatology associated with Stx2 toxicity. Fostering experiments demonstrated that anti-Stx2B neutralizing IgG antibodies were transmitted through breast-feeding. Pups that survived the EHEC infection due to maternally transferred immunity prolonged an active and specific immune response that protected them against a subsequent challenge with intravenous Stx2. Our study shows that maternal immunization with BLS-Stx2B was very effective at promoting the transfer of specific antibodies, and suggests that preexposure of adult females to this immunogen could protect their offspring during the early phase of life. PMID:24421050

  6. Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri.

    PubMed

    Yang, Mingbo; Li, Na; Li, Fang; Zhu, Qianqian; Liu, Xi; Han, Qunying; Wang, Yawen; Chen, Yanping; Zeng, Xiaoyan; Lv, Yi; Zhang, Pingping; Yang, Cuiling; Liu, Zhengwen

    2013-08-01

    Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor β1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation.

  7. Blocking of bradykinin receptor B1 protects from focal closed head injury in mice by reducing axonal damage and astroglia activation.

    PubMed

    Albert-Weissenberger, Christiane; Stetter, Christian; Meuth, Sven G; Göbel, Kerstin; Bader, Michael; Sirén, Anna-Leena; Kleinschnitz, Christoph

    2012-09-01

    The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.

  8. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis.

    PubMed

    Kraft, Peter; Schwarz, Tobias; Göb, Eva; Heydenreich, Nadine; Brede, Marc; Meuth, Sven G; Kleinschnitz, Christoph

    2013-09-01

    Blood-brain-barrier (BBB) disruption, inflammation and thrombosis are important steps in the pathophysiology of acute ischemic stroke but are still inaccessible to therapeutic interventions. Rolipram specifically inhibits the enzyme phosphodiesterase (PDE) 4 thereby preventing the inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to relief inflammation and BBB damage in a variety of neurological disorders. We investigated the therapeutic potential of rolipram in a model of brain ischemia/reperfusion injury in mice. Treatment with 10mg/kg rolipram, but not 2 mg/kg rolipram, 2 h after 60 min of transient middle cerebral artery occlusion (tMCAO) reduced infarct volumes by 50% and significantly improved clinical scores on day 1 compared with vehicle-treated controls. Rolipram maintained BBB function upon stroke as indicated by preserved expression of the tight junction proteins occludin and claudin-5. Accordingly, the formation of vascular brain edema was strongly attenuated in mice receiving rolipram. Moreover, rolipram reduced the invasion of neutrophils as well as the expression of the proinflammatory cytokines IL-1β and TNFα but increased the levels of TGFβ-1. Finally, rolipram exerted antithrombotic effects upon stroke and fewer neurons in the rolipram group underwent apoptosis. Rolipram is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.

  9. Roles of MgO release from polyethylene glycol 6000-based solid dispersions on microenvironmental pH, enhanced dissolution and reduced gastrointestinal damage of telmisartan.

    PubMed

    Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Seung Aeon; Nho, Vo Hong; Chi, Sang-Cheol; Lee, Beom-Jin

    2011-05-01

    The roles of magnesium oxide (MgO) release from solid dispersions (SDs) in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and water were investigated to elucidate the enhanced dissolution and reduced intestinal damages of telmisartan as a model drug. The polyethylene glycol 6000 (PEG 6000) was used to prepare the SDs. Three SDs were prepared: SD1 (PEG, MgO, TEL), SD2 (PEG 6000, TEL), SD3 (MgO, TEL). The physical mixture (PM) consisting of SD2 and MgO was also prepared. A binary SD without MgO (SD2) was also prepared for comparison in microenvironmental pH (pH(M)) modulation. The faster MgO released, the less control of pH(M) and the less enhanced dissolution of TEL were in consequences. SD3 increased dissolution in SIF and water (about 67%). Interestingly, ternary SD1 showed almost complete dissolution in all three media but dissolution of PM was the lowest due to the fast release of MgO and poor modulation of pH(M). MgO did not change the drug crystallinity but did have a strong molecular interaction with the drug. Additionally, the SD3-bearing tablet quickly increased pH(M) but then gradually decreased due to faster release of MgO while the SD1-bearing tablet gradually increased pH(M) at all fractional dimensions of the tablet by the MgO slowly released. The pH(M) of PM-bearing tablets was not varied as a function of time. Thus, the MgO-bearing SD1 also minimized gastrointestinal tissue damage caused by the model drug.

  10. Peripheral blood mononuclear cell supernatants from asymptomatic dogs immunized and experimentally challenged with Leishmania chagasi can stimulate canine macrophages to reduce infection in vitro.

    PubMed

    Rodrigues, Cleusa Alves Theodoro; Batista, Luís Fábio da Silva; Teixeira, Márcia Cristina Aquino; Pereira, Andréa Mendes; Santos, Patrícia Oliveira Meira; de Sá Oliveira, Geraldo Gileno; de Freitas, Luiz Antônio Rodrigues; Veras, Patrícia Sampaio Tavares

    2007-02-28

    Leishmania chagasi is the causative agent of visceral leishmaniasis in both humans and dogs in the New World. The dog is the main domestic reservoir and its infection displays different clinical presentations, from asymptomatic to severe disease. Macrophages play an important role in the control of Leishmania infection. Although it is not an area of intense study, some data suggest a role for canine macrophages in parasite killing by a NO-dependent mechanism. It has been proposed that control of human disease could be possible with the development of an effective vaccine against canine visceral leishmaniasis. Development of a rapid in vitro test to predict animal responses to Leishmania infection or vaccination should be helpful. In this study, an in vitro model was established to test whether peripheral blood mononuclear cell (PBMC) supernatants from dogs immunized with promastigote lysates and infected with L. chagasi promastigotes could stimulate macrophages from healthy dogs in order to control parasite infection. PBMC from a majority of the immunized and experimentally infected dogs expressed IFN-gamma mRNA and secreted IFN-gamma when stimulated with soluble L. chagasi antigen (SLA) in vitro. Additionally, the supernatants from stimulated PBMC were able to reduce the percentage of infected donor macrophages. The results also indicate that parasite killing in this system is dependent on NO, since aminoguanidine (AMG) reversed this effect. This in vitro test appears to be useful for screening animal responses to parasite inoculation as well as studying the lymphocyte effector mechanisms involved in pathogen killing by canine macrophages.

  11. Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Vella, Jennifer L.; Reis, Isildinha M.; De la fuente, Adriana C.; Gomez, Carmen; Sargi, Zoukaa; Nazarian, Ronen; Califano, Joseph; Borrello, Ivan

    2015-01-01

    Purpose Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. Experimental Design First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 μg/day, 20 μg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment. Results MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. Conclusions Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. PMID:25320361

  12. Perfluorocarbon reduces cell damage from blast injury by inhibiting signal paths of NF-κB, MAPK and Bcl-2/Bax signaling pathway in A549 cells

    PubMed Central

    Li, Huaidong; Li, Chunsun; Yang, Zhen; Li, Yanqin; She, Danyang; Cao, Lu; Wang, Wenjie; Liu, Changlin; Chen, Liangan

    2017-01-01

    Background and objective Blast lung injury is a common type of blast injury and has very high mortality. Therefore, research to identify medical therapies for blast injury is important. Perfluorocarbon (PFC) is used to improve gas exchange in diseased lungs and has anti-inflammatory functions in vitro and in vivo. The aim of this study was to determine whether PFC reduces damage to A549 cells caused by blast injury and to elucidate its possible mechanisms of action. Study design and methods A549 alveolar epithelial cells exposed to blast waves were treated with and without PFC. Morphological changes and apoptosis of A549 cells were recorded. PCR and enzyme-linked immunosorbent assay (ELISA) were used to measure the mRNA or protein levels of IL-1β, IL-6 and TNF-α. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity levels were detected. Western blot was used to quantify the expression of NF-κB, Bax, Bcl-2, cleaved caspase-3 and MAPK cell signaling proteins. Results A549 cells exposed to blast wave shrank, with less cell-cell contact. The morphological change of A549 cells exposed to blast waves were alleviated by PFC. PFC significantly inhibited the apoptosis of A549 cells exposed to blast waves. IL-1β, IL-6 and TNF-α cytokine and mRNA expression levels were significantly inhibited by PFC. PFC significantly increased MDA levels and decreased SOD activity levels. Further studies indicated that NF-κB, Bax, caspase-3, phospho-p38, phosphor-ERK and phosphor-JNK proteins were also suppressed by PFC. The quantity of Bcl-2 protein was increased by PFC. Conclusion Our research showed that PFC reduced A549 cell damage caused by blast injury. The potential mechanism may be associated with the following signaling pathways: 1) the signaling pathways of NF-κB and MAPK, which inhibit inflammation and reactive oxygen species (ROS); and 2) the signaling pathways of Bcl-2/Bax and caspase-3, which inhibit apoptosis. PMID:28323898

  13. Heme on innate immunity and inflammation

    PubMed Central

    Dutra, Fabianno F.; Bozza, Marcelo T.

    2014-01-01

    Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases. PMID:24904418

  14. HTLV-1 Tax-Specific CTL Epitope-Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax.

    PubMed

    Ando, Satomi; Hasegawa, Atsuhiko; Murakami, Yuji; Zeng, Na; Takatsuka, Natsuko; Maeda, Yasuhiro; Masuda, Takao; Suehiro, Youko; Kannagi, Mari

    2017-02-01

    Adult T cell leukemia/lymphoma (ATL), a CD4(+) T cell malignancy with a poor prognosis, is caused by human T cell leukemia virus type 1 (HTLV-1) infection. High proviral load (PVL) is a risk factor for the progression to ATL. We previously reported that some asymptomatic carriers had severely reduced functions of CTLs against HTLV-1 Tax, the major target Ag. Furthermore, the CTL responses tended to be inversely correlated with PVL, suggesting that weak HTLV-1-specific CTL responses may be involved in the elevation of PVL. Our previous animal studies indicated that oral HTLV-1 infection, the major route of infection, caused persistent infection with higher PVL in rats compared with other routes. In this study, we found that Tax-specific CD8(+) T cells were present, but not functional, in orally infected rats as observed in some human asymptomatic carriers. Even in the infected rats with immune unresponsiveness against Tax, Tax-specific CTL epitope-pulsed dendritic cell (DC) therapy reduced the PVL and induced Tax-specific CD8(+) T cells capable of proliferating and producing IFN-γ. Furthermore, we found that monocyte-derived DCs from most infected individuals still had the capacity to stimulate CMV-specific autologous CTLs in vitro, indicating that DC therapy may be applicable to most infected individuals. These data suggest that peptide-pulsed DC immunotherapy will be useful to induce functional HTLV-1-specific CTLs and decrease PVL in infected individuals with high PVL and impaired HTLV-1-specific CTL responses, thereby reducing the risk of the development of ATL.

  15. Combined immunization using DNA-Sm14 and DNA-Hsp65 increases CD8+ memory T cells, reduces chronic pathology and decreases egg viability during Schistosoma mansoni infection

    PubMed Central

    2014-01-01

    Background Schistosomiasis is one of the most important neglected diseases found in developing countries and affects 249 million people worldwide. The development of an efficient vaccination strategy is essential for the control of this disease. Previous work showed partial protection induced by DNA-Sm14 against Schistosoma mansoni infection, whereas DNA-Hsp65 showed immunostimulatory properties against infectious diseases, autoimmune diseases, cancer and antifibrotic properties in an egg-induced granuloma model. Methods C57BL/6 mice received 4 doses of DNA-Sm14 (100 μg/dose) and DNA-Hsp65 (100 μg/dose), simultaneously administrated, or DNA-Sm14 alone, once a week, during four weeks. Three groups were included: 1- Control (no immunization); 2- DNA-Sm14; 3- DNA-Sm14/DNA-Hsp65. Two weeks following last immunization, animals were challenged subcutaneously with 30 cercariae. Fifteen, 48 and 69 days after infection splenocytes were collected to evaluate the number of CD8+ memory T cells (CD44highCD62low) using flow cytometry. Forty-eight days after challenge adult worms were collected by portal veins perfusion and intestines were collected to analyze the intestinal egg viability. Histological, immunohistochemical and soluble quantification of collagen and α-SMA accumulation were performed on the liver. Results In the current work, we tested a new vaccination strategy using DNA-Sm14 with DNA-Hsp65 to potentiate the protection against schistosomiasis. Combined vaccination increased the number of CD8+ memory T cells and decreased egg viability on the intestinal wall of infected mice. In addition, simultaneous vaccination with DNA-Sm14/DNA-Hsp65 reduced collagen and α-SMA accumulation during the chronic phase of granuloma formation. Conclusion Simultaneous vaccination with DNA-Sm14/DNA-Hsp65 showed an immunostimulatory potential and antifibrotic property that is associated with the reduction of tissue damage on Schistosoma mansoni experimental infection. PMID

  16. Water-filtered infrared A reduces chlamydial infectivity in vitro without causing ex vivo eye damage in pig and mouse models.

    PubMed

    Rahn, Carolin; Marti, Hanna; Frohns, Antonia; Frohns, Florian; Blenn, Christian; Leonard, Cory Ann; Barisani-Asenbauer, Talin; Stein, Elisabeth; Borel, Nicole

    2016-12-01

    Repeated ocular infections with Chlamydia trachomatis trigger the development of trachoma, the most common cause of infectious blindness worldwide. Water-filtered infrared A (wIRA) has shown positive effects on cultured cells and human skin. Our aim was to evaluate the potential of wIRA as a possible non-chemical treatment for trachoma patients. We both modeled ocular chlamydial infections using C. trachomatis B to infect human conjunctival epithelial cells (HCjE) and studied the effects of wIRA on non-infected ocular structures with two ex vivo eye models. We focused on the temperature development during wIRA irradiation in cell culture and perfused pig eyes to exclude potentially harmful side effects. Furthermore, cell viability of HCjE and cytotoxicity in mouse retina explants was analyzed. We demonstrated a significant wIRA-dependent reduction of chlamydial infectivity in HCjE cells. Moreover, we observed that wIRA treatment of HCjE prior to infection was sufficient to inhibit chlamydial infectivity and that visible light enhances the effect of wIRA. Irradiation did not reduce cell viability and there was no indication of retinal damage post treatment. Additionally, temperatures during wIRA exposure did not markedly exceed physiological eye temperatures, suggesting that hyperthermia-related lesions are unlikely. For clinical applications, further exploration of wIRA as a non-chemical treatment device in an experimental animal model is essential.

  17. Delayed IGF-1 treatment reduced long-term hypoxia-ischemia-induced brain damage and improved behavior recovery of immature rats.

    PubMed

    Zhong, Jin; Zhao, Limin; Du, Yansheng; Wei, Gang; Yao, Wei-Guo; Lee, Wei-Hua

    2009-06-01

    Cerebral hypoxia-ischemia during the perinatal period is the single most important cause of acute newborn mortality and chronic disability. Despite our increasing understanding of the mechanisms of neuronal injury, an effective clinical therapy has yet to be established to mitigate brain damage and improve the prognosis and well-being of these newborn patients. Insulin-like growth factor 1 (IGF-1) is a well-known neurotrophic factor, essential for the survival and functional maturation of immature neurons. This study demonstrated that subcutaneous administration of IGF-1 at 24 and 48 hours of recovery significantly reduced hypoxia-ischemia-induced injury to immature rat brains and improved long-term memory and cognitive behavior. IGF-1's therapeutic effects likely involve its ability to prevent delayed apoptosis, as we demonstrated in primary cortical neuronal cultures under oxygen and glucose deprivation. IGF-1's neuroprotective effects parallel the activities of phosphatidylinositol-3/Akt and its down-stream signaling pathway, suggesting a potential mechanistic link. Overall, evidence from this investigation strongly supports IGF-1's potential therapeutic use in the treatment of hypoxic-ischemic encephalopathy in newborn patients.

  18. Induction of Wnt-inducible signaling protein-1 correlates with invasive breast cancer oncogenesis and reduced type 1 cell-mediated cytotoxic immunity: a retrospective study.

    PubMed

    Klinke, David J

    2014-01-01

    Innate and type 1 cell-mediated cytotoxic immunity function as important extracellular control mechanisms that maintain cellular homeostasis. Interleukin-12 (IL12) is an important cytokine that links innate immunity with type 1 cell-mediated cytotoxic immunity. We recently observed in vitro that tumor-derived Wnt-inducible signaling protein-1 (WISP1) exerts paracrine action to suppress IL12 signaling. The objective of this retrospective study was three fold: 1) to determine whether a gene signature associated with type 1 cell-mediated cytotoxic immunity was correlated with overall survival, 2) to determine whether WISP1 expression is increased in invasive breast cancer, and 3) to determine whether a gene signature consistent with inhibition of IL12 signaling correlates with WISP1 expression. Clinical information and mRNA expression for genes associated with anti-tumor immunity were obtained from the invasive breast cancer arm of the Cancer Genome Atlas study. Patient cohorts were identified using hierarchical clustering. The immune signatures associated with the patient cohorts were interpreted using model-based inference of immune polarization. Reverse phase protein array, tissue microarray, and quantitative flow cytometry in breast cancer cell lines were used to validate observed differences in gene expression. We found that type 1 cell-mediated cytotoxic immunity was correlated with increased survival in patients with invasive breast cancer, especially in patients with invasive triple negative breast cancer. Oncogenic transformation in invasive breast cancer was associated with an increase in WISP1. The gene expression signature in invasive breast cancer was consistent with WISP1 as a paracrine inhibitor of type 1 cell-mediated immunity through inhibiting IL12 signaling and promoting type 2 immunity. Moreover, model-based inference helped identify appropriate immune signatures that can be used as design constraints in genetically engineering better pre

  19. Reducing vibration damage claims: Field application of strong public relations and one method of using commonly available seismograph and video taping equipment to document blast vibration regression at the nearest structure

    SciTech Connect

    Fritzen, M.R.; Fritzen, T.A.

    1994-12-31

    Anytime that blasting operations will be conducted near existing inhabited structures, vibration damage claims are a major concern of the blasting contractor. It has been the authors` experience that even when vibration and airblast levels generated from a blast are well below accepted damage thresholds, damage claims can still arise. The single greatest source of damage claims is the element of surprise associated with not knowing that blasting operations are being conducted nearby. The second greatest source of damage claims arise form the inability to produce accurate and detailed records of all blasting activity which provides evidence that vibration and air blast levels from each blast had been taken by seismic recording equipment. Using a two part plan consisting of extensive public relations followed by a detailed and accurate monitoring and recording of blasting operations has resulted in no substantiated claims of damage since its` incorporation. The authors experience shows that by using this two part process when conducting blasting operations near inhabited structures, unsubstantiated blast vibration damage claims may be significantly reduced.

  20. The role of tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in mediating autophagy in myositis skeletal muscle: A potential non-immune mechanism of muscle damage

    PubMed Central

    Alger, Heather M.; Raben, Nina; Pistilli, Emidio; Francia, Dwight; Rawat, Rashmi; Getnet, Derese; Ghimbovschi, Svetlana; Chen, Yi-Wen; Lundberg, Ingrid E.; Nagaraju, Kanneboyina

    2011-01-01

    Objective Multinucleated cells are relatively resistant to classical apoptosis, and the factors initiating cell-death and damage in myositis are not well defined. We hypothesized that non-immune autophagic cell death may play a role in muscle fiber damage. Recent literature indicates that tumor necrosis factor-alpha-related apoptosis inducing ligand (TRAIL) may induce both NFκB (nuclear factor kappa-light chain enhancer of activated B cells) activation and autophagic cell death in other systems. Here, we have investigated its role in cell death and pathogenesis in vitro and in vivo using myositis (human and mouse) muscle tissues. Methods Gene expression profiling indicated that expression of TRAIL and several autophagy markers was specifically upregulated in myositis muscle tissue; these results were confirmed by immunohistochemistry and immunoblotting. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NFκB activation in vitro in cultured cells. Results TRAIL was expressed predominantly in muscle fibers of myositis, but not in biopsies from normal or other dystrophic-diseased muscle. Autophagy markers were upregulated in human and mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NFκB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but undergo autophagic cell death. Conclusion Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NFκB and autophagic cell death in myositis. Thus, this non-immune pathway may be an attractive target for therapeutic intervention in myositis. PMID:21769834

  1. The effects of reduced gluten barley diet on humoral and cell-mediated systemic immune responses of gluten-sensitive rhesus macaques.

    PubMed

    Sestak, Karol; Thwin, Hazel; Dufour, Jason; Aye, Pyone P; Liu, David X; Moehs, Charles P

    2015-03-06

    Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten sources from the diet. Since required adherence to a gluten-free diet (GFD) is difficult to accomplish, efforts to develop alternative treatments have been intensifying in recent years. In this study, the non-human primate model of CD/NCGS, e.g., gluten-sensitive rhesus macaque, was utilized with the objective to evaluate the treatment potential of reduced gluten cereals using a reduced gluten (RG; 1% of normal gluten) barley mutant as a model. Conventional and RG barleys were used for the formulation of experimental chows and fed to gluten-sensitive (GS) and control macaques to determine if RG barley causes a remission of dietary gluten-induced clinical and immune responses in GS macaques. The impacts of the RG barley diet were compared with the impacts of the conventional barley-containing chow and the GFD. Although remission of the anti-gliadin antibody (AGA) serum responses and an improvement of clinical diarrhea were noted after switching the conventional to the RG barley diet, production of inflammatory cytokines, e.g., interferon-gamma (IFN-γ), tumor necrosis factor (TNF) and interleukin-8 (IL-8) by peripheral CD4+ T helper lymphocytes, persisted during the RG chow treatment and were partially abolished only upon re-administration of the GFD. It was concluded that the RG barley diet might be used for the partial improvement of gluten-induced disease but its therapeutic value still requires upgrading-by co-administration of additional treatments.

  2. The Effects of Reduced Gluten Barley Diet on Humoral and Cell-Mediated Systemic Immune Responses of Gluten-Sensitive Rhesus Macaques

    PubMed Central

    Sestak, Karol; Thwin, Hazel; Dufour, Jason; Aye, Pyone P.; Liu, David X.; Moehs, Charles P.

    2015-01-01

    Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten sources from the diet. Since required adherence to a gluten-free diet (GFD) is difficult to accomplish, efforts to develop alternative treatments have been intensifying in recent years. In this study, the non-human primate model of CD/NCGS, e.g., gluten-sensitive rhesus macaque, was utilized with the objective to evaluate the treatment potential of reduced gluten cereals using a reduced gluten (RG; 1% of normal gluten) barley mutant as a model. Conventional and RG barleys were used for the formulation of experimental chows and fed to gluten-sensitive (GS) and control macaques to determine if RG barley causes a remission of dietary gluten-induced clinical and immune responses in GS macaques. The impacts of the RG barley diet were compared with the impacts of the conventional barley-containing chow and the GFD. Although remission of the anti-gliadin antibody (AGA) serum responses and an improvement of clinical diarrhea were noted after switching the conventional to the RG barley diet, production of inflammatory cytokines, e.g., interferon-gamma (IFN-γ), tumor necrosis factor (TNF) and interleukin-8 (IL-8) by peripheral CD4+ T helper lymphocytes, persisted during the RG chow treatment and were partially abolished only upon re-administration of the GFD. It was concluded that the RG barley diet might be used for the partial improvement of gluten-induced disease but its therapeutic value still requires upgrading—by co-administration of additional treatments. PMID:25756783

  3. Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes.

    PubMed

    Cortese, Giuseppe P; Barrientos, Ruth M; Maier, Steven F; Patterson, Susan L

    2011-03-16

    For reasons that are not well understood, aging significantly increases brain vulnerability to challenging life events. High-functioning older individuals often experience significant cognitive decline after an inflammatory event such as surgery, infection, or injury. We have modeled this phenomenon in rodents and have previously reported that a peripheral immune challenge (intraperitoneal injection of live Escherichia coli) selectively disrupts consolidation of hippocampus-dependent memory in aged (24-month-old), but not young (3-month-old), F344xBN rats. More recently, we have demonstrated that this infection-evoked memory deficit is mirrored by a selective deficit in long-lasting synaptic plasticity in the hippocampus. Interestingly, these deficits occur in forms of long-term memory and synaptic plasticity known to be strongly dependent on brain-derived neurotrophic factor (BDNF). Here, we begin to test the hypothesis that the combination of aging and an infection might disrupt production or processing of BDNF protein in the hippocampus, decreasing the availability of BDNF for plasticity-related processes at synaptic sites. We find that mature BDNF is markedly reduced in Western blots of hippocampal synaptoneurosomes prepared from aged animals following infection. This reduction is blocked by intra-cisterna magna administration of the anti-inflammatory cytokine IL-1Ra (interleukin 1-specific receptor antagonist). Levels of the pan-neurotrophin receptor p75(NTR) and the BDNF receptor TrkB (tropomyosin receptor kinase B) are not significantly altered in these synaptoneurosomes, but phosphorylation of TrkB and downstream activation of PLCγ1 (phospholipase Cγ1) and ERK (extracellular response kinase) are attenuated-observations consistent with reduced availability of mature BDNF to activate TrkB signaling. These data suggest that inflammation-evoked reductions in BDNF at synapses might contribute to inflammation-evoked disruptions in long-term memory and synaptic

  4. Immune System

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Immune System KidsHealth > For Teens > Immune System A A A ... could put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  5. Caloric Restriction reduces inflammation and improves T cell-mediated immune response in obese mice but concomitant consumption of curcumin/piperine adds no further benefit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-...

  6. The Bacterial Mfd Protein Prevents DNA Damage Induced by the Host Nitrogen Immune Response in a NER-Independent but RecBC-Dependent Pathway

    PubMed Central

    Darrigo, Claire; Guillemet, Elisabeth; Dervyn, Rozenn; Ramarao, Nalini

    2016-01-01

    Production of reactive nitrogen species is an important component of the host immune defence against bacteria. Here, we show that the bacterial protein Mfd (Mutation frequency decline), a highly conserved and ubiquitous bacterial protein involved in DNA repair, confers bacterial resistance to the eukaryotic nitrogen response produced by macrophage cells and during mice infection. In addition, we show that RecBC is also necessary to survive this stress. The inactivation of recBC and mfd genes is epistatic showing that Mfd follows the RecBC repair pathway to protect the bacteria against the genotoxic effect of nitrite. Surprisingly given the role of Mfd in transcription-coupled repair, UvrA is not necessary to survive the nitrite response. Taken together, our data reveal that during the eukaryotic nitrogen response, Mfd is required to maintain bacterial genome integrity in a NER-independent but RecBC-dependent pathway. PMID:27711223

  7. Salicylic acid alleviates aluminum toxicity in rice seedlings better than magnesium and calcium by reducing aluminum uptake, suppressing oxidative damage and increasing antioxidative defense.

    PubMed

    Pandey, Poonam; Srivastava, Rajneesh Kumar; Dubey, R S

    2013-05-01

    Aluminum toxicity is a major constraint to crop production in acid soils. The present study was undertaken to examine the comparative ameliorating effects of salicylic acid, Ca and Mg on Al toxicity in rice (Oryza sativa L.) seedlings grown in hydroponics. Al treatment (0.5 mM AlCl3) caused decrease in plant vigour, loss of root plasma membrane integrity, increased contents of O 2 (∙-) , H2O2, lipid peroxidation, protein carbonyls and decline in the level of protein thiol. Al treatment caused significant changes in activity of antioxidative enzymes in rice seedlings. Exogenously added salicylic acid (60 μM), Ca (1 mM) and Mg (0.25 mM) significantly alleviated Al toxicity effects in the seedlings marked by restoration of growth, suppression of Al uptake, restoration of root plasma membrane integrity and decline in O 2 (∙-) , H2O2, lipid peroxidation and protein carbonyl contents. Salicylic acid, Ca and Mg suppressed Al-induced increase in SOD, GPX and APX activities while it elevated Al-induced decline in CAT activity. By histochemical staining of O 2 (∙-) using NBT and H2O2 using DAB, it was further confirmed that added salicylic acid, Ca or Mg decreased Al-induced accumulation of O 2 (∙-) and H2O2 in the leaf tissues. Results indicate that exogenously added salicylic acid, Ca or Mg alleviates Al toxicity in rice seedlings by suppressing Al uptake, restoring root membrane integrity, reducing ROS level and ROS induced oxidative damage and regulating the level of antioxidative enzyme activities. Further salicylic appears to be superior to Mg and Ca in alleviating Al toxicity effects in rice plants.

  8. L-arginine and aminoguanidine reduce colonic damage of acetic acid-induced colitis in rats: potential modulation of nuclear factor-κB/p65.

    PubMed

    Farghaly, Hanan S M; Thabit, Romany H

    2014-10-01

    The transcription factor, nuclear factor-κB (NF-κB) is a key inducer of inducible nitric oxide synthase (iNOS) gene expression. The aim of the present study was to investigate the potential protective effect of l-arginine (Arg; nitric oxide precursor) and aminoguanidine (inducible nitric oxide synthase inhibitor) against acetic acid (AA)-induced colitis in rats, and the potential role of NF-κB. Colitis was induced by intrarectal inoculation of rats with 4% acetic acid for three consecutive days. The effect of Arg and aminoguanidine on nitric oxide levels was assessed by Greiss assay and protein expression of NF-κB/p65, and inducible nitric oxide synthase was also investigated by immunohistochemistry. Slides were examined using ImageJ, and results reported as the percent area positive for each marker. Intrarectal AA caused a significant increase in bodyweight loss and colon weights. Arg at 100 mg/day for 7 days before induction of colitis diminished the changes in both bodyweight loss and colon weights. Furthermore, Arg attenuated the colonic tissues macroscopic and microscopic damage induced by acetic acid. In addition, i.p. AG 100 mg/kg given during and after induction of colitis recovered the colonic ulcerative lesion induced by AA. Arg can protect against colonic inflammation; an effect that probably be attributed to its nitric oxide-donating property, resulting in modulatory effects on the expression of NF-κB/p65 in the colon tissues. The results suggested that Arg might reduce the inflammation associated with colitis as confirmed by histopathological investigations. Arg might inhibit AA-induced colitis through the NF-κB/nitric oxide pathway.

  9. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease.

    PubMed

    Yin, Xiangling; Manczak, Maria; Reddy, P Hemachandra

    2016-05-01

    The objective of this study was to determine the protective effects of the mitochondria-targeted molecules MitoQ and SS31 in striatal neurons that stably express mutant huntingtin (Htt) (STHDhQ111/Q111) in Huntington's disease (HD). We studied mitochondrial and synaptic activities by measuring mRNA and the protein levels of mitochondrial and synaptic genes, mitochondrial function, and ultra-structural changes in MitoQ- and SS31-treated mutant Htt neurons relative to untreated mutant Htt neurons. We used gene expression analysis, biochemical methods, transmission electron microscopy (TEM) and confocal microscopy methods. In the MitoQ- and SS31-treated mutant Htt neurons, fission genes Drp1 and Fis1 were down-regulated, and fusion genes Mfn1, Mfn2 and Opa1 were up-regulated relative to untreated neurons, suggesting that mitochondria-targeted molecules reduce fission activity. Interestingly, the mitochondrial biogenesis genes PGC1α, PGC1β, Nrf1, Nrf2 and TFAM were up-regulated in MitoQ- and SS31-treated mutant Htt neurons. The synaptic genes synaptophysin and PSD95 were up-regulated, and mitochondrial function was normal in the MitoQ- and SS31-treated mutant Htt neurons. Immunoblotting findings of mitochondrial and synaptic proteins agreed with the mRNA findings. TEM studies revealed decreased numbers of structurally intact mitochondria in MitoQ- and SS31-treated mutant Htt neurons. These findings suggest that mitochondria-targeted molecules MitoQ and SS31 are protective against mutant Htt-induced mitochondrial and synaptic damage in HD neurons, and these mitochondria-targeted molecules are potential therapeutic molecules for the treatment of HD neurons.

  10. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease

    PubMed Central

    Ilan, Yaron

    2016-01-01

    Inflammatory bowel diseases (IBD) are associated with an altered systemic immune response leading to inflammation-mediated damage to the gut and other organs. Oral immune therapy is a method of systemic immune modulation via alteration of the gut immune system. It uses the inherit ability of the innate system of the gut to redirect the systemic innate and adaptive immune responses. Oral immune therapy is an attractive clinical approach to treat autoimmune and inflammatory disorders. It can induce immune modulation without immune suppression, has minimal toxicity and is easily administered. Targeting the systemic immune system via the gut immune system can serve as an attractive novel therapeutic method for IBD. This review summarizes the current data and discusses several examples of oral immune therapeutic methods for using the gut immune system to generate signals to reset systemic immunity as a treatment for IBD. PMID:26900473

  11. Oral immune