Science.gov

Sample records for immunization reduces damage

  1. Immune suppression prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension.

    PubMed

    Tian, N; Gu, J-W; Jordan, S; Rose, R A; Hughson, M D; Manning, R D

    2007-02-01

    The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-kappaB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg.kg(-1).day(-1)), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-kappaB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-kappaB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 +/- 5 mmHg, and MMF reduced this arterial pressure to 124 +/- 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-kappaB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension.

  2. 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.

  3. [Bone marrow stromal damage mediated by immune response activity].

    PubMed

    Vojinović, J; Kamenov, B; Najman, S; Branković, Lj; Dimitrijević, H

    1994-01-01

    The aim of this work was to estimate influence of activated immune response on hematopoiesis in vitro, using the experimental model of BCG immunized BALB/c mice and in patients with chronic immunoactivation: long-lasting infections, autoimmunity or malignancy. We correlated changes in long term bone marrow cultures (Dexter) and NBT reduction with appearance of anemia in patients and experimental model of immunization by BCG. Increased spontaneous NBT reduction pointed out role of macrophage activation in bone marrow stroma damage. Long-term bone marrow cultures showed reduced number of hematopoietic cells, with predomination of fibroblasts and loss of fat cells. This results correlated with anemia and leucocytosis with stimulated myelopoiesis in peripheral blood. Activation of immune response, or acting of any agent that directly changes extracellular matrix and cellularity of bone marrow, may result in microenviroment bone marrow damage that modify hematopoiesis.

  4. Inflammation, Immunity, and Hypertensive End-Organ Damage

    PubMed Central

    McMaster, William G.; Kirabo, Annet; Madhur, Meena S.; Harrison, David G.

    2015-01-01

    For more than 50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, DOCA-salt and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including IL-17, IFN-γ, TNFα and IL-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption and increased renal fibrosis. Very recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension including myocardial infarction, heart failure, renal failure and stroke. PMID:25767287

  5. Floating intake reduces pump damage

    SciTech Connect

    Kronig, A.

    1993-12-31

    The solution to a costly sand erosion problem at the Grande Dixence hydroelectric project in Switzerland turned out to be as simple as a floating pump. The 726-MW Grande Dixence project drains a 350-square-kilometer reach of the Zermatt and Herens valleys in the southwestern Swiss Alps. About half of the drainage area is covered by active glaciers. Because the glaciers in Zermatt Valley are so low in altitude, their water is collected in Z`mutt Reservoir at the base of the Matterhorn, then pumped up 500 meters for transport to the main Grande Disence Reservoir near Sion. The glacier water is heavily laden with sand. In spite of a gravel pass and a desilter, the 700,000-acubic-meter Z`mutt Reservoir receives large quantities of sand. The sand tends to remain in solution because of the low water temperatures (1 to 2 degrees Centigrade). In the original intake system, the sand would be sucked into the pump intakes, causing extensive erosion to the pump wheels and an expensive yearly program of repair. (Pump damage averaged 200,000 Swiss Francs ($284,000 U.S.) per year between 1980 and 1985.)

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

    PubMed

    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

  7. 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

  8. Increasing Immunization Compliance by Reducing Provisional Admittance.

    PubMed

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

    2016-08-01

    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 student compliance with Vermont immunization regulations using a collaborative learning approach with public health school liaisons and school nurses from public schools to reduce provisional admittance in 2011-2012. Strategies included using a tracking system, accessing the immunization registry, promoting immunization importance, tracking immunization plans, and working with medical homes to update records. Participating school nurses observed decreases in the number of provisionally admitted students, although this reduction was not significantly different than matched comparison schools. We also found the number of provisionally admitted students fluctuated throughout the year and resolving the immunization status of New Americans and exchange students required special attention. Our approach supports the coordinated school health model and demonstrates the critical role school nurses play in improving population health outcomes. PMID:26699951

  9. Increasing Immunization Compliance by Reducing Provisional Admittance.

    PubMed

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

    2016-08-01

    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 student compliance with Vermont immunization regulations using a collaborative learning approach with public health school liaisons and school nurses from public schools to reduce provisional admittance in 2011-2012. Strategies included using a tracking system, accessing the immunization registry, promoting immunization importance, tracking immunization plans, and working with medical homes to update records. Participating school nurses observed decreases in the number of provisionally admitted students, although this reduction was not significantly different than matched comparison schools. We also found the number of provisionally admitted students fluctuated throughout the year and resolving the immunization status of New Americans and exchange students required special attention. Our approach supports the coordinated school health model and demonstrates the critical role school nurses play in improving population health outcomes.

  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. 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.

  12. 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…

  13. Damage detection based on acceleration data using artificial immune system

    NASA Astrophysics Data System (ADS)

    Chartier, Sandra; Mita, Akira

    2009-03-01

    Nowadays, Structural Health Monitoring (SHM) is essential in order to prevent damages occurrence in civil structures. This is a particularly important issue as the number of aged structures is increasing. Damage detection algorithms are often based on changes in the modal properties like natural frequencies, modal shapes and modal damping. In this paper, damage detection is completed by using Artificial Immune System (AIS) theory directly on acceleration data. Inspired from the biological immune system, AIS is composed of several models like negative selection which has a great potential for this study. The negative selection process relies on the fact that T-cells, after their maturation, are sensitive to non self cells and can not detect self cells. Acceleration data were provided by using the numerical model of a 3-story frame structure. Damages were introduced, at particular times, by reduction of story's stiffness. Based on these acceleration data, undamaged data (equivalent to self data) and damaged data (equivalent to non self data) can be obtained and represented in the Hamming shape-space with a binary representation. From the undamaged encoded data, detectors (equivalent to T-cells) are derived and are able to detect damaged encoded data really efficiently by using the rcontiguous bits matching rule. Indeed, more than 95% of detection can be reached when efficient combinations of parameters are used. According to the number of detected data, the localization of damages can even be determined by using the differences between story's relative accelerations. Thus, the difference which presents the highest detection rate, generally up to 89%, is directly linked to the location of damage.

  14. 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.

  15. 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.

  16. Despite violation of law, government immune from damages.

    PubMed

    1996-10-01

    The U.S. Supreme Court ruled that Congress does not waive the government's sovereign immunity against monetary damages for violations of the Rehabilitation Act. As a result, the Federal government does not have to pay damages to the estate of Dr. [name removed], a physician for the [name removed]. The FBI, suspecting that [name removed] had AIDS, refused to send agents to him for physical examinations. The Supreme Court's ruling overturns that of the 9th U.S. Circuit Court of Appeals. In August 1988, the FBI learned that [name removed] had AIDS. The FBI's San Francisco office stopped sending personnel to the [name removed], [name removed]'s employer. [Name removed] sued under the Rehabilitation Act and the litigation continued for 8 years. After [name removed] died, his estate pursued to suit. In a related case, the Supreme Court discharged a student of the U.S. Merchant Marine Academy when he discovered he had diabetes. The student sued, alleging that his termination violated Section 504 of the Rehabilitation Act. The Supreme Court agreed that monetary damages could not be paid based on the Federal government's unequivocal sovereign immunity. PMID:11363872

  17. 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

  18. 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.

  19. Thin layered interference mirrors to reduce radiation damage

    SciTech Connect

    Csonka, P.L.

    1985-01-01

    Calculations have been performed which show that damage induced by radiation of wavelength lambda, incident on mirrors (and other optical elements) can be significantly reduced by a multilayered construction, in which the layers most sensitive to radiation damage have thickness d << lambda. The layers may or may not be free-standing. The threshold to radiation damage in certain cases is calculated to increase by a factor approx. = 10/sup 2/.

  20. Immune stimulation reduces sleep and memory ability in Drosophila melanogaster

    PubMed Central

    Alghamdi, Akram; Holdbrook, Robert T.K.; Rosato, Ezio

    2014-01-01

    Psychoneuroimmunology studies the increasing number of connections between neurobiology, immunology and behaviour. We demonstrate the effects of the immune response on two fundamental behaviours: sleep and memory ability in Drosophila melanogaster. We used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep. Immune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. Immune stimulated flies also showed a reduction in memory abilities. These results lend support to Drosophila as a model for immune–neural interactions and provide a possible role for sleep in the interplay between the immune response and memory. PMID:24949247

  1. Altered Immunity in Crowded Locust Reduced Fungal (Metarhizium anisopliae) Pathogenesis

    PubMed Central

    Wang, Yundan; Yang, Pengcheng; Cui, Feng; Kang, Le

    2013-01-01

    The stress of living conditions, similar to infections, alters animal immunity. High population density is empirically considered to induce prophylactic immunity to reduce the infection risk, which was challenged by a model of low connectivity between infectious and susceptible individuals in crowded animals. The migratory locust, which exhibits polyphenism through gregarious and solitary phases in response to population density and displays different resistance to fungal biopesticide (Metarhizium anisopliae), was used to observe the prophylactic immunity of crowded animals. We applied an RNA-sequencing assay to investigate differential expression in fat body samples of gregarious and solitary locusts before and after infection. Solitary locusts devoted at least twice the number of genes for combating M. anisopliae infection than gregarious locusts. The transcription of immune molecules such as pattern recognition proteins, protease inhibitors, and anti-oxidation proteins, was increased in prophylactic immunity of gregarious locusts. The differentially expressed transcripts reducing gregarious locust susceptibility to M. anisopliae were confirmed at the transcriptional and translational level. Further investigation revealed that locust GNBP3 was susceptible to proteolysis while GNBP1, induced by M. anisopliae infection, resisted proteolysis. Silencing of gnbp3 by RNAi significantly shortened the life span of gregarious locusts but not solitary locusts. By contrast, gnbp1 silencing did not affect the life span of both gregarious and solitary locusts after M. anisopliae infection. Thus, the GNBP3-dependent immune responses were involved in the phenotypic resistance of gregarious locusts to fungal infection, but were redundant in solitary locusts. Our results indicated that gregarious locusts prophylactically activated upstream modulators of immune cascades rather than downstream effectors, preferring to quarantine rather than eliminate pathogens to conserve energy

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

    PubMed Central

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

    2012-01-01

    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. PMID:22654121

  3. 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. PMID

  4. 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

  5. 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.

  6. Surface modification of intraocular lenses to reduce corneal endothelial damage.

    PubMed

    Knight, P M; Link, W J

    1979-04-01

    Two methods of surface modification of PMMA, permanent and temporary, were investigated for use on intraocular lenses to reduce corneal endothelial damage due to corneal-IOL touch. Monomer grafting using gamma irradiation was found to produce permanently hydrophilic surfaces. Temporary surface modifications developed and tested were peelable and dissolvable coatings. Test samples were touched to freshly excised rabbit corneas to evaluate the effectiveness of the various surface modifications in reducing endothelial cell damage. This touch testing was performed using static testing in which the test sample was touched to the cornea without movement and dynamic testing in which there was relative movement between the cornea and the test sample. While unmodified PMMA did significant cell damage in both static and dynamic tests perpamently modified (hydrophilic grafted) surfaces were found to perform well in the static, but not in the dynamic tests. Dissolvable coatings performed well in both tests, even with very thin coatings. There was little differentiation between the various water-soluble coatings tested. Due to its characteristics and rate of dissolution, polyvinyl alcohol appears to be an optimum material for coating IOLs. A series of in vitro and in vivo tests performed to assess its safety indicate that PVA is nontoxic and safe in animal eyes. PMID:479004

  7. Reduced calcium-dependent mitochondrial damage underlies the reduced vulnerability of excitotoxicity-tolerant hippocampal neurons.

    PubMed

    Pivovarova, Natalia B; Stanika, Ruslan I; Watts, Charlotte A; Brantner, Christine A; Smith, Carolyn L; Andrews, S Brian

    2008-03-01

    In central neurons, over-stimulation of NMDA receptors leads to excessive mitochondrial calcium accumulation and damage, which is a critical step in excitotoxic death. This raises the possibility that low susceptibility to calcium overload-induced mitochondrial damage might characterize excitotoxicity-resistant neurons. In this study, we have exploited two complementary models of preconditioning-induced excitotoxicity resistance to demonstrate reduced calcium-dependent mitochondrial damage in NMDA-tolerant hippocampal neurons. We have further identified adaptations in mitochondrial calcium handling that account for enhanced mitochondrial integrity. In both models, enhanced tolerance was associated with improved preservation of mitochondrial membrane potential and structure. In the first model, which exhibited modest neuroprotection, mitochondria-dependent calcium deregulation was delayed, even though cytosolic and mitochondrial calcium loads were quantitatively unchanged, indicating that enhanced mitochondrial calcium capacity accounts for reduced injury. In contrast, the second model, which exhibited strong neuroprotection, displayed further delayed calcium deregulation and reduced mitochondrial damage because downregulation of NMDA receptor surface expression depressed calcium loading. Reducing calcium entry also modified the chemical composition of the calcium-buffering precipitates that form in calcium-loaded mitochondria. It thus appears that reduced mitochondrial calcium loading is a major factor underlying the robust neuroprotection seen in highly tolerant cells. PMID:18036152

  8. 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

  9. 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

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

    PubMed

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

    2015-04-28

    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.

  11. 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

  12. 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. PMID:25660564

  13. 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.

  14. 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

  15. Evaluation of hepatic damage and local immune response in goats immunized with native glutathione S-transferase of Fasciola hepatica.

    PubMed

    Zafra, R; Pérez-Ecija, R A; Buffoni, L; Mendes, R E; Martínez-Moreno, A; Martínez-Moreno, F J; Galisteo, M E Martínez; Pérez, J

    2010-01-01

    Worm burden, hepatic damage and local cellular and humoral immune responses were assessed in goats immunized with glutathione-S-transferase and challenged with Fasciola hepatica. Infected but unimmunized and uninfected control groups were also studied. Hepatic damage was evaluated grossly and microscopically. Local immune response was evaluated by (1) microscopical examination of hepatic lymph nodes (HLNs); (2) analysis of the distribution of CD2(+), CD4(+), CD8(+), T-cell receptor gammadelta(+) lymphocytes and immunoglobulin (Ig) G(+) plasma cells; and (3) investigation of the distribution of cells expressing interleukin (IL)-4 and interferon (IFN)-gamma in the hepatic inflammatory infiltrates and HLNs. Immunized animals did not have significant reduction in fluke number, but there was significant (P<0.05) reduction of fluke size relative to the control groups. The lesions in the two infected groups were similar and consisted of fibrous perihepatitis and white tortuous tracts, mainly involving the left hepatic lobe. Microscopical lesions were similar in both infected groups and were typical of chronic fascioliosis. These included portal fibrosis, inflammatory infiltration with plasma cells, formation of lymphoid follicles, accumulation of haemosiderin-laden macrophages and granulomatous foci. Both infected groups had a marked local immune response characterized by infiltration of CD2(+), CD4(+) and CD8(+) T lymphocytes, and IgG(+) plasma cells in hepatic lesions and in HLNs. There was no expression of IL-4 or INF-gamma by cells in the hepatic inflammatory infiltrate, but expression of INF-gamma in HLNs was much lower than that of IL-4, suggesting an immune response dominated by T helper 2 cells.

  16. Sub-meninges implantation reduces immune response to neural implants.

    PubMed

    Markwardt, Neil T; Stokol, Jodi; Rennaker, Robert L

    2013-04-15

    Glial scar formation around neural interfaces inhibits their ability to acquire usable signals from the surrounding neurons. To improve neural recording performance, the inflammatory response and glial scarring must be minimized. Previous work has indicated that meningeally derived cells participate in the immune response, and it is possible that the meninges may grow down around the shank of a neural implant, contributing to the formation of the glial scar. This study examines whether the glial scar can be reduced by placing a neural probe completely below the meninges. Rats were implanted with sets of loose microwire implants placed either completely below the meninges or implanted conventionally with the upper end penetrating the meninges, but not attached to the skull. Histological analysis was performed 4 weeks following surgical implantation to evaluate the glial scar. Our results found that sub-meninges implants showed an average reduction in reactive astrocyte activity of 63% compared to trans-meninges implants. Microglial activity was also reduced for sub-meninges implants. These results suggest that techniques that isolate implants from the meninges offer the potential to reduce the encapsulation response which should improve chronic recording quality and stability.

  17. Sub-meninges Implantation Reduces Immune Response to Neural Implants

    PubMed Central

    Markwardt, Neil T.; Stokol, Jodi; Rennaker, Robert L.

    2013-01-01

    Glial scar formation around neural interfaces inhibits their ability to acquire usable signals from the surrounding neurons. To improve neural recording performance, the inflammatory response and glial scarring must be minimized. Previous work has indicated that meningeally derived cells participate in the immune response, and it is possible that the meninges may grow down around the shank of a neural implant, contributing to the formation of the glial scar. This study examines whether the glial scar can be reduced by placing a neural probe completely below the meninges. Rats were implanted with sets of loose microwire implants placed either completely below the meninges or implanted conventionally with the upper end penetrating the meninges, but not attached to the skull. Histological analysis was performed 4 weeks following surgical implantation to evaluate the glial scar. Our results found that sub-meninges implants showed an average reduction in reactive astrocyte activity of 63% compared to trans-meninges implants. Microglial activity was also reduced for sub-meninges implants. These results suggest that techniques that isolate implants from the meninges offer the potential to reduce the encapsulation response which should improve chronic recording quality and stability. PMID:23370311

  18. A robust damage detection method developed for offshore jacket platforms using modified artificial immune system algorithm

    NASA Astrophysics Data System (ADS)

    Mojtahedi, A.; Lotfollahi Yaghin, M. A.; Hassanzadeh, Y.; Abbasidoust, F.; Ettefagh, M. M.; Aminfar, M. H.

    2012-09-01

    Steel jacket-type platforms are the common kind of the offshore structures and health monitoring is an important issue in their safety assessment. In the present study, a new damage detection method is adopted for this kind of structures and inspected experimentally by use of a laboratory model. The method is investigated for developing the robust damage detection technique which is less sensitive to both measurement and analytical model uncertainties. For this purpose, incorporation of the artificial immune system with weighted attributes (AISWA) method into finite element (FE) model updating is proposed and compared with other methods for exploring its effectiveness in damage identification. Based on mimicking immune recognition, noise simulation and attributes weighting, the method offers important advantages and has high success rates. Therefore, it is proposed as a suitable method for the detection of the failures in the large civil engineering structures with complicated structural geometry, such as the considered case study.

  19. The involvement of immune reactions in cardiac damage during acute myocardial infarction: role of cell-mediated immune response.

    PubMed

    Dimitrijevic, M; Vasiljevic, Z; Vuckovic-Dekic, L; Spasic, S

    1997-06-01

    This study was undertaken with the aim of investigating humoral and cell-mediated immune response in acute myocardial infarction (AMI) as possible mechanisms involved in the infarction enlargement. Twenty three patients with first AMI and 15 healthy volunteers were examined. Of the AMI patients, 14 had extensive infarction (group A), while 9 patients had small infarction (group B). Immunologic analyses were performed at admission, and repeated after 3, 7, 14 and 21 days of the acute event. Following parameters were tested: number of CD3+, CD4+, CD8+ and CD20+ cells; serum IgG, IgA, IgM, C3, C4, immune complex and anticardiac antibody levels; polymorphonuclear cell (PMN) function (chemotaxis, phagocytosis, metabolic activity); leukocyte migration in vitro in the presence of water-soluble homologous heart extract. It was demonstrated that the number of B cells, serum IgG, C3, immune complex and anticardiac antibody levels were elevated from 7th-14th days after AMI. Concerning these parameters, however, no significant differences were obtained between group A and group B of AMI patients. Chemotaxis and metabolic activity of peripheral blood PMN, but not phagocytosis, were enhanced during AMI, again changes of PMN did not correlate with the extension of infarction. In contrast, leukocyte migration inhibition in vitro revealed that only patients with extensive AMI have developed positive reaction during the first 14 days after the onset of the disease, while leukocyte inhibition reaction appeared in patients with nonextensive AMI not earlier than the 21st day after the infarction. These findings demonstrate generation of immune reactivity during AMI and indicate that humoral immune response seems more likely to be an epiphenomenon related to tissue necrosis, while cell-mediated immune reactions could influence the extensiveness of cardiac damage.

  20. Electrochemically reduced water protects neural cells from oxidative damage.

    PubMed

    Kashiwagi, Taichi; Yan, Hanxu; Hamasaki, Takeki; Kinjo, Tomoya; Nakamichi, Noboru; Teruya, Kiichiro; Kabayama, Shigeru; Shirahata, Sanetaka

    2014-01-01

    Aging-related neurodegenerative disorders are closely associated with mitochondrial dysfunction and oxidative stresses and their incidence tends to increase with aging. Brain is the most vulnerable to reactive species generated by a higher rate of oxygen consumption and glucose utilization compared to other organs. Electrochemically reduced water (ERW) was demonstrated to scavenge reactive oxygen species (ROS) in several cell types. In the present study, the protective effect of ERW against hydrogen peroxide (H2O2) and nitric oxide (NO) was investigated in several rodent neuronal cell lines and primary cells. ERW was found to significantly suppress H2O2 (50-200 μM) induced PC12 and SFME cell deaths. ERW scavenged intracellular ROS and exhibited a protective effect against neuronal network damage caused by 200 μM H2O2 in N1E-115 cells. ERW significantly suppressed NO-induced cytotoxicity in PC12 cells despite the fact that it did not have the ability to scavenge intracellular NO. ERW significantly suppressed both glutamate induced Ca(2+) influx and the resulting cytotoxicity in primary cells. These results collectively demonstrated for the first time that ERW protects several types of neuronal cells by scavenging ROS because of the presence of hydrogen and platinum nanoparticles dissolved in ERW. PMID:25383141

  1. 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

  2. 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.

  3. Innate immune memory: Implications for host responses to damage-associated molecular patterns.

    PubMed

    Crișan, Tania O; Netea, Mihai G; Joosten, Leo A B

    2016-04-01

    Cells of the innate immune system build immunological memory via epigenetic reprogramming after stimulations with microbial ligands. This functional readjustment allows for enhanced nonspecific inflammatory responses upon secondary challenges, a process termed "trained immunity." The epigenomic blueprint of trained monocytes has been recently reported, which revealed several important immunologic and metabolic mechanisms that underlie these changes. Interestingly, similar long-term reprogramming of cytokine production has also been described to be induced by endogenous damage-associated molecular patterns (DAMPs). Here, we present an overview of the novel data showing that endogenous alarm signals associated with tissue damage and sterile inflammation can induce trained immunity through epigenetic regulation of transcriptional programs. We describe new and old evidence of persistent effects of DAMPs in driving inflammation and enforce the concept that the influence of tissue-derived signals is critical in adjusting the magnitude and type of immune response built by the host. The better characterization of trained immunity for the persistence of inflammation induced by DAMPs would provide new possibilities for intervention in aging and autoinflammatory disorders. PMID:26970440

  4. Reducing methane emissions in sheep by immunization against rumen methanogens.

    PubMed

    Wright, A D G; Kennedy, P; O'Neill, C J; Toovey, A F; Popovski, S; Rea, S M; Pimm, C L; Klein, L

    2004-09-28

    This work was conducted to determine if methane emissions from sheep immunized with an anti-methanogen vaccine were significantly lower than methane emissions from non-immunized sheep, to test the effectiveness of two different vaccine formulations (VF) on methane abatement, and to compare methane emissions measured using a closed-circuit respiration chamber and the sulphur-hexafluoride (SF6) tracer technique. Thirty mature wether sheep were randomly allocated to three treatment groups (n = 10). One group received an immunization of adjuvant only on days 0 and 153 (control), a second group received an immunization with a 3-methanogen mix on days 0 and 153 (VF3 + 3), and a third group received an immunization of a 7-methanogen mix on day 0 followed by a 3-methanogen mix on day 153 (VF7 + 3). Four weeks post-secondary immunization, there was a significant 7.7% reduction in methane production per kg dry matter intake in the VF7 + 3 group compared to the controls (P = 0.051). However, methane emissions from sheep immunized with VF7 + 3 were not significantly different when compared to the sheep in the control group (P = 0.883). The average IgG and IgA antibody titres in both plasma and saliva of the VF3 + 3 immunized sheep were four to nine times higher than those immunized with VF7 + 3 (P< 0.001) at both 3 and 6 weeks post-secondary immunization. Data also revealed that SF6 methane estimates were consistently higher than the respiration chamber estimates and that there was no significant correlation between the SF6 methane estimates and the respiration chamber methane estimates (R2 = 0.11).

  5. AID and APOBEC deaminases: balancing DNA damage in epigenetics and immunity.

    PubMed

    Franchini, Don-Marc; Petersen-Mahrt, Svend K

    2014-01-01

    DNA mutations and genomic recombinations are the origin of oncogenesis, yet parts of developmental programs as well as immunity are intimately linked to, or even depend on, such DNA damages. Therefore, the balance between deleterious DNA damages and organismal survival utilizing DNA editing (modification and repair) is in continuous flux. The cytosine deaminases AID/APOBEC are a DNA editing family and actively participate in various biological processes. In conjunction with altered DNA repair, the mutagenic potential of the family allows for APOBEC3 proteins to restrict viral infection and transposons propagation, while AID can induce somatic hypermutation and class switch recombination in antibody genes. On the other hand, the synergy between effective DNA repair and the nonmutagenic potential of the DNA deaminases can induce local DNA demethylation to support epigenetic cellular identity. Here, we review the current state of knowledge on the mechanisms of action of the AID/APOBEC family in immunity and epigenetics.

  6. Reproductive effort reduces specific immune response and parasite resistance

    PubMed Central

    Nordling, D.; Andersson, M.; Zohari, S.; Gustafsson, L.

    1998-01-01

    If a trade-off exists between reproductive effort and immune function, life-history decisions may have important implications for parasite resistance. Here, we report effects of experimental manipulation of reproductive effort on subsequent specific immune function and parasite resistance in the collared flycatcher, Ficedula albicollis. Our results show that increased reproductive effort of females immunized with Newcastle disease virus (NDV) vaccine negatively affected the ability to respond with NDV-specific antibodies. We further show that increased reproductive effort increased the intensity of Haemoproteus infections and that such infections are associated with higher mortality. Our results thus provide support for the hypothesis that immune suppression caused by reproductive effort may be an important mechanism mediating the life-history cost of reproduction.

  7. Damaged membrane fragments and immune complexes in the blood of patients with Behcet's syndrome.

    PubMed Central

    Lehner, T; Almeida, J D; Levinsky, R J

    1978-01-01

    Electron microscopic examination of centrifuged pellets of serum from patients with Behcet's syndrome and recurrent oral ulcers revealed the presence of a large number of membrane fragments. Some of these membranes showed numerous 10 nm holes that were identical to lesions produced by the action of complement. An attempt was made to correlate complement levels, antibodies and cellular immunity with the presence of the membrane fragments, without success. However, a significant correlation was found between the membranes and the IgG class of immune complexes. The finding of membrane fragments with complement-induced damage predominantly in the blood of patients with Behcet's syndrome, and the association with soluble immune complexes suggest that the latter may generate C5b-9 complexes which may bind to the surface of cells in result in cell lysis. Images FIG. 1 FIG. 2 PMID:737904

  8. Control of in vivo collateral damage generated by T cell immunity.

    PubMed

    Thangavelu, Govindarajan; Gill, Ronald G; Boon, Louis; Ellestad, Kristofor K; Anderson, Colin C

    2013-08-15

    An ongoing dilemma faced during an immune response is generating an effective, often proinflammatory response to eliminate pathogens and/or infected cells while also minimizing collateral damage to adjacent noninfected tissues. The factors limiting bystander cell injury during an Ag-specific immune response in vivo are largely unknown. In this study, using an in vivo model of islet transplants in TCR transgenic mice, we show that both CD4 and CD8 T cells do have the capacity to inflict adjacent tissue damage and that this injury is greatly enhanced in sensitized hosts. CD4 T cell-mediated killing of specific and bystander cells occurred via different mechanisms. Unlike specific target cell killing, CD4-mediated bystander injury required tissue Fas expression and was inhibited with anti-IFN-γ Ab treatment in vivo. Moreover, bystander cell injury was not entirely nonspecific but rather required, in naive recipients, that the MHC allele expressed by the bystanders was self. Importantly, the coinhibitor programmed death-1 plays an important role in restraining bystander cell injury mediated either by defined TCR transgenic T cells or by polyclonal T cell populations. Thus, the differential requirements for specific versus bystander cell injury suggest that there are opportunities for inhibiting immune pathology without compromising Ag-specific immunity in vivo.

  9. 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

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

    PubMed Central

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

    2016-01-01

    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. PMID:27184722

  11. 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.

  12. 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.

  13. Putting technology to work in reducing cavitation damage

    SciTech Connect

    Shanahan, T.B.

    1995-09-01

    Cavitation has been a persistent problem on the large-sized hydro generating units at the 10,300-MW Guri project in Venezuela. Project owners used a state-of-the-art acoustic testing program to determine power ranges that would minimize cavitation damage while meeting operating goals.

  14. 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…

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

    PubMed

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

    2016-04-01

    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

  16. 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

  17. 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

  18. Prolonged organ culture reduces the incidence of endothelial immune reactions.

    PubMed

    Maier, P; Heinzelmann, S; Böhringer, D; Reinhard, T

    2016-01-01

    PURPOSE The number of antigen-presenting cells decreases during organ culture of corneoscleral discs. This might result in a decrease of immune reactions with increasing duration of organ culture. To investigate this hypothesis, we performed a retrospective analysis of all penetrating keratoplasties that were consecutively performed over the last 5 years.PATIENTS AND METHODS All cases of penetrating keratoplasties (n=1006) were divided into two groups, with the division made at the median of the storage time (21 days). These two groups were compared by a Cox proportional hazards survival model regarding the incidence of endothelial immune reactions, clear graft survival, and chronic endothelial cell loss following penetrating keratoplasty considering patient's age, donor's age, and risk situation as co-variates.RESULTS We observed statistically significantly fewer endothelial immune reactions (20.1% (95% confidence interval 15.5-24.5%) after 2 years) in the group with a storage time of more than 21 days compared with the group with a storage time of <21 days (26.5% (95% confidence interval 21.6-31.2%) after 2 years). However, the duration of organ culture did not have a statistically significant effect on clear graft survival or chronic endothelial cell loss.CONCLUSION Our results demonstrate that an increased duration of organ culture leads to a lower incidence of endothelial immune reactions following penetrating keratoplasty. However, we do not recommend increased storage times in general as overall graft survival did not improve. The reason for this apparent paradox may be that the endothelial cell count decreases during storage time. PMID:26493031

  19. Molybdenum nano emitters: the effect of the structural feature on oxygen damage immunity

    NASA Astrophysics Data System (ADS)

    Shen, Yan; Deng, Shaozhi; Xu, Ningsheng; Ye, Peng; Zhang, Yu; Liu, Fei; Chen, Jun; She, Juncong

    2016-04-01

    The structural feature of molybdenum (Mo) nano emitters has a significant effect on their field emission reliability in the oxidizing environment. Mo nanowalls have been studied to exhibit high oxygen damage immunity. The two-dimensional (2D) nanostructure has shown stable and recoverable field emission performance during oxygen exposure in the order of magnitude of 10‑4 Pa. By contrast, quasi 1D nanoscrews have more easily suffered irreversible emission degradation due to more serious oxygen molecule and ion erosion at a higher local electric field around the emitter surface. The 2D wall-like structure with a large emission edge has been proven to contribute to such strong immunity. The results indicate that the Mo nanowall emitter apparently could work properly in the vacuum environment with a certain amount of oxygen.

  20. 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

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

    PubMed Central

    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. PMID:26576074

  2. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury.

    PubMed

    Zweckberger, K; Hackenberg, K; Jung, C S; Hertle, D N; Kiening, K L; Unterberg, A W; Sakowitz, O W

    2014-07-11

    Following traumatic brain injury (TBI) SUR1-regulated NCCa-ATP (SUR1/TRPM4) channels are transcriptionally up-regulated in ischemic astrocytes, neurons, and capillaries. ATP depletion results in depolarization and opening of the channel leading to cytotoxic edema. Glibenclamide is an inhibitor of SUR-1 and, thus, might prevent cytotoxic edema and secondary brain damage following TBI. Anesthetized adult Sprague-Dawley rats underwent parietal craniotomy and were subjected to controlled cortical impact injury (CCI). Glibenclamide was administered as a bolus injection 15min after CCI injury and continuously via osmotic pumps throughout 7days. In an acute trial (180min) mean arterial blood pressure, heart rate, intracranial pressure, encephalographic activity, and cerebral metabolism were monitored. Brain water content was assessed gravimetrically 24h after CCI injury and contusion volumes were measured by MRI scanning technique at 8h, 24h, 72h, and 7d post injury. Throughout the entire time of observation neurological function was quantified using the "beam-walking" test. Glibenclamide-treated animals showed a significant reduction in the development of brain tissue water content(80.47%±0.37% (glibenclamide) vs. 80.83%±0.44% (control); p<0.05; n=14). Contusion sizes increased continuously within 72h following CCI injury, but glibenclamide-treated animals had significantly smaller volumes at any time-points, like 172.53±38.74mm(3) (glibenclamide) vs. 299.20±64.02mm(3) (control) (p<0.01; n=10; 24h) or 211.10±41.03mm(3) (glibenclamide) vs. 309.76±19.45mm(3) (control) (p<0.05; n=10; 72h), respectively. An effect on acute parameters, however, could not be detected, most likely because of the up-regulation of the channel within 3-6h after injury. Furthermore, there was no significant effect on motor function assessed by the beam-walking test throughout 7days. In accordance to these results and the available literature, glibenclamide seems to have promising potency in

  3. [Ecodialysis: first strategies to limit damages and reduce costs].

    PubMed

    Ferraresi, Martina; Nazha, Marta; Vigotti, Federica Neve; Pereno, Amina; Di Giorgio, Gerardo; Gatti, Rachele; Luisa, Bevilacqua Maria; Miriam, Cagnazzo; Barbara, Cassetta; Giovanna, Denti; Gaetana, Grimaldi; Monterossi, Marianna; Barbero, Silvia; Piccoli, Giorgina Barbara

    2014-01-01

    In the medical field, the attention to the environmental impact of industrial processes and products is still limited. In recent years there has been an increased sensitivity towards the environment; meanwhile, the economic burden of hazardous waste disposal is becoming evident. Dialysis is a "big producer" of waste and it has been estimated that disposal costs can be up to 10-40% of the cost of disposables. So there are several reasons of interest on "ecodialysis": the high amount of waste defined as "potentially hazardous", which requires a very expensive management and the recyclability potential of the non-contaminated waste, that has not yet been fully explored in dialysis. This primary study has been performed in collaboration with the Politecnico di Torino. Its aim has been to define a schedule of activities by a few brainstorming sessions. This schedule is to be readily performed or it should be developed in detail to optimize, by reducing and recycling, the waste production during the dialysis session. The discussion identified seven basic points for the eco-sustainability of haemodialysis to: [1] reduce packaging; [2] facilitate separation of materials, and [3] their discharge; [4] differentiate materials; [5] clearly highlight the potentially hazardous materials; [6] improve the recyclability of plastic products; [7] propose a path of recovery and reuse. Although a full optimization requires a close cooperation with the manufacturers and is achievable only in the long term, the reduction of one pound of potentially contaminated materials could presently lead, on a national scale, to a saving of several million euros, which can be better employed in investments to improve our treatments. PMID:25315732

  4. Tinospora cordifolia inhibits autoimmune arthritis by regulating key immune mediators of inflammation and bone damage.

    PubMed

    Sannegowda, K M; Venkatesha, S H; Moudgil, K D

    2015-12-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints leading to tissue damage. Despite the availability of potent drugs including the biologics, many patients fail to respond to them, whereas others suffer adverse effects following long-term use of these drugs. Accordingly, the use of natural herbal products by RA patients has been increasing over the years. However, limited information about the mechanism of action of these natural products is a major shortcoming that prevents the widespread acceptance of herbal therapy by professionals and patients alike. In this study, we demonstrated the anti-arthritic activity of Tinospora cordifolia extract (TCE) using the rat adjuvant-induced arthritis model of human RA and elaborated the immune mechanisms underlying this effect. TCE treatment suppressed arthritic inflammation and bone and cartilage damage. The anti-inflammatory effect of TCE was mediated via reduction of the pro-inflammatory cytokines such as: IL-1β, TNF-α, IL-6, and IL-17; the frequency of IL-17-producing T cells; and the production of chemokines such as RANTES. Furthermore, TCE treatment limited bone damage by shifting the balance of mediators of bone remodeling (e.g., receptor activator of nuclear factor-kB ligand [RANKL] and MMP-9) in favor of anti-osteoclastic activity. Our results suggest that TCE and its bioactive components should be evaluated for their utility as therapeutic adjuncts to conventional drugs against RA. PMID:26467057

  5. 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 ...

  6. Glycine reduces cadmium-induced teratogenic damage in mice.

    PubMed

    Paniagua-Castro, Norma; Escalona-Cardoso, Gerardo; Chamorro-Cevallos, Germán

    2007-01-01

    The effect of glycine in preventing cadmium (Cd) teratogenicity in mice was studied. Cadmium chloride (CdCl2) was administered subcutaneously at 1, 2 or 4 mg/kg doses on gestation days (GD) 7, 8 and 9. Glycine was given ad libitum (in the drinking water) from GD0 through GD18 (the day when animals were killed), as a 1% and 2% drinking water solution. Cd and nucleic acid concentrations in embryos were determined. The most common finding seen after CdCl2 4 mg/kg exposure was exencephaly. The incidence of this malformation was significantly reduced in mice receiving 2% glycine while fetal Cd significantly decreased as compared to cadmium-treated positive control animals. Increased nucleic acid levels were seen in the same embryos. In glycine non-supplemented mice given CdCl2 4 mg/kg, embryonic lipid peroxidation proved to be increased. In conclusion, lipid peroxidation was associated with cadmium-induced teratogenicity, and glycine inhibited the cadmium-induced effect by inhibiting placental transport of cadmium. However, further detailed studies are needed to establish the mechanism(s) of action.

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

    PubMed Central

    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.

    2011-01-01

    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. PMID:21444772

  8. 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. PMID:27130682

  9. 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. PMID:25540276

  10. 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.

  11. 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

  12. 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.

  13. Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation.

    PubMed

    Kekre, Natasha; Kim, Haesook T; Thanarajasingam, Gita; Armand, Philippe; Antin, Joseph H; Cutler, Corey; Nikiforow, Sarah; Ho, Vincent T; Koreth, John; Alyea, Edwin P; Soiffer, Robert J

    2015-09-01

    For patients who relapse after allogeneic hematopoietic stem cell transplantation while still on immune suppression, there is anecdotal evidence that tapering the immune suppression may result in graft-versus-tumor activity. We reviewed the medical records of all patients with documented histological or radiographic disease recurrence within 1 year of stem cell transplantation while on immune suppression at our institution. The median time to relapse was 110 days (range, 18-311) after transplant. Among 123 patients with relapse treated with immune suppression tapering without chemotherapy, radiation, or donor lymphocyte infusion, 34 responded (33/101 reduced intensity conditioning transplant and 1/22 myeloablative conditioning transplant, 32.7% and 4.5% respectively; P=0.007). The median time to response after initiation of immune suppression tapering was 82 days (range, 16-189). Thirty-three patients (97.1%) had development or progression of acute or chronic graft-versus-host disease as a consequence of immune suppression tapering, at a median time of 39 days (range, 16-98). Six patients subsequently relapsed late after initial response to immune suppression tapering at a median time of 2 years (range, 0.9-3.8). The median overall survival from immune suppression tapering for responders was 5.1 years (range, 1.9-not estimable). When clinically feasible, immune suppression tapering alone in patients who relapse early after reduced intensity conditioning allogeneic stem cell transplantation can produce durable remissions, but is almost always associated with graft-versus-host disease.

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

    PubMed

    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.

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

    PubMed

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

    2014-07-01

    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

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

    PubMed

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

    2014-07-01

    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.

  17. 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

  18. BPC-15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats.

    PubMed

    Veljaca, M; Lesch, C A; Pllana, R; Sanchez, B; Chan, K; Guglietta, A

    1995-01-01

    The effect of BPC-15 (Booly Protection Compound-15) was evaluated in a rat model of colonic injury. A single intracolonic administration of trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol induces severe colonic damage, which is characterized by areas of necrosis surrounded by areas of acute inflammation. The damage is associated with high myeloperoxidase (MPO) activity, mainly as a reflection of neutrophilic infiltration into the damaged tissue. In this study, 1 hr before a single intracolonic administration of 50 mg/kg of TNBS in 50% ethanol, the animals were treated with one of the following doses of BPC-15: 0.0001, 0.001, 0.01, 0.1, 1 or 10 nmol/kg administered i.p. or with a dose of 10 nmol/kg administered intracolonically. The animals were sacrificed 3 days later and the extent of colonic necrosis and hyperemia was measured with an image analyzer. The i.p. administration of BPC-15 significantly reduced the extent of TNBS-induced colonic damage in a dose-dependent manner. This was associated with a statistically significant and dose-dependent reduction in colonic tissue MPO activity. At the dose tested (10 nmol/kg), intracolonic administration of BPC-15 did not significantly reduce either the extent of the colonic damage or the increase in MPO activity induced by TNBS. In conclusion, this study showed that i.p. administration of BPC-15 reduced TNBS-induced colonic damage in rats. PMID:7815358

  19. Immunobiotic lactobacilli reduce viral-associated pulmonary damage through the modulation of inflammation-coagulation interactions.

    PubMed

    Zelaya, Hortensia; Tsukida, Kohichiro; Chiba, Eriko; Marranzino, Gabriela; Alvarez, Susana; Kitazawa, Haruki; Agüero, Graciela; Villena, Julio

    2014-03-01

    The exacerbated disease due to immune- and coagulative-mediated pulmonary injury during acute respiratory viruses infection results in severe morbidity and mortality. Identifying novel approaches to modulate virus-induced inflammation-coagulation interactions could be important alternatives for treating acute respiratory viruses infections. In this study we investigated the effect of the probiotic strain Lactobacillus rhamnosus CRL1505 on lung TLR3-mediated inflammation, and its ability to modulate inflammation-coagulation interaction during respiratory viral infection. Our findings reveal for the first time that a probiotic bacterium is able to influence lung immune-coagulative reaction triggered by TLR3 activation, by modulating the production of proinflammatory and anti-inflammatory cytokines as well as expression of tissue factor and thrombomodulin in the lung. We also demonstrated that the preventive treatment with the probiotic bacteria beneficially modulates the fine tune balance between clearing respiratory viruses (respiratory syncytial virus and influenza virus) and controlling immune-coagulative responses in the lung, allowing normal lung function to be maintained in the face of a viral attack. Our data also pinpoint a crucial role for IL-10 in the immune protection induced by L. rhamnosus CRL1505 during respiratory viral infections. These observations might be helpful to propose new preventive or therapeutic approaches to better control virus-inflammatory lung damage using probiotic functional foods.

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

    PubMed

    Tessier, Jack T

    2014-05-20

    • 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.

  1. Modelling the interaction between the host immune response, bacterial dynamics and inflammatory damage in comparison with immunomodulation and vaccination experiments.

    PubMed

    Jarrett, Angela M; Cogan, N G; Shirtliff, M E

    2015-09-01

    The immune system is a complex system of chemical and cellular interactions that responds quickly to queues that signal infection and then reverts to a basal level once the challenge is eliminated. Here, we present a general, four-component model of the immune system's response to a Staphylococcal aureus (S. aureus) infection, using ordinary differential equations. To incorporate both the infection and the immune system, we adopt the style of compartmenting the system to include bacterial dynamics, damage and inflammation to the host, and the host response. We incorporate interactions not previously represented including cross-talk between inflammation/damage and the infection and the suppression of the anti-inflammatory pathway in response to inflammation/damage. As a result, the most relevant equilibrium of the system, representing the health state, is an all-positive basal level. The model is able to capture eight different experimental outcomes for mice challenged with intratibial osteomyelitis due to S. aureus, primarily involving immunomodulation and vaccine therapies. For further validation and parameter exploration, we perform a parameter sensitivity analysis which suggests that the model is very stable with respect to variations in parameters, indicates potential immunomodulation strategies and provides a possible explanation for the difference in immune potential for different mouse strains.

  2. 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

  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. 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.

  5. Reduced Tumor Growth after Low-Dose Irradiation or Immunization against Blastic Suppressor T Cells

    NASA Astrophysics Data System (ADS)

    Tilkin, A. F.; Schaaf-Lafontaine, N.; van Acker, A.; Boccadoro, M.; Urbain, J.

    1981-03-01

    Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

  6. 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. PMID:27427985

  7. 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

  8. 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

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

    2013-07-01

    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.

  9. Human immune responses that reduce the transmission of Plasmodium falciparum in African populations

    PubMed Central

    Bousema, Teun; Sutherland, Colin J.; Churcher, Thomas S.; Mulder, Bert; Gouagna, Louis C.; Riley, Eleanor M.; Targett, Geoffrey A.T.; Drakeley, Chris J.

    2011-01-01

    Malaria-infected individuals can develop antibodies which reduce the infectiousness of Plasmodium gametocytes to biting Anopheles mosquitoes. When ingested in a bloodmeal together with gametocytes, these antibodies reduce or prevent subsequent parasite maturation in the insect host. This transmission-blocking immunity is usually measured in human sera by testing its effect on the infectivity of gametocytes grown in vitro. Here we evaluate evidence of transmission-blocking immunity in eight studies conducted in three African countries. Plasmodium falciparum gametocytes isolated from each individual were fed to mosquitoes in both autologous plasma collected with the parasites, and permissive serum from non-exposed donors. Evidence of transmission reducing effects of autologous plasma was found in all countries. Experiments involving 116 Gambian children (aged 0.5–15 years) were combined to determine which factors were associated with transmission reducing immune responses. The chances of infecting at least one mosquito and the average proportion of infected mosquitoes were negatively associated with recent exposure to gametocytes and sampling late in the season. These results suggest that effective malaria transmission-reducing antibodies do not commonly circulate in African children, and that recent gametocyte carriage is required to initiate and/or boost such responses. PMID:20974145

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

    PubMed

    Majeed, Beenish; Tawinwung, Supannikar; 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, [Val(5)]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

  11. 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. PMID:20857741

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

    PubMed

    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. 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

  14. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  15. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  16. Blocking B7-1/CD28 Pathway Diminished Long-Range Brain Damage by Regulating the Immune and Inflammatory Responses in a Mouse Model of Intracerebral Hemorrhage.

    PubMed

    Ma, Lu; Shen, Xi; Gao, Yuan; Wu, Qiong; Ji, Mengmeng; Luo, Chengliang; Zhang, Mingyang; Wang, Tao; Chen, Xiping; Tao, Luyang

    2016-07-01

    Acute brain injuries can activate bidirectional crosstalk between the injured brain and the immune system. The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) binding cognate receptor provides a secondary signaling to T cell activation. The aim of our study was to explore the effects of anti-B7-1 antibody on the development and prognosis of cerebral hemorrhage and to investigate the possible underlying mechanism. Mice were inner canthus veniplex administered with anti-B7-1 antibody at 10 min and 24 h after ICH and sacrificed on the third day after ICH. Immune function was assessed via splenocyte proliferation assay and organism index, respectively. IFN-γ and IL-4 were detected by enzyme-linked immuno sorbent assay. The cerebral edema was evaluated via brain water content. The levels of autophagy and apoptosis related proteins were measured by western blotting analysis. In addition, functional outcome was studied with pole-climbing test and morris water maze. The mice were weighed on 0, 1, 3, 14 and 21 days after ICH. The treatment with anti-B7-1 antibody significantly lowered immune function, and reduced the latency of water maze on 18 and 20 days, the ratio of IFN-γ/IL-4 as well as body weight on day 3 after cerebral hemorrhage. Our study suggests that in the cerebral hemorrhage mice brain anti-B7-1 antibody may reduce long-range brain damage by reversing immune imbalance. PMID:26980009

  17. 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

  18. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  19. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC.

  20. Cationic liposomes containing antioxidants reduces pulmonary injury in experimental model of sepsis: Liposomes antioxidants reduces pulmonary damage.

    PubMed

    Galvão, Andre Martins; Galvão, Júlia Siqueira; Pereira, Marcela Araújo; Cadena, Pabyton Gonçalves; Magalhães, Nereide Stella Santos; Fink, James B; de Andrade, Armele Dornelas; Castro, Celia Maria Machado Barbosa de; de Sousa Maia, Maria Bernadete

    2016-09-01

    The intracellular redox state of alveolar cells is a determining factor for tolerance to oxidative and pro-inflammatory stresses. This study investigated the effects of intratracheal co-administration of antioxidants encapsulated in liposomes on the lungs of rats subjected to sepsis. For this, male rats subjected to sepsis induced by lipopolysaccharide from Escherichia coli or placebo operation were treated (intratracheally) with antibiotic, 0.9% saline and antioxidants encapsulated or non-encapsulated in liposomes. Experimental model of sepsis by cecal ligation and puncture (CLP) was performed in order to expose the cecum. The cecum was then gently squeezed to extrude a small amount of feces from the perforation site. As an index of oxidative damage, superoxide anions, lipid peroxidation, protein carbonyls, catalase activity, nitrates/nitrites, cell viability and mortality rate were measured. Infected animals treated with antibiotic plus antioxidants encapsulated in liposomes showed reduced levels of superoxide anion (54% or 7.650±1.263 nmol/min/mg protein), lipid peroxidation (33% or 0.117±0.041 nmol/mg protein), protein carbonyl (57% or 0.039 ± 0.022 nmol/mg protein) and mortality rate (3.3%), p value <0.001. This treatment also reduced the level of nitrite/nitrate and increased cell viability (90.7%) of alveolar macrophages. Taken togheter, theses results support that cationic liposomes containing antioxidants should be explored as coadjuvants in the treatment of pulmonary oxidative damage. PMID:27267466

  1. Curcumin reduces oxidative damage by increasing reduced glutathione and preventing membrane permeability transition in isolated brain mitochondria.

    PubMed

    Jat, D; Parihar, P; Kothari, S C; Parihar, M S

    2013-12-31

    Mitochondria are critical regulators of energy metabolism and programmed cell death pathways. Mitochondria are also the major site for the production of reactive oxygen species which make this organelle more susceptible to oxidative damage and impairments of mitochondrial functions. Antioxidants have been of limited therapeutic success to ameliorate the toxic effects of oxidative stress in mitochondria. One reason may be the inability of mitochondria to selectively take up antioxidants. In the present study we synthesized mitochondrially targeted curcumin with an aim of delivering this polyphenolic compound to isolated mitochondria. Our observations show the strong anti-oxidative effects of curcumin and mitochondrially targeted curcumin against the lipid peroxidation, protein carbonylation and mitochondrial permeability transition induced by tert-butylhydroperoxide. Both curcumin and mitochondrially targeted curcumin significantly enhanced endogenous reduced glutathione level in the mitochondria thus preserving mitochondrial defense system against oxidative stress. We concluded that curcumin and mitochondrially targeted curcumin protected mitochondria against tert-butylhydroperoxide by lowering the oxidative damage, increasing the availability of endogenous reduced glutathione and preserving the mitochondrial integrity. Importantly, mitochondrially targeted curcumin was found most effective in ameliorating oxidative stress and preserving mitochondrial integrity than curcumin.

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

    PubMed

    Hermans, David; Van Steendam, Katleen; Verbrugghe, Elin; Verlinden, Marc; Martel, An; Seliwiorstow, Tomasz; Heyndrickx, Marc; Haesebrouck, Freddy; De Zutter, Lieven; Deforce, Dieter; Pasmans, Frank

    2014-03-04

    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.

  3. Great tits (Parus major) reduce caterpillar damage in commercial apple orchards.

    PubMed

    Mols, Christel M M; Visser, Marcel E

    2007-02-07

    Alternative ways to control caterpillar pests and reduce the use of pesticides in apple orchards are in the interest of the environment, farmers and the public. Great tits have already been shown to reduce damage under high caterpillar density when breeding in nest boxes in an experimental apple orchard. We tested whether this reduction also occurs under practical conditions of Integrated Pest Management (IPM), as well as Organic Farming (OF), by setting up an area with nest boxes while leaving a comparable area as a control within 12 commercial orchards. We showed that in IPM orchards, but not in OF orchards, in the areas with breeding great tits, apples had 50% of the caterpillar damage of the control areas. Offering nest boxes to attract insectivorous passerines in orchards can thus lead to more limited pesticide use, thereby adding to the natural biological diversity in an agricultural landscape, while also being economically profitable to the fruit growers.

  4. Thiazolides Elicit Anti-Viral Innate Immunity and Reduce HIV Replication

    PubMed Central

    Trabattoni, Daria; Gnudi, Federica; Ibba, Salomè V.; Saulle, Irma; Agostini, Simone; Masetti, Michela; Biasin, Mara; Rossignol, Jean-Francois; Clerici, Mario

    2016-01-01

    Nitazoxanide (Alinia®, NTZ) and tizoxanide (TIZ), its active circulating metabolite, belong to a class of agents known as thiazolides (TZD) endowed with broad anti-infective activities. TIZ and RM-4848, the active metabolite of RM-5038, were shown to stimulate innate immunity in vitro. Because natural resistance to HIV-1 infection in HIV-exposed seronegative (HESN) individuals is suggested to be associated with strong innate immune responses, we verified whether TIZ and RM-4848 could reduce the in vitro infectiousness of HIV-1. Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were infected in vitro with HIV-1BaL in the presence/absence of TIZ or RM4848. HIV-1 p24 were measured at different timepoints. The immunomodulatory abilities of TZD were evaluated by the expression of type I IFN pathway genes and the production of cytokines and chemokines. TZD drastically inhibited in vitro HIV-1 replication (>87%). This was associated with the activation of innate immune responses and with the up-regulation of several interferon-stimulated genes (ISGs), including those involved in cholesterol pathway, particularly the cholesterol-25 hydroxylase (CH25H). TZD inhibition of HIV-1 replication in vitro could be due to their ability to stimulate potent and multifaceted antiviral immune responses. These data warrant the exploration of TZD as preventive/therapeutic agent in HIV infection. PMID:27250526

  5. 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

  6. 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.

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

    PubMed

    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

  8. 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

  9. Community-Provider Partnerships to Reduce Immunization Disparities: Field Report From Northern Manhattan

    PubMed Central

    Findley, Sally E.; Irigoyen, Matilde; See, Donna; Sanchez, Martha; Chen, Shaofu; Sternfels, Pamela; Caesar, Arturo

    2003-01-01

    In 1996 we launched a community–provider partnership to raise immunization coverage for children aged younger than 3 years in Northern Manhattan, New York City. The partnership was aimed at fostering provider knowledge and accountability, practice improvements, and community outreach. By 1999 the partnership included 26 practices and 20 community groups. Between 1996 and 1999, immunization coverage rates increased in Northern Manhattan 5 times faster than in New York City and 8 times faster than in the United States (respectively, 3.4% vs 0.4% [t = 6.05, p < 0.001] and vs 0.6% [t = 5.65, p < 0.001]). The coverage rate for Northern Manhattan stayed constant through 2000, although it declined during this period for the United States and New York City. We attribute the success at reducing the gap to the effectiveness of our partnership. PMID:12835176

  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. 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

  12. Ionizing radiation selectively reduces skin regulatory T cells and alters immune function.

    PubMed

    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.

  13. 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

  14. 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

  15. Protected areas mitigate diseases of reef-building corals by reducing damage from fishing.

    PubMed

    Lamb, Joleah B; Williamson, David H; Russ, Garry R; Willis, Bette L

    2015-09-01

    Parks and protected areas have been instrumental in reducing anthropogenic sources of damage in terrestrial and aquatic environments. Pathogen invasion often succeeds physical wounding and injury, yet links between the reduction of damage and the moderation of disease have not been assessed. Here, we examine the utility of no-take marine reserves as tools for mitigating diseases that affect reef-building corals. We found that sites located within reserves had fourfold reductions in coral disease prevalence compared to non-reserve sites (80466 corals surveyed). Of 31 explanatory variables assessed, coral damage and the abundance of derelict fishing line best explained differences in disease assemblages between reserves and non-reserves. Unexpectedly, we recorded significantly higher levels of disease, coral damage, and derelict fishing line in non-reserves with fishing gear restrictions than in those without gear restrictions. Fishers targeting stocks perceived to be less depleted, coupled with enhanced site access from immediately adjacent boat moorings, may explain these unexpected patterns. Significant correlations between the distance from mooring sites and prevalence values for a ciliate disease known to infest wounded tissue (r = -0.65), coral damage (r = -0.64), and the abundance of derelict fishing line (r = -0.85) corroborate this interpretation. This is the first study to link disease with recreational use intensity in a park, emphasizing the need to evaluate the placement of closures and their direct relationship to ecosystem health. Since corals are modular, ecological processes that govern reproductive and competitive fitness are frequently related to colony surface area therefore, even low levels of cumulative tissue loss from progressing diseases pose significant threats to reef coral persistence. Disease mitigation through reductions in physical injury in areas where human activities are concentrated is another mechanism by which protected areas may

  16. Protected areas mitigate diseases of reef-building corals by reducing damage from fishing.

    PubMed

    Lamb, Joleah B; Williamson, David H; Russ, Garry R; Willis, Bette L

    2015-09-01

    Parks and protected areas have been instrumental in reducing anthropogenic sources of damage in terrestrial and aquatic environments. Pathogen invasion often succeeds physical wounding and injury, yet links between the reduction of damage and the moderation of disease have not been assessed. Here, we examine the utility of no-take marine reserves as tools for mitigating diseases that affect reef-building corals. We found that sites located within reserves had fourfold reductions in coral disease prevalence compared to non-reserve sites (80466 corals surveyed). Of 31 explanatory variables assessed, coral damage and the abundance of derelict fishing line best explained differences in disease assemblages between reserves and non-reserves. Unexpectedly, we recorded significantly higher levels of disease, coral damage, and derelict fishing line in non-reserves with fishing gear restrictions than in those without gear restrictions. Fishers targeting stocks perceived to be less depleted, coupled with enhanced site access from immediately adjacent boat moorings, may explain these unexpected patterns. Significant correlations between the distance from mooring sites and prevalence values for a ciliate disease known to infest wounded tissue (r = -0.65), coral damage (r = -0.64), and the abundance of derelict fishing line (r = -0.85) corroborate this interpretation. This is the first study to link disease with recreational use intensity in a park, emphasizing the need to evaluate the placement of closures and their direct relationship to ecosystem health. Since corals are modular, ecological processes that govern reproductive and competitive fitness are frequently related to colony surface area therefore, even low levels of cumulative tissue loss from progressing diseases pose significant threats to reef coral persistence. Disease mitigation through reductions in physical injury in areas where human activities are concentrated is another mechanism by which protected areas may

  17. Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity.

    PubMed

    Erttmann, Saskia F; Härtlova, Anetta; Sloniecka, Marta; Raffi, Faizal A M; Hosseinzadeh, Ava; Edgren, Tomas; Rofougaran, Reza; Resch, Ulrike; Fällman, Maria; Ek, Torben; Gekara, Nelson O

    2016-07-19

    The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection. PMID:27421701

  18. 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.

  19. 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

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

    PubMed

    Hermans, David; Van Steendam, Katleen; Verbrugghe, Elin; Verlinden, Marc; Martel, An; Seliwiorstow, Tomasz; Heyndrickx, Marc; Haesebrouck, Freddy; De Zutter, Lieven; Deforce, Dieter; Pasmans, Frank

    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

  1. 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

  2. Drug treatment of malaria infections can reduce levels of protection transferred to offspring via maternal immunity

    PubMed Central

    Staszewski, Vincent; Reece, Sarah E.; O'Donnell, Aidan J.; Cunningham, Emma J. A.

    2012-01-01

    Maternally transferred immunity can have a fundamental effect on the ability of offspring to deal with infection. However, levels of antibodies in adults can vary both quantitatively and qualitatively between individuals and during the course of infection. How infection dynamics and their modification by drug treatment might affect the protection transferred to offspring remains poorly understood. Using the rodent malaria parasite Plasmodium chabaudi, we demonstrate that curing dams part way through infection prior to pregnancy can alter their immune response, with major consequences for offspring health and survival. In untreated maternal infections, maternally transferred protection suppressed parasitaemia and reduced pup mortality by 75 per cent compared with pups from naïve dams. However, when dams were treated with anti-malarial drugs, pups received fewer maternal antibodies, parasitaemia was only marginally suppressed, and mortality risk was 25 per cent higher than for pups from dams with full infections. We observed the same qualitative patterns across three different host strains and two parasite genotypes. This study reveals the role that within-host infection dynamics play in the fitness consequences of maternally transferred immunity. Furthermore, it highlights a potential trade-off between the health of mothers and offspring suggesting that anti-parasite treatment may significantly affect the outcome of infection in newborns. PMID:22357264

  3. Plant diversity affects behavior of generalist root herbivores, reduces crop damage, and enhances crop yield.

    PubMed

    Staudacher, Karin; Schallhart, Nikolaus; Thalinger, Bettina; Wallinger, Corinna; Juen, Anita; Traugott, Michael

    2013-07-01

    Soil-dwelling pests inflict considerable economic damage in agriculture but are hard to control. A promising strategy to reduce pest pressure on crops is to increase the plant diversity in agroecosystems. This approach, however, demands a sound understanding of species' interactions, which is widely lacking for subterranean herbivore-plant systems. Here, we examine the effects of plant diversification on wireworms, the soil-dwelling larvae of click beetles that threaten crops worldwide. We conducted a field experiment employing plant diversification by adding either wheat or a mix of six associated plants (grasses, legumes, and forbs) between rows of maize to protect it from Agriotes wireworms. Wireworm feeding behavior, dispersal between crop and associated plants, as well as maize damage and yield were examined. The former was assessed combining molecular gut content and stable isotope analysis. The pests were strongly attracted by the associated plants in August, when the crop was most vulnerable, whereas in September, shortly before harvest, this effect occurred only in the plant mix. In maize monoculture, the larvae stayed in the principal crop throughout the season. Larval delta13C signatures revealed that maize feeding was reduced up to sevenfold in wireworms of the vegetationally diversified treatments compared to those of the maize monoculture. These findings were confirmed by molecular analysis, which additionally showed a dietary preference of wireworms for specific plants in the associated plant mix. Compared to the monoculture, maize damage was reduced by 38% and 55% in the wheat and plant mix treatment, which translated into a yield increase of 30% and 38%, respectively. The present findings demonstrate that increasing the plant diversity in agroecosystems provides an effective insurance against soil pests. The underlying mechanisms are the diversion of the pest from the principle crop and a changed feeding behavior. The deployment of diverse mixes of

  4. Medical Malpractice Reform: Noneconomic Damages Caps Reduced Payments 15 Percent, With Varied Effects By Specialty

    PubMed Central

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

    2014-01-01

    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 220,653 malpractice claims from 1985–2010 merged with information on state liability reforms. We estimated the impact of state noneconomic damage caps on average malpractice payment size for physicians overall and for 10 different specialties, and compared how the effects differed according to the restrictiveness of the cap ($250,000 vs. $500,000 cap). We found noneconomic damage caps reduced payments by $42,980 (15%; p<0.001), with a $250,000 cap reducuing average payments by $59,331 (20%; p<0.001), while a $500,000 cap had no significant effect. Effects varied according to specialty and were largest in specialties with high average payments, such as pediatrics. This suggests that the effect of noneconomic damage caps differs by specialty, and only more restrictive caps result in lower average payments. PMID:25339633

  5. Exogenous spermidine alleviates oxidative damage and reduce yield loss in rice submerged at tillering stage

    PubMed Central

    Liu, Ming; Chu, Meijie; Ding, Yanfeng; Wang, Shaohua; Liu, Zhenghui; Tang, She; Ding, Chengqiang; Li, Ganghua

    2015-01-01

    To figure out whether spermidine (Spd) can alleviate oxidative damage on rice (Oryza sativa L.) caused by submergence stress, Ningjing 3 was used in this study. The results showed that, spraying Spd on rice leaves at a concentration of 0.5 mM promoted the growth recovery of rice after drainage, such as green leaves, tillers, and aboveground dry mass. According to physiological analysis, Spd accelerate restored chlorophylls damage by submergence, and decreased the rate of O2·− generation and H2O2 content, inhibited submergence-induced lipid peroxidation. Spd also helped to maintain antioxidant enzyme activities after drainage, such as superoxide dismutase, peroxidase, and GR, which ultimately improved the recovery ability of submerged rice. With the effect of Spd, the rice yields increased by 12.1, 17.9, 13.5, and 18.0%, of which submerged for 1, 3, 5, 7 days, respectively. It is supposed that exogenous Spd really has an alleviate effect on submergence damage and reduce yield loss of rice. PMID:26583021

  6. 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

  7. 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.

  8. Reduced short-interval intracortical inhibition after eccentric muscle damage in human elbow flexor muscles.

    PubMed

    Pitman, Bradley M; Semmler, John G

    2012-09-01

    The purpose of this study was to use paired-pulse transcranial magnetic stimulation (TMS) to examine the effect of eccentric exercise on short-interval intracortical inhibition (SICI) after damage to elbow flexor muscles. Nine young (22.5 ± 0.6 yr; mean ± SD) male subjects performed maximal eccentric exercise of the elbow flexor muscles until maximal voluntary contraction (MVC) force was reduced by ∼40%. TMS was performed before, 2 h after, and 2 days after exercise under Rest and Active (5% MVC) conditions with motor-evoked potentials (MEPs) recorded from the biceps brachii (BB) muscle. Peripheral electrical stimulation of the brachial plexus was used to assess maximal M-waves, and paired-pulse TMS with a 3-ms interstimulus interval was used to assess changes in SICI at each time point. The eccentric exercise resulted in a 34% decline in strength (P < 0.001), a 41% decline in resting M-wave (P = 0.01), changes in resting elbow joint angle (10°, P < 0.001), and a shift in the optimal elbow joint angle for force production (18°, P < 0.05) 2 h after exercise. This was accompanied by impaired muscle strength (27%, P < 0.001) and increased muscle soreness (P < 0.001) 2 days after exercise, which is indicative of muscle damage. When the test MEP amplitudes were matched between sessions, we found that SICI was reduced by 27% in resting and 23% in active BB muscle 2 h after exercise. SICI recovered 2 days after exercise when muscle pain and soreness were present, suggesting that delayed onset muscle soreness from eccentric exercise does not influence SICI. The change in SICI observed 2 h after exercise suggests that eccentric muscle damage has widespread effects throughout the motor system that likely includes changes in motor cortex. PMID:22837166

  9. Red yeast rice repairs kidney damage and reduces inflammatory transcription factors in rat models of hyperlipidemia

    PubMed Central

    DING, MEI; SI, DAOYUAN; ZHANG, WENQI; FENG, ZHAOHUI; HE, MIN; YANG, PING

    2014-01-01

    Xuezhikang (XZK), an extract of red yeast rice, has been widely used for the management of hyperlipidemia and coronary heart disease (CHD); however, the effects of XZK treatment on kidney injury have not yet been fully identified. The aim of the current study was to evaluate the effects of XZK on the kidneys and investigate the related mechanisms in a rat model of hyperlipidemia. Thus, the effect on inflammatory transcription factors and kidney damage was investigated with in vitro and in vivo experiments on hyperlipidemic rats following XZK treatment. The results revealed that the plasma levels of total cholesterol (TC), triglycerides (TG) and low-density lipoprotein-cholesterol (LDL-C) were significantly decreased, while the levels of high-density lipoprotein-cholesterol (HDL-C) were significantly upregulated in the XZK treatment group, as compared with those in the hyperlipidemia group (P<0.05). In addition, the results demonstrated that XZK was able to repair the kidney damage caused by hyperlipidemia. Furthermore, the expression levels of the inflammatory transcription factors, tumor necrosis factor-α and interleukin-6, were shown to be reduced in the XZK group when compared with the hyperlipidemia group. In summary, XZK reduces kidney injury, downregulates the levels of TG, TC and LDL-C, as well as the expression levels of inflammatory transcription factors, and upregulates HDL-C. These results further the understanding of the molecular pathogenic mechanisms underlying hyperlipidemia and aid the development of XZK as an effective therapeutic agent for hyperlipidemia. PMID:25371725

  10. 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

  11. Male reproductive senescence: the price of immune-induced oxidative damage on sexual attractiveness in the blue-footed booby.

    PubMed

    Torres, Roxana; Velando, Alberto

    2007-11-01

    In animals, male reproduction is commonly a function of sexual attractiveness, based on the expression of sexually dimorphic traits that advertise genuinely the male's quality. Male performance may decline with age because physiological functions underlying sexual attractiveness may be affected by senescence. Here we show that a sexual signal (foot colour) declines with age, due probably to the deleterious effects of oxidative damage. We found that in the blue-footed booby Sula nebouxii foot colour during courtship was less attractive in senescent than in middle-aged males. In addition, we increased reactive oxygen species experimentally by immunizing males with lipopolysaccharide, a bacterial cell wall component that induces marked oxidative stress in animals. The immune system activation induced greater lipid peroxidation and invoked changes on colour expression (less attractive), particularly in senescent males. These results support the idea that oxidative stress affects reproductive senescence, and suggest that oxidative damage might be a proximal mechanism underlying age-reproductive patterns in long-lived animals.

  12. Male reproductive senescence: the price of immune-induced oxidative damage on sexual attractiveness in the blue-footed booby.

    PubMed

    Torres, Roxana; Velando, Alberto

    2007-11-01

    In animals, male reproduction is commonly a function of sexual attractiveness, based on the expression of sexually dimorphic traits that advertise genuinely the male's quality. Male performance may decline with age because physiological functions underlying sexual attractiveness may be affected by senescence. Here we show that a sexual signal (foot colour) declines with age, due probably to the deleterious effects of oxidative damage. We found that in the blue-footed booby Sula nebouxii foot colour during courtship was less attractive in senescent than in middle-aged males. In addition, we increased reactive oxygen species experimentally by immunizing males with lipopolysaccharide, a bacterial cell wall component that induces marked oxidative stress in animals. The immune system activation induced greater lipid peroxidation and invoked changes on colour expression (less attractive), particularly in senescent males. These results support the idea that oxidative stress affects reproductive senescence, and suggest that oxidative damage might be a proximal mechanism underlying age-reproductive patterns in long-lived animals. PMID:17922712

  13. Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis.

    PubMed

    Ge, Yan; Jiang, Chao; Sung, Sun-Sang J; Bagavant, Harini; Dai, Chao; Wang, Hongyang; Kannapell, Carol C; Cathro, Helen P; Gaskin, Felicia; Fu, Shu Man

    2013-10-21

    Cgnz1 and Agnz1 on the distal region of mouse chromosome 1 are associated with chronic glomerulonephritis (cGN) and acute GN (aGN). NZM2328.Lc1R27 (R27) was generated by introgressing a C57L/J region where Cgnz1 is located to NZM2328. R27 female mice developed aGN mediated by immune complex (IC) deposition and complement activation without progression to cGN with severe proteinuria. End stage renal disease (ESRD) was not seen in R27 mice as old as 15 mo. Thus, aGN and cGN are under separate genetic control, and IC-mediated proliferative GN need not progress to cGN and ESRD. NZM2328 and R27 female mice have comparable immune and inflammatory parameters. In contrast to NZM2328, R27 mice were resistant to sheep anti-mouse GBM serum-induced nephritis, supporting the hypothesis that aGN is mediated by autoimmunity and resistance to the development of cGN is mediated by end organ resistance to damage. Thus, autoimmunity should be considered distinct from end organ damage. The Cgnz1 region has been mapped to a 1.34 MB region with 45 genes. Nine candidate genes were identified. Clinical relevance of these observations is supported by case studies. Clinical implications and the significance to human lupus and other diseases are presented.

  14. Extracorporeal immune therapy with immobilized agonistic anti-Fas antibodies leads to transient reduction of circulating neutrophil numbers and limits tissue damage after hemorrhagic shock/resuscitation in a porcine model

    PubMed Central

    2010-01-01

    Background Hemorrhagic shock/resuscitation is associated with aberrant neutrophil activation and organ failure. This experimental porcine study was done to evaluate the effects of Fas-directed extracorporeal immune therapy with a leukocyte inhibition module (LIM) on hemodynamics, neutrophil tissue infiltration, and tissue damage after hemorrhagic shock/resuscitation. Methods In a prospective controlled double-armed animal trial 24 Munich Mini Pigs (30.3 ± 3.3 kg) were rapidly haemorrhaged to reach a mean arterial pressure (MAP) of 35 ± 5 mmHg, maintained hypotensive for 45 minutes, and then were resuscitated with Ringer' solution to baseline MAP. With beginning of resuscitation 12 pigs underwent extracorporeal immune therapy for 3 hours (LIM group) and 12 pigs were resuscitated according to standard medical care (SMC). Haemodynamics, haematologic, metabolic, and organ specific damage parameters were monitored. Neutrophil infiltration was analyzed histologically after 48 and 72 hours. Lipid peroxidation and apoptosis were specifically determined in lung, bowel, and liver. Results In the LIM group, neutrophil counts were reduced versus SMC during extracorporeal immune therapy. After 72 hours, the haemodynamic parameters MAP and cardiac output (CO) were significantly better in the LIM group. Histological analyses showed reduction of shock-related neutrophil tissue infiltration in the LIM group, especially in the lungs. Lower amounts of apoptotic cells and lipid peroxidation were found in organs after LIM treatment. Conclusions Transient Fas-directed extracorporeal immune therapy may protect from posthemorrhagic neutrophil tissue infiltration and tissue damage. PMID:20406470

  15. 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." PMID:26145166

  16. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.

    PubMed

    Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

    2016-05-01

    Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

  17. 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.

  18. 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.

  19. Pomegranate extract attenuates unilateral ureteral obstruction-induced renal damage by reducing oxidative stress

    PubMed Central

    Otunctemur, Alper; Ozbek, Emin; Cakir, Suleyman Sami; Polat, Emre Can; Dursun, Murat; Cekmen, Mustafa; Somay, Adnan; Ozbay, Nurver

    2015-01-01

    Aims: Ureteral obstruction may cause permanent kidney damage at late period. We know that the pomegranate extract (PE) play a strong role on removal of free oxygen radicals and prevention of oxidative stress. In the current study study, we evaluated the effect of PE on kidney damage after unilateral ureteral obstruction (UUO). Settings and Design: A total of 32 rats were divided into four groups. Group 1 was a control, Group 2 was a sham, Group 3 was rats with UUO and Group 4 was rats with UUO that were given PE (oral 100 μL/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Subjects and Methods: Tubular necrosis, mononuclear cell infiltration, and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in the other part of kidneys. Statistical Analysis Used: Statistical analyses were performed by the Chi-square test and one-way analysis of variance. Results: There was no difference significantly for urea-creatinine levels between groups. Pathologically, there was serious tubular necrosis, mononuclear cell infiltration and fibrosis in Group 3, and there was significantly decreasing for tubular necrosis, mononuclear cell infiltration and fibrosis in Group 4 (P < 0.005). Furthermore, there was significantly increasing for NO and MDA levels; decreasing for GSH levels in Group 3 compared the other groups (P < 0.005). Conclusions: We think that the PE prevents kidney damage by decreasing oxidative stress in kidney. PMID:25838069

  20. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers.

    PubMed

    Dziaman, Tomasz; Huzarski, Tomasz; Gackowski, Daniel; Rozalski, Rafal; Siomek, Agnieszka; Szpila, Anna; Guz, Jolanta; Lubinski, Jan; Wasowicz, Wojciech; Roszkowski, Krzysztof; Olinski, Ryszard

    2009-11-01

    Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy. PMID:19843683

  1. 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…

  2. Antibodies Fused to Innate Immune Molecules Reduce Initiation of Cryptosporidium parvum Infection in Mice▿

    PubMed Central

    Imboden, Michael; Riggs, Michael W.; Schaefer, Deborah A.; Homan, E. Jane; Bremel, Robert D.

    2010-01-01

    At present no completely effective treatments are available for Cryptosporidium parvum infections in humans and livestock. Based on previous data showing the neutralizing potential of a panel of monoclonal antibodies developed against C. parvum, and based on the fact that innate immune peptides and enzymes have anticryptosporidial activity, we engineered several of these antibodies into antibody-biocide fusion proteins. We hypothesized that the combination of high-affinity antibody targeting with innate immune molecule-mediated killing would result in a highly effective new antiprotozoal agent. To test this hypothesis, we expressed antibody-biocide fusion proteins in a mammalian cell culture system and used the resulting products for in vitro and in vivo efficacy experiments. Antibody-biocide fusion proteins efficiently bound to, and destroyed, C. parvum sporozoites in vitro through a membrane-disruptive mechanism. When antibody-biocide fusion proteins were administered orally to neonatal mice in a prophylactic model of cryptosporidiosis, the induction of infection was reduced by as much as 81% in the mucosal epithelium of the gut, as determined on the basis of histopathological scoring of infectious stages. Several versions of antibody fusion proteins that differed in antigen specificity and in the biocide used had strong inhibitory effects on the initiation of infection. The results lay the groundwork for the development of a new class of antimicrobials effective against Cryptosporidium. PMID:20086143

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

    PubMed

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

    2015-09-01

    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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. Impact of antiretroviral therapy (ART) timing on chronic immune activation/inflammation and end-organ damage

    PubMed Central

    Rajasuriar, Reena; Wright, Edwina; Lewin, Sharon R.

    2015-01-01

    Purpose of review The purpose of this review was to summarize recent studies on the effect of early antiretroviral therapy (ART) in HIV-infected patients on markers of immune activation/inflammation, viral persistence and serious non-AIDS events. Recent findings Early ART, initiated within days to months of HIV infection, was associated with marked reduction in T-cell activation often reaching levels observed in HIV-uninfected individuals. However, the impact of early ART on markers of innate immune activation, microbial translocation and inflammation/coagulation was less clear. Early ART has also been associated with a significant reduction in the frequency of latently infected cells, which was greater if ART was initiated within days to weeks rather than months following infection. However, few studies have evaluated the relationship between immune activation and viral reservoirs, specifically following early ART. Early ART may potentially reduce serious non-AIDS events and associated mortality, but most of these studies have extrapolated from changes in surrogate markers, such as CD4 : CD8 ratio. Summary Early ART was associated with beneficial effects on multiple markers of immune activation, inflammation and viral persistence. Longer term prospective studies are still needed to determine whether early ART translates to a significant reduction in serious non-AIDS events and mortality. PMID:25415420

  9. 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.

  10. Syzigium cumini seed extracts reduce tissue damage in diabetic rat brain.

    PubMed

    Stanely Mainzen Prince, P; Kamalakkannan, N; Menon, Venugopal P

    2003-02-01

    Syzigium cumini commonly known as Jamun, is widely used in different parts of India for the treatment of diabetes mellitus. Oral administration of an aqueous Jamun seed extract (JSEt) for 6 weeks caused a significant decrease in lipids, thiobarbituric acid reactive substances (TBARS) and an increase in catalase and superoxide dismutase in the brain of alloxan induced diabetic rats. Oral administration of an alcoholic JSEt for 6 weeks brought back all the parameters to near normal. The effect of alcoholic JSEt (100 mg/kg) was better than aqueous JSEt (5 g/kg). The effect of both these extracts was better than glibenclamide (600 microg/kg). Thus, our study shows that S. cumini seed extracts reduce tissue damage in diabetic rat brain. PMID:12648817

  11. 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.

  12. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse.

    PubMed

    Lim, G P; Chu, T; Yang, F; Beech, W; Frautschy, S A; Cole, G M

    2001-11-01

    Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease. PMID:11606625

  13. 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.

  14. Antioxidant treatment reduces blast-induced cochlear damage and hearing loss.

    PubMed

    Ewert, Donald L; Lu, Jianzhong; Li, Wei; Du, Xiaoping; Floyd, Robert; Kopke, Richard

    2012-03-01

    Exposure to blast overpressure has become one of the hazards of both military and civilian life in many parts of the world due to war and terrorist activity. Auditory damage is one of the primary sequela of blast trauma, affecting immediate situational awareness and causing permanent hearing loss. Protecting against blast exposure is limited by the inability to anticipate the timing of these exposures, particularly those caused by terrorists. Therefore a therapeutic regimen is desirable that is able to ameliorate auditory damage when administered after a blast exposure has occurred. The purpose of this study was to determine if administration of a combination of antioxidants 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) beginning 1 h after blast exposure could reduce both temporary and permanent hearing loss. To this end, a blast simulator was developed and the operational conditions established for exposing rats to blast overpressures comparable to those encountered in an open-field blast of 14 pounds per square inch (psi). This blast model produced reproducible blast overpressures that resulted in physiological and physical damage to the auditory system that was proportional to the number and amplitude of the blasts. After exposure to 3 consecutive 14 psi blasts 100% of anesthetized rats had permanent hearing loss as determined at 21 days post exposure by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Animals treated with HPN-07 and NAC after blast exposure showed a significant reduction in ABR threshold shifts and DPOAE level shifts at 2-16 kHz with significant reduction in inner hair cell (IHC) and outer hair cell (OHC) loss across the 5-36 kHz region of the cochlea compared with control animals. The time course of changes in the auditory system was documented at 3 h, 24 h, 7 day and 21 day after blast exposure. At 3 h after blast exposure the auditory brainstem response (ABR

  15. 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. PMID:26108285

  16. 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

  17. 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.

  18. 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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:25710927

  20. 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.

  1. 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.

  2. Antimicrobial proteins from snake venoms: direct bacterial damage and activation of innate immunity against Staphylococcus aureus skin infection.

    PubMed

    Samy, R P; Stiles, B G; Gopalakrishnakone, P; Chow, V T K

    2011-01-01

    The innate immune system is the first line of defense against microbial diseases. Antimicrobial proteins produced by snake venoms have recently attracted significant attention due to their relevance to bacterial infection and potential development into new therapeutic agents. Staphylococcus aureus is one of the major human pathogens causing a variety of infections involving pneumonia, toxic shock syndrome, and skin lesions. With the recent emergence of methicillin (MRSA) and vancomycin (VRSA) resistance, S. aureus infection is a serious clinical problem that will have a grave socio-economic impact in the near future. Although S. aureus susceptibility to innate antimicrobial peptides has been reported recently, the protective effect of snake venom phospholipase A₂ (svPLA₂) proteins on the skin from S. aureus infection has been understudied. This review details the protective function of svPLA₂s derived from venoms against skin infections caused by S. aureus. We have demonstrated in vivo that local application of svPLA₂ provides complete clearance of S. aureus within 2 weeks after treatment compared to fusidic acid ointment (FAO). In vitro experiments also demonstrate that svPLA₂ proteins have inhibitory (bacteriostatic) and killing (bactericidal) effects on S. aureus in a dose-dependant manner. The mechanism of bacterial membrane damage and perturbation was clearly evidenced by electron microscopic studies. In summary, svPLA₂s from Viperidae and Elapidae snakes are novel molecules that can activate important mechanisms of innate immunity in animals to endow them with protection against skin infection caused by S. aureus.

  3. 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

  4. Caspase inhibition reduces lymphocyte apoptosis and improves host immune responses to Trypanosoma cruzi infection.

    PubMed

    Silva, Elisabeth M; Guillermo, Landi V C; Ribeiro-Gomes, Flávia L; De Meis, Juliana; Nunes, Marise P; Senra, Juliana F V; Soares, Milena B P; DosReis, George A; Lopes, Marcela F

    2007-03-01

    In experimental Chagas' disease, lymphocytes from mice infected with Trypanosoma cruzi show increased apoptosis in vivo and in vitro. Treatment with a pan-caspase blocker peptide inhibited expression of the active form of effector caspase-3 in vitro and rescued both B and T cells from cell death. Injection of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone, but not a control peptide, reduced parasitemia and lymphocyte apoptosis in T. cruzi-infected mice. Moreover, treatment with caspase inhibitor throughout acute infection increased the absolute numbers of B and T cells in the spleen and lymph nodes, without affecting cell infiltrates in the heart. Following treatment, we found increased accumulation of memory/activated CD4 and CD8 T cells, and secretion of IFN-gamma by splenocytes stimulated with T. cruzi antigens. Caspase inhibition in the course of infection reduced the intracellular load of parasites in peritoneal macrophages, and increased the production of TNF-alpha and nitric oxide upon activation in vitro. Our results indicate that inhibition of caspases with a pan-caspase blocker peptide improves protective type-1 immune responses to T. cruzi infection. We suggest that mechanisms of apoptosis are potential therapeutic targets in Chagas' disease.

  5. Inosine-containing RNA is a novel innate immune recognition element and reduces RSV infection.

    PubMed

    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.

  6. 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

  7. Therapeutic Immunization with HIV-1 Tat Reduces Immune Activation and Loss of Regulatory T-Cells and Improves Immune Function in Subjects on HAART

    PubMed Central

    Ensoli, Barbara; Bellino, Stefania; Tripiciano, Antonella; Longo, Olimpia; Francavilla, Vittorio; Marcotullio, Simone; Cafaro, Aurelio; Picconi, Orietta; Paniccia, Giovanni; Scoglio, Arianna; Arancio, Angela; Ariola, Cristina; Ruiz Alvarez, Maria J.; Campagna, Massimo; Scaramuzzi, Donato; Iori, Cristina; Esposito, Roberto; Mussini, Cristina; Ghinelli, Florio; Sighinolfi, Laura; Palamara, Guido; Latini, Alessandra; Angarano, Gioacchino; Ladisa, Nicoletta; Soscia, Fabrizio; Mercurio, Vito S.; Lazzarin, Adriano; Tambussi, Giuseppe; Visintini, Raffaele; Mazzotta, Francesco; Di Pietro, Massimo; Galli, Massimo; Rusconi, Stefano; Carosi, Giampiero; Torti, Carlo; Di Perri, Giovanni; Bonora, Stefano; Ensoli, Fabrizio; Garaci, Enrico

    2010-01-01

    Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the

  8. 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. PMID:26254283

  9. 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.

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

    PubMed

    Nachbagauer, Raffael; Miller, Matthew S; Hai, Rong; Ryder, Alex B; Rose, John K; Palese, Peter; García-Sastre, Adolfo; Krammer, Florian; Albrecht, Randy A

    2015-12-30

    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.

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

    PubMed

    Nachbagauer, Raffael; Miller, Matthew S; Hai, Rong; Ryder, Alex B; Rose, John K; Palese, Peter; García-Sastre, Adolfo; Krammer, Florian; Albrecht, Randy A

    2016-03-01

    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

  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. 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. PMID:27341891

  14. Transgenic tobacco plants accumulating osmolytes show reduced oxidative damage under freezing stress.

    PubMed

    Parvanova, Daniela; Ivanov, Sergei; Konstantinova, Tatyana; Karanov, Emanuil; Atanassov, Atanas; Tsvetkov, Tsvetan; Alexieva, Vera; Djilianov, Dimitar

    2004-01-01

    We studied the reaction to the oxidative component of freezing in several tobacco lines, transformed with genes coding for enzymes involved in the synthesis of osmoprotectants (proline, fructan or glycine betaine) along with their wild type. The levels of some oxidative stress markers (leakage of electrolytes, hydrogen peroxide and malondialdehyde) as well as the activity of antioxidative enzymes catalase (EC 1.11.1.6.) and guaiacol peroxidase (EC 1.11.1.7.) have been followed at acclimation, 12 and 24 h freezing and at recovery. Freezing for 24 h resulted in severe damages for the wild type. A corresponding increase of electrolyte leakage, hydrogen peroxide and malondialdehyde contents, a rise of peroxidase activity and inhibition of catalase activity occurred in the non-transformants. Similar, but significantly lower trend of the same parameters has been found for the transgenic lines. Moreover, the oxidative markers returned to their normal levels when the transformants were able to recover from freezing. It could be speculated that transfer of genes, coding for accumulation of osmoprotectants, is related to reduced intensity of freezing-induced oxidative processes. Our lines and model system could serve as a good prerequisite for additional studies to gain further insights into the complex role of osmoprotectants in freezing tolerance.

  15. 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.

  16. 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.

  17. 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.

  18. Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

    PubMed Central

    Bin-Umer, Mohamed Anwar; McLaughlin, John E.; Butterly, Matthew S.; McCormick, Susan; Tumer, Nilgun E.

    2014-01-01

    Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as a novel mechanism for trichothecene-induced cell death. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin (Tcin) and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains had significantly higher reactive oxygen species (ROS) levels relative to the parental strain. A dose-dependent increase in ROS levels was observed in the parental strain treated with different trichothecenes, but not in a petite version of the parental strain or in the presence of a mitochondrial membrane uncoupler, indicating that mitochondria are the main site of ROS production due to toxin exposure. Cytotoxicity of trichothecenes was alleviated after treatment of the parental strain and highly sensitive mutants with antioxidants, suggesting that oxidative stress contributes to trichothecene sensitivity. Cotreatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in mitophagy deficient mutants, suggesting that elimination of trichothecene-damaged mitochondria by mitophagy improves cell survival. These results reveal that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and a potential target for trichothecene resistance. PMID:25071194

  19. Alpinia protocatechuic acid protects against oxidative damage in vitro and reduces oxidative stress in vivo.

    PubMed

    Shi, Gui-Fang; An, Li-Jia; Jiang, Bo; Guan, Shui; Bao, Yong-Ming

    2006-08-01

    In this study, the neuroprotective effects of Alpinia protocatechuic acid (PCA), a phenolic compound isolated from the dried fruits of Alpinia Oxyphylla Miq. was found. The protective effect of Alpinia PCA against H2O2-induced oxidative damage on PC12 cells was investigated by measuring cell viability via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Rats were injected intraperitoneally with Alpinia PCA at a dose of 5mg/kg per day for 7 days, behavioral testing was performed in Y-maze. In order to make clear the neuroprotective mechanism of Alpinia PCA, the activities of endogenous antioxidants and the content of lipid peroxide in brain were assayed. The results proved that Alpinia PCA significantly prevented the H2O2-induced reduction in cell survival, improved the cognition of aged rats, reduced the content of lipid peroxide, increased the activity of glutathione peroxidase and superoxide dismutase. All these suggested that Alpinia PCA was a potential neuroprotective agent and its neuroprotective effects were achieved at least partly by promoting endogenous antioxidant enzymatic activities and inhibiting free radical generation.

  20. Reduced antioxidant level and increased oxidative damage in intact liver lobes during ischaemia-reperfusion

    PubMed Central

    Váli, László; Taba, Gabriella; Szentmihályi, Klára; Fébel, Hedvig; Kurucz, Tímea; Pallai, Zsolt; Kupcsulik, Péter; Blázovics, Anna

    2006-01-01

    AIM: To determine whether increased blood flow of the liver can cause oxidative stress and hepatocyte damage, and to elaborate methods suitable for measuring the antioxidant defence during hepatic surgery on rat model. METHODS: In nembutal narcosis, the left lateral and the medial lobes of the liver were clipped for 45 min to make the total blood supply flow through the other lobes. Total antioxidant status, glutathione peroxidase and superoxide dysmutase activity, as well as the concentrations of diene conjugates and free sulphydril groups, H-donating ability and reducing power of the liver samples were determined. Chemiluminescent intensity of the liver was also measured. Metal ions (Al, Ca, Cu, Fe, Mg, Mn, Zn) and P and S concentrations of the liver were determined with an inductively coupled plasma optical emission spectrometer and Se content was measured by cathodic stripping voltammetry. RESULTS: Glutathione peroxidase and superoxide dysmutase activities of the liver decreased significantly in the hyperemia group compared to those observed in the sham operated group. The level of total antioxidant status was also significantly lower in the hyperemia group. H-donating ability, reducing power and free sulphydril group concentration showed the same tendency. A significant correlation (P<0.05) was found between the changes in non-specific antioxidant activities. This pointed to simultaneous activity of the antioxidant defence system. Al, Cu, Mn, Zn, and S were lower in the hyperemia group than in the sham operated group when the levels of Ca, Fe, Mg, Se and P ions were higher during hyperemia. CONCLUSION: Oxidative stress is one of the main factors for the injury of intact liver lobes during ischaemia-reperfusion. PMID:16534850

  1. 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

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

    PubMed

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

    2016-06-01

    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

  3. Ferroportin-encapsulated nanoparticles reduce infection and improve immunity in mice infected with Leishmania major.

    PubMed

    Rafiee, Aras; Riazi-Rad, Farhad; Darabi, Haiedeh; Khaze, Vahid; Javadian, Seifoddin; Ajdary, Soheila; Bahrami, Fariborz; Alimohammadian, Mohammad Hossein

    2014-05-15

    Inoculation of inbred mice by Leishmania major results in two different patterns. C57BL/6 mice display resistance against L. major but BALB/c mice show susceptibility to L. major with visceral infection, anemia and death. In this study, the effects of treatment of L. major-infected BALB/c mice with a ferroportin (Fpn)-encoding construct via nanoparticles were evaluated. A fragment encoding Fpn, a major regulator of iron homeostasis, was amplified and sub-cloned to a GFP expression vector to express Fpn-EGFP protein. This construct was incorporated in nanoparticles of alginate/chitosan polymers and orally administered to L. major-infected BALB/c mice. Blood hematocrit and iron, footpad size, parasite load and concentration of IFNG, IL4 and IL10 by ELISA were measured in the treated and untreated mice. The results indicated that the treated mice had significantly higher hematocrit and iron levels while exhibited significantly lower footpad size and parasite load measurements. Moreover, lower levels of IL4 and IL10 and higher ratios of IFNG/IL4 or IFNG/IL10 were shown in the treated, compared to the untreated mice. In conclusion, treating BALB/c mice infected with L. major with encapsulated Fpn-encoding construct in alginate/chitosan nanoparticles were shown to reduce the infection and improve anemia and immunity in the animal model of leishmaniasis.

  4. Experimental cooling during incubation leads to reduced innate immunity and body condition in nestling tree swallows.

    PubMed

    Ardia, Daniel R; Pérez, Jonathan H; Clotfelter, Ethan D

    2010-06-22

    Nest microclimate can have strong effects that can carry over to later life-history stages. We experimentally cooled the nests of tree swallows (Tachycineta bicolor). Females incubating in cooled nests reduced incubation time and allowed egg temperatures to drop, leading to extended incubation periods. We partially cross-fostered nestlings to test carry-over effects of cooling during incubation on nestling innate constitutive immunity, assessed through bacteria killing ability (BKA) of blood. Nestlings that had been cooled as eggs showed a lower ability to kill bacteria than control nestlings, regardless of the treatment of their foster mother. However, there was no effect of treatment of rearing females on nestling BKA in control nestlings, even though cooled females made significantly fewer feeding visits than did control females. This suggests that the effect of cooling occurred during incubation and was not due to carry-over effects on nestling condition. Nestlings that were exposed to experimental cooling as embryos had lower residual body mass and absolute body mass at all four ages measured. Our results indicate that environmental conditions and trade-offs experienced during one stage of development can have important carry-over effects on later life-history stages.

  5. 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…

  6. 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

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

    PubMed

    Vicetti Miguel, Rodolfo D; 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

  8. Pertussis immunity and response to tetanus-reduced diphtheria-reduced pertussis vaccine (Tdap) after autologous peripheral blood stem cell transplantation.

    PubMed

    Small, Trudy N; Zelenetz, Andrew D; Noy, Ariela; Rice, R David; Trippett, Tanya M; Abrey, Lauren; Portlock, Carol S; McCullagh, Emily J; Vanak, Jill M; Mulligan, Ann Marie; Moskowitz, Craig H

    2009-12-01

    Pertussis is a highly contagious respiratory infection characterized by prolonged cough and inspiratory whoop. Despite widespread vaccination of children aged<7 years, its incidence is steadily increasing in adolescents and adults, because of the known decrease in immunity following childhood immunization. In an effort to reduce pertussis in adolescents and adults, 2 vaccines containing tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) (BOOSTRIX and Adacel) were licensed in 2005 for use in adolescents, 1 of which (Adacel) contains less pertussis toxoid (PT) for use in adults. This study assessed pertussis titers in 57 adult survivors of an autologous peripheral blood stem cell transplantation (PBSCT; median age, 37.5 years), 28 of whom were subsequently vaccinated with Tdap containing 2.5microg of PT (Adacel). The median time to Tdap administration was 3 years posttransplantation. Before vaccination, 87% of the patients lacked pertussis immunity. Only 2 of the 28 patients developed a >2-fold response to PT following vaccination with Tdap. These data suggest that autologous transplantation recipients are highly susceptible to pertussis and that immunization with 2.5microg of PT induces an inadequate response. Prospective trials evaluating BOOSTRIX, containing 8microg/dose of PT (approved for adults in December 2008) are warranted in this vulnerable population undergoing transplantation.

  9. 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

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

    PubMed

    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; Marta, Rosana F

    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

  11. Coagulin-L ameliorates TLR4 induced oxidative damage and immune response by regulating mitochondria and NOX-derived ROS.

    PubMed

    Reddy, Sukka Santosh; Chauhan, Parul; Maurya, Preeti; Saini, Deepika; Yadav, Prem Prakash; Barthwal, Manoj Kumar

    2016-10-15

    Withanolides possess diverse biological and pharmacological activity but their immunomodulatory function is less realized. Hence, coagulin-L, a withanolide isolated from Withania coagulans Dunal has been studied for such an effect in human and murine cells, and mice model. Coagulin-L (1, 3, 10μM) exhibited immunomodulatory effect by suppressing TLR4 induced immune mediators such as cytokines (GMCSF, IFNα, IFNγ, IL-1α, IL-1Rα, IL-1β, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17), chemokines (IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10, KC, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, eotaxin/CCL11), growth factors (FGF-basic, VEGF), nitric oxide and intracellular superoxide. Mechanistically, coagulin-L abrogated LPS induced total and mitochondrial ROS generation, NOX2, NOX4 mRNA expression, IRAK and MAPK (p38, JNK, ERK) activation. Coagulin-L also attenuated IκBα degradation, which prevented NFκB downstream iNOS expression and pro-inflammatory cytokine release. Furthermore, coagulin-L (10, 25, 50mg/kg, p.o.), undermined the LPS (10mg/kg, i.p.) induced endotoxemia response in mice as evinced from diminished cytokine release, nitric oxide, aortic p38 MAPK activation and endothelial tissue impairment besides suppressing NOX2 and NOX4 expression in liver and aorta. Moreover, coagulin-L also alleviated the ROS mediated oxidative damage which was assessed through protein carbonyl, lipid hydroperoxide, 8-isoprostane and 8-hydroxy-2-deoxyguanosine quantification. To extend, coagulin-L also suppressed carrageenan-induced paw edema and thioglycollate-induced peritonitis in mice. Therefore, coagulin-L can be of therapeutic importance in pathological conditions induced by oxidative damage. PMID:27568862

  12. Coagulin-L ameliorates TLR4 induced oxidative damage and immune response by regulating mitochondria and NOX-derived ROS.

    PubMed

    Reddy, Sukka Santosh; Chauhan, Parul; Maurya, Preeti; Saini, Deepika; Yadav, Prem Prakash; Barthwal, Manoj Kumar

    2016-10-15

    Withanolides possess diverse biological and pharmacological activity but their immunomodulatory function is less realized. Hence, coagulin-L, a withanolide isolated from Withania coagulans Dunal has been studied for such an effect in human and murine cells, and mice model. Coagulin-L (1, 3, 10μM) exhibited immunomodulatory effect by suppressing TLR4 induced immune mediators such as cytokines (GMCSF, IFNα, IFNγ, IL-1α, IL-1Rα, IL-1β, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17), chemokines (IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10, KC, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, eotaxin/CCL11), growth factors (FGF-basic, VEGF), nitric oxide and intracellular superoxide. Mechanistically, coagulin-L abrogated LPS induced total and mitochondrial ROS generation, NOX2, NOX4 mRNA expression, IRAK and MAPK (p38, JNK, ERK) activation. Coagulin-L also attenuated IκBα degradation, which prevented NFκB downstream iNOS expression and pro-inflammatory cytokine release. Furthermore, coagulin-L (10, 25, 50mg/kg, p.o.), undermined the LPS (10mg/kg, i.p.) induced endotoxemia response in mice as evinced from diminished cytokine release, nitric oxide, aortic p38 MAPK activation and endothelial tissue impairment besides suppressing NOX2 and NOX4 expression in liver and aorta. Moreover, coagulin-L also alleviated the ROS mediated oxidative damage which was assessed through protein carbonyl, lipid hydroperoxide, 8-isoprostane and 8-hydroxy-2-deoxyguanosine quantification. To extend, coagulin-L also suppressed carrageenan-induced paw edema and thioglycollate-induced peritonitis in mice. Therefore, coagulin-L can be of therapeutic importance in pathological conditions induced by oxidative damage.

  13. Evaluation of Formation Damage Caused by Drilling Fluids Specifically in Pressure-Reduced Formation

    SciTech Connect

    Marx, C.; Rahman, S.S.

    1984-02-01

    The paper describes a method for evaluating formation damage caused by drilling fluid in reservoirs which may have pressure considerably less than hydrostatic pressure. The problem is of specific interest for enhanced oil recovery and/or underground gas storage projects. The method is flexible and practically oriented. It allows formation damage evaluation under the conditions of differential pressure of up to 100 bar (1400 psi) temperature of 140/sup 0/C (300 /sup 0/F), annular velocity of 2 m/s (.6 ft/s), 1 - 2,5 cm (0,4 - 1'') core diameter and length of 25 cm (10 ''). Formation damage is evaluated by 2 factors: damage ratio (DR) and sectional damage ratio (SDR). The residual permeability is expressed in terms of relative values using the initial permeability as reference. The depth of permeability impairment is determined by measuring the permeability of segmented cores of 5 cm (2 '') length (fig. 1). For this criterion the term sectional damage ratio is introduced. The method as described in this paper was applied to evaluate formation damage caused by a KC1-Chalk-Mud in two sandstones of 10 mD and 1000 mD range with pressure difference, temperature, annular velocity and time of contamination as the influencing variables.

  14. 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.

  15. 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.

  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. Dimethylformamide improves the in vitro characteristics of thawed stallion spermatozoa reducing sublethal damage.

    PubMed

    Morillo Rodriguez, A; Balao da Silva, C; Macías-García, B; Gallardo Bolaños, J M; Tapia, J A; Aparicio, I M; Ortega-Ferrusola, C; Peña, F J

    2012-12-01

    A total of 42 ejaculates were used in the experiment; six ejaculates per stallion, obtained from seven Pure Spanish stallions (PRE), were split and frozen in freezing media with different concentrations and combinations of cryoprotectant (CPA): (i) Cáceres (skim milk based extender) containing 2.5% glycerol (2.5GL), (ii) Cáceres containing 1.5% glycerol and 1.5% dimethylformamide (1.5%GL-1.5%DMFA), (iii) Cáceres extender supplemented with 1.5% glycerol and 2.5% dimethylformamide (1.5%GL-2.5%DMFA) and (iv) Cáceres extender supplemented with 4% dimethylformamide (4%DMFA). After at least 4 weeks of storage in liquid nitrogen (LN), straws were thawed and semen analysed by computer-assisted sperm analysis and flow cytometry (membrane lipid architecture (Merocyanine 540), integrity and sublethal damage (YoPro-1) and mitochondrial membrane potential (JC-1)). After thawing, better results were observed in samples frozen in 4%DMFA or in combinations of 1.5%GL-2.5%DMFA, in fact total motility increased by 16% in the 4%DMFA group compared to 2.5%GL (P < 0.05). Also, there was an increment in the percentage of progressive motile sperm in the 1.5%GL-2.5%DMFA group (9.8% 2.5GL vs 19% in the 1.5%GL-2.5%DMFA group p < 0.05); also, samples frozen in the 4%DMFA group had more intact (YoPro-1 negative) sperm post-thawing, 29.3% in 2.5%GL vs 36.7% in 4%DMFA group (p < 0.05). Membrane lipid architecture was not affected by any of the cryoprotectants tested, while samples frozen in 4%DFMA had a lower percentage of mitochondria with lower membrane potential. It is concluded that DMFA improves the outcome of cryopreservation of stallion spermatozoa mainly reducing sublethal cryodamage.

  18. 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

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

    PubMed

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

    2014-03-10

    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.

  20. Laboratory models available to study alcohol-induced organ damage and immune variations; choosing the appropriate model

    PubMed Central

    D’Souza El-Guindy, Nympha B.; Kovacs, Elizabeth J.; De Witte, Philippe; Spies, Claudia; Littleton, John M.; de Villiers, Willem J. S.; Lott, Amanda J.; Plackett, Timothy P.; Lanzke, Nadine; Meadows, Gary G.

    2010-01-01

    The morbidity and mortality resulting from alcohol-related diseases impose a substantive cost to society globally. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, researchers in the alcohol field are focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most is performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium “Methods of Ethanol Application in Alcohol Model – How Long is Long Enough” at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans. PMID:20586763

  1. Laboratory models available to study alcohol-induced organ damage and immune variations: choosing the appropriate model.

    PubMed

    D'Souza El-Guindy, Nympha B; Kovacs, Elizabeth J; De Witte, Philippe; Spies, Claudia; Littleton, John M; de Villiers, Willem J S; Lott, Amanda J; Plackett, Timothy P; Lanzke, Nadine; Meadows, Gary G

    2010-09-01

    The morbidity and mortality resulting from alcohol-related diseases globally impose a substantive cost to society. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, substantial research in the alcohol field is focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most studies are performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium "Methods of Ethanol Application in Alcohol Model-How Long is Long Enough" at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans.

  2. Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

    PubMed Central

    Held, Katherine S.; Steward, Oswald; Blanc, Caroline; Lane, Thomas E.

    2016-01-01

    Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un-injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4+ T lymphocyte proliferation and IFN-γ production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses. PMID:20832407

  3. 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.

  4. The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models.

    PubMed

    Revy, Patrick; Buck, Dietke; le Deist, Françoise; de Villartay, Jean-Pierre

    2005-01-01

    The immune system is the site of various genotoxic stresses that occur during its maturation as well as during immune responses. These DNA lesions/modifications are primarily the consequences of specific physiological processes such as the V(D)J recombination, the immunoglobulin class switch recombination (CSR), and the generation of somatic hypermutations (SHMs) within Ig variable domains. The DNA lesions can be introduced either by specific factors (RAG1 and RAG2 in the case of V(D)J recombination and AID in the case of CSR and SHM) or during the various phases of cellular proliferation and cellular activation. All these DNA lesions are taken care of by the diverse DNA repair machineries of the cell. Several animal models as well as human conditions have established the critical importance of these DNA lesions/modifications and their repair in the physiology of the immune system. Indeed their defects have consequences ranging from immune deficiency to development of immune malignancy. The survey of human pathology has been highly instrumental in the past in identifying key factors involved in the generation of DNA modifications (AID for the Ig CSR and generation of SHM) or the repair of specific DNA damages (Artemis for V(D)J recombination). Defects in factors involved in the cell cycle checkpoints following DNA damage also have deleterious consequences on the immune system. The continuous survey of human diseases characterized by primary immunodeficiency associated with increased sensitivity to ionizing radiation should help identify other important DNA repair factors essential for the development and maintenance of the immune system. PMID:16102576

  5. 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.

  6. 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

  7. PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

    SciTech Connect

    Lee, Seong-Ryong; Kim, Hahn-Young; Hong, Jung-Suk; Baek, Won-Ki; Park, Jong-Wook

    2009-02-27

    Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

  8. 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...

  9. Regular black tea habit could reduce tobacco associated ROS generation and DNA damage in oral mucosa of normal population.

    PubMed

    Pal, Debolina; Sur, Subhayan; Mandal, Shyamsundar; Das, Sukta; Panda, Chinmay Kumar

    2012-09-01

    Tobacco and tea habit are very common in world wide. In the present study, an attempt was made to evaluate the effect of regular drinking of black tea on reactive oxygen species (ROS) generation and DNA damage in buccal cells of normal subjects with or without tobacco habit. Expression of ROS associated proteins IκB, NF-κB as well as DNA repair associated proteins p53, MLH1 were also analyzed. Exfoliated buccal cells were collected from 308 healthy individuals and classified according to age, tobacco and tea habits. In all age groups, comparatively high ROS level and significantly high DNA damage frequency were seen in individuals with tobacco habit than the subjects without tea and tobacco habits. Tea habit effectively lowered ROS level and restrict DNA damage in tobacco users irrespective of ages. The DNA damage seen in the subjects was not associated with apoptosis. Moreover, tea habit effectively lowered the expression of IκB, NF-κB, p53 and MLH1 in tobacco users in all age groups. It seems that regular black tea habit could have anti-genotoxic effect as revealed by reduced tobacco associated ROS generation and DNA damage in buccal cells.

  10. PARP2 Is the Predominant Poly(ADP-Ribose) Polymerase in Arabidopsis DNA Damage and Immune Responses

    PubMed Central

    Song, Junqi; Keppler, Brian D.; Wise, Robert R.; Bent, Andrew F.

    2015-01-01

    Poly (ADP-ribose) polymerases (PARPs) catalyze the transfer of multiple poly(ADP-ribose) units onto target proteins. Poly(ADP-ribosyl)ation plays a crucial role in a variety of cellular processes including, most prominently, auto-activation of PARP at sites of DNA breaks to activate DNA repair processes. In humans, PARP1 (the founding and most characterized member of the PARP family) accounts for more than 90% of overall cellular PARP activity in response to DNA damage. We have found that, in contrast with animals, in Arabidopsis thaliana PARP2 (At4g02390), rather than PARP1 (At2g31320), makes the greatest contribution to PARP activity and organismal viability in response to genotoxic stresses caused by bleomycin, mitomycin C or gamma-radiation. Plant PARP2 proteins carry SAP DNA binding motifs rather than the zinc finger domains common in plant and animal PARP1 proteins. PARP2 also makes stronger contributions than PARP1 to plant immune responses including restriction of pathogenic Pseudomonas syringae pv. tomato growth and reduction of infection-associated DNA double-strand break abundance. For poly(ADP-ribose) glycohydrolase (PARG) enzymes, we find that Arabidopsis PARG1 and not PARG2 is the major contributor to poly(ADP-ribose) removal from acceptor proteins. The activity or abundance of PARP2 is influenced by PARP1 and PARG1. PARP2 and PARP1 physically interact with each other, and with PARG1 and PARG2, suggesting relatively direct regulatory interactions among these mediators of the balance of poly(ADP-ribosyl)ation. As with plant PARP2, plant PARG proteins are also structurally distinct from their animal counterparts. Hence core aspects of plant poly(ADP-ribosyl)ation are mediated by substantially different enzymes than in animals, suggesting the likelihood of substantial differences in regulation. PMID:25950582

  11. 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

  12. Association of postpartum maternal tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine administration and timeliness of infant immunization.

    PubMed

    Kaur, Ishminder; George, Krissa J; Pena-Ricardo, Carolina; Kelly, Barbara A; Watson, Barbara

    2013-11-01

    A retrospective cohort study was conducted on infants of mothers delivering at an inner-city hospital in October 2009 where postpartum maternal tetanus toxoid, reduced diptheria toxoid and acellular pertussis (Tdap) vaccination had been initiated in May 2008. We compared mothers and infants in a Tdap intervention group discharged July 2008 (n=250) with a pre-Tdap control group discharged July 2007 (n=238). Postpartum maternal Tdap impacted positively timeliness of early infant immunization.

  13. Study of biomaterial-induced macrophage activation, cell-mediated immune response and molecular oxidative damage in patients with dermal bioimplants.

    PubMed

    Sánchez, Olga; Rodríguez-Sureda, Víctor; Domínguez, Carmen; Fernández-Figueras, Teresa; Vilches, Angel; Llurba, Elisa; Alijotas-Reig, Jaume

    2012-01-01

    Several soft-tissue dermal fillers have been reported to provoke immunogenicity and may cause adverse reactions despite claims regarding their safety. This study aimed to assess biomaterial-induced macrophage activation, cell-mediated immune response and oxidative stress in 169 patients with dermal bioimplants. To this end, we analysed plasma concentrations of myeloperoxidase (MPO), the chitinase-like proteins chitotriosidase and YKL-40 and molecular oxidative damage. The present study shows, for the first time, that the components of innate immunity: chitotriosidase and YKL-40, are significantly higher in patients with certain bioimplants and these markers of monocyte/macrophage activation rose progressively as adverse reactions (AR) evolved. Plasma MPO levels increased 4-fold in filler users with AR and 3-fold in those without. Analysis by filler type showed subjects injected with calcium hydroxylapatite, methacrylate, acrylamides and silicone to have values significantly above those of non-filler subjects for at least two plasma biomarkers, probably because the afore-mentioned biomaterials are permanent and prone to trigger AR in the long term. By contrast, hyaluronic acid alone elicited little immune response. Plasma concentrations of markers of oxidative damage to lipids and proteins were found to be significantly higher in users of four of the nine dermal fillers studied. These diffusible products of molecular peroxidation would stem from the reaction catalysed by MPO that generates potent oxidants, leading to cell oxidative damage which, in turn, may exert deleterious effects on the organism. Overall, the results of this study on the effects of a range of dermal fillers point to chronic activation of the immune response mediated by macrophages and PMNs. The increases in plasma of MPO, chitotriosidase and YKL-40 proteins and products of macromolecular peroxidation suggests that these molecules could serve as blood-based biochemical markers and alert to the

  14. 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

  15. 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

  16. 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.

  17. 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

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

    SciTech Connect

    Petersen, J.C.; Plancher, H.

    1982-04-20

    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.

  19. 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.

  20. Pre-treatment with glutamine reduces genetic damage due to cancer treatment with cisplatin.

    PubMed

    Oliveira, R J; Sassaki, E S; Monreal, A C D; Monreal, M T F D; Pesarini, J R; Mauro, M O; Matuo, R; Silva, A F; Zobiole, N N; Siqueira, J M; Ribeiro, L R; Mantovani, M S

    2013-12-02

    Cisplatin is an effective antineoplastic drug. However, it provokes considerable collateral effects, including genotoxic and clastogenic activity. It has been reported that a diet rich in glutamine can help inhibit such collateral effects. We evaluated this activity in 40 Swiss mice, distributed into eight experimental groups: G1 - Control group (PBS 0.1 mL/10 g body weight); G2 - cisplatin group (cisplatin 6 mg/kg intraperitoneally); G3, G4, G5 - glutamine groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally); G6, G7, G8 - Pre-treatment groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally and cisplatin 6 mg/kg intraperitonially). For the micronucleus assay, samples of blood were collected (before the first use of the drugs at T0, then 24 (T1) and 48 (T2) hours after the first administration). For the comet assay, blood samples were collected only at T2. The damage reduction percentages for the micronucleus assay were 90.0, 47.3, and 37.3% at T1 and 46.0, 38.6, and 34.7% at T2, for G6, G7, and G8 groups, respectively. For the comet assay, the damage reduction percentages were 113.0, 117.4, and 115.0% for G6, G7, and G8, respectively. We conclude that glutamine is able to prevent genotoxic and clastogenic damages caused by cisplatin.

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

    PubMed

    Mabuchi, Yuko; Frankel, Theresa L

    2016-03-01

    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.

  3. 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.

  4. 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.

  5. 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

  6. Intermittent hypoxia reduces microglia proliferation and induces DNA damage in vitro

    PubMed Central

    Liu, Song; Wang, Zhonghua; Xu, Bo; Chen, Kui; Sun, Jinyuan; Ren, Lianping

    2016-01-01

    Objective(s): Intermittent hypoxia (IH), caused by obstructive sleep apnea (OSA), could cause hippocampus or neuron damage through multiple signaling pathways, while the underlying mechanisms are still unclear. Thus, the present study aimed to explore the effect of IH on the biological functions of microglia cells. Materials and Methods: Cell proliferation of BV2 cells after exposure to IH were observed by MTT assay and then DNA damage was detected by comet assay. RNA-sequencing assay was performed in cells under IH condition and normal conditions to find out the differentially expressed genes, which were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot assay. Results: As results, IH inhibited the proliferation of BV2 cells, as well as caused DNA damage. RNA-sequencing assay revealed 4 differentially expressed genes (p21, Cyclin D1, Cyclin E2, and Gadd45α) which were associated with the network of P53 signaling pathways in BV2 cells, among which, p21 and Gadd45α were dramatically increased while Cyclin D1 and Cyclin E2 were both decreased significantly. Moreover, inflammatory factors including IL-6, TNF-α and iNOS were significantly up-regulated in microglia cells under IH conditions for 8 hr. Conclusion: Our results indicated that IH could inhibit cyclin D1 and cyclin E2 expression via initiating multiple P53 pathways, which further blocked cell cycle transition and attenuated proliferative capability of BV2 cells. Meanwhile, IH activated inflammation reactions in BV2 cells. Present study elaborate the effects of IH on biological functions of microglia and provide theoretical foundation for further study on new therapy methods for OSA. PMID:27403256

  7. Norepinephrine Reduces Reactive Oxygen Species (ROS) and DNA Damage in Ovarian Surface Epithelial Cells

    PubMed Central

    Patel, Pooja R; Hegde, Muralidhar L; Theruvathu, Jacob; Mitra, Sankar A; Boldogh, Istvan; Sowers, Lawrence

    2015-01-01

    Objective To determine the role of norepinephrine (NE) on DNA damage and reactive oxygen species (ROS) generation in ovarian surface epithelial cells. Method Non-tumorigenic, immortalized ovarian surface epithelial cells were treated with NE, bleomycin, and bleomycin followed by NE. The comet assay was performed on each treatment group to determine the amount of single and double-strand breaks induced by treatments. ROS levels for each treatment group were measured using the H2DCF-DA fluorescence assay. Finally, RNA transcripts were measured for each treatment group with regards to the expression of DNA repair and oxidative stress genes. Results The mean tail moment of untreated cells was significantly greater than that of cells treated with NE (p=0.02). The mean tail moment of cells treated with bleomycin was significantly greater than that of cells treated with bleomycin followed by NE (p<0.01). Treatment with NE resulted in significantly less ROS generation than in untreated cells (p<0.01). NE treatment after hydrogen peroxide treatment resulted in a noticeable decrease in ROS generation. Genes associated with oxidative stress were upregulated in cells treated with bleomycin, however this upregulation was blunted when bleomycin-treated cells were treated subsequently with NE. Conclusion NE is associated with decreased DNA damage and ROS production in ovarian surface epithelial cells. This effect is protective in the presence of the oxidative-damaging agent bleomycin. These results suggest an additional physiologic role for the stress hormone NE, in protecting ovarian surface epithelial cells from oxidative stress. PMID:26167254

  8. Deferoxamine reduces tissue damage during endotoxin-induced mastitis in dairy cows.

    PubMed

    Lauzon, K; Zhao, X; Lacasse, P

    2006-10-01

    The protective effects of 3 antioxidants on polymorphonuclear neutrophil-induced damage to mammary cells were evaluated in vivo using an endotoxin-induced mastitis model. Fifteen healthy, midlactation cows with no history of clinical Escherichia coli mastitis were randomly assigned to 1 of the 3 treatment groups corresponding to each modulator to be evaluated, that is, deferoxamine, catechin, and glutathione ethyl ester. Each cow had 1 quarter infused with saline and 1 quarter infused with the selected modulator; a third quarter was infused with lipopolysaccharides (LPS), whereas the fourth quarter received a combination of LPS and the modulator. Infusion of LPS caused acute mastitis as determined by visual observations and by large increases in milk somatic cell count, BSA, and proteolytic activity. These parameters were not affected by antioxidant administration. The extent of cell damage was evaluated by measuring milk levels of lactate dehydrogenase and N-acetyl-beta-D-glucosaminidase activity. Levels of these parameters were several times higher after LPS administration. Intramammary infusions of catechin or glutathione ethyl ester did not exert any protective effect, whereas infusion of deferoxamine, a chelator of iron, decreased milk lactate dehydrogenase and NA-Gase activity, suggesting a protective effect against neutrophil-induced damage. The protective effect of deferoxamine was also evidenced by a lower milk level of haptoglobin. The proteolytic activity of mastitic milk was not influenced by the presence of deferoxamine. Overall, our results suggest that local infusion of deferoxamine may be an effective tool to protect mammary tissue against neutrophil-induced oxidative stress during bovine mastitis. PMID:16960060

  9. 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.

  10. Can mass trapping reduce thrips damage and is it economically viable? Management of the Western flower thrips in strawberry.

    PubMed

    Sampson, Clare; Kirk, William D J

    2013-01-01

    The western flower thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) is a cosmopolitan, polyphagous insect pest that causes bronzing to fruit of strawberry (Fragaria x ananassa). The main aim of this study was to test whether mass trapping could reduce damage and to predict whether this approach would be economically viable. In semi-protected strawberry crops, mass trapping of F. occidentalis using blue sticky roller traps reduced adult thrips numbers per flower by 61% and fruit bronzing by 55%. The addition of the F. occidentalis aggregation pheromone, neryl (S)-2-methylbutanoate, to the traps doubled the trap catch, reduced adult thrips numbers per flower by 73% and fruit bronzing by 68%. The factors affecting trapping efficiency through the season are discussed. Damage that would result in downgrading of fruit to a cheaper price occurred when bronzing affected about 10% of the red fruit surface. Cost-benefit analysis using this threshold showed that mass trapping of thrips using blue sticky roller traps can be cost-effective in high-value crops. The addition of blue sticky roller traps to an integrated pest management programme maintained thrips numbers below the damage threshold and increased grower returns by a conservative estimate of £2.2k per hectare. Further work is required to develop the F. occidentalis aggregation pheromone for mass trapping and to determine the best timing for trap deployment. Mass trapping of thrips is likely to be cost-effective in other countries and other high-value crops affected by F. occidentalis damage, such as cucumber and cut flowers. PMID:24282554

  11. Can Mass Trapping Reduce Thrips Damage and Is It Economically Viable? Management of the Western Flower Thrips in Strawberry

    PubMed Central

    Sampson, Clare; Kirk, William D. J.

    2013-01-01

    The western flower thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) is a cosmopolitan, polyphagous insect pest that causes bronzing to fruit of strawberry (Fragaria x ananassa). The main aim of this study was to test whether mass trapping could reduce damage and to predict whether this approach would be economically viable. In semi-protected strawberry crops, mass trapping of F. occidentalis using blue sticky roller traps reduced adult thrips numbers per flower by 61% and fruit bronzing by 55%. The addition of the F. occidentalis aggregation pheromone, neryl (S)-2-methylbutanoate, to the traps doubled the trap catch, reduced adult thrips numbers per flower by 73% and fruit bronzing by 68%. The factors affecting trapping efficiency through the season are discussed. Damage that would result in downgrading of fruit to a cheaper price occurred when bronzing affected about 10% of the red fruit surface. Cost-benefit analysis using this threshold showed that mass trapping of thrips using blue sticky roller traps can be cost-effective in high-value crops. The addition of blue sticky roller traps to an integrated pest management programme maintained thrips numbers below the damage threshold and increased grower returns by a conservative estimate of £2.2k per hectare. Further work is required to develop the F. occidentalis aggregation pheromone for mass trapping and to determine the best timing for trap deployment. Mass trapping of thrips is likely to be cost-effective in other countries and other high-value crops affected by F. occidentalis damage, such as cucumber and cut flowers. PMID:24282554

  12. Can mass trapping reduce thrips damage and is it economically viable? Management of the Western flower thrips in strawberry.

    PubMed

    Sampson, Clare; Kirk, William D J

    2013-01-01

    The western flower thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) is a cosmopolitan, polyphagous insect pest that causes bronzing to fruit of strawberry (Fragaria x ananassa). The main aim of this study was to test whether mass trapping could reduce damage and to predict whether this approach would be economically viable. In semi-protected strawberry crops, mass trapping of F. occidentalis using blue sticky roller traps reduced adult thrips numbers per flower by 61% and fruit bronzing by 55%. The addition of the F. occidentalis aggregation pheromone, neryl (S)-2-methylbutanoate, to the traps doubled the trap catch, reduced adult thrips numbers per flower by 73% and fruit bronzing by 68%. The factors affecting trapping efficiency through the season are discussed. Damage that would result in downgrading of fruit to a cheaper price occurred when bronzing affected about 10% of the red fruit surface. Cost-benefit analysis using this threshold showed that mass trapping of thrips using blue sticky roller traps can be cost-effective in high-value crops. The addition of blue sticky roller traps to an integrated pest management programme maintained thrips numbers below the damage threshold and increased grower returns by a conservative estimate of £2.2k per hectare. Further work is required to develop the F. occidentalis aggregation pheromone for mass trapping and to determine the best timing for trap deployment. Mass trapping of thrips is likely to be cost-effective in other countries and other high-value crops affected by F. occidentalis damage, such as cucumber and cut flowers.

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

    PubMed

    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

  14. Anthocyanin/polyphenolic-rich fruit juice reduces oxidative cell damage in an intervention study with patients on hemodialysis.

    PubMed

    Spormann, Thomas M; Albert, Franz W; Rath, Thomas; Dietrich, Helmut; Will, Frank; Stockis, Jean-Pierre; Eisenbrand, Gerhard; Janzowski, Christine

    2008-12-01

    Hemodialysis patients face an elevated risk of cancer, arteriosclerosis, and other diseases, ascribed in part to increased oxidative stress. Red fruit juice with high anthocyanin/polyphenol content had been shown to reduce oxidative damage in healthy probands. To test its preventive potential in hemodialysis patients, 21 subjects in a pilot intervention study consumed 200 mL/day of red fruit juice (3-week run-in; 4-week juice uptake; 3-week wash-out). Weekly blood sampling was done to monitor DNA damage (comet assay +/- formamidopyrimidine-DNA glycosylase enzyme), glutathione, malondialdehyde, protein carbonyls, trolox equivalent antioxidant capacity, triglycerides, and DNA binding capacity of the transcription factor nuclear factor-kappaB. Results show a significant decrease of DNA oxidation damage (P < 0.0001), protein and lipid peroxidation (P < 0.0001 and P < 0.001, respectively), and nuclear factor-kappaB binding activity (P < 0.01), and an increase of glutathione level and status (both P < 0.0001) during juice uptake. We attribute this reduction in oxidative (cell) damage in hemodialysis patients to the especially high anthocyanin/polyphenol content of the juice. This provides promising perspectives into the prevention of chronic diseases such as cancer and cardiovascular disease in population subgroups exposed to enhanced oxidative stress like hemodialysis patients.

  15. 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

  16. Ketoconazole-induced testicular damage in rats reduced by Gentiana extract.

    PubMed

    Amin, Amr

    2008-04-01

    Ketoconazole (KET) is an antifungal drug with a broad spectrum of activity that also induces reproductive toxicity in humans and animals. The protective effect of Gentiana (GEN) extract (Gentiana lutea) against KET-induced testicular damage was evaluated in male Wistar rats. GEN extract was administered orally (1g/kgbwt/day) for 26 days. Three weeks after extract administration, KET was co-administered intraperitoneally at a dose of 100mg/kg once a day for 5 days. KET-induced reproductive toxicity was associated with clear reductions of the weights of testes and epididymides, sperm indices and serum testosterone levels. KET also induced severe testicular histopathological lesions such as degeneration of the seminiferous tubules and depletion of germ cells. In addition, marked oxidative damage to testicular lipids and alterations of natural antioxidants (catalase (CAT) and superoxide dismutase (SOD)) were reported in association with KET toxicity. Most of the KET-induced effects were greatly decreased with the concomitant application of GEN extract. This study suggests a protective role of GEN extract that could be attributed to its antioxidant properties.

  17. The combination of naproxen and citral reduces nociception and gastric damage in rats.

    PubMed

    Ortiz, Mario I; Ramírez-Montiel, Martha L; González-García, Martha P; Ponce-Monter, Héctor A; Castañeda-Hernández, Gilberto; Cariño-Cortés, Raquel

    2010-10-01

    It has been shown that the association of non-steroidal anti-inflammatory drugs with plant extracts can increase their antinociceptive activity, allowing the use of lower doses and, thus, limiting side effects. Therefore, the aim of this study was to examine the effects of the interaction between naproxen and citral on nociception and gastric injury in rats. Naproxen, citral, or combinations of naproxen and citral produced an antinociceptive effect. The administration of naproxen produced significant gastric damage, but this effect was not obtained with either citral or the naproxen-citral combination. The ED(50) value was estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED(50) for the antinociceptive effect (423.8 mg/kg) was not significantly different from the observed experimental value (359.0 mg/kg); hence, the interaction between naproxen and citral mediating the antinociceptive effect is additive. These data suggest that the naproxen-citral combination interacts at the systemic level, produces minor gastric damage, and potentially has therapeutic advantages for the clinical treatment of inflammatory pain.

  18. 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.

  19. 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

  20. 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.

  1. 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. PMID:27293759

  2. 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.

  3. Pyruvate kinase M2 interacts with DNA damage-binding protein 2 and reduces cell survival upon UV irradiation.

    PubMed

    Xie, Xiao; Wang, Mingsong; Mei, Ju; Hu, Fengqing; Ding, Fangbao; Lv, Lei

    2015-11-13

    Pyruvate Kinase M2 (PKM2) is highly expressed in many solid tumors and associated with metabolism reprogramming and proliferation of tumors. Here, we report that PKM2 can bind to DNA Damage-Binding Protein 2 (DDB2), which is necessary for global nucleotide excision repair of UV induced DNA damage. The binding is promoted by UV irradiation and K433 acetylation of PKM2. Over expression of PKM2 facilitates phosphorylation of DDB2 and impairs DDB2-DDB1 binding. Furthermore, knocking down of PKM2 increases cell survival upon UV irradiation, while over expression of PKM2 reduces cell survival and over expression of DDB2-DDB1 reverts this effect. These results reveal a previously unknown regulation of PKM2 on DDB2 and provide a possible mechanism for UV induced tumorigenesis.

  4. [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.

  5. Vitamin d deficiency reduces the immune response, phagocytosis rate, and intracellular killing rate of microglial cells.

    PubMed

    Djukic, Marija; 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

    2014-06-01

    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

  6. 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

  7. Community empowerment to reduce childhood immunization disparities in New York City.

    PubMed

    Findley, Sally; Irigoyen, Matilde; Sanchez, Martha; Guzman, Letty; Mejia, Miriam; Sajous, Michelle; Levine, Deborah; Chimkin, Frank; Chen, Shaofu

    2004-01-01

    This paper reports on the impact of the community-based Start Right program on childhood immunization coverage in 2 communities of color in New York City. Fully launched in 2002, Start Right operates through the major social service programs of its 23 member organizations. Immunization promotion strategies are based on the following guiding principles: community leadership; integration with community programs; parental empowerment; peer health educators; tracking and feedback; and linkage with health providers. By September 2003, 2,433 children under age 5 years (14% of that age group in the community) were enrolled in Start Right. The rates for the cohort of children enrolled in 2003 were substantially higher than for those enrolled in 2002. Among the 2003 cohort of 19- to 35-month-old children, the coverage rate was 88%, significantly more than national rates: 75% for total population, 68% for African Americans, and 73% for Hispanics. The rate for our 2003 enrollment cohort exceeded the rate for New York City (78%) but did not exceed the New York City average for Hispanics (79%). Of the 2003 enrollment cohort, the Washington Heights children had the highest rates for enrollment (89.6%), exceeding New York City rates. Parents reported a high level of satisfaction with the program.

  8. 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.

  9. Immunization with chlamydial type III secretion antigens reduces vaginal shedding and prevents fallopian tube pathology following live C. muridarum challenge.

    PubMed

    Bulir, David C; Liang, Steven; Lee, Amanda; Chong, Sylvia; Simms, Elizabeth; Stone, Christopher; Kaushic, Charu; Ashkar, Ali; Mahony, James B

    2016-07-25

    Chlamydia trachomatis infections in women are often asymptomatic and if left untreated can lead to significant late sequelae including pelvic inflammatory disease and tubal factor infertility. Vaccine development efforts over the past three decades have been unproductive and there is no vaccine approved for use in humans. The existence of serologically distinct strains or serovars of C. trachomatis mandates a vaccine that will provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of both structural and effector proteins which is an essential virulence factor for infection and intracellular replication. In this study we evaluated a novel fusion protein antigen (BD584) which consists of three T3SS proteins from C. trachomatis (CopB, CopD, and CT584) as a potential chlamydial vaccine candidate. Intranasal immunization with BD584 elicited serum neutralizing antibodies that inhibited C. trachomatis infection in vitro. Following intravaginal challenge with C. muridarum, immunized mice had a 95% reduction in chlamydial shedding from the vagina at the peak of infection and cleared the infection sooner than control mice. Immunization with BD584 also reduced the rate of hydrosalpinx by 87.5% compared to control mice. Together, these results suggest that highly conserved proteins of the chlamydial T3SS may represent good candidates for a Chlamydia vaccine. PMID:27325352

  10. Curcumin reduces oxidative and nitrative DNA damage through balancing of oxidant-antioxidant status in hamsters infected with Opisthorchis viverrini.

    PubMed

    Pinlaor, Somchai; Yongvanit, Puangrat; Prakobwong, Suksanti; Kaewsamut, Butsara; Khoontawad, Jarinya; Pinlaor, Porntip; Hiraku, Yusuke

    2009-10-01

    Opisthorchis viverrini (OV) infection is endemic in northeastern Thailand. We have previously reported that OV infection induces oxidative and nitrative DNA damage via chronic inflammation, which contributes to the disease and cholangiocarcinogenesis. Here, we examined the effect of curcumin, an antioxidant, on pathogenesis in OV-infected hamsters. DNA lesions were detected by double immunofluorescence and the hepatic expression of oxidant-generating and antioxidant genes was assessed by quantitative RT-PCR analysis. Dietary 1.0% curcumin significantly decreased OV-induced accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative DNA lesion, and 8-nitroguanine, a nitrative DNA lesion, in the nucleus of bile duct epithelial and inflammatory cells. Expression of oxidant-generating genes (inducible nitric oxide synthase; iNOS, its nuclear transcriptional factor, NF-kappaB, and cyclooxygenase-2), and plasma levels of nitrate, malondialdehyde, and alanine aminotransferase, were also decreased in curcumin-treated group. In contrast, curcumin increased the mRNA expression of antioxidant enzymes (Mn-superoxide dismutase and catalase), and ferric-reducing anti-oxidant power in the plasma. In conclusion, curcumin reduced oxidative and nitrative DNA damage by suppression of oxidant-generating genes and enhancement of antioxidant genes, leading to inhibition of oxidative and nitrative stress. Therefore, curcumin may be used as a chemopreventive agent to reduce the severity of OV-associated diseases and the risk of cholangiocarcinoma (CCA).

  11. Epicatechin Reduces Striatal MPP+-Induced Damage in Rats through Slight Increases in SOD-Cu,Zn Activity

    PubMed Central

    Rubio-Osornio, M.; Gorostieta-Salas, E.; Montes, S.; Pérez-Severiano, F.; Rubio, C.; Gómez, C.; Ríos, C.; Guevara, J.

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder characterized by movement alterations caused by reduced dopaminergic neurotransmission in the nigrostriatal pathway, presumably by oxidative stress (OS). MPP+ intrastriatal injection leads to the overproduction of free radicals (FR). The increasing formation of FR produces OS, a decline in dopamine (DA) content, and behavioral disorders. Epicatechin (EC) has shown the ability to be FR scavenger, an antioxidant enzyme inductor, a redox state modulator, and transition metal chelator. Acute administration of 100 mg/kg of EC significantly prevented (P < 0.05) the circling MPP+-induced behavior (10 μg/8 μL). Likewise, EC significantly (P < 0.05) reduced the formation of fluorescent lipid products caused by MPP+. MPP+ injection produced (P < 0.05) increased enzymatic activity of the constitutive nitric oxide synthase (cNOS). This effect was blocked with acute EC pretreatment. Cu/Zn-dependent superoxide dismutase (Cu/Zn-SOD) activity was significantly (P < 0.05) reduced as a consequence of MPP+ damage. EC produced a slight increase (≈20%) in Cu/Zn-SOD activity in the control group. Such effects persisted in animals injured with MPP+. The results show that EC is effective against MPP+-induced biochemical and behavioral damage, which is possible by an increase in Cu/Zn-SOD activity. PMID:26301040

  12. Antioxidant-rich coffee reduces DNA damage, elevates glutathione status and contributes to weight control: results from an intervention study.

    PubMed

    Bakuradze, Tamara; Boehm, Nadine; Janzowski, Christine; Lang, Roman; Hofmann, Thomas; Stockis, Jean-Pierre; Albert, Franz W; Stiebitz, Herbert; Bytof, Gerhard; Lantz, Ingo; Baum, Matthias; Eisenbrand, Gerhard

    2011-05-01

    Epidemiological and experimental evidence increasingly suggests coffee consumption to be correlated to prevention or delay of degenerative diseases connected with oxidative cellular stress. In an intervention study comprising 33 healthy volunteers, we examined DNA-protective and antioxidative effects exerted in vivo by daily ingestion of 750 mL of freshly brewed coffee rich in both green coffee bean constituents as well as roast products. The study design encompassed an initial 4 wk of wash-out, followed by 4 wk of coffee intake and 4 wk of second wash-out. At the start and after each study phase blood samples were taken to monitor biomarkers of oxidative stress response. In addition, body weight/composition and intake of energy/nutrients were recorded. In the coffee ingestion period, the primary endpoint, oxidative DNA damage as measured by the Comet assay (± FPG), was markedly reduced (p<0.001). Glutathione level (p<0.05) and GSR-activity (p<0.01) were elevated. Body weight (p<0.01)/body fat (p<0.05) and energy (p<0.001)/nutrient (p<0.001-0.05) intake were reduced. Our results allow to conclude that daily consumption of 3-4 cups of brew from a special Arabica coffee exerts health beneficial effects, as evidenced by reduced oxidative damage, body fat mass and energy/nutrient uptake.

  13. DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication.

    PubMed

    Bristol, Molly L; Wang, Xu; Smith, Nathan W; Son, Minkyeong P; Evans, Michael R; Morgan, Iain M

    2016-01-01

    Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer. PMID:27338449

  14. DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication

    PubMed Central

    Bristol, Molly L.; Wang, Xu; Smith, Nathan W.; Son, Minkyeong P.; Evans, Michael R.; Morgan, Iain M.

    2016-01-01

    Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer. PMID:27338449

  15. Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage

    PubMed Central

    Purwantini, Endang; Mukhopadhyay, Biswarup

    2009-01-01

    In mycobacteria, F420, a deazaflavin derivative, acts as a hydride transfer coenzyme for an F420-specific glucose-6-phosphate dehydrogenase (Fgd). Physiologically relevant reactions in the mycobacteria that use Fgd-generated reduced F420 (F420H2) are unknown. In this work, F420H2 was found to be oxidized by NO only in the presence of oxygen. Further analysis demonstrated that NO2, produced from NO and O2, was the oxidant. UV-visible spectroscopic and NO-sensor-based analyses proved that F420H2 reduced NO2 to NO. This reaction could serve as a defense system for Mycobacterium tuberculosis, which is more sensitive to NO2 than NO under aerobic conditions. Activated macrophages produce NO, which in acidified phagosomes is converted to NO2. Hence, by converting NO2 back to NO with F420H2, M. tuberculosis could decrease the effectiveness of antibacterial action of macrophages; such defense would correspond to active tuberculosis conditions where the bacterium grows aerobically. This hypothesis was consistent with the observation that a mutant strain of Mycobacterium smegmatis, a nonpathogenic relative of M. tuberculosis, which either did not produce or could not reduce F420, was ≈4-fold more sensitive to NO2 than the wild-type strain. The phenomenon is reminiscent of the anticancer activity of γ-tocopherol, which reduces NO2 to NO and protects human cells from NO2-induced carcinogenesis. PMID:19325122

  16. Sublingual immunization with the phosphate-binding-protein (PstS) reduces oral colonization by Streptococcus mutans.

    PubMed

    Ferreira, E L; Batista, M T; Cavalcante, R C M; Pegos, V R; Passos, H M; Silva, D A; Balan, A; Ferreira, L C S; Ferreira, R C C

    2016-10-01

    Bacterial ATP-binding cassette (ABC) transporters play a crucial role in the physiology and pathogenicity of different bacterial species. Components of ABC transporters have also been tested as target antigens for the development of vaccines against different bacterial species, such as those belonging to the Streptococcus genus. Streptococcus mutans is the etiological agent of dental caries, and previous studies have demonstrated that deletion of the gene encoding PstS, the substrate-binding component of the phosphate uptake system (Pst), reduced the adherence of the bacteria to abiotic surfaces. In the current study, we generated a recombinant form of the S. mutans PstS protein (rPstS) with preserved structural features, and we evaluated the induction of antibody responses in mice after sublingual mucosal immunization with a formulation containing the recombinant protein and an adjuvant derived from the heat-labile toxin from enterotoxigenic Escherichia coli strains. Mice immunized with rPstS exhibited systemic and secreted antibody responses, measured by the number of immunoglobulin A-secreting cells in draining lymph nodes. Serum antibodies raised in mice immunized with rPstS interfered with the adhesion of bacteria to the oral cavity of naive mice challenged with S. mutans. Similarly, mice actively immunized with rPstS were partially protected from oral colonization after challenge with the S. mutans NG8 strain. Therefore, our results indicate that S. mutans PstS is a potential target antigen capable of inducing specific and protective antibody responses after sublingual administration. Overall, these observations raise interesting perspectives for the development of vaccines to prevent dental caries. PMID:26462737

  17. Reducing IRF-1 to Levels Observed in HESN Subjects Limits HIV Replication, But Not the Extent of Host Immune Activation.

    PubMed

    Su, Ruey-Chyi; Plesniarski, Andrew; Ao, Zhujun; Kimani, Joshua; Sivro, Aida; Jaoko, Walter; Plummer, Frank A; Yao, Xiaojian; Ball, Terry Blake

    2015-01-01

    Cells from women who are epidemiologically deemed resistant to HIV infection exhibit a 40-60% reduction in endogenous IRF-1 (interferon regulatory factor-1), an essential regulator of host antiviral immunity and the early HIV replication. This study examined the functional consequences of reducing endogenous IRF-1 on HIV-1 replication and immune response to HIV in natural HIV target cells. IRF-1 knockdown was achieved in ex vivo CD4(+) T cells and monocytes with siRNA. IRF-1 level was assessed using flow cytometry, prior to infection with HIV-Bal, HIV-IIIB, or HIV-VSV-G. Transactivation of HIV long terminal repeats was assessed by p24 secretion (ELISA) and Gag expression (reverse transcription-polymerase chain reaction (RT-PCR)). The expression of IRF-1-regulated antiviral genes was quantitated with RT-PCR. A modest 20-40% reduction in endogenous IRF-1 was achieved in >87% of ex vivo-derived peripheral CD4(+) T cells and monocytes, resulted in >90% reduction in the transactivation of the HIV-1 genes (Gag, p24) and, hence, HIV replication. Curiously, these HIV-resistant women demonstrated normal immune responses, nor an increased susceptibility to other infection. Similarly, modest IRF-1 knockdown had limited impact on the magnitude of HIV-1-elicited activation of IRF-1-regulated host immunologic genes but resulted in lessened duration of these responses. These data suggest that early expression of HIV-1 genes requires a higher IRF-1 level, compared to the host antiviral genes. Together, these provide one key mechanism underlying the natural resistance against HIV infection and further suggest that modest IRF-1 reduction could effectively limit productive HIV infection yet remain sufficient to activate a robust but transient immune response. PMID:26506037

  18. 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

  19. 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.

  20. 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

  1. Reduced 5-HT2A receptor signaling following selective bilateral amygdala damage

    PubMed Central

    Schlaepfer, Thomas E.; Matusch, Andreas; Reich, Harald; Shah, Nadim J.; Zilles, Karl; Maier, Wolfgang; Bauer, Andreas

    2009-01-01

    Neurobiological evidence implicates the amygdala as well as serotonergic (serotonin, 5-HT) signaling via postsynaptic 5-HT2A receptors as essential substrates of anxiety behaviors. Assuming a functional interdependence of these substrates, we hypothesized that a low-fear behavioral phenotype due to bilateral lesion of the amygdala would be associated with significant 5-HT2A receptor changes. Thus, we used [18F]altanserin positron emission tomography (PET) referenced to radioligand plasma levels and corrected for partial volume effects to quantify the spatial distribution of 5-HT2A receptor binding potential (BPP) in a rare patient with Urbach–Wiethe disease and selective bilateral amygdala calcification damage relative to 10 healthy control subjects. Consistent with our a priori hypothesis, we observed a 70% global decrease in 5-HT2A receptor BPP in the Urbach–Wiethe patient relative to controls. Thus, brain abnormalities in this patient are not restricted to the amygdala, but extend to overall 5-HT neurotransmission via 5-HT2A receptors. Our findings provide important insights into the molecular architecture of human anxiety behaviors and suggest the 5-HT2A receptor as a promising pharmacological target to control pathological anxiety. PMID:19015089

  2. 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. PMID:16485161

  3. 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.

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

    PubMed

    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

  5. alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes.

    PubMed

    Kadekaro, Ana Luisa; Kavanagh, Renny; Kanto, Hiromi; Terzieva, Silva; Hauser, Jennifer; Kobayashi, Nobuhiko; Schwemberger, Sandy; Cornelius, James; Babcock, George; Shertzer, Howard G; Scott, Glynis; Abdel-Malek, Zalfa A

    2005-05-15

    UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with alpha-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.

  6. 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

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

    PubMed

    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

  8. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury.

  9. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury. PMID:25424430

  10. 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.

  11. Prenatal lipopolysaccharide reduces motor activity after an immune challenge in adult male offspring.

    PubMed

    Kirsten, Thiago Berti; Taricano, Marina; Flório, Jorge Camilo; Palermo-Neto, João; Bernardi, Maria Martha

    2010-07-29

    Prenatal lipopolysaccharide (LPS) exposure causes reproductive, behavioral and neurochemical injuries in both the mother and pups. Previous investigations by our group showed that prenatal LPS administration (100 microg/kg, i.p.) on gestational day 9.5 impaired the male offspring's social behavior in infancy and adulthood. In the present study, we investigated whether these social behavioral changes were associated with motor activity impairment. Male rat pups treated prenatally with LPS or not were tested for reflexological development and open field general activity during infancy. In adulthood, animals were tested for open field general activity, haloperidol-induced catalepsy and apomorphine-induced stereotypy; striatal dopamine levels and turnover were also measured. Moreover, LPS-treated or untreated control pups were challenged with LPS in adulthood and observed for general activity in the open field. In relation to the control group, the motor behavior of prenatally treated male pups was unaffected at basal levels, both in infancy and in adulthood, but decreased general activity was observed in adulthood after an immune challenge. Also, striatal dopamine and metabolite levels were decreased in adulthood. In conclusion, prenatal LPS exposure disrupted the dopaminergic system involved with motor function, but this neurochemical effect was not accompanied by behavioral impairment, probably due to adaptive plasticity processes. Notwithstanding, behavioral impairment was revealed when animals were challenged with LPS, resulting in enhanced sickness behavior.

  12. Galactoxylomannan-mediated immunological paralysis results from specific B cell depletion in the context of widespread immune system damage

    PubMed Central

    De Jesus, Magdia; Nicola, André Moraes; Frases, Susana; Lee, Ian R.; Mieses, Steven; Casadevall, Arturo

    2009-01-01

    The mechanisms responsible for polysaccharide-induced immunological paralysis have remained unexplained almost a century after this phenomenon was first described. Cryptococcus neoformans capsular polysaccharides glucuronoxylomannan (GXM) and galactoxylomannan (GalXM) elicit little or no antibody responses. This study investigates the immunological and biological effects of GalXM in mice. GalXM immunization elicits a state of immunological paralysis in mice characterized by the disappearance of antibody-producing cells in the spleen. Immunological paralysis and lack of immunogenicity could not be overcome by immunization with GalXM conjugated to a protein carrier, Bacillus anthracis protective antigen. Additionally, immunization with GalXM in either complete or incomplete Freund's adjuvant was associated with spleen enlargement in Balb/c mice. Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) and flow cytometry revealed widespread apoptosis in the spleen after GalXM administration. Administration of a cocktail of Caspase-3 Inhibitor Z-DEVD-FMK and General Caspase Inhibitor Z-VAD-FMK or Fas-deficient mice abrogated the complete disappearance of antibody producing cells. Analysis of spleen cytokine expression in response to GalXM systemic injection revealed that GalXM down-regulated the production of inflammatory cytokines. Hence, we conclude that GalXM-induced immune paralysis is a result of specific B-cell depletion mediated by its pro-apoptotic properties in the context of widespread dysregulation of immune function. PMID:19684080

  13. Galactoxylomannan-mediated immunological paralysis results from specific B cell depletion in the context of widespread immune system damage.

    PubMed

    De Jesus, Magdia; Nicola, André Moraes; Frases, Susana; Lee, Ian R; Mieses, Steven; Casadevall, Arturo

    2009-09-15

    The mechanisms responsible for polysaccharide-induced immunological paralysis have remained unexplained almost a century after this phenomenon was first described. Cryptococcus neoformans capsular polysaccharides glucuronoxylomannan and galactoxylomannan (GalXM) elicit little or no Ab responses. This study investigates the immunological and biological effects of GalXM in mice. GalXM immunization elicits a state of immunological paralysis in mice characterized by the disappearance of Ab-producing cells in the spleen. Immunological paralysis and lack of immunogenicity could not be overcome by immunization with GalXM conjugated to a protein carrier, Bacillus anthracis protective Ag. Additionally, immunization with GalXM in either complete or IFA was associated with spleen enlargement in BALB/c mice. TUNEL and flow cytometry revealed widespread apoptosis in the spleen after GalXM administration. Administration of a cocktail of caspase-3 inhibitor Z-DEVD-FMK and general caspase inhibitor Z-VAD-FMK or Fas-deficient mice abrogated the complete disappearance of Ab-producing cells. Analysis of spleen cytokine expression in response to GalXM systemic injection revealed that GalXM down-regulated the production of inflammatory cytokines. Hence, we conclude that GalXM-induced immune paralysis is a result of specific B cell depletion mediated by its proapoptotic properties in the context of widespread dysregulation of immune function.

  14. Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/K(ATP) signaling pathway.

    PubMed

    Silva, Renan O; Lucetti, Larisse T; Wong, Deysi V T; Aragão, Karoline S; Junior, Eudmar M A; Soares, Pedro M G; Barbosa, André Luiz R; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Medeiros, Jand-Venes R

    2014-08-31

    Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, L-arginine (L-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with L-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400 W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or L-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and L-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or L-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and L-Arg. L-NAME, 1400 W, or L-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.

  15. Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

    PubMed Central

    Leak, Rehana K.; Li, Peiying; Zhang, Feng; Sulaiman, Hassan H.; Weng, Zhongfang; Wang, Guohua; Stetler, R. Anne; Shi, Yejie; Cao, Guodong

    2015-01-01

    Abstract Aims: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI). Results: Upregulation of APE1 by low-dose proton irradiation (PI) or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced after tGCI, and this effect was blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. Innovation: This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact. Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury. Antioxid. Redox Signal. 22, 135–148. PMID:24180454

  16. Ginsenoside-Rb2 displays anti-osteoporosis effects through reducing oxidative damage and bone-resorbing cytokines during osteogenesis.

    PubMed

    Huang, Qiang; Gao, Bo; Jie, Qiang; Wei, Bo-Yuan; Fan, Jing; Zhang, Hong-Yang; Zhang, Jin-Kang; Li, Xiao-Jie; Shi, Jun; Luo, Zhuo-Jing; Yang, Liu; Liu, Jian

    2014-09-01

    Reactive oxygen species (ROS) are a significant pathogenic factor of osteoporosis. Ginsenoside-Rb2 (Rb2), a 20(S)-protopanaxadiol glycoside extracted from ginseng, is a potent antioxidant that generates interest regarding the bone metabolism area. We tested the potential anti-osteoporosis effects of Rb2 and its underlying mechanism in this study. We produced an oxidative damage model induced by hydrogen peroxide (H2O2) in osteoblastic MC3T3-E1 cells to test the essential anti-osteoporosis effects of Rb2in vitro. The results indicated that treatment of 0.1 to 10μM Rb2 promoted the proliferation of MC3T3-E1 cells, improved alkaline phosphatase (ALP) expression, elevated calcium mineralization and mRNA expressions of Alp, Col1a1, osteocalcin (Ocn) and osteopontin (Opn) against oxidative damage induced by H2O2. Importantly, Rb2 reduced the expression levels of receptor activator of nuclear factor kappa-B ligand (RANKL) and IL-6 and inhibited the H2O2-induced production of ROS. The in vivo study indicated that the Rb2 administered for 12weeks partially decreased blood malondialdehyde (MDA) activity and elevated the activity of reduced glutathione (GSH) in ovariectomized (OVX) mice. Moreover, Rb2 improved the micro-architecture of trabecular bones and increased bone mineral density (BMD) of the 4th lumbar vertebrae (L4) and the distal femur. Altogether, these results demonstrated that the potential anti-osteoporosis effects of Rb2 were linked to a reduction of oxidative damage and bone-resorbing cytokines, which suggests that Rb2 might be effective in preventing and alleviating osteoporosis. PMID:24933344

  17. Andrographolide interferes quorum sensing to reduce cell damage caused by avian pathogenic Escherichia coli.

    PubMed

    Guo, Xun; Zhang, Li-Yan; Wu, Shuai-Cheng; Xia, Fang; Fu, Yun-Xing; Wu, Yong-Li; Leng, Chun-Qing; Yi, Peng-Fei; Shen, Hai-Qing; Wei, Xu-Bin; Fu, Ben-Dong

    2014-12-01

    Avian pathogenic Escherichia coli (APEC) induce septicemia in chickens by invading type II pneumocytes to breach the blood-air barrier. The virulence of APEC can be regulated by quorum sensing (QS). Andrographolide is a QS inhibitor of Pseudomonas aeruginosa (P. aeruginosa). Therefore, we investigate whether andrographolide inhibits the injury of chicken type II pneumocytes by avian pathogenic E. coli O78 (APEC-O78) by disrupting the bacterial QS system. The results showed that sub-MIC of andrographolide significantly reduced the release of lactate dehydrogenase (LDH), F-actin cytoskeleton polymerization, and the degree of the adherence to chicken type II pneumocytes induced by APEC-O78. Further, we found that andrographolide significantly decreased the autoinducer-2 (AI-2) activity and the expression of virulence factors of APEC-O78. These results suggest that andrographolide reduce the pathogenicity of APEC-O78 in chicken type II pneumocytes by interfering QS and decreasing virulence. These results provide new evidence for colibacillosis prevention methods in chickens.

  18. Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss.

    PubMed

    Le Prell, Colleen G; Gagnon, Patricia M; Bennett, David C; Ohlemiller, Kevin K

    2011-07-01

    Oxidative stress has been implicated broadly 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, which were 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 with 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 toward less noise-induced loss in strial cell density in animals maintained on the supplemented diet. Taken together, our data suggest that prenoise oral treatment with the high-nutrient diet can protect cells in the inner ear and reduce PTS in mice. The demonstration of functional and morphologic 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

  19. 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

  20. Administration of PPARβ/δ agonist reduces copper-induced liver damage in mice: possible implications in clinical practice.

    PubMed

    Sanchez-Siles, Alvaro A; Ishimura, Norihisa; Rumi, Mohammad A K; Tamagawa, Yuji; Ito, Satoko; Ishihara, Shunji; Nabika, Toru; Kinoshita, Yoshikazu

    2011-07-01

    In this study we investigated if peroxisome proliferator-activated receptor β/δ activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor α and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2'-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor β/δ agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor α, macrophage inflammatory protein-2 and 8-hydroxy-2'-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor β/δ antagonist GSK0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor β/δ expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferator-activated receptor β/δ activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor β/δ agonists could become useful in the management of copper-induced liver damage.

  1. 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. PMID:25339633

  2. Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats.

    PubMed

    Chtourou, Y; Garoui, Em; Boudawara, T; Zeghal, N

    2013-01-01

    Oxidative stress has been proposed as a possible mechanism involved in manganese (Mn) toxicity. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. The present study investigated the beneficial role of silymarin, a natural flavonoid, in Mn-induced hepatotoxicity focusing on histopathology and biochemical approaches. Male Wistar rats were exposed orally to manganese chloride (20 mg/mL) for 30 days followed by intraperitoneal cotreatment with silymarin (100 mg/kg). Exposure to Mn resulted in a significant elevation of the plasma marker enzyme activities and bilirubin level related to liver dysfunction of reactive oxygen species (ROS) production and hepatic oxidative stress indices. This metal reduced the activities of superoxide dismutase, catalase and glutathione peroxidase and nonenzymatic antioxidant levels such as reduced glutathione, total sulfhydryl groups and vitamin C. In addition, it caused hepatic hemorrhage, cellular degeneration and necrosis of hepatocytes as indicated by liver histopathology and DNA fragmentation studies. Coadministration of silymarin alleviated Mn oxidative damage effects by inhibiting ROS generation. Histological studies also supported the beneficial role of silymarin against Mn-induced hepatic damages. Combining all, results suggested that silymarin could protect hepatic tissues against Mn-induced oxidative stress probably through its antioxidant activity. Therefore, its supplementation could provide a new approach for the reduction in hepatic complication due to Mn poisoning.

  3. 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.

  4. 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. PMID:19558415

  5. 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.

  6. 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

  7. Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

    PubMed Central

    Wroblewska, Aleksandra; van Haren, Simon D.; Herczenik, Eszter; Kaijen, Paul; Ruminska, Aleksandra; Jin, Sheng-Yu; Zheng, X. Long; van den Biggelaar, Maartje; ten Brinke, Anja; Meijer, Alexander B.

    2012-01-01

    Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4+ T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. PMID:22498747

  8. Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice.

    PubMed

    Wroblewska, Aleksandra; van Haren, Simon D; Herczenik, Eszter; Kaijen, Paul; Ruminska, Aleksandra; Jin, Sheng-Yu; Zheng, X Long; van den Biggelaar, Maartje; ten Brinke, Anja; Meijer, Alexander B; Voorberg, Jan

    2012-05-31

    Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. PMID:22498747

  9. Osmoconditioning reduces physiological and biochemical damage induced by chilling in soybean seeds.

    PubMed

    Posmyk, Malgorzata Maria; Corbineau, Françoise; Vinel, Dominique; Bailly, Christophe; Côme, Daniel

    2001-04-01

    The aim of the present work was to investigate the effects of osmoconditioning on chilling injury in soybean (Glycine max (L.) Merr.) seeds during imbibition. Soybean seeds germinated readily over a large range of temperatures (10-35 degrees C), the thermal optimum being 25-30 degrees C. Low temperatures reduced the germination rate and no seed germinated at 1 degrees C. Pre-treatment of seeds at 1 degrees C reduced further germination at the optimal temperature (25 degrees C). This deleterious effect of chilling increased with duration of the treatment, and was maximal after 4 days. Osmoconditioning of seeds at 20 degrees C with a polyethylene glycol-8000 solution at -1.5 MPa for at least 24 h followed by drying back the seeds to their initial moisture content reduced their chilling sensitivity and even allowed germination at 1 degrees C. Chilling of control seeds resulted in a sharp decline in in vivo ACC-dependent ethylene production and in an increase in electrolyte leakage in the medium, which indicated deterioration of membrane properties. Osmoconditioned seeds placed at 1 degrees C did not show any reduction in their ability to convert ACC to ethylene nor any strong increase in electrolyte leakage. Imbibition of both control and osmoconditioned seeds at 1 degrees C resulted in a marked increase in ATP level (more than 50% of the total nucleotides) and energy charge; however, the latter cannot be considered as an indicator of chilling since it remained high (0.74-0.88) throughout the cold treatment. Chilling treatment longer than 6 days induced accumulation of malondialdehyde in the embryonic axis, which was more marked in control seeds than in osmoconditioned seeds, suggesting that chilling sensitivity was associated with lipid peroxidation. Imbibition of seeds at 1 degrees C resulted in an increase in superoxide dismutase, catalase and glutathione reductase activity, which was generally higher in osmoconditioned seeds than in control ones. This stimulation

  10. High dietary protein exacerbates hypertension and renal damage in Dahl SS rats by increasing infiltrating immune cells in the kidney.

    PubMed

    De Miguel, Carmen; Lund, Hayley; Mattson, David L

    2011-02-01

    The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153 ± 7 mm Hg and 8.0 ± 2.4, respectively) compared to rats fed normal protein (132 ± 3 mm Hg, 1.2 ± 0.3) or low-protein (132 ± 6 mm Hg, 0.3 ± 0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9 ± 3 × 10⁵ cells) than in rats fed the low-protein diet (9.1 ± 3 × 10⁵ cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9 ± 2.7 to 10.6 ± 2.0 × 10⁵ cells) while decreasing blood pressure (from 133 ± 3 to 113 ± 4 mm Hg) and the albumin/creatinine ratio (from 10.9 ± 2.3 to 5.4 ± 1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake.

  11. 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

  12. 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.

  13. 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

    2013-05-01

    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.

  14. mTOR Inhibition Improves Anaemia and Reduces Organ Damage in a Murine Model of Sickle Cell Disease

    PubMed Central

    Wang, Jintao; Tran, Jennifer; Wang, Hui; Guo, Chiao; Harro, David; Campbell, Andrew D.; Eitzman, Daniel T.

    2016-01-01

    Summary Mechanistic target of rapamycin (mTOR) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease (SCD), mice with SCD were treated with the dual mTORC1/2 inhibitor, INK128. 1 week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD. PMID:27030515

  15. 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

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

    PubMed

    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

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

    PubMed

    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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26439902

  19. HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity

    PubMed Central

    Li, Yang; Yang, Yue-Feng; Xiao, Feng-Jun; Zhang, Yi-Kun; Wang, Shao-Xia; Sun, Hui-Yan; Zhang, Qun-Wei; Wu, Chu-Tse; Wang, Li-Sheng

    2015-01-01

    Background Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII). Methods Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis. Results The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer’s patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells. Conclusions Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII

  20. 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.

  1. 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

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

    PubMed

    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

  3. Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage.

    PubMed

    Ning, Yi-Chun; Cai, Guang-Yan; Zhuo, Li; Gao, Jian-Jun; Dong, Dan; Cui, Shaoyuan; Feng, Zhe; Shi, Suo-Zhu; Bai, Xue-Yuan; Sun, Xue-Feng; Chen, Xiang-Mei

    2013-01-01

    To explore the effect of short-term calorie restriction (CR) on renal aging, 8-week CR with 60% of the food intake of the ad libitum group was administered in 25-month-old male Sprague-Dawley rats. Aged rats subjected to short-term CR had lower body weight, level of triglycerides and ratio of urine protein to urine creatinine, respectively. Short-term CR blunted the increased glomerular volume, the degree of fibrosis, p16 and the positive rate of senescence-associated β-galactosidase staining of the kidneys in old ad libitum group. Light chain 3/Atg8 as an autophagy marker exhibited a marked decline in aged kidneys, which was increased by short-term CR. The levels of p62/SQSTM1 and polyubiquitin aggregates, which were increased in older kidneys, were blunted by short-term CR. Short-term CR retarded the level of 8-hydroxydeoxyguanosine, a marker of mitochondrial DNA oxidative damage. Moreover, we found an increased level of SIRT1 and AMPK, and a decreased level of mTOR in aged kidneys after short-term CR. These results suggested that short-term CR could be considered as a potential intervention for retardation of renal senescence by increasing autophagy and subsequently reducing oxidative damage. Three master regulators of energy metabolism, SIRT1, AMPK and mTOR are associated with these effects.

  4. 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

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

    PubMed

    Pedersen, Rune Troelsgaard; Kruse, Thomas; Nilsson, Jakob; Oestergaard, Vibe H; Lisby, Michael

    2015-08-17

    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.

  6. Use of predator odors as repellents to reduce feeding damage by herbivores : II. Black-tailed deer (Odocoileus hemionus columbianus).

    PubMed

    Sullivan, T P; Nordstrom, L O; Sullivan, D S

    1985-07-01

    The effectiveness of predator odors (fecal and urine) in suppressing feeding damage by black-tailed deer was investigated in pen bioassays at the University of British Columbia Research Forest, Maple Ridge, British Columbia, Canada. A total of eight bioassay trials tested the effects of these odors on deer consumption of salal leaves and coniferous seedlings. Cougar, coyote,and wolf feces as well as coyote, wolf, fox, wolverine, lynx, and bobcat urines provided the most effective suppression of deer feeding damage. Novel odors of ammonia and human urine did not reduce feeding. Predator fecal odor formulations in direct foliar application, adhesive application, and in plastic vials were all effective in suppressing deer feeding. Of all urines tested, coyote provided the most consistent suppression of deer browsing on salal. Deer consumed significantly more untreated Douglas fir and western red cedar seedlings than those protected by coyote urine odor. The active repellent components of predator odors which suppress deer feeding may be suitable for encapsulation in controlled-release devices which could provide long-term protection for forest and agricultural crops.

  7. 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.

  8. Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid.

    PubMed

    Gatei, M; Shkedy, D; Khanna, K K; Uziel, T; Shiloh, Y; Pandita, T K; Lavin, M F; Rotman, G

    2001-01-18

    Cells from patients with the genetic disorder ataxia-telangiectasia (A-T) are hypersensitive to ionizing radiation and radiomimetic agents, both of which generate reactive oxygen species capable of causing oxidative damage to DNA and other macromolecules. We describe in A-T cells constitutive activation of pathways that normally respond to genotoxic stress. Basal levels of p53 and p21(WAF1/CIP1), phosphorylation on serine 15 of p53, and the Tyr15-phosphorylated form of cdc2 are chronically elevated in these cells. Treatment of A-T cells with the antioxidant alpha-lipoic acid significantly reduced the levels of these proteins, pointing to the involvement of reactive oxygen species in their chronic activation. These findings suggest that the absence of functional ATM results in a mild but continuous state of oxidative stress, which could account for several features of the pleiotropic phenotype of A-T.

  9. 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. PMID:14680076

  10. 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.

  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. 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

  13. 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.

  14. Reduced immune responsiveness and lymphoid depletion in mice infected with Ehrlichia risticii.

    PubMed Central

    Rikihisa, Y; Johnson, G C; Burger, C J

    1987-01-01

    The histopathology of the thymus and spleen and the response of spleen cells to mitogenic stimuli were evaluated in Sprague-Dawley CF-1 mice infected with Ehrlichia risticii. Intraperitoneal injection of 10(4) or 10(6) E. risticii-infected U-937 cells into mice resulted in 100% morbidity and partial mortality. Thymic atrophy became significant between 1 and 2 weeks postinfection and remained for the duration of the study. The atrophy appeared associated with antecedent destruction and rarefaction of lymphocytes, resulting in the loss of corticomedullary demarcation. Splenomegaly was prominent; significantly increased weights were detected 7 days postinfection. Histopathologic examination revealed rarefaction of lymphocytes around central arteries, the presence of necrotic debris in histiocytes, and replacement of erythropoiesis by granulopoiesis in the red pulp. Marked and acute reduction of in vitro proliferative responses of spleen cells to concanavalin A (ConA) and phytohemagglutinin were observed in mice infected with 10(4) or 10(6) E. risticii-infected U-937 cells. Interleukin-2 activity in the supernatant of ConA-stimulated spleen cells was also severely reduced. Both changes were time- and dose-dependent and were not associated with decreased spleen cell viability. Neither morbidity nor mortality occurred in mice infected with 10(2) E. risticii-infected U-937 cells. Although there was temporal reduction in phytohemagglutinin-driven lymphocyte proliferation, reduction in neither ConA-driven lymphocyte proliferation nor interleukin-2 activity was observed with this dosage. All E. risticii-inoculated mice seroconverted between days 18 and 25, as detected by the indirect fluorescent-antibody procedure. The findings indicate for the first time the hypoimmune responsiveness and histopathologic changes in lymphoid organs associated with E. risticii infection. Images PMID:3497879

  15. 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.

  16. 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. PMID:25841250

  17. Chronic caloric restriction reduces tissue damage and improves spatial memory in a rat model of traumatic brain injury.

    PubMed

    Rich, Nicholas J; Van Landingham, Jacob W; Figueiroa, Silvia; Seth, Rohit; Corniola, Rikki S; Levenson, Cathy W

    2010-10-01

    Although it has been known for some time that chronic caloric or dietary restriction reduces the risk of neurodegenerative disorders and injury following ischemia, the possible role of chronic restriction in improving outcomes after traumatic brain injury (TBI) has not been previously studied. Therefore, 2-month-old male Sprague-Dawley rats were divided into two dietary groups, an ad libitum fed group (AL) and a caloric-restriction group (CR) that was provided with 70% of the food intake of AL rats (n = 10/group). After 4 months, a weight-drop device (300 g) was used to produce a 2-mm bilateral medial frontal cortex contusion following craniotomy. Additional animals in each dietary group (n = 10) were used as sham-operated controls. The CR diet resulted in body weights that were reduced by 30% compared with AL controls. Not only did CR decrease the size of the cortical lesion after injury, there were marked improvements in spatial memory as measured by Morris water maze that included an increase in the number of animals successfully finding the platform as well as significantly reduced time to finding the hidden platform. Western analysis, used to examine the expression of proteins that play a role in neuronal survival, revealed significant increases in brain-derived neurotrophic factor (BDNF) in the cortical region around the site of injury and in the hippocampus in CR rats after injury. These findings suggest that molecular mechanisms involved in cell survival may play a role in reducing tissue damage and improving cognition after TBI and that these mechanisms can be regulated by dietary interventions. PMID:20544832

  18. Immune Mechanisms in Arterial Hypertension.

    PubMed

    Wenzel, Ulrich; Turner, Jan Eric; Krebs, Christian; Kurts, Christian; Harrison, David G; Ehmke, Heimo

    2016-03-01

    Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to hemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign organisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Renal inflammation results in injury and impaired urinary sodium excretion, and vascular inflammation leads to endothelial dysfunction, increased vascular resistance, and arterial remodeling and stiffening. Notably, modulation of the immune response can reduce the severity of BP elevation and hypertensive end-organ damage in several animal models. Indeed, recent studies have improved our understanding of how the immune response affects the pathogenesis of arterial hypertension, but the remarkable advances in basic immunology made during the last few years still await translation to the field of hypertension. This review briefly summarizes recent advances in immunity and hypertension as well as hypertensive end-organ damage.

  19. 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. PMID:27133563

  20. The Potential of Five Winter-grown Crops to Reduce Root-knot Nematode Damage and Increase Yield of Tomato

    PubMed Central

    López-Pérez, Jose Antonio; Roubtsova, Tatiana; de Cara García, Miguel

    2010-01-01

    Broccoli (Brassica oleracea), carrot (Daucus carota), marigold (Tagetes patula), nematode-resistant tomato (Solanum lycopersicum), and strawberry (Fragaria ananassa) were grown for three years during the winter in a root-knot nematode (Meloidogyne incognita) infested field in Southern California. Each year in the spring, the tops of all crops were shredded and incorporated in the soil. Amendment with poultry litter was included as a sub-treatment. The soil was then covered with clear plastic for six weeks and M. incognita-susceptible tomato was grown during the summer season. Plastic tarping raised the average soil temperature at 13 cm depth by 7°C.The different winter-grown crops or the poultry litter did not affect M. incognita soil population levels. However, root galling on summer tomato was reduced by 36%, and tomato yields increased by 19% after incorporating broccoli compared to the fallow control. This crop also produced the highest amount of biomass of the five winter-grown crops. Over the three-year trial period, poultry litter increased tomato yields, but did not affect root galling caused by M. incognita. We conclude that cultivation followed by soil incorporation of broccoli reduced M. incognita damage to tomato. This effect is possibly due to delaying or preventing a portion of the nematodes to reach the host roots. We also observed that M. incognita populations did not increase under a host crop during the cool season when soil temperatures remained low (< 18°C). PMID:22736848

  1. 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.

  2. 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

  3. 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

  4. Disturbance of the immune system by electromagnetic fields-A potentially underlying cause for cellular damage and tissue repair reduction which could lead to disease and impairment.

    PubMed

    Johansson, Olle

    2009-08-01

    A number of papers dealing with the effects of modern, man-made electromagnetic fields (EMFs) on the immune system are summarized in the present review. EMFs disturb immune function through stimulation of various allergic and inflammatory responses, as well as effects on tissue repair processes. Such disturbances increase the risks for various diseases, including cancer. These and the EMF effects on other biological processes (e.g. DNA damage, neurological effects, etc.) are now widely reported to occur at exposure levels significantly below most current national and international safety limits. Obviously, biologically based exposure standards are needed to prevent disruption of normal body processes and potential adverse health effects of chronic exposure. Based on this review, as well as the reviews in the recent Bioinitiative Report [http://www.bioinitiative.org/] [C.F. Blackman, M. Blank, M. Kundi, C. Sage, D.O. Carpenter, Z. Davanipour, D. Gee, L. Hardell, O. Johansson, H. Lai, K.H. Mild, A. Sage, E.L. Sobel, Z. Xu, G. Chen, The Bioinitiative Report-A Rationale for a Biologically-based Public Exposure Standard for Electromagnetic Fields (ELF and RF), 2007)], it must be concluded that the existing public safety limits are inadequate to protect public health, and that new public safety limits, as well as limits on further deployment of untested technologies, are warranted.

  5. 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. PMID:26906265

  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. Nest-building behavior of Monk Parakeets and insights into potential mechanisms for reducing damage to utility poles

    PubMed Central

    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. PMID:25289186

  8. 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.

  9. 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.

  10. 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

  11. Machine perfusion at 20°C reduces preservation damage to livers from non-heart beating donors.

    PubMed

    Ferrigno, Andrea; Rizzo, Vittoria; Boncompagni, Eleonora; Bianchi, Alberto; Gringeri, Enrico; Neri, Daniele; Richelmi, Plinio; Freitas, Isabel; Cillo, Umberto; Vairetti, Mariapia

    2011-04-01

    We previously reported that machine perfusion (MP) performed at 20°C enhanced the preservation of steatotic rat livers. Here, we tested whether rat livers retrieved 30 min after cardiac arrest (NHBDs) were better protected by MP at 20°C than with cold storage. We compared the recovery of livers from NHBDs with organs obtained from heart beating donors (HBDs) preserved by cold storage. MP technique: livers were perfused for 6h with UW-G modified at 20°C. Cold storage: livers were perfused in situ and preserved with UW solution at 4°C for 6h. Both MP and cold storage preserved livers were reperfused with Krebs-Heinselet buffer (2h at 37°C). AST and LDH release and mitochondrial glutamate dehydrogenase (GDH) levels were evaluated. Parameters assessed included: bile production and biliary enzymes; tissue ATP; reduced and oxidized glutathione (GSH/GSSG); protein-SH group concentration. Livers preserved by MP at 20°C showed significantly lower hepatic damage at the end of reperfusion compared with cold storage. GDH release was significantly reduced and bile production, ATP levels, GSH/GSSG and protein-SH groups were higher in livers preserved by MP at 20°C than with cold storage. The best preserved morphology and high glycogen content was obtained with livers submitted to MP at 20°C. Liver recovery using MP at 20°C was comparable to recovery with HBDs. MP at 20°C improves cell survival and gives a better-quality of preservation for livers obtained from NHBDs and may provide a new method for the successful utilization of marginal livers.

  12. Galvanic zinc-copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin.

    PubMed

    Kaur, Simarna; Lyte, Peter; Garay, Michelle; Liebel, Frank; Sun, Ying; Liu, Jue-Chen; Southall, Michael D

    2011-10-01

    The human body has its own innate electrical system that regulates the body's functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn-Cu induced the electrical potential recorded on intact skin, enhanced H(2)O(2) production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn-Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn-Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn-Cu exerted its inflammatory effects. Topical application of Zn-Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn-Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn-Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin. PMID:21465312

  13. Galvanic zinc-copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin.

    PubMed

    Kaur, Simarna; Lyte, Peter; Garay, Michelle; Liebel, Frank; Sun, Ying; Liu, Jue-Chen; Southall, Michael D

    2011-10-01

    The human body has its own innate electrical system that regulates the body's functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn-Cu induced the electrical potential recorded on intact skin, enhanced H(2)O(2) production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn-Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn-Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn-Cu exerted its inflammatory effects. Topical application of Zn-Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn-Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn-Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.

  14. 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.

  15. Exercise-induced muscle damage is reduced in resistance-trained males by branched chain amino acids: a randomized, double-blind, placebo controlled study

    PubMed Central

    2012-01-01

    Background It is well documented that exercise-induced muscle damage (EIMD) decreases muscle function and causes soreness and discomfort. Branched-chain amino acid (BCAA) supplementation has been shown to increase protein synthesis and decrease muscle protein breakdown, however, the effects of BCAAs on recovery from damaging resistance training are unclear. Therefore, the aim of this study was to examine the effects of a BCAA supplementation on markers of muscle damage elicited via a sport specific bout of damaging exercise in trained volunteers. Methods Twelve males (mean ± SD age, 23 ± 2 y; stature, 178.3 ± 3.6 cm and body mass, 79.6 ± 8.4 kg) were randomly assigned to a supplement (n = 6) or placebo (n = 6) group. The damaging exercise consisted of 100 consecutive drop-jumps. Creatine kinase (CK), maximal voluntary contraction (MVC), muscle soreness (DOMS), vertical jump (VJ), thigh circumference (TC) and calf circumference (CC) were measured as markers of muscle damage. All variables were measured immediately before the damaging exercise and at 24, 48, 72 and 96 h post-exercise. Results A significant time effect was seen for all variables. There were significant group effects showing a reduction in CK efflux and muscle soreness in the BCAA group compared to the placebo (P<0.05). Furthermore, the recovery of MVC was greater in the BCAA group (P<0.05). The VJ, TC and CC were not different between groups. Conclusion The present study has shown that BCAA administered before and following damaging resistance exercise reduces indices of muscle damage and accelerates recovery in resistance-trained males. It seems likely that BCAA provided greater bioavailablity of substrate to improve protein synthesis and thereby the extent of secondary muscle damage associated with strenuous resistance exercise. Clinical Trial Registration Number: NCT01529281. PMID:22569039

  16. Cytoprotection against Cr(6+)-induced DNA damage by alpha-lipoic acid: implications in reducing occupational cancer risk.

    PubMed

    Kumar, Sushil; Budhwar, Roli; Nigam, Akanksha; Priya, Shivam

    2009-11-01

    Alpha-lipoic acid (LA), the metabolic antioxidant, was evaluated for its potential to protect against Cr(6+)-induced DNA damage. Potassium dichromate was administered to Swiss albino mice orally ad libitum at the doses of 5, 10 or 25 mg/kg body weight in drinking water to set DNA damage in cells, which was characterized in mouse peripheral blood mononuclear cells and bone marrow cells using single-cell gel electrophoresis and analyses of generated comets for Tail moment, Tail DNA and Tail length. DNA damage was dose dependent. Cytoprotection by LA was remarkable. LA (5, 10 and 25 mg/kg body weight intraperitoneally) in pre-, co- and post-toxicant administration schedule abrogated DNA damage substantially in both cell types. Protection by LA was also dose dependent. LA annulled DNA damage by Cr(6+) in plasmid relaxation assay. A negligible DNA damage resulted during interaction of Cr(6+) and LA. Compared to ascorbate, LA emerged as a better antioxidant and least DNA damaging. In conclusion, our study advocated an experimental therapeutic research potential in LA against Cr(6+)-induced DNA damage for reduction of occupational cancer risk in humans. PMID:19710206

  17. Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity.

    PubMed

    Kocak, Ergun; Lute, Kenneth; Chang, Xing; May, Kenneth F; Exten, Katie R; Zhang, Huiming; Abdessalam, Shahab F; Lehman, Amy M; Jarjoura, David; Zheng, Pan; Liu, Yang

    2006-07-15

    The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity.

  18. Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes

    PubMed Central

    Aryal, Baikuntha; Rao, V. Ashutosh

    2016-01-01

    Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities. PMID:27434059

  19. 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.

  20. 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

  1. 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.

  2. Skin Immunization Obviates Alcohol-Related Immune Dysfunction.

    PubMed

    Brand, Rhonda M; Stottlemyer, John Mark; Cline, Rachel A; Donahue, Cara; Behari, Jaideep; Falo, Louis D

    2015-01-01

    Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results in lower alcohol levels in skin than blood, we hypothesized that the skin immune network may be relatively preserved, enabling skin-targeted immunizations to obviate the immune inhibitory effects of alcohol consumption on conventional vaccines. We employed the two most common chronic EtOH mouse feeding models, the liver-damaging Lieber-DeCarli (LD) and liver-sparing Meadows-Cook (MC) diets, to examine the roles of EtOH and/or EtOH-induced liver dysfunction on alcohol related immunosuppression. Pair-fed mice were immunized against the model antigen ovalbumin (OVA) by DNA immunization or against flu by administering the protein-based influenza vaccine either systemically (IV, IM), directly to liver (hydrodynamic), or cutaneously (biolistic, ID). We measured resulting tissue EtOH levels, liver stress, regulatory T cell (Treg), and myeloid-derived suppressor cell (MDSC) populations. We compared immune responsiveness by measuring delayed-type hypersensitivity (DTH), antigen-specific cytotoxic T lymphocyte (CTL), and antibody induction as a function of delivery route and feeding model. We found that, as expected, and independent of the feeding model, EtOH ingestion inhibits DTH, CTL lysis, and antigen-specific total IgG induced by traditional systemic vaccines. On the other hand, skin-targeted vaccines were equally immunogenic in alcohol-exposed and non-exposed subjects, suggesting that cutaneous immunization may result in more efficacious vaccination in alcohol-ingesting subjects. PMID:26561838

  3. 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

  4. Reduced T-cell-dependent humoral immune response in microsomal prostaglandin E synthase-1 null mice is mediated by non-hematopoietic cells

    PubMed Central

    Kojima, Fumiaki; Frolov, Andrey; Matnani, Rahul; Woodward, Jerold G.; Crofford, Leslie J.

    2013-01-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme that specifically catalyzes the conversion of prostaglandin (PG)H2 to PGE2. We showed that mPGES-1 null mice had a significantly reduced incidence and severity of collagen-induced arthritis (CIA) compared to wild-type (WT) mice associated with a marked reduction in antibodies to type II collagen. In the present study, we further elucidated the role of mPGES-1 in the humoral immune response. Basal levels of serum IgM and IgG were significantly reduced in mPGES-1 null mice. Compared with WT mice, mPGES-1 null mice exhibited a significant reduction of hapten-specific serum antibodies in response to immunization with the T-cell dependent antigen DNP-KLH. Immunization with the T-cell independent type-1 antigen TNP-LPS or the T-cell independent type-2 antigen DNP-Ficoll revealed minimal differences between strains. Germinal center formation in the spleens of mPGES-1 null and WT mice were similar after immunization with DNP-KLH. To determine if the effect of mPGES-1 and PGE2 was localized to hematopoietic or non-hematopoietic cells, we generated bone marrow chimeras. We demonstrated that mPGES-1 deficiency in non-hematopoietic cells was the critical factor for reduced T-cell dependent antibody production. We conclude that mPGES-1 and PGE2-dependent phenotypic changes of non-hematopoietic/mesenchymal stromal cells play a key role in T-cell dependent humoral immune responses in vivo. These findings may have relevance to the pathogenesis of rheumatoid arthritis and other autoimmune inflammatory diseases associated with autoantibody formation. PMID:24127557

  5. 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.

  6. Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.

    PubMed

    Koo, Mi-Sun; Manca, Claudia; Yang, Guibin; O'Brien, Paul; Sung, Nackmoon; Tsenova, Liana; Subbian, Selvakumar; Fallows, Dorothy; Muller, George; Ehrt, Sabine; Kaplan, Gilla

    2011-02-25

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

  7. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage

    PubMed Central

    Reeder, A; Attar, M; Nazario, L; Bathula, C; Zhang, A; Hochbaum, D; Roy, E; Cooper, K L; Oesterreich, S; Davidson, N E; Neumann, C A; Flint, M S

    2015-01-01

    Background: The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy. Methods: We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel. Results: We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel. Conclusion: We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC. PMID:25880007

  8. 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.

  9. Oil rich in carotenoids instead of vitamins C and E as a better option to reduce doxorubicin-induced damage to normal cells of Ehrlich tumor-bearing mice: hematological, toxicological and histopathological evaluations.

    PubMed

    Miranda-Vilela, Ana Luisa; Grisolia, Cesar K; Longo, João Paulo F; Peixoto, Raphael C A; de Almeida, Marcos Célio; Barbosa, Lilian Carla P; Roll, Mariana M; Portilho, Flávia A; Estevanato, Luciana L C; Bocca, Anamélia L; Báo, Sônia N; Lacava, Zulmira G M

    2014-11-01

    The development of therapeutic strategies to attenuate chemotherapy toxicity represents an area of great interest in cancer research, and among them is nutritional therapy based on antioxidants. As research on this topic is still controversial and scarce, we aim to investigate the effects of antioxidant supplementation with vitamin C, vitamin E or pequi oil, a carotenoid-rich oil extracted from pequi (Caryocar brasiliense), on doxorubicin (DX)-induced oxidative damage to normal cells in Ehrlich solid tumor-bearing mice. Tumor weight and volume, histopathology, morphometry and immunohistochemistry were used to assess the treatments' efficacy in containing tumor aggressiveness and regression, while possible toxicity of treatments was assessed by animals' weight, morphological analysis of the heart, liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. Although all the chemotherapeutic treatments increased internal necrosis area and reduced the positive Ki-67 cells compared to non-treated tumors, the treatments with pequi oil provided before tumor inoculation (PTDX) or in continuous and concurrent administration with doxorubicin (PTPDX) were more effective in containing tumor growth, besides increasing lymphocyte-dependent immunity and reducing the adverse side effects associated with DX-induced oxidative damage to normal cells, mainly the PTDX treatment. Vitamins C and E given before tumor inoculation and chemotherapy were not successful against doxorubicin-induced cardiotoxicity, besides increasing doxorubicin-induced nephrotoxicity, indicating that, at least for doxorubicin, pequi oil instead of vitamins C and E would be the best option to reduce its adverse effects.

  10. 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

  11. 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.

  12. 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.

  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. PMID:23815735

  14. Zinc transporter 3 (ZnT3) gene deletion reduces spinal cord white matter damage and motor deficits in a murine MOG-induced multiple sclerosis model.

    PubMed

    Choi, Bo Young; Kim, In Yeol; Kim, Jin Hee; Kho, A Ra; Lee, Song Hee; Lee, Bo Eun; Sohn, Min; Koh, Jae-Young; Suh, Sang Won

    2016-10-01

    The present study aimed to evaluate the role of zinc transporter 3 (ZnT3) on multiple sclerosis (MS) pathogenesis. Experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, was induced by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) in female mice. Three weeks after the initial immunization, demyelination, immune cell infiltration and blood brain barrier (BBB) disruption in the spinal cord were analyzed. Clinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. ZnT3 gene deletion profoundly reduced the daily clinical score of EAE. The ZnT3 gene deletion-mediated inhibition of the clinical course of EAE was accompanied by suppression of inflammation and demyelination in the spinal cord. The motor deficit accompanying neuropathological changes associated with EAE were mild in ZnT3 gene deletion mice. This reduction in motor deficit was accompanied by coincident reductions in demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, CD20+ B cells and F4/80+ microglia in the spinal cord. These results demonstrate that ZnT3 gene deletion inhibits the clinical features and neuropathological changes associated with EAE. ZnT3 gene deletion also remarkably inhibited formation of EAE-associated aberrant synaptic zinc patches, matrix metalloproteinases-9 (MMP-9) activation and BBB disruption. Therefore, amelioration of EAE-induced clinical and neuropathological changes by ZnT3 gene deletion suggests that vesicular zinc may be involved in several steps of MS pathogenesis.

  15. Anthocyanin-rich fractions of blackberry extracts reduce UV-induced free radicals and oxidative damage in keratinocytes.

    PubMed

    Murapa, Patience; Dai, Jin; Chung, Michael; Mumper, Russell J; D'Orazio, John

    2012-01-01

    Hull blackberries were purified using solid phase extraction to obtain anthocyanin-rich methanol fractions. This method concentrated phenolics and anthocyanins, recovering 97% and 76% of the total yield in puree or powder extracts, respectively, which represented a 24-63 fold increase of the total antioxidant capacity when compared with either the water fraction or the original extract. The ability of these fractions to protect primary keratinocytes against UV-induced oxidative damage was assessed. Anthocyanin-rich methanol fractions derived from either blackberry powder or puree exhibited strong antioxidant properties, protecting against UV-induced ROS nearly as efficiently as N-acetyl cysteine. Furthermore, the fractions up-regulated the expression of catalase, MnSOD, Gpx1/2 and Gsta1 antioxidant enzymes. Thus, it is concluded that blackberry extracts may protect keratinocytes against UV-mediated oxidative damage.

  16. Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function

    PubMed Central

    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.

    2016-01-01

    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. PMID:26938530

  17. Use of tertiary nitrogen heterocyclic material to reduce moisture-induced damage in asphalt-aggregate mixtures

    SciTech Connect

    Plancher, H.; Petersen, J.C.

    1981-01-15

    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.

  18. 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

  19. 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

  20. Propofol Increases Host Susceptibility to Microbial Infection by Reducing Subpopulations of Mature Immune Effector Cells at Sites of Infection

    PubMed Central

    Visvabharathy, Lavanya; Xayarath, Bobbi; Weinberg, Guy; Shilling, Rebecca A.; Freitag, Nancy E.

    2015-01-01

    Anesthetics are known to modulate host immune responses, but separating the variables of surgery from anesthesia when analyzing hospital acquired infections is often difficult. Here, the bacterial pathogen Listeria monocytogenes (Lm) was used to assess the impact of the common anesthetic propofol on host susceptibility to infection. Brief sedation of mice with physiologically relevant concentrations of propofol increased bacterial burdens in target organs by more than 10,000-fold relative to infected control animals. The adverse effects of propofol sedation on immune clearance of Lm persisted after recovery from sedation, as animals given the drug remained susceptible to infection for days following anesthesia. In contrast to propofol, sedation with alternative anesthetics such as ketamine/xylazine or pentobarbital did not increase susceptibility to systemic Lm infection. Propofol altered systemic cytokine and chemokine expression during infection, and prevented effective bacterial clearance by inhibiting the recruitment and/or activity of immune effector cells at sites of infection. Propofol exposure induced a marked reduction in marginal zone macrophages in the spleens of Lm infected mice, resulting in bacterial dissemination into deep tissue. Propofol also significantly increased mouse kidney abscess formation following infection with the common nosocomial pathogen Staphylococcus aureus. Taken together, these data indicate that even brief exposure to propofol severely compromises host resistance to microbial infection for days after recovery from sedation. PMID:26381144

  1. Maternal immunization

    PubMed Central

    Moniz, Michelle H; Beigi, Richard H

    2014-01-01

    Maternal immunization holds tremendous promise to improve maternal and neonatal health for a number of infectious conditions. The unique susceptibilities of pregnant women to infectious conditions, as well as the ability of maternally-derived antibody to offer vital neonatal protection (via placental transfer), together have produced the recent increased attention on maternal immunization. The Advisory Committee on Immunization Practices (ACIP) currently recommends 2 immunizations for all pregnant women lacking contraindication, inactivated Influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap). Given ongoing research the number of vaccines recommended during pregnancy is likely to increase. Thus, achieving high vaccination coverage of pregnant women for all recommended immunizations is a key public health enterprise. This review will focus on the present state of vaccine acceptance in pregnancy, with attention to currently identified barriers and determinants of vaccine acceptance. Additionally, opportunities for improvement will be considered. PMID:25483490

  2. Immune response

    MedlinePlus

    Innate immunity; Humoral immunity; Cellular immunity; Immunity; Inflammatory response; Acquired (adaptive) immunity ... and usually does not react against them. INNATE IMMUNITY Innate, or nonspecific, immunity is the defense system ...

  3. 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.

  4. Fish oil-supplemented parenteral nutrition could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis.

    PubMed

    Li, Xiaolong; Zhang, Xianxiang; Yang, Enqin; Zhang, Nanyang; Cao, Shougen; Zhou, Yanbing

    2015-09-01

    The objectives were to confirm that intravenous fish oil (FO) emulsions could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis and to explore the mechanisms of these effects. Thirty-six adult male Sprague-Dawley rats were divided into 4 groups randomly. Two days after central venous catheterization, rats were subjected to cecal ligation and puncture to produce abdominal sepsis. Rats were assigned to receive normal saline or total parenteral nutrition (TPN) containing standard soybean oil emulsions or FO-supplemented TPN at the onset of sepsis for 5 days. A sham operation and control treatment were performed in control group rats. Acute lung injury scores, peripheral blood lymphocyte subsets, plasma cytokines, and Foxp3 expression in the spleen were determined. Compared with the normal saline and TPN without FO, FO-supplemented TPN beneficially altered the distributions of the T-lymphocyte subsets and downregulated the acute lung injury scores, plasma cytokines, and expression of Foxp3 due to sepsis. Fish oil-supplemented TPN can decrease acute lung injury scores, alleviate histopathology, reduce the bacterial load in the peritoneal lavage fluid, modulate the lymphocyte subpopulation in the peripheral blood, downregulate Foxp3 expression in the spleen, and reduce plasma cytokines, which means that FO-supplemented TPN can alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis.

  5. Community Immunity (Herd Immunity)

    MedlinePlus

    ... Content Marketing Share this: Main Content Area ​Community Immunity ("Herd" Immunity) Vaccines can prevent outbreaks of disease and save ... disease is contained. This is known as "community immunity." In the illustration below, the top box depicts ...

  6. Indomethacin reduces glomerular and tubular damage markers but not renal inflammation in chronic kidney disease patients: a post-hoc analysis.

    PubMed

    de Borst, Martin H; Nauta, Ferdau L; Vogt, Liffert; Laverman, Gozewijn D; Gansevoort, Ron T; Navis, Gerjan

    2012-01-01

    Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38-513] vs NSAID 38[17-218] mg/24 h, p<0.01; IgG4: 50[16-68] vs 10[1-38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55-404] vs 50[28-110] ug/24 h, p = 0.03; KIM-1: 9[5]-[14] vs 5[2]-[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal

  7. Resistance to Bleomycin in Cancer Cell Lines Is Characterized by Prolonged Doubling Time, Reduced DNA Damage and Evasion of G2/M Arrest and Apoptosis

    PubMed Central

    Espin-Garcia, Osvaldo; Cheng, Dangxiao; Qiu, Xiaoping; Chen, Zhuo; Moore, Malcolm; Bristow, Robert G.; Xu, Wei; Der, Sandy; Liu, Geoffrey

    2013-01-01

    Background To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM) resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines. Results Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352%) in BLM-resistant sub-clones (p<0.05 for both). Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05). Significantly reduced DNA damage (COMET and γ-H2AX assays), G2/M arrest, and apoptosis (p<0.05 for each set of comparison) following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05). Conclusion Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis. PMID:24349265

  8. The duration of Chlamydia muridarum genital tract infection and associated chronic pathological changes are reduced in IL-17 knockout mice but protection is not increased further by immunization.

    PubMed

    Andrew, Dean W; Cochrane, Melanie; Schripsema, Justin H; Ramsey, Kyle H; Dando, Samantha J; O'Meara, Connor P; Timms, Peter; Beagley, Kenneth W

    2013-01-01

    IL-17 is believed to be important for protection against extracellular pathogens, where clearance is dependent on neutrophil recruitment and local activation of epithelial cell defences. However, the role of IL-17 in protection against intracellular pathogens such as Chlamydia is less clear. We have compared (i) the course of natural genital tract C. muridarum infection, (ii) the development of oviduct pathology and (iii) the development of vaccine-induced immunity against infection in wild type (WT) BALB/c and IL-17 knockout mice (IL-17-/-) to determine if IL-17-mediated immunity is implicated in the development of infection-induced pathology and/or protection. Both the magnitude and duration of genital infection was significantly reduced in IL-17-/- mice compared to BALB/c. Similarly, hydrosalpinx was also greatly reduced in IL-17-/- mice and this correlated with reduced neutrophil and macrophage infiltration of oviduct tissues. Matrix metalloproteinase (MMP) 9 and MMP2 were increased in WT oviducts compared to IL-17-/- animals at day 7 post-infection. In contrast, oviducts from IL-17-/- mice contained higher MMP9 and MMP2 at day 21. Infection also elicited higher levels of Chlamydia-neutralizing antibody in serum of IL-17-/- mice than WT mice. Following intranasal immunization with C. muridarumMajor Outer Membrane Protein (MOMP) and cholera toxin plus CpG adjuvants, significantly higher levels of chlamydial MOMP-specific IgG and IgA were found in serum and vaginal washes of IL-17-/- mice. T cell proliferation and IFNγ production by splenocytes was greater in WT animals following in vitro re-stimulation, however vaccination was only effective at reducing infection in WT, not IL-17-/- mice. Intranasal or transcutaneous immunization protected WT but not IL-17-/- mice against hydrosalpinx development. Our data show that in the absence of IL-17, the severity of C. muridarum genital infection and associated oviduct pathology are significantly attenuated, however

  9. The Duration of Chlamydia muridarum Genital Tract Infection and Associated Chronic Pathological Changes Are Reduced in IL-17 Knockout Mice but Protection Is Not Increased Further by Immunization

    PubMed Central

    Andrew, Dean W.; Cochrane, Melanie; Schripsema, Justin H.; Ramsey, Kyle H.; Dando, Samantha J.; O’Meara, Connor P.; Timms, Peter; Beagley, Kenneth W.

    2013-01-01

    IL-17 is believed to be important for protection against extracellular pathogens, where clearance is dependent on neutrophil recruitment and local activation of epithelial cell defences. However, the role of IL-17 in protection against intracellular pathogens such as Chlamydia is less clear. We have compared (i) the course of natural genital tract C. muridarum infection, (ii) the development of oviduct pathology and (iii) the development of vaccine-induced immunity against infection in wild type (WT) BALB/c and IL-17 knockout mice (IL-17-/-) to determine if IL-17-mediated immunity is implicated in the development of infection-induced pathology and/or protection. Both the magnitude and duration of genital infection was significantly reduced in IL-17-/- mice compared to BALB/c. Similarly, hydrosalpinx was also greatly reduced in IL-17-/- mice and this correlated with reduced neutrophil and macrophage infiltration of oviduct tissues. Matrix metalloproteinase (MMP) 9 and MMP2 were increased in WT oviducts compared to IL-17-/- animals at day 7 post-infection. In contrast, oviducts from IL-17-/- mice contained higher MMP9 and MMP2 at day 21. Infection also elicited higher levels of Chlamydia-neutralizing antibody in serum of IL-17-/- mice than WT mice. Following intranasal immunization with C. muridarum Major Outer Membrane Protein (MOMP) and cholera toxin plus CpG adjuvants, significantly higher levels of chlamydial MOMP-specific IgG and IgA were found in serum and vaginal washes of IL-17-/- mice. T cell proliferation and IFNγ production by splenocytes was greater in WT animals following in vitro re-stimulation, however vaccination was only effective at reducing infection in WT, not IL-17-/- mice. Intranasal or transcutaneous immunization protected WT but not IL-17-/- mice against hydrosalpinx development. Our data show that in the absence of IL-17, the severity of C. muridarum genital infection and associated oviduct pathology are significantly attenuated, however

  10. 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. PMID:25569210

  11. Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

    PubMed Central

    Dijkstra, Anke A.; Ingrassia, Angela; de Menezes, Renee X.; van Kesteren, Ronald E.; Rozemuller, Annemieke J. M.; Heutink, Peter; van de Berg, Wilma D. J.

    2015-01-01

    Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD. PMID:26087293

  12. Reduced innate immune response, apoptosis, and virus release in cells cured of respiratory syncytial virus persistent infection.

    PubMed

    Herranz, Cristina; Melero, José A; Martínez, Isidoro

    2011-02-01

    It has been reported that cell clones isolated at different passages from a culture of HEp-2 cells infected persistently with human respiratory syncytial virus (HRSV) were cured of the virus. Further studies on one of these clones (31C1) are reported here, showing that 31C1 cells can still be infected by HRSV but release low amounts of virus to the culture supernatant, develop smaller and less numerous syncytia than the original HEp-2 cells, and display only a weak innate immune response to the infection. Accordingly, uninfected 31C1 cells, but not clones derived from uninfected HEp-2 cells, express low levels of TLR3 and RIG-I. In addition, 31C1 cells are partly resistant to apoptosis. These results indicate that persistent infection of HEp-2 cells by HRSV has selected cell variants, with changes affecting cell survival, virus growth and the innate immune response that may be valuable for studies of virus-cell interaction. PMID:21093006

  13. Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction.

    PubMed

    Huang, Chien-Hua; Tsai, Min-Shan; Chiang, Chih-Yen; Su, Yu-Jen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

    2015-11-01

    While therapeutic hypothermia improves the outcomes of individuals in cardiac arrest, the hemodynamic responses and mechanisms which underlie hypothermia-induced cardioprotection are not fully understood. Therefore, we investigated the mechanism by which induced hypothermia preserves cardiac function and protects against mitochondrial damage following cardiac arrest. Cardiac arrest was induced in adult male Wistar rats by asphyxiation for 8.5 min. Following resuscitation, the animals were randomly assigned to a hypothermia (32 °C) or normothermia (37 °C) group. Monitoring results showed that cardiac output at the fourth hour after resuscitation was significantly better in rats treated with hypothermia when compared to rats treated with normothermia (P < 0.01). Examinations by transmission electron microscopy showed that mitochondria in the left ventricle of rats in the hypothermia group were significantly less swollen compared to such mitochondria in the normothermia group (P < 0.001). Additionally, opening of mitochondrial permeability transition pores occurred less frequently in the hypothermic group. While complex I/III activity in the electron transport reaction was damaged after cardiac arrest and resuscitation, the degree of injury was ameliorated by hypothermia treatment (P < 0.05). The amount of STAT-3 phosphorylated at tyrosine 705 and its expression in mitochondria were significantly higher under hypothermia treatment compared to normothermia treatment. In vitro studies showed that inhibition STAT-3 activation abolished the ability of hypothermia to protect H9C2 cardiomyocytes against injury produced by simulated ischemia and reperfusion. Therapeutic hypothermia treatment can ameliorate cardiac dysfunction and help preserve both mitochondrial integrity and electron transport activity. PMID:26471891

  14. Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction.

    PubMed

    Huang, Chien-Hua; Tsai, Min-Shan; Chiang, Chih-Yen; Su, Yu-Jen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

    2015-11-01

    While therapeutic hypothermia improves the outcomes of individuals in cardiac arrest, the hemodynamic responses and mechanisms which underlie hypothermia-induced cardioprotection are not fully understood. Therefore, we investigated the mechanism by which induced hypothermia preserves cardiac function and protects against mitochondrial damage following cardiac arrest. Cardiac arrest was induced in adult male Wistar rats by asphyxiation for 8.5 min. Following resuscitation, the animals were randomly assigned to a hypothermia (32 °C) or normothermia (37 °C) group. Monitoring results showed that cardiac output at the fourth hour after resuscitation was significantly better in rats treated with hypothermia when compared to rats treated with normothermia (P < 0.01). Examinations by transmission electron microscopy showed that mitochondria in the left ventricle of rats in the hypothermia group were significantly less swollen compared to such mitochondria in the normothermia group (P < 0.001). Additionally, opening of mitochondrial permeability transition pores occurred less frequently in the hypothermic group. While complex I/III activity in the electron transport reaction was damaged after cardiac arrest and resuscitation, the degree of injury was ameliorated by hypothermia treatment (P < 0.05). The amount of STAT-3 phosphorylated at tyrosine 705 and its expression in mitochondria were significantly higher under hypothermia treatment compared to normothermia treatment. In vitro studies showed that inhibition STAT-3 activation abolished the ability of hypothermia to protect H9C2 cardiomyocytes against injury produced by simulated ischemia and reperfusion. Therapeutic hypothermia treatment can ameliorate cardiac dysfunction and help preserve both mitochondrial integrity and electron transport activity.

  15. 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. PMID:24614817

  16. 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.

  17. Oxidative damage-induced PCNA complex formation is efficient in xeroderma pigmentosum group A but reduced in Cockayne syndrome group B cells.

    PubMed

    Balajee, A S; Dianova, I; Bohr, V A

    1999-11-15

    Proliferating cell nuclear antigen (PCNA), a processivity factor for DNA polymerases delta and epsilon, is essential for both DNA replication and repair. PCNA is required in the resynthesis step of nucleotide excision repair (NER). After UV irradiation, PCNA translocates into an insoluble protein complex, most likely associated with the nuclear matrix. It has not previously been investigated in vivo whether PCNA complex formation also takes place after oxidative stress. In this study, we have examined the involvement of PCNA in the repair of oxidative DNA damage. PCNA complex formation was studied in normal human cells after treatment with hydrogen peroxide, which generates a variety of oxidative DNA lesions. PCNA was detected by two assays, immunofluorescence and western blot analyses. We observed that PCNA redistributes from a soluble to a DNA-bound form during the repair of oxidative DNA damage. PCNA complex formation was analyzed in two human natural mutant cell lines defective in DNA repair: xeroderma pigmentosum group A (XP-A) and Cockayne syndrome group B (CS-B). XP-A cells are defective in overall genome NER while CS-B cells are defective only in the preferential repair of active genes. Immunofluorescent detection of PCNA complex formation was similar in normal and XP-A cells, but was reduced in CS-B cells. Consistent with this observation, western blot analysis in CS-B cells showed a reduction in the ratio of PCNA relocated as compared to normal and XP-A cells. The efficient PCNA complex formation observed in XP-A cells following oxidative damage suggests that formation of PCNA-dependent repair foci may not require the XPA gene product. The reduced PCNA complex formation observed in CS-B cells suggests that these cells are defective in the processing of oxidative DNA damage. PMID:10536158

  18. 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.

  19. Spironolactone promotes autophagy via inhibiting PI3K/AKT/mTOR signalling pathway and reduce adhesive capacity damage in podocytes under mechanical stress

    PubMed Central

    Li, Dong; Lu, Zhenyu; Xu, Zhongwei; Ji, Junya; Zheng, Zhenfeng; Lin, Shan; Yan, Tiekun

    2016-01-01

    Mechanical stress which would cause deleterious adhesive effects on podocytes is considered a major contributor to the early progress of diabetic nephropathy (DN). Our previous study has shown that spironolactone could ameliorate podocytic adhesive capacity in diabetic rats. Autophagy has been reported to have a protective role against renal injury. The present study investigated the underlying mechanisms by which spironolactone reduced adhesive capacity damage in podocytes under mechanical stress, focusing on the involvement of autophagy. Human conditional immortalized podocytes exposed to mechanical stress were treated with spironolactone, LY294002 or rapamycin for 48 h. The accumulation of LC3 puncta was detected by immunofluorescence staining. Podocyte expression of mineralocorticoid receptor (MR), integrin β1, LC3, Atg5, p85-PI3K, p-Akt, p-mTOR were detected by Western blotting. Podocyte adhesion to collagen type IV was also performed with spectrophotometry. Immunofluorescence staining showed that the normal level of autophagy was reduced in podocytes under mechanical stress. Decreased integrin β1, LC3, Atg5 and abnormal activation of the PI3K/Akt/mTOR pathway were also detected in podocytes under mechanical stress. Spironolactone up-regulated integrin β1, LC3, Atg5 expression, down-regulated p85-PI3K, p-Akt, p-mTOR expression and reduced podocytic adhesive capacity damage. Our data demonstrated that spironolactone inhibited mechanical-stress-induced podocytic adhesive capacity damage through blocking PI3K/Akt/mTOR pathway and restoring autophagy activity. PMID:27129295

  20. 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

    2002-06-01

    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. PMID:12084616

  1. Ultraviolet C irradiation at 0.5 kJ.m(-)(2) reduces decay without causing damage or affecting postharvest quality of star ruby grapefruit (C. paradisi Macf.).

    PubMed

    D'hallewin, G; Schirra, M; Pala, M; Ben-Yehoshua, S

    2000-10-01

    Star Ruby grapefruit [Citrus paradisi (Macf.)] were harvested in November, February, and May, treated with ultraviolet C (UV-C) light at 0.5, 1.5, or 3.0 kJ.m(-)(2), and then stored at 7 degrees C and 90-95% relative humidity (RH) for 4 weeks with 1 additional week at 20 degrees C and approximately 80% RH. Untreated fruits were used as control. UV-C irradiation at 0.5 kJ.m(-)(2) effectively reduced decay development as compared to nontreated fruit without causing damage. Irradiation at dosages >0.5 kJ.m(-)(2) did not further improve decay control and caused rind browning and necrotic peel, the extent of damage depending on treatment dosage and harvest date. The percentage of damaged fruit after irradiation at the higher UV-C dosages was significantly higher in fruit harvested in November; differences between fruits harvested in February and May were negligible. After UV-C irradiation, the phytoalexins scoparone and scopoletin accumulated in flavedo tissue, their amounts depending on harvest date and UV-C dosage. Both phytoalexins showed similar accumulation patterns, although the concentrations of scoparone were much lower than those of scopoletin. Phytoalexin levels increased in most samples as the treatment dosage increased. No detectable levels of scoparone and scopoletin could be found in nonirradiated fruit. The influence of UV-C treatments on soluble solids concentration and titratable acidity of juice was negligible. PMID:11052702

  2. Accelerated Repair and Reduced Mutagenicity of DNA Damage Induced by Cigarette Smoke in Human Bronchial Cells Transfected with E.coli Formamidopyrimidine DNA Glycosylase

    PubMed Central

    Foresta, Mara; Izzotti, Alberto; La Maestra, Sebastiano; Micale, Rosanna; Poggi, Alessandro; Vecchio, Donatella; Frosina, Guido

    2014-01-01

    Cigarette smoke (CS) is associated to a number of pathologies including lung cancer. Its mutagenic and carcinogenic effects are partially linked to the presence of reactive oxygen species and polycyclic aromatic hydrocarbons (PAH) inducing DNA damage. The bacterial DNA repair enzyme formamidopyrimidine DNA glycosylase (FPG) repairs both oxidized bases and different types of bulky DNA adducts. We investigated in vitro whether FPG expression may enhance DNA repair of CS-damaged DNA and counteract the mutagenic effects of CS in human lung cells. NCI-H727 non small cell lung carcinoma cells were transfected with a plasmid vector expressing FPG fused to the Enhanced Green Fluorescent Protein (EGFP). Cells expressing the fusion protein EGFP-FPG displayed accelerated repair of adducts and DNA breaks induced by CS condensate. The mutant frequencies induced by low concentrations of CS condensate to the Na+K+-ATPase locus (ouar) were significantly reduced in cells expressing EGFP-FPG. Hence, expression of the bacterial DNA repair protein FPG stably protects human lung cells from the mutagenic effects of CS by improving cells’ capacity to repair damaged DNA. PMID:24498234

  3. Ultraviolet C irradiation at 0.5 kJ.m(-)(2) reduces decay without causing damage or affecting postharvest quality of star ruby grapefruit (C. paradisi Macf.).

    PubMed

    D'hallewin, G; Schirra, M; Pala, M; Ben-Yehoshua, S

    2000-10-01

    Star Ruby grapefruit [Citrus paradisi (Macf.)] were harvested in November, February, and May, treated with ultraviolet C (UV-C) light at 0.5, 1.5, or 3.0 kJ.m(-)(2), and then stored at 7 degrees C and 90-95% relative humidity (RH) for 4 weeks with 1 additional week at 20 degrees C and approximately 80% RH. Untreated fruits were used as control. UV-C irradiation at 0.5 kJ.m(-)(2) effectively reduced decay development as compared to nontreated fruit without causing damage. Irradiation at dosages >0.5 kJ.m(-)(2) did not further improve decay control and caused rind browning and necrotic peel, the extent of damage depending on treatment dosage and harvest date. The percentage of damaged fruit after irradiation at the higher UV-C dosages was significantly higher in fruit harvested in November; differences between fruits harvested in February and May were negligible. After UV-C irradiation, the phytoalexins scoparone and scopoletin accumulated in flavedo tissue, their amounts depending on harvest date and UV-C dosage. Both phytoalexins showed similar accumulation patterns, although the concentrations of scoparone were much lower than those of scopoletin. Phytoalexin levels increased in most samples as the treatment dosage increased. No detectable levels of scoparone and scopoletin could be found in nonirradiated fruit. The influence of UV-C treatments on soluble solids concentration and titratable acidity of juice was negligible.

  4. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

    PubMed

    Kashyap, Sonu; Warner, Gina M; Hartono, Stella P; Boyilla, Rajendra; Knudsen, Bruce E; Zubair, Adeel S; Lien, Karen; Nath, Karl A; Textor, Stephen C; Lerman, Lilach O; Grande, Joseph P

    2016-03-01

    Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH. PMID:26661648

  5. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

    PubMed

    Kashyap, Sonu; Warner, Gina M; Hartono, Stella P; Boyilla, Rajendra; Knudsen, Bruce E; Zubair, Adeel S; Lien, Karen; Nath, Karl A; Textor, Stephen C; Lerman, Lilach O; Grande, Joseph P

    2016-03-01

    Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

  6. 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

  7. Eliminating bistability and reducing sample damage through frequency and amplitude modulation in tapping-mode atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Solares, Santiago D.

    2007-03-01

    Since its invention, amplitude-modulation tapping-mode atomic force microscopy (AM-AFM) has rapidly developed into a common high-resolution surface characterization tool. However, despite the technical advances, imaging bistability caused by the coexistence of the so-called attractive and repulsive imaging regimes, and potential sample damage in the repulsive regime (often critical in biological and other soft-sample applications) still remain as fundamental barriers which prevent users from consistently obtaining high-quality images. This report proposes a new intermittent-contact AFM imaging concept, frequency- and amplitude-modulation atomic force microscopy (FAM-AFM), which offers the potential to overcome both issues. This imaging method combines existing knowledge from non-contact frequency-modulation atomic force microscopy (FM-AFM) and AM-AFM in a new control scheme involving the use of variable excitation force amplitude and frequency to control the cantilever effective frequency and limit the magnitude of the tip-sample repulsive forces. As in FM-AFM, within the new scheme the cantilever is continuously excited at its (variable) effective frequency so it is not prone to bistability. Control of the repulsive forces is achieved through the adjustment of the excitation force amplitude, so that the effective frequency always remains below the free resonant frequency. Promising results from numerical simulations are presented for single-walled carbon nanotube (SWNT) and silicon tips interacting with a Si(100)-OH surface, and for SWNT tips interacting with the same surface while intermittently forming and breaking covalent bonds, and while experiencing attractive electrostatic interactions.

  8. 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.

  9. 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.

  10. Reducing the risk of unsafe injections in immunization programmes: financial and operational implications of various injection technologies.

    PubMed Central

    Aylward, B.; Lloyd, J.; Zaffran, M.; McNair-Scott, R.; Evans, P.

    1995-01-01

    The unsafe use and disposal of injection equipment continues to put patients, health care workers, and the general community at risk of infections such as hepatitis B virus and human immunodeficiency virus. Although the potential for unsafe injection practices varies substantially with the type of equipment that is used, technology alone cannot totally eliminate the risk. A knowledge of the cost, practicality and, most importantly, the potential for misuse, is critical for selecting the most appropriate injection equipment for each immunization setting. Four types of injection equipment are currently available for administering vaccines: sterilizable needles and syringes; standard disposable needles and syringes; autodestruct needles and syringes; and jet injectors. In general, the cost per injection is lowest with sterilizable equipment and highest with autodestruct. However, only autodestruct syringes virtually eliminate the risk of unsafe injection practices. Owing to differences in cost and programme factors, in some settings it may be appropriate to use a combination of equipment. For example, autodestruct syringes may be used in areas where it is difficult to ensure adequate supervision, while in medium-sized, fixed-site clinics with safe injection practices, sterilizable equipment will be the most cost-effective. PMID:7554027

  11. 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.

  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. PMID:26965219

  13. Encenicline, an α7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice.

    PubMed

    Salaga, M; Blomster, L V; Piechota-Polańczyk, A; Zielińska, M; Jacenik, D; Cygankiewicz, A I; Krajewska, W M; Mikkelsen, J D; Fichna, Jakub

    2016-01-01

    The α7 pentamer nicotinic acetylcholine receptors (nAChRs) are a target in transduction of anti-inflammatory signals from the central nervous system to the gastrointestinal (GI) tract. The aim of this study was to investigate the anti-inflammatory action of the novel α7 nAChR partial agonist encenicline and to determine the mechanism underlying its activity. Anti-inflammatory activity of encenicline was evaluated using trinitrobenzenesulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced models of colitis. Macroscopic score, ulcer score, colon length and thickness, as well as myeloperoxidase (MPO) activity were recorded. Immunohistochemistry (IHC) was used to measure the infiltration of immune cells in the colon. Furthermore, we employed flow cytometry to determine the effect of encenicline on frequencies of FoxP3(+) and interleukin (IL)-17A(+) T cells in the mouse colon. Encenicline attenuated TNBS- and DSS-induced colitis in mice via α7 nAChRs, as indicated by significantly reduced macroscopic parameters and MPO activity. Treatment with encenicline significantly reduced the infiltration of macrophages, neutrophils, and B cells in the colon of TNBS-treated animals, as indicated by IHC. In the TNBS model encenicline reduced the frequency of FoxP3(+) IL-17A(+) T cells in the colon. In the DSS-model treatment encenicline increased the frequency of FoxP3(+) T cells and reduced IL-17A(+) T cells. Stimulation of α7 nAChR with partial agonist encenicline alleviates colitis via alteration of the number and/or activation status of the immune cells in the gut, emphasizing a potential role of α7 nAChRs as a target for anticolitic drugs. PMID:26462538

  14. Comparative Transcriptomic Analysis of Rectal Tissue from Beef Steers Revealed Reduced Host Immunity in Escherichia coli O157:H7 Super-Shedders.

    PubMed

    Wang, Ou; Liang, Guanxiang; McAllister, Tim A; Plastow, Graham; Stanford, Kim; Selinger, Brent; Guan, Le Luo

    2016-01-01

    Super-shedder cattle are a major disseminator of E. coli O157:H7 into the environment, and the terminal rectum has been proposed as the primary E. coli O157:H7 colonization site. This study aimed to identify host factors that are associated with the super-shedding process by comparing transcriptomic profiles in rectal tissue collected from 5 super-shedder cattle and 4 non-shedder cattle using RNA-Seq. In total, 17,859 ± 354 genes and 399 ± 16 miRNAs were detected, and 11,773 genes were expressed in all animals. Fifty-eight differentially expressed (DE) genes (false discovery rate < 0.05) including 11 up-regulated and 47 down-regulated (log 2 (fold change) ranged from -5.5 to 4.2), and 2 up-regulated DE miRNAs (log 2 (fold change) = 2.1 and 2.5, respectively) were identified in super-shedders compared to non-shedders. Functional analysis of DE genes revealed that 31 down-regulated genes were potentially associated with reduced innate and adaptive immune functions in super-shedders, including 13 lymphocytes membrane receptors, 3 transcription factors and 5 cytokines, suggesting the decreased key host immune functions in the rectal tissue of super-shedders, including decreased quantity and migration of immune cells such as lymphocytes, neutrophils and dendritic cells. The up-regulation of bta-miR-29d-3p and the down regulation of its predicted target gene, regulator of G-protein signaling 13, suggested a potential regulatory role of this miRNA in decreased migration of lymphocytes in super-shedders. Based on these findings, the rectal tissue of super-shedders may inherently exhibit less effective innate and adaptive immune protection. Further study is required to confirm if such effect on host immunity is due to the nature of the host itself or due to actions mediated by E. coli O157:H7. PMID:26959367

  15. 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

  16. Comparative Transcriptomic Analysis of Rectal Tissue from Beef Steers Revealed Reduced Host Immunity in Escherichia coli O157:H7 Super-Shedders

    PubMed Central

    Wang, Ou; Liang, Guanxiang; McAllister, Tim A.; Plastow, Graham; Stanford, Kim; Selinger, Brent; Guan, Le Luo

    2016-01-01

    Super-shedder cattle are a major disseminator of E. coli O157:H7 into the environment, and the terminal rectum has been proposed as the primary E. coli O157:H7 colonization site. This study aimed to identify host factors that are associated with the super-shedding process by comparing transcriptomic profiles in rectal tissue collected from 5 super-shedder cattle and 4 non-shedder cattle using RNA-Seq. In total, 17,859 ± 354 genes and 399 ± 16 miRNAs were detected, and 11,773 genes were expressed in all animals. Fifty-eight differentially expressed (DE) genes (false discovery rate < 0.05) including 11 up-regulated and 47 down-regulated (log 2 (fold change) ranged from -5.5 to 4.2), and 2 up-regulated DE miRNAs (log 2 (fold change) = 2.1 and 2.5, respectively) were identified in super-shedders compared to non-shedders. Functional analysis of DE genes revealed that 31 down-regulated genes were potentially associated with reduced innate and adaptive immune functions in super-shedders, including 13 lymphocytes membrane receptors, 3 transcription factors and 5 cytokines, suggesting the decreased key host immune functions in the rectal tissue of super-shedders, including decreased quantity and migration of immune cells such as lymphocytes, neutrophils and dendritic cells. The up-regulation of bta-miR-29d-3p and the down regulation of its predicted target gene, regulator of G-protein signaling 13, suggested a potential regulatory role of this miRNA in decreased migration of lymphocytes in super-shedders. Based on these findings, the rectal tissue of super-shedders may inherently exhibit less effective innate and adaptive immune protection. Further study is required to confirm if such effect on host immunity is due to the nature of the host itself or due to actions mediated by E. coli O157:H7. PMID:26959367

  17. Inhibition of the group I mGluRs reduces acute brain damage and improves long-term histological outcomes after photothrombosis-induced ischaemia

    PubMed Central

    Li, Hailong; Zhang, Nannan; Sun, Grace; Ding, Shinghua

    2013-01-01

    Group I mGluRs (metabotropic glutamate receptors), including mGluR1 and mGluR5, are GPCRs (G-protein coupled receptors) and play important roles in physiology and pathology. Studies on their role in cerebral ischaemia have provided controversial results. In this study, we used a PT (photothrombosis)-induced ischaemia model to investigate whether antagonists to the group I mGluRs may offer acute and long-term protective effects in adult mice. Our results demonstrated that administration with mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 antagonist LY367385 by intraperitoneal injection at 3 h after PT decreased brain infarct volume evaluated one day after ischaemia. Additive effects on infarct volume were observed upon co-injection with MPEP and LY367385. These antagonists also significantly alleviated neurodegeneration and apoptosis in the penumbra. In addition, when evaluated 2 weeks after PT, they reduced infarct volume and tissue loss, attenuated glial scar formation, and inhibited cell proliferation in the penumbra. Importantly, co-injection with MPEP and LY367385 reduced the expression levels of calpain, a Ca2+-activated protease known to mediate ischaemia-induced neuronal death. Injection of calpeptin, a calpain inhibitor, could inhibit neuronal death and brain damage after PT but injection of calpeptin together with MPEP and LY367385 did not further improve the protective effects mediated by MPEP and LY367385. These results suggest that inhibition of group I mGluRs is sufficient to protect ischaemic damage through the calpain pathway. Taken together, our results demonstrate that inhibition of group I mGluRs can mitigate PT-induced brain damage through attenuating the effects of calpain, and improve long-term histological outcomes. PMID:23772679

  18. Emu Oil Combined with Lyprinol™ Reduces Small Intestinal Damage in a Rat Model of Chemotherapy-Induced Mucositis.

    PubMed

    Mashtoub, Suzanne; Lampton, Lorrinne S; Eden, Georgina L; Cheah, Ker Y; Lymn, Kerry A; Bajic, Juliana E; Howarth, Gordon S

    2016-10-01

    Chemotherapy-induced mucositis is characterized by inflammation and ulcerating lesions lining the alimentary tract. Emu Oil and Lyprinol™ have independently demonstrated their therapeutic potential in intestinal inflammatory disorders, including mucositis. We investigated Emu Oil and Lyprinol™ in combination for their further potential to alleviate chemotherapy-induced mucositis in rats. Rats were gavaged with (1 ml) water, Olive Oil, Emu Oil + Olive Oil, Lyprinol™ + Olive Oil or Emu Oil + Lyprinol™ from Days 0 to 7, injected with saline (control) or 5-Fluorouracil (5-FU) on Day 5 and euthanized on Day 8. Myeloperoxidase (MPO) activity (indicative of acute inflammation), histological severity scores, and intestinal architecture were quantified. Myeloperoxidase activity was significantly increased in the jejunum and ileum following 5-FU, compared to saline controls. Both Olive Oil and Emu Oil + Lyprinol™ significantly reduced jejunal MPO levels (1.8-fold and 1.7-fold, respectively), whereas only Emu Oil + Lyprinol™ significantly decreased ileal MPO levels, relative to 5-FU controls. All oil treatments decreased histological severity scores in the jejunum and ileum, and normalized crypt depth in the mid small intestine, relative to 5-FU controls. Emu Oil combined with Lyprinol™ partially reduced acute small intestinal inflammation. Isolating bioactive constituents of these naturally sourced oils could provide a more targeted strategy to protect against intestinal mucositis. PMID:27618153

  19. Antagonism of N-methyl-D-aspartate receptors reduces the vulnerability of the immune system to stress after chronic morphine.

    PubMed

    Alonzo, Norma C; Bayer, Barbara M

    2003-11-01

    It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress. PMID:12966157

  20. Depletion of Bone Marrow-derived Macrophages Perturbs the Innate Immune Response to Surgery and Reduces Postoperative Memory Dysfunction

    PubMed Central

    Degos, Vincent; Vacas, Susana; Han, Zhenying; van Rooijen, Nico; Gressens, Pierre; Su, Hua; Young, William L.; Maze, Mervyn

    2013-01-01

    Background According to rodent models of postoperative cognitive decline, activation of the innate immune response following aseptic surgical trauma results in the elaboration of hippocampal proinflammatory cytokines, which are capable of disrupting long-term potentiation, the neurobiologic correlate of memory. We hypothesize that hippocampal recruitment of bone marrow-derived (BMD) macrophages plays a causal role in these processes, resulting in memory dysfunction. Methods Clodrolip injection (liposomal formulation of clodronate) prior to stabilized tibial fracture under general anesthesia was used to deplete BMD macrophages. Systemic and neuroinflammation were studied on postoperative day 1, and memory in a fear-trace conditioning paradigm was assessed on postoperative day 3. CX3CR1GFP/+ CCR2RFP/+ mice were used to identify BMD macrophages. Results Clodrolip effectively depleted splenic CCR2+ BMD macrophages. It also attenuated the surgery-induced increase of interleukin-6 in the serum and the hippocampus, and prevented hippocampal infiltration of CCR2+ cells without affecting the number of CX3CR1+ microglia. It did not alter the surgery-induced increase in hippocampal MCP-1, the recruitment signal for CCR2+ cells. Clodrolip prevented surgery-induced memory dysfunction, as evidenced by a significant increase in freezing time (29%, 95% CI: 21 to 38% vs. 48%, 95% CI: 38 to 58%, n= 20, P = 0.004), but did not affect memory in nonsurgical mice. Conclusion Depletion of BMD macrophages prevents hippocampal neuroinflammation and memory dysfunction after experimental tibial fracture. These data suggest that the hippocampal recruitment of BMD macrophages is a necessary mechanism in murine postoperative cognitive dysfunction. Interventions designed to prevent its activation and/or migration into the brain may represent a feasible preemptive strategy. PMID:23426204

  1. 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

  2. Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility

    PubMed Central

    Riquelme, Sebastián A; Bueno, Susan M; Kalergis, Alexis M

    2015-01-01

    Carbon monoxide (CO) has been recently reported as the main anti-inflammatory mediator of the haem-degrading enzyme haem-oxygenase 1 (HO-1). It has been shown that either HO-1 induction or CO treatment reduces the ability of monocytes to respond to inflammatory stimuli, such as lipopolysaccharide (LPS), due to an inhibition of the signalling pathways leading to nuclear factor-κB, mitogen-activated protein kinases and interferon regulatory factor 3 activation. Hence, it has been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells. However, whether CO can negatively modulate the surface expression of the TLR4/MD2 complex in immune cells remains unknown. Here we report that either HO-1 induction or treatment with CO decreases the surface expression of TLR4/MD2 in dendritic cells (DC) and neutrophils. In addition, in a septic shock model of mice intraperitoneally injected with lipopolysaccharide (LPS), prophylactic treatment with CO protected animals from hypothermia, weight loss, mobility loss and death. Further, mice pre-treated with CO and challenged with LPS showed reduced recruitment of DC and neutrophils to peripheral blood, suggesting that this gas causes a systemic tolerance to endotoxin challenge. No differences in the amount of innate cells in lymphoid tissues were observed in CO-treated mice. Our results suggest that CO treatment reduces the expression of the TLR4/MD2 complex on the surface of myeloid cells, which renders them resistant to LPS priming in vitro, as well as in vivo in a model of endotoxic shock. PMID:25179131

  3. Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility.

    PubMed

    Riquelme, Sebastián A; Bueno, Susan M; Kalergis, Alexis M

    2015-02-01

    Carbon monoxide (CO) has been recently reported as the main anti-inflammatory mediator of the haem-degrading enzyme haem-oxygenase 1 (HO-1). It has been shown that either HO-1 induction or CO treatment reduces the ability of monocytes to respond to inflammatory stimuli, such as lipopolysaccharide (LPS), due to an inhibition of the signalling pathways leading to nuclear factor-κB, mitogen-activated protein kinases and interferon regulatory factor 3 activation. Hence, it has been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells. However, whether CO can negatively modulate the surface expression of the TLR4/MD2 complex in immune cells remains unknown. Here we report that either HO-1 induction or treatment with CO decreases the surface expression of TLR4/MD2 in dendritic cells (DC) and neutrophils. In addition, in a septic shock model of mice intraperitoneally injected with lipopolysaccharide (LPS), prophylactic treatment with CO protected animals from hypothermia, weight loss, mobility loss and death. Further, mice pre-treated with CO and challenged with LPS showed reduced recruitment of DC and neutrophils to peripheral blood, suggesting that this gas causes a systemic tolerance to endotoxin challenge. No differences in the amount of innate cells in lymphoid tissues were observed in CO-treated mice. Our results suggest that CO treatment reduces the expression of the TLR4/MD2 complex on the surface of myeloid cells, which renders them resistant to LPS priming in vitro, as well as in vivo in a model of endotoxic shock.

  4. 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

  5. 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.

  6. 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.

  7. Ambient UV-B exposure reduces the binding of ofloxacin with bacterial DNA gyrase and induces DNA damage mediated apoptosis.

    PubMed

    Singh, Jyoti; Dwivedi, Ashish; Mujtaba, Syed Faiz; Singh, Krishna P; Pal, Manish Kumar; Chopra, Deepti; Goyal, Shruti; Srivastav, Ajeet K; Dubey, Divya; Gupta, Shailendra K; Haldar, Chandana; Ray, Ratan Singh

    2016-04-01

    Ofloxacin (OFLX) is a broad spectrum antibiotic, which generates photo-products under sunlight exposure. Previous studies have failed to explain the attenuated anti-bacterial activity of OFLX. The study was extended to explore the unknown molecular mechanism of photogenotoxicity on human skin cell line (HaCaT) under environmental UV-B irradiation. Photochemically OFLX generates ROS and caused 2'-dGuO photodegradation. We have addressed the binding affinity of OFLX and its photo-products against DNA gyrase. Significant free radical generation such as (1)O2, O2(•-) and (•)OH reduces antioxidants and demonstrated the ROS mediated OFLX phototoxicity. However, the formation of micronuclei and CPDs showed photogenotoxic potential of OFLX. OFLX induced cell cycle arrest in sub-G1 peak. OFLX triggers apoptosis via permeabilization of mitochondrial membrane with the downregulation of anti-apoptotic Bcl-2 and caspase-3 whereas, upregulation of pro-apoptotic Bax and Cyto-C proteins. Our study illustrated that binding affinity of OFLX photo-products with DNA gyrase was mainly responsible for the attenuated antimicrobial activity. It was proved through molecular docking study. Thus, study suggests that sunlight exposure should avoid by drug users especially during peak hours for their safety from photosensitivity. Clinicians may guide patients regarding the safer use of photosensitive drugs during treatment.

  8. Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model.

    PubMed

    Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H; Monte, Louise; Rice, Kenner C; Rissman, Robert A

    2015-01-01

    Reports from Alzheimer’s disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S- glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology. Furthermore, evidence suggests that oxidative stress may be associated with dysfunction of the hypothalamic-pituitary-adrenal axis, leading to activation of inflammatory pathways and increased production of corticotropin-releasing factor (CRF). Therefore, to investigate whether oxidative insults can be attenuated by reduction of central CRF signaling, we administered the type-1 CRF receptor (CRFR1) selective antagonist, R121919, to AD-transgenic mice beginning in the preclinical/prepathologic period (30-day-old) for 150 days, a time point where behavioral impairments and pathologic progression should be measureable. Our results indicate that R121919 treatment can significantly reduce Pr-SSG levels and increase glutathione peroxide activity, suggesting that interference of CRFR1 signaling may be useful as a preventative therapy for combating oxidative stress in AD. PMID:25649650

  9. 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.

  10. Ambient UV-B exposure reduces the binding of ofloxacin with bacterial DNA gyrase and induces DNA damage mediated apoptosis.

    PubMed

    Singh, Jyoti; Dwivedi, Ashish; Mujtaba, Syed Faiz; Singh, Krishna P; Pal, Manish Kumar; Chopra, Deepti; Goyal, Shruti; Srivastav, Ajeet K; Dubey, Divya; Gupta, Shailendra K; Haldar, Chandana; Ray, Ratan Singh

    2016-04-01

    Ofloxacin (OFLX) is a broad spectrum antibiotic, which generates photo-products under sunlight exposure. Previous studies have failed to explain the attenuated anti-bacterial activity of OFLX. The study was extended to explore the unknown molecular mechanism of photogenotoxicity on human skin cell line (HaCaT) under environmental UV-B irradiation. Photochemically OFLX generates ROS and caused 2'-dGuO photodegradation. We have addressed the binding affinity of OFLX and its photo-products against DNA gyrase. Significant free radical generation such as (1)O2, O2(•-) and (•)OH reduces antioxidants and demonstrated the ROS mediated OFLX phototoxicity. However, the formation of micronuclei and CPDs showed photogenotoxic potential of OFLX. OFLX induced cell cycle arrest in sub-G1 peak. OFLX triggers apoptosis via permeabilization of mitochondrial membrane with the downregulation of anti-apoptotic Bcl-2 and caspase-3 whereas, upregulation of pro-apoptotic Bax and Cyto-C proteins. Our study illustrated that binding affinity of OFLX photo-products with DNA gyrase was mainly responsible for the attenuated antimicrobial activity. It was proved through molecular docking study. Thus, study suggests that sunlight exposure should avoid by drug users especially during peak hours for their safety from photosensitivity. Clinicians may guide patients regarding the safer use of photosensitive drugs during treatment. PMID:26812543

  11. Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice.

    PubMed

    Stern, Nora; Hochman, Ayala; Zemach, Naty; Weizman, Nir; Hammel, Ilan; Shiloh, Yosef; Rotman, Galit; Barzilai, Ari

    2002-01-01

    Ataxia-telangiectasia (A-T) is a human genetic disorder caused by mutational inactivation of the ATM gene. A-T patients display a pleiotropic phenotype, in which a major neurological feature is progressive ataxia due to degeneration of cerebellar Purkinje and granule neurons. Disruption of the mouse Atm locus creates a murine model of A-T that exhibits most of the clinical and cellular features of the human disease, but the neurological phenotype is barely expressed. We present evidence for the accumulation of DNA strand breaks in the brains of Atm(-/-), supporting the notion that ATM plays a major role in maintaining genomic stability. We also show a perturbation of the steady state levels of pyridine nucleotides. There is a significant decrease in both the reduced and the oxidized forms of NAD and in the total levels of NADP(T) and NADP(+) in the brains of Atm(-/-) mice. The changes in NAD(T), NADH, NAD(+), NADP(T), and NADP(+) were progressive and observed primarily in the cerebellum of 4-month-old Atm(-/-) mice. Higher rates of mitochondrial respiration were also recorded in 4-month-old Atm(-/-) cerebella. Taken together, our findings support the hypothesis that absence of functional ATM results in continuous stress, which may be an important cause of the degeneration of cerebellar neurons in A-T. PMID:11679583

  12. A botanical containing freeze dried açai pulp promotes healthy aging and reduces oxidative damage in sod1 knockdown flies.

    PubMed

    Laslo, Mara; Sun, Xiaoping; Hsiao, Cheng-Te; Wu, Wells W; Shen, Rong-Fong; Zou, Sige

    2013-08-01

    Superoxide dismutase 1 (SOD1), a critical enzyme against oxidative stress, is implicated in aging and degenerative diseases. We previously showed that a nutraceutical containing freeze-dried açai pulp promotes survival of flies fed a high-fat diet or sod1 knockdown flies fed a standard diet. Here, we investigated the effect of açai supplementation initiated at the early or late young adulthood on lifespan, physiological function, and oxidative damage in sod1 knockdown flies. We found that Açai supplementation extended lifespan even when started at the age of 10 days, which is the time shortly before the mortality rate of flies accelerated. Life-long açai supplementation increased lifetime reproductive output in sod1 knockdown flies. Our molecular studies indicate that açai supplementation reduced the protein levels of genes involved in oxidative stress response, cellular growth, and nutrient metabolism. Açai supplementation also affected the protein levels of ribosomal proteins. In addition, açai supplementation decreased the transcript levels of genes involved in oxidative stress response and gluconeogenesis, while increasing the transcript levels of mitochondrial biogenesis genes. Moreover, açai supplementation reduced the level of 4-hydroxynonenal-protein adducts, a lipid peroxidation marker. Our findings suggest that açai supplementation promotes healthy aging in sod1-deficient flies partly through reducing oxidative damage, and modulating nutrient metabolism and oxidative stress response pathways. Our findings provide a foundation to further evaluate the viability of using açai as an effective dietary intervention to promote healthy aging and alleviate symptoms of diseases with a high level of oxidative stress. PMID:22639178

  13. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord.

    PubMed

    Cusimano, Melania; Biziato, Daniela; Brambilla, Elena; Donegà, Matteo; Alfaro-Cervello, Clara; Snider, Silvia; Salani, Giuliana; Pucci, Ferdinando; Comi, Giancarlo; Garcia-Verdugo, Jose Manuel; De Palma, Michele; Martino, Gianvito; Pluchino, Stefano

    2012-02-01

    Transplanted neural stem/precursor cells possess peculiar therapeutic plasticity and can simultaneously instruct several therapeutic mechanisms in addition to cell replacement. Here, we interrogated the therapeutic plasticity of neural stem/precursor cells after their focal implantation in the severely contused spinal cord. We injected syngeneic neural stem/precursor cells at the proximal and distal ends of the contused mouse spinal cord and analysed locomotor functions and relevant secondary pathological events in the mice, cell fate of transplanted neural stem/precursor cells, and gene expression and inflammatory cell infiltration at the injured site. We used two different doses of neural stem/precursor cells and two treatment schedules, either subacute (7 days) or early chronic (21 days) neural stem/precursor cell transplantation after the induction of experimental thoracic severe spinal cord injury. Only the subacute transplant of neural stem/precursor cells enhanced the recovery of locomotor functions of mice with spinal cord injury. Transplanted neural stem/precursor cells survived undifferentiated at the level of the peri-lesion environment and established contacts with endogenous phagocytes via cellular-junctional coupling. This was associated with significant modulation of the expression levels of important inflammatory cell transcripts in vivo. Transplanted neural stem/precursor cells skewed the inflammatory cell infiltrate at the injured site by reducing the proportion of 'classically-activated' (M1-like) macrophages, while promoting the healing of the injured cord. We here identify a precise window of opportunity for the treatment of complex spinal cord injuries with therapeutically plastic somatic stem cells, and suggest that neural stem/precursor cells have the ability to re-programme the local inflammatory cell microenvironment from a 'hostile' to an 'instructive' role, thus facilitating the healing or regeneration past the lesion.

  14. 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.

  15. 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

  16. Active immunization with GnRH-tandem-dimer peptide in young male rats reduces serum reproductive hormone concentrations, testicular development and spermatogenesis.

    PubMed

    Han, Xing-Fa; Li, Jun-Li; Zhou, Yu-Qin; Ren, Xiao-Hua; Liu, Gong-Cheng; Cao, Xiao-Han; Du, Xiao-Gang; Zeng, Xian-Yin

    2016-01-01

    GnRH sterilization vaccines have been developed for various practical and clinical reasons. However, conjugation of GnRH peptide to carrier protein has many drawbacks, hampering the further commercialization of GnRH vaccines. In this study, a new nonconjugated GnRH vaccine, D-Lys6-GnRH-tandem-dimer peptide (TDK), emulsified in Specol adjuvant was investigated for its immunocastration efficacy in young male rats. Prepubertal male rats were randomly allocated into three groups (n = 12): control (no treatment), surgically castrated or immunized against 100 μg TDK in Specol adjuvant at 6 weeks of age (with a booster 8 weeks later). Blood samples (for antibody titers and hormone concentrations) were collected at 2-week intervals until rats were killed (18 weeks of age). Compared to intact controls, active immunization against TDK reduced (P < 0.05) serum concentrations of testosterone, inhibin B, LH and FSH, prevented the onset of spermatogenesis at puberty. Furthermore, mRNA expressions of GnRH receptor, LH-β and FSH-β in the pituitary, LH receptor, FSH receptor, inhibin α, βA and βB subunit in the testes were decreased in immunocastrated rats compared to intact controls (P < 0.05). These results demonstrate for the first time that GnRH-tandem-dimer peptide emulsified in Specol is a promising veterinary sterilization medicine.

  17. Active immunization with GnRH-tandem-dimer peptide in young male rats reduces serum reproductive hormone concentrations, testicular development and spermatogenesis

    PubMed Central

    Han, Xing-Fa; Li, Jun-Li; Zhou, Yu-Qin; Ren, Xiao-Hua; Liu, Gong-Cheng; Cao, Xiao-Han; Du, Xiao-Gang; Zeng, Xian-Yin

    2016-01-01

    GnRH sterilization vaccines have been developed for various practical and clinical reasons. However, conjugation of GnRH peptide to carrier protein has many drawbacks, hampering the further commercialization of GnRH vaccines. In this study, a new nonconjugated GnRH vaccine, D-Lys6-GnRH-tandem-dimer peptide (TDK), emulsified in Specol adjuvant was investigated for its immunocastration efficacy in young male rats. Prepubertal male rats were randomly allocated into three groups (n = 12): control (no treatment), surgically castrated or immunized against 100 μg TDK in Specol adjuvant at 6 weeks of age (with a booster 8 weeks later). Blood samples (for antibody titers and hormone concentrations) were collected at 2-week intervals until rats were killed (18 weeks of age). Compared to intact controls, active immunization against TDK reduced (P < 0.05) serum concentrations of testosterone, inhibin B, LH and FSH, prevented the onset of spermatogenesis at puberty. Furthermore, mRNA expressions of GnRH receptor, LH-β and FSH-β in the pituitary, LH receptor, FSH receptor, inhibin α, βA and βB subunit in the testes were decreased in immunocastrated rats compared to intact controls (P < 0.05). These results demonstrate for the first time that GnRH-tandem-dimer peptide emulsified in Specol is a promising veterinary sterilization medicine. PMID:26208395

  18. Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling

    PubMed Central

    Liu, Ping; Yang, Xiao; Hei, Changchun; Meli, Yvonne; Niu, Jianguo; Sun, Tao; Li, P. Andy

    2016-01-01

    The objectives of the present study are to investigate the activation of mTOR and ERK1/2 signaling after cerebral ischemia in diabetic rats and to examine the neuroprotective effects of rapamycin. Ten minutes transient global cerebral ischemia was induced in straptozotocin-induced diabetic hyperglycemic rats and non-diabetic, euglycemic rats. Brain samples were harvested after 16 h of reperfusion. Rapamycin or vehicle was injected 1 month prior to the induction of ischemia. The results showed that diabetes increased ischemic neuronal cell death and associated with elevations of p-P70S6K and Ras/ERK1/2 and suppression of p-AMPKα. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and suppressed phosphorylation of P70S6K and ERK1/2. It is concluded that diabetes activates mTOR and ERK1/2 signaling pathways in rats subjected to transient cerebral ischemia and inhibition of mTOR by rapamycin reduces ischemic brain damage and suppresses the mTOR and ERK1/2 signaling in diabetic settings. PMID:27489506

  19. 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.

  20. Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling.

    PubMed

    Liu, Ping; Yang, Xiao; Hei, Changchun; Meli, Yvonne; Niu, Jianguo; Sun, Tao; Li, P Andy

    2016-01-01

    The objectives of the present study are to investigate the activation of mTOR and ERK1/2 signaling after cerebral ischemia in diabetic rats and to examine the neuroprotective effects of rapamycin. Ten minutes transient global cerebral ischemia was induced in straptozotocin-induced diabetic hyperglycemic rats and non-diabetic, euglycemic rats. Brain samples were harvested after 16 h of reperfusion. Rapamycin or vehicle was injected 1 month prior to the induction of ischemia. The results showed that diabetes increased ischemic neuronal cell death and associated with elevations of p-P70S6K and Ras/ERK1/2 and suppression of p-AMPKα. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and suppressed phosphorylation of P70S6K and ERK1/2. It is concluded that diabetes activates mTOR and ERK1/2 signaling pathways in rats subjected to transient cerebral ischemia and inhibition of mTOR by rapamycin reduces ischemic brain damage and suppresses the mTOR and ERK1/2 signaling in diabetic settings. PMID:27489506

  1. Regulation of the host immune system by helminth parasites.

    PubMed

    Maizels, Rick M; McSorley, Henry J

    2016-09-01

    Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research. PMID:27476889

  2. 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

  3. Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury

    PubMed Central

    2012-01-01

    Background Emerging evidence indicates that reactive microglia-initiated inflammatory responses are responsible for secondary damage after primary traumatic spinal cord injury (SCI); epidermal growth factor receptor (EGFR) signaling may be involved in cell activation. In this report, we investigate the influence of EGFR signaling inhibition on microglia activation, proinflammatory cytokine production, and the neuronal microenvironment after SCI. Methods Lipopolysaccharide-treated primary microglia/BV2 line cells and SCI rats were used as model systems. Both C225 and AG1478 were used to inhibit EGFR signaling activation. Cell activation and EGFR phosphorylation were observed after fluorescent staining and western blot. Production of interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNFα) was tested by reverse transcription PCR and ELISA. Western blot was performed to semi-quantify the expression of EGFR/phospho-EGFR, and phosphorylation of Erk, JNK and p38 mitogen-activated protein kinases (MAPK). Wet-dry weight was compared to show tissue edema. Finally, axonal tracing and functional scoring were performed to show recovery of rats. Results EGFR phosphorylation was found to parallel microglia activation, while EGFR blockade inhibited activation-associated cell morphological changes and production of IL-1β and TNFα. EGFR blockade significantly downregulated the elevated MAPK activation after cell activation; selective MAPK inhibitors depressed production of cytokines to a certain degree, suggesting that MAPK mediates the depression of microglia activation brought about by EGFR inhibitors. Subsequently, seven-day continual infusion of C225 or AG1478 in rats: reduced the expression of phospho-EGFR, phosphorylation of Erk and p38 MAPK, and production of IL-1β and TNFα; lessened neuroinflammation-associated secondary damage, like microglia/astrocyte activation, tissue edema and glial scar/cavity formation; and enhanced axonal outgrowth and functional

  4. Worm Proteins of Schistosoma mansoni Reduce the Severity of Experimental Chronic Colitis in Mice by Suppressing Colonic Proinflammatory Immune Responses

    PubMed Central

    Heylen, Marthe; Ruyssers, Nathalie E.; De Man, Joris G.; Timmermans, Jean-Pierre; Pelckmans, Paul A.; Moreels, Tom G.; De Winter, Benedicte Y.

    2014-01-01

    Although helminthic therapy as a possible new option to treat inflammatory bowel disease is a well-established concept by now, the search for immunomodulatory helminth-derived compounds and their mechanisms of action is still ongoing. We investigated the therapeutic potential and the underlying immunological mechanisms of Schistosoma mansoni soluble worm proteins (SmSWP) in an adoptive T cell transfer mouse model of chronic colitis. Both a curative and a preventive treatment protocol were included in this study. The curative administration of SmSWP (started when colitis was established), resulted in a significant improvement of the clinical disease score, colonoscopy, macroscopic and microscopic inflammation score, colon length and myeloperoxidase activity. The therapeutic potential of the preventive SmSWP treatment (started before colitis was established), was less pronounced compared with the curative SmSWP treatment but still resulted in an improved clinical disease score, body weight loss, colon length and microscopic inflammation score. Both the curative and preventive SmSWP treatment downregulated the mRNA expression of the proinflammatory cytokines IFN-γ and IL-17A and upregulated the mRNA expression of the anti-inflammatory cytokine IL-4 in the colon at the end of the experiment. This colonic immunomodulatory effect of SmSWP could not be confirmed at the protein level. Moreover, the effect of SmSWP appeared to be a local colonic phenomenon, since the flow cytometric T cell characterization of the mesenteric lymph nodes and the cytokine measurements in the serum did not reveal any effect of SmSWP treatment. In conclusion, SmSWP treatment reduced the severity of colitis in the adoptive transfer mouse model via the suppression of proinflammatory cytokines and the induction of an anti-inflammatory response in the colon. PMID:25313594

  5. Autophagy and Immune Senescence.

    PubMed

    Zhang, Hanlin; Puleston, Daniel J; Simon, Anna Katharina

    2016-08-01

    With extension of the average lifespan, aging has become a heavy burden in society. Immune senescence is a key risk factor for many age-related diseases such as cancer and increased infections in the elderly, and hence has elicited much attention in recent years. As our body's guardian, the immune system maintains systemic health through removal of pathogens and damage. Autophagy is an important cellular 'clearance' process by which a cell internally delivers damaged organelles and macromolecules to lysosomes for degradation. Here, we discuss the most current knowledge of how impaired autophagy can lead to cellular and immune senescence. We also provide an overview, with examples, of the clinical potential of exploiting autophagy to delay immune senescence and/or rejuvenate immunity to treat various age-related diseases.

  6. Autophagy and Immune Senescence.

    PubMed

    Zhang, Hanlin; Puleston, Daniel J; Simon, Anna Katharina

    2016-08-01

    With extension of the average lifespan, aging has become a heavy burden in society. Immune senescence is a key risk factor for many age-related diseases such as cancer and increased infections in the elderly, and hence has elicited much attention in recent years. As our body's guardian, the immune system maintains systemic health through removal of pathogens and damage. Autophagy is an important cellular 'clearance' process by which a cell internally delivers damaged organelles and macromolecules to lysosomes for degradation. Here, we discuss the most current knowledge of how impaired autophagy can lead to cellular and immune senescence. We also provide an overview, with examples, of the clinical potential of exploiting autophagy to delay immune senescence and/or rejuvenate immunity to treat various age-related diseases. PMID:27395769

  7. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP).

    PubMed

    Broder, Karen R; Cortese, Margaret M; Iskander, John K; Kretsinger, Katrina; Slade, Barbara A; Brown, Kristin H; Mijalski, Christina M; Tiwari, Tejpratap; Weston, Emily J; Cohn, Amanda C; Srivastava, Pamela U; Moran, John S; Schwartz, Benjamin; Murphy, Trudy V

    2006-03-24

    During spring 2005, two tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) products formulated for use in adolescents (and, for one product, use in adults) were licensed in the United States (BOOSTRIX, GlaxoSmithKline Biologicals, Rixensart, Belgium [licensed May 3, 2005, for use in persons aged 10-18 years], and ADACEL, sanofi pasteur, Toronto, Ontario, Canada [licensed June 10, 2005, for use in persons aged 11-64 years]). Prelicensure studies demonstrated safety and efficacy against tetanus, diphtheria, and pertussis when Tdap was administered as a single booster dose to adolescents. To reduce pertussis morbidity in adolescents and maintain the standard of care for tetanus and diphtheria protection, the Advisory Committee on Immunization Practices (ACIP) recommends that: 1) adolescents aged 11-18 years should receive a single dose of Tdap instead of tetanus and diphtheria toxoids vaccine (Td) for booster immunization against tetanus, diphtheria, and pertussis if they have completed the recommended childhood diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTP)/ diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) vaccination series (five doses of pediatric DTP/DTaP before the seventh birthday; if the fourth dose was administered on or after the fourth birthday, the fifth dose is not needed) and have not received Td or Tdap. The preferred age for Tdap vaccination is 11-12 years; 2) adolescents aged 11-18 years who received Td, but not Tdap, are encouraged to receive a single dose of Tdap to provide protection against pertussis if they have completed the recommended childhood DTP/DTaP vaccination series. An interval of at least 5 years between Td and Tdap is encouraged to reduce the risk for local and systemic reactions after Tdap vaccination. However, an interval less than 5 years between Td and Tdap can be used; and 3) vaccine providers should administer Tdap and tetravalent meningococcal conjugate

  8. Saccharomyces cerevisiae strain 905 reduces the translocation of Salmonella enterica serotype Typhimurium and stimulates the immune system in gnotobiotic and conventional mice.

    PubMed

    Martins, Flaviano S; Rodrigues, Ana Cristina P; Tiago, Fabiana C P; Penna, Francisco J; Rosa, Carlos A; Arantes, Rosa M E; Nardi, Regina M D; Neves, Maria J; Nicoli, Jacques R

    2007-03-01

    Previous results in the laboratory of the authors showed that Saccharomyces cerevisiae strain 905, isolated during 'cachaça' production, was able to colonize and survive in the gastrointestinal tract of germ-free and conventional mice, and to protect these animals against oral challenge with Salmonella enterica serotype Typhimurium or Clostridium difficile. In the present work, the effects of S. cerevisiae 905 on the translocation of Salm. Typhimurium (mesenteric lymph nodes, Peyer's patches, spleen, liver) as well as on the immune system (number of Küpffer cells, immunoglobulin production, clearance of Escherichia coli B41) were evaluated in gnotobiotic and/or conventional mice. The treatment with the yeast reduced significantly the translocation of Salm. Typhimurium to liver in gnotobiotic animals and to all the organs tested in conventional mice. The number of Küpffer cells per 100 hepatocytes in liver was significantly higher (P<0.05) in yeast mono-associated mice (52.9+/-15.7) than in germ-free controls (38.1+/-9.0). Probably as a consequence, clearance of E. coli B41 from the bloodstream was more efficient in yeast mono-associated animals when compared to germ-free mice. Higher levels (P<0.05) of secretory IgA in intestinal content and of IgA and IgM in serum were observed in yeast mono-associated mice when compared to germ-free group. Concluding, the protection against pathogenic bacteria observed in a previous study was probably due to a modulation of both local and systemic immunity of mice treated with S. cerevisiae 905.

  9. Functional and mutational analyses of an omega-class glutathione S-transferase (GSTO2) that is required for reducing oxidative damage in Apis cerana cerana.

    PubMed

    Zhang, Y-Y; Guo, X-L; Liu, Y-L; Liu, F; Wang, H-F; Guo, X-Q; Xu, B-H

    2016-08-01

    Glutathione S-transferases perform a variety of vital functions, particularly in reducing oxidative damage. Here, we investigated the expression patterns of Apis cerana cerana omega-class glutathione S-transferase 2 (AccGSTO2) under various stresses and explored its connection with antioxidant defences. We found that AccGSTO2 knockdown by RNA interference triggered increased mortality in Ap. cerana cerana, and immunohistochemistry revealed significantly decreased AccGSTO2 expression, particularly in the midgut and fat body. Further analyses indicated that AccGSTO2 knockdown resulted in decreases in catalase and glutathione reductase activities, ascorbate content and the ratio of reduced to oxidized glutathione, and increases in H2 O2 , malondialdehyde and carbonyl contents. We also analysed the transcripts of other antioxidant genes and found that many genes were down-regulated in the AccGSTO2 knockdown samples, revealing that AccGSTO2 may be indispensable for attaining a normal lifespan by enhancing cellular oxidative resistance. In addition, the roles of cysteine residues in AccGSTO2 were explored using site-directed mutagenesis. Mutants of Cys(28) and Cys(124) significantly affected the enzyme and antioxidant activities of AccGSTO2, which may be attributed to the changes in the spatial structures of mutants as determined by homology modelling. In summary, these observations provide novel insight into the structural and functional characteristics of GSTOs. PMID:27170478

  10. 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

  11. Early MEK1/2 Inhibition after Global Cerebral Ischemia in Rats Reduces Brain Damage and Improves Outcome by Preventing Delayed Vasoconstrictor Receptor Upregulation

    PubMed Central

    Johansson, Sara Ellinor; Larsen, Stine Schmidt; Povlsen, Gro Klitgaard; Edvinsson, Lars

    2014-01-01

    Background Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence. Results Enhanced vasoconstriction peaked in fore- and midbrain arteries 3 days after ischemia. Neuronal cell death appeared initially in the hippocampus 3 days after ischemia and gradually increased until 7 days post-ischemia. Treatment with U0126 normalised cerebrovascular ETB and 5-HT1B receptor expression and contractile function, reduced hippocampal cell death and improved survival rate compared to vehicle treated animals. Conclusions Excessive cerebrovascular expression of contractile ETB and 5-HT1B receptors is a delayed response to global cerebral ischemia peaking 3 days after the insult, which likely contributes to the development of delayed neuronal damage. The enhanced cerebrovascular contractility can be

  12. Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine, adsorbed (Boostrix®): a review of its properties and use as a single-dose booster immunization.

    PubMed

    McCormack, Paul L

    2012-09-10

    Reduced-antigen, combined diphtheria, tetanus and three-component acellular pertussis vaccine (Tdap; Boostrix®) is indicated for booster vaccination against diphtheria, tetanus and pertussis in individuals from age four years onwards in Europe and from age 10 years onwards in the US. Compared with infant formulations used for primary vaccination, Tdap contains reduced quantities (10-50%) of all toxoids and antigens, which are adsorbed to either ≤0.39 mg/dose (US licensed formulation) or 0.5 mg/dose (rest-of-world formulation) of aluminium adjuvant. The reduced antigen content is designed to avoid the increasing reactogenicity historically seen with the fourth and fifth doses of infant vaccine. This article reviews the immunogenicity, protective efficacy and reactogenicity of Tdap booster administered to children, adolescents and adults, including those aged ≥65 years. In clinical trials, a single booster dose of Tdap induced seroprotective levels of antibodies to diphtheria and tetanus toxoids in virtually all children and adolescents, and in a high proportion of adults and elderly individuals at approximately 1 month post-vaccination irrespective of their vaccination history. In all age groups, seropositivity rates for antibodies against pertussis antigens were ≥90% (including in unvaccinated adolescents), and booster response rates were high. Tdap was safely co-administered with other common vaccines without significantly affecting the immune responses. The immunogenicity and reactogenicity profiles of booster doses of Tdap were generally similar to those of infant diphtheria-tetanus-whole-cell pertussis vaccine and infant diphtheria-tetanus-acellular pertussis vaccine in children aged 4-6 years, and infant diphtheria-tetanus vaccine in older children. In adolescents and adults, the immunogenicity and reactogenicity of Tdap were generally similar to those of reduced-antigen diphtheria-tetanus vaccine, reduced-antigen diphtheria

  13. 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

  14. Immune System

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immune System KidsHealth > For Teens > Immune System Print A A ... could put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  15. Adult immunization

    PubMed Central

    Mehta, Bharti; Chawla, Sumit; Kumar Dharma, Vijay; Jindal, Harashish; Bhatt, Bhumika

    2014-01-01

    Vaccination is recommended throughout life to prevent vaccine-preventable diseases and their sequel. The primary focus of vaccination programs has historically been directed to childhood immunizations. For adults, chronic diseases have been the primary focus of preventive and medical health care, though there has been increased emphasis on preventing infectious diseases. Adult vaccination coverage, however, remains low for most of the routinely recommended vaccines. Though adults are less susceptible to fall prey to traditional infectious agents, the probability of exposure to infectious agents has increased manifold owing to globalization and increasing travel opportunities both within and across the countries. Thus, there is an urgent need to address the problem of adult immunization. The adult immunization enterprise is more complex, encompassing a wide variety of vaccines and a very diverse target population. There is no coordinated public health infrastructure to support an adult immunization program as there is for children. Moreover, there is little coordination among adult healthcare providers in terms of vaccine provision. Substantial improvement in adult vaccination is needed to reduce the health consequences of vaccine-preventable diseases among adults. Routine assessment of adult patient vaccination needs, recommendation, and offer of needed vaccines for adults should be incorporated into routine clinical care of adults. PMID:24128707

  16. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses.

    PubMed

    Lee, Jong Kil; Jin, Hee Kyung; Endo, Shogo; Schuchman, Edward H; Carter, Janet E; Bae, Jae-Sung

    2010-02-01

    Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta peptide (Abeta) and the formation of neurofibrillary tangles. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been suggested as a potential therapeutic approach to prevent various neurodegenerative disorders, including AD. However, the actual therapeutic impact of BM-MSCs and their mechanism of action in AD have not yet been ascertained. The aim of this study was therefore to evaluate the therapeutic effect of BM-MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin one (PS1) double-transgenic mice. Here we show that intracerebral transplantation of BM-MSCs into APP/PS1 mice significantly reduced amyloid beta-peptide (Abeta) deposition. Interestingly, these effects were associated with restoration of defective microglial function, as evidenced by increased Abeta-degrading factors, decreased inflammatory responses, and elevation of alternatively activated microglial markers. Furthermore, APP/PS1 mice treated with BM-MSCs had decreased tau hyperphosphorylation and improved cognitive function. In conclusion, BM-MSCs can modulate immune/inflammatory responses in AD mice, ameliorate their pathophysiology, and improve the cognitive decline associated with Abeta deposits. These results demonstrate that BM-MSCs are a potential new therapeutic agent for AD.

  17. Reduced mitochondrial ROS, enhanced antioxidant defense, and distinct age-related changes in oxidative damage in muscles of long-lived Peromyscus leucopus.

    PubMed

    Shi, Yun; Pulliam, Daniel A; Liu, Yuhong; Hamilton, Ryan T; Jernigan, Amanda L; Bhattacharya, Arunabh; Sloane, Lauren B; Qi, Wenbo; Chaudhuri, Asish; Buffenstein, Rochelle; Ungvari, Zoltan; Austad, Steven N; Van Remmen, Holly

    2013-03-01

    Comparing biological processes in closely related species with divergent life spans is a powerful approach to study mechanisms of aging. The oxidative stress hypothesis of aging predicts that longer-lived species would have lower reactive oxygen species (ROS) generation and/or an increased antioxidant capacity, resulting in reduced oxidative damage with age than in shorter-lived species. In this study, we measured ROS generation in the young adult animals of the long-lived white-footed mouse, Peromyscus leucopus (maximal life span potential, MLSP = 8 yr) and the common laboratory mouse, Mus musculus (C57BL/6J strain; MLSP = 3.5 yr). Consistent with the hypothesis, our results show that skeletal muscle mitochondria from adult P. leucopus produce less ROS (superoxide and hydrogen peroxide) compared with M. musculus. Additionally, P. leucopus has an increase in the activity of antioxidant enzymes superoxide dismutase 1, catalase, and glutathione peroxidase 1 at young age. P. leucopus compared with M. musculus display low levels of lipid peroxidation (isoprostanes) throughout life; however, P. leucopus although having elevated protein carbonyls at a young age, the accrual of protein oxidation with age is minimal in contrast to the linear increase in M. musculus. Altogether, the results from young animals are in agreement with the predictions of the oxidative stress hypothesis of aging with the exception of protein carbonyls. Nonetheless, the age-dependent increase in protein carbonyls is more pronounced in short-lived M. musculus, which supports enhanced protein homeostasis in long-lived P. leucopus.

  18. 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.

  19. 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

    2015-03-01

    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

  20. 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-...

  1. Lactate Reduces Organ Injury in Toll-like Receptor- and Inflammasome-Mediated Inflammation via GPR81-mediated Suppression of Innate Immunity

    PubMed Central

    Hoque, Rafaz; Farooq, Ahmad; Ghani, Ayaz; Gorelick, Fred; Mehal, Wajahat Zafar

    2014-01-01

    BACKGROUND & AIMS The NLRP3 inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, GPR81, regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-IL1β, NLRP3, and CASP1; release of IL1β; and activation of NFκB and caspase 1. Small interfering (si)RNAs were used to reduce levels of GPR81andARRB2, and an NFκB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharaide (LPS) and D-galactosamine. Acute pancreatitis was induced by administration of LPS and caerulein. Some mice were given intraperitoneal injections of sodium lactate or siRNA against Gpr81. Activation of NFκB in tissue macrophages was assessed in mice that express a reporter transgene. RESULTS In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NFκB; release of IL1β; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. Administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NFκB in macrophages of mice, and when given following injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81. Lactate could be a promising

  2. 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

  3. [The ageing immune system].

    PubMed

    Djukic, M; Nau, R; Sieber, C

    2014-10-01

    The aging of the immune system, also called immunosenescence, contributes to the increased morbidity and mortality from infections, autoimmune diseases and cancer as well as to the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in cell-mediated immune function and by reduced humoral immune responses caused by age-related changes in the innate immune system and age-dependent defects in T-and B-cell function. This paper gives an overview of the most important modifications in the different compartments of the immune system during the ageing process.

  4. [The ageing immune system].

    PubMed

    Djukic, M; Nau, R; Sieber, C

    2014-10-01

    The aging of the immune system, also called immunosenescence, contributes to the increased morbidity and mortality from infections, autoimmune diseases and cancer as well as to the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in cell-mediated immune function and by reduced humoral immune responses caused by age-related changes in the innate immune system and age-dependent defects in T-and B-cell function. This paper gives an overview of the most important modifications in the different compartments of the immune system during the ageing process. PMID:25254392

  5. Hericium erinaceus mushroom extracts protect 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

    2012-06-01

    The present study investigated the antibacterial effect of four extracts from the fruitbody of the edible medicinal mushroom Hericium erinaceus (hot water extract, HWE; microwave/50% ethanol extract, MWE; acid extract, ACE; and alkaline extract, AKE) against murine salmonellosis. The extracts had no effect on Salmonella ser. Typhimurium growth in culture. Nor were the extracts toxic to murine macrophage cells, RAW 264.7. HWE and MWE stimulated uptake of the bacteria into the macrophage cells as indicated by increased colony-forming unit (CFU) counts of the contents of the lysed macrophages infected with Salmonella Typhimurium for 30 and 60 min. Two hours postinfection, the bacterial counts increased in the macrophages, but 4 and 8 h postinfection the HWE- and MWE-treated cells showed greater activity against the bacteria than the control. HWE- and MWE-treated noninfected macrophages had altered morphology and elevated inducible nitric oxide (NO) synthase (iNOS) mRNA expression. In the presence of S. Typhimurium, iNOS mRNA expression was further increased, accompanied by an increase in NO production. Histology assays of the livers of mice infected with a sublethal dose (1 × 10(4) CFU) of S. Typhimurium showed that HWE and MWE, administered by daily intraperitoneal injection, protected against necrosis of the liver, a biomarker of in vivo salmonellosis. The lifespans of mice similarly infected with a lethal dose of S. Typhimurium (1 × 10(5) CFU) were significantly extended by HWE and MWE. β-Glucan, known to stimulate the immune system, was previously found to be present in high amounts in the active extracts. These results suggest that the mushroom extract activities against bacterial infection in mice occur through the activation of innate immune cells.

  6. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease.

    PubMed

    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.

  7. 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

  8. Damage from dissection is associated with reduced neuro-musclar transmission and gap junction coupling between circular muscle cells of guinea pig ileum, in vitro.

    PubMed

    Carbone, Simona E; Wattchow, David A; Spencer, Nick J; Hibberd, Timothy J; Brookes, Simon J H

    2014-01-01

    Excitatory and inhibitory junction potentials of circular smooth muscle cells in guinea pig ileum and colon are suppressed 30-90 min after setting up in vitro preparations. We have previously shown this "unresponsive" period is associated with a transient loss of dye coupling between smooth muscle cells, which subsequently recovers over the ensuing 30-90 min; junction potentials recover in parallel with dye coupling (Carbone et al., 2012). Here, we investigated which components of dissection trigger the initial loss of coupling. Intracellular recordings were made from circular muscle cells of guinea pig ileum with micropipettes containing 5% carboxyfluorescein. After allowing 90-120 min for junction potentials to reach full amplitude, we re-cut all 4 edges of the preparation more than 1 mm from the recording sites. This caused a reduction in the amplitude of IJPs from 17.2 ± 0.7 mV to 9.5 ± 1.5 mV (P < 0.001, n = 12) and a significant reduction in dye couplin