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Sample records for attenuates secondary inflammatory

  1. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    NASA Astrophysics Data System (ADS)

    Borovikova, Lyudmila V.; Ivanova, Svetlana; Zhang, Minghuang; Yang, Huan; Botchkina, Galina I.; Watkins, Linda R.; Wang, Haichao; Abumrad, Naji; Eaton, John W.; Tracey, Kevin J.

    2000-05-01

    Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

  2. Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base

    PubMed Central

    Landis, R. Clive; Brown, Jeremiah R.; Fitzgerald, David; Likosky, Donald S.; Shore-Lesserson, Linda; Baker, Robert A.; Hammon, John W.

    2014-01-01

    Abstract: A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture “self-identified” anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the “Outcomes 2010” consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a “multiple hit” hypothesis, whereby clinically effective suppression of the systemic inflammatory response

  3. Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base.

    PubMed

    Landis, R Clive; Brown, Jeremiah R; Fitzgerald, David; Likosky, Donald S; Shore-Lesserson, Linda; Baker, Robert A; Hammon, John W

    2014-09-01

    A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture "self-identified" anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the "Outcomes 2010" consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a "multiple hit" hypothesis, whereby clinically effective suppression of the systemic inflammatory response requires hitting multiple

  4. Sleep deprivation attenuates inflammatory responses and ischemic cell death.

    PubMed

    Weil, Zachary M; Norman, Greg J; Karelina, Kate; Morris, John S; Barker, Jacqueline M; Su, Alan J; Walton, James C; Bohinc, Steven; Nelson, Randy J; DeVries, A Courtney

    2009-07-01

    Although the biological function of sleep remains uncertain, the consequences of sleep deprivation are well-described and are reported to be detrimental to cognitive function and affective well-being. Sleep deprivation also is strongly associated with elevated risk factors for cardiovascular disease. We used a mouse model of cardiac arrest/cardiopulmonary resuscitation to test the hypothesis that acute sleep deprivation would exacerbate neuroinflammation and neurodegeneration after global ischemia. The resulting data led to a rejection of our hypothesis that sleep deprivation is necessarily detrimental. Indeed, acute sleep deprivation (ASD) was associated with a reduction in ischemia-induced interleukin 1beta (IL-1beta) gene expression and attenuation of neuronal damage in the hippocampus. Further, sleep deprivation increased gene expression of two anti-inflammatory cytokines, IL-6 and IL-10 that are associated with improved ischemic outcome. To determine whether the anti-inflammatory properties of ASD were specific to ischemia, mice were treated systemically with lipopolysaccharide (LPS), a potent inflammogen. Acute sleep deprivation attenuated the central and peripheral increase in tumor necrosis factor-alpha (TNFalpha) and increased IL-10 expression. Together, the ischemia and LPS data suggest that, ASD produces an anti-inflammatory bias that could be exploited to improve medical procedures that are compromised by inflammation. PMID:19409382

  5. Glucocorticoid-Induced Attenuation of the Inflammatory Response in Zebrafish.

    PubMed

    Chatzopoulou, Antonia; Heijmans, Jeroen P M; Burgerhout, Erik; Oskam, Nienke; Spaink, Herman P; Meijer, Annemarie H; Schaaf, Marcel J M

    2016-07-01

    Glucocorticoids are steroid hormones that are secreted upon stress. Their effects are mediated by the glucocorticoid receptor, which acts as a transcription factor. Because the antiinflammatory activity of glucocorticoids has been well established, they are widely used clinically to treat many inflammatory and immune-related diseases. However, the exact specificity, mechanisms, and level of regulation of different inflammatory pathways have not been fully elucidated. In the present study, a tail fin amputation assay was used in 3-day-old zebrafish larvae to study the immunomodulatory effects of the synthetic glucocorticoid beclomethasone. First, a transcriptome analysis was performed, which showed that upon amputation mainly immune-related genes are regulated. This regulation was inhibited by beclomethasone for 86% of regulated genes. For two immune-related genes, tlr4bb and alox5ap, the amputation-induced increase was not attenuated by beclomethasone. Alox5ap is involved in eicosanoid biosynthesis, but the increase in leukotriene B4 concentration upon amputation was abolished, and lipoxin A4 levels were unaffected by beclomethasone. Furthermore, we studied the migration of neutrophils and macrophages toward the wound site. Our results show that amputation induced migration of both types of leukocytes and that this migration was dependent on de novo protein synthesis. Beclomethasone treatment attenuated the migratory behavior of neutrophils in a glucocorticoid receptor-dependent manner but left the migration of macrophages unaffected. In conclusion, beclomethasone has a dramatic inhibitory effect on the amputation-induced proinflammatory gene regulation, and this is reflected in an inhibition of the neutrophil migration but not the migration of macrophages, which are likely to be involved in inflammation resolution. PMID:27219276

  6. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis

    PubMed Central

    Masterson, Joanne C; McNamee, Eóin N; Fillon, Sophie A; Hosford, Lindsay; Harris, Rachel; Fernando, Shahan D; Jedlicka, Paul; Iwamoto, Ryo; Jacobsen, Elizabeth; Protheroe, Cheryl; Eltzschig, Holger K; Colgan, Sean P; Arita, Makoto; Lee, James J; Furuta, Glenn T

    2015-01-01

    Objective Eosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice. Design Acute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy. Results Eosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration. Conclusions Eosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid

  7. Arsenic cycling in hydrocarbon plumes: secondary effects of natural attenuation

    USGS Publications Warehouse

    Cozzarelli, Isabelle M.; Schreiber, Madeline E.; Erickson, Melinda L.; Ziegler, Brady A.

    2016-01-01

    Monitored natural attenuation is widely applied as a remediation strategy at hydrocarbon spill sites. Natural attenuation relies on biodegradation of hydrocarbons coupled with reduction of electron acceptors, including solid phase ferric iron (Fe(III)). Because arsenic (As) adsorbs to Fe-hydroxides, a potential secondary effect of natural attenuation of hydrocarbons coupled with Fe(III) reduction is a release of naturally occurring As to groundwater. At a crude-oil-contaminated aquifer near Bemidji, Minnesota, anaerobic biodegradation of hydrocarbons coupled to Fe(III) reduction has been well documented. We collected groundwater samples at the site annually from 2009 to 2013 to examine if As is released to groundwater and, if so, to document relationships between As and Fe inside and outside of the dissolved hydrocarbon plume. Arsenic concentrations in groundwater in the plume reached 230 µg/L, whereas groundwater outside the plume contained less than 5 µg/L As. Combined with previous data from the Bemidji site, our results suggest that (1) naturally occurring As is associated with Fe-hydroxides present in the glacially derived aquifer sediments; (2) introduction of hydrocarbons results in reduction of Fe-hydroxides, releasing As and Fe to groundwater; (3) at the leading edge of the plume, As and Fe are removed from groundwater and retained on sediments; and (4) downgradient from the plume, patterns of As and Fe in groundwater are similar to background. We develop a conceptual model of secondary As release due to natural attenuation of hydrocarbons that can be applied to other sites where an influx of biodegradable organic carbon promotes Fe(III) reduction.

  8. Arsenic Cycling in Hydrocarbon Plumes: Secondary Effects of Natural Attenuation.

    PubMed

    Cozzarelli, Isabelle M; Schreiber, Madeline E; Erickson, Melinda L; Ziegler, Brady A

    2016-01-01

    Monitored natural attenuation is widely applied as a remediation strategy at hydrocarbon spill sites. Natural attenuation relies on biodegradation of hydrocarbons coupled with reduction of electron acceptors, including solid phase ferric iron (Fe(III)). Because arsenic (As) adsorbs to Fe-hydroxides, a potential secondary effect of natural attenuation of hydrocarbons coupled with Fe(III) reduction is a release of naturally occurring As to groundwater. At a crude-oil-contaminated aquifer near Bemidji, Minnesota, anaerobic biodegradation of hydrocarbons coupled to Fe(III) reduction has been well documented. We collected groundwater samples at the site annually from 2009 to 2013 to examine if As is released to groundwater and, if so, to document relationships between As and Fe inside and outside of the dissolved hydrocarbon plume. Arsenic concentrations in groundwater in the plume reached 230 µg/L, whereas groundwater outside the plume contained less than 5 µg/L As. Combined with previous data from the Bemidji site, our results suggest that (1) naturally occurring As is associated with Fe-hydroxides present in the glacially derived aquifer sediments; (2) introduction of hydrocarbons results in reduction of Fe-hydroxides, releasing As and Fe to groundwater; (3) at the leading edge of the plume, As and Fe are removed from groundwater and retained on sediments; and (4) downgradient from the plume, patterns of As and Fe in groundwater are similar to background. We develop a conceptual model of secondary As release due to natural attenuation of hydrocarbons that can be applied to other sites where an influx of biodegradable organic carbon promotes Fe(III) reduction. PMID:25612004

  9. Barotrauma secondary to inflammatory maxillary sinus polyp: a case report.

    PubMed

    Baughman, Steven M; Brennan, Joseph

    2002-11-01

    Sinus barotrauma, secondary to mucosal disturbances, is a common finding within the aviation community. Multiple etiologies have all led to mucosal inflammation and thickening with potential obstruction of the sinus osteomeatal complex, especially during the barometric changes of flight. Obstruction can, therefore, lead to problems with sinus pressure equilibration with atmospheric pressure, and can lead to barosinusitis. We present a case of a U.S. Air Force Command Pilot with acute left sinus barotrauma during descent while flying a T-37 aircraft, along with a brief review of the pathophysiologic processes involved during barotrauma. An inflammatory polyp within his sinus was identified by plain radiography, confirmed with computed tomography, and subsequently excised. The patient had complete resolution and clearance to fly after an uneventful 4-wk convalescence and altitude chamber flight. This is the first case of sinus barotrauma secondary to an inflammatory maxillary sinus polyp, confirmed by histologic diagnosis, reported in the aeromedical literature. PMID:12433240

  10. Selective Inhibition of Matrix Metalloproteinase-9 Attenuates Secondary Damage Resulting from Severe Traumatic Brain Injury

    PubMed Central

    Gooyit, Major; Chen, Shanyan; Purdy, Justin J.; Walker, Jennifer M.; Giritharan, Andrew B.; Purnell, Whitley; Robinson, Christopher R.; Shin, Dmitriy; Schroeder, Valerie A.; Suckow, Mark A.; Simonyi, Agnes; Y. Sun, Grace; Mobashery, Shahriar; Cui, Jiankun; Chang, Mayland; Gu, Zezong

    2013-01-01

    Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, p-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor–with such desirable pharmacokinetic properties–holds considerable promise as a potential pharmacological treatment of TBI. PMID:24194849

  11. Benfotiamine Attenuates Inflammatory Response in LPS Stimulated BV-2 Microglia

    PubMed Central

    Bozic, Iva; Savic, Danijela; Laketa, Danijela; Bjelobaba, Ivana; Milenkovic, Ivan; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

    2015-01-01

    Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may

  12. Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy

    PubMed Central

    Cham, Abdourahman; Bansal, Mayank; Banda, Himanshu K; Kwon, Young; Tlucek, Paul S; Bassuk, Alexander G; Tsang, Stephen H; Sobol, Warren M; Folk, James C; Yeh, Steven; Mahajan, Vinit B

    2016-01-01

    Objective The objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5. Patients and methods A retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed. Results Nine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT. Conclusion ADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony. PMID:27390515

  13. BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.

    PubMed

    Chen, Jinjing; Wang, Zhen; Hu, Xiangming; Chen, Ruichuan; Romero-Gallo, Judith; Peek, Richard M; Chen, Lin-Feng

    2016-05-15

    Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer. PMID:27084101

  14. Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis

    PubMed Central

    Adán, Norma; Guzmán-Morales, Jessica; Ledesma-Colunga, Maria G.; Perales-Canales, Sonia I.; Quintanar-Stéphano, Andrés; López-Barrera, Fernando; Méndez, Isabel; Moreno-Carranza, Bibiana; Triebel, Jakob; Binart, Nadine; Martínez de la Escalera, Gonzalo; Thebault, Stéphanie; Clapp, Carmen

    2013-01-01

    Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3–dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor–null (Prlr–/–) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA. PMID:23908112

  15. Brazilian Red Propolis Attenuates Inflammatory Signaling Cascade in LPS-Activated Macrophages

    PubMed Central

    Bueno-Silva, Bruno; Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Alencar, Severino M.; Rosalen, Pedro L.; Mayer, Marcia P. A.

    2015-01-01

    Although previous studies suggested an anti-inflammatory property of Brazilian red propolis (BRP), the mechanisms involved in the anti-inflammatory effects of BRP and its activity on macrophages were still not elucidated. This study aimed to evaluate whether BRP attenuates the inflammatory effect of LPS on macrophages and to investigate its underlying mechanisms. BRP was added to RAW 264.7 murine macrophages after activation with LPS. NO production, cell viability, cytokines profile were evaluated. Activation of inflammatory signaling pathways and macrophage polarization were determined by RT-qPCR and Western blot. BRP at 50 μg/ml inhibited NO production by 78% without affecting cell viability. Cd80 and Cd86 were upregulated whereas mrc1 was down regulated by BRP indicating macrophage polarization at M1. BRP attenuated the production of pro-inflammatory mediators IL-12, GM-CSF, IFN-Ɣ, IL-1β in cell supernatants although levels of TNF- α and IL-6 were slightly increased after BRP treatment. Levels of IL-4, IL-10 and TGF-β were also reduced by BRP. BRP significantly reduced the up-regulation promoted by LPS of transcription of genes in inflammatory signaling (Pdk1, Pak1, Nfkb1, Mtcp1, Gsk3b, Fos and Elk1) and of Il1β and Il1f9 (fold-change rate > 5), which were further confirmed by the inhibition of NF-κB and MAPK signaling pathways. Furthermore, the upstream adaptor MyD88 adaptor-like (Mal), also known as TIRAP, involved in TLR2 and TLR4 signaling, was down- regulated in BRP treated LPS-activated macrophages. Given that BRP inhibited multiple signaling pathways in macrophages involved in the inflammatory process activated by LPS, our data indicated that BRP is a noteworthy food-source for the discovery of new bioactive compounds and a potential candidate to attenuate exhacerbated inflammatory diseases. PMID:26660901

  16. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  17. Angiotensin peptides attenuate platelet-activating factor-induced inflammatory activity in rats.

    PubMed

    Sato, Akira; Yokoyama, Izumi; Ebina, Keiichi

    2015-11-01

    Angiotensin (Ang)--a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF. PMID:26348270

  18. Digibind attenuates cytokine TNFα-induced endothelial inflammatory response: potential benefit role of Digibind in preeclampsia

    PubMed Central

    Wang, Y; Lewis, DF; Adair, CD; Gu, Y; Mason, L; Kipikasa, JH

    2011-01-01

    Objective Exaggerated inflammatory response occurs in preeclampsia. Preeclampsia is also associated with elevated endogenous digoxin-like factors (EDLFs). Clinical data suggest that Digibind (a polyclonal sheep digoxin binding Fab fragment) binds to EDLF and may have the potential to attenuate vasoconstriction and other clinical symptoms of preeclampsia. This study was undertaken to determine if Digibind could attenuate increased endothelial inflammatory response induced by tumor necrosis factor-α (TNFα). Study Design Confluent endothelial cells were treated with TNFα at different concentrations with or without Digibind in culture. Endothelial adhesion molecule ICAM, VCAM and E-selectin expressions were determined by an immunoassay directly detected on the endothelial surface. Effects of Digibind on TNFα-induced extracellular signal-regulated kinase and Na+/K+-ATPase expressions were also examined. Result (1) TNFα induced dose-dependent increases in ICAM, VCAM and E-selectin expressions in endothelial cells; (2) Digibind could attenuate and reduce TNFα-induced upregulation of endothelial E-selectin, ICAM and VCAM expressions. The blocking effect was in a concentration dependent manner; (3) Digibind had no effects on TNFα-induced upregulation of extracellular signal-regulated kinase phosphorylation, but could block TNFα-induced downregulation of Na+/K+-ATPase β1 expression. Conclusion Digibind may exert beneficial effects by preserving cell membrane Na+/K+-ATPase function and consequently to offset increased inflammatory response in endothelial cells. PMID:19148111

  19. Dexamethasone Coated Neural Probes Elicit Attenuated Inflammatory Response and Neuronal Loss Compared to Uncoated Neural Probes

    PubMed Central

    Zhong, Yinghui; Bellamkonda, Ravi V.

    2007-01-01

    Glial scar formation around implanted silicon neural probes compromises their ability to facilitate long-term recordings. One approach to modulate the tissue reaction around implanted probes in the brain is to develop probe coatings that locally release antiinflammatory drugs. In this study, we developed a nitrocellulose-based coating for the local delivery of the anti-inflammatory drug dexamethasone (DEX). Silicon neural probes with and without nitrocellulose-DEX coatings were implanted into rat brains, and inflammatory response was evaluated 1 week and 4 weeks post implantation. DEX coatings significantly reduced the reactivity of microglia and macrophages one week post implantation as evidenced by ED1 immunostaining. CS56 staining demonstrated that DEX treatment significantly reduced chondroitin sulfate proteoglycan (CSPG) expression one week post implantation. Both at one week and at four week time points, GFAP staining for reactive astrocytes and neurofilament (NF) staining revealed that local DEX treatment significantly attenuated astroglial response and reduced neuronal loss in the vicinity of the probes. Weak ED1, neurocan, and NG2 positive signal was detected four weeks post implantation for both coated and uncoated probes, suggesting a stabilization of the inflammatory response over time in this implant model. In conclusion, this study demonstrates that the nitrocellulose-DEX coating can effectively attenuate the inflammatory response to the implanted neural probes, and reduce neuronal loss in the vicinity of the coated probes. Thus anti-inflammatory probe coatings may represent a promising approach to attenuate astroglial scar and reduce neural loss around implanted neural probes. PMID:17376408

  20. Pycnogenol attenuates the inflammatory and nitrosative stress on joint inflammation induced by urate crystals.

    PubMed

    Peng, Yi-Jen; Lee, Chian-Her; Wang, Chih-Chien; Salter, Donald M; Lee, Herng-Sheng

    2012-02-15

    Acute gouty arthritis results from monosodium urate (MSU) crystal deposition in joint tissues. Deposited MSU crystals induce an acute inflammatory response which leads to damage of joint tissue. Pycnogenol (PYC), an extract from the bark of Pinus maritime, has documented antiinflammatory and antioxidant properties. The present study aimed to investigate whether PYC had protective effects on MSU-induced inflammatory and nitrosative stress in joint tissues both in vitro and in vivo. MSU crystals upregulated cyclooxygenase 2 (COX-2), interleukin 8 (IL-8) and inducible nitric oxide synthase (iNOS) gene expression in human articular chondrocytes, but only COX-2 and IL-8 in synovial fibroblasts. PYC inhibited the up-regulation of COX-2, and IL-8 in both articular chondrocytes and synovial fibroblasts. PYC attenuated MSU crystal induced iNOS gene expression and NO production in chondrocytes. Activation of NF-κB and SAPK/JNK, ERK1/2 and p38 MAP kinases by MSU crystals in articular chondrocytes and synovial fibroblasts in vitro was attenuated by treatment with PYC. The acute inflammatory cell infiltration and increased expression of COX-2 and iNOS in synovial tissue and articular cartilage following intra-articular injection of MSU crystals in a rat model was inhibited by coadministration of PYC. Collectively, this study demonstrates that PYC may be of value in treatment of MSU crystal-induced arthritis through its anti-inflammatory and anti-nitrosative activities. PMID:22198264

  1. Red laser attenuation in biological tissues: study of the inflammatory process and pigmentation influence

    NASA Astrophysics Data System (ADS)

    Sabino, Caetano P.; Meneguzzo, Daiane T.; Benetti, Endi; Kato, Ilka T.; Prates, Renato A.; Ribeiro, Martha S.

    2012-03-01

    Several studies indicate that low level laser therapy (LLLT) accelerates the healing process, however, for a determined pathology, dosimetry remains difficult to be established. To understand the tissue optical properties under different conditions is extremely relevant since the dose delivered to the target tissue is known to be critical. The skin pigmentation influence on the laser attenuation is not yet well established on different mice lineages or human ethnical groups, making the dose problematic. Along the same line, inflammatory processes may cause similar problems since the tissues in this condition change their optical properties due to inflammatory cell accumulation. This work evaluated the attenuation pattern of a HeNe laser (λ=632.8 nm) using ex vivo skin samples from Balb/C and C57BL/6 mice under inflammatory stages induced in their paw by local carrageenan inoculation. The samples were placed between two microscope slides, and a CCD camera was placed orthogonal to the beam path. The intensity distribution of the scattered light was photographed in grayscale and analyzed by ImageJ software. Our findings suggest that even slight differences of the epithelial pigmentation could result in a relevant dose loss delivered to the deeper tissues. The increase of the inflammatory cell density in the connective tissue indicated a highly scattering area also resulting in a dose loss for the deeper tissues when compared to control group.

  2. Lactodifucotetraose, a human milk oligosaccharide, attenuates platelet function and inflammatory cytokine release.

    PubMed

    Newburg, David S; Tanritanir, Ayse C; Chakrabarti, Subrata

    2016-07-01

    Human milk strongly quenches inflammatory processes in vitro, and breastfed infants have lower incidence of inflammatory diseases than those fed artificially. Platelets from neonates, in contrast to those from adults, are less responsive to platelet agonists such as collagen, thrombin, ADP, and epinephrine. Breastfed infants absorb oligosaccharides intact from the human milk in their gut to the circulation. This study was to determine whether these oligosaccharides can attenuate platelet function and platelet secretion of pro-inflammatory proteins, and to identify the active component. The natural mixture of oligosaccharides from human milk and pure individual human milk oligosaccharides were tested for their ability to modulate responses of platelets isolated from human blood following exposure to thrombin, ADP, and collagen. Human milk and the natural mixture of human milk oligosaccharides inhibited platelet release of inflammatory proteins. Of the purified human milk oligosaccharides tested, only lactodifucotetraose (LDFT) significantly inhibited thrombin induced release of the pro-inflammatory proteins RANTES and sCD40L. LDFT also inhibited platelet adhesion to a collagen-coated surface, as well as platelet aggregation induced by ADP or collagen. These data indicate that LDFT may help modulate hemostasis by suppressing platelet-induced inflammatory processes in breastfed infants. This activity suggests further study of LDFT for its potential as a therapeutic agent in infants and adults. PMID:26743063

  3. Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation

    PubMed Central

    2012-01-01

    Background Ethyl pyruvate (EP) possesses anti-inflammatory activity. However, the potential anti-nociceptive value of EP for the treatment of the inflammatory nociception is largely unknown. We investigated whether EP could have any anti-nociceptive effect on inflammatory pain, after systemic administration of EP (10, 50, and 100 mg/kg, i.p.), 1 hour before formalin (5%, 50 μl) injection into the plantar surface of the hind paws of rats. Results EP significantly decreased formalin-induced nociceptive behavior during phase II, the magnitude of paw edema, and the activation of c-Fos in L4-L5 spinal dorsal horn. EP also attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) in the neurons of L4-L5 spinal dorsal horn after formalin injection. Interestingly, the i.t. administration of PD98059, an ERK upstream kinase (MEK) inhibitor, completely blocked the formalin-induced inflammatory nociceptive responses. Conclusions These results demonstrate that EP may effectively inhibit formalin-induced inflammatory nociception via the inhibition of neuronal ERK phosphorylation in the spinal dorsal horn, indicating its therapeutic potential in suppressing acute inflammatory pain. PMID:22640699

  4. A murine model of stress controllability attenuates Th2-dominant airway inflammatory responses

    PubMed Central

    Deshmukh, Aniket; Kim, Byung-Jin; Gonzales, Xavier; Caffrey, James; Vishwanatha, Jamboor; Jones, Harlan P.

    2010-01-01

    Epidemiological and experimental studies suggest a positive correlation between chronic respiratory inflammatory disease and the ability to cope with adverse stress. Interactions between neuroendocrine and immune systems are believed to provide insight toward the biological mechanisms of action. The utility of an experimental murine model was employed to investigate the immunological consequences of stress-controllability and ovalbumin-induced airway inflammation. Pre-conditioned uncontrollable stress exacerbated OVA-induced lung histopathological changes that were typical of Th2-predominant inflammatory response along respiratory tissues. Importantly, mice given the ability to exert control over aversive stress attenuated inflammatory responses and reduced lung pathology. This model represents a means of investigating the neuro-immune axis in defining mechanisms of stress and respiratory disease. PMID:20462642

  5. dl-2-Hydroxyisocaproic Acid Attenuates Inflammatory Responses in a Murine Candida albicans Biofilm Model

    PubMed Central

    Nieminen, M. T.; Hernandez, M.; Novak-Frazer, L.; Kuula, H.; Ramage, G.; Bowyer, P.; Warn, P.; Sorsa, T.

    2014-01-01

    Chronic biofilm infections are often accompanied by a chronic inflammatory response, leading to impaired healing and increased, irreversible damage to host tissues. Biofilm formation is a major virulence factor for Candida albicans and a challenge for treatment. Most current antifungals have proved ineffective in eradicating infections attributed to biofilms. The biofilm structure protects Candida species against antifungals and provides a way for them to evade host immune systems. This leads to a very distinct inflammatory response compared to that seen in planktonic infections. Previously, we showed the superior efficacy of dl-2-hydroxyisocaproic acid (HICA) against various bacteria and fungi. However, the immunomodulatory properties of HICA have not been studied. Our aim was to investigate the potential anti-inflammatory response to HICA in vivo. We hypothesized that HICA reduces the levels of immune mediators and attenuates the inflammatory response. In a murine model, a robust biofilm was formed for 5 days in a diffusion chamber implanted underneath mouse skin. The biofilm was treated for 12 h with HICA, while caspofungin and phosphate-buffered saline (PBS) were used as controls. The pathophysiology and immunoexpression in the tissues surrounding the chamber were determined by immunohistochemistry. Histopathological examination showed an attenuated inflammatory response together with reduced expression of matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) compared to those of chambers containing caspofungin and PBS. Interestingly, the expression of developmental endothelial locus 1 (Del-1), an antagonist of neutrophil extravasation, increased after treatment with HICA. Considering its anti-inflammatory and antimicrobial activity, HICA may have enormous therapeutic potential in the treatment of chronic biofilm infections and inflammation, such as those seen with chronic wounds. PMID:24990903

  6. Human adipose-derived stem cells attenuate inflammatory bowel disease in IL-10 knockout mice.

    PubMed

    Jung, Woo Yeun; Kang, Joo Hwan; Kim, Kyung Gon; Kim, Hee Snn; Jang, Byung Ik; Park, Yong Hoon; Song, In-Hwan

    2015-02-01

    Inflammatory bowel disease (IBD) is a complex immunological disorder characterized by chronic inflammation caused mainly by unknown factors. The interleukin-10 knockout (IL-10 KO) mouse is a well-established murine model of IBD which develops spontaneous intestinal inflammation that resembles Crohn's disease. In the present study, human adipose-derived mesenchymal stem cells (hAMSCs) were administrated to IL-10 KO mice to evaluate the anti-inflammatory effects of hAMSCs that may attenuate the progress of or treat IBD. After IBD was induced by feeding the IL-10 KO mouse a 125-250 ppm piroxicam mixed diet for 1 week, 2×10(6) hAMSCs were injected into the peritoneum and the mice were switched to a normal diet. After 1 week, the mice were sacrificed and tissue samples were harvested. Tissue scores for inflammation and inflammation-related genes expression were determined. The hAMSC-treated group showed significantly reduced inflammatory changes in histological analysis. Reverse transcription-PCR analysis showed that RANTES, Toll-like receptor 9, and IL-4 expression levels were not significantly different between the groups while IL-12, INF-γ, and TNF-α levels were significantly decreased in the hAMSC treated group. hAMSC attenuated IBD in the IL-10 KO mice by suppressing inflammatory cytokine expression, was mediated by the type 1 helper T cell pathway. Even though only a single injection of hAMSCs was delivered, the effect influenced chronic events associated with inflammatory changes and demonstrated that hAMSCs are a powerful candidate for IBD therapy. PMID:25544730

  7. Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection

    PubMed Central

    Howe, Charles L.; LaFrance-Corey, Reghann G.; Sundsbak, Rhianna S.; Sauer, Brian M.; LaFrance, Stephanie J.; Buenz, Eric J.; Schmalstieg, William F.

    2012-01-01

    Neuronal injury during acute viral infection of the brain is associated with the development of persistent cognitive deficits and seizures in humans. In C57BL/6 mice acutely infected with the Theiler's murine encephalomyelitis virus, hippocampal CA1 neurons are injured by a rapid innate immune response, resulting in profound memory deficits. In contrast, infected SJL and B6xSJL F1 hybrid mice exhibit essentially complete hippocampal and memory preservation. Analysis of brain-infiltrating leukocytes revealed that SJL mice mount a sharply attenuated inflammatory monocyte response as compared to B6 mice. Bone marrow transplantation experiments isolated the attenuation to the SJL immune system. Adoptive transfer of B6 inflammatory monocytes into acutely infected B6xSJL hosts converted these mice to a hippocampal damage phenotype and induced a cognitive deficit marked by failure to recognize a novel object. These findings show that inflammatory monocytes are the critical cellular mediator of hippocampal injury during acute picornavirus infection of the brain. PMID:22848791

  8. Silencing MR-1 attenuates inflammatory damage in mice heart induced by AngII

    SciTech Connect

    Dai, Wenjian; Chen, Haiyang; Jiang, Jiandong; Kong, Weijia; Wang, Yiguang

    2010-01-15

    Myofibrillogenesis regulator-1(MR-1) can aggravate cardiac hypertrophy induced by angiotensin(Ang) II in mice through activation of NF-{kappa}B signaling pathway, and nuclear transcription factor (NF)-{kappa}B and activator protein-1(AP-1) regulate inflammatory and immune responses by increasing the expression of specific inflammatory genes in various tissues including heart. Whether inhibition of MR-1 expression will attenuate AngII-induced inflammatory injury in mice heart has not been explored. Herein, we monitored the activation of NF-{kappa}B and AP-1, together with expression of pro-inflammatory of interleukin(IL)-6, tumor necrosis factor(TNF)-{alpha}, vascular-cell adhesion molecule (VCAM)-1, platelet endothelial cell adhesion molecule (PECAM), and inflammatory cell infiltration in heart of mice which are induced firstly by AngII (PBS),then received MR-1-siRNA or control-siRNA injecting. We found that the activation of NF-{kappa}B and AP-1 was inhibited significantly, together with the decreased expression of IL-6, TNF-{alpha}, VCAM-1, and PECAM in AngII-induced mice myocardium in MR-1-siRNA injection groups compared with control-siRNA injecting groups. However, the expression level of MR-1 was not an apparent change in PBS-infused groups than in unoperation groups, and MR-1-siRNA do not affect the expression of MR-1 in PBS-infused mice. Our findings suggest that silencing MR-1 protected mice myocardium against inflammatory injury induced by AngII by suppression of pro-inflammatory transcription factors NF-{kappa}B and AP-1 signaling pathway.

  9. Systemic Pregabalin Attenuates Sensorimotor Responses and Medullary Glutamate Release in Inflammatory Tooth Pain Model

    PubMed Central

    Narita, Noriyuki; Kumar, Naresh; Cherkas, Pavel S.; Chiang, Chen Yu; Dostrovsky, Jonathan O.; Coderre, Terence J.; Sessle, Barry J.

    2012-01-01

    Our previous studies have demonstrated that application to the tooth pulp of the inflammatory irritant mustard oil (MO) induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0~1.2 %), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (ANOVA, p<0.05). These results suggest that pregabalin may attenuate the medullary release of glutamate and associated nociceptive sensorimotor responses in this acute inflammatory pulpal pain model, and that it may prove useful for the treatment of orofacial inflammatory pain states

  10. Systemic pregabalin attenuates sensorimotor responses and medullary glutamate release in inflammatory tooth pain model.

    PubMed

    Narita, N; Kumar, N; Cherkas, P S; Chiang, C Y; Dostrovsky, J O; Coderre, T J; Sessle, B J

    2012-08-30

    Our previous studies have demonstrated that application of inflammatory irritant mustard oil (MO) to the tooth pulp induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0-1.2%), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (analysis of variance (ANOVA), p<0.05). These results suggest that pregabalin may attenuate the medullary release of glutamate and associated nociceptive sensorimotor responses in this acute inflammatory pulpal pain model, and that it may prove useful for the treatment of orofacial

  11. LXW7 ameliorates focal cerebral ischemia injury and attenuates inflammatory responses in activated microglia in rats

    PubMed Central

    Fang, T.; Zhou, D.; Lu, L.; Tong, X.; Wu, J.; Yi, L.

    2016-01-01

    Inflammation plays a pivotal role in ischemic stroke, when activated microglia release excessive pro-inflammatory mediators. The inhibition of integrin αvβ3 improves outcomes in rat focal cerebral ischemia models. However, the mechanisms by which microglia are neuroprotective remain unclear. This study evaluated whether post-ischemic treatment with another integrin αvβ3 inhibitor, the cyclic arginine-glycine-aspartic acid (RGD) peptide-cGRGDdvc (LXW7), alleviates cerebral ischemic injury. The anti-inflammatory effect of LXW7 in activated microglia within rat focal cerebral ischemia models was examined. A total of 108 Sprague-Dawley rats (250–280 g) were subjected to middle cerebral artery occlusion (MCAO). After 2 h, the rats were given an intravenous injection of LXW7 (100 μg/kg) or phosphate-buffered saline (PBS). Neurological scores, infarct volumes, brain water content (BWC) and histology alterations were determined. The expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], and Iba1-positive activated microglia, within peri-ischemic brain tissue, were assessed with ELISA, western blot and immunofluorescence staining. Infarct volumes and BWC were significantly lower in LXW7-treated rats compared to those in the MCAO + PBS (control) group. The LXW7 treatment lowered the expression of pro-inflammatory cytokines. There was a reduction of Iba1-positive activated microglia, and the TNF-α and IL-1β expressions were attenuated. However, there was no difference in the Zea Longa scores between the ischemia and LXW7 groups. The results suggest that LXW7 protected against focal cerebral ischemia and attenuated inflammation in activated microglia. LXW7 may be neuroprotective during acute MCAO-induced brain damage and microglia-related neurodegenerative diseases. PMID:27533766

  12. Myrrh attenuates oxidative and inflammatory processes in acetic acid-induced ulcerative colitis

    PubMed Central

    Fatani, Amal Jamil; Alrojayee, Fatima Salih; Parmar, Mihir Yogeshkumar; Abuohashish, Hatem Mustafa; Ahmed, Mohammed Mahboobuddin; Al-Rejaie, Salim Salih

    2016-01-01

    The pathogenesis of ulcerative colitis (UC) has been associated with a weakened antioxidant capacity and increased inflammatory processes. Myrrh is traditionally used for the treatment of inflammatory diseases due to its antioxidant and anti-inflammatory properties. The present study aimed to evaluate the effects of myrrh on an experimental rat model of UC. UC was induced in rats using acetic acid (AA) after pre-treatment with myrrh (125, 250 or 500 mg/kg/day) or mesalazine (MES; 300 mg/kg/day) for 7 days. The levels of various inflammatory cytokines, prostaglandin E2 (PGE2) and nitric oxide (NO) in the rat colon tissues were assessed. In addition, the colonic levels of thiobarbituric acid reactive substances (TBARS) and non-protein sulfhydryl groups (NP-SH), as well as the activities of superoxide dismutase (SOD) and catalase (CAT), were estimated. Furthermore, total protein (TP) contents and the levels of DNA and RNA were measured, and histopathological changes in colonic tissues were analyzed. The results indicated that the levels of pro-inflammatory cytokines, PGE2, NO and TBARS were markedly increased. By contrast, the levels of interleukin-10, NP-SH, TP and nucleic acids, and the enzymatic activities of SOD and CAT were significantly decreased in the AA model group. In addition, pretreatment with myrrh and MES was able to attenuate the impaired oxidative stress response and upregulation of inflammatory biomarkers. Furthermore, the enzymatic activities of SOD and CAT were near to normal in the myrrh and MES pretreated groups. The ability of myrrh to protect against UC was further confirmed by histopathological analysis, and the high dose of myrrh exerted an effect comparable to MES. In conclusion, the results of the present study suggested that myrrh has potent therapeutic value in the amelioration of experimental colitis in laboratory animals by downregulating the expression of proinflammatory mediators and improving endogenous antioxidative activities. PMID

  13. Gemfibrozil attenuates the inflammatory response and protects rats from abdominal sepsis

    PubMed Central

    CÁMARA-LEMARROY, CARLOS R.; GUZMAN-DE LA GARZA, FRANCISCO J.; CORDERO-PEREZ, PAULA; IBARRA-HERNANDEZ, JUAN M.; MUÑOZ-ESPINOSA, LINDA E.; FERNANDEZ-GARZA, NANCY E.

    2015-01-01

    Sepsis is a serious condition characterized by an infectious process that induces a severe systemic inflammatory response. In this study, the effects of gemfibrozil (GFZ) on the inflammatory response associated with abdominal sepsis were investigated using a rat model of cecal-ligation and puncture (CLP). Male Wistar rats were randomly divided into three groups: Sham-operated group (sham), where laparotomy was performed, the intestines were manipulated, and the cecum was ligated but not punctured; control group, subjected to CLP; and GFZ group, which received GFZ prior to undergoing CLP. The groups were then subdivided into three different time-points: 2, 4 and 24 h, indicating the time at which blood samples were obtained for analysis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were determined. The LDH, AST and ALT values were significantly elevated following CLP compared with those in the sham group, and GFZ treatment was able to reduce these elevations. GFZ also reduced the sepsis-induced elevations of TNF-α and IL-1. In conclusion, GFZ treatment was able to attenuate the inflammatory response associated with CLP-induced sepsis, by diminishing the release of inflammatory cytokines, thereby reducing tissue injury and oxidative stress. PMID:25667670

  14. Mesenchymal stem cells attenuate inflammatory processes in the heart and lung via inhibition of TNF signaling.

    PubMed

    Martire, Alessandra; Bedada, Fikru B; Uchida, Shizuka; Pöling, Jochen; Krüger, Marcus; Warnecke, Henning; Richter, Manfred; Kubin, Thomas; Herold, Susanne; Braun, Thomas

    2016-09-01

    Mesenchymal stem cells (MSC) have been used to treat different clinical conditions although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have previously analyzed the homing of bone marrow-derived MSC to diseased tissues characterized by a high degree of mononuclear cell infiltration and postulated that MSC might modulate inflammatory responses. Here, we demonstrate that MSC mitigate adverse tissue remodeling, improve organ function, and extend lifespan in a mouse model of inflammatory dilative cardiomyopathy (DCM). Furthermore, MSC attenuate Lipopolysaccharide-induced acute lung injury indicating a general role in the suppression of inflammatory processes. We found that MSC released sTNF-RI, which suppressed activation of the NFκBp65 pathway in cardiomyocytes during DCM in vivo. Substitution of MSC by recombinant soluble TNF-R partially recapitulated the beneficial effects of MSC while knockdown of TNF-R prevented MSC-mediated suppression of the NFκBp65 pathway and improvement of tissue pathology. We conclude that sTNF-RI is a major part of the paracrine machinery by which MSC effect local inflammatory reactions. PMID:27435289

  15. Inflammatory Lung Injury After Cardiopulmonary Bypass is Attenuated by Adenosine A2A Receptor Activation

    PubMed Central

    Lisle, Turner C; Gazoni, Leo M; Fernandez, Lucas G; Sharma, Ashish K; Bellizzi, Andrew M; Schifflett, Grant D; Laubach, Victor E; Kron, Irving L

    2008-01-01

    Objectives Cardiopulmonary bypass has been shown to exert an inflammatory response within the lung, often resulting in postoperative pulmonary dysfunction. Several studies have shown that adenosine A2A receptor (A2AR) activation attenuates lung ischemia-reperfusion injury, however the effect of A2AR activation on cardiopulmonary bypass-induced lung injury has not been studied. We hypothesized that specific A2AR activation by ATL313 would attenuate inflammatory lung injury following cardiopulmonary bypass. Methods Adult male Sprague-Dawley rats were randomly divided into three groups: 1) SHAM group (underwent cannulation+heparinization only); 2) CONTROL group (underwent 90-minutes of normothermic cardiopulmonary bypass with normal whole-blood priming solution; 3) ATL group (underwent 90-minutes of normothermic cardiopulmonary bypass with ATL313 added to the normal priming solution). Results There was significantly less pulmonary edema and lung injury in the ATL group compared to the CONTROL group. The ATL group had significant reductions in bronchoalveolar lavage interleukin-1, interleukin-6, interferon-γ and myeloperoxidase levels compared to the CONTROL group. Similarly, lung tissue interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly decreased in the ATL group compared to the CONTROL group. There was no significant difference between the SHAM and ATL groups in the amount of pulmonary edema, lung injury, or levels of pro-inflammatory cytokines. Conclusions The addition of a potent A2AR agonist to the normal priming solution prior to the initiation of CPB significantly protects the lung from the inflammatory effects of CPB and reduces the amount of lung injury. A2AR agonists could represent a new therapeutic strategy for reducing the potentially devastating consequences of the inflammatory response associated with CPB. Ultra-mini Abstract Pharmacologic activation of the adenosine A2A receptor during cardiopulmonary bypass resulted in

  16. Iron Supplementation Attenuates the Inflammatory Status of Anemic Piglets by Regulating Hepcidin.

    PubMed

    Pu, Yutian; Guo, Bingxiu; Liu, Dan; Xiong, Haitao; Wang, Yizhen; Du, Huahua

    2015-09-01

    Iron deficiency is common throughout the world and has been linked to immunity impairments. Using piglets to model human infants, we assessed the impact of systemic iron homeostasis on proinflammatory status. Artificially reared piglets were parenterally supplied with iron dextran by intramuscular administration at the age of 3 days. Relative to no iron supplementation (control), iron dextran-treated (FeDex) piglets increased hematological parameters as well as iron levels in serum and tissues from days 21 to 49. High expression of hepcidin was observed in FeDex-treated piglets, which correlated with suppressed expression of ferroportin in duodenum. Lower levels of proinflammatory cytokine (IL-6, TNF-α, IFN-γ, and IL-1β) transcripts were detected in ileum of FeDex-treated piglets, which indicated that iron supplementation could attenuate the increase of inflammatory cytokines caused by iron deficiency. Histopathological analysis of liver and duodenum proved the less inflammatory responses after iron supplementation. Hepcidin was highly stimulated by FeDex supplementation and attenuated the inflammation of anemia, which implied that hepcidin might had antiinflammatory function and is a candidate regulator of the cross-talk between iron regulation and inflammation. PMID:25774043

  17. Psychotropic drugs attenuate lipopolysaccharide-induced hypothermia by altering hypothalamic levels of inflammatory mediators in rats.

    PubMed

    Nassar, Ahmad; Sharon-Granit, Yael; Azab, Abed N

    2016-07-28

    Recent evidence suggests that inflammation may contribute to the pathophysiology of mental disorders and that psychotropic drugs exert various effects on brain inflammation. The administration of bacterial endotoxin (lipopolysaccharide, LPS) to mammals is associated with robust production of inflammatory mediators and pathological changes in body temperature. The objective of the present study was to examine the effects of four different psychotropic drugs on LPS-induced hypothermia and production of prostaglandin (PG) E2, tumor necrosis factor (TNF)-α and phosphorylated-p65 (P-p65) levels in hypothalamus of LPS-treated rats. Rats were treated once daily with lithium (100mg/kg), carbamazepine (40mg/kg), haloperidol (2mg/kg), imipramine (20mg/kg) or vehicle (NaCl 0.9%) for 29 days. On day 29, rats were injected with LPS (1mg/kg) or saline. At 1.5h post LPS injection body temperature was measured, rats were sacrificed, blood was collected and their hypothalami were excised, homogenized and centrifuged. PGE2, TNF-α and nuclear P-p65 levels were determined by specific ELISA kits. We found that lithium, carbamazepine, haloperidol and imipramine significantly attenuated LPS-induced hypothermia, resembling the effect of classic anti-inflammatory drugs. Moreover, lithium, carbamazepine, haloperidol and imipramine differently but significantly affected the levels of PGE2, TNF-α and P-p65 in plasma and hypothalamus of LPS-treated rats. The results suggest that psychotropic drugs attenuate LPS-induced hypothermia by reducing hypothalamic production of inflammatory constituents, particularly PGE2. The effects of psychotropic drugs on brain inflammation may contribute to their therapeutic mechanism but also to their toxicological profile. PMID:27181513

  18. Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway.

    PubMed

    Mao, Yuanjie; Tokudome, Takeshi; Kishimoto, Ichiro; Otani, Kentaro; Nishimura, Hirohito; Yamaguchi, Osamu; Otsu, Kinya; Miyazato, Mikiya; Kangawa, Kenji

    2015-06-01

    Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin's ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1β and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload-induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway. PMID:25870195

  19. Ameliorative effects of Trichosanthes dioica Extract in suppressing inflammatory mediators and attenuating oxidative stress.

    PubMed

    Kharbanda, Chetna; Alam, Mohammad Sarwar; Hamid, Hinna; Javed, Kalim; Bano, Sameena; Ali, Yakub; Nazreen, Syed; Haider, Saqlain

    2015-03-01

    The present study aimed to investigate the anti-inflammatory activity of the ethanolic extract of the aerial parts of Trichosanthes dioica and its successive fractions. The effect on oxidative stress involved in the pathogenesis of inflammation was evaluated. The ethanolic extract and its successive fractions were administered at a dose of 150 and 300 mg/kg b. w. for testing their anti-inflammatory activity by a carrageenan-induced edema model. The results showed that the ethyl acetate fraction exhibited significant potency against inflammation. Pertaining to mechanistic insight, the anti-inflammatory effect might be attributed to the attenuation in tumor necrosis factor-α level (ELISA assay) and reduced expression of cyclooxygenase-2 and nuclear transcription factor-κB (immunohistochemistry). The alleviation in oxidative stress has been pertinent to the elevation in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) by active fractions. Furthermore, the ulcerogenic effect was insignificant even at a three times higher dose. Finally, it was concluded that the ethyl acetate fraction which showed significant biological potential against inflammation and oxidative stress could be viewed as a source of effective treatment. PMID:25782035

  20. Inhibition of TLR4 Signalling-Induced Inflammation Attenuates Secondary Injury after Diffuse Axonal Injury in Rats

    PubMed Central

    Zhao, Yonglin; Zhang, Ming; Zhao, Junjie; Ma, Xudong; Huang, Tingqin; Pang, Honggang

    2016-01-01

    Increasing evidence suggests that secondary injury after diffuse axonal injury (DAI) damages more axons than the initial insult, but the underlying mechanisms of this phenomenon are not fully understood. Recent studies show that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and have been shown to be associated with brain damage. The purpose of this study was to investigate the role of the TLR4 signalling pathway in secondary axonal injury in the cortices of DAI rats. TLR4 was mainly localized in microglial cells and neurons, and the levels of TLR4 downstream signalling molecules, including TLR4, myeloid differentiation primary response gene 88, toll/IR-1-(TIR-) domain-containing adaptor protein inducing interferon-beta, interferon regulatory factor 3, interferon β, nuclear factor κB (NF-κB) p65, and phospho-NF-κB p65, significantly increased and peaked at 1 d after DAI. Inhibition of TLR4 by TAK-242 attenuated apoptosis, neuronal and axonal injury, and glial responses. The neuroprotective effects of TLR4 inhibition were associated with decreases in the levels of TLR4 downstream signalling molecules and inflammatory factors, including interleukin-1β, interleukin-6, and tumour necrosis factor-α. These results suggest that the TLR4 signalling pathway plays an important role in secondary injury and may be an important therapeutic target following DAI. PMID:27478307

  1. DJ-1 deficiency attenuates expansion of liver progenitor cells through modulating the inflammatory and fibrogenic niches.

    PubMed

    Chen, L; Luo, M; Sun, X; Qin, J; Yu, C; Wen, Y; Zhang, Q; Gu, J; Xia, Q; Kong, X

    2016-01-01

    Our previous study suggested that DJ-1 has a critical role in initiating an inflammatory response, but its role in the liver progenitor cell (LPC) expansion, a process highly dependent on the inflammatory niche, remains elusive. The objective of this study is to determine the role of DJ-1 in LPC expansion. The correlation of DJ-1 expression with LPC markers was examined in the liver of patients with hepatitis B or hepatitis C virus (HBV and HCV, respectively) infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), cirrhosis or hepatocellular carcinoma (HCC), respectively. The role of DJ-1 in LPC expansion and the formation of LPC-associated fibrosis and inflammation was examined in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced liver injury murine model. We also determined the ability of hepatic stellate cells (HSCs) in recruiting macrophages in DJ-1 knockout (KO) mice. The expression levels of DJ-1 were upregulated in the liver of HBV, HCV, PBC and PSC patients and DDC-fed mice. Additionally, DJ-1 expression was positively correlated with LPC proliferation in patients with liver injury and mice with DDC exposure. DJ-1 has no direct effect on LPC proliferation. Reduced activation of HSCs and collagen deposition were observed in DJ-1 KO mice. Furthermore, infiltrated CD11b(+)Gr-1(low) macrophages and pro-inflammatory factors (IL-6, TNF-α) were attenuated in DJ-1 KO mice. Mechanistically, we found that HSCs isolated from DJ-1 KO mice had decreased secretion of macrophage-mobilizing chemokines, such as CCL2 and CX3CL1, resulting in impaired macrophage infiltration. DJ-1 positively correlates with LPC expansion during liver injury. DJ-1 deficiency negatively regulates LPC proliferation by impairing the formation of LPC-associated fibrosis and inflammatory niches. PMID:27277679

  2. Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model

    PubMed Central

    LU, WEI; WANG, LIN; WO, CHUNXIN; YAO, JING

    2016-01-01

    The aim of the present study was to investigate the efficacy of ketamine in attenuating osteoarthritis (OA) and modulating the expression of inflammatory mediators. A rabbit OA model was established by knee immobilization using plaster bandages. After six weeks, rabbits were randomly allocated into four groups (n=6/group): Normal saline, Ket60, Ket100, and Ket200 and twice a week for four weeks the rabbits received an intra-articular injection of saline, or 60, 100 or 200 µmol/l ketamine, respectively. One week after the final injection, samples of synovial membrane, synovial fluid and articular cartilage were isolated. The pathological changes were assessed by general observation, hematoxylin and eosin staining and Alcian blue/periodic-acid Schiff staining. Cartilage pathology was assessed using Mankin's scoring system. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 levels in the synovial fluid were measured by enzyme-linked immunosorbent assays. The nuclear factor (NF)-κB p65 subunit expression level in cartilage samples was determined by immunohistochemistry. OA was characterized by morphological changes in the articular surface, cartilage lesions, infiltration of inflammatory cells and a significantly increased Mankin's score. Elevated TNF-α and reduced IL-10 levels in the synovial fluid, along with increased p65 expression levels in the cartilage were observed in OA rabbits. Intra-articular injection of ketamine ameliorated the pathological characteristics of OA, reduced the Mankin's score, decreased TNF-α and NF-κB p65 expression levels, and increased the level of IL-10 expression in a dose-dependent manner. Thus is was demonstrated that Ketamine suppresses the inflammatory response in OA by modulating inflammatory mediator expression levels in a rabbit model of OA. PMID:27109206

  3. Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model.

    PubMed

    Lu, Wei; Wang, Lin; Wo, Chunxin; Yao, Jing

    2016-06-01

    The aim of the present study was to investigate the efficacy of ketamine in attenuating osteoarthritis (OA) and modulating the expression of inflammatory mediators. A rabbit OA model was established by knee immobilization using plaster bandages. After six weeks, rabbits were randomly allocated into four groups (n=6/group): Normal saline, Ket60, Ket100, and Ket200 and twice a week for four weeks the rabbits received an intra‑articular injection of saline, or 60, 100 or 200 µmol/l ketamine, respectively. One week after the final injection, samples of synovial membrane, synovial fluid and articular cartilage were isolated. The pathological changes were assessed by general observation, hematoxylin and eosin staining and Alcian blue/periodic‑acid Schiff staining. Cartilage pathology was assessed using Mankin's scoring system. Tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 levels in the synovial fluid were measured by enzyme‑linked immunosorbent assays. The nuclear factor (NF)‑κB p65 subunit expression level in cartilage samples was determined by immunohistochemistry. OA was characterized by morphological changes in the articular surface, cartilage lesions, infiltration of inflammatory cells and a significantly increased Mankin's score. Elevated TNF‑α and reduced IL-10 levels in the synovial fluid, along with increased p65 expression levels in the cartilage were observed in OA rabbits. Intra‑articular injection of ketamine ameliorated the pathological characteristics of OA, reduced the Mankin's score, decreased TNF‑α and NF‑κB p65 expression levels, and increased the level of IL‑10 expression in a dose-dependent manner. Thus is was demonstrated that Ketamine suppresses the inflammatory response in OA by modulating inflammatory mediator expression levels in a rabbit model of OA. PMID:27109206

  4. Attenuated mRNA expression of inflammatory mediators in neonatal rat lung following lipopolysaccharide treatment

    PubMed Central

    Le Rouzic, Valerie; Wiedinger, Kari; Zhou, Heping

    2012-01-01

    Neonates are known to exhibit increased susceptibility to bacterial and viral infections and increasing evidence demonstrates that the increased susceptibility is related to their attenuated immune response to infections. The lung is equipped with an innate defense system involving both cellular and humoral mediators. The present study was performed to characterize the expression of inflammatory mediators in the lung of neonatal rats in comparison with older animals. Rats at postnatal day 1 (P1), P21, and P70 were treated with saline or 0.25 mg/kg lipopolysaccharide (LPS) via intraperitoneal injection. Two hours later, animals were sacrificed and the transcriptional response of key inflammatory mediators and enzyme activity of myeloperoxidase (MPO) in the lung of these animals were examined. LPS-induced messenger RNA (mRNA) expression of pro-inflammatory cytokines, namely interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, antiinflammatory cytokines, namely IL-10 and IL-1 receptor antagonist (IL-1ra), and chemokines, namely macrophage inflammatory protein (MIP)-1β, MIP-2, and monocyte chemotactic protein-1, in P1 lung was much reduced compared to that in P21 and P70 animals at 2 hours postinjection. These data suggest that LPS-induced transcriptional response of cytokines and chemokines was much reduced in P1 lung even though the protein levels of these genes were not ascertained and mRNA levels of these genes may not reflect their final protein levels. MPO activity in LPS-treated P1 lung was also significantly attenuated compared to that in LPS-treated P70 lung, suggesting impaired neutrophil infiltration in P1 lung at 2 hours following LPS treatment. In parallel, the baseline mRNA expression of LPS-binding protein (LBP) in P1 lung was much lower than that in P21 and P70 lungs. While the protein level of LBP was not examined and the mRNA level of LBP may not reflect its final protein level, the reduced transcriptional response of cytokines and chemokines in

  5. Zingiber officinale attenuates retinal microvascular changes in diabetic rats via anti-inflammatory and antiangiogenic mechanisms

    PubMed Central

    Dongare, Shirish; Mathur, Rajani; Saxena, Rohit; Mathur, Sandeep; Agarwal, Renu; Nag, Tapas C.; Srivastava, Sushma; Kumar, Pankaj

    2016-01-01

    Purpose Diabetic retinopathy is a common microvascular complication of long-standing diabetes. Several complex interconnecting biochemical pathways are activated in response to hyperglycemia. These pathways culminate into proinflammatory and angiogenic effects that bring about structural and functional damage to the retinal vasculature. Since Zingiber officinale (ginger) is known for its anti-inflammatory and antiangiogenic properties, we investigated the effects of its extract standardized to 5% 6-gingerol, the major active constituent of ginger, in attenuating retinal microvascular changes in rats with streptozotocin-induced diabetes. Methods Diabetic rats were treated orally with the vehicle or the ginger extract (75 mg/kg/day) over a period of 24 weeks along with regular monitoring of bodyweight and blood glucose and weekly fundus photography. At the end of the 24-week treatment, the retinas were isolated for histopathological examination under a light microscope, transmission electron microscopy, and determination of the retinal tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and vascular endothelial growth factor (VEGF) levels. Results Oral administration of the ginger extract resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and vascular basement membrane thickness. Improvement in the architecture of the retinal vasculature was associated with significantly reduced expression of NF-κB and reduced activity of TNF-α and VEGF in the retinal tissue in the ginger extract–treated group compared to the vehicle-treated group. Conclusions The current study showed that ginger extract containing 5% of 6-gingerol attenuates the retinal microvascular changes in rats with streptozotocin-induced diabetes through anti-inflammatory and antiangiogenic actions. Although precise molecular targets remain to be determined, 6-gingerol seems to be a potential candidate for further investigation. PMID:27293376

  6. Attenuated viral hepatitis in Trem1-/- mice is associated with reduced inflammatory activity of neutrophils.

    PubMed

    Kozik, Jan-Hendrik; Trautmann, Tanja; Carambia, Antonella; Preti, Max; Lütgehetmann, Marc; Krech, Till; Wiegard, Christiane; Heeren, Joerg; Herkel, Johannes

    2016-01-01

    TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1-/- mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1-/- mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils. PMID:27328755

  7. Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.

    PubMed

    Kruidenier, Laurens; Kuiper, Ineke; Van Duijn, Wim; Mieremet-Ooms, Marij A C; van Hogezand, Ruud A; Lamers, Cornelis B H W; Verspaget, Hein W

    2003-09-01

    Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of

  8. Cyclo-Gly-Pro, a cyclic dipeptide, attenuates nociceptive behaviour and inflammatory response in mice.

    PubMed

    Ferro, Jamylle Nunes de Souza; de Aquino, Fernanda Lima Torres; de Brito, Renan Guedes; dos Santos, Priscila Laíse; Quintans, Jullyana de Souza Siqueira; de Souza, Lucas Costa; de Araújo, Almair Ferreira; Diaz, Bruno Lourenço; Lucca-Júnior, Waldecy; Quintans-Júnior, Lucindo José; Barreto, Emiliano

    2015-12-01

    The present study aimed to investigate the antinociceptive and anti-inflammatory effects of the cyclic dipeptide cyclo-Gly-Pro (CGP) in mice. Antinociceptive activity was assessed by employing different pain models, such as formalin test, acetic acid-induced writhing, hot plate test, and carrageenan-induced hyperalgesia, in mice. The number of c-Fos-immunoreactive cells in the periaqueductal gray (PAG) was evaluated in CGP-treated mice. Anti-inflammatory activity was evaluated using paw oedema induced by carrageenan, compound 48/80, serotonin, and prostaglandin E2 (PGE2) and analyzed by plethysmometry. Quantitation of myeloperoxidase (MPO) in the paw was carried out to analyze the presence of neutrophils in the tissue. Intraperitoneal injection of CGP produced a significant inhibition in both neurogenic and inflammatory phases of formalin-induced pain. The antinociceptive effect of CGP, evaluated in the acetic acid-induced writhing test, was detected for up to 6 h after treatment. Further, in the hot plate test, antinociceptive behaviour was evoked by CGP, and this response was inhibited by naloxone. Animals treated with CGP did not present changes in motor performance. In CGP-treated mice there was an increase in the number of c-Fos-positive neurons in the periaqueductal gray. In another set of experiments, CGP attenuated the hyperalgesic response induced by carrageenan. Furthermore, CGP also reduced the carrageenan-increased MPO activity in paws. In addition, CGP also reduced the paw oedema evoked by compound 48/80, serotonin, and PGE2 . Taken together, these results may support a possible therapeutic application of the cyclic dipeptide cyclo-Gly-Pro toward alleviating nociception and damage caused by inflammation conditions. PMID:26277051

  9. Tumor suppressor death-associated protein kinase attenuates inflammatory responses in the lung.

    PubMed

    Nakav, Sigal; Cohen, Shmuel; Feigelson, Sara W; Bialik, Shani; Shoseyov, David; Kimchi, Adi; Alon, Ronen

    2012-03-01

    Death-associated protein kinase (DAPk) is a tumor suppressor thought to inhibit cancer by promoting apoptosis and autophagy. Because cancer progression is linked to inflammation, we investigated the in vivo functions of DAPk in lung responses to various acute and chronic inflammatory stimuli. Lungs of DAPk knockout (KO) mice secreted higher concentrations of IL-6 and keratinocyte chemoattractant (or chemokine [C-X-C motif] ligand 1) in response to transient intranasal administrations of the Toll-like receptor-4 (TLR4) agonist LPS. In addition, DAPk-null macrophages and neutrophils were hyperresponsive to ex vivo stimulation with LPS. DAPk-null neutrophils were also hyperresponsive to activation via Fc receptor and Toll-like receptor-3, indicating that the suppressive functions of this kinase are not restricted to TLR4 pathways. Even after the reconstitution of DAPk-null lungs with DAPk-expressing leukocytes by transplanting wild-type (WT) bone marrow into lethally irradiated DAPk KO mice, the chimeric mice remained hypersensitive to both acute and chronic LPS challenges, as well as to tobacco smoke exposure. DAPk-null lungs reconstituted with WT leukocytes exhibited elevated neutrophil content and augmented cytokine secretion in the bronchoalveolar space, as well as enhanced epithelial cell injury in response to both acute and chronic inflammatory conditions. These results suggest that DAPk attenuates a variety of inflammatory responses, both in lung leukocytes and in lung epithelial cells. The DAPk-mediated suppression of lung inflammation and airway injury may contribute to the tumor-suppressor functions of this kinase in epithelial carcinogenesis. PMID:21997486

  10. Activation of Endogenous Anti-Inflammatory Mediator Cyclic AMP Attenuates Acute Pyelonephritis in Mice Induced by Uropathogenic Escherichia coli

    PubMed Central

    Wei, Yang; Li, Ke; Wang, Na; Cai, Gui-Dong; Zhang, Ting; Lin, Yan; Gui, Bao-Song; Liu, En-Qi; Li, Zong-Fang; Zhou, Wuding

    2015-01-01

    The pathogenesis of pyelonephritis caused by uropathogenic Escherichia coli (UPEC) is not well understood. Here, we show that besides UPEC virulence, the severity of the host innate immune response and invasion of renal epithelial cells are important pathogenic factors. Activation of endogenous anti-inflammatory mediator cAMP significantly attenuated acute pyelonephritis in mice induced by UPEC. Administration of forskolin (a potent elevator of intracellular cAMP) reduced kidney infection (ie, bacterial load, tissue destruction); this was associated with attenuated local inflammation, as evidenced by the reduction of renal production of proinflammatory mediators, renal infiltration of inflammatory cells, and renal myeloperoxidase activity. In primary cell culture systems, forskolin not only down-regulated UPEC-stimulated production of proinflammatory mediators by renal tubular epithelial cells and inflammatory cells (eg, monocyte/macrophages) but also reduced bacterial internalization by renal tubular epithelial cells. Our findings clearly indicate that activation of endogenous anti-inflammatory mediator cAMP is beneficial for controlling UPEC-mediated acute pyelonephritis in mice. The beneficial effect can be explained at least in part by limiting excessive inflammatory responses through acting on both renal tubular epithelial cells and inflammatory cells and by inhibiting bacteria invasion of renal tubular epithelial cells. PMID:25478807

  11. Activation of endogenous anti-inflammatory mediator cyclic AMP attenuates acute pyelonephritis in mice induced by uropathogenic Escherichia coli.

    PubMed

    Wei, Yang; Li, Ke; Wang, Na; Cai, Gui-Dong; Zhang, Ting; Lin, Yan; Gui, Bao-Song; Liu, En-Qi; Li, Zong-Fang; Zhou, Wuding

    2015-02-01

    The pathogenesis of pyelonephritis caused by uropathogenic Escherichia coli (UPEC) is not well understood. Here, we show that besides UPEC virulence, the severity of the host innate immune response and invasion of renal epithelial cells are important pathogenic factors. Activation of endogenous anti-inflammatory mediator cAMP significantly attenuated acute pyelonephritis in mice induced by UPEC. Administration of forskolin (a potent elevator of intracellular cAMP) reduced kidney infection (ie, bacterial load, tissue destruction); this was associated with attenuated local inflammation, as evidenced by the reduction of renal production of proinflammatory mediators, renal infiltration of inflammatory cells, and renal myeloperoxidase activity. In primary cell culture systems, forskolin not only down-regulated UPEC-stimulated production of proinflammatory mediators by renal tubular epithelial cells and inflammatory cells (eg, monocyte/macrophages) but also reduced bacterial internalization by renal tubular epithelial cells. Our findings clearly indicate that activation of endogenous anti-inflammatory mediator cAMP is beneficial for controlling UPEC-mediated acute pyelonephritis in mice. The beneficial effect can be explained at least in part by limiting excessive inflammatory responses through acting on both renal tubular epithelial cells and inflammatory cells and by inhibiting bacteria invasion of renal tubular epithelial cells. PMID:25478807

  12. Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity

    PubMed Central

    ZHU, GUANG-FA; GUO, HONG-JUAN; HUANG, YAN; WU, CHUN-TING; ZHANG, XIANG-FENG

    2015-01-01

    Acute lung injury (ALI) is characterized by excessive inflammatory responses and oxidative injury in the lung tissue. It has been suggested that anti-inflammatory or antioxidative agents could have therapeutic effects in ALI, and eriodictyol has been reported to exhibit antioxidative and anti-inflammatory activity in vitro. The aim of the present study was to investigate the effect of eriodictyol on lipopolysaccharide (LPS)-induced ALI in a mouse model. The mice were divided into four groups: Phosphate-buffered saline-treated healthy control, LPS-induced ALI, vehicle-treated ALI (LPS + vehicle) and eriodictyol-treated ALI (LPS + eriodictyol). Eriodictyol (30 mg/kg) was administered orally once, 2 days before the induction of ALI. The data showed that eriodictyol pretreatment attenuated LPS-induced ALI through its antioxidative and anti-inflammatory activity. Furthermore, the eriodictyol pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in the ALI mouse model, which attenuated the oxidative injury and inhibited the inflammatory cytokine expression in macrophages. In combination, the results of the present study demonstrated that eriodictyol could alleviate the LPS-induced lung injury in mice by regulating the Nrf2 pathway and inhibiting the expression of inflammatory cytokines in macrophages, suggesting that eriodictyol could be used as a potential drug for the treatment of LPS-induced lung injury. PMID:26668626

  13. Notoginsenoside R1 attenuates experimental inflammatory bowel disease via pregnane X receptor activation.

    PubMed

    Zhang, Jingjing; Ding, Lili; Wang, Baocan; Ren, Gaiyan; Sun, Aning; Deng, Chao; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao; Dou, Wei

    2015-02-01

    Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling. PMID:25472953

  14. Notoginsenoside R1 Attenuates Experimental Inflammatory Bowel Disease via Pregnane X Receptor Activation

    PubMed Central

    Zhang, Jingjing; Ding, Lili; Wang, Baocan; Ren, Gaiyan; Sun, Aning; Deng, Chao; Wei, Xiaohui; Mani, Sridhar

    2015-01-01

    Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium–induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket–filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)–luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid–induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling. PMID:25472953

  15. Dietary L-arginine supplementation attenuates lipopolysaccharide-induced inflammatory response in broiler chickens.

    PubMed

    Tan, Jianzhuang; Liu, Shasha; Guo, Yuming; Applegate, Todd J; Eicher, Susan D

    2014-04-28

    In the present study, two experiments were conducted to investigate the effect of dietary L-arginine (Arg) supplementation on the inflammatory response and innate immunity of broiler chickens. Expt 1 was designed as a 2 × 3 factorial arrangement (n 8 cages/treatment; n 6 birds/cage) with three dietary Arg concentrations (1.05, 1.42 and 1.90%) and two immune treatments (injection of lipopolysaccharide (LPS) or saline) given at an interval of 48 h between 14 and 21 d of age. In Expt 2, correlation between dietary Arg concentration (0.99, 1.39, 1.76, 2.13 or 2.53%) and percentage of circulating B cells (percentage of circulating lymphocytes) was determined. In Expt 1, LPS injection decreased body-weight gain and feed intake and increased feed conversion ratio of the challenged broilers (14-21 d; P< 0.05). LPS injection suppressed (P< 0.05) the percentages of splenic CD11+ and B cells (percentages of splenic lymphocytes) and phagocytic activity of splenic heterophils and macrophages; Arg supplementation linearly decreased the percentages of CD11+, CD14+ and B cells in the spleen (P< 0.10). LPS injection increased (P< 0.05) the expression of IL-1β and IL-6 mRNA in the spleen and caecal tonsils. Arginine supplementation decreased (P< 0.05) the expression of IL-1β, Toll-like receptor 4 (TLR4) and PPAR-γ mRNA in the spleen and IL-1β, IL-10, TLR4 and NF-κB mRNA in the caecal tonsils. In Expt 2, increasing dietary Arg concentrations linearly and quadratically reduced the percentage of circulating B cells (P< 0.01). Collectively, Arg supplementation attenuated the overexpression of pro-inflammatory cytokines probably through the suppression of the TLR4 pathway and CD14+ cell percentage. Furthermore, excessive Arg supplementation (1.76%) suppressed the percentages of circulating and splenic B cells. PMID:24330949

  16. uPA Attenuated LPS-induced Inflammatory Osteoclastogenesis through the Plasmin/PAR-1/Ca2+/CaMKK/AMPK Axis

    PubMed Central

    Kanno, Yosuke; Ishisaki, Akira; Kawashita, Eri; Kuretake, Hiromi; Ikeda, Kanako; Matsuo, Osamu

    2016-01-01

    Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis-caused bone destruction, results from an increase of bone-resorbing osteoclasts (OCs) induced by inflammation. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated that the effect of urokinase-type plasminogen activator (uPA) on inflammatory osteoclastogenesis induced by lipopolysaccharide (LPS), which is a potent stimulator of bone resorption in inflammatory diseases. We found that the uPA deficiency promoted inflammatory osteoclastogenesis and bone loss induced by LPS. We also showed that LPS induced the expression of uPA, and the uPA treatment attenuated the LPS-induced inflammatory osteoclastogenesis of RAW264.7 mouse monocyte/macrophage lineage cells. Additionally, we showed that the uPA-attenuated inflammatory osteoclastgenesis is associated with the activation of plasmin/protease-activated receptor (PAR)-1 axis by uPA. Moreover, we examined the mechanism underlying the effect of uPA on inflammatory osteoclastogenesis, and found that uPA/plasmin/PAR-1 activated the adenosine monophosphate-activated protein kinase (AMPK) pathway through Ca2+/calmodulin dependent protein kinase kinase (CaMKK) activation, and attenuated inflammatory osteoclastogenesis by inactivation of NF-κB in RAW264.7 cells. These data suggest that uPA attenuated inflammatory osteoclastogenesis through the plasmin/PAR-1/Ca2+/CaMKK/AMPK axis. Our findings may provide a novel therapeutic approach to bone loss caused by inflammatory diseases. PMID:26722218

  17. Exercise training can attenuate the inflammatory milieu in women with systemic lupus erythematosus.

    PubMed

    Perandini, Luiz A; Sales-de-Oliveira, Diego; Mello, Suzana B V; Camara, Niels O; Benatti, Fabiana B; Lima, Fernanda R; Borba, Eduardo; Bonfa, Eloisa; Sá-Pinto, Ana L; Roschel, Hamilton; Gualano, Bruno

    2014-09-15

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation. This study sought to assess the effects of an exercise training program on cytokines and soluble TNF receptors (sTNFRs) in response to acute exercise in SLE women. Eight SLE women and 10 sex-, age-, and body mass index-comparable healthy controls (HC) participated in this study. Before and after a 12-wk aerobic exercise training program, cytokines and sTNFRs were assessed at rest and in response to single bouts of acute moderate/intense exercise. HC performed the acute exercise bouts only at baseline. After the exercise training program, there was a decrease in resting TNFR2 levels (P = 0.025) and a tend to reduction interleukin (IL)-10 levels (P = 0.093) in SLE. The resting levels of IL-6, IL-10, and TNF-α after the exercise training in SLE reached HC levels (P > 0.05). In response to a single bout of acute moderate exercise, the area under the curve (AUC) of IL-10 was significantly reduced after the exercise training program in SLE (P = 0.043), and the AUC of IL-10, IL-6, TNF-α, and sTNFR1 of SLE approached control values (P > 0.05). In response to a single bout of acute intense exercise, the AUC of IL-10 was significantly reduced in SLE (P = 0.015). Furthermore, the AUC of sTNFR2 tended to decrease after exercise training program in SLE (P = 0.084), but it did not reach control values (P = 0.001). An aerobic exercise training program attenuated the inflammatory milieu in SLE women, revealing a novel homeostatic immunomodulatory role of exercise in an autoimmunity condition. PMID:25038103

  18. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway.

    PubMed

    Liu, Zhaoguo; Wang, Yueping; Wang, Yaoqi; Ning, Qiaoqing; Zhang, Yong; Gong, Chunzhi; Zhao, Wenxiang; Jing, Guangjian; Wang, Qianqian

    2016-06-01

    Dexmedetomidine (Dex) is a highly selective α2-adrenergic receptor agonist that is widely used for sedation in intensive care units and in clinical anesthesia. Dex has also been shown to possess anti-inflammatory benefits. However, the underlying mechanism by which Dex relieves the inflammatory reaction in the lung tissues of septic mice has not been fully elucidated. In this study, we aimed to evaluate the protective effects and possible mechanism of Dex on the sepsis-induced lung inflammatory response in mice. Sepsis was induced in mice models through the intraperitoneal injection of lipopolysaccharide (LPS). The preemptive administration of Dex substantially abated sepsis-induced pulmonary edema, pulmonary histopathological changes, and NF-κB p65 activity. The production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) at both the mRNA and protein levels was also reduced. Moreover, these effects were significantly blocked by the α7 nicotinic acetylcholine receptor (α7nAChR) antagonist α-bungarotoxin (α-Bgt). α-Bgt aggravated pulmonary edema and pulmonary histopathological changes, as well as increased NF-κB p65 activity and TNF-α and IL-6 expression at both the mRNA and protein levels. The overall results demonstrate that Dex inhibits the LPS-induced inflammatory reaction in the lung tissues of septic mice partly through the α7nAChR-dependent cholinergic anti-inflammatory pathway. PMID:27074053

  19. Atorvastatin along with imipenem attenuates acute lung injury in sepsis through decrease in inflammatory mediators and bacterial load.

    PubMed

    Choudhury, Soumen; Kandasamy, Kannan; Maruti, Bhojane Somnath; Addison, M Pule; Kasa, Jaya Kiran; Darzi, Sazad A; Singh, Thakur Uttam; Parida, Subhashree; Dash, Jeevan Ranjan; Singh, Vishakha; Mishra, Santosh Kumar

    2015-10-15

    Lung is one of the vital organs which is affected during the sequential development of multi-organ dysfunction in sepsis. The purpose of the present study was to examine whether combined treatment with atorvastatin and imipenem could attenuate sepsis-induced lung injury in mice. Sepsis was induced by caecal ligation and puncture. Lung injury was assessed by the presence of lung edema, increased vascular permeability, increased inflammatory cell infiltration and cytokine levels in broncho-alveolar lavage fluid (BALF). Treatment with atorvastatin along with imipenem reduced the lung bacterial load and pro-inflammatory cytokines (IL-1β and TNFα) level in BALF. The markers of pulmonary edema such as microvascular leakage and wet-dry weight ratio were also attenuated. This was further confirmed by the reduced activity of MPO and ICAM-1 mRNA expression, indicating the lesser infiltration and adhesion of inflammatory cells to the lungs. Again, expression of mRNA and protein level of iNOS in lungs was also reduced in the combined treatment group. Based on the above findings it can be concluded that, combined treatment with atorvastatin and imipenem dampened the inflammatory response and reduced the bacterial load, thus seems to have promising therapeutic potential in sepsis-induced lung injury in mice. PMID:26375251

  20. Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response

    PubMed Central

    Hu, Dan; Yang, Xiaohua; Xiang, Yianxiao; Li, Hui; Yan, Hui; Zhou, Jun; Caudle, Yi; Zhang, Xiumei; Yin, Deling

    2015-01-01

    Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. Toll-like receptors (TLRs) play a fundamental role in induction of hyperinflammation and tissue damage in sepsis. In this study, we demonstrate a protective role of TLR9 inhibition against the dysregulated inflammatory response and tissue injury in sepsis. TLR9 deficiency decreased the mortality of mice following cecal ligation and puncture (CLP) -induced sepsis. TLR9 knockout mice showed dampened p38 activation and augmented Akt phosphorylation in the spleen, lung and liver. In addition, TLR9 deficiency decreased the levels of inflammatory cytokines and attenuated splenic apoptosis after CLP. These results indicate that TLR9 inhibition might offer a novel therapeutic strategy for the management of sepsis. PMID:25880099

  1. Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: A randomized controlled trial.

    PubMed

    Kuebler, Ulrike; Arpagaus, Angela; Meister, Rebecca E; von Känel, Roland; Huber, Susanne; Ehlert, Ulrike; Wirtz, Petra H

    2016-10-01

    Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality, but underlying mechanisms are elusive. We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress. Healthy men, aged 20-50years, were randomly assigned to a single intake of either 50g of flavanol-rich dark chocolate (n=31) or 50g of optically identical flavanol-free placebo-chocolate (n=34). Two hours after chocolate intake, both groups underwent the 15-min Trier Social Stress Test. We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1β and IL-6, and the anti-inflammatory cytokine IL-10, prior to chocolate intake as well as before and several times after stress. We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva, respectively. Compared to the placebo-chocolate-group, the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress (p=0.065), and a significantly blunted stress reactivity of NF-κB-BA, IL-1β mRNA, and IL-6 mRNA (p's⩽0.036) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity (p's⩽0.033). Stress hormone changes to stress were controlled. None of the other measures showed a significant chocolate effect (p's⩾0.19). Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response. This mechanism may add to beneficial effects of dark chocolate on cardiovascular health. PMID:27091601

  2. Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells

    SciTech Connect

    Pan, Hong; Wu, Xinyi

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer Hypoxia attenuates Acanthamoeba-induced the production of IL-8 and IFN-{beta}. Black-Right-Pointing-Pointer Hypoxia inhibits TLR4 expression in a time-dependent manner in HCECs. Black-Right-Pointing-Pointer Hypoxia inhibits Acanthamoeba-induced the activation of NF-{kappa}B and ERK1/2 in HCECs. Black-Right-Pointing-Pointer Hypoxia decreases Acanthamoeba-induced inflammatory response via TLR4 signaling. Black-Right-Pointing-Pointer LPS-induced the secretion of IL-6 and IL-8 is abated by hypoxia via TLR4 signaling. -- Abstract: Acanthamoeba keratitis (AK) is a vision-threatening corneal infection that is intimately associated with contact lens use which leads to hypoxic conditions on the corneal surface. However, the effect of hypoxia on the Acanthamoeba-induced host inflammatory response of corneal epithelial cells has not been studied. In the present study, we investigated the effect of hypoxia on the Acanthamoeba-induced production of inflammatory mediators interleukin-8 (IL-8) and interferon-{beta} (IFN-{beta}) in human corneal epithelial cells and then evaluated its effects on the Toll-like receptor 4 (TLR4) signaling, including TLR4 and myeloid differentiation primary response gene (88) (MyD88) expression as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and extracellular signal-regulated kinases 1/2 (ERK1/2). We then studied the effect of hypoxia on a TLR4-specific inflammatory response triggered by the TLR4 ligand lipopolysaccharide (LPS). Our data showed that hypoxia significantly decreased the production of IL-8 and IFN-{beta}. Furthermore, hypoxia attenuated Acanthamoeba-triggered TLR4 expression as well as the activation of NF-{kappa}B and ERK1/2, indicating that hypoxia abated Acanthamoeba-induced inflammatory responses by affecting TLR4 signaling. Hypoxia also inhibited LPS-induced IL-6 and IL-8 secretion, myeloid differentiation primary response gene (88

  3. Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation

    PubMed Central

    Xin, Hong; Wang, Minjun; Tang, Wenbo; Shen, Zhuqing; Miao, Lei; Wu, Weijun; Li, Chengyi; Wang, Xiling; Xin, Xiaoming

    2016-01-01

    Abstract Aims: Anemia of inflammation is quite prevalent in hospitalized patients with poor prognosis. Concerns about the effectiveness and safety of iron supplementation have arisen, driving the demand for alternative therapies. Induction of hepatic hepcidin, the master hormone of iron homeostasis, causes anemia under inflammatory conditions. Previous studies indicated that hydrogen sulfide (H2S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H2S on inflammatory hepcidin induction. Results: H2S suppressed lipopolysaccharide (LPS)-induced hepcidin production and regulated iron homeostasis in mice by decreasing serum interleukin-6 (IL-6) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation; similar results were obtained in Huh7 cells exposed to conditioned medium from LPS-challenged THP-1 macrophages. Intriguingly, we found H2S also attenuated hepcidin levels in Huh7 cells and mouse primary hepatocytes in a sirtuin 1 (SIRT1)-dependent manner. By promoting SIRT1 expression and stabilizing SIRT1-STAT3 interactions, H2S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H2S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine γ-lyase (CSE), an endogenous H2S synthase, exaggerated inflammatory hepcidin expression in mice. Innovation: For the first time, we elucidated the effects and possible mechanisms of H2S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin. Conclusion: Our work demonstrates that H2S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation. Antioxid. Redox Signal. 24, 70–83. PMID:26154696

  4. Social interaction attenuates the extent of secondary neuronal damage following closed head injury in mice

    PubMed Central

    Doulames, Vanessa M.; Vilcans, Meghan; Lee, Sangmook; Shea, Thomas B.

    2015-01-01

    Recovery following Traumatic Brain Injury (TBI) can vary tremendously among individuals. Lifestyle following injury, including differential social interactions, may modulate the extent of secondary injury following TBI. To examine this possibility under controlled conditions, closed head injury (CHI) was induced in C57Bl6 mice using a standardized weight drop device after which mice were either housed in isolation or with their original cagemates (“socially-housed”) for 4 weeks. CHI transiently impaired novel object recognition (NOR) in both isolated and social mice, confirming physical and functional injury. By contrast, Y maze navigation was impaired in isolated but not social mice at 1–4 weeks post CHI. CHI increased excitotoxic signaling in hippocampal slices from all mice, which was transiently exacerbated by isolation at 2 weeks post CHI. CHI slightly increased reactive oxygen species and did not alter levels of amyloid beta (Abeta), total or phospho-tau, total or phosphorylated neurofilaments. CHI increased serum corticosterone in both groups, which was exacerbated by isolation. These findings support the hypothesis that socialization may attenuate secondary damage following TBI. In addition, a dominance hierarchy was noted among socially-housed mice, in which the most submissive mouse displayed indices of stress in the above analyses that were statistically identical to those observed for isolated mice. This latter finding underscores that the nature and extent of social interaction may need to vary among individuals to provide therapeutic benefit. PMID:26528156

  5. Secondary cell wall development in cotton fibers as examined with attenuated total reflection Fourier transform infrared spectroscopy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cotton fibers harvested at 18, 20, 24, 28, 32, 36 and 40 days after flowering were examined using attenuated total reflection Fourier transform-infrared (ATR FT-IR) spectroscopy. The selected harvesting points coincide with secondary cell wall (SCW) development in the fibers. Progressive but moderat...

  6. Chongcao-Shencha Attenuates Liver and Kidney Injury through Attenuating Oxidative Stress and Inflammatory Response in D-Galactose-Treated Mice

    PubMed Central

    Li, Cailan; Mo, Zhizhun; Xie, Jianhui; Xu, Lieqiang; Tan, Lihua; Luo, Dandan; Chen, Hanbin; Yang, Hongmei; Li, Yucui; Su, Ziren; Su, Zuqing

    2016-01-01

    The Chongcao-Shencha (CCSC), a Chinese herbal compound formula, has been widely used as food material and medicine for enhancing physical strength. The present study investigated the possible effect of CCSC in alleviating the liver and kidney injury in D-galactose- (D-gal-) treated mice and the underlying mechanism. Mice were given a subcutaneous injection of D-gal (200 mg/kg) and orally administered CCSC (200, 400, and 800 mg/kg) daily for 8 weeks. Results indicated that CCSC increased the depressed body weight and organ index induced by D-gal, ameliorated the histological deterioration, and decreased the levels of ALT, AST, BUN, and CRE as compared with D-gal group. Furthermore, CCSC not only elevated the activities of antioxidant enzymes SOD, CAT, and GPx but also upregulated the mRNA expression of SOD1, CAT, and GPx1, while decreasing the MDA level in D-gal-treated mice. Results of western blotting analysis showed that CCSC significantly inhibited the upregulation of expression of nuclear factor kappa B (NF-κB) p65, p-p65, p-IκBα, COX2, and iNOS and inhibited the downregulation of IκBα protein expression caused by D-gal. This study demonstrated that CCSC could attenuate the liver and kidney injury in D-gal-treated mice, and the mechanism might be associated with attenuating oxidative stress and inflammatory response. PMID:27340415

  7. Guggulsterone Attenuated Lipopolysaccharide-Induced Inflammatory Responses in Mouse Inner Medullary Collecting Duct-3 Cells.

    PubMed

    Kim, Dong-Goo; Bae, Gi-Sang; Jo, Il-Joo; Choi, Sun-Bok; Kim, Myoung-Jin; Jeong, Jun-Hyeok; Kang, Dae-Gil; Lee, Ho-Sub; Song, Ho-Joon; Park, Sung-Joo

    2016-02-01

    Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection. PMID:26260258

  8. Anti-B7-H3 monoclonal antibody ameliorates the damage of acute experimental pancreatitis by attenuating the inflammatory response.

    PubMed

    Zhuang, Xiaohui; Shen, Jiaqing; Jia, Zhengyu; Wu, Airong; Xu, Ting; Shi, Yuqi; Xu, Chunfang

    2016-06-01

    B7-H3, a recently discovered B7 family member, is documented as a regulator in the inflammatory response as well as T cell-mediated immune responses. In this paper, we find that patients with acute pancreatitis revealed overwhelming levels of serum soluble B7-H3 (sB7-H3) associated with the clinical outcomes. Furthermore, B7-H3 protein was marked increased in l-arginine-induced acute experimental pancreatitis. Anti-B7-H3 monoclonal antibody treatment attenuated the proinflammatory cytokine production, downregulated the activation of the NF-κB signaling pathway, and ameliorated the pancreas disruption in l-arginine-induced pancreatitis. In addition, although l-arginine alone failed to induce the production of proinflammatory cytokine and anti-B7-H3 mAb had no effect on the proinflammatory cytokine production of acinar cells, administration of anti-B7-H3 mAb in the coculture model of acinar cells and macrophages stimulated by l-arginine displayed the similar effects. On the whole, B7-H3 participates in the development of acute pancreatitis, and anti-B7-H3 monoclonal antibody ameliorates severity of acute experimental pancreatitis via attenuation of the inflammatory response. PMID:27003113

  9. Does Moderate Intensity Exercise Attenuate the Postprandial Lipemic and Airway Inflammatory Response to a High-Fat Meal?

    PubMed Central

    Kurti, Stephanie P.; Rosenkranz, Sara K.; Levitt, Morton; Cull, Brooke J.; Teeman, Colby S.; Emerson, Sam R.; Harms, Craig A.

    2015-01-01

    We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM) compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F) physically active (≥150 min/week of moderate-vigorous physical activity (MVPA)) subjects were randomly assigned to an exercise (EX; 60% VO2peak) or sedentary (CON) condition after a HFM (10 kcal/kg, 63% fat). Blood analytes and airway inflammation via exhaled nitric oxide (eNO) were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P < 0.05), but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%), but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P < 0.05,  η2 = 0.36). Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal. PMID:26000301

  10. Does moderate intensity exercise attenuate the postprandial lipemic and airway inflammatory response to a high-fat meal?

    PubMed

    Kurti, Stephanie P; Rosenkranz, Sara K; Levitt, Morton; Cull, Brooke J; Teeman, Colby S; Emerson, Sam R; Harms, Craig A

    2015-01-01

    We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM) compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F) physically active (≥ 150 min/week of moderate-vigorous physical activity (MVPA)) subjects were randomly assigned to an exercise (EX; 60% VO 2peak) or sedentary (CON) condition after a HFM (10 kcal/kg, 63% fat). Blood analytes and airway inflammation via exhaled nitric oxide (eNO) were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P < 0.05), but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%), but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P < 0.05, η (2) = 0.36). Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal. PMID:26000301

  11. JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells

    SciTech Connect

    Das, Amitabh; Chai, Jin Choul; Jung, Kyoung Hwa; Das, Nando Dulal; Kang, Sung Chul; Lee, Young Seek; Seo, Hyemyung; Chai, Young Gyu

    2014-11-01

    JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53{sup −/−} NE-4Cs). We determined the effect of LPS as a model of inflammation in p53{sup −/−} NE-4Cs and investigated whether the epigenetic modifier JMJD2A alter the expression of tumourigenic inflammatory genes. Global gene expression was measured in JMJD2A knockdown (kd) p53{sup −/−} NE-4Cs and in LPS-stimulated JMJD2A-kd p53{sup −/−} NE-4C cells. JMJD2A attenuation significantly down-regulated genes were Cdca2, Ccnd2, Ccnd1, Crebbp, IL6rα, and Stat3 related with cell cycle, proliferation, and inflammatory-disease responses. Importantly, some tumour-suppressor genes including Dapk3, Timp2 and TFPI were significantly up-regulated but were not affected by silencing of the JMJD2B. Furthermore, we confirmed the attenuation of JMJD2A also down-regulated Cdca2, Ccnd2, Crebbp, and Rest in primary NSCs isolated from the forebrains of E15 embryos of C57/BL6J mice with effective p53 inhibitor pifithrin-α (PFT-α). Transcription factor (TF) motif analysis revealed known binding patterns for CDC5, MYC, and CREB, as well as three novel motifs in JMJD2A-regulated genes. IPA established molecular networks. The molecular network signatures and functional gene-expression profiling data from this study warrants further investigation as an effective therapeutic target, and studies to elucidate the molecular mechanism of JMJD2A-kd-dependent effects in neuroectodermal stem cells should be performed. - Highlights: • Significant up-regulation of epigenetic modifier JMJD2A mRNA upon LPS treatment. • Inhibition of JMJD2A attenuated key inflammatory and tumourigenic genes. • Establishing IPA based functional genomics in JMJD2A-attenuated p53{sup

  12. Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat

    PubMed Central

    Wang, Xiaoning; Zhao, Binjiang; Li, Xue

    2015-01-01

    As a kind of α2 adrenergic receptor agonists, dexmedetomidine generates sedation, anti-anxiety and anesthesia effects by hyperpolarizing noradrenergic nerve cells in locus coeruleus. This study was designed to investigate the neuroprotective of dexmedetomidine attenuates isoflurane-induced cognitive impairment, and the possible underlying mechanism in aging rat. Firstly, we used isoflurane-induced aging rat model to analyze the therapeutical effect of dexmedetomidine on cognitive impairment. Next, commercial ELISA kits were used to analyze tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD) and caspase-3 levels. In addition, Western blotting was used to detect the protein expression of P38 MAPK, PTEN and phosphorylation-Akt (p-Akt) expression. Our results showed that the neuroprotective of dexmedetomidine significantly attenuates isoflurane-induced cognitive impairment in aging rat. Moreover, dexmedetomidine significantly inhibited these TNF-α, IL-1β, MDA, SOD and caspase-3 activities in isoflurane-induced aging rat. Meanwhile, the neuroprotective effects of dexmedetomidine on isoflurane-induced cognitive impairment significantly suppressed Bcl-xL/Bad rate, P38 MAPK and PTEN protein expression and activated p-Akt protein expression in aging rat. Collectively, neuroprotective effect of dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat. PMID:26770320

  13. Sirtuin inhibition attenuates the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages

    SciTech Connect

    Fernandes, Claudia A.; Fievez, Laurence; Neyrinck, Audrey M.; Delzenne, Nathalie M.; Bureau, Fabrice; Vanbever, Rita

    2012-04-20

    Highlights: Black-Right-Pointing-Pointer Lipopolysaccharide-stimulated macrophages were treated with cambinol and sirtinol. Black-Right-Pointing-Pointer Cambinol and sirtinol decreased lipopolysaccharide-induced cytokines. Black-Right-Pointing-Pointer Cambinol decreased NF-{kappa}B activity but had no impact on p38 MAPK activation. Black-Right-Pointing-Pointer Sirtuins are an interesting target for the treatment of inflammatory diseases. -- Abstract: In several inflammatory conditions such as rheumatoid arthritis or sepsis, the regulatory mechanisms of inflammation are inefficient and the excessive inflammatory response leads to damage to the host. Sirtuins are class III histone deacetylases that modulate the activity of several transcription factors that are implicated in immune responses. In this study, we evaluated the impact of sirtuin inhibition on the activation of lipopolysaccharide (LPS)-stimulated J774 macrophages by assessing the production of inflammatory cytokines. The pharmacologic inhibition of sirtuins decreased the production of tumour necrosis factor-alpha (TNF-{alpha}) interleukin 6 (IL-6) and Rantes. The reduction of cytokine production was associated with decreased nuclear factor kappa B (NF-{kappa}B) activity and inhibitor kappa B alpha (I{kappa}B{alpha}) phosphorylation while no impact was observed on the phosphorylation status of p38 mitogen-activated kinase (p38 MAPK). This work shows that sirtuin pharmacologic inhibitors are a promising tool for the treatment of inflammatory conditions.

  14. Berberine inhibits inflammatory mediators and attenuates acute pancreatitis through deactivation of JNK signaling pathways.

    PubMed

    Choi, Sun-Bok; Bae, Gi-Sang; Jo, Il-Joo; Wang, Shaofan; Song, Ho-Joon; Park, Sung-Joo

    2016-06-01

    Acute pancreatitis (AP) is a life-threatening disease. Berberine (BBR), a well-known plant alkaloid, is reported to have anti-inflammatory activity in many diseases. However, the effects of BBR on AP have not been clearly elucidated. Therefore, the present study aimed to investigate the effects of BBR on cerulein-induced AP in mice. AP was induced by either cerulein or l-arginine. In the BBR treated group, BBR was administered intraperitoneally 1h before the first cerulein or l-arginine injection. Blood samples were obtained to determine serum amylase and lipase activities and nitric oxide production. The pancreas and lung were rapidly removed for examination of histologic changes, myeloperoxidase (MPO) activity, and real-time reverse transcription-polymerase chain reaction. Furthermore, the regulating mechanisms of BBR were evaluated. Treatment of mice with BBR reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury, as well as inhibited several inflammatory parameters such as the expression of pro-inflammatory cytokines and inducible nitric oxide synthesis (iNOS). Furthermore, BBR administration significantly inhibited c-Jun N-terminal kinase (JNK) activation in the cerulein-induced AP. Deactivation of JNK resulted in amelioration of pancreatitis and the inhibition of inflammatory mediators. These results suggest that BBR exerts anti-inflammatory effects on AP via JNK deactivation on mild and severe acute pancreatitis model, and could be a beneficial target in the management of AP. PMID:27148818

  15. EGCG Attenuates Uric Acid-Induced Inflammatory and Oxidative Stress Responses by Medicating the NOTCH Pathway

    PubMed Central

    Xie, Hua; Sun, Jianqin; Chen, Yanqiu; Zong, Min; Li, Shijie; Wang, Yan

    2015-01-01

    Background. The aim of this study is to investigate whether (-)-epigallocatechin-3-gallate (EGCG) can prevent the UA-induced inflammatory effect of human umbilical vein endothelial cells (HUVEC) and the involved mechanisms in vitro. Methods. HUVEC were subjected to uric acid (UA) with or without EGCG treatment. RT-PCR and western blots were performed to determine the level of inflammation marker. The antioxidant activity was evaluated by measuring scavenged reactive oxygen species (ROS). Functional studies of the role of Notch-1 in HUVEC lines were performed using RNA interference analyses. Results. UA significantly increased the expressions of IL-6, ICAM-1, TNF-α, and MCP-1 and the production of ROS in HUVEC. Meanwhile, the expression of Notch-1 and its downstream effects significantly increased. Using siRNA, inhibition of Notch-1 signaling significantly impeded the expressions of inflammatory cytokines under UA treatment. Interestingly, EGCG suppressed the expressions of inflammatory cytokines and the generation of ROS. Western blot analysis of Notch-1 showed that EGCG significantly decreased the expressions of inflammatory cytokines through Notch-1 signaling pathways. Conclusions. In summary, our findings indicated that Notch-1 plays an important role in the UA-induced inflammatory response, and the downregulation of Notch-1 by EGCG could be an effective approach to decrease inflammation and oxidative stress induced by UA. PMID:26539255

  16. Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

    PubMed

    Arab, Hany H; Al-Shorbagy, Muhammad Y; Abdallah, Dalaal M; Nassar, Noha N

    2014-01-01

    Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis. PMID:24831514

  17. Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury

    PubMed Central

    Choi, Sang-Ho; Langenbach, Robert; Bosetti, Francesca

    2008-01-01

    Cyclooxygenase (COX)-1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1−/−) mice or wild type (COX-1+/+) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty four hours after LPS injection, COX-1−/− mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared to COX-1+/+ mice. COX-1−/− mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, iNOS, and NADPH oxidase. The transcriptional downregulation of cytokines and other inflammatory markers in COX-1−/− mice was mediated by a reduced activation of NF-κB and STAT3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E2, PGD2, PGF2α, and thromboxane B2 (TXB2), as well as the expression of pro-inflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage. PMID:18162486

  18. Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice.

    PubMed

    Lingaraju, Madhu Cholenahalli; Pathak, Nitya Nand; Begum, Jubeda; Balaganur, Venkanna; Bhat, Rafia Ahmad; Ramachandra, Harish Darasaguppe; Ayanur, Anjaneya; Ram, Mahendra; Singh, Vishakha; Kumar, Dhirendra; Kumar, Dinesh; Tandan, Surendra Kumar

    2015-01-01

    Sepsis commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity and mortality. Septic ALI is characterized by excessive production of proinflammatory mediators. It remained refractory to present therapies and new therapies need to be developed to improve further clinical outcomes. Betulinic acid (BA), a pentacyclic lupane group triterpenoid has been shown to have anti-inflammatory activities in many studies. However, its therapeutic efficacy in polymicrobial septic ALI is yet unknown. Therefore, we investigated the effects of BA on septic ALI using cecal ligation and puncture (CLP) model in mice. Vehicle or BA (3, 10, and 30mg/kg) was administered intraperitoneally, 3 times (0, 24 and 48h) before CLP and CLP was done on 49(th)h of the study. Survival rate was observed till 120h post CLP. Lung tissues were collected for analysis by sacrificing mice 18h post CLP. BA at 10 and 30mg/kg dose significantly reduced sepsis-induced mortality and lung injury as implied by attenuated lung histopathological changes, decreased protein and neutrophils infiltration. BA also decreased lung NF-κB expression, cytokine, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 levels. These evidences suggest that, the protective effects of BA on lungs are associated with defending action against inflammatory response and BA could be a potential modulatory agent of inflammation in sepsis-induced ALI. PMID:25277468

  19. Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice

    PubMed Central

    Watari, Kosuke; Shibata, Tomohiro; Nabeshima, Hiroshi; Shinoda, Ai; Fukunaga, Yuichi; Kawahara, Akihiko; Karasuyama, Kazuyuki; Fukushi, Jun-ichi; Iwamoto, Yukihide; Kuwano, Michihiko; Ono, Mayumi

    2016-01-01

    N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot–Marie–Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages. PMID:26778110

  20. Unfractionated bone marrow cells attenuate paraquat-induced glomerular injury and acute renal failure by modulating the inflammatory response

    PubMed Central

    Gu, Sing-Yi; Yeh, Ti-Yen; Lin, Shih-Yi; Peng, Fu-Chuo

    2016-01-01

    The aim of this study was to evaluate the efficacy of unfractionated bone marrow cells (BMCs) in attenuating acute kidney injury (AKI) induced by paraquat (PQ) in a mouse model. PQ (55 mg/kg BW) was intraperitoneally injected into C57BL/6 female mice to induce AKI, including renal function failure, glomerular damage and renal tubule injury. Glomerular podocytes were the first target damaged by PQ, which led to glomerular injury. Upon immunofluorescence staining, podocytes depletion was validated and accompanied by increased urinary podocin levels, measured on days 1 and 6. A total of 5.4 × 106 BMCs obtained from the same strain of male mice were injected into AKI mice through the tail vein at 3, 24, and 48 hours after PQ administration. As a result, renal function increased, tubular and glomerular injury were ameliorated, podocytes loss improved, and recipient mortality decreased. In addition, BMCs co-treatment decreased the extent of neutrophil infiltration and modulated the inflammatory response by shifting from pro-inflammatory Th1 to an anti-inflammatory Th2 profile, where IL-1β, TNF-α, IL-6 and IFN-γ levels declined and IL-10 and IL-4 levels increased. The present study provides a platform to investigate PQ-induced AKI and repeated BMCs injection represents an efficient therapeutic strategy. PMID:26988026

  1. Variation in Inflammatory/Regulatory Cytokines in Secondary, Tertiary, and Quaternary Challenges with Dengue Virus

    PubMed Central

    Sierra, Beatriz; Pérez, Ana B.; Alvarez, Mayling; García, Gissel; Vogt, Katrin; Aguirre, Eglys; Schmolke, Kathrin; Volk, Hans-Dieter; Guzmán, María G.

    2012-01-01

    Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-β after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections. PMID:22802438

  2. Dietary L-arginine supplementation attenuates lipopolysaccharide-induced inflammatory response in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two experiments were conducted to investigate the effect of dietary L-arginine (Arg) supplementation on inflammatory response and innate immunity of broilers. Experiment 1 was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatment; 6 birds/cage) with 3 dietary Arg concentrations (1.05, 1.4...

  3. Acai juice attenuates atherosclerosis in apoe deficient mice through antioxidant and anti-inflammatory activities

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective - Acai fruit pulp has received much attention because of its high antioxidant capacity and potential anti-inflammatory effects. In this study, athero-protective effects of açaí juice were investigated in apolipoprotein E deficient (apoE -/-) mice. Methods and Results - ApoE-/- mice were f...

  4. Salidroside attenuates inflammatory response via suppressing JAK2-STAT3 pathway activation and preventing STAT3 transfer into nucleus.

    PubMed

    Qi, Zhilin; Qi, Shimei; Ling, Liefeng; Lv, Jun; Feng, Zunyong

    2016-06-01

    Salidroside (SAL) is an active ingredient isolated from the Rhodiola rosea, has potent anti-inflammatory effect, but the mechanism is still elusive. The purpose of this study is to verify the effects of SAL on LPS-induced inflammatory response and investigate the possible underlying molecular mechanism. RAW264.7 cells were pre-incubated with SAL for 2h, then stimulated with or without LPS for another 16h. The levels of TNF-α, MCP-1, IL-6, and PGE2 were detected by ELISA, and the production of NO was determined by nitrite analysis. The expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by Western blotting. In RAW264.7 cells and murine peritoneal macrophages, the activation of signal molecules was also measured by Western blot. The nuclear translocation of STAT3 was determined by Laser confocal and nucleocytoplasmic separation experiments. Our results showed that SAL attenuated the productions of TNF-α, IL-6, MCP-1, PGE2 and NO dose dependently. SAL also suppressed LPS-induced expressions of iNOS and COX-2 significantly. Further studies revealed that SAL down-regulated the phosphorylation of JAK2-STAT3 signaling pathway and reduced the nuclear translocation of STAT3 induced by LPS in RAW264.7 cells and primary peritoneal macrophages. In addition, consistent with the results in vitro, in the model of mice acute lung injury (ALI) induced by LPS, SAL reduced the infiltration of inflammatory cells and decreased the levels of serum TNF-α and IL-6 obviously. Taken together, these data indicated that SAL exerted anti-inflammatory action via down-regulating LPS-induced activation of JAK2-STAT3 pathway and suppressing STAT3 transfer into the nucleus at least in part. PMID:27085677

  5. Anti-inflammatory effects of secondary metabolites of marine Pseudomonas sp. in human neutrophils are through inhibiting P38 MAPK, JNK, and calcium pathways.

    PubMed

    Yang, Shun-Chin; Sung, Ping-Jyun; Lin, Chwan-Fwu; Kuo, Jimmy; Chen, Chun-Yu; Hwang, Tsong-Long

    2014-01-01

    Activated neutrophils play a significant role in the pathogenesis of many inflammatory diseases. The metabolites of marine microorganisms are increasingly employed as sources for developing new drugs; however, very few marine drugs have been studied in human neutrophils. Herein, we showed that secondary metabolites of marine Pseudomonas sp. (N11) significantly inhibited superoxide anion generation and elastase release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils, with IC50 values of 0.67±0.38 µg/ml and 0.84±0.12 µg/ml, respectively. In cell-free systems, neither superoxide anion-scavenging effect nor inhibition of elastase activity was associated with the suppressive effects of N11. N11 inhibited the phosphorylation of p38 MAP kinase and JNK, but not Erk and Akt, in FMLP-induced human neutrophils. Also, N11 dose-dependently attenuated the transient elevation of intracellular calcium concentration in activated neutrophils. In contrast, N11 failed to alter phorbol myristate acetate-induced superoxide anion generation, and the inhibitory effects of N11 were not reversed by protein kinase A inhibitor. In conclusion, the anti-inflammatory effects of N11 on superoxide anion generation and elastase release in activated human neutrophils are through inhibiting p38 MAP kinase, JNK, and calcium pathways. Our results suggest that N11 has the potential to be developed to treat neutrophil-mediated inflammatory diseases. PMID:25474595

  6. Dynamic functional modulation of CD4+ T cell recall responses is dependent on the inflammatory environment of the secondary stimulus.

    PubMed

    Kim, Chulwoo; Jay, David C; Williams, Matthew A

    2014-05-01

    The parameters that modulate the functional capacity of secondary Th1 effector cells are poorly understood. In this study, we employ a serial adoptive transfer model system to show that the functional differentiation and secondary memory potential of secondary CD4+ effector T cells are dependent on the inflammatory environment of the secondary challenge. Adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus (LCMV) Glycoprotein-specific SMARTA memory cells into LCMV-immune hosts, followed by secondary challenge with Listeria monocytogenes recombinantly expressing a portion of the LCMV Glycoprotein (Lm-gp61), resulted in the rapid emergence of SMARTA secondary effector cells with heightened functional avidity (as measured by their ability to make IFNγ in response to ex vivo restimulation with decreasing concentrations of peptide), limited contraction after pathogen clearance and stable maintenance secondary memory T cell populations. In contrast, transfer of SMARTA memory cells into naïve hosts prior to secondary Lm-gp61 challenge, which resulted in a more extended infectious period, resulted in poor functional avidity, increased death during the contraction phase and poor maintenance of secondary memory T cell populations. The modulation of functional avidity during the secondary Th1 response was independent of differences in antigen load or persistence. Instead, the inflammatory environment strongly influenced the function of the secondary Th1 response, as inhibition of IL-12 or IFN-I activity respectively reduced or increased the functional avidity of secondary SMARTA effector cells following rechallenge in a naïve secondary hosts. Our findings demonstrate that secondary effector T cells exhibit inflammation-dependent differences in functional avidity and memory potential, and have direct bearing on the design of strategies aimed at boosting memory T cell responses. PMID:24854337

  7. Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus

    PubMed Central

    Shukitt-Hale, Barbara; Lau, Francis C.; Carey, Amanda N.; Galli, Rachel L.; Spangler, Edward L.; Ingram, Donald K.; Joseph, James A.

    2016-01-01

    Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study, we investigated whether polyphenols in blueberries can reduce the deleterious effects of inflammation induced by central administration of kainic acid by altering the expression of genes associated with inflammation. To this end, 4-month-old male Fischer-344 (F344) rats were fed a control, 0.015% piroxicam (an NSAID) or 2% blueberry diet for 8 weeks before either Ringer's buffer or kainic acid was bilaterally micro-infused into the hippocampus. Two weeks later, following behavioral evaluation, the rats were killed and total RNA from the hippocampus was extracted and used in real-time quantitative RT-PCR (qRT-PCR) to analyze the expression of inflammation-related genes. Kainic acid had deleterious effects on cognitive behavior as kainic acid-injected rats on the control diet exhibited increased latencies to find a hidden platform in the Morris water maze compared to Ringer's buffer-injected rats and utilized non-spatial strategies during probe trials. The blueberry diet, and to a lesser degree the piroxicam diet, was able to improve cognitive performance. Immunohistochemical analyses of OX-6 expression revealed that kainic acid produced an inflammatory response by increasing the OX-6 positive areas in the hippocampus of kainic acid-injected rats. Kainic acid up-regulated the expression of the inflammatory cytokines IL-1β and TNF-α, the neurotrophic factor IGF-1, and the transcription factor NF-κB. Blueberry and piroxicam supplementations were found to attenuate the kainic acid-induced increase in the expression of IL-1β, TNF-α, and NF-κB, while only blueberry was able to augment the increased IGF-1 expression. These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions

  8. TSG attenuates LPC-induced endothelial cells inflammatory damage through notch signaling inhibition.

    PubMed

    Zhao, Jing; Liang, Yuan; Song, Fan; Xu, Shouzhu; Nian, Lun; Zhou, Xuanxuan; Wang, Siwang

    2016-01-01

    Lysophosphatidylcholine (LPC) induces inflammation in endothelial cells (ECs) but the mechanism is not fully understood. The Notch signaling pathway is involved in chronic EC inflammation, but its functions in LPC-induced endothelial inflammatory damage and 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside's (TSG) protective effect during LPC-induced inflammatory damage in human umbilical vein endothelial cells (HUVECs) is largely unknown. We report that Notch signaling activation contributed to LPC-induced injury in HUVECs, and that TSG protected HUVECs from LPC-induced injury by antagonizing Notch signaling activation by LPC. γ-secretase inhibitor (DAPT), a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to inhibit Notch activity. HUVECs were exposed to LPC in the presence or absence of TSG, DAPT, and Notch1 siRNA. LPC treatment of HUVECs resulted in reduced cell viability, and Notch1 and Hes1 upregulation. Either silencing of Notch1 by siRNA or pharmacological inhibition of Notch signaling by DAPT prevented the loss of cell viability, and induction of apoptosis, and enhanced expression Notch1, Hes1 and MCP-1 by LPC in HUVECs. Similarly, TSG reduced LPC stimulation of Notch1, Hes1, and MCP-1 expression, prevented the release of IL-6 and CRP and rescued HUVECs from LPC-induced cell damage. Our data indicate that the Notch signaling pathway is a crucial mediator of endothelial inflammatory damage and that TSG protects against endothelial inflammatory damage by inhibiting the Notch signaling pathway. Our findings suggest that targeting Notch signaling by natural products such as TSG is a promising strategy for the prevention and treatment of chronic inflammation associated diseases, including atherosclerosis. © 2015 IUBMB Life, 68(1):37-50, 2016. PMID:26662286

  9. Bensal HP Attenuates the Inflammatory Response in Hair Shaving Associated Dermatitis.

    PubMed

    Ray, Anjana; Mordorski, Breanne; Landriscina, Angelo; Rosen, Jamie; Nosanchuk, Joshua; Friedman, Adam

    2016-07-01

    Shaving is an ubiquitous practice, and cutaneous irritation and inflammation are common sequelae, which may be worsened by underlying skin conditions or poor hair removal techniques. Moisturizing shaving creams and aftershaves are available to help maintain or restore the epidermal barrier; however, many continue to suffer from post-shave redness, itching, and pain. To reduce post-shave inflammation, some products have included botanical and other natural ingredients, which are often favored by consumers. We evaluated Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, which has documented anti-inflammatory and antimicrobial properties, in a murine model of shave irritation to determine whether it would be useful in this clinical setting. Shaving dermatitis was simulated using a depilatory agent and electric clippers, and the shaved area was photographed and treated with Bensal HP daily for four days. Compared to untreated controls, mice treated with Bensal HP experienced a visible reduction in skin irritation and inflammation. These findings were mirrored on histology, as Bensal HP-treated areas demonstrated increased epidermal integrity and decreased dermal inflammatory infiltrate compared to untreated skin. Using immunohistochemistry, fewer neutrophils and macrophages were noted, and cytokine analysis also revealed decreased IL-6 in Bensal HP-treated skin at 24 and 96 hours after shaving. These results highlight the potential of Bensal HP as an anti-inflammatory treatment for shave irritation. Given the product's application against a variety of inflammatory and infectious skin disorders, its use against shave irritation may also improve comorbid skin conditions, such as pseudofolliculitis barbae.

    J Drugs Dermatol. 2016;15(7):836-840. PMID:27391633

  10. Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis.

    PubMed

    Umar, Sadiq; Umar, Khalid; Sarwar, Abu Hasnath Md Golam; Khan, Altaf; Ahmad, Niyaz; Ahmad, Sayeed; Katiyar, Chandra Kant; Husain, Syed Akhtar; Khan, Haider A

    2014-05-15

    Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system. PMID:24667331

  11. Light-emitting diodes at 940nm attenuate colitis-induced inflammatory process in mice.

    PubMed

    Belém, Mônica O; de Andrade, Giovana M M; Carlos, Thalita M; Guazelli, Carla F S; Fattori, Victor; Toginho Filho, Dari O; Dias, Ivan F L; Verri, Waldiceu A; Araújo, Eduardo J A

    2016-09-01

    Inflammatory bowel disease (IBD) presents intense inflammatory infiltrate, crypt abscesses, ulceration and even loss of function. Despite the clinical relevance of IBD, its current therapy remains poorly effective. Infrared wavelength phototherapy shows therapeutic potential on inflammation. Our goal was to evaluate whether light-emitting diodes (LED) at 940nm are capable of mitigating the colitis-induced inflammatory process in mice. Forty male Swiss mice were assigned into five groups: control; control treated with LED therapy; colitis without treatment; colitis treated with LED therapy; colitis treated with Prednisolone. Experimental colitis was induced by acetic acid 7.5% (pH2.5) rectal administration. LED therapy was performed with light characterized by wavelength of 940nm, 45nm bandwidth, intensity of 4.05J/cm(2), total power of 270mW and total dose of 64.8J for 4min in a single application. Colitis-induced intestinal transit delay was inhibited by LED therapy. Colitis caused an increase of colon dimensions (length, diameter, total area) and colon weight (edema), which were inhibited by LED therapy. LED therapy also decreased colitis-induced tissue gross lesion, myeloperoxidase activity, microscopic tissue damage score and the presence of inflammatory infiltrate in all intestinal layers. Furthermore, LED therapy inhibited colitis-induced IL-1β, TNF-α, and IL-6 production. We conclude LED therapy at 940nm inhibited experimental colitis-induced colon inflammation in mice, therefore, rendering it a promising therapeutic approach that deserves further investigation. PMID:27424097

  12. Gelam Honey Attenuates the Oxidative Stress-Induced Inflammatory Pathways in Pancreatic Hamster Cells

    PubMed Central

    Qvist, Rajes; Mohd Yusof, Kamaruddin; Ismail, Ikram Shah

    2016-01-01

    Purpose. Type 2 diabetes consists of progressive hyperglycemia and insulin resistance, which could result from glucose toxicity, inflammatory cytokines, and oxidative stress. In the present study we investigated the effect of Gelam honey and quercetin on the oxidative stress-induced inflammatory pathways and the proinflammatory cytokines. Methods. HIT-T15 cells were cultured and preincubated with the extract of Gelam honey (20, 40, 60, and 80 μg/mL), as well as quercetin (20, 40, 60, and 80 μM), prior to stimulation by 20 and 50 mM glucose. Results. HIT-T15 cells cultured under hyperglycemic condition showed a significant increase in the inflammatory pathways by phosphorylating JNK, IKK-β, and IRS-1 at Ser307 (p < 0.05). There was a significant decrease in the phosphorylation of Akt at Ser473 (p < 0.05). Pretreatment with Gelam honey and quercetin reduced the expression of phosphorylated JNK, IKK-β, and IRS-1, thereby significantly reducing the expression of proinflammatory cytokines like TNF-α, IL-6, and IL-1β (p < 0.05). At the same time there was a significant increase in the phosphorylated Akt showing the protective effects against inflammation and insulin resistance (p < 0.05). In conclusion, our data suggest the potential use of the extract from Gelam honey and quercetin in modulating the inflammation induced insulin signaling pathways. PMID:27034691

  13. CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis

    PubMed Central

    Castoldi, Angela; Amano, Mariane Tami; Nunes, Valeria Sutti; Quintao, Eder Carlos Rocha; Cazita, Patrícia Miralda

    2016-01-01

    Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases. PMID:27293313

  14. Accurate and precise measurement of oxygen isotopic fractions and diffusion profiles by selective attenuation of secondary ions (SASI).

    PubMed

    Téllez, Helena; Druce, John; Hong, Jong-Eun; Ishihara, Tatsumi; Kilner, John A

    2015-03-01

    The accuracy and precision of isotopic analysis in Time-of-Flight secondary ion mass spectrometry (ToF-SIMS) relies on the appropriate reduction of the dead-time and detector saturation effects, especially when analyzing species with high ion yields or present in high concentrations. Conventional approaches to avoid these problems are based on Poisson dead-time correction and/or an overall decrease of the total secondary ion intensity by reducing the target current. This ultimately leads to poor detection limits for the minor isotopes and high uncertainties of the measured isotopic ratios. An alternative strategy consists of the attenuation of those specific secondary ions that saturate the detector, providing an effective extension of the linear dynamic range. In this work, the selective attenuation of secondary ion signals (SASI) approach is applied to the study of oxygen transport properties in electroceramic materials by isotopic labeling with stable (18)O tracer and ToF-SIMS depth profiling. The better analytical performance in terms of accuracy and precision allowed a more reliable determination of the oxygen surface exchange and diffusion coefficients while maintaining good mass resolution and limits of detection for other minor secondary ion species. This improvement is especially relevant to understand the ionic transport mechanisms and properties of solid materials, such as the parallel diffusion pathways (e.g., oxygen diffusion through bulk, grain boundary, or dislocations) in electroceramic materials with relevant applications in energy storage and conversion devices. PMID:25647357

  15. Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury.

    PubMed

    Saxena, Tarun; Loomis, Kristin H; Pai, S Balakrishna; Karumbaiah, Lohitash; Gaupp, Eric; Patil, Ketki; Patkar, Radhika; Bellamkonda, Ravi V

    2015-02-24

    Spinal cord injury (SCI) can lead to permanent motor and sensory deficits. Following the initial traumatic insult, secondary injury mechanisms characterized by persistent heightened inflammation are initiated and lead to continued and pervasive cell death and tissue damage. Anti-inflammatory drugs such as methylprednisolone (MP) used clinically have ambiguous benefits with debilitating side effects. Typically, these drugs are administered systemically at high doses, resulting in toxicity and paradoxically increased inflammation. Furthermore, these drugs have a small time window postinjury (few hours) during which they need to be infused to be effective. As an alternative to MP, we investigated the effect of a small molecule inhibitor (Chicago sky blue, CSB) of macrophage migration inhibitory factor (MIF) for treating SCI. The pleiotropic cytokine MIF is known to contribute to upregulation of several pro-inflammatory cytokines in various disease and injury states. In vitro, CSB administration alleviated endotoxin-mediated inflammation in primary microglia and macrophages. Nanocarriers such as liposomes can potentially alleviate systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. However, the therapeutic window of 100 nm scale nanoparticle localization to the spinal cord after contusion injury is not fully known. Thus, we first investigated the ability of nanocarriers of different sizes to localize to the injured spinal cord up to 2 weeks postinjury. Results from the study showed that nanocarriers as large as 200 nm in diameter could extravasate into the injured spinal cord up to 96 h postinjury. We then formulated nanocarriers (liposomes) encapsulating CSB and administered them intravenously 48 h postinjury, within the previously determined 96 h therapeutic window. In vivo, in this clinically relevant contusion injury model in rats, CSB administration led to preservation of vascular and white matter integrity

  16. Nrf2 Knockout Attenuates the Anti-Inflammatory Effects of Phenethyl Isothiocyanate and Curcumin

    PubMed Central

    2015-01-01

    The role of phytochemicals in preventive and therapeutic medicine is a major area of scientific research. Several studies have illustrated the mechanistic roles of phytochemicals in Nrf2 transcriptional activation. The present study aims to examine the importance of the transcription factor Nrf2 by treating peritoneal macrophages from Nrf2+/+ and Nrf2–/– mice ex vivo with phenethyl isothiocyanate (PEITC) and curcumin (CUR). The peritoneal macrophages were pretreated with the drugs and challenged with lipopolysaccharides (LPSs) alone and in combination with PEITC or CUR to assess their anti-inflammatory and antioxidative effects based on gene and protein expression in the treated cells. LPS treatment resulted in an increase in the expression of inflammatory markers such as cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in both Nrf2+/+ and Nrf2–/– macrophages, detected by quantitative polymerase chain reaction (qPCR). Nrf2+/+ macrophages treated with PEITC and CUR exhibited a significant decrease in the expression of these anti-inflammatory genes along with an increase in the expression of hemeoxygenase-1 (HO-1), which is an antioxidative stress gene downstream of the Nrf2 transcription factor battery. Although there was no significant decrease in the expression of the anti-inflammatory genes or an increase in HO-1 expression in Nrf2–/– macrophages treated with either PEITC or CUR, there was a significant decrease in the protein expression of COX-2 and an increase in the expression of HO-1 in Nrf2+/+ macrophages treated with PEITC compared to that with CUR treatment. No significant changes were observed in the macrophages from knockout animals. Additionally, there was a significant decrease in LPS-induced IL-6 and TNF-α production following PEITC treatment compared with that following CUR in Nrf2+/+ macrophages, whereas no change was observed in the macrophages from knockout

  17. JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells.

    PubMed

    Das, Amitabh; Chai, Jin Choul; Jung, Kyoung Hwa; Das, Nando Dulal; Kang, Sung Chul; Lee, Young Seek; Seo, Hyemyung; Chai, Young Gyu

    2014-11-01

    JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53(-/-) NE-4Cs). We determined the effect of LPS as a model of inflammation in p53(-/-) NE-4Cs and investigated whether the epigenetic modifier JMJD2A alter the expression of tumourigenic inflammatory genes. Global gene expression was measured in JMJD2A knockdown (kd) p53(-/-) NE-4Cs and in LPS-stimulated JMJD2A-kd p53(-/-) NE-4C cells. JMJD2A attenuation significantly down-regulated genes were Cdca2, Ccnd2, Ccnd1, Crebbp, IL6rα, and Stat3 related with cell cycle, proliferation, and inflammatory-disease responses. Importantly, some tumour-suppressor genes including Dapk3, Timp2 and TFPI were significantly up-regulated but were not affected by silencing of the JMJD2B. Furthermore, we confirmed the attenuation of JMJD2A also down-regulated Cdca2, Ccnd2, Crebbp, and Rest in primary NSCs isolated from the forebrains of E15 embryos of C57/BL6J mice with effective p53 inhibitor pifithrin-α (PFT-α). Transcription factor (TF) motif analysis revealed known binding patterns for CDC5, MYC, and CREB, as well as three novel motifs in JMJD2A-regulated genes. IPA established molecular networks. The molecular network signatures and functional gene-expression profiling data from this study warrants further investigation as an effective therapeutic target, and studies to elucidate the molecular mechanism of JMJD2A-kd-dependent effects in neuroectodermal stem cells should be performed. PMID:25193078

  18. Camellia Oil-Enriched Diet Attenuates Oxidative Stress and Inflammatory Markers in Hypercholesterolemic Subjects.

    PubMed

    Bumrungpert, Akkarach; Pavadhgul, Patcharanee; Kalpravidh, Ruchaneekorn W

    2016-09-01

    Camellia oil is commonly used as an adjuvant in medicine. It is rich in monounsaturated fatty acids, vitamin E, and phytochemicals. The objective of this study was to examine effects of camellia oil consumption on oxidative stress, low-density lipoprotein-cholesterol (LDL-C) oxidation, and inflammatory markers in hypercholesterolemic subjects. The study design was a randomized, single-blind controlled trial. Women with hypercholesterolemia (n = 50) were randomly divided into two groups. The treatment group (n = 25) was provided camellia oil-enriched diets and the control group (n = 25) was provided diets cooked with soybean oil three meals (45 mL oil) a day for 8 weeks. Biomarkers of oxidative stress and inflammatory cytokines were assessed before and the after intervention. Camellia oil consumption significantly decreased malondialdehyde (11.2%; P < .001) whereas glutathione was not changed (P = .382). Moreover, the camellia oil group exhibited a statistically significant decrease in oxidized LDL-C (8.7%; P < .001) compared with the control group. Furthermore, camellia oil consumption significantly decreased high-sensitivity C-reactive protein (12.3%; P < .001) whereas tumor necrosis factor-α and interleukin-6 were not different (P = .079; P = .660, respectively) compared with the control group. These data indicate that the consumption of camellia oil-enriched diet could decrease oxidative stress and inflammatory markers in hypercholesterolemic women. Therefore, camellia oil consumption may reduce cardiovascular disease risk factors. PMID:27627703

  19. Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

    PubMed Central

    Rubio-Ruiz, María Esther; Pérez-Torres, Israel; Diaz-Diaz, Eulises; Pavón, Natalia; Guarner-Lans, Verónica

    2014-01-01

    Aim: Metabolic syndrome (MS) and aging are low-grade systemic inflammatory conditions, and inflammation is a key component of endothelial dysfunction. The aim of this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) upon the vascular reactivity in aging MS rats. Methods: MS was induced in young male rats by adding 30% sucrose in drinking water over 6, 12, and 18 months. When the treatment was finished, the blood samples were collected, and aortas were dissected out. The expression of COX isoenzymes and PLA2 in the aortas was analyzed using Western blot analysis. The contractile responses of aortic rings to norepinephrine (1 μmol/L) were measured in the presence or absence of different NSAIDs (10 μmol/L for each). Results: Serum levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in control rats were remained stable during the aging process, whereas serum IL-6 in MS rats were significantly increased at 12 and 18 months. The levels of COX isoenzyme and PLA2 in aortas from control rats increased with the aging, whereas those in aortas from MS rats were irregularly increased with the highest levels at 6 months. Pretreatment with acetylsalicylic acid (a COX-1 preferential inhibitor), indomethacin (a non-selective COX inhibitor) or meloxicam (a COX-2 preferential inhibitor) decreased NE-induced contractions of aortic rings from MS rats at all the ages, with meloxicam being the most potent. Acetylsalicylic acid also significantly reduced the maximum responses of ACh-induced vasorelaxation of aortic rings from MS rats, but indomethacin and meloxicam had no effect. Conclusion: NSAIDs can directly affect vascular responses in aging MS rats. Understanding the effects of NSAIDs on blood vessels may improve the treatment of cardiovascular diseases and MS in the elders. PMID:25263337

  20. Croton antisyphiliticus Mart. attenuates the inflammatory response to carrageenan-induced pleurisy in mice.

    PubMed

    Dos Reis, Gustavo Oliveira; Vicente, Geison; de Carvalho, Francieli Kanumfre; Heller, Melina; Micke, Gustavo Amadeu; Pizzolatti, Moacir Geraldo; Fröde, Tânia Silvia

    2014-04-01

    The aim of this study was to investigate the anti-inflammatory effect of the crude hydroalcoholic extract (CHE) from the aerial parts of Croton antisyphiliticus, its fractions and isolated compounds derived from it on the mouse model of pleurisy induced by carrageenan. The aerial parts of C. antisyphiliticus were dried, macerated and extracted with ethanol to obtain the CHE, which was fractionated by liquid-liquid extraction using solvents with increasing polarity to obtain hexane (Hex), ethyl acetate (EA) and aqueous (Aq) fractions. Vitexin and quinic acid were isolated from Aq fraction. Capillary electrophoresis analysis, physical characteristics and spectral data produced by infrared (IR), nuclear magnetic resonance ((1)H and (13)C NMR) and mass spectrometry analyses were used to identify and elucidate the structure of the isolated compounds. The experimental model of pleurisy was induced in mice by a single intrapleural injection of carrageenan (1 %). Leukocytes, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities and nitrate/nitrite (NOx), tumor necrosis factor-α (TNF-α) and interleukin-17 (IL-17) levels were determined in the pleural fluid leakage at 4 h after pleurisy induction. Animals pre-treated with CHE, Hex, EA, Aq, vitexin and quinic acid exhibited decreases in leukocytes, exudate concentrations, MPO and ADA activities and NOx levels (p < 0.05). Also CHE, Hex, EA and vitexin but not quinic acid inhibited TNF-α and IL-17 levels (p < 0.05). C. antisyphiliticus caused anti-inflammatory effect by inhibiting the activated leukocytes, exudate concentrations, NOx, TNF-α, and IL-17 levels. The compounds vitexin and quinic acid may be responsible for this anti-inflammatory action. PMID:23990384

  1. Alpinetin attenuates inflammatory responses by suppressing TLR4 and NLRP3 signaling pathways in DSS-induced acute colitis.

    PubMed

    He, Xuexiu; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Fu, Yunhe; Yang, Zhengtao

    2016-01-01

    Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment. PMID:27321991

  2. Alpinetin attenuates inflammatory responses by suppressing TLR4 and NLRP3 signaling pathways in DSS-induced acute colitis

    PubMed Central

    He, Xuexiu; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Fu, Yunhe; Yang, Zhengtao

    2016-01-01

    Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment. PMID:27321991

  3. Attenuated viral hepatitis in Trem1−/− mice is associated with reduced inflammatory activity of neutrophils

    PubMed Central

    Kozik, Jan-Hendrik; Trautmann, Tanja; Carambia, Antonella; Preti, Max; Lütgehetmann, Marc; Krech, Till; Wiegard, Christiane; Heeren, Joerg; Herkel, Johannes

    2016-01-01

    TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1−/− mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1−/− mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils. PMID:27328755

  4. Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs.

    PubMed

    Avishek, Kumar; Kaushal, Himanshu; Gannavaram, Sreenivas; Dey, Ranadhir; Selvapandiyan, Angamuthu; Ramesh, V; Negi, Narender Singh; Dubey, Uma S; Nakhasi, Hira L; Salotra, Poonam

    2016-01-01

    Currently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1(-/-) and Ldp27(-/-)) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1(-/-) and Ldp27(-/-) in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1(-/-) and Ldp27(-/-) strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-γ, TNF-α, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-γ secreting CD4(+) and CD8(+) T cells and IL-17 secreting CD4(+) cells in PBMCs from HVL cases with no increase in IL-10 secreting T cells. Hence, LdCen1(-/-) and Ldp27(-/-) are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure. PMID:27624408

  5. Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain.

    PubMed

    Jha, Mithilesh Kumar; Rahman, Md Habibur; Park, Dong Ho; Kook, Hyun; Lee, In-Kyu; Lee, Won-Ha; Suk, Kyoungho

    2016-09-01

    Pyruvate dehydrogenase (PDH) kinases (PDKs) 1-4, expressed in peripheral and central tissues, regulate the activity of the PDH complex (PDC). The PDC is an important mitochondrial gatekeeping enzyme that controls cellular metabolism. The role of PDKs in diverse neurological disorders, including neurometabolic aberrations and neurodegeneration, has been described. Implications for a role of PDKs in inflammation and neurometabolic coupling led us to investigate the effect of genetic ablation of PDK2/4 on nociception in a mouse model of acute inflammatory pain. Deficiency in Pdk2 and/or Pdk4 in mice led to attenuation of formalin-induced nociceptive behaviors (flinching, licking, biting, or lifting of the injected paw). Likewise, the pharmacological inhibition of PDKs substantially diminished the nociceptive responses in the second phase of the formalin test. Furthermore, formalin-provoked paw edema formation and mechanical and thermal hypersensitivities were significantly reduced in Pdk2/4-deficient mice. Formalin-driven neutrophil recruitment at the site of inflammation, spinal glial activation, and neuronal sensitization were substantially lessened in the second or late phase of the formalin test in Pdk2/4-deficient animals. Overall, our results suggest that PDK2/4 can be a potential target for the development of pharmacotherapy for the treatment of acute inflammatory pain. © 2016 Wiley Periodicals, Inc. PMID:26931482

  6. Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response.

    PubMed

    Yang, Yang; Zhang, Yan; Wang, Zhaotao; Wang, Shanshan; Gao, Mou; Xu, Ruxiang; Liang, Chunyang; Zhang, Hongtian

    2016-04-01

    The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1β, TNF-α and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden-1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri-hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood-brain barrier permeability. PMID:26498936

  7. Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling.

    PubMed

    Liu, Meng-Han; Lin, An-Hsuan; Lee, Hung-Fu; Ko, Hsin-Kuo; Lee, Tzong-Shyuan; Kou, Yu Ru

    2014-01-01

    Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have previously reported that cigarette smoke (CS) activates reactive oxygen species- (ROS-) sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling leading to induction of lung inflammation. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we showed that chronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration, increased lung vascular permeability, elevated lung levels of chemokines, cytokines, and 4-hydroxynonenal (an oxidative stress biomarker), and induced lung inflammation; all of these CS-induced events were suppressed by chronic treatment with paeonol. Using human bronchial epithelial cells (HBECs), we demonstrated that cigarette smoke extract (CSE) sequentially increased extracellular and intracellular levels of ROS, activated the MAPKs/NF-κB signaling, and induced interleukin-8 (IL-8); all these CSE-induced events were inhibited by paeonol pretreatment. Our findings suggest a novel role for paeonol in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing CSE-induced IL-8 in vitro via its antioxidant function and an inhibition of the MAPKs/NF-κB signaling. PMID:25165413

  8. Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response

    PubMed Central

    Lee, Yun-Hee; Kim, Joung-Hee; Kim, Sou Hyun; Oh, Ji Youn; Seo, Woo Duck; Kim, Kyung-Mi; Jung, Jae-Chul; Jung, Young-Suk

    2016-01-01

    It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF)-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH) level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol. PMID:27455313

  9. Celastrol Attenuates Inflammatory and Neuropathic Pain Mediated by Cannabinoid Receptor Type 2

    PubMed Central

    Yang, Longhe; Li, Yanting; Ren, Jie; Zhu, Chenggang; Fu, Jin; Lin, Donghai; Qiu, Yan

    2014-01-01

    Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, generated by carrageenan injection and spared nerve injury (SNI), respectively, to evaluate the effect of celastrol and to address the mechanisms underlying pain processing. Intraperitoneal (i.p.) injection of celastrol produced a dose-dependent inhibition of carrageenan-induced edema and allodynia. Real-time PCR analysis showed that celastrol (0.3 mg/kg, i.p.) significantly reduced mRNA expressions of inflammatory cytokines, TNF-α, IL-6, IL-1β, in carrageenan-injected mice. In SNI mice, pain behavior studies showed that celastrol (1 mg/kg, i.p.) effectively prevented the hypersensitivity of mechanical nociceptive response on the third day post-surgery and the seventh day post-surgery. Furthermore, the anti-hyperalgesic effects of celastrol in carrageenan-injected mice and SNI mice were reversed by SR144528 (1 mg/kg, i.p.), a specific cannabinoid receptor-2 (CB2) receptor antagonist, but not by SR141716 (1 mg/kg, i.p.), a specific cannabinoid receptor-1 (CB1) receptor antagonist. Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief. PMID:25101848

  10. Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response.

    PubMed

    Lee, Yun-Hee; Kim, Joung-Hee; Kim, Sou Hyun; Oh, Ji Youn; Seo, Woo Duck; Kim, Kyung-Mi; Jung, Jae-Chul; Jung, Young-Suk

    2016-01-01

    It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF)-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH) level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol. PMID:27455313

  11. Low-level laser therapy attenuates the acute inflammatory response induced by muscle traumatic injury.

    PubMed

    Silveira, Paulo Cesar Lock; Scheffer, Debora da Luz; Glaser, Viviane; Remor, Aline Pertile; Pinho, Ricardo Aurino; Aguiar Junior, Aderbal Silva; Latini, Alexandra

    2016-01-01

    The purpose of this work was to investigate the effect of early and long-term low-level laser therapy (LLLT) on oxidative stress and inflammatory biomarkers after acute-traumatic muscle injury in Wistar rats. Animals were randomly divided into the following four groups: control group (CG), muscle injury group (IG), CG + LLLT, and IG + LLLT: laser treatment with doses of 3 and 5 J/cm(2). Muscle traumatic injury was induced by a single-impact blunt trauma in the rat gastrocnemius. Irradiation for 3 or 5 J/cm(2) was initiated 2, 12, and 24 h after muscle trauma induction, and the treatment was continued for five consecutive days. All the oxidant markers investigated. namely thiobarbituric acid-reactive substance, carbonyl, superoxide dismutase, glutathione peroxidase, and catalase, were increased as soon as 2 h after muscle injury and remained increased up to 24 h. These alterations were prevented by LLLT at a 3 J/cm(2) dose given 2 h after the trauma. Similarly, LLLT prevented the trauma-induced proinflammatory state characterized by IL-6 and IL-10. In parallel, trauma-induced reduction in BDNF and VEGF, vascular remodeling and fiber-proliferating markers, was prevented by laser irradiation. In order to test whether the preventive effect of LLLT was also reflected in muscle functionality, we tested the locomotor activity, by measuring distance traveled and the number of rearings in the open field test. LLLT was effective in recovering the normal locomotion, indicating that the irradiation induced biostimulatory effects that accelerated or resolved the acute inflammatory response as well as the oxidant state elicited by the muscle trauma. PMID:26983894

  12. Eicosapentaenoic acid attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling

    PubMed Central

    Liu, Meng-Han; Lin, An-Hsuan; Lu, Shing-Hwa; Peng, Ruo-Yun; Lee, Tzong-Shyuan; Kou, Yu Ru

    2014-01-01

    Cigarette smoking causes chronic lung inflammation that is mainly regulated by redox-sensitive pathways. Our previous studies have demonstrated that cigarette smoke (CS) activates reactive oxygen species (ROS)-sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling resulting in induction of lung inflammation. Eicosapentaenoic acid (EPA), a major type of omega-3 polyunsaturated fatty acid, is present in significant amounts in marine-based fish and fish oil. EPA has been shown to possess antioxidant and anti-inflammatory properties in vitro and in vivo. However, whether EPA has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we show that subchronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration (total cell count in bronchoalveolar lavage fluid (BALF), 11.0-fold increase), increased lung vascular permeability (protein level in BALF, 3.1-fold increase), elevated levels of chemokines (11.4–38.2-fold increase) and malondialdehyde (an oxidative stress biomarker; 2.0-fold increase) in the lungs, as well as lung inflammation; all of these CS-induced events were suppressed by daily supplementation with EPA. Using human bronchial epithelial cells, we further show that CS extract (CSE) sequentially activated NADPH oxidase (NADPH oxidase activity, 1.9-fold increase), increased intracellular levels of ROS (3.0-fold increase), activated both MAPKs and NF-κB, and induced interleukin-8 (IL-8; 8.2-fold increase); all these CSE-induced events were inhibited by pretreatment with EPA. Our findings suggest a novel role for EPA in alleviating the oxidative stress and lung inflammation induced by subchronic CS exposure in vivo and in suppressing the CSE-induced IL-8 in vitro via its antioxidant function and by inhibiting MAPKs/NF-κB signaling. PMID:25452730

  13. Danaparoid sodium attenuates the increase in inflammatory cytokines and preserves organ function in endotoxemic rats

    PubMed Central

    Iba, Toshiaki; Miyasho, Taku

    2008-01-01

    Introduction Anticoagulant therapy attracts much attention for the treatment of severe sepsis since recent studies have revealed that some anticoagulants have the ability to regulate the inflammatory response. The purpose of this study was to examine whether danaparoid sodium (DA) is effective for the treatment of organ dysfunction in sepsis. Methods Sixty-four Wistar rats were intravenously injected with 5.0 mg/kg of lipopolysaccharide (LPS) and then divided into two groups: the DA group and the control group (n = 32 each). The DA group was injected intravenously with 400 U/kg of DA immediately after LPS injection, whereas the control group received saline. Blood samples were drawn at 1, 6, 12, and 24 hours after LPS injection, and organ damage markers and coagulation markers were measured. In the other series, 10 rats treated with LPS were divided into DA and control groups (n = 5 each). Blood samples were collected at 1, 3, and 6 hours after LPS injection and served for the cytokine measurements. Results The elevation of the organ damage markers, such as alanine aminotransferase and lactate dehydrogenase, was significantly suppressed in the DA group. Coagulation markers, such as AT activity and fibrinogen levels, were maintained better in the DA group at 6 hours. The elevation of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 was significantly suppressed in the DA group. On the other hand, there was no significant difference in anti-inflammatory cytokines such as IL-4 and IL-10. Conclusion DA preserves the organ dysfunction in LPS-challenged rats. Although the mechanism is not fully elucidated, not only the improvement of coagulation disorder but also the regulation of circulating levels of proinflammatory cytokines may play a role in the mechanism. PMID:18601748

  14. Wogonin attenuates diabetic cardiomyopathy through its anti-inflammatory and anti-oxidative properties.

    PubMed

    Khan, Shahzad; Zhang, Deling; Zhang, Yemin; Li, Mingxin; Wang, Changhua

    2016-06-15

    Among diabetic cardiovascular complications cardiomyopathy is major event which if not well controlled culminates in cardiac failure. Wogonin from the root of Scutellaria baicalensis Georgi has shown specific anti-diabetes bioactivity. However, its effect on diabetic complications remains unclear. The main purpose of this study is to investigate the potential effects of wogonin on diabetic cardiomyopathy and to figure out its underlying mechanism. We found that wogonin administration suppressed hyperglycemia, improved cardiac function, and mitigated cardiac fibrosis in STZ-induced diabetic mice. Wogonin supplementation also attenuated diabetic-induced cardiomyocyte apoptosis and necrosis. In addition, wogonin treatment exhibited the properties of anti-oxidative stress and anti-inflammation in STZ diabetic mice, evidenced by improved activities of anti-oxidases including SOD1/2 and CAT, decreased ROS and MDA production, suppressed expression of inflammation factors such as IL-1β, IL-6, TNFα, and PAI-1, and inhibited NF-κB signaling. These results suggested that wogonin potentially mitigate hyperglycemia-related cardiomyocyte impairment through inhibiting inflammation and oxidative stress. PMID:27013352

  15. Anti-Inflammatory Effect ofEmodin via Attenuation of NLRP3 Inflammasome Activation

    PubMed Central

    Han, Ji-Won; Shim, Do-Wan; Shin, Woo-Young; Heo, Kang-Hyuk; Kwak, Su-Bin; Sim, Eun-Jeong; Jeong, Jae-Hyun; Kang, Tae-Bong; Lee, Kwang-Ho

    2015-01-01

    Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders. PMID:25867480

  16. Puerarin attenuates the inflammatory response and apoptosis in LPS-stimulated cardiomyocytes

    PubMed Central

    YUAN, YUAN; ZHOU, HENG; WU, QING-QING; LI, FANG-FANG; BIAN, ZHOU-YAN; DENG, WEI; ZHOU, MENG-QIAO; TANG, QI-ZHU

    2016-01-01

    Patients with septic shock suffer from high mortality rates, particularly when complicated by severe myocardial depression which is characterized by hypotension and a reduction in cardiac output. Inflammation is an important factor involved in the early stages of sepsis. The aim of the present study was to investigate the effect of the Chinese herbal compound puerarin (1, 5, 10, 20 and 40 µM) on cardiomyocyte inflammatory response in a sepsis model using H9c2 cardiomyocytes stimulated with 1 µg/ml lipopolysaccharide (LPS). The mRNA expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-β were evaluated using reverse transcription-quantitative polymerase chain reaction. In addition, the protein expression levels of various factors were determined using western blot analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was used to evaluate the apoptosis rates in the various groups, and immunocytochemical analysis was employed to determine the effect of puerarin on the nuclear translocation of p65 protein. The present study demonstrated that LPS stimulation increased IL-1β and TNF-α mRNA expression levels, as compared with the controls (P<0.05). Following treatment with various concentrations of puerarin, the expression levels of IL-1β and TNF-α were markedly blunted, particularly in the LPS + 40 µM puerarin group (P<0.05 vs. the LPS group). Furthermore, puerarin administration significantly inhibited LPS-induced apoptosis in H9c2 cardiomyocytes, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining (TUNEL positive cells: LPS + 40 µM puerarin group, 5.5% vs. LPS group, 10.5%; P<0.01). In addition, puerarin significantly decreased LPS-induced phosphorylated nuclear factor (p-NF)-κB p65 and Bax expression levels, and increased the expression levels of Bcl-2, as compared with the LPS group (P<0.05). These data indicated that puerarin may serve as a valuable protective

  17. Neonatal overfeeding attenuates acute central pro-inflammatory effects of short-term high fat diet

    PubMed Central

    Cai, Guohui; Dinan, Tara; Barwood, Joanne M.; De Luca, Simone N.; Soch, Alita; Ziko, Ilvana; Chan, Stanley M. H.; Zeng, Xiao-Yi; Li, Songpei; Molero, Juan; Spencer, Sarah J.

    2015-01-01

    Neonatal obesity predisposes individuals to obesity throughout life. In rats, neonatal overfeeding also leads to early accelerated weight gain that persists into adulthood. The phenotype is associated with dysfunction in a number of systems including paraventricular nucleus of the hypothalamus (PVN) responses to psychological and immune stressors. However, in many cases weight gain in neonatally overfed rats stabilizes in early adulthood so the animal does not become more obese as it ages. Here we examined if neonatal overfeeding by suckling rats in small litters predisposes them to exacerbated metabolic and central inflammatory disturbances if they are also given a high fat diet in later life. In adulthood we gave the rats normal chow, 3 days, or 3 weeks high fat diet (45% kcal from fat) and measured peripheral indices of metabolic disturbance. We also investigated hypothalamic microglial changes, as an index of central inflammation, as well as PVN responses to lipopolysaccharide (LPS). Surprisingly, neonatal overfeeding did not predispose rats to the metabolic effects of a high fat diet. Weight changes and glucose metabolism were unaffected by the early life experience. However, short term (3 day) high fat diet was associated with more microglia in the hypothalamus and a markedly exacerbated PVN response to LPS in control rats; effects not seen in the neonatally overfed. Our findings indicate neonatally overfed animals are not more susceptible to the adverse metabolic effects of a short-term high fat diet but may be less able to respond to the central effects. PMID:25628527

  18. Wild bitter gourd protects against alcoholic fatty liver in mice by attenuating oxidative stress and inflammatory responses.

    PubMed

    Lu, Kuan-Hung; Tseng, Hui-Chun; Liu, Chun-Ting; Huang, Ching-Jang; Chyuan, Jong-Ho; Sheen, Lee-Yan

    2014-05-01

    Bitter gourd (Momordica charantia L.) is a common vegetable grown widely in Asia that is used as a traditional medicine. The objective of this study was to investigate whether wild bitter gourd possessed protective effects against chronic alcohol-induced liver injury in mice. C57BL/6 mice were fed an alcohol-containing liquid diet for 4 weeks to induce alcoholic fatty liver. Meanwhile, mice were treated with ethanol extracts from four different wild bitter gourd cultivars: Hualien No. 1', Hualien No. 2', Hualien No. 3' and Hualien No. 4'. The results indicated that the daily administration of 500 mg kg body weight(-1) of a Hualien No. 3' extract (H3E) or a Hualien No. 4' extract (H4E) markedly reduced the steatotic alternation of liver histopathology. In addition, the activation of serum aminotransferases (AST and ALT) and the accumulation of hepatic TG content caused by alcohol were ameliorated. The hepatoprotective effects of H3E and H4E involved the enhancement of the antioxidant defence system (GSH, GPx, GRd, CAT and SOD), inhibition of lipid peroxidation (MDA) and reduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the liver. Moreover, H3E and H4E supplementation suppressed the alcohol-induced elevation of CYP2E1, SREBP-1, FAS and ACC protein expression. These results demonstrated that ethanol extracts of Hualien No. 3' and Hualien No. 4' have beneficial effects against alcoholic fatty liver, in which they attenuate oxidative stress and inflammatory responses. PMID:24664243

  19. β-Nicotinamide adenine dinucleotide attenuates lipopolysaccharide-induced inflammatory effects in a murine model of acute lung injury.

    PubMed

    Umapathy, Nagavedi Siddaramappa; Gonzales, Joyce; Fulzele, Sadanand; Kim, Kyung-mi; Lucas, Rudolf; Verin, Alexander Dimitrievich

    2012-06-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) occur in approximately 200,000 patients per year. Studies indicate that lung endothelium plays a significant role in ALI. The authors' recent in vitro studies demonstrate a novel mechanism of β-nicotinamide adenine dinucleotide (β-NAD)-induced protection against gram-positive (pneumolysin, PLY) and gram-negative (lipopolysaccharide, LPS) toxin-induced lung endothelial cell (EC) barrier dysfunction. The objective of the current study was to evaluate the protective effect of β-NAD against LPS-induced ALI in mice. C57BL/6J mice were randomly divided into 4 groups: vehicle, β-NAD, LPS, and LPS/β-NAD. After surgery, mice were allowed to recover for 24 hours. Evans blue dye-albumin (EBA) was given through the internal jugular vein 2 hours prior to the termination of the experiments. Upon sacrificing the animals, bronchoalveolar lavage fluid (BALF) was collected and the lungs were harvested. β-NAD treatment significantly attenuated the inflammatory response by means of reducing the accumulation of cells and protein in BALF, blunting the parenchymal neutrophil infiltration, and preventing capillary leak. In addition, the histological examination demonstrated decreased interstitial edema in the LPS/β-NAD specimens, as compared to the LPS-only specimens. The mRNA levels of the anti-inflammatory cytokines were up-regulated in the LPS group treated with β-NAD compared to the LPS-only-treated group. β-NAD treatment down-regulated the mRNA levels of the proinflammatory cytokines. These findings suggest that β-NAD could be investigated as a therapeutic option against bacterial toxin-induced lung inflammation and ALI in mice. PMID:22563684

  20. IGF-1 attenuates LPS induced pro-inflammatory cytokines expression in buffalo (Bubalus bubalis) granulosa cells.

    PubMed

    Onnureddy, K; Ravinder; Onteru, Suneel Kumar; Singh, Dheer

    2015-03-01

    Interaction between immune and endocrine system is a diverse process influencing cellular function and homeostasis in animals. Negative energy balance (NEB) during postpartum period in dairy animals usually suppresses these systems resulting in reproductive tract infection and infertility. These negative effects could be due to competition among endocrine and immune signaling pathways for common signaling molecules. The present work studied the effect of IGF-1 (50 ng/ml) on LPS (1 μg/ml) mediated pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6) and aromatase (CYP19A1) genes' expressions as well as proliferation of buffalo granulosa cells. The crosstalk between LPS and IGF-1 was also demonstrated through studying the activities of downstream signaling molecules (ERK1/2, Akt, NF-κB) by western blot and immunostaining. Gene expression analysis showed that IGF-1 significantly reduced the LPS induced expression of IL-1β, TNF-α and IL-6. LPS alone inhibited the CYP19A1 expression. However, co-treatment with IGF-1 reversed the inhibitory effect of LPS on CYP19A1 expression. LPS alone did not affect granulosa cell proliferation, but co-treatment with IGF-1, and IGF-1 alone enhanced the proliferation. Western blot results demonstrated that LPS caused the nuclear translocation of the NF-κB and increased the phosphorylation of ERK1/2 and Akt maximum at 15 min and 60 min, respectively. Nonetheless, co-treatment with IGF-1 delayed LPS induced phosphorylation of ERK1/2 (peak at 120 min), while promoting early Akt phosphorylation (peak at 5 min) with no effect on NF-κB translocation. Overall, IGF-1 delayed and reversed the effects of LPS, suggesting that high IGF-1 levels may combat infection during critical periods like NEB in postpartum dairy animals. PMID:25433435

  1. Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: induced diabetic cardiomyopathy.

    PubMed

    Zhang, Ning; Yang, Zheng; Xiang, Shi-Zhao; Jin, Ya-Ge; Wei, Wen-Ying; Bian, Zhou-Yan; Deng, Wei; Tang, Qi-Zhu

    2016-06-01

    Diabetic cardiomyopathy, characterized by the presence of diastolic and/or systolic myocardial dysfunction, is one of the major causes of heart failure. Nobiletin, which is extracted from the fruit peel of citrus, is reported to possess anti-inflammatory, anti-oxidative, and hypolipidemic properties. The purpose of this study was to investigate whether nobiletin exerts the therapeutic effect on streptozotocin-induced diabetic cardiomyopathy (DCM) in mice. 80 experimental male C57BL mice were randomly assigned into four groups: sham + vehicle (VEH/SH), sham + nobiletin (NOB/SH), DCM + vehicle (VEH/DM), and DCM + nobiletin (NOB/DM). Nobiletin treatment ameliorated cardiac dysfunction in the DCM group, as shown by the result of echocardiography and hemodynamic measurements. Nobiletin treatment also blunted the mRNA expression of NADPH oxidase isoforms p67(phox), p22(phox), and p91(phox), and abated oxidative stress. Although administration of diabetic mice with nobiletin did not significantly effect the level of blood glucose, it decreased the TGF-β1, CTGF, fibronectin, and collagen Iα expressions and blunted cardiac fibrosis. In addition, nobiletin inhibited the activation of c-Jun NH2-terminal kinase (JNK), P38, and NF-κB in the cardiac tissue of diabetic mice. Collectively, our study indicates that treatment with nobiletin mitigates cardiac dysfunction and interstitial fibrosis, and these beneficial of nobiletin may belong to the suppression of JNK, P38, and NF-κB signaling pathways. PMID:27160937

  2. Tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury in different models possibly through suppression of NF-κB activation.

    PubMed

    Zhao, Zhanzhong; Tang, Xiangfang; Zhao, Xinghui; Zhang, Minhong; Zhang, Weijian; Hou, Shaohua; Yuan, Weifeng; Zhang, Hongfu; Shi, Lijun; Jia, Hong; Liang, Lin; Lai, Zhi; Gao, Junfeng; Zhang, Keyu; Fu, Ling; Chen, Wei

    2014-07-01

    Tylvalosin, a new broad-spectrum, third-generation macrolides, may exert a variety of pharmacological activities. Here, we report on its anti-oxidative and anti-inflammatory activity in RAW 264.7 macrophages and mouse treated with lipopolysaccharide (LPS) as well as piglet challenged with porcine reproductive and respiratory syndrome virus (PRRSV). Tylvalosin treatment markedly decreased IL-8, IL-6, IL-1β, PGE2, TNF-α and NO levels in vitro and in vivo. LPS and PRRSV-induced reactive oxygen species (ROS) production, and the lipid peroxidation in mice lung tissues reduced after tylvalosin treatments. In mouse acute lung injury model induced by LPS, tylvalosin administration significantly attenuated tissues injury, and reduced the inflammatory cells recruitment and activation. The evaluated phospholipase A2 (PLA2) activity and the increased expressions of cPLA2-IVA, p-cPLA2-IVA and sPLA2-IVE were lowered by tylvalosin. Consistent with the mouse results, tylvalosin pretreatment attenuated piglet lung scores with improved growth performance and normal rectal temperature in piglet model induced by PRRSV. Furthermore, tylvalosin attenuated the IκBα phosphorylation and degradation, and blocked the NF-κB p65 translocation. These results indicate that in addition to its direct antimicrobial effect, tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury through suppression of NF-κB activation. PMID:24792436

  3. In vivo anti-inflammatory activity of some naturally occurring O- and N-prenyl secondary metabolites.

    PubMed

    Epifano, Francesco; Genovese, Salvatore; Fiorito, Serena; della Loggia, Roberto; Tubaro, Aurelia; Sosa, Silvio

    2014-01-01

    A series of O- and N-prenyl secondary metabolites of insect, fungal, and plant origin have been evaluated for their topical anti-inflammatory activity using the Croton oil ear test in mice as a model of acute inflammation. Some of the tested compounds revealed an effect (ID50 = 0.31 divided by 0.56 micromol/cm2) comparable with that of the reference non-steroidal anti-inflammatory drug indomethacin (ID50 = 0.23 micromol/cm2). PMID:24660470

  4. Repetitive Hyperbaric Oxygenation Attenuates Reactive Astrogliosis and Suppresses Expression of Inflammatory Mediators in the Rat Model of Brain Injury

    PubMed Central

    Lavrnja, Irena; Parabucki, Ana; Dacic, Sanja; Savic, Danijela; Pantic, Igor; Stojiljkovic, Mirjana; Pekovic, Sanja

    2015-01-01

    The exact mechanisms by which treatment with hyperbaric oxygen (HBOT) exerts its beneficial effects on recovery after brain injury are still unrevealed. Therefore, in this study we investigated the influence of repetitive HBOT on the reactive astrogliosis and expression of mediators of inflammation after cortical stab injury (CSI). CSI was performed on male Wistar rats, divided into control, sham, and lesioned groups with appropriate HBO. The HBOT protocol was as follows: 10 minutes of slow compression, 2.5 atmospheres absolute (ATA) for 60 minutes, and 10 minutes of slow decompression, once a day for 10 consecutive days. Data obtained using real-time polymerase chain reaction, Western blot, and immunohistochemical and immunofluorescence analyses revealed that repetitive HBOT applied after the CSI attenuates reactive astrogliosis and glial scarring, and reduces expression of GFAP (glial fibrillary acidic protein), vimentin, and ICAM-1 (intercellular adhesion molecule-1) both at gene and tissue levels. In addition, HBOT prevents expression of CD40 and its ligand CD40L on microglia, neutrophils, cortical neurons, and reactive astrocytes. Accordingly, repetitive HBOT, by prevention of glial scarring and limiting of expression of inflammatory mediators, supports formation of more permissive environment for repair and regeneration. PMID:25972624

  5. High frequency and intensity of drinking may attenuate elevated inflammatory cytokine levels of major depression in alcohol-use disorders

    PubMed Central

    Neupane, Sudan Prasad; Lien, Lars; Martinez, Priscilla; Aukrust, Pål; Ueland, Thor; Mollnes, Tom Eirik; Hestad, Knut; Bramness, Jørgen G.

    2014-01-01

    Aims Since major depression (MD) is often comorbid with alcohol-use disorders (AUD) and alcohol itself modulates the immune system, we examined serum levels of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF) and interferon (IFN)-γ in AUD patients with and without MD. Putative interactions between alcohol variables and MD on cytokine levels were also assessed. Methods A consecutive sample of AUD inpatients (N=176) from eight alcohol treatment centers in Kathmandu, Nepal was assessed for alcohol use and depression by administering fully-structured psychiatric interviews. Serum cytokine levels were determined using multiplex technology. Results AUD patients with a positive history of MD had higher levels of the inflammatory cytokines IL-6 (p =0.019), TNF (p =0.020) and IFN-γ (p =0.001), but not of IL-10 (p= 0.853). AUD patients with MD had higher concentrations of cytokines compared with those without, regardless of the severity of the alcohol problem, but the difference was greater among those drinking in lower frequency and intensity. Conclusion These findings provide evidence for altered functioning of the immune system in AUD patients with comorbid MD. However, frequent and intense drinking may attenuate the difference in the cytokine profiles between AUD patients with and without MD. PMID:24995667

  6. Differential contributions of A- and C-nociceptors to primary and secondary inflammatory hypersensitivity in the rat

    PubMed Central

    Hsieh, Meng-Tzu; Donaldson, Lucy F.; Lumb, Bridget M.

    2015-01-01

    Abstract Primary hyperalgesia is characterized by increased responsiveness to both heat and mechanical stimulation in the area of injury. By contrast, secondary hyperalgesia is generally associated with increased responses to mechanical but not heat stimuli. We tested the hypothesis that sensitization in secondary hyperalgesia is dependent on the class of peripheral nociceptor (C- or A-nociceptor) rather than the modality of stimulation (mechanical vs heat). A- and C-nociceptors were selectively activated using contact heat ramps applied to the hind paw dorsum in animals with hind paw inflammation (primary hyperalgesia) and knee inflammatory arthritis (secondary hyperalgesia). Sensitization to A- and C-nociceptor activation in primary and secondary hyperalgesia was assessed by reflex withdrawal thresholds and by Fos immunocytochemistry in the dorsal horn of the spinal cord, as an index of neuronal activation. In primary hyperalgesia, only C-nociceptor-evoked withdrawal reflexes were sensitized. This was associated with increased spinal lamina I neuronal activation to both A- and C-nociceptor activation. Fos-like immunoreactivity (FLI) was unchanged in other dorsal horn laminae. In secondary hyperalgesia, only A-nociceptor-evoked withdrawal reflexes were sensitized, and FLI was increased in both superficial and deep dorsal laminae. Neurons in the superficial dorsal horn receive and process nociceptor inputs from the area of primary hyperalgesia, resulting in functional sensitization to C-nociceptive inputs. In inflammatory arthritis, secondary hyperalgesia is evoked by A-nociceptor thermal stimulation, suggesting that secondary hyperalgesia is A-nociceptor, rather than stimulus modality (mechanical vs thermal), dependent. Fos-like immunoreactivity evoked by A-nociceptor stimulation in secondary hyperalgesia suggests that the sensitization is underpinned by spinal neuronal sensitization in laminae I and IV/V. PMID:25760474

  7. Differential contributions of A- and C-nociceptors to primary and secondary inflammatory hypersensitivity in the rat.

    PubMed

    Hsieh, Meng-Tzu; Donaldson, Lucy F; Lumb, Bridget M

    2015-06-01

    Primary hyperalgesia is characterized by increased responsiveness to both heat and mechanical stimulation in the area of injury. By contrast, secondary hyperalgesia is generally associated with increased responses to mechanical but not heat stimuli. We tested the hypothesis that sensitization in secondary hyperalgesia is dependent on the class of peripheral nociceptor (C- or A-nociceptor) rather than the modality of stimulation (mechanical vs heat). A- and C-nociceptors were selectively activated using contact heat ramps applied to the hind paw dorsum in animals with hind paw inflammation (primary hyperalgesia) and knee inflammatory arthritis (secondary hyperalgesia). Sensitization to A- and C-nociceptor activation in primary and secondary hyperalgesia was assessed by reflex withdrawal thresholds and by Fos immunocytochemistry in the dorsal horn of the spinal cord, as an index of neuronal activation. In primary hyperalgesia, only C-nociceptor-evoked withdrawal reflexes were sensitized. This was associated with increased spinal lamina I neuronal activation to both A- and C-nociceptor activation. Fos-like immunoreactivity (FLI) was unchanged in other dorsal horn laminae. In secondary hyperalgesia, only A-nociceptor-evoked withdrawal reflexes were sensitized, and FLI was increased in both superficial and deep dorsal laminae. Neurons in the superficial dorsal horn receive and process nociceptor inputs from the area of primary hyperalgesia, resulting in functional sensitization to C-nociceptive inputs. In inflammatory arthritis, secondary hyperalgesia is evoked by A-nociceptor thermal stimulation, suggesting that secondary hyperalgesia is A-nociceptor, rather than stimulus modality (mechanical vs thermal), dependent. Fos-like immunoreactivity evoked by A-nociceptor stimulation in secondary hyperalgesia suggests that the sensitization is underpinned by spinal neuronal sensitization in laminae I and IV/V. PMID:25760474

  8. Fibrin Accumulation Secondary to Loss of Plasmin-Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice

    PubMed Central

    Cole, Heather A.; Ohba, Tetsuro; Nyman, Jeffry S.; Hirotaka, Haro; Cates, Justin M. M.; Flick, Matthew J.; Degen, Jay L.; Schoenecker, Jonathan G.

    2015-01-01

    Objective Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis-related co-morbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis. Methods Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen-deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the αMβ2 binding motif. Results Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)-mediated activation of osteoclasts via activation of the leukocyte integrin receptor αMβ2 on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the αMβ2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels. Conclusion Taken together, these data reveal for the first time that fibrin promotes inflammation-driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology. PMID:24664548

  9. Investigating the secondary structures for long oligonucleotides using attenuated-total-reflection nanoplasmon-enhanced Raman scattering

    NASA Astrophysics Data System (ADS)

    Chiu, K.-C.; Yu, L.-Y.; Lin, C.-Y.; Chen, S.-J.

    2007-09-01

    This study utilizes a nanoplasmon-enhanced Raman scattering based on the attenuated-total-reflection (ATR) method to investigate the secondary structures of long oligonucleotides and their influence on the DNA hybridization. It is found that the ring-breathing modes of adenine, thymine, guanine, and cytosine in Raman fingerprint associated with three 60mer oligonucleotides with prominent secondary structures are lower than those observed for the two oligonucleotides with no obvious secondary structures. It is also determined that increasing the DNA hybridization temperature from 35 °C to 45 °C reduces secondary structure effects. The kinetics of biomolecular interaction analysis can be performed by using surface plasmons resonance biosensor, but the structural information of the oligonucleotides can not observed directly. The ATR-Raman spectrum can provide the structural information of the oligonucleotide monolayer on the sensing surface with the help of a silver patterned nanostructure film based on the finite-difference time-domain simulation and the e-beam lithography fabrication adapted as an ATR-Raman active substrate.

  10. The chemerin receptor 23 agonist, chemerin, attenuates monosynaptic C-fibre input to lamina I neurokinin 1 receptor expressing rat spinal cord neurons in inflammatory pain

    PubMed Central

    2014-01-01

    Background Recent evidence has shown that the chemerin receptor 23 (ChemR23) represents a novel inflammatory pain target, whereby the ChemR23 agonists, resolvin E1 and chemerin, can inhibit inflammatory pain hypersensitivity, by a mechanism that involves normalisation of potentiated spinal cord responses. This study has examined the ability of the ChemR23 agonist, chemerin, to modulate synaptic input to lamina I neurokinin 1 receptor expressing (NK1R+) dorsal horn neurons, which are known to be crucial for the manifestation of inflammatory pain. Results Whole-cell patch-clamp recordings from pre-identified lamina I NK1R+ neurons, in rat spinal cord slices, revealed that chemerin significantly attenuates capsaicin potentiation of miniature excitatory postsynaptic current (mEPSC) frequency, but is without effect in non-potentiated conditions. In tissue isolated from complete Freund’s adjuvant (CFA) treated rats, chemerin significantly reduced the peak amplitude of monosynaptic C-fibre evoked excitatory postsynaptic currents (eEPSCs) in a subset of lamina I NK1R+ neurons, termed chemerin responders. However, chemerin did not alter the peak amplitude of monosynaptic C-fibre eEPSCs in control tissue. Furthermore, paired-pulse recordings in CFA tissue demonstrated that chemerin significantly reduced paired-pulse depression in the subset of neurons classified as chemerin responders, but was without effect in non-responders, indicating that chemerin acts presynaptically to attenuate monosynaptic C-fibre input to a subset of lamina I NK1R+ neurons. Conclusions These results suggest that the reported ability of ChemR23 agonists to attenuate inflammatory pain hypersensitivity may in part be due to a presynaptic inhibition of monosynaptic C-fibre input to lamina I NK1R+ neurons and provides further evidence that ChemR23 represents a promising inflammatory pain target. PMID:24716552

  11. Human CD34+ Progenitor Cells Freshly Isolated from Umbilical Cord Blood Attenuate Inflammatory Lung Injury following LPS Challenge

    PubMed Central

    Huang, Xiaojia; Sun, Kai; Zhao, Yidan D.; Vogel, Stephen M.; Song, Yuanling; Mahmud, Nadim; Zhao, You-Yang

    2014-01-01

    Adult stem cell-based therapy is a promising novel approach for treatment of acute lung injury. Here we investigated the therapeutic potential of freshly isolated human umbilical cord blood CD34+ progenitor cells (fCB-CD34+ cells) in a mouse model of acute lung injury. At 3 h post-lipopolysaccharide (LPS) challenge, fCB-CD34+ cells were transplanted i.v. to mice while CD34− cells or PBS were administered as controls in separate cohorts of mice. We observed that fCB-CD34+ cell treatment inhibited lung vascular injury evident by decreased lung vascular permeability. In contrast, CD34− cells had no effects on lung vascular injury. Lung inflammation determined by myeloperoxidase activity, neutrophil sequestration and expression of pro-inflammatory mediators was attenuated in fCB-CD34+ cell-treated mice at 26 h post-LPS challenge compared to PBS or CD34− cell-treated controls. Importantly, lung inflammation in fCB-CD34+ cell-treated mice was returned to normal levels as seen in basal mice at 52 h post-LPS challenge whereas PBS or CD34− cell-treated control mice exhibited persistent lung inflammation. Accordingly, fCB-CD34+ cell-treated mice exhibited a marked increase of survival rate. Employing in vivo 5-bromo-2′-deoxyuridine incorporation assay, we found a drastic induction of lung endothelial proliferation in fCB-CD34+ cell-treated mice at 52 h post-LPS compared to PBS or CD34− cell-treated controls, which contributed to restoration of vascular integrity and thereby inhibition of lung inflammation. Taken together, these data have demonstrated the protective effects of fCB-CD34+ cell on acute lung injury induced by LPS challenge, suggesting fCB-CD34+ cells are an important source of stem cells for the treatment of acute lung injury. PMID:24558433

  12. Adenovirus-delivered angiopoietin-1 suppresses NF-κB and p38 MAPK and attenuates inflammatory responses in phosgene-induced acute lung injury.

    PubMed

    He, Dai-Kun; Shao, Yi-Ru; Zhang, Lin; Shen, Jie; Zhong, Zhi-Yue; Wang, Jing; Xu, Guoxiong

    2014-02-01

    Animals exposed to phosgene (Psg) result in acute lung injury (ALI). We have recently reported that angiopoietin-1 (Ang1) reduces inflammation and vascular hyperpermeability in ALI animals. In this study, we examined whether the beneficial effects of adenovirus-delivered Ang1 (Ad/Ang1) on inflammatory responses in Psg-induced ALI rats are due to the suppression of the nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways, which play crucial roles in inflammatory responses in ALI. We demonstrated that Psg increased Ang2 and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-4 (IL-4), IL-6, IL-8, and IL-10, in the serum and bronchoalveolar lavage fluid of ALI rats, determined by ELISA. Ang1 inhibits pro-inflammatory mediators (TNF-α, IL-6 and IL-8) and has no effect on anti-inflammatory mediators (IL-4 and IL-10). Furthermore, the inhibitory action of Ang1 was mediated by the suppression of the NF-κB and p38 MAPK pathways, leading to the attenuation of inflammatory responses of ALI. Thus, Ad/Ang1 may provide a useful tool for the effective treatment in Psg-induced ALI. PMID:24517841

  13. Determination of secondary structural changes in gluten proteins during mixing using Fourier transform horizontal attenuated total reflectance spectroscopy.

    PubMed

    Seabourn, Bradford W; Chung, Okkyung K; Seib, Paul A; Mathewson, Paul R

    2008-06-11

    Fourier transform horizontal attenuated total reflectance (FT-HATR) was used to examine changes in the secondary structure of gluten proteins in a flour-water dough system during mixing. Midinfrared spectra of mixed dough revealed changes in four bands in the amide III region associated with secondary structure in proteins: 1317 (alpha-helix), 1285 (beta-turn), 1265 (random coil), and 1242 cm (-1) (beta-sheet). The largest band, which also showed the greatest change in second derivative band area (SDBA) during mixing, was located at 1242 cm (-1). The bands at 1317 and 1285 cm (-1) also showed an increase in SDBA over time. Conversely, the band at 1265 cm (-1) showed a corresponding decrease over time as the doughs were mixed. All bands reached an optimum corresponding to the minimum mobility of the dough as determined by the mixograph. Increases in alpha-helix, beta-turn, and beta-sheet secondary structures during mixing suggest that the dough proteins assume a more ordered conformation. These results demonstrate that it is possible, using infrared spectroscopic techniques, to relate the rheological behavior of developing dough in a mixograph directly to changes in the structure of the gluten protein system. PMID:18489117

  14. Intensive Atorvastatin Therapy Attenuates the Inflammatory Responses in Monocytes of Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention via Peroxisome Proliferator-Activated Receptor γ Activation.

    PubMed

    Yang, Jing; Liu, Changqing; Zhang, Linxia; Liu, Yanhui; Guo, Aihua; Shi, Huiwu; Liu, Xiaoxia; Cheng, Ying

    2015-08-01

    Periprocedural myocardial injury is a prognostically important complication of percutaneous coronary intervention (PCI). However, it still remains unclear whether and how intensive atorvastatin therapy attenuates the unfavorable inflammatory responses of monocytes associated with PCI. The aim of the study was to investigate the impact of intensive atorvastatin therapy on inflammatory responses of monocytes in Chinese patients with unstable angina who received PCI in order to explore the potential anti-inflammatory mechanism. Ninety-six patients with unstable angina were randomly assigned to atorvastatin 80 mg (intensive) or atorvastatin 20 mg (conventional) treatment at a 1:1 ratio. Creatine kinase MB (CK-MB), cTnI, hs-CRP, and IL-6 were assessed, and circulating CD14(+) monocytes were simultaneously obtained using CD14 MicroBeads 2 h before and 24 h after PCI. Plasma levels of CK-MB, cTnI, hs-CRP, and IL-6 were higher in the conventional dose group versus those in the intensive dose group following PCI. Furthermore, intensive atorvastatin treatment markedly reduced the expressions and responses of Toll-like receptor 2 (TLR2), TLR4, and CCR2 of CD14(+) monocytes versus the conventional dose group and significantly increased the activated peroxisome-proliferator-activated receptor (PPAR) γ in the CD14(+) monocytes post-PCI. Notably, the changes in responses of TLR2, TLR4, and CCR2 of CD14(+) monocytes between the two groups were all reversed by PPARγ antagonist and augmented by PPARγ agonist. In conclusion, a single high (80 mg) loading dose of atorvastatin reduced the inflammatory response in Chinese patients with unstable angina following PCI. The anti-inflammatory role of intensive atorvastatin was possibly due to attenuation of inflammatory response in monocytes via PPARγ activation. PMID:25604313

  15. Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

    PubMed Central

    Neacsu, Patricia; Mazare, Anca; Schmuki, Patrik; Cimpean, Anisoara

    2015-01-01

    Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity. PMID:26491301

  16. Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart.

    PubMed

    Pan, Yong; Zhu, Guanghui; Wang, Yi; Cai, Lu; Cai, Yuepiao; Hu, Jie; Li, Yilan; Yan, Yongbo; Wang, Zengshou; Li, Xiaokun; Wei, Tiemin; Liang, Guang

    2013-01-01

    There is increasing evidence indicating that inflammatory processes are involved in the development and progression of diabetic complications. However, effective anti-inflammatory treatments for patients who have diabetic complications have yet been practically identified. Curcumin is a main component of Curcuma longa with numerous pharmacological activities. Previously, we synthesized a novel curcumin analogue (B06) that exhibited an improved pharmacokinetic and enhanced anti-inflammatory activity compared to curcumin. The present study aimed to test the hypothesis that B06 may reduce high-glucose-induced inflammation and inflammation-mediated diabetic complications. In vitro, pretreatment with B06 at a concentration of 5 μM significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages. This anti-inflammatory activity of B06 is associated with its inhibition of c-Jun N-terminal kinase/nuclear factor κB activation. In vivo, despite that B06 administration at 0.2 mg · kg(-1) · d(-1) for 6 weeks did not affect the blood glucose profile of diabetic rats, the B06-treated animals displayed significant decreases in inflammatory mediators in the serum, kidney, and heart and renal macrophage infiltration. This was accompanied with an attenuation of diabetes-induced structural and functional abnormalities in the kidney and heart. Taken together, these data suggest that the novel derivative B06 might be a potential therapeutic agent for diabetic complications via an anti-inflammatory mechanism and support the potential application in diabetic complication therapy via anti-inflammatory strategy. PMID:22819547

  17. The blocking of uPAR suppresses lipopolysaccharide‐induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway

    PubMed Central

    Ishisaki, Akira; Miyashita, Mei; Matsuo, Osamu

    2016-01-01

    Abstract Introduction Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone‐resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation. Methods We investigated that the effect of uPAR on inflammatory OC formation induced by lipopolysaccharide (LPS) in inflammatory diseases. Results We found that the LPS more weakly induced OC formation and the resultant bone loss in uPAR‐deficient mice than in wild‐type mice. Additionally, we demonstrated that uPAR significantly potentiated LPS‐induced OC formation of RAW264.7 mouse monocyte/macrophage linage cells in integrin β3/Akt‐dependent manner. Moreover, we showed that the blocking of uPAR function by the administration of anti‐uPAR neutralizing antibody significantly attenuated the LPS‐induced OC formation and the resultant bone loss in mice. Conclusions These results strongly suggest that uPAR negatively regulates the LPS‐induced inflammatory OC formation and the resultant bone loss mediated through the integrin β3/Akt pathway. Our findings partly clarify the molecular mechanisms underlying bone destruction caused by chronic inflammatory diseases, and would benefit research on identifying antibody therapy for the treatment of these diseases. PMID:27621816

  18. A novel imidazopyridine derivative, X22, attenuates sepsis-induced lung and liver injury by inhibiting the inflammatory response in vitro and in vivo

    PubMed Central

    Ge, Xiangting; Feng, Zhiguo; Xu, Tingting; Wu, Beibei; Chen, Hongjin; Xu, Fengli; Fu, Lili; Shan, Xiaoou; Dai, Yuanrong; Zhang, Yali; Liang, Guang

    2016-01-01

    Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases. PMID:27390516

  19. Receptor-selective IL-4 mutein modulates inflammatory vascular cell phenotypes and attenuates atherogenesis in apolipoprotein E-knockout mice.

    PubMed

    Lin, Yanhui; Chen, Zhiheng; Kato, Seiya

    2015-08-01

    The therapeutic potential of interleukin-4-mediated immunomodulation has not been proven in atherogenesis. Type I IL-4 receptor consists of IL-4Rα and a common γ chain, whereas type II IL-4R is a heterodimer of IL-4Rα and IL-13Rα1. Reportedly, the human IL-4 mutein IL-4/R121E is able to act as an IL-4RI-specific agonist. Here, we investigated the effect of receptor-specific IL-4 mutein on vascular cell phenotypes and atherogenesis. Initially, a plasmid expressing murine IL-4/Q116E, analogous to human IL-4/R121E, was transfected to vascular lineage cells in-vitro. IL-4/Q116E induced the activation of STAT6 in b.End3 endothelial cells, Mm1 macrophages, and splenocytes isolated from C57BL6/J (B6) mice, but it failed to activate STAT6 in SMC and J774.1 macrophages. IL-4/Q116E induced the expression of vascular cell adhesion protein-1 in b.End3 cells but not in SMC. IL-4/Q116E did not exhibit pro-inflammatory actions in either macrophage cell line. Splenocytes were also infected with an adenovirus vector expressing IL-4/Q116E (AdIL-4/Q116E). Enzyme-linked immunosorbent assay for interferon-γ, IL-10 and IL-13 revealed that AdIL-4/Q116E-infected splenocytes showed Th2 deviation. Th2 deviation and M2 marker up-regulation were further revealed in ex-vivo assays using the splenocytes isolated from AdIL-4/Q116E-infected apolipoprotein-E knockout (ApoEKO) mice. Finally, adenoviral induction of IL-4/Q116E, but not wild type IL-4, double mutein IL-4/Q116D/Y119D or control β-galactosidase, significantly attenuated in-vivo atherogenesis of ApoEKO mice. Our data suggest that IL-4 signaling plays a pivotal role in the regulation of vascular cell phenotypes, and atherogenesis. The IL-4RI-selective mutein IL-4/Q116E may have therapeutic potential in vascular diseases. PMID:26093164

  20. A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

    SciTech Connect

    Fang, Qilu; Zhao, Leping; Wang, Yi; Zhang, Yali; Li, Zhaoyu; Pan, Yong; Kanchana, Karvannan; Wang, Jingying; Tong, Chao; Li, Dan; Liang, Guang

    2015-01-15

    Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future. - Highlights: • Inflammation plays a central role in the development of diabetic nephropathy. • Compound L6H21 reduced the high glucose-mediated inflammation in NRK-52E cells. • Compound L6H21 attenuated the inflammation-mediated renal injury. • L6H21 exhibited anti-inflammatory effects via inactivation of NF-κB/MAPKs. • MAPKs/NF-κB may be a novel therapeutic target in diabetic nephropathy treatment.

  1. Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages.

    PubMed

    Banerjee, Somenath; Bose, Dipayan; Chatterjee, Nabanita; Das, Subhadip; Chakraborty, Sreeparna; Das, Tanya; Saha, Krishna Das

    2016-01-01

    Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future. PMID:26928472

  2. Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages

    PubMed Central

    Banerjee, Somenath; Bose, Dipayan; Chatterjee, Nabanita; Das, Subhadip; Chakraborty, Sreeparna; Das, Tanya; Saha, Krishna Das

    2016-01-01

    Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future. PMID:26928472

  3. Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway

    PubMed Central

    Veras, Flávio P.; Peres, Raphael S.; Saraiva, André L. L.; Pinto, Larissa G.; Louzada-Junior, Paulo; Cunha, Thiago M.; Paschoal, Jonas A. R.; Cunha, Fernando Q.; Alves-Filho, José C.

    2015-01-01

    Fructose 1,6-bisphosphate (FBP) is an endogenous intermediate of the glycolytic pathway. Exogenous administration of FBP has been shown to exert protective effects in a variety of ischemic injury models, which are attributed to its ability to sustain glycolysis and increase ATP production. Here, we demonstrated that a single treatment with FBP markedly attenuated arthritis, assessed by reduction of articular hyperalgesia, joint swelling, neutrophil infiltration and production of inflammatory cytokines, TNF and IL-6, while enhancing IL-10 production in two mouse models of arthritis. Our mechanistic studies showed that FBP reduces joint inflammation through the systemic generation of extracellular adenosine and subsequent activation of adenosine receptor A2a (A2aR). Moreover, we showed that FBP-induced adenosine generation requires hydrolysis of extracellular ATP through the activity of the ectonucleosides triphosphate diphosphohydrolase-1 (ENTPD1, also known as CD39) and ecto-5′-nucleotidase (E5NT, also known as CD73). In accordance, inhibition of CD39 and CD73 abolished anti-arthritic effects of FBP. Taken together, our findings provide a new insight into the molecular mechanism underlying the anti-inflammatory effect of FBP, showing that it effectively attenuates experimental arthritis by activating the anti-inflammatory adenosinergic pathway. Therefore, FBP may represent a new therapeutic strategy for treatment of rheumatoid arthritis (RA). PMID:26478088

  4. Pinocembrin attenuates lipopolysaccharide-induced inflammatory responses in Labeo rohita macrophages via the suppression of the NF-κB signalling pathway.

    PubMed

    Giri, Sib Sankar; Sen, Shib Sankar; Sukumaran, Venkatachalam; Park, Se Chang

    2016-09-01

    Pinocembrin is a flavonoid that has been reported to exhibit various pharmacological and biological activities including antimicrobial, antioxidant, and anti-inflammatory. To explore the anti-inflammatory activity of pinocembrin in a fish cell line, we investigated its ability to regulate the inflammatory mediators elevated by lipopolysaccharide (LPS) in Labeo rohita head-kidney (HK) macrophages. HK macrophages of L. rohita were treated with LPS (1 μg mL(-1)) in the presence or absence of pinocembrin. We examined the inhibitory effect of pinocembrin on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. The inhibitory effect of pinocembrin on nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was investigated by RT-PCR and western blot. The effect of pinocembrin on pro-inflammatory cytokines (tumour necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β)) and anti-inflammatory cytokine IL-10 was investigated by ELISA and RT-PCR. The phosphorylation of three mitogen activated protein kinases (MAPKs) ERK, JNK, and p38 was analysed by western blot. Pinocembrin inhibited LPS-induced productions of NO and PGE2, and also markedly inhibited TNF-α, IL-1β, iNOS, and COX-2 production in a concentration-dependent manner. In addition, TNF-α and IL-1β mRNA expression levels decreased significantly, while IL-10 mRNA expression increased (P < 0.05) with pinocembrin pre-treatment. RT-PCR and western blot analysis showed that pinocembrin decreased both the mRNA and protein expression levels of LPS-induced iNOS and COX-2 in HK macrophages. Pinocembrin suppressed the phosphorylation of MAPK in LPS-stimulated HK macrophages. Further, pinocembrin significantly inhibited LPS-induced NF-κB transcriptional activity via the attenuation of IκBα degradation. Taken together, pinocembrin reduced the levels of pro-inflammatory mediators, such as iNOS, COX-2, TNF-α, and IL-1β, by inhibiting NF-κB activation via the suppression of ERK and p38

  5. Agaricoglycerides Protect against Hepatic Ischemia/Reperfusion Injury by Attenuating Inflammatory Response, Oxidative Stress, and Expression of NF-κB

    PubMed Central

    Zhao, Xiang-qian; Liang, Bin; Liu, Yang; Huang, Xiao-qiang

    2015-01-01

    We have investigated the effects of agaricoglycerides (AG) in a mouse model of hepatic I/R injury. I/R triggered increases/changes in markers of liver injury, hepatic oxidative stress, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor κB (NF-κB). AG significantly reduced the extent of liver inflammation and oxidative stress and also attenuated the NF-κB activation as well as TNF-α and IL-1β production. Our results indicate that AG may represent a novel protective strategy against I/R-induced injury and inflammatory diseases. PMID:25960746

  6. Zhen-wu-tang attenuates cationic bovine serum albumin-induced inflammatory response in membranous glomerulonephritis rat through inhibiting AGEs/RAGE/NF-κB pathway activation.

    PubMed

    Wu, Junbiao; Liu, Bihao; Liang, Chunling; Ouyang, Hui; Lin, Jin; Zhong, Yanchun; He, Yu; Zhou, Jie; Zhou, Yuan; Zhou, Jiuyao

    2016-04-01

    Zhen-wu-tang (ZWT), a traditional Chinese compound formula recorded in the Treatise on Febrile Diseases, has significant inhibitory effects on inflammatory damage and oxidative lesions in rats, but its mechanism of action remains unclear. The aim of the present study was to explore whether the anti-inflammatory and anti-oxidative effects of ZWT were mediated by the AGEs/RAGE/NF-κB signaling pathway in rats with cationic bovine serum albumin (C-BSA)-induced membranous glomerulonephritis (MGN). We found that ZWT significantly reduced the production of malondialdehyde (MDA), but enhanced the superoxide dismutase (SOD) activity. The ELISA results showed that ZWT not only reduced the serum levels of AGEs but also decreased the release of inflammatory mediators (TNF-α, IL-1β, and IL-6). Meanwhile, HE staining showed that pathological kidney injury was alleviated by ZWT. In addition, ZWT suppressed the expression of RAGE1 and NF-κB p65, as well as the nuclear translocation of NF-κB p65. The accumulation of AGEs, oxidative lesions and inflammation damage were reduced by an AGE inhibitor. Thus, the present study demonstrates that AGEs play a role in the pathogenesis of MGN and that AGE inhibition could reduce the inflammatory reactions and oxidative lesions in MGN. In general, ZWT attenuated MGN, in part, by inhibiting the AGEs/RAGE/NF-κB pathway. PMID:26851631

  7. Antigen replacement of domains D2 and D3 in flagellin promotes mucosal IgA production and attenuates flagellin-induced inflammatory response after intranasal immunization

    PubMed Central

    Yang, Jingyi; Zhong, Maohua; Zhang, Yan; Zhang, Ejuan; Sun, Ying; Cao, Yuan; Li, Yaoming; Zhou, Dihan; He, Benxia; Chen, Yaoqing; Yang, Yi; Yu, Jie; Yan, Huimin

    2013-01-01

    Targeting early infection in mucosal sites is one of the primary goals for mucosal vaccines so as to prevent pathogen mucosal transmission and infection. The TLR5 agonist flagellin was deemed to be a mucosal adjuvant candidate for clinical usage. However, the high antigenicity of flagellin and the possible inflammatory injury induced by flagellin might restrict its clinical usage. Here HIV-1 p24 protein was selected as an antigen model and we replaced the main antigenicity region domains D2 and D3 of non-pathogenic E.coli-derived flagellin (KF). The derived soluble protein KFD-p24 3D was then compared with KF-p24, which fused p24 directly to the C-terminal of KF. In vitro and ex vivo experiments showed that KFD-p24 3D has lower TLR5 agonist efficacy and less immunocyte-activating efficacy. Interestingly, the production of KF- specific antibody was highly reduced, and KFD-p24 3D induced IgA-biased antibody responses in mucosal sites. Moreover, KFD-p24 3D induced far fewer systemic inflammatory responses and abrogated detectable inflammatory side effects on mice, even at the high dose. The properties of enhanced IgA generation and attenuated inflammatory responses broaden the safe-dose range of KFD-p24 3D flagellin, creating a potentially promising mucosal adjuvant. PMID:23377752

  8. Pattern of pro-inflammatory cytokine induction in RAW264.7 mouse macrophages is identical for virulent and attenuated Borrelia burgdorferi1

    PubMed Central

    Wang, Guiqing; Petzke, Mary M.; Iyer, Radha; Wu, Hongyan; Schwartz, Ira

    2008-01-01

    Lyme disease pathogenesis results from a complex interaction between Borrelia burgdorferi and the host immune system. The intensity and nature of the inflammatory response of host immune cells to B. burgdorferi may be a determining factor in disease progression. Gene array analysis was used to examine the expression of genes encoding cytokines, chemokines, and related factors in the joint tissue of infected C3H/HeJ mice and in a murine macrophage-like cell line in response to a disseminating or attenuated clinical isolate of B. burgdorferi. Both isolates elicited a robust pro-inflammatory response in RAW264.7 cells characterized by an increase in transcript levels of genes encoding CC and CXC chemokines, pro-inflammatory cytokines, and TNF superfamily members. Transcription of genes encoding IL-1β, IL-6, MCP-1, MIP-1α, CXCR4 and TLR2 induced in RAW264.7 cells by either live or heat-killed spirochetes did not differ significantly at any time point over a 24-hour period, nor was there a difference in the protein levels of IL-10, TNF-α, IL-6 and IL-12p70 in culture supernatants. Thus, induction of host macrophage expression of pro-inflammatory mediators by host macrophages does not contribute to the differential pathogenicity of different B. burgdorferi strains. PMID:18523297

  9. Date syrup-derived polyphenols attenuate angiogenic responses and exhibits anti-inflammatory activity mediated by vascular endothelial growth factor and cyclooxygenase-2 expression in endothelial cells.

    PubMed

    Taleb, Hajer; Morris, R Keith; Withycombe, Cathryn E; Maddocks, Sarah E; Kanekanian, Ara D

    2016-07-01

    Bioactive components such as polyphenols, present in many plants, are purported to have anti-inflammatory and antiangiogenic properties. Date syrup, produced from date fruit of the date palm tree, has traditionally been used to treat a wide range of diseases with etiologies involving angiogenesis and inflammation. It was hypothesized that polyphenols in date syrup reduce angiogenic responses such as cell migration, tube formation, and matrix metalloproteinase activity in an inflammatory model by exhibiting anti-inflammatory activity mediated by vascular endothelial growth factor (VEGF) and the prostaglandin enzyme cyclooxygenase-2 (COX-2) in endothelial cells. Date syrup polyphenols at 60 and 600μg/mL reduced inflammation and suppressed several stages of angiogenesis, including endothelial cell migration, invasion, matrix metalloproteinase activity, and tube formation, without evidence of cytotoxicity. VEGF and COX-2 expression induced by tumor necrosis factor-alpha at both gene expression and protein level was significantly reduced by date syrup polyphenols in comparison to untreated cells. In conclusion, polyphenols in date syrup attenuated angiogenic responses and exhibited anti-inflammatory activity mediated by VEGF and COX-2 expression in endothelial cells. PMID:27333954

  10. Systemic administration of Rosmarinus officinalis attenuates the inflammatory response induced by carrageenan in the mouse model of pleurisy.

    PubMed

    da Rosa, Julia Salvan; Facchin, Bruno Matheus; Bastos, Juliana; Siqueira, Mariana Araújo; Micke, Gustavo Amadeu; Dalmarco, Eduardo Monguilhott; Pizzolatti, Moacir Geraldo; Fröde, Tânia Silvia

    2013-11-01

    Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma. PMID:24288274

  11. Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats.

    PubMed

    Liao, S-J; Gong, Q; Chen, X-R; Ye, L-X; Ding, Q; Zeng, J-S; Yu, J

    2013-02-12

    Neurological deficit following cerebral infarction correlates with not only primary injury, but also secondary neuronal apoptosis in remote loci connected to the infarction. Netrin-1 is crucial for axonal guidance by interacting with its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H (UNC5H). DCC and UNC5H are also dependence receptors inducing cell apoptosis when unbound by netrin-1. The present study is to investigate the role of netrin-1 and its receptors in ipsilateral ventroposterior thalamic nucleus (VPN) injury secondary to stroke in hypertensive rats. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO). Continuous intracerebroventricular infusion of netrin-1 (600 ng/d for 7 days) or vehicle (IgG/Fc) was given 24h after MCAO. Neurological function was evaluated by postural reflex 8 and 14 days after MCAO. Then, immunoreactivity was determined in the ipsilateral VPN for NeuN, glial fibrillary acidic protein, netrin-1 and its receptors (DCC and UNC5H2), apoptosis was detected with Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling (TUNEL) assay, and the expressions of caspase-3, netrin-1, DCC, and UNC5H2 were quantified by western blot analysis. MCAO resulted in the impaired postural reflex after 8 and 14 days, with decreased NeuN marked neurons and increased TUNEL-positive cells, as well as an up-regulation in the levels of cleaved caspase-3 and UNC5H2 protein in the ipsilateral VPN, without significant change in DCC or netrin-1 expression. By exogenous netrin-1 infusion, the number of neurons was increased in the ipsilateral VPN, and both TUNEL-positive cell number and caspase-3 protein level were reduced, while UNC5H2 expression remained unaffected, simultaneously, the impairment of postural reflex was improved. Taken together, the present study indicates that exogenous netrin-1 could rescue neuron loss by attenuating secondary apoptosis in the

  12. Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.

    PubMed

    Zhao, Hong-Wei; Zhang, Zhen-Fang; Chai, Xuan; Li, Guang-Quan; Cui, He-Rong; Wang, Hong-Bo; Meng, Ya-Kun; Liu, Hui-Min; Wang, Jia-Bo; Li, Rui-Sheng; Bai, Zhao-Fang; Xiao, Xiao-He

    2016-07-01

    Oxymatrine (OMT) is able to effectively protect against hepatic fibrosis because of its anti-inflammatory property, while the underlying mechanism remains incompletely understood. In this study, forty rats were randomly divided into five groups: control group, model group (carbon tetrachloride, CCl4) and three OMT treatment groups (30, 60, 120mg/kg). After CCl4 alone, the fibrosis score was 20.2±0.8, and the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline content, and collagen I expression was elevated, but OMT blunted these parameters. Treatment with OMT prevented CCl4-induced increases in expression of pro-inflammatory and pro-fibrotic cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α, meanwhile OMT promoted the expression of anti-inflammatory and anti-fibrotic factors such as interleukin (IL)-10 and bone morphogenetic protein and activin membrane-bound inhibitor (Bambi). Moreover, lipopolysaccharides (LPS) and high mobility group box-1 (HMGB1), which activates Toll-like receptor 4 (TLR4) and modulate hepatic fibrogenesis through hepatic stellate cells (HSCs) or Kupffer cells, were significantly decreased by OMT treatment. These results were further supported by in vitro data. First, OMT suppressed the expression of TLR4 and its downstream pro-inflammatory cytokines, lowered the level of HMGB1, TGF-β1 in macrophages. Then, OMT promoted Bambi expression and thereby inhibited activation of HSCs mediated by transforming growth factor (TGF)-β1. In conclusion, this study showed that OMT could effectively attenuate the CCl4-induced hepatic fibrosis, and this effect may be due to modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways. PMID:27179304

  13. Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model.

    PubMed

    Zhu, Ya-Juan; Peng, Ke; Meng, Xiao-Wen; Ji, Fu-Hai

    2016-08-01

    Sustained neuroinflammation contributes to the pathogenesis of postoperative cognitive dysfunction. Dexmedetomidine, a selective α-2 adrenergic receptor agonist, exhibits a protective role in the brain. This study investigated whether dexmedetomidine pretreatment attenuates neuroinflammation induced by tibial fracture in rats, as well as the mechanism by which dexmedetomidine provides its neuroprotection. In our study, we observed that tibial fracture significantly increased the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and the expression of nuclear factor-kappa B (NF-κB) in the hippocampus. Overexpression of microglial (CD11b) and astrocytic (GFAP) responses to injury were observed in the hippocampus. Dexmedetomidine pretreatment significantly suppressed the inflammatory responses, as evidenced by lower TNF-α and IL-1β levels, significantly inhibited NF-κB activity, and alleviated overexpression of microglia and astrocytes in the hippocampus. However, pretreatment with dexmedetomidine failed to attenuate cytokine responses and activity of NF-κB, CD11b and GFAP after vagotomy or treatment with methyllycaconitine, an α-7 nicotinic acetylcholine receptor (α7nAChR) antagonist. These results suggest that pretreatment with dexmedetomidine may attenuate neuroinflammation caused by tibial fracture in rats through vagal-dependent and α7nAChR-dependent mechanisms. PMID:27163720

  14. A rare case of immune reconstitution inflammatory syndrome presenting as secondary syphilis.

    PubMed

    Khatri, Asma; Skalweit, Marion J

    2015-09-01

    Immune reconstitution syndrome has rarely been reported in the context of syphilis infection. We report a patient with AIDS (CD4 42 cells/mm(3), viral load 344,000 cp/ml), treated previously for secondary syphilis and started on an integrase inhibitor-based single-tablet antiretroviral treatment regimen. After four weeks of antiretroviral treatment, he presented with non-tender, non-blanching erythematous nodules on his chest, an elevated rapid plasma reagin (1:1024) and immune reconstitution (CD4 154 cells/mm(3), HIV-RNA 130 cp/ml). A detailed workup to exclude opportunistic infections including secondary and neurosyphilis was performed. The patient was continued on antiretroviral treatment and treated empirically for neurosyphilis given cerebrospinal lymphocytosis and dermatopathology suggesting treponemal antigen-driven B-cell hyperplasia. We favour a diagnosis of immune reconstitution in association with prior syphilis infection attributable to rapid and potent immune restoration afforded by integrase inhibitors. PMID:25311145

  15. Therapeutic treatment with ascorbate rescues mice from heat stroke-induced death by attenuating systemic inflammatory response and hypothalamic neuronal damage.

    PubMed

    Chang, Chia-Yu; Chen, Jen-Yin; Chen, Sheng-Hsien; Cheng, Tain-Junn; Lin, Mao-Tsun; Hu, Miao-Lin

    2016-04-01

    The impact of ascorbate on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, recent evidence of the clinical benefit of parenteral vitamin C administration has emerged, especially in critical care. Heatstroke is defined as a form of excessive hyperthermia associated with a systemic inflammatory response that results in multiple organ dysfunctions in which central nervous system disorders such as delirium, convulsions, and coma are predominant. The thermoregulatory, immune, coagulation and tissue injury responses of heatstroke closely resemble those observed during sepsis and are likely mediated by similar cellular mechanisms. This study was performed by using the characteristic high lethality rate and sepsis-mimic systemic inflammatory response of a murine model of heat stroke to test our hypothesis that supra-physiological doses of ascorbate may have therapeutic use in critical care. We demonstrated that parenteral administration of ascorbate abrogated the lethality and thermoregulatory dysfunction in murine model of heat stroke by attenuating heat stroke-induced accelerated systemic inflammatory, coagulation responses and the resultant multiple organ injury, especially in hypothalamus. Overall, our findings support the hypothesis and notion that supra-physiological doses of ascorbate may have therapeutic use in critical care. PMID:26703968

  16. Mainstream cigarette smoke exposure attenuates airway immune inflammatory responses to surrogate and common environmental allergens in mice, despite evidence of increased systemic sensitization.

    PubMed

    Robbins, Clinton S; Pouladi, Mahmoud A; Fattouh, Ramzi; Dawe, David E; Vujicic, Neda; Richards, Carl D; Jordana, Manel; Inman, Mark D; Stampfli, Martin R

    2005-09-01

    The purpose of this study was to investigate the impact of mainstream cigarette smoke exposure (MTS) on allergic sensitization and the development of allergic inflammatory processes. Using two different experimental murine models of allergic airways inflammation, we present evidence that MTS increased cytokine production by splenocytes in response to OVA and ragweed challenge. Paradoxically, MTS exposure resulted in an overall attenuation of the immune inflammatory response, including a dramatic reduction in the number of eosinophils and activated (CD69+) and Th2-associated (T1ST2+) CD4 T lymphocytes in the lung. Although MTS did not impact circulating levels of OVA-specific IgE and IgG1, we observed a striking reduction in OVA-specific IgG2a production and significantly diminished airway hyperresponsiveness. MTS, therefore, plays a disparate role in the development of allergic responses, inducing a heightened state of allergen-specific sensitization, but dampening local immune inflammatory processes in the lung. PMID:16116169

  17. Resolvin D1 Attenuates Poly(I:C)-Induced Inflammatory Signaling in Human Airway Epithelial Cells via TAK1

    PubMed Central

    Hsiao, Hsi-Min; Thatcher, Thomas H.; Levy, Elizabeth P.; Fulton, Robert A.; Owens, Kristina M.; Phipps, Richard P.; Sime, Patricia J.

    2014-01-01

    The respiratory epithelium are lung sentinel cells and are the first to contact inhaled inflammatory insults including air pollutants, smoke and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation-resolution is now known to be an active process involving a new genus of lipid mediators called “specialized pro-resolving lipid mediators” (SPMs) that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts pro-inflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. Here, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic poly(I:C) in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and pro-inflammatory signaling involving MAP kinases and NF-κB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1, a key upstream regulatory kinase common to both the MAP kinase and NF-κB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 and TRAF6. We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on hSAEC. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. Herein, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and pro-resolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses. PMID:25320283

  18. Inflammatory polyp in the middle ear with secondary suppurative meningoencephalitis in a cat.

    PubMed

    Cook, Laurie B; Bergman, Robert L; Bahr, Anne; Boothe, Harry W

    2003-01-01

    A 15-month-old male Maine Coon Cat presented with persistent auricular discharge and progressive head tilt, ataxia, and loss of blink on the right side. Using computed tomography a hyperattenuating, contrast-enhancing material within a thickened right tympanic bulla and contrast enhancement of the adjacent cerebellum were identified. Marked suppurative inflammation was identified on cerebrospinal fluid analysis with no growth on bacterial culture. Ventral bulla osteotomy was performed to remove a soft tissue mass, and an inflammatory polyp with chronic severe suppurative inflammation was confirmed using histology. Staphylococcus auricularis was grown on aerobic culture and Fusobacterium necrophorum and Peptostreptococcus anaerobius were grown on anaerobic culture. The cat was treated for 10 weeks with amoxicillin/clavulinic acid and metronidazole. Dramatic improvement in body weight, appetite, energy level, balance, and resolution of right-sided facial paralysis were noted, but the cat retained a head tilt. PMID:14703245

  19. Sesquiterpene lactone parthenolide attenuates production of inflammatory mediators by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-κB pathways.

    PubMed

    Nam, Yoon Jeong; Lee, Da Hee; Lee, Min Sung; Lee, Chung Soo

    2015-09-01

    Microbial product lipopolysaccharide has been shown to be involved in the pathogenesis of inflammatory skin diseases. Parthenolide present in extracts of the herb feverfew has demonstrated an anti-inflammatory effect. However, the effect of parthenolide on the Akt/mTOR and NF-κB pathway activation-induced productions of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we investigated the effect of parthenolide on the inflammatory mediator production in relation to the Toll-like receptor-4-mediated-Akt/mTOR and NF-κB pathways, which regulate the transcription genes involved in immune and inflammatory responses. Parthenolide, Akt inhibitor, Bay 11-7085, and N-acetylcysteine each attenuated the lipopolysaccharide-induced production of IL-1β and PGE2, increase in the levels of cyclooxygenase, formation of reactive oxygen species, increase in the levels of Toll-like receptor-4, and activation of the Akt/mTOR and NF-κB in keratinocytes. The results show that parthenolide appears to attenuate the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-κB pathways. The activation of signaling transduction pathways appear to be regulated by reactive oxygen species. Parthenolide appears to attenuate the microbial product-mediated inflammatory skin diseases. PMID:25971793

  20. Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression

    PubMed Central

    Hu, Xiang; Han, Chaofeng; Jin, Jing; Qin, Kewei; Zhang, Hua; Li, Tianliang; Li, Nan; Cao, Xuetao

    2016-01-01

    Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11bhi regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam−/−) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses. PMID:27188220

  1. Acai Juice Attenuates Atherosclerosis Through Antioxidant and Anti-Inflammatory Effects in ApoE Deficient Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: Acai fruit (Euterpe oleracea Mart.) has been shown to exhibit extremely high antioxidant capacity. Antioxidant capacities and anti-inflammatory effects of acai pulp or acai juices have been studied in human, animal and cell culture models. However, their potential effects on atheroscl...

  2. Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study we investigated whether polyphenols in blueberries (BBs) can reduce the deleterious effects o...

  3. Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression.

    PubMed

    Hu, Xiang; Han, Chaofeng; Jin, Jing; Qin, Kewei; Zhang, Hua; Li, Tianliang; Li, Nan; Cao, Xuetao

    2016-01-01

    Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11b(hi) regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam(-/-)) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses. PMID:27188220

  4. Resveratrol Attenuates Acute Inflammatory Injury in Experimental Subarachnoid Hemorrhage in Rats via Inhibition of TLR4 Pathway

    PubMed Central

    Zhang, Xiang-Sheng; Li, Wei; Wu, Qi; Wu, Ling-Yun; Ye, Zhen-Nan; Liu, Jing-Peng; Zhuang, Zong; Zhou, Meng-Liang; Zhang, Xin; Hang, Chun-Hua

    2016-01-01

    Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway. PMID:27529233

  5. Chondroitin-6-sulfate attenuates inflammatory responses in murine macrophages via suppression of NF-κB nuclear translocation.

    PubMed

    Tan, Guak-Kim; Tabata, Yasuhiko

    2014-06-01

    Inflammation is a host protective response to noxious stimuli, and excessive production of pro-inflammatory mediators by macrophages (mφ) can lead to numerous pathological conditions. In this study, immunomodulatory effects of immobilized and soluble glycosaminoglycans (GAGs) on mouse-bone-marrow-derived mφ were compared by measuring nitric oxide (NO). We demonstrate here that all GAGs studied except for heparin were able to modulate interferon-γ/lipopolysaccharide (IFN-γ/LPS)-induced NO release by mφ to varying extents after 24h of incubation. In particular, the modulatory activities of soluble chondroitin-6-sulfate (C6S), hyaluronic acid and heparan sulfate altered markedly after covalent immobilization. Of these, soluble C6S exhibited the strongest NO inhibitory activity, and the inhibition was dose- and time-dependent. Moreover, C6S significantly reduced pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α production by IFN-γ/LPS- or LPS-activated mφ. Specifically, the C6S-mediated suppression of mφ pro-inflammatory phenotype was accompanied by an increase in the IL-10 level, suggesting a possible switch towards anti-inflammatory/wound healing M2 state. In addition, the highest magnitude of inhibitory effects was obtained when cells were pre-treated with C6S prior to IFN-γ/LPS or LPS challenge, suggesting an additional role for C6S in protection against microbial infection. Further investigations reveal that the anti-inflammatory effects of C6S on activated mφ may be ascribed at least in part to suppression of NF-κB nuclear translocation. PMID:24561712

  6. Resveratrol Attenuates Acute Inflammatory Injury in Experimental Subarachnoid Hemorrhage in Rats via Inhibition of TLR4 Pathway.

    PubMed

    Zhang, Xiang-Sheng; Li, Wei; Wu, Qi; Wu, Ling-Yun; Ye, Zhen-Nan; Liu, Jing-Peng; Zhuang, Zong; Zhou, Meng-Liang; Zhang, Xin; Hang, Chun-Hua

    2016-01-01

    Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway. PMID:27529233

  7. Adenosine A2A receptor signaling attenuates LPS-induced pro-inflammatory cytokine formation of mouse macrophages by inducing the expression of DUSP1.

    PubMed

    Köröskényi, Krisztina; Kiss, Beáta; Szondy, Zsuzsa

    2016-07-01

    Adenosine is known to reduce inflammation by suppressing the activity of most immune cells. Previous studies have shown that lipopolysaccharide (LPS) stimulated mouse macrophages produce adenosine, and the adenosine A2A receptor (A2AR) signaling activated in an autocrine manner attenuates LPS-induced pro-inflammatory cytokine formation. It has been suggested that A2AR signaling inhibits LPS-induced pro-inflammatory cytokine production through a unique cAMP-dependent, but PKA- and Epac-independent signaling pathway. However, the mechanism of inhibition was not identified so far. Here we report that LPS stimulation enhances A2AR expression in mouse bone marrow derived macrophages, and loss of A2ARs results in enhanced LPS-induced pro-inflammatory response. Loss of A2ARs in A2AR null macrophages did not alter the LPS-induced NF-κB activation, but an enhanced basal and LPS-induced phosphorylation of MAP kinases (especially that of JNKs) was detected in A2AR null cells. A2AR signaling did not alter the LPS-induced phosphorylation of their upstream kinases, but by regulating adenylate cyclase activity it enhanced the expression of dual specific phosphatase (DUSP)1, a negative regulator of MAP kinases. As a result, lower basal and LPS-induced DUSP1 mRNA and protein levels can be detected in A2AR null macrophages. Silencing of DUSP1 mRNA expression resulted in higher basal and LPS-induced JNK phosphorylation and LPS-induced pro-inflammatory cytokine formation in wild type macrophages, but had no effect on that in A2AR null cells. Our data indicate that A2AR signaling regulates both basal and LPS-induced DUSP1 levels in macrophages via activating the adenylate cyclase pathway. PMID:27066978

  8. 2-phenylethynesulfonamide Prevents Induction of Pro-inflammatory Factors and Attenuates LPS-induced Liver Injury by Targeting NHE1-Hsp70 Complex in Mice

    PubMed Central

    Huang, Chao; Wang, Jia; Chen, Zhuo; Wang, Yuzhe; Zhang, Wei

    2013-01-01

    The endotoxin-mediated production of pro-inflammatory cytokines plays an important role in the pathogenesis of liver disorders. Heat shock protein (Hsp70) overexpression has established functions in lipopolysaccharide (LPS)-mediated inflammatory response. However, little is known about the role of Hsp70 activity in LPS signaling. We hypothesized that inhibition of Hsp70 substrate binding activity can ameliorate LPS-induced liver injury by decreasing induction of pro-inflammatory factors. In this study, C57/BL6 mice were injected intraperitoneally with LPS and 2-phenylethynesulfonamide (PES), an inhibitor of Hsp70 substrate binding activity. We found that i. PES prevented LPS-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, infiltration of inflammatory cells, and liver cell apoptosis; ii. PES reduced inducible nitric oxide synthase (iNOS) protein expression as well as serum nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) content in LPS-stimulated mice; iii. PES reduced the mRNA level of iNOS, TNF-α, and IL-6 in LPS-stimulated liver. iiii. PES attenuated the degradation of inhibitor of κB-α (IκB-α) as well as the phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB) in LPS-stimulated liver. Similar changes in the protein expression of inflammatory markers, IκB-α degradation, and NF-κB phosphorylation and nuclear translocation were observed in RAW 264.7 cells. Further mechanistic studies revealed that PES remarkably reduced the elevation of [Ca2+]i and intracellular pH value (pHi) in LPS-stimulated RAW 264.7 cells. Furthermore, PES significantly reduced the increase in Na+/H+ exchanger 1 (NHE1) association to Hsp70 in LPS-stimulated macrophages and liver, suggesting that NHE1-Hsp70 interaction is required for the involvement of NHE1 in the inflammation response. In conclusion, inhibition of Hsp70 substrate binding activity in vivo reduces the induction of

  9. Escin attenuates cognitive deficits and hippocampal injury after transient global cerebral ischemia in mice via regulating certain inflammatory genes.

    PubMed

    Zhang, Leiming; Fu, Fenghua; Zhang, Xiumei; Zhu, Mei; Wang, Tian; Fan, Huaying

    2010-09-01

    Considerable evidence has been accumulated demonstrating an important role for inflammation in ischemic brain injury and its contribution to greater cerebral damage after ischemia. Blocking the inflammatory reaction promotes neuroprotection and shows therapeutic potential for clinical treatment of ischemic brain injury. Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, demonstrates antiedematous and anti-inflammatory effects. Here we assessed neuroprotective effects of escin with a transient global cerebral ischemia model. Global cerebral ischemia was induced by occluding both common carotid arteries and withdrawing 0.3ml of blood from the tail vein in mice. Treatment with escin was initiated 0.5h after ischemia induction and given once a day for three consecutive days. Then animals were assessed using the Morris water-maze test and step-down passive avoidance test. Acetylcholinesterase (AChE) activity, histological pathology, and expression of inflammatory genes in the hippocampus were determined. The results showed escin significantly improved learning and memory recovery and reduced hippocampal damage in the cerebral ischemic mice. However, donepezil merely improved learning and memory recovery but did not ameliorate hippocampal damage in the cerebral ischemic mice. Furthermore, we found escin significantly downregulated certain inflammatory gene expression and upregulated expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was recently reported as a neuroprotective protein in the brain. Our results indicate that inhibition of inflammation and protection of hippocampal neurons by escin may be a potentially useful therapy for ischemic brain injury. PMID:20466027

  10. Apigenin attenuates acute myocardial infarction of rats via the inhibitions of matrix metalloprotease-9 and inflammatory reactions

    PubMed Central

    Du, Hong; Hao, Jie; Liu, Fan; Lu, Jingchao; Yang, Xiuchun

    2015-01-01

    Acute myocardial infarction (AMI) is the myocardial necrosis caused by coronary artery acute and persistent ischemia and hypoxia. Matrix metalloprotease-9 (MMP-9) plays an important role in a series of process of occurrence and development of AMI. Inflammatory reaction plays the key role in all kinds of damage factors in AMI. Apigenin (API) has effectively restrained the activity of MMP-9, anti-inflammatory and hepatic fat oxidizing properties. API significantly improved AMI of rats through inhibiting MMP-9 and inflammatory reactions in a few recent studies. Our investigation detected the infarct size of AMI rats, casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) activities in AMI rats were also analyzed with commercial kits. Additionally, Nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) levels of whole bloods of AMI rats were also detected using commercial kits. Next, MMP-9 protein of cardiac in AMI rats was measured with gelatin zymography assays. Finally, caspase-3 and caspase-9 activities in AMI rats were analyzed with commercial kits. In the present study, our work indicated API might significantly reduce the infarction size of AMI rat. It was shown that the treatment of API could decrease the expression of MMP-9 level and reduce the activities of NF-κB, TNF-α, IL-1β and IL-6 in AMI rats. Next, API treatment could reduce caspase-3 and caspase-9 activities and decrease cellular apoptosis of AMI rats. Our findings concluded that API ameliorates acute myocardial infarction of rats via inhibiting MMP-9 and inflammatory reactions. PMID:26309539

  11. Optimization and pharmacological validation of a leukocyte migration assay in zebrafish larvae for the rapid in vivo bioactivity analysis of anti-inflammatory secondary metabolites.

    PubMed

    Cordero-Maldonado, María Lorena; Siverio-Mota, Dany; Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V; de Witte, Peter A M; Crawford, Alexander D

    2013-01-01

    Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487

  12. Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

    PubMed Central

    Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V.; de Witte, Peter A. M.; Crawford, Alexander D.

    2013-01-01

    Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487

  13. β-Caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia mediated oxidative and inflammatory stress in experimental diabetic rats.

    PubMed

    Basha, Rafeek Hidhayath; Sankaranarayanan, Chandrasekaran

    2016-02-01

    Oxidative and inflammatory stress has been implicated in the onset and progression of diabetes mellitus and its complications. The present study was designed to evaluate the effect of β-Caryophyllene (BCP) on hyperglycemia mediated oxidative and inflammatory stress in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in experimental rats by a single intraperitoneal injection of STZ (40 mg/kg b.w.) dissolved in 0.1 M citrate buffer (pH 4.5). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes and the levels of non-enzymic antioxidants were decreased while increases in the levels of lipidperoxidative markers, protein carbonyls and conjugated dienes were observed in pancreatic tissues of diabetic rats. An elevation of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were observed in plasma and pancreatic tissues of diabetic rats. Intragastric administration of BCP (200 mg/kg b.w) for 45 days significantly decreased glucose and increased insulin levels in diabetic rats. BCP administration significantly restored antioxidant status and decreased proinflammatory cytokines in diabetic rats. These findings were supported by histological and immunohistochemical studies. Thus, we conclude that oral administration of BCP effectively rescued β-cells by mitigating hyperglycemia through enhancing insulin release and also averted oxidative/inflammatory stress in pancreatic tissue of diabetic rats. The efficacy of BCP was compared with glibenclamide, a standard antidiabetic drug. PMID:26748309

  14. PMEA coating of pump circuit and oxygenator may attenuate the early systemic inflammatory response in cardiopulmonary bypass surgery.

    PubMed

    Ueyama, K; Nishimura, K; Nishina, T; Nakamura, T; Ikeda, T; Komeda, M

    2004-01-01

    We investigated the effects of coating a cardiopulmonary bypass (CPB) circuit and oxygenator with poly-2-methoxy-ethyl acrylate (PMEA) on the systemic inflammatory response during and after CPB. Thirty patients undergoing elective cardiac surgery were randomized into three groups (each group n = 10): noncoated (group N), heparin coated (group H), and PMEA coated circuit and oxygenator (group X). Bradykinin (BK), complement 3 activation (C3a) and interleukin-6 (IL-6) levels were measured as early phase indicators of inflammatory response, as were maximum C reactive proteins (CRP) and white blood cell (WBC) levels. The alveolar-arterial oxygen gradient (A-a DO2) was measured as a parameter of respiratory function. IL-6 levels after CPB were significantly higher in group N than in groups H and X (p < 0.05). Serum BK and C3a levels showed similar patterns in all groups. A-a DO2 was lower at the end of and 3 hours after CPB in groups H and X than in group N (p < 0.05). Maximum CRP levels were lower in group X than in groups N (p < 0.05). This prospective study suggests that PMEA coated CPB may improve respiratory function and decrease systemic inflammatory response after cardiac surgery, possibly because this circuit is as biocompatible as heparin coated CPB circuit. PMID:15307550

  15. Geraniol attenuates fibrosis and exerts anti-inflammatory effects on diet induced atherogenesis by NF-κB signaling pathway.

    PubMed

    Jayachandran, Muthukumaran; Chandrasekaran, Balaji; Namasivayam, Nalini

    2015-09-01

    Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor nuclear factor kappa B (NF-κB) is a key regulator of inflammation, immune responses, cell survival and cell proliferation. Tissue remodeling plays a significant role during the phase of inflammation and oxidative stress. In our study we have evaluated the effect of geraniol (GOH), a natural terpenoid on oxidative stress, inflammation and tissue remodeling in experimental animals. Experimental animals (hamsters) were divided into four groups; group 1 were control animals; group 2 were animals fed GOH alone (100mg/kg b.w. p.o); group 3 were animals fed atherogenic diet (standard pellet diet+10% coconut oil+0.25% cholesterol); group 4 animals were fed atherogenic diet as in group 3+GOH (100mg/kg b.w). At the end of the experimental period animals were killed and liver, heart and aorta tissues were analyzed for lipid peroxidation markers, non enzymic antioxidants and collagen distribution using histological studies like Milligan's trichrome and Picrosirius red staining. As inflammation plays a key role in tissue remodeling we also targeted the key inflammatory cytokine, NF-κB. GOH supplementation greatly prevented the remodeling of tissues by enhancing the free radical scavenging and anti-inflammatory effects. Thus in conclusion it can be suggested that GOH (100mg/kg b.w) prevents the atherogenic diet induced fibrosis in experimental hamsters. PMID:26004525

  16. Palmatine from Mahonia bealei attenuates gut tumorigenesis in ApcMin/+ mice via inhibition of inflammatory cytokines

    PubMed Central

    MA, WEI-KUN; LI, HUI; DONG, CUI-LAN; HE, XIN; GUO, CHANG-RUN; ZHANG, CHUN-FENG; YU, CHUN-HAO; WANG, CHONG-ZHI; YUAN, CHUN-SU

    2016-01-01

    Mahonia bealei is a Chinese folk medicine used to treat various ailments, in particular gastrointestinal inflammation-related illnesses, and palmatine is one of its active constituents. In this study, ApcMin/+ mice, a genetically engineered model, were used to investigate the effects of palmatine on the initiation and progression of gut inflammation and tumorigenesis enhanced by a high-fat diet. The in vitro antiproliferation and anti-inflammation effects of palmatine were evaluated on HT-29 and SW-480 human colorectal cancer cell lines. The concentration-related antiproliferative effects of palmatine on both cell lines (P<0.01) were observed. Palmatine significantly inhibited lipopolysaccharide-induced increase in cytokine interleukin (IL)-8 levels in the HT-29 cells (P<0.01). In the in vivo studies with ApcMin/+ mice, after 10 or 20 mg/kg/day oral palmatine treatment, tumor numbers were significantly reduced in the small intestine and colon in a dose-dependent manner (P<0.01 compared with the model group). The results were supported by tumor distribution data, body weight changes and organ index. The effect on survival was also dose-dependent. Both the low- and high-dose palmatine treatments significantly increased the life span of the mice (P<0.01). The gut histology from the model group showed a prominent adenomatous change along with inflammatory lesions. With palmatine treatment, however, the dysplastic changes were greatly reduced in the small intestine and colon tissue. Reverse transcription-quantitative polymerase chain reaction analysis of interleukin (IL)-1α, IL1-β, IL-8, granulocyte-colony stimulating factor and granulocyte macrophage colony-stimulating factor in the gut tissue showed that these inflammatory cytokines were reduced significantly following treatment (all P<0.01); serum cytokine levels were also decreased. Data suggests that palmatine has a clinical value in colorectal cancer therapeutics, and this action is likely linked to the

  17. Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates DSS-induced colitis

    PubMed Central

    Luther, Jay; Owyang, Stephanie Y.; Takeuchi, Tomomi; Cole, Tyler; Zhang, Min; Liu, Maochang; Erb-Downward, John; Rubenstein, Joel H.; Kao, John Y.

    2012-01-01

    Background & Aims Recently there has been emerging epidemiological data to suggest Helicobacter pylori (H. pylori) may protect against certain chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, the mechanism for the observed inverse association between H. pylori and IBD has not been described. Methods The frequency of immunoregulatory (IRS) to immunostimulatory (ISS) sequences within the genome of various bacteria was calculated using MacVector software. The induction of type I IFN and IL-12 responses by DNA-pulsed murine bone marrow–derived dendritic cells (BMDC) and human plasmacytoid dendritic cells (pDC) was analyzed by cytokine production. The effect of H. pylori DNA on E. coli DNA production of type I IFN and IL-12 was assessed. The in vivo significance of H. pylori DNA suppression was assessed in a DSS-model of colitis. The systemic levels of type I IFN were assessed in H. pylori-colonized and non-colonized patients. Results We showed that H. pylori DNA has a significantly elevated IRS:ISS ratio. In vitro experiments revealed the inability of H. pylori DNA to stimulate type I IFN or IL-12 production from mouse BMDCs or human pDCs. Additionally, H. pylori DNA was able to suppress E. coli-DNA production of type I IFN and IL-12. Administration of H. pylori DNA prior to the induction of DSS colitis significantly ameliorated the severity of colitis as compared to E. coli DNA or vehicle control in both an acute and chronic model. Finally, the systemic levels of type I IFN were found to be lower in H. pylori-colonized patients versus non-colonized controls. Conclusions Overall, our study indicates that H pylori DNA has the ability to down-regulate pro-inflammatory responses from DCs and this may in part explain the inverse association between H. pylori and IBD. PMID:21471567

  18. Hydrogen Sulfide Therapy Attenuates the Inflammatory Response in a Porcine Model of Myocardial Ischemia – Reperfusion Injury

    PubMed Central

    Sodha, Neel R.; Clements, Richard T.; Feng, Jun; Liu, Yuhong; Bianchi, Cesario; Horvath, Eszter M.; Szabo, Csaba; Stahl, Gregory L.; Sellke, Frank W.

    2009-01-01

    Introduction Hydrogen sulfide (H2S) is produced endogenously in response to myocardial ischemia and thought to be cardioprotective. The mechanism underlying this protection has yet to be fully elucidated, but may be related sulfide’s ability to limit inflammation. This study investigates the cardioprotection provided by exogenous H2S, and its potential anti-inflammatory mechanism of action. Methods The mid-LAD coronary artery in 14 Yorkshire swine was acutely occluded for 60 minutes, followed by reperfusion for 120 minutes. Controls(7) received placebo, and treatment animals(7) received sulfide 10 minutes prior to and throughout reperfusion. Hemodynamic and functional measurements were obtained. Evans blue and TTC staining identified the area-at-risk and infarction. Coronary microvascular reactivity was assessed. Tissue was assayed for myeloperoxidase activity and pro-inflammatory cytokines. Results Pre-I/R hemodynamics were similar between groups, whereas post-I/R mean arterial pressure (mmHg) was reduced by 28.7±5.0 in controls vs. 6.7±6.2 in treatment animals (p=0.03). +LV dP/dt (mmHg/sec) was reduced by 1325±455 in controls vs. 416±207 in treatment animals (p=0.002). Segmental shortening in the area-at-risk was better in treatment animals. Infarct size (% of area-at-risk) in controls was 41.0±7.8% vs. 21.2±2.5% in the treated group (p=0.036). Tissue levels of IL-6, IL-8, and TNFα and MPO activity decreased in the treatment group. Treated animals demonstrated improved microvascular reactivity. Conclusions Therapeutic sulfide provides protection in response to I/R injury, improving myocardial function, reducing infarct size, and improving coronary microvascular reactivity, potentially through its anti-inflammatory properties. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered. PMID:19660398

  19. Yerba mate extract (Ilex paraguariensis) attenuates both central and peripheral inflammatory effects of diet-induced obesity in rats.

    PubMed

    Pimentel, Gustavo D; Lira, Fábio S; Rosa, José C; Caris, Aline V; Pinheiro, Fernanda; Ribeiro, Eliane B; Oller do Nascimento, Cláudia M; Oyama, Lila M

    2013-05-01

    To clarify the effects of natural dietary components on the metabolic consequences of obesity, we examined the effects of yerba mate extract Ilex paraguariensis on both central and peripheral inflammatory effects of diet-induced obesity and correlated the hypothalamic tumor necrosis factor (TNF)-α level with adipose depot weight. Wistar rats were divided into four groups: a control group (CTL) fed with chow diet, a second group fed with chow diet plus yerba mate extract (CTL+E), a third group fed with a high-fat diet rich in saturated fatty acids (HFD) and a fourth group fed with HFD plus yerba mate extract (HFD+E). Enzyme-linked immunosorbent assay, Western blotting, colorimetric method and treatment by gavage were utilized as materials and methods. The HFD groups showed a significant increase in food intake (kcal), body weight, adipose tissue and leptin level in comparison to CTL and CTL+E. HFD leads to increase of both central and peripheral inflammatory effects, and deregulation of insulin pathway. In addition, yerba mate extract intake blunted the proinflammatory effects of diet-induced obesity in rats by reducing the phosphorylation of hypothalamic IKK and NFκBp65 expression and increasing the phosphorylation of IκBα, the expression of adiponectin receptor-1 and consequently the amount of IRS-2. Moreover, the increase in interleukin (IL)-6 levels in the liver and muscle and of the IL-10/TNF-α ratio in groups that received yerba mate extract showed the anti-inflammatory effects of this natural substance. Taken together, our data suggest that the use of yerba mate extract may be useful for reducing low-grade obesity-associated inflammation. PMID:22841395

  20. Ethanol extract of Cordyceps militaris grown on germinated soybeans attenuates dextran-sodium-sulfate- (DSS-) induced colitis by suppressing the expression of matrix metalloproteinases and inflammatory mediators.

    PubMed

    Park, Dong Ki; Park, Hye-Jin

    2013-01-01

    The effect of Cordyceps militaris (CM) grown on germinated soybeans (GSC) in the inflammatory bowel disease (IBD) model was studied. To demonstrate the preventive effect of GSC extract in a dextran-sodium-sulfate- (DSS-) induced acute colitis mouse model, GSC was administered 2 days before DSS coadministration. GSC significantly suppressed DSS-induced disease activity index (DAI) as well as histopathological scores, compared to control or CM-treated group. To elucidate the anti-IBD activity of GSC, we checked the level of matrix metalloproteinases (MMPs) and inflammatory mediators. GSC extract decreased the level of MMP-3 and -9 mRNAs and p53 proteins. The level and activity of LPS-induced MMP-9 were reduced in GSC-treated RAW264.7 cells. It also attenuated the level of inducible nitric oxide synthase (iNOS) and tumor necrosis factor- (TNF-) α mRNAs both in colon tissue and in macrophage cells. These results suggest that GSC can be applied as a protective agent against IBDs. PMID:23841050

  1. Cynandione A from Cynanchum wilfordii attenuates the production of inflammatory mediators in LPS-induced BV-2 microglial cells via NF-κB inactivation.

    PubMed

    Yang, Seung Bo; Lee, Sang Min; Park, Ji-Hae; Lee, Tae Hoon; Baek, Nam-In; Park, Hi-Joon; Lee, Hyejung; Kim, Jiyoung

    2014-01-01

    Cynanchum wilfordii is one of most widely used medicinal plants in Oriental medicine for the treatment of various conditions. In the present study, we isolated cynandione A (CA) from an extract of Cynanchum wilfordii roots (CWE) and investigated the effects of CA on the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines in lipopolysaccharide (LPS)-induced BV-2 microglial cells. CWE and CA significantly decreased LPS-induced nitric oxide production and the expression of iNOS in a concentration-dependent manner, while they (CWE up to 500 µg/mL and CA up to 80 µM) did not exhibit cytotoxic activity. Results from reverse transcription-polymerase chain reaction (RT-PCR) analysis and enzyme-linked immunosorbent assay (ELISA) showed that CA significantly attenuated the expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in LPS-stimulated BV-2 cells. Furthermore, CA inhibited the phosphorylation of inhibitor kappa B-alpha (IκB-α) and translocation of nuclear factor-kappa B (NF-κB) to the BV-2 cell nucleus, indicating that CWE and CA may have effective anti-inflammatory activities via NF-κB inactivation in stimulated microglial cells. PMID:25087960

  2. Forsythiaside attenuates lipopolysaccharide-induced inflammatory responses in the bursa of Fabricius of chickens by downregulating the NF-κB signaling pathway

    PubMed Central

    CHENG, GUANGDONG; ZHAO, YULIAN; LI, HE; WU, YUE; LI, XIANXIAN; HAN, QIANG; DAI, CHONGSHAN; LI, YANHUA

    2014-01-01

    Forsythiaside, a phenylethanoside product isolated from air-dried fruits of Forsythia suspensa, has been demonstrated to exhibit antioxidant, antibacterial and anti-inflammatory activities in vitro. However, its mechanism and the effects of lipopolysaccharide (LPS)-induced injury on the bursa of Fabricius (BF) of chickens are poorly understood. The present study aimed to investigate the anti-inflammatory effects of forsythiaside on LPS-induced acute inflammation. In addition, the potential molecular mechanisms of forsythiaside were analyzed in the BF, a special immune organ in chickens. Forty 15-day-old chickens were randomly divided into control, LPS and LPS plus forsythiaside (30 or 60 mg/kg) groups (n=10 for each group). In the LPS plus forsythiaside (30 or 60 mg/kg) groups, the chickens were orally administered with forsythiaside at doses of 30 and 60 mg/kg for seven days. At 21 days old, the chickens were intravenously injected with 200 μg/kg body weight LPS. Chickens in the control and LPS groups were only administered with vehicle or LPS, respectively, at day 21. At 3 h post-injection, the body temperature and nitric oxide (NO) levels were analyzed. In addition, the levels and mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β, and the mRNA expression of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were examined in the BFs isolated from the chickens. The results revealed that forsythiaside was able to attenuate the LPS-induced inflammatory responses in the BFs of the chickens. The mechanisms by which forsythiaside exerted its anti-inflammatory effect were found to correlate with the inhibition of IL-6, IL-1β, TNF-α and COX-2 production, via the inactivation of NF-κB, indicating that the NF-κB-iNOS-NO signaling pathway may be important in this process. PMID:24348786

  3. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway.

    PubMed

    Jiao, M; Ren, F; Zhou, L; Zhang, X; Zhang, L; Wen, T; Wei, L; Wang, X; Shi, H; Bai, L; Zhang, X; Zheng, S; Zhang, J; Chen, Y; Han, Y; Zhao, C; Duan, Z

    2014-01-01

    Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment. PMID:25165883

  4. Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis

    PubMed Central

    Sukumaran, Vijayakumar; Watanabe, Kenichi; Veeraveedu, Punniyakoti T.; Gurusamy, Narasimman; Ma, Meilei; Thandavarayan, Rajarajan A.; Lakshmanan, Arun Prasath; Yamaguchi, Ken'ichi; Suzuki, Kenji; Kodama, Makoto

    2011-01-01

    Studies have demonstrated that angiotensin II has been involved in immune and inflammatory responses which might contribute to the pathogenesis of immune-mediated diseases. Recent evidence suggests that oxidative stress may play a role in myocarditis. Here, we investigated whether olmesartan, an AT1R antagonist protects against experimental autoimmune myocarditis (EAM) by suppression of oxidative stress, endoplasmic reticulum (ER) stress and inflammatory cytokines. EAM was induced in Lewis rats by immunization with porcine cardiac myosin, were divided into two groups and treated with either olmesartan (10 mg/kg/day) or vehicle for a period of 21 days. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Treatment with olmesartan attenuated the myocardial mRNA expressions of proinflammatory cytokines, [Interleukin (IL)-1β, monocyte chemoattractant protein-1, tumor necrosis factor-α and interferon-γ)] and the protein expression of tumor necrosis factor-α compared with that of vehicle-treated rats. Myocardial protein expressions of AT1R, NADPH oxidase subunits (p47phox, p67phox, gp91phox) and the expression of markers of oxidative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), and the cardiac apoptosis were also significantly decreased by the treatment with olmesartan compared with those of vehicle-treated rats. Furthermore, olmesartan treatment down-regulated the myocardial expressions of glucose regulated protein-78, growth arrest and DNA damage-inducible gene, caspase-12, phospho-p38 mitogen-activated protein kinase (MAPK) and phospho-JNK. These findings suggest that olmesartan protects against EAM in rats, at least in part via suppression of oxidative stress, ER stress and inflammatory cytokines. PMID:21383952

  5. Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord.

    PubMed

    Lu, Cui'e; Liu, Yue; Sun, Bei; Sun, Yu'e; Hou, Bailing; Zhang, Yu; Ma, Zhengliang; Gu, Xiaoping

    2015-10-01

    Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain. However, its complex cellular and molecular mechanisms in bone cancer pain remain unclear. And less relevant reports concerned its time-dependent effects on the long-lasting modifications of behavior, spinal inflammatory cytokines levels, astrocytes activity induced by bone cancer pain. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells was utilized. Pain behaviors at different time points were assessed by ambulatory pain scores and paw withdrawal mechanical threshold (PWMT). Pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor alpha (TNF-α), were quantitated by Western blots. Glial activity was assessed by immunohistochemistry. Intra-tibia inoculation of Walker 256 mammary gland carcinoma cells induced progressive bone cancer pain; a long-term up-regulation of IL-1β, IL-6, IL-18, and TNF-α; and the activation of glia in spinal cord. Activation of microglia was first evident on day 4 after surgery and reached to a peak on day 7 while activation of astrocytes was on day 10. A single intrathecal injection of JWH-015 attenuated bone cancer induced spontaneous pain and mechanical allodynia, reduced the expression of pro-inflammatory cytokines, and inhibited the activity of astrocytes. All the modifications were transient and peaked at 24 h after JWH-015 administration. Furthermore, the protective effects of JWH-015 were reversed in the presence of CB2-selective antagonist AM630. Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect. PMID:25896633

  6. Luteolin is a bioflavonoid that attenuates adipocyte-derived inflammatory responses via suppression of nuclear factor-κB/mitogen-activated protein kinases pathway

    PubMed Central

    Nepali, Sarmila; Son, Ji-Seon; Poudel, Barun; Lee, Ji-Hyun; Lee, Young-Mi; Kim, Dae-Ki

    2015-01-01

    Background: Inflammation of adipocytes has been a therapeutic target for treatment of obesity and metabolic disorders which cause insulin resistance and hence lead to type II diabetes. Luteolin is a bioflavonoid with many beneficial properties such as antioxidant, antiproliferative, and anti-cancer. Objectives: To elucidate the potential anti-inflammatory response and the underlying mechanism of luteolin in 3T3-L1 adipocytes. Materials and Methods: We stimulated 3T3-L1 adipocytes with the mixture of tumor necrosis factor-α, lipopolysaccharide, and interferon-γ (TLI) in the presence or absence of luteolin. We performed Griess’ method for nitric oxide (NO) production and measure mRNA and protein expressions by real-time polymerase chain reaction and western blotting, respectively. Results: Luteolin opposed the stimulation of inducible nitric oxide synthase and NO production by simultaneous treatment of adipocytes with TLI. Furthermore, it reduced the pro-inflammatory genes such as cyclooxygenase-2, interleukin-6, resistin, and monocyte chemoattractant protein-1. Furthermore, luteolin improved the insulin sensitivity by enhancing the expression of insulin receptor substrates (IRS1/2) and glucose transporter-4 via phosphatidylinositol-3K signaling pathway. This inhibition was associated with suppression of Iκ-B-α degradation and subsequent inhibition of nuclear factor-κB (NF-κB) p65 translocation to the nucleus. In addition, luteolin blocked the phosphorylation of ERK1/2, c-Jun N-terminal Kinases and also p38 mitogen-activated protein kinases (MAPKs). Conclusions: These results illustrate that luteolin attenuates inflammatory responses in the adipocytes through suppression of NF-κB and MAPKs activation, and also improves insulin sensitivity in 3T3-L1 cells, suggesting that luteolin may represent a therapeutic agent to prevent obesity-associated inflammation and insulin resistance. PMID:26246742

  7. Atorvastatin attenuates contrast-induced nephropathy by modulating inflammatory responses through the regulation of JNK/p38/Hsp27 expression.

    PubMed

    He, Xuyu; Li, Liwen; Tan, Hong; Chen, Jiyan; Zhou, Yingling

    2016-05-01

    This study aimed to investigate whether atorvastatin reduce the contrast-induced nephropathy inflammatory response and apoptosis of renal tubular epithelial cells and the relationship with MAPK signaling pathway. We utilized the iopamidol-induced contrast-induced nephropathy (CIN) rat model which was induced by a single dose of iopamidol (2.9 g iodine/kg) and a cell model in which human embryonic proximal tubular (HK2) cells were treated with iopamidol. The rats were divided into five groups: (1) control rats (CR); (2) atorvastatin (CA); (3) iopamidol (CM); (4) iopamidol and atorvastatin (20 mg/kg d) (CMA2); (5) iopamidol and atorvastatin (40 mg/kg d) (CMA4). On days 1, 2 and 6 after iopamidol injection, the urea nitrogen and cystatin C increased in CM compared with CR but decreased in CMA compared with CM. Inflammatory parameters and the percentage of apoptotic cells were increased in CM compared with CR and CA, but they were decreased in CMA compared with CM. We also found that atorvastatin ameliorated the renal tubular necrosis, apoptosis, and the deterioration of renal function in a dose dependent manner (P < 0.05). Furthermore, in vivo, both of SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor) could decrease the expression of Bax and caspase-3, but increase Bcl-2 levels in HK2 cells treated with iopamidol. Our study demonstrates that high-dosage atorvastatin treatment attenuates both the inflammatory processes and apoptosis in contrast-induced acute kidney injury, and that the JNK/p38 MAPK pathway participates in the contrast-induced apoptosis of renal tubular cells. Finally, atorvastatin reduces CIN by suppression of apoptosis, which may be through inhibition of JNK/p38 MAPK pathways. PMID:27156929

  8. Prophylactic acetylsalicylic acid attenuates the inflammatory response but fails to protect exercise-induced liver damage in exercised rats.

    PubMed

    Huang, Kuo-Chin; Chiu, Yi-Han; Liao, Kuang-Wen; Ke, Chun-Yen; Lee, Chung-Jen; Chao, Yann-Fen C; Lee, Ru-Ping

    2016-09-01

    This study evaluated the effects of acetylsalicylic acid (ASA) on exercise-induced inflammatory response, muscle damage, and liver injury in rats. Wistar-Kyoto (WKY) rats were divided into six groups: control (C), exercise (E), C+20mg ASA, E+20mg ASA, C+100mg/kg ASA, and E+100mg ASA groups. ASA or a vehicle was orally administered through gavage 1h before a treadmill test. Upon trial completion, blood was drawn at 1, 12, and 24h for biochemical analysis, and livers were excised at 24h for a histological assessment. Our results revealed that 100mg/kg ASA significantly reduced interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the E groups; however, the IL-10 level was considerably increased. Moreover, aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and histological hepatic damage increased significantly in the E+100mg ASA group compared with the corresponding changes in the E group. These results suggest that the prophylactic administration of particularly high-dose ASA alleviates exercise-induced inflammatory response but exacerbates liver injury. PMID:27262381

  9. Therapeutic Effects of Acetone Extract of Saraca asoca Seeds on Rats with Adjuvant-Induced Arthritis via Attenuating Inflammatory Responses

    PubMed Central

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

    Saraca asoca has been traditionally used in Indian system for treatment of uterine, genital, and other reproductive disorders in women, fever, pain, and inflammation. The hypothesis of this study is that acetone extract of Saraca asoca seeds is an effective anti-inflammatory treatment for arthritis in animal experiments. The antiarthritic effect of its oral administration on Freund's adjuvant-induced arthritis has been studied in Wistar albino rats after acute and subacute toxicities. Phytochemical analysis revealed presence of high concentrations of phenolic compounds such as flavonoids and tannins, while no mortality or morbidity was observed up to 1000 mg/kg dose during acute and subacute toxicity assessments. Regular treatment up to 21 days of adjuvant-induced arthritic rats with Saraca asoca acetone extract (at 300 and 500 mg/kg doses) increases RBC and Hb, decreases WBC, ESR, and prostaglandin levels in blood, and restores body weight when compared with control (normal saline) and standard (Indomethacin) groups. Significant (P < 0.05) inhibitory effect was observed especially at higher dose on paw edema, ankle joint inflammation, and hydroxyproline and glucosamine concentrations in urine. Normal radiological images of joint and histopathological analysis of joint, liver, stomach, and kidney also confirmed its significant nontoxic, antiarthritic, and anti-inflammatory effect. PMID:24729890

  10. The anti-inflammatory properties of Satureja khuzistanica Jamzad essential oil attenuate the effects of traumatic brain injuries in rats

    PubMed Central

    Abbasloo, Elham; Dehghan, Fatemeh; Khaksari, Mohammad; Najafipour, Hamid; Vahidi, Reza; Dabiri, Shahriar; Sepehri, Gholamreza; Asadikaram, Golamreza

    2016-01-01

    Traumatic brain injury (TBI) is a major health concern affecting the general public as well as military personnel. However, there is no FDA-approved therapy for the treatment of TBIs. In this work, we investigated the neurotherapeutic effects of the well-known natural Iranian medicine Satureja Khuzistanica Jamzad (SKJ) essential oil (SKEO) on the outcomes of diffused experimental TBI, with particular attention paid to its anti-inflammatory and anti-apoptotic effects. Male Wistar rats were treated with doses of 50, 100 and 200 (mg/kg, i.p) SKEO after induction of diffused TBIs. The results showed that injecting SKEO (200 mg/kg) 30 minutes after TBI significantly reduced brain oedema and damage to the blood-brain barrier (BBB) and limited the post-TBI increase in intracranial pressure. The veterinary coma scale (VCS) scores significantly improved in the treatment group. Also, inflammatory marker assays showed reduced levels of TNF-α, IL-1β, and IL-6 and increased IL-10 in the treated groups. Moreover, the immunohistochemical results indicated that SKEO not only reduced neuronal death and BBB permeability but also affected astrocytic activation. Overall, our data indicate potential clinical neurological applications for SKEO. PMID:27535591

  11. Therapeutic Effects of Acetone Extract of Saraca asoca Seeds on Rats with Adjuvant-Induced Arthritis via Attenuating Inflammatory Responses.

    PubMed

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

    Saraca asoca has been traditionally used in Indian system for treatment of uterine, genital, and other reproductive disorders in women, fever, pain, and inflammation. The hypothesis of this study is that acetone extract of Saraca asoca seeds is an effective anti-inflammatory treatment for arthritis in animal experiments. The antiarthritic effect of its oral administration on Freund's adjuvant-induced arthritis has been studied in Wistar albino rats after acute and subacute toxicities. Phytochemical analysis revealed presence of high concentrations of phenolic compounds such as flavonoids and tannins, while no mortality or morbidity was observed up to 1000 mg/kg dose during acute and subacute toxicity assessments. Regular treatment up to 21 days of adjuvant-induced arthritic rats with Saraca asoca acetone extract (at 300 and 500 mg/kg doses) increases RBC and Hb, decreases WBC, ESR, and prostaglandin levels in blood, and restores body weight when compared with control (normal saline) and standard (Indomethacin) groups. Significant (P < 0.05) inhibitory effect was observed especially at higher dose on paw edema, ankle joint inflammation, and hydroxyproline and glucosamine concentrations in urine. Normal radiological images of joint and histopathological analysis of joint, liver, stomach, and kidney also confirmed its significant nontoxic, antiarthritic, and anti-inflammatory effect. PMID:24729890

  12. The anti-inflammatory properties of Satureja khuzistanica Jamzad essential oil attenuate the effects of traumatic brain injuries in rats.

    PubMed

    Abbasloo, Elham; Dehghan, Fatemeh; Khaksari, Mohammad; Najafipour, Hamid; Vahidi, Reza; Dabiri, Shahriar; Sepehri, Gholamreza; Asadikaram, Golamreza

    2016-01-01

    Traumatic brain injury (TBI) is a major health concern affecting the general public as well as military personnel. However, there is no FDA-approved therapy for the treatment of TBIs. In this work, we investigated the neurotherapeutic effects of the well-known natural Iranian medicine Satureja Khuzistanica Jamzad (SKJ) essential oil (SKEO) on the outcomes of diffused experimental TBI, with particular attention paid to its anti-inflammatory and anti-apoptotic effects. Male Wistar rats were treated with doses of 50, 100 and 200 (mg/kg, i.p) SKEO after induction of diffused TBIs. The results showed that injecting SKEO (200 mg/kg) 30 minutes after TBI significantly reduced brain oedema and damage to the blood-brain barrier (BBB) and limited the post-TBI increase in intracranial pressure. The veterinary coma scale (VCS) scores significantly improved in the treatment group. Also, inflammatory marker assays showed reduced levels of TNF-α, IL-1β, and IL-6 and increased IL-10 in the treated groups. Moreover, the immunohistochemical results indicated that SKEO not only reduced neuronal death and BBB permeability but also affected astrocytic activation. Overall, our data indicate potential clinical neurological applications for SKEO. PMID:27535591

  13. Palmatine from Mahonia bealei attenuates gut tumorigenesis in ApcMin/+ mice via inhibition of inflammatory cytokines.

    PubMed

    Ma, Wei-Kun; Li, Hui; Dong, Cui-Lan; He, Xin; Guo, Chang-Run; Zhang, Chun-Feng; Yu, Chun-Hao; Wang, Chong-Zhi; Yuan, Chun-Su

    2016-07-01

    Mahonia bealei is a Chinese folk medicine used to treat various ailments, in particular gastrointestinal inflammation‑related illnesses, and palmatine is one of its active constituents. In this study, ApcMin/+ mice, a genetically engineered model, were used to investigate the effects of palmatine on the initiation and progression of gut inflammation and tumorigenesis enhanced by a high‑fat diet. The in vitro antiproliferation and anti‑inflammation effects of palmatine were evaluated on HT‑29 and SW‑480 human colorectal cancer cell lines. The concentration‑related antiproliferative effects of palmatine on both cell lines (P<0.01) were observed. Palmatine significantly inhibited lipopolysaccharide‑induced increase in cytokine interleukin (IL)‑8 levels in the HT‑29 cells (P<0.01). In the in vivo studies with ApcMin/+ mice, after 10 or 20 mg/kg/day oral palmatine treatment, tumor numbers were significantly reduced in the small intestine and colon in a dose‑dependent manner (P<0.01 compared with the model group). The results were supported by tumor distribution data, body weight changes and organ index. The effect on survival was also dose‑dependent. Both the low‑ and high‑dose palmatine treatments significantly increased the life span of the mice (P<0.01). The gut histology from the model group showed a prominent adenomatous change along with inflammatory lesions. With palmatine treatment, however, the dysplastic changes were greatly reduced in the small intestine and colon tissue. Reverse transcription‑quantitative polymerase chain reaction analysis of interleukin (IL)‑1α, IL1‑β, IL‑8, granulocyte‑colony stimulating factor and granulocyte macrophage colony‑stimulating factor in the gut tissue showed that these inflammatory cytokines were reduced significantly following treatment (all P<0.01); serum cytokine levels were also decreased. Data suggests that palmatine has a clinical value in colorectal cancer therapeutics, and

  14. Fluoxetine stimulates anti-inflammatory IL-10 cytokine production and attenuates sensory deficits in a rat model of decompression sickness.

    PubMed

    Blatteau, Jean-Eric; de Maistre, Sébastien; Lambrechts, Kate; Abraini, Jacques; Risso, Jean-Jacques; Vallée, Nicolas

    2015-12-15

    Despite "gold standard" hyperbaric oxygen treatment, 30% of patients suffering from neurological decompression sickness still exhibit incomplete recovery, including sensory impairments. Fluoxetine, a well-known antidepressant, is recognized as having anti-inflammatory effects in the setting of cerebral ischemia. In this study, we focused on the assessment of sensory neurological deficits and measurement of circulating cytokines after decompression in rats treated or not with fluoxetine. Seventy-eight rats were divided into a clinical (n = 38) and a cytokine (n = 40) group. In both groups, the rats were treated with fluoxetine (30 mg/kg po, 6 h beforehand) or with a saccharine solution. All of the rats were exposed to 90 m seawater for 45 min before staged decompression. In the clinical group, paw withdrawal force after mechanical stimulation and paw withdrawal latency after thermal stimulation were evaluated before and 1 and 48 h after surfacing. At 48 h, a dynamic weight-bearing device was used to assess postural stability, depending on the time spent on three or four paws. For cytokine analysis, blood samples were collected from the vena cava 1 h after surfacing. Paw withdrawal force and latency were increased after surfacing in the controls, but not in the fluoxetine group. Dynamic weight-bearing assessment highlighted a better stability on three paws for the fluoxetine group. IL-10 levels were significantly decreased after decompression in the controls, but maintained at baseline level with fluoxetine. This study suggests that fluoxetine has a beneficial effect on sensory neurological recovery. We hypothesize that the observed effect is mediated through maintained anti-inflammatory cytokine IL-10 production. PMID:26494447

  15. Neurotropin attenuates local inflammatory response and inhibits demyelination induced by chronic constriction injury of the mouse sciatic nerve.

    PubMed

    Nishimoto, Shunsuke; Okada, Kiyoshi; Tanaka, Hiroyuki; Okamoto, Michio; Fujisawa, Hiroki; Okada, Tomoyuki; Naiki, Mitsuru; Murase, Tsuyoshi; Yoshikawa, Hideki

    2016-07-01

    Neuropathic pain caused by nerve damage in the central and/or peripheral nervous systems is a refractory disorder and the management of such chronic pain has become a major issue. Neurotropin is a drug widely used in Japan and China to treat chronic pain. Although Neurotropin has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the mechanism of analgesic action in the peripheral nervous system remains to be elucidated. In this study, we investigated the local effects of Neurotropin on peripheral nerve damage in a chronic constriction injury (CCI) model. Neurotropin reduced mRNA expressions of IL-1β, IL-6, and TNF-α in the sciatic nerve 1 day after the injury. Activation of Erk was also inhibited locally in the Neurotropin treatment group. Since Erk activation results in demyelination along with dedifferentiation of Schwann cells, we investigated the expression level of myelin basic protein. Five days after the injury, Neurotropin attenuated the downregulation of myelin basic protein in the sciatic nerve in the CCI model. Local effects of Neurotropin around the injury site may result in discovery of new treatments for not only neuropathic pain but also demyelinating diseases and peripheral nervous system injury. PMID:27233579

  16. Extracts of Bauhinia championii (Benth.) Benth. attenuate the inflammatory response in a rat model of collagen-induced arthritis

    PubMed Central

    XU, WEI; HUANG, MINGQING; ZHANG, YUQIN; LI, HUANG; ZHENG, HAIYIN; YU, LISHUANG; CHU, KEDAN; LIN, YU; CHEN, LIDIAN

    2016-01-01

    Rheumatoid arthritis is considered a serious public health problem, which is commonly treated with traditional Chinese or herbal medicine. The present study evaluated the effects of Bauhinia championii (Benth.) Benth. extraction (BCBE) on a type II collagen-induced arthritis (CIA) rat model. Wistar rats with CIA received either 125 or 500 mg/kg BCBE, after which, paw swelling was markedly suppressed compared with in the model group. In addition, BCBE significantly ameliorated pathological joint alterations, including synovial hyperplasia, and cartilage and bone destruction. The protein and mRNA expression levels of interleukin (IL)-6, IL-8, tumor necrosis factor-α and nuclear factor-κB in synovial tissue were determined by immunohistochemical staining, western blot analysis and reverse transcription-polymerase chain reaction. The results demonstrated that the expression levels of these factors were significantly downregulated in the BCBE-treated group compared with in the model group. These results indicated that BCBE may exert an inhibitory effect on the CIA rat model, and its therapeutic potential is associated with its anti-inflammatory action. PMID:27035125

  17. 1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain.

    PubMed

    Bladen, Chris; Gadotti, Vinicius M; Gündüz, Miyase G; Berger, N Daniel; Şimşek, Rahime; Şafak, Cihat; Zamponi, Gerald W

    2015-06-01

    We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-type over L-type calcium channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-type channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Cav3.2 over Cav1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Cav3.2 channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Cav3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies. PMID:24990197

  18. Vitamin E and telmisartan attenuates doxorubicin induced cardiac injury in rat through down regulation of inflammatory response

    PubMed Central

    2012-01-01

    Background The importance of doxorubicin (Dox), as a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy. It has been shown that free radicals are involved in acute doxorubicin-induced toxicity. The aim of this study was to determine the protective effect of vitamin E and telmisartan in acute doxorubicin induced cardiotoxicity. Methods Thirty two male Sprague - Dawly rats were involved in this study and were randomly separated into 4 groups, eight rats in each group, one group received normal saline I.P as control and second group received doxorubicin 20 mg/kg I.P, the other two groups also received doxorubicin 20 mg/kg I.P as single dose after seven cumulative doses (for seven days) of vitamin E (100 mg/kg) and telmisartan (1 mg/kg) respectively. Immunofluorescent staining for monocytes infiltration and analyses of plasma by (ELISAs) for MCP-1and troponin I. Western immunoblotting assay for ICAM-1, while left ventricular function was analyzed by microcatheter, also estimated the level of oxidative stress parameters (MDA and Catalase) and cardiac enzymes activities (CK-MB and LDH) before starting drugs treatment and after treatment period by 48 hours. Results The immunofluorescent staining showed that administration of vitamin E and telmisartan are attenuated of mononuclear cell infiltration; (p < 0.05 vs. Dox group), also reduced the level of chemokines MCP-1 and ICAM-1 expression compared with Dox group only, and there is marked reduction of myocardial troponin-I levels with improved LV function in vitamin E and telmisartan treated group. Doxorubicin treatment increased MDA, LDH, CK-MB levels significantly (P < 0.01), and were counteracted by administration of vitamin E and telmisartan, but did not significantly affect serum catalase activity. Conclusions Antioxidant effect (Vitamin E and telmisartan) have been shown to decrease doxorubicininduced cardiotoxicity. PMID:22867422

  19. PF-04886847 (an inhibitor of plasma kallikrein) attenuates inflammatory mediators and activation of blood coagulation in rat model of lipopolysaccharide (LPS) - induced sepsis

    PubMed Central

    Kolte, D; Bryant, JW; Gibson, GW; Wang, J; Shariat-Madar, Z

    2016-01-01

    The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide (LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg) prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced the elevated plasma 6-keto PGF1α levels in LPS treated rats, suggesting that PF-04886847 could be useful in preventing hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-α level. Pretreatment of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein (the zymogen form of plasma kallikrein) deficient patients have prolonged aPPT without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847 was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events, PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both activated partial thromboplastin time (aPTT) and prothrombin time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin mediated diseases. PMID:22352684

  20. Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-κB-mediated inflammatory response

    PubMed Central

    Xia, YF; Zhang, JH; Xu, ZF; Deng, XM

    2015-01-01

    Background: During mechanical ventilation, high end-inspiratory lung volume results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). The pathophysiology of ventilator-induced lung injury involves multiple mechanisms, such as excessive inflammation. And pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have anti-inflammatory activity. Objective: We investigated the effects of pyncogenol on ventilator-induced lung injury in rats. Methods: Rats were orally administrated with pycnogenol once (30 mg/kg) 2 days before lung injury induction with mechanical ventilation, then the rats were divided into three groups: lung-protective ventilation (LV group, n = 20), injurious ventilation (HV group, n = 20), HV + pycnogenol group (HV + Pyc group, n = 20). Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses. Results: Pretreatment with pycnogenol could markedly decrease lung wet/dry ratio, lower myeloperoxidase (MPO) activity and total protein concentration and reduce the production of TNF-α, IL-6, IL-1β and MIP-2 in the BALF in ventilator-induced lung injury rats. Additionally, pycnogenol improved the histology of the lung and significantly inhibited the phosphorylation of NF-κB p65 and the degradation of IκB-α. Conclusion: Pycnogenol treatment could attenuate ventilator-induced lung injury in rats, at least in part, through its ability to reduce the production of inflammatory cytokines via inhibiting the activation of NF-κB, indicating it as a potential therapeutic candidate for ventilator-induced lung injury. PMID:25932110

  1. Inhibiting High-Mobility Group Box 1 (HMGB1) Attenuates Inflammatory Cytokine Expression and Neurological Deficit in Ischemic Brain Injury Following Cardiac Arrest in Rats.

    PubMed

    Xu, Mei; Zhou, Gui-Ming; Wang, Li-Hua; Zhu, Li; Liu, Jin-Mei; Wang, Xiao-Dong; Li, Hong-Tao; Chen, Lei

    2016-08-01

    Cardiac arrest (CA), if untreated for more than 5 min, can induce severe brain damage, the underlying mechanism of which is still unclear. Previous studies have indicated that high-mobility group box 1 (HMGB1), a nuclear protein implicated in several inflammatory disorders, is involved in the inflammatory processes following brain ischemia. However, the role of HMGB1 in brain dysfunction after CA is yet to be determined. In a rat CA model, HMGB1 protein expression was higher at 1, 3, and 7 days post-CA, compared to that in naïve and sham-treated rats. Following injection of HMGB1 antibody (anti-HMGB1) into the cerebral ventricles, neurological deficit scores were significantly decreased in the CA group as compared to that in the naïve and sham group. Nissl staining showed significant neuronal loss in the hippocampal CA1 region following CA, which was significantly attenuated by anti-HMGB1-treatment (10 and 50 μg) in comparison with the vehicle-injected control. CA induced a significant increase in the levels of the cytokine interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in the hippocampus as revealed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Treatment with anti-HMGB1 significantly inhibited IL-1β and TNF-α expression. Our study suggests that HMGB1 contributes significantly to CA-induced brain dysfunction and that inhibiting HMGB1 function and expression may be an effective therapeutic approach to CA-induced ischemic brain injury. PMID:27363991

  2. Dietary Blueberry Attenuates Whole-Body Insulin Resistance in High Fat-Fed Mice by Reducing Adipocyte Death and Its Inflammatory Sequelae1–3

    PubMed Central

    DeFuria, Jason; Bennett, Grace; Strissel, Katherine J.; Perfield, James W.; Milbury, Paul E.; Greenberg, Andrew S.; Obin, Martin S.

    2009-01-01

    Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMΦ). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMΦ (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMΦ gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-κB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology. PMID:19515743

  3. TLR4 inhibitor attenuates amyloid-β-induced angiogenic and inflammatory factors in ARPE-19 cells: Implications for age-related macular degeneration.

    PubMed

    Chen, Li; Bai, Yujing; Zhao, Min; Jiang, Yanrong

    2016-04-01

    Subretinally-deposited amyloid-β (Aβ) is an important factor in age‑related macular degradation (AMD) often leading to irreversible blindness in the elderly population. The molecular mechanism underlying Aβ deposition during AMD remains unclear. The expression of inflammatory and angiogenic factors was examined by treatment of retinal pigment epithelial (RPE) cells with the oligomeric form of Aβ (OAβ1-42). Changes in the mRNA expression levels of various cytokines was detected by the QuantiGenePlex 6.0 Reagent system, and the protein expression level was determined by western blotting. Culture supernatants were detected using a multiplex cytokine assay and enzyme-linked immunosorbent assays. The in vitro tube formation was evaluated by a Matrigel assay. The present study highlights that OAβ1‑42 activates the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 and phosphorylation nuclear factor-κB signaling pathway in RPE cells. Additionally, it increased the mRNA and protein expression of interleukin (IL)-6, IL-8, IL-33, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiopoietin 2. Furthermore, the TLR4 inhibitor (COBRA) attenuated the expression of inflammatory and angiogenesis factors, particularly IL-6, IL-8, IL-33, bFGF and VEGF. When human umbilical vein endothelial cells (HUVECs) were co-cultured with the COBRA-treated RPE cell culture supernatant the length of the endothelial cell network (measured by calculating tip cell lengths of endothelial cells) was impaired when compared with the HUVECs that were co‑cultured with the cell supernatant exposed to OAβ1‑42. These results suggest that the TLR4-associated pathway may be a potential target for the treatment of AMD. PMID:26936827

  4. Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates Dahl salt-sensitive hypertension via inflammatory modulation.

    PubMed

    Rudemiller, Nathan P; Lund, Hayley; Priestley, Jessica R C; Endres, Bradley T; Prokop, Jeremy W; Jacob, Howard J; Geurts, Aron M; Cohen, Eric P; Mattson, David L

    2015-05-01

    Human genome-wide association studies have linked SH2B adaptor protein 3 (SH2B3, LNK) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the Sh2b3(em1Mcwi) mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3(em1Mcwi) mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3(em1Mcwi) mutant bone marrow. Rats that received Sh2b3(em1Mcwi) mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease. PMID:25776069

  5. Sinularin from Indigenous Soft Coral Attenuates Nociceptive Responses and Spinal Neuroinflammation in Carrageenan-Induced Inflammatory Rat Model

    PubMed Central

    Huang, Shi-Ying; Chen, Nan-Fu; Chen, Wu-Fu; Hung, Han-Chun; Lee, Hsin-Pai; Lin, Yen-You; Wang, Hui-Min; Sung, Ping-Jyun; Sheu, Jyh-Horng; Wen, Zhi-Hong

    2012-01-01

    Three decades ago, the marine-derived compound sinularin was shown to have anti-edematous effects on paw edema induced by carrageenan or adjuvant. To the best of our knowledge, no new studies were conducted to explore the bioactivity of sinularin until we reported the analgesic properties of sinularin based on in vivo experiments. In the present study, we found that sinularin significantly inhibits the upregulation of proinflammatory proteins, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and upregulates the production of transforming growth factor-β (TGF-β) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells according to western blot analysis. We found that subcutaneous (s.c.) administration of sinularin (80 mg/kg) 1 h before carrageenan injection significantly inhibited carrageenan-induced nociceptive behaviors, including thermal hyperalgesia, mechanical allodynia, cold allodynia, and hindpaw weight-bearing deficits. Further, s.c. sinularin (80 mg/kg) significantly inhibited carrageenan-induced microglial and astrocyte activation as well as upregulation of iNOS in the dorsal horn of the lumbar spinal cord. Moreover, s.c. sinularin (80 mg/kg) inhibited carrageenan-induced tissue inflammatory responses, redness and edema of the paw, and leukocyte infiltration. The results of immunohistochemical studies indicate that s.c. sinularin (80 mg/kg) could upregulate production of TGF-β1 in carrageenan-induced inflamed paw tissue. The present results demonstrate that systemic sinularin exerts analgesic effects at the behavioral and spinal levels, which are associated with both inhibition of leukocyte infiltration and upregulation of TGF-β1. PMID:23118711

  6. Protocatechuic Acid Attenuates Osteoclastogenesis by Downregulating JNK/c-Fos/NFATc1 Signaling and Prevents Inflammatory Bone Loss in Mice.

    PubMed

    Park, Sun-Hyang; Kim, Ju-Young; Cheon, Yoon-Hee; Baek, Jong Min; Ahn, Sung-Jun; Yoon, Kwon-Ha; Lee, Myeung Su; Oh, Jaemin

    2016-04-01

    Protocatechuic acid (PCA) plays a critical role in nutritional metabolism; it is a major metabolite of anthocyanins, which are flavonoids with a range of health benefits. PCA has a variety of biological activities including anti-oxidant, antiinflammatory, anti-apoptosis, and anti-microbial activities. However, the pharmacological effect of PCA, especially on osteoclastogenesis, remains unknown. We examined the effect of PCA on receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption. PCA dose-dependently inhibited RANKL-induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and suppressed the bone-resorbing activity of mature osteoclasts. At the molecular level, PCA suppressed RANKL-induced phosphorylation of JNK among MAPKs only, without significantly affecting the early signaling pathway. PCA also suppressed RANKL-stimulated expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1) at the mRNA and protein levels, without altering c-Fos mRNA expression. Additionally, PCA down-regulated the expression of downstream osteoclastogenesis-related genes including β3-integrin, DC-STAMP, OC-STAMP, Atp6v0d2, CTR, and CtsK. Mice treated with PCA efficiently recovered from lipopolysaccharide-induced bone loss in vivo. Thus, PCA inhibits RANKL-induced osteoclast differentiation and function by suppressing JNK signaling, c-Fos stability, and expression of osteoclastic marker genes. These results suggest that PCA could be useful in treatment of inflammatory bone disorders. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26792397

  7. Influence of Age on Brain Edema Formation, Secondary Brain Damage and Inflammatory Response after Brain Trauma in Mice

    PubMed Central

    Timaru-Kast, Ralph; Luh, Clara; Gotthardt, Philipp; Huang, Changsheng; Schäfer, Michael K.; Engelhard, Kristin; Thal, Serge C.

    2012-01-01

    After traumatic brain injury (TBI) elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months) and old (21 months) male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI) on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count) were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2%) compared to young (0%). This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral inflammation

  8. Endothelin receptor antagonists attenuate the inflammatory response of human pulmonary vascular smooth muscle cells to bacterial endotoxin.

    PubMed

    Knobloch, Jürgen; Feldmann, Maria; Wahl, Chiara; Jungck, David; Behr, Jürgen; Stoelben, Erich; Koch, Andrea

    2013-08-01

    Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl][1-(methoxycarbonyl)-d-tryptophyl]amino}hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage-colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteria-induced exacerbations of chronic lung diseases. Inhibition of the endothelin

  9. T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production.

    PubMed

    Jubin, Virginie; Ventre, Erwan; Leverrier, Yann; Djebali, Sophia; Mayol, Katia; Tomkowiak, Martine; Mafille, Julien; Teixeira, Marie; Teoh, Denise Y-L; Lina, Bruno; Walzer, Thierry; Arpin, Christophe; Marvel, Jacqueline

    2012-06-01

    Besides the classically described subsets of memory CD8 T cells generated under infectious conditions, are T inflammatory memory cells generated under sterile priming conditions, such as sensitization to allergens. Although not fully differentiated as pathogen-induced memory cells, they display memory properties that distinguish them from naive CD8 T cells. Given these memory cells are generated in an antigen-specific context that is devoid of pathogen-derived danger signals and CD4 T cell help, we herein questioned whether they maintained their activation and differentiation potential, could be recruited in an immune response directed against a pathogen expressing their cognate antigen and further differentiate in fully competent secondary memory cells. We show that T inflammatory memory cells can indeed take part to the immune response triggered by a viral infection, differentiate into secondary effectors and further generate typical central memory CD8 T cells and effector memory CD8 T cells. Furthermore, the secondary memory cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-α and the XCL1 chemokine. These results suggest that cross-reactive stimulations and differentiation of cells directed against allergens or self into fully competent pathogen-induced memory cells might have incidences in inflammatory immuno-pathologies. PMID:22528127

  10. A retinoic acid receptor agonist Am80 rescues neurons, attenuates inflammatory reactions, and improves behavioral recovery after intracerebral hemorrhage in mice.

    PubMed

    Matsushita, Hideaki; Hijioka, Masanori; Hisatsune, Akinori; Isohama, Yoichiro; Shudo, Koichi; Katsuki, Hiroshi

    2011-01-01

    Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH. PMID:20551971

  11. A retinoic acid receptor agonist Am80 rescues neurons, attenuates inflammatory reactions, and improves behavioral recovery after intracerebral hemorrhage in mice

    PubMed Central

    Matsushita, Hideaki; Hijioka, Masanori; Hisatsune, Akinori; Isohama, Yoichiro; Shudo, Koichi; Katsuki, Hiroshi

    2011-01-01

    Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH. PMID:20551971

  12. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

    PubMed Central

    Jarvis, Michael F.; Honore, Prisca; Shieh, Char-Chang; Chapman, Mark; Joshi, Shailen; Zhang, Xu-Feng; Kort, Michael; Carroll, William; Marron, Brian; Atkinson, Robert; Thomas, James; Liu, Dong; Krambis, Michael; Liu, Yi; McGaraughty, Steve; Chu, Katharine; Roeloffs, Rosemarie; Zhong, Chengmin; Mikusa, Joseph P.; Hernandez, Gricelda; Gauvin, Donna; Wade, Carrie; Zhu, Chang; Pai, Madhavi; Scanio, Marc; Shi, Lei; Drizin, Irene; Gregg, Robert; Matulenko, Mark; Hakeem, Ahmed; Gross, Michael; Johnson, Matthew; Marsh, Kennan; Wagoner, P. Kay; Sullivan, James P.; Faltynek, Connie R.; Krafte, Douglas S.

    2007-01-01

    Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Nav1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC50 = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Nav1.8 (IC50 = 8 nM) and was >100-fold selective vs. human Nav1.2, Nav1.3, Nav1.5, and Nav1.7 (IC50 values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED50 = 47 mg/kg, i.p.), sciatic nerve injury (ED50 = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED50 ≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED50 = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Nav1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain. PMID:17483457

  13. Asiaticoside attenuates the effects of spinal cord injury through antioxidant and anti‑inflammatory effects, and inhibition of the p38‑MAPK mechanism.

    PubMed

    Luo, Yang; Fu, Changfeng; Wang, Zhenyu; Zhang, Zhuo; Wang, Hongxia; Liu, Yi

    2015-12-01

    Asiaticoside has potent pharmacological activity and broader pharmacological effects, including anti‑oxidant, antidepressant and hepatic protection effects, and the inhibition of tumor cell proliferation. However, the mechanism underlying the effects of asiaticoside on neurological pain in spinal cord injury (SCI) remain to be fully elucidated. Therefore, the present study investigated the specific mechanism underlying the beneficial action of asiaticoside in a SCI rat model. In the present study, Basso, Beattie and Bresnahan scores was determined to analyze the therapeutic effects of asiaticoside on the neurological function of the SCI rat model. The water content of the spinal cord was also determined to measure its effects on the SCI rats. Oxidative stress, levels of nitric oxide and inflammation were detected using commercial kits. Western blot analysis was used to measure the protein expression levels of p38‑mitogen‑activated protein kinase (MAPK) in the SCI rat. Asiaticoside effectively augmented the Basso, Beattie and Bresnahan scores of the SCI rats. Significant reductions in the water content of the spinal cord, the levels of inducible nitric oxide synthase (iNOS), and the activities of the nuclear factor‑κB p65 unit, tumor necrosis factor‑α, interleukin(IL)‑1β and IL‑6 were observed in the experimental animals. Furthermore, on examination of the oxidative stress‑associated parameters, increased production of malondialdehyde and decreased levels of superoxide dismutase, glutathione and glutathione peroxidase were detected in the SCI rat model. Asiaticoside also significantly suppressed the expression of p38‑MAPK, which indicated that the therapeutic effects of asiaticoside may be associated with the p38‑MAPK pathway. These data confirmed that asiaticoside attenuates SCI through antioxidant and anti‑inflammatory effects, and through inhibition of the p38‑MAPK mechanism. PMID:26458544

  14. N(6)-(2-Hydroxyethyl)adenosine in the Medicinal Mushroom Cordyceps cicadae Attenuates Lipopolysaccharide-Stimulated Pro-inflammatory Responses by Suppressing TLR4-Mediated NF-κB Signaling Pathways.

    PubMed

    Lu, Meng-Ying; Chen, Chin-Chu; Lee, Li-Ya; Lin, Ting-Wei; Kuo, Chia-Feng

    2015-10-23

    Natural products play an important role in promoting health with relation to the prevention of chronic inflammation. N(6)-(2-Hydroxyethyl)adenosine (HEA), a physiologically active compound in the medicinal mushroom Cordyceps cicadae, has been identified as a Ca(2+) antagonist and shown to control circulation and possess sedative activity in pharmacological tests. The fruiting body of C. cicadae has been widely applied in Chinese medicine. However, neither the anti-inflammatory activities of HEA nor the fruiting bodies of C. cicadae have been carefully examined. In this study, we first cultured the fruiting bodies of C. cicadae and then investigated the anti-inflammatory activities of water and methanol extracts of wild and artificially cultured C. cicadae fruiting bodies. Next, we determined the amount of three bioactive compounds, adenosine, cordycepin, and HEA, in the extracts and evaluated their synergistic anti-inflammatory effects. Moreover, the possible mechanism involved in anti-inflammatory action of HEA isolated from C. cicadae was investigated. The results indicate that cordycepin is more potent than adenosine and HEA in suppressing the lipopolysaccharide (LPS)-stimulated release of pro-inflammatory cytokines by RAW 264.7 macrophages; however, no synergistic effect was observed with these three compounds. HEA attenuated the LPS-induced pro-inflammatory responses by suppressing the toll-like receptor (TLR)4-mediated nuclear factor-κB (NF-κB) signaling pathway. This result will support the use of HEA as an anti-inflammatory agent and C. cicadae fruiting bodies as an anti-inflammatory mushroom. PMID:26394068

  15. Surgical management of malignant cerebral edema secondary to immune reconstitution inflammatory syndrome from natalizumab-associated progressive multifocal encephalopathy.

    PubMed

    Tan, Lee A; Lopes, Demetrius K

    2015-10-01

    We report a rare multiple sclerosis (MS) patient who developed malignant cerebral edema related to progressive multifocal encephalopathy (PML) immune reconstitution inflammatory syndrome (IRIS) after natalizumab discontinuation. The patient subsequently required a decompressive hemicraniectomy to reduce intracranial pressure and to avoid uncal herniation. PML is a demyelinating disease of the central nervous system (CNS) which affects oligodendrocytes and is caused by reactivation of latent John Cunningham virus. Natalizumab is a known risk factor (1 in 1000) for MS patients treated with this drug. Discontinuation of natalizumab treatment decreases the risk of PML progression, but a massive inflammatory response can occur after cell-mediated immune surveillance is reestablished in the CNS, causing immune reconstitution inflammatory syndrome (IRIS). Treatment of IRIS usually consists of steroids and plasma exchange to lessen the immune response, however, mortality has been reported at up to 29.4%, despite aggressive medical treatment. We discuss our management strategy with a review of the pertinent literature. PMID:26115897

  16. Proteomic and Metabolomic Analyses Reveal Contrasting Anti-Inflammatory Effects of an Extract of Mucor Racemosus Secondary Metabolites Compared to Dexamethasone.

    PubMed

    Meier, Samuel M; Muqaku, Besnik; Ullmann, Ronald; Bileck, Andrea; Kreutz, Dominique; Mader, Johanna C; Knasmüller, Siegfried; Gerner, Christopher

    2015-01-01

    Classical drug assays are often confined to single molecules and targeting single pathways. However, it is also desirable to investigate the effects of complex mixtures on complex systems such as living cells including the natural multitude of signalling pathways. Evidence based on herbal medicine has motivated us to investigate potential beneficial health effects of Mucor racemosus (M rac) extracts. Secondary metabolites of M rac were collected using a good-manufacturing process (GMP) approved production line and a validated manufacturing process, in order to obtain a stable product termed SyCircue (National Drug Code USA: 10424-102). Toxicological studies confirmed that this product does not contain mycotoxins and is non-genotoxic. Potential effects on inflammatory processes were investigated by treating stimulated cells with M rac extracts and the effects were compared to the standard anti-inflammatory drug dexamethasone on the levels of the proteome and metabolome. Using 2D-PAGE, slight anti-inflammatory effects were observed in primary white blood mononuclear cells, which were more pronounced in primary human umbilical vein endothelial cells (HUVECs). Proteome profiling based on nLC-MS/MS analysis of tryptic digests revealed inhibitory effects of M rac extracts on pro-inflammatory cytoplasmic mediators and secreted cytokines and chemokines in these endothelial cells. This finding was confirmed using targeted proteomics, here treatment of stimulated cells with M rac extracts down-regulated the secretion of IL-6, IL-8, CXCL5 and GROA significantly. Finally, the modulating effects of M rac on HUVECs were also confirmed on the level of the metabolome. Several metabolites displayed significant concentration changes upon treatment of inflammatory activated HUVECs with the M rac extract, including spermine and lysophosphatidylcholine acyl C18:0 and sphingomyelin C26:1, while the bulk of measured metabolites remained unaffected. Interestingly, the effects of M rac

  17. Proteomic and Metabolomic Analyses Reveal Contrasting Anti-Inflammatory Effects of an Extract of Mucor Racemosus Secondary Metabolites Compared to Dexamethasone

    PubMed Central

    Meier, Samuel M.; Muqaku, Besnik; Ullmann, Ronald; Bileck, Andrea; Kreutz, Dominique; Mader, Johanna C.; Knasmüller, Siegfried; Gerner, Christopher

    2015-01-01

    Classical drug assays are often confined to single molecules and targeting single pathways. However, it is also desirable to investigate the effects of complex mixtures on complex systems such as living cells including the natural multitude of signalling pathways. Evidence based on herbal medicine has motivated us to investigate potential beneficial health effects of Mucor racemosus (M rac) extracts. Secondary metabolites of M rac were collected using a good-manufacturing process (GMP) approved production line and a validated manufacturing process, in order to obtain a stable product termed SyCircue (National Drug Code USA: 10424–102). Toxicological studies confirmed that this product does not contain mycotoxins and is non-genotoxic. Potential effects on inflammatory processes were investigated by treating stimulated cells with M rac extracts and the effects were compared to the standard anti-inflammatory drug dexamethasone on the levels of the proteome and metabolome. Using 2D-PAGE, slight anti-inflammatory effects were observed in primary white blood mononuclear cells, which were more pronounced in primary human umbilical vein endothelial cells (HUVECs). Proteome profiling based on nLC-MS/MS analysis of tryptic digests revealed inhibitory effects of M rac extracts on pro-inflammatory cytoplasmic mediators and secreted cytokines and chemokines in these endothelial cells. This finding was confirmed using targeted proteomics, here treatment of stimulated cells with M rac extracts down-regulated the secretion of IL-6, IL-8, CXCL5 and GROA significantly. Finally, the modulating effects of M rac on HUVECs were also confirmed on the level of the metabolome. Several metabolites displayed significant concentration changes upon treatment of inflammatory activated HUVECs with the M rac extract, including spermine and lysophosphatidylcholine acyl C18:0 and sphingomyelin C26:1, while the bulk of measured metabolites remained unaffected. Interestingly, the effects of M rac

  18. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity

    PubMed Central

    Leus, Niek G.J.; van der Wouden, Petra E.; van den Bosch, Thea; Hooghiemstra, Wouter T.R.; Ourailidou, Maria E.; Kistemaker, Loes E.M.; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J.; Dekker, Frank J.

    2016-01-01

    The increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases. PMID:26993378

  19. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity.

    PubMed

    Leus, Niek G J; van der Wouden, Petra E; van den Bosch, Thea; Hooghiemstra, Wouter T R; Ourailidou, Maria E; Kistemaker, Loes E M; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J; Dekker, Frank J

    2016-05-15

    The increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases. PMID:26993378

  20. Consumption of dairy yogurt with the polysaccharide rhamnogalacturonan from the peel of the Korean citrus hallabong enhances immune function and attenuates the inflammatory response.

    PubMed

    Lee, Mi-Hyang; Kim, Minjoo; Kim, Minkyung; Kwak, Jung Hyun; Chang, Dong Hoon; Yu, Won Kyu; Lee, Sang-Hyun; Lee, Jong Ho

    2016-06-15

    The aim of this study was to investigate the impact of consuming dairy yogurt supplemented with rhamnogalacturonan (RG), a polysaccharide from the peel of the Korean citrus hallabong, on natural killer (NK) cell activity and circulating cytokine levels. A randomized, double-blind, placebo-controlled study was conducted on 120 nondiabetic and nonobese subjects. Over an eight-week period, the test group consumed one pack (150 mL) of dairy yogurt containing 50 mg of probiotics and 100 mg of hallabong peel polysaccharide (60% RG) each day, whereas the placebo group consumed the same product without the hallabong peel supplement. NK cell activity (%) was measured based on the ratios of the effector cells (E; peripheral blood mononuclear cells, PBMCs) from each participant relative to the target cells (T; K562 cells) at E : T ratios of 10 : 1, 5 : 1, 2.5 : 1, or 1.25 : 1. NK cell activities under all assay conditions and interleukin (IL)-12 and interferon (IFN)-γ levels were significantly increased in the test group at eight weeks compared to the baseline values, whereas the placebo group showed a significant increase only in NK cell activity at E : T = 1.25 : 1. The test group had significantly greater increases in the changes in serum NK cell activity at the E : T ratios of 10 : 1, 5 : 1, and 2.5 : 1 and in the increases in IL-12 and IFN-γ levels than were observed in the placebo group, after adjusting for baseline values. After eight weeks of treatment, significant reductions were found in IL-6 and IL-1β levels in both the placebo and test groups. The daily consumption of dairy yogurt supplemented with RG, a polysaccharide from the peel of the Korean citrus hallabong, enhanced NK cell function and attenuated pro-inflammatory cytokine levels (ClinicalTrials.gov: NCT02535663). PMID:27225729

  1. Acute inflammatory response of the male breasts secondary to self-injection of petroleum jelly: a case report.

    PubMed

    Chen, Ming; Yalamanchili, Chandana; Hamous, James; Piskun, Mary A; Weis, Brian

    2008-04-01

    The injection of liquid foreign materials such as petroleum jelly and paraffin oil was used as an early medical intervention for the augmentation of body contour in the late 19th century. These practices were associated with severe late onset complications and they have been abandoned by plastic surgeons today. This article discusses a male-to-female transsexual patient with an acute inflammatory response with early sclerosing lipogranuloma of breasts associated with the self-injection of large amounts of petroleum jelly. The inflammation is successfully controlled with the early administration of prophylactic broad-spectrum antibiotics, steroids, and nonsteroid anti-inflammatory agents followed by a subcutaneous mastectomy. The importance of medical education and psychology counseling is discussed. PMID:18360333

  2. Anti-inflammatory activities of light emitting diode irradiation on collagen-induced arthritis in mice (a secondary publication)

    PubMed Central

    Ohta, Mitsuhiro; Sato, Yusuke; Abiko, Yoshimitsu

    2014-01-01

    Background and aims: Rheumatoid arthritis (RA) is an auto-immune disease afflicting multiple joints of the body, where as a result of the increase in inflammatory cytokines and tissue destructive factors such as matrix metalloproteinase (MMP)-3, deterioration of the bones and cartilages of the joints occurs. The present investigation was carried out to study the anti-inflammatory activities of light emitting diode (LED) irradiation on hind paw inflammation in collagen-induced arthritis (CIA) mice models. Materials and method: RA in the CIA mouse model was induced by immunization of DBA/1J mice with intradermal injections of an emulsion of bovine type II collagen and complete Freund's adjuvant. A total of 20 CIA mice were subdivided into the following groups: control group, CIA group and 2 groups of LED irradiated CIA mice (LED groups) (n=5 per group). The mouse knee joint area in the LED groups (the 570 nm and 940 nm groups) was irradiated with LED energy, three times a week for 500 s per session over 8 weeks at a dose of 5 J/cm2. The hind paw swelling was assessed by the increase in hind paw thickness. The serum levels of the inflammatory cytokines and arthritic factor MMP-3 were determined with an enzyme-linked immunosorbent assay (ELISA). Results: In the LED-570 and LED-940 groups at 4 weeks after arthritis induction, the swelling inhibition index was 18.1±4.9 and 29.3±4.0 respectively. Interleukin (IL)-1β, IL-6 and MMP-3 serum levels were significantly lower in the LED-940 group. Conclusions: LED irradiation, particularly in the near-infrared was effective for inhibition of the inflammatory reactions caused by RA. PMID:25368445

  3. Baicalein attenuates the quorum sensing-controlled virulence factors of Pseudomonas aeruginosa and relieves the inflammatory response in P. aeruginosa-infected macrophages by downregulating the MAPK and NFκB signal-transduction pathways

    PubMed Central

    Luo, Jing; Kong, Jin-liang; Dong, Bi-ying; Huang, Hong; Wang, Ke; Wu, Li-hong; Hou, Chang-chun; Liang, Yue; Li, Bing; Chen, Yi-qiang

    2016-01-01

    Burgeoning antibiotic resistance and unfavorable outcomes of inflammatory injury after Pseudomonas aeruginosa infection have necessitated the development of novel agents that not only target quorum sensing (QS) but also combat inflammatory injury with the least risk of resistance. This study aimed to assess the anti-QS and anti-inflammatory activities of baicalein, a traditional herbal medicine that is widely used in the People’s Republic of China, against P. aeruginosa infection. We found that subminimum inhibitory concentrations of baicalein efficiently interfered with the QS-signaling pathway of P. aeruginosa via downregulation of the transcription of QS-regulated genes and the translation of QS-signaling molecules. This interference resulted in the global attenuation of QS-controlled virulence factors, such as motility and biofilm formation, and the secretion into the culture supernatant of extracellular virulence factors, including pyocyanin, LasA protease, LasB elastase, and rhamnolipids. Moreover, we examined the anti-inflammatory activity of baicalein and its mode of action via a P. aeruginosa-infected macrophage model to address its therapeutic effect. Baicalein reduced the P. aeruginosa-induced secretion of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNFα. In addition, baicalein suppressed P. aeruginosa-induced activation of the MAPK and NFκB signal-transduction pathways in cocultured macrophages; this may be the mechanism by which baicalein inhibits the production of proinflammatory cytokines. Therefore, our study demonstrates that baicalein represents a potential treatment for P. aeruginosa infection because it clearly exhibits both antibacterial and anti-inflammatory activities. PMID:26792984

  4. Melatonin Counteracts at a Transcriptional Level the Inflammatory and Apoptotic Response Secondary to Ischemic Brain Injury Induced by Middle Cerebral Artery Blockade in Aging Rats

    PubMed Central

    Paredes, Sergio D.; Rancan, Lisa; Kireev, Roman; González, Alberto; Louzao, Pedro; González, Pablo; Rodríguez-Bobada, Cruz; García, Cruz; Vara, Elena; Tresguerres, Jesús A.F.

    2015-01-01

    Abstract Aging increases oxidative stress and inflammation. Melatonin counteracts inflammation and apoptosis. This study investigated the possible protective effect of melatonin on the inflammatory and apoptotic response secondary to ischemia induced by blockade of the right middle cerebral artery (MCA) in aging male Wistar rats. Animals were subjected to MCA obstruction. After 24 h or 7 days of procedure, 14-month-old nontreated and treated rats with a daily dose of 10 mg/kg melatonin were sacrificed and right and left hippocampus and cortex were collected. Rats aged 2 and 6 months, respectively, were subjected to the same brain injury protocol, but they were not treated with melatonin. mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX), glial fibrillary acidic protein (GFAP), B-cell lymphoma 2 (Bcl-2), and sirtuin 1 was measured by reverse transcription–polymerase chain reaction. In nontreated animals, a significant time-dependent increase in IL-1β, TNF-α, BAD, and BAX was observed in the ischemic area of both hippocampus and cortex, and to a lesser extent in the contralateral hemisphere. Hippocampal GFAP was also significantly elevated, while Bcl-2 and sirtuin 1 decreased significantly in response to ischemia. Aging aggravated these changes. Melatonin administration was able to reverse significantly these alterations. In conclusion, melatonin may ameliorate the age-dependent inflammatory and apoptotic response secondary to ischemic cerebral injury. PMID:26594596

  5. Cynandione A attenuates lipopolysaccharide-induced production of inflammatory mediators via MAPK inhibition and NF-κB inactivation in RAW264.7 macrophages and protects mice against endotoxin shock.

    PubMed

    Kim, Sung Hwan; Lee, Tae Hoon; Lee, Sang Min; Park, Ji Hae; Park, Keun Hyung; Jung, Mira; Jung, Hana; Mohamed, Mohamed Antar Aziz; Baek, Nam-In; Chung, In Sik; Kim, Jiyoung

    2015-07-01

    Cynanchum wilfordii has been traditionally used in eastern Asia for the treatment of various diseases such as gastrointestinal diseases and arteriosclerosis. Cynandione A (CA), an acetophenone, is one of major constituents from roots of C. wilfordii. In the present study, the anti-inflammatory activities of CA were investigated in lipopolysaccharide (LPS)-treated RAW264.7 macrophages and LPS-administered C57BL/6 N mice. CA significantly decreased LPS-induced production of nitric oxide and prostaglandin E2 in a dose-dependent manner, while CA up to 200 μM did not exhibit cytotoxic activity. Our data also showed that CA significantly attenuated expression of iNOS and COX-2 in LPS-stimulated macrophages. CA inhibited phosphorylation of IκB-α and MAP kinases such as ERK and p38. Furthermore, we demonstrated that CA inhibited translocation of NF-κB to the nucleus, transcription of the NF-κB minimal promoter and NF-κB DNA binding activity. Administration of CA significantly decreased the plasma levels of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β in LPS-injected mice and improved survival of septic mice with lethal endotoxemia. These results demonstrate that CA has effective inhibitory effects on production of inflammatory mediators via suppressing activation of NF-κB and MAPK signaling pathways, suggesting that CA may be used as a potential anti-inflammatory agent for the prevention and treatment of inflammatory diseases. PMID:25361770

  6. Methyl 9-Oxo-(10E,12E)-octadecadienoate Isolated from Fomes fomentarius Attenuates Lipopolysaccharide-Induced Inflammatory Response by Blocking Phosphorylation of STAT3 in Murine Macrophages

    PubMed Central

    Choe, Ji-Hyun; Yi, Young-Joo; Lee, Myeong-Seok; Seo, Dong-Won

    2015-01-01

    Fomes fomentarius is a fungus of the Polyporaceae family and is used in traditional oriental therapies. Although the anti-inflammatory activities of this species have been previously reported, the identity of the bioactive compounds responsible for this activity remains unknown. Here, we investigated whether methyl 9-oxo-(10E,12E)-octadecadienoate (FF-8) purified from F. fomentarius exerts anti-inflammatory activity in murine macrophages stimulated with lipopolysaccharide (LPS). FF-8 suppressed secretion of nitric oxide (NO) and prostaglandin E2 through downregulation of inducible NO synthase and cyclooxygenase-2 expression induced by LPS. In addition, pretreatment of cells with FF-8 led to a reduction in levels of secreted inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in macrophages stimulated with LPS. Conversely, FF-8 did not affect nuclear factor κB, p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase pathways. Instead, FF-8 specifically interfered with signal transducer and activator of transcription 3 (STAT3) phosphorylation induced by LPS. Collectively, this study demonstrated that FF-8 purified from F. fomentarius suppresses inflammatory responses in macrophages stimulated with LPS by inhibiting STAT3 activation. Further studies will be required to elucidate the anti-inflammatory effect of FF-8 in vivo. PMID:26539049

  7. Benzyl alcohol derivatives from the mushroom Hericium erinaceum attenuate LPS-stimulated inflammatory response through the regulation of NF-κB and AP-1 activity.

    PubMed

    Noh, Hyung Jun; Yoon, Ju Young; Kim, Geum Sook; Lee, Seung Eun; Lee, Dae Young; Choi, Je Hun; Kim, Seung Yu; Kang, Ki Sung; Cho, Jae Youl; Kim, Ki Hyun

    2014-10-01

    On the search for anti-inflammatory compounds from natural Korean medicinal sources, a bioassay-guided fractionation and chemical investigation of the MeOH extract from the fruiting bodies of Hericium erinaceum resulted in the isolation and identification of five benzyl alcohol derivatives (1-5). In this study, their anti-inflammatory effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators were examined using RAW 264.7 macrophage cells. The structures of isolates were identified by comparing their spectroscopic data with previously reported values. The analysis of their inhibitory activities on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophage cells showed that erinacerin B (2) and hericenone E (4) decreased the levels of NO and PGE2 production in a concentration-dependent manner. Next, this study was performed to examine their mechanism of action on the regulation of NO and PGE2 production. Compounds 2 and 4 were found to block the LPS-induced phosphorylation of two major inflammatory transcription factors, NF-κB (p65/p50) and AP-1 (c-Jun and c-Fos). Taken together, these results suggest that down-regulation of LPS-induced NO and PGE2 production by compounds 2 and 4 is mediated through the modulation of NF-κB and AP-1 activation in macrophage cells. These results impact the development of potential health products for preventing and treating inflammatory diseases. PMID:25090632

  8. Polyandric acid A, a clerodane diterpenoid from the Australian medicinal plant Dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo.

    PubMed

    Simpson, Bradley S; Luo, Xianling; Costabile, Maurizio; Caughey, Gillian E; Wang, Jiping; Claudie, David J; McKinnon, Ross A; Semple, Susan J

    2014-01-24

    Dodonaea polyandra is a medicinal plant used traditionally by the Kuuku I'yu (Northern Kaanju) indigenous people of Cape York Peninsula, Australia. The most potent of the diterpenoids previously identified from this plant, polyandric acid A (1), has been examined for inhibition of pro-inflammatory cytokine production and other inflammatory mediators using well-established acute and chronic mouse ear edema models and in vitro cellular models. Topical application of 1 significantly inhibited interleukin-1β production in mouse ear tissue in an acute model. In a chronic skin inflammation model, a marked reduction in ear thickness, associated with significant reduction in myeloperoxidase accumulation, was observed. Treatment of primary neonatal human keratinocytes with 1 followed by activation with phorbol ester/ionomycin showed a significant reduction in IL-6 secretion. The present study provides evidence that the anti-inflammatory properties of 1 are due to inhibition of pro-inflammatory cytokines associated with skin inflammation and may be useful in applications for skin inflammatory conditions including psoriasis and dermatitis. PMID:24400858

  9. Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We evaluated whether a water extract of cinnamon (CE = Cinnulin PF®) attenuates the dyslipidemia induced by TNF-alpha in Triton WR-1339-treated hamsters, and whether CE inhibited the over-secretion of apoB48-induced by TNF-alpha in enterocytes in a 35S-labelling study. In vivo, oral treatment with C...

  10. Enhancement of Anti-Inflammatory Activity of Aloe vera Adventitious Root Extracts through the Alteration of Primary and Secondary Metabolites via Salicylic Acid Elicitation

    PubMed Central

    Lee, Yun Sun; Ju, Hyun Kyoung; Kim, Yeon Jeong; Lim, Tae-Gyu; Uddin, Md Romij; Kim, Yeon Bok; Baek, Jin Hong; Kwon, Sung Won; Lee, Ki Won; Seo, Hak Soo; Park, Sang Un; Yang, Tae-Jin

    2013-01-01

    Aloe vera (Asphodeloideae) is a medicinal plant in which useful secondary metabolites are plentiful. Among the representative secondary metabolites of Aloe vera are the anthraquinones including aloe emodin and chrysophanol, which are tricyclic aromatic quinones synthesized via a plant-specific type III polyketide biosynthesis pathway. However, it is not yet clear which cellular responses can induce the pathway, leading to production of tricyclic aromatic quinones. In this study, we examined the effect of endogenous elicitors on the type III polyketide biosynthesis pathway and identified the metabolic changes induced in elicitor-treated Aloe vera adventitious roots. Salicylic acid, methyl jasmonate, and ethephon were used to treat Aloe vera adventitious roots cultured on MS liquid media with 0.3 mg/L IBA for 35 days. Aloe emodin and chrysophanol were remarkably increased by the SA treatment, more than 10–11 and 5–13 fold as compared with untreated control, respectively. Ultra-performance liquid chromatography-electrospray ionization mass spectrometry analysis identified a total of 37 SA-induced compounds, including aloe emodin and chrysophanol, and 3 of the compounds were tentatively identified as tricyclic aromatic quinones. Transcript accumulation analysis of polyketide synthase genes and gas chromatography mass spectrometry showed that these secondary metabolic changes resulted from increased expression of octaketide synthase genes and decreases in malonyl-CoA, which is the precursor for the tricyclic aromatic quinone biosynthesis pathway. In addition, anti-inflammatory activity was enhanced in extracts of SA-treated adventitious roots. Our results suggest that SA has an important role in activation of the plant specific-type III polyketide biosynthetic pathway, and therefore that the efficacy of Aloe vera as medicinal agent can be improved through SA treatment. PMID:24358188

  11. Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli.

    PubMed

    Henriksen, Peter A; Hitt, Mary; Xing, Zhou; Wang, Jun; Haslett, Chris; Riemersma, Rudolph A; Webb, David J; Kotelevtsev, Yuri V; Sallenave, Jean-Michel

    2004-04-01

    Atherosclerosis is a chronic inflammatory disease affecting arterial vessels. Strategies to reduce the inflammatory responses of endothelial cells and macrophages may slow lesion development and prevent complications such as plaque rupture. The human protease human neutrophil elastase (HNE), oxidized low density lipoprotein, LPS, and TNF-alpha were chosen as model stimuli of arterial wall inflammation and led to production of the chemokine IL-8 in endothelial cells. To counteract the activity of HNE, we have examined the effects of adenoviral gene delivery of the anti-elastases elafin, previously demonstrated within human atheroma, and murine secretory leukocyte protease inhibitor (SLPI), a related molecule, on the inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. We developed a technique of precomplexing adenovirus with cationic lipid to augment adenoviral infection efficiency in endothelial cells and to facilitate infection in macrophages. Elafin overexpression protected endothelial cells from HNE-induced IL-8 production and cytotoxicity. Elafin and murine SLPI also reduced endothelial IL-8 release in response to oxidized low density lipoprotein, LPS, and TNF-alpha and macrophage TNF-alpha production in response to LPS. This effect was associated with reduced activation of the inflammatory transcription factor NF-kappaB, through up-regulation of IkappaBalpha, in both cell types. Our work suggests a novel and extended anti-inflammatory role for these HNE inhibitors working as effectors of innate immunity to protect tissues against maladaptive inflammatory responses. Our findings indicate that elafin and SLPI may be gene therapy targets for the treatment of atheroma. PMID:15034071

  12. Attenuation of Inflammatory Mediators (TNF-α and Nitric Oxide) and Up-Regulation of IL-10 by Wild and Domesticated Basidiocarps of Amauroderma rugosum (Blume & T. Nees) Torrend in LPS-Stimulated RAW264.7 Cells

    PubMed Central

    2015-01-01

    Amauroderma rugosum, commonly known as “Jiǎzī” in China, is a wild mushroom traditionally used by the Chinese to reduce inflammation, to treat diuretic and upset stomach, and to prevent cancer. It is also used by the indigenous communities in Malaysia to prevent epileptic episodes and incessant crying by babies. The aim of this study was to compare the wild and domesticated basidiocarps of A. rugosum for antioxidant and in vitro anti-inflammatory effects in LPS-stimulated RAW264.7 cells. The wild basidiocarps of A. rugosum were collected from the Belum Forest, Perak, Malaysia and the domesticated basidiocarps of A. rugosum were cultivated in the mushroom house located in the University of Malaya, Kuala Lumpur, Malaysia. Both the wild and domesticated basidiocarps were subjected to ethanolic extraction and the extracts were tested for antioxidant and anti-inflammatory activities. In this study, the crude ethanolic extract of wild (WB) and domesticated (DB) basidiocarps of A. rugosum had comparable total phenolic content and DPPH scavenging activity. However, WB (EC50 = 222.90 μg/mL) displayed a better ABTS cation radical scavenging activity than DB (EC50 = 469.60 μg/mL). Both WB and DB were able to scavenge nitric oxide (NO) radical and suppress the NO production in LPS-stimulated RAW264.7 cells and this effect was mediated through the down-regulation of inducible nitric oxide synthase (iNOS) gene. In addition, both WB and DB caused down-regulation of the inflammatory gene TNF-α and the up-regulation of the anti-inflammatory gene IL-10. There was no inhibitory effect of WB and DB on nuclear translocation of NF-κB p65. In conclusion, the wild and domesticated basidiocarps of A. rugosum possessed antioxidant and in vitro anti-inflammatory properties. WB and DB inhibited downstream inflammatory mediators (TNF-α and NO) and induced anti-inflammatory cytokine IL-10 production. No inhibitory effects shown on upstream nuclear translocation of NF-κB p65. WB and

  13. Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair.

    PubMed

    Mohajeri, Maryam; Sadeghizadeh, Majid; Najafi, Farhood; Javan, Mohammad

    2015-12-01

    Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of central nervous system (CNS). Polyphenol curcumin has been used in traditional medicine as an effective drug for a variety of diseases. Different formulations of curcumin are introduced to increase its stability and effectiveness. Here we have examined the effect of polymerized form of nano-curcumin (PNC) on experimental autoimmune encephalomyelitis (EAE) as an animal model of MS. EAE was induced in female Lewis rats and PNC or curcumin was daily administrated intraperitonealy from day 12-29 post immunization. When the prophylactic effect of PNC was under investigation, rats received PNC from the first day of immunization. Treatment with PNC resulted in decreased scores of disease in therapeutic and prophylactic administration when compared with control group. Staining by luxol fast blue and H&E and immuno-staining of lumbar spinal cord cross sections, confirmed a significant decrease in the amounts of demyelination, inflammation and BBB breaking down. Gene expression studies in lumbar spinal cord showed a corrected balance of pro-inflammatory and anti-inflammatory genes expression, decreased oxidative stress, improved remyelination and increased progenitor cell markers after treatment with PNC. Our results demonstrated an efficient therapeutic effect of PNC as an anti-inflammatory and anti-oxidative stress agent, with significant effects on the EAE scores and myelin repair mechanisms. PMID:26211978

  14. Hederagenin, a major component of Clematis mandshurica Ruprecht root, attenuates inflammatory responses in RAW 264.7 cells and in mice.

    PubMed

    Lee, Chul Won; Park, Sang Mi; Zhao, Rongjie; Lee, Chu; Chun, Wonjoo; Son, Yonghae; Kim, Sung Hun; Jung, Ji Yun; Jegal, Kyung Hwan; Cho, Il Je; Ku, Sae Kwang; Kim, Young Woo; Ju, Seong A; Kim, Sang Chan; An, Won G

    2015-12-01

    Clematis mandshurica Ruprecht root has been used in Asia as a traditional anti-inflammatory, analgesic, and antitumor agent. Its main active component is hederagenin, a naturally occurring triterpene, and in this study, we examined the anti-inflammatory effects of hederagenin in lipopolysaccharide-stimulated RAW 264.7 cells using an enzyme-linked immunosorbent assay, Western blot, and RT-PCR. In addition, its effects on acute inflammation in vivo were observed using a carrageenan-induced mouse hind paw edema assay. Furthermore, the changes on the histopathology and histomorphometry of hind paw skins were examined using carrageenan-treated mice. Treatment with hederagenin (10, 30 and 100μM) resulted in inhibited levels of protein expression of lipopolysaccharide-stimulated iNOS, COX-2, and NF-κB as well as production of NO, PGE2, TNF-α, IL-1β, and IL-6 induced by lipopolysaccharide. Consistent with these results, hederagenin also dose-dependently reduced the lipopolysaccharide-induced mRNA levels of iNOS and COX-2, and of the above-mentioned cytokines. Interestingly, results of the carrageenan-induced mouse hind paw edema assay showed an anti-edema effect of hederagenin. Furthermore, hederagenin (30mg/kg) inhibited the carrageenan-induced increases in skin thicknesses, infiltrated inflammatory cells, and mast cell degranulation. These results suggest that hederagenin may possess anti-inflammatory activities. PMID:26481049

  15. MK615 attenuates Porphyromonas gingivalis lipopolysaccharide-induced pro-inflammatory cytokine release via MAPK inactivation in murine macrophage-like RAW264.7 cells.

    PubMed

    Morimoto, Yoko; Kikuchi, Kiyoshi; Ito, Takashi; Tokuda, Masayuki; Matsuyama, Takashi; Noma, Satoshi; Hashiguchi, Teruto; Torii, Mitsuo; Maruyama, Ikuro; Kawahara, Ko-Ichi

    2009-11-01

    The Japanese apricot, known as Ume in Japanese, has been a traditional Japanese medicine for centuries, and is a familiar and commonly consumed food. The health benefits of Ume are now being widely recognized and have been strengthened by recent studies showing that MK615, an extract of compounds from Ume, has strong anticancer and anti-inflammatory effects. However, the potential role of MK615 in the periodontal field remains unknown. Here, we found that MK615 significantly reduced the production of pro-inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) induced by Porphyromonas gingivalis lipopolysaccharide (LPS), a major etiological agent in localized chronic periodontitis, in murine macrophage-like RAW264.7 cells. MK615 markedly inhibited the phosphorylation of ERK1/2, p38MAPK, and JNK, which is associated with pro-inflammatory mediator release pathways. Moreover, MK615 completely blocked LPS-triggered NF-kappaB activation. The present results suggest that MK615 has potential as a therapeutic agent for treating inflammatory diseases such as periodontitis. PMID:19706286

  16. Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1

    PubMed Central

    Sun, Grace Y.; Chen, Zihong; Jasmer, Kimberly J.; Chuang, Dennis Y.; Gu, Zezong; Hannink, Mark; Simonyi, Agnes

    2015-01-01

    A large group of flavonoids found in fruits and vegetables have been suggested to elicit health benefits due mainly to their anti-oxidative and anti-inflammatory properties. Recent studies with immune cells have demonstrated inhibition of these inflammatory responses through down-regulation of the pro-inflammatory pathway involving NF-κB and up-regulation of the anti-oxidative pathway involving Nrf2. In the present study, the murine BV-2 microglial cells were used to compare anti-inflammatory activity of quercetin and cyanidin, two flavonoids differing by their alpha, beta keto carbonyl group. Quercetin was 10 folds more potent than cyanidin in inhibition of lipopolysaccharide (LPS)-induced NO production as well as stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression. In addition, quercetin demonstrated enhanced ability to stimulate HO-1 protein expression when cells were treated with LPS. In an attempt to unveil mechanism(s) for quercetin to enhance Nrf2/HO-1 activity under endotoxic stress, results pointed to an increase in phospho-p38MAPK expression upon addition of quercetin to LPS. In addition, pharmacological inhibitors for phospho-p38MAPK and MEK1/2 for ERK1/2 further showed that these MAPKs target different sites of the Nrf2 pathway that regulates HO-1 expression. However, inhibition of LPS-induced NO by quercetin was not fully reversed by TinPPIX, a specific inhibitor for HO-1 activity. Taken together, results suggest an important role of quercetin to regulate inflammatory responses in microglial cells and its ability to upregulate HO-1 against endotoxic stress through involvement of MAPKs. PMID:26505893

  17. Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain.

    PubMed

    Cevey, Ágata Carolina; Mirkin, Gerardo Ariel; Penas, Federico Nicolás; Goren, Nora Beatriz

    2016-04-01

    Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE. PMID:26862474

  18. Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain

    PubMed Central

    Cevey, Ágata Carolina; Mirkin, Gerardo Ariel; Penas, Federico Nicolás; Goren, Nora Beatriz

    2015-01-01

    Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE. PMID:26862474

  19. Effect of vitamin D supplementation on selected inflammatory biomarkers in older adults: a secondary analysis of data from a randomised, placebo-controlled trial.

    PubMed

    Waterhouse, Mary; Tran, Bich; Ebeling, Peter R; English, Dallas R; Lucas, Robyn M; Venn, Alison J; Webb, Penelope M; Whiteman, David C; Neale, Rachel E

    2015-09-14

    Observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) levels are associated with inflammatory markers. Most trials reporting significant associations between vitamin D intake and inflammatory markers used specific patient groups. Thus, we aimed to determine the effect of supplementary vitamin D using secondary data from a population-based, randomised, placebo-controlled, double-blind trial (Pilot D-Health trial 2010/0423). Participants were 60- to 84-year-old residents of one of the four eastern states of Australia. They were randomly selected from the electoral roll and were randomised to one of three trial arms: placebo (n 214), 750 μg (n 215) or 1500 μg (n 215) vitamin D3, each taken once per month for 12 months. Post-intervention blood samples for the analysis of C-reactive protein (CRP), IL-6, IL-10, leptin and adiponectin levels were available for 613 participants. Associations between intervention group and biomarker levels were evaluated using quantile regression. There were no statistically significant differences in distributions of CRP, leptin, adiponectin, leptin:adiponectin ratio or IL-10 levels between the placebo group and either supplemented group. The 75th percentile IL-6 level was 2·8 pg/ml higher (95 % CI 0·4, 5·8 pg/ml) in the 1500 μg group than in the placebo group (75th percentiles:11·0 v. 8·2 pg/ml), with a somewhat smaller, non-significant difference in 75th percentiles between the 750 μg and placebo groups. Despite large differences in serum 25(OH)D levels between the three groups after 12 months of supplementation, we found little evidence of an effect of vitamin D supplementation on cytokine or adipokine levels, with the possible exception of IL-6. PMID:26206095

  20. Anti-inflammatory mechanisms of apolipoprotein A-I mimetic peptide in acute respiratory distress syndrome secondary to sepsis.

    PubMed

    Sharifov, Oleg F; Xu, Xin; Gaggar, Amit; Grizzle, William E; Mishra, Vinod K; Honavar, Jaideep; Litovsky, Silvio H; Palgunachari, Mayakonda N; White, C Roger; Anantharamaiah, G M; Gupta, Himanshu

    2013-01-01

    Acute respiratory distress syndrome (ARDS) due to sepsis has a high mortality rate with limited treatment options. High density lipoprotein (HDL) exerts innate protective effects in systemic inflammation. However, its role in ARDS has not been well studied. Peptides such as L-4F mimic the secondary structural features and functions of apolipoprotein (apo)A-I, the major protein component of HDL. We set out to measure changes in HDL in sepsis-mediated ARDS patients, and to study the potential of L-4F to prevent sepsis-mediated ARDS in a rodent model of lipopolysaccharide (LPS)-mediated acute lung injury, and a combination of primary human leukocytes and human ARDS serum. We also analyzed serum from non-lung disease intubated patients (controls) and sepsis-mediated ARDS patients. Compared to controls, ARDS demonstrates increased serum endotoxin and IL-6 levels, and decreased HDL, apoA-I and activity of anti-oxidant HDL-associated paraoxanase-1. L-4F inhibits the activation of isolated human leukocytes and neutrophils by ARDS serum and LPS in vitro. Further, L-4F decreased endotoxin activity and preserved anti-oxidant properties of HDL both in vitro and in vivo. In a rat model of severe endotoxemia, L-4F significantly decreased mortality and reduces lung and liver injury, even when administered 1 hour post LPS. Our study suggests the protective role of the apoA-I mimetic peptide L-4F in ARDS and gram-negative endotoxemia and warrant further clinical evaluation. The main protective mechanisms of L-4F are due to direct inhibition of endotoxin activity and preservation of HDL anti-oxidant activity. PMID:23691230

  1. MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis

    PubMed Central

    Wang, Yi; Shan, Xiaoou; Chen, Gaozhi; Jiang, Lili; Wang, Zhe; Fang, Qilu; Liu, Xing; Wang, Jingying; Zhang, Yali; Wu, Wencan; Liang, Guang

    2015-01-01

    Background and Purpose Myeloid differentiation 2 (MD-2) recognizes LPS, which is required for TLR4 activation, and represents an attractive therapeutic target for severe inflammatory disorders. We previously found that a chalcone derivative, L6H21, could inhibit LPS-induced overexpression of TNF-α and IL-6 in macrophages. Here, we performed a series of biochemical experiments to investigate whether L6H21 specifically targets MD-2 and inhibits the interaction and signalling transduction of LPS-TLR4/MD-2. Experimental Approach The binding affinity of L6H21 to MD-2 protein was analysed using computer docking, surface plasmon resonance analysis, elisa, fluorescence measurements and flow cytometric analysis. The effects of L6H21 on MAPK and NF-κB signalling were determined using EMSA, fluorescence staining, Western blotting and immunoprecipitation. The anti-inflammatory effects of L6H21 were confirmed using elisa and RT-qPCR in vitro. The anti-inflammatory effects of L6H21 were also evaluated in septic C57BL/6 mice. Key Results Compound L6H21 inserted into the hydrophobic region of the MD-2 pocket, forming hydrogen bonds with Arg90 and Tyr102 in the MD-2 pocket. In vitro, L6H21 subsequently suppressed MAPK phosphorylation, NF-κB activation and cytokine expression in macrophages stimulated by LPS. In vivo, L6H21 pretreatment improved survival, prevented lung injury, decreased serum and hepatic cytokine levels in mice subjected to LPS. In addition, mice with MD-2 gene knockout were universally protected from the effects of LPS-induced septic shock. Conclusions and Implications Overall, this work demonstrated that the new chalcone derivative, L6H21, is a potential candidate for the treatment of sepsis. More importantly, the data confirmed that MD-2 is an important therapeutic target for inflammatory disorders. PMID:26076332

  2. Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts and collagen-induced arthritis in mouse model.

    PubMed

    Moon, Dong-Oh; Kim, Mun-Ok; Choi, Yung Hyun; Park, Yung-Min; Kim, Gi-Young

    2010-05-01

    Curcumin, a major component of turmeric, has been shown to exhibit anti-oxidant and anti-inflammatory activities. The present study was performed to determine whether curcumin is efficacious against both collagen-induced arthritis (CIA) in mice and IL-1beta-induced activation in fibroblast-like synoviocytes (FLSs). DBA/1 mice were immunized with bovine type II collagen (CII) and treated with curcumin every other day for 2weeks after the initial immunization. For arthritis, we evaluated the incidence of disease and used an arthritis index based on paw thickness. In vitro proliferation of CII- or concanavalin A-induced splenic T cells was examined using IFN-gamma production. Pro-inflammatory cytokines TNF-alpha and IL-1beta were examined in the mouse ankle joint and serum IgG1 and IgG2a isotypes were analyzed. The expression levels of prostaglandin E(2) (PGE(2)), cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) in human FLSs were also determined. The results showed that compared with untreated CIA mice, curcumin-treated mice downregulated clinical arthritis score, the proliferation of splenic T cells, expression levels of TNF-alpha and IL-1beta in the ankle joint, and expression levels of IgG2a in serum. Additionally, by altering nuclear factor (NF)-kappaB transcription activity in FLSs, curcumin inhibited PGE(2) production, COX-2 expression, and MMP secretion. These results suggest that curcumin can effectively suppress inflammatory response by inhibiting pro-inflammatory mediators and regulating humoral and cellular immune responses. PMID:20188213

  3. St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

    SciTech Connect

    Hu Zeping; Yang Xiaoxia; Chan Suiyung; Xu Anlong; Duan Wei; Zhu Yizhun; Sheu, F.-S.; Boelsterli, Urs Alex; Chan, Eli; Zhang Qiang; Wang, J.-C.; Ee, Pui Lai Rachel; Koh, H.L.; Huang Min; Zhou Shufeng . E-mail: phazsf@nus.edu.sg

    2006-10-15

    Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1{beta}, IL-2, IL-6), interferon (IFN-{gamma}) and tumor necrosis factor-{alpha} (TNF-{alpha}) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1{beta}, IL-2, IL-6, IFN-{gamma} and TNF-{alpha} and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1{beta}, IFN-{gamma} and TNF-{alpha} was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-{alpha} mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.

  4. Autophagy attenuates the catabolic effect during inflammatory conditions in nucleus pulposus cells, as sustained by NF-κB and JNK inhibition

    PubMed Central

    XU, KANG; CHEN, WEIJIAN; WANG, XIAOFEI; PENG, YAN; LIANG, ANJING; HUANG, DONGSHENG; LI, CHUNHAI; YE, WEI

    2015-01-01

    Proteoglycan degradation contributing to the pathogenesis of intervertebral disc (IVD) degeneration is induced by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Cell autophagy exists in degenerative diseases, including osteoarthritis and inter-vertebral disc degeneration. However, the autophagy induced by TNF-α and IL-1β and the corresponding molecular mechanism appear to be cell-type dependent. The effect and mechanism of autophagy regulated by TNF-α and IL-1β in IVDs remains unclear. Additionally, the impact of autophagy on the catabolic effect in inflammatory conditions also remains elusive. In the present study, autophagy activator and inhibitor were used to demonstrate the impact of autophagy on the catabolic effect induced by TNF-α. A critical role of autophagy was identified in rat nucleus pulposus (NP) cells: Inhibition of autophagy suppresses, while activation of autophagy enhances, the catabolic effect of cytokines. Subsequently, the autophagy-related gene expression in rat NP cells following TNF-α and IL-1β treatment was observed using immunofluorescence, quantitative polymerase chain reaction and western blot analysis; however, no association was present. In addition, nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases and p38 mitogen-activated protein kinase inhibitors and TNF-α were used to determine the molecular mechanism of autophagy during the inflammatory conditions, and only the NF-κB and JNK inhibitor were found to enhance the autophagy of rat NP cells. Finally, IKKβ knockdown was used to further confirm the effect of the NF-κB signal on human NP cells autophagy, and the data showed that IKKβ knockdown upregulated the autophagy of NP cells during inflammatory conditions. PMID:26165348

  5. The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response.

    PubMed

    Xian, Wenjing; Wu, Yan; Xiong, Wei; Li, Longyan; Li, Tong; Pan, Shangwen; Song, Limin; Hu, Lisha; Pei, Lei; Yao, Shanglong; Shang, You

    2016-03-25

    Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brain tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. PMID:26915798

  6. Lactobacillus rhamnosus GR-1 Limits Escherichia coli-Induced Inflammatory Responses via Attenuating MyD88-Dependent and MyD88-Independent Pathway Activation in Bovine Endometrial Epithelial Cells.

    PubMed

    Liu, Mingchao; Wu, Qiong; Wang, Mengling; Fu, Yunhe; Wang, Jiufeng

    2016-08-01

    Intrauterine Escherichia coli infection after calving reduces fertility and causes major economic losses in the dairy industry. We investigated the protective effect of the probiotic Lactobacillus rhamnosus GR-1 on E. coli-induced cell damage and inflammation in primary bovine endometrial epithelial cells (BEECs). L. rhamnosus GR-1 reduced ultrastructure alterations and the percentage of BEECs apoptosis after E. coli challenge. Increased messenger RNA (mRNA) expression of immune response indicators, including pattern recognition receptors (toll-like receptor [TLR]2, TLR4, nucleotide-binding oligomerization domain [NOD]1, and NOD2), inflammasome proteins (NOD-like receptor family member pyrin domain-containing protein 3, apoptosis-associated speck-like protein, and caspase-1), TLR4 downstream adaptor molecules (myeloid differentiation antigen 88 [MyD88], toll-like receptor adaptor molecule 2 [TICAM2]), nuclear transcription factor kB (NF-kB), and the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-18, and interferon (IFN)-β, was observed following E. coli challenge. However, these increases were attenuated by L. rhamnosus GR-1 pretreatment. Our data indicate that L. rhamnosus GR-1 ameliorates the E. coli-induced disruption of cellular ultrastructure, subsequently reducing the percentage of BEECs apoptosis and limiting inflammatory responses, partly via attenuation of MyD88-dependent and MyD88-independent pathway activation. Certain probiotics could potentially prevent postpartum uterine diseases in dairy cows, ultimately reducing the use of antibiotics. PMID:27236308

  7. Recombinant bovine respiratory syncytial virus with deletion of the SH gene induces increased apoptosis and pro-inflammatory cytokines in vitro, and is attenuated and induces protective immunity in calves

    PubMed Central

    Wyld, Sara; Valarcher, Jean-Francois; Guzman, Efrain; Thom, Michelle; Widdison, Stephanie; Buchholz, Ursula J.

    2014-01-01

    Bovine respiratory syncytial virus (BRSV) causes inflammation and obstruction of the small airways, leading to severe respiratory disease in young calves. The virus is closely related to human (H)RSV, a major cause of bronchiolitis and pneumonia in young children. The ability to manipulate the genome of RSV has provided opportunities for the development of stable, live attenuated RSV vaccines. The role of the SH protein in the pathogenesis of BRSV was evaluated in vitro and in vivo using a recombinant (r)BRSV in which the SH gene had been deleted. Infection of bovine epithelial cells and monocytes with rBRSVΔSH, in vitro, resulted in an increase in apoptosis, and higher levels of TNF-α and IL-1β compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSVΔSH and WT rBRSV, in vitro, were similar, the replication of rBRSVΔSH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSVΔSH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSVΔSH-infected calves was significantly reduced compared with that in calves inoculated with WT rBRSV, 6 days previously. Virus lacking SH appeared to be as immunogenic and effective in inducing resistance to virulent virus challenge, 6 months later, as the parental rBRSV. These findings suggest that rBRSVΔSH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity. PMID:24700100

  8. Attenuating effect of Acorus calamus extract in chronic constriction injury induced neuropathic pain in rats: an evidence of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory effects

    PubMed Central

    2011-01-01

    Background Acorus calamus (family: Araceae), is an indigenous plant, traditionally it is used as an ingredient of various cocktail preparations and for the management of severe inflammatory disorders in Indian system of medicine. Present study investigated the attenuating role of Acorus calamus plant extract in chronic constriction injury (CCI) of sciatic nerve induced peripheral neuropathy in rats. Methods Hot plate, plantar, Randall Selitto, Von Frey Hair, pin prick, acetone drop, photoactometer and rota-rod tests were performed to assess degree of thermal, radiant, mechanical, chemical sensation, spontaneous motor activity and motor co-ordination changes respectively, at different time intervals i.e., day 0, 1, 3, 6, 9, 12, 15, 18 and 21. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after 21st day to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) were administered from the day of surgery for 14 days. Results CCI of sciatic nerve significantly induced thermal, radiant, mechanical hyperalgesia and thermal, chemical, tactile allodynia, along with increase in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover significant histological changes were also observed. HAE-AC attenuated CCI induced development of painful behavioural, biochemical and histological changes in a dose dependent manner similar to that of pregabalin serving as positive control. Conclusions Acorus calamus prevented CCI induced neuropathy which may be attributed to its multiple actions including anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions. PMID:21426568

  9. Flavonoid fraction of guava leaf extract attenuates lipopolysaccharide-induced inflammatory response via blocking of NF-κB signalling pathway in Labeo rohita macrophages.

    PubMed

    Sen, Shib Sankar; Sukumaran, V; Giri, Sib Sankar; Park, Se Chang

    2015-11-01

    Psidium guajava L. is a well-known traditional medicinal plant widely used in folk medicine. To explore the anti-inflammatory activity of the flavonoid fraction of guava leaf extract (FGLE), we investigated its ability to suppress the levels of inflammatory mediators elevated by lipopolysaccharide (LPS) in Labeo rohita head-kidney (HK) macrophages. HK macrophages of L. rohita were treated with LPS in the presence or absence of the FGLE. We examined the inhibitory effect of FGLE on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. The inhibitory effect of FGLE on nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were investigated by RT-PCR and western blot. The effect of FGLE on proinflammatory cytokines tumour necrosis factor alpha (TNF-α) or interleukin-1β (IL-1β) was also investigated by ELISA and RT-PCR. The phosphorylation of three mitogen activated protein kinases (MAPK) molecules ERK, JNK and p38 was analysed by western blot analysis. FGLE inhibited LPS-induced NO and PGE2 production. It also effectively inhibited TNF-α, IL-1β, IL-10, iNOS, and COX-2 production in a concentration-dependent manner. In addition, FGLE suppressed the mRNA expression levels of TNF-α and IL-1β in LPS-stimulated HK macrophages. RT-PCR and western blot analysis showed that FGLE decreased both the mRNA and protein expression levels of LPS-induced iNOS and COX-2 in HK macrophages. FGLE suppresses the phosphorylation of MAPK molecules in LPS-stimulated HK macrophages. FGLE also significantly inhibited LPS-induced NF-κB transcriptional activity. The molecular mechanism by which FGLE suppresses the expression of inflammatory mediators appears to involve the inhibition of NF-κB activation, through the suppression of LPS-induced IκB-α degradation. Together these results suggest that FGLE contains potential therapeutic agent(s), which regulate NF-κB activation, for the treatment of inflammatory conditions in L. rohita macrophages. PMID:26327113

  10. 4(α-l-rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical that attenuates secondary damage in an experimental model of spinal cord injury.

    PubMed

    Giacoppo, Sabrina; Galuppo, Maria; De Nicola, Gina Rosalinda; Iori, Renato; Bramanti, Placido; Mazzon, Emanuela

    2015-01-01

    4(α-l-Rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) is released from the precursor 4(α-l-rhamnosyloxy)-benzyl glucosinolate (glucomoringin; GMG) by myrosinase (β-thioglucoside glucohydrolase; E.C. 3.2.1.147) catalyzed hydrolysis. GMG is an uncommon member of the glucosinolate group as it presents a unique characteristic consisting in a second glycosidic residue within the side chain. It is a typical glucosinolate found in large amounts in the seeds of Moringa oleifera Lam., the most widely distributed plant of the Moringaceae family. GMG was purified from seed-cake of M. oleifera and was hydrolyzed by myrosinase at neutral pH in order to form the corresponding GMG-ITC. This bioactive phytochemical can play a key role in counteracting the inflammatory response connected to the oxidative-related mechanisms as well as in the control of the neuronal cell death process, preserving spinal cord tissues after injury in mice. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24g) for 1 min., via four-level T5-T8 after laminectomy. In particular, the purpose of this study was to investigate the dynamic changes occurring in the spinal cord after ip treatment with bioactive GMG-ITC produced 15 min before use from myrosinase-catalyzed hydrolysis of GMG (10mg/kg body weight+5 μl Myr mouse/day). The following parameters, such as histological damage, distribution of reticular fibers in connective tissue, nuclear factor (NF)-κB translocation and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) degradation, expression of inducible Nitric Oxide Synthases (iNOS), as well as apoptosis, were evaluated. In conclusion, our results show a protective effect of bioactive GMG-ITC on the secondary damage, following spinal cord injury, through an antioxidant mechanism of neuroprotection. Therefore, the bioactive phytochemical GMG-ITC freshly produced before use by myrosinase

  11. Withania somnifera and Its Withanolides Attenuate Oxidative and Inflammatory Responses and Up-Regulate Antioxidant Responses in BV-2 Microglial Cells.

    PubMed

    Sun, Grace Y; Li, Runting; Cui, Jiankun; Hannink, Mark; Gu, Zezong; Fritsche, Kevin L; Lubahn, Dennis B; Simonyi, Agnes

    2016-09-01

    Withania somnifera (L.) Dunal, commonly known as Ashwagandha, has been used in Ayurvedic medicine for promoting health and quality of life. Recent clinical trials together with experimental studies indicated significant neuroprotective effects of Ashwagandha and its constituents. This study is aimed to investigate anti-inflammatory and anti-oxidative properties of this botanical and its two withanolide constituents, namely, Withaferin A and Withanolide A, using the murine immortalized BV-2 microglial cells. Ashwagandha extracts not only effectively inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) and reactive oxygen species (ROS) production in BV-2 cells, but also stimulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, leading to induction of heme oxygenase-1 (HO-1), both in the presence and absence of LPS. Although the withanolides were also capable of inhibiting LPS-induced NO production and stimulating Nrf2/HO-1 pathway, Withaferin A was tenfold more effective than Withanolide A. In serum-free culture, LPS can also induce production of long thin processes (filopodia) between 4 and 8 h in BV-2 cells. This morphological change was significantly suppressed by Ashwagandha and both withanolides at concentrations for suppressing LPS-induced NO production. Taken together, these results suggest an immunomodulatory role for Ashwagandha and its withanolides, and their ability to suppress oxidative and inflammatory responses in microglial cells by simultaneously down-regulating the NF-kB and upregulating the Nrf2 pathways. PMID:27209361

  12. Citrus bergamia Juice Extract Attenuates β-Amyloid-Induced Pro-Inflammatory Activation of THP-1 Cells Through MAPK and AP-1 Pathways

    PubMed Central

    Currò, Monica; Risitano, Roberto; Ferlazzo, Nadia; Cirmi, Santa; Gangemi, Chiara; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

    2016-01-01

    Flavonoids have been shown to be effective in protecting against age-related cognitive and motor decline in both in vitro and in vivo models. Recently, a flavonoid-rich extract of Citrus bergamia juice (BJe) has been shown to display anti-oxidant and anti-inflammatory properties against LPS-induced activation of human THP-1 monocytes. In the light of these observations, we wondered whether BJe may be beneficial against neuroinflammatory processes, such as those observed in Alzheimer’s disease. To this aim we used THP-1 monocytes to investigate the mechanisms underlying the beneficial potential of BJe against amyloid-beta1–42 (Aβ1−42) -mediated inflammation. Exposure of THP-1 cells to Aβ1−42 significantly induced the expression and secretion of IL-6 and IL-1β in THP-1 cells and increased the phosphorylation of ERK 1/2 as well as p46 and p54 members of JNK family. Moreover, Aβ1−42 raises AP-1 DNA binding activity in THP-1-treated cells. Interestingly, all these effects were reduced in the presence of BJe. Our data indicate that BJe may effectively counteract the pro-inflammatory activation of monocytes/microglial cells exposed to amyloid fibrils, suggesting a promising role as a natural drug against neuroinflammatory processes. PMID:26853104

  13. IMM-H004, a novel coumarin derivative compound, attenuates the production of inflammatory mediatory mediators in lipopolysaccharide-activated BV2 microglia.

    PubMed

    Song, Xiu-Yun; Hu, Jin-Feng; Sun, Ming-Na; Li, Zhi-Peng; Zhu, Zhi-Xiang; Song, Lian-Kun; Yuan, Yu-He; Liu, Gang; Chen, Nai-Hong

    2014-07-01

    Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) is a novel compound and has been reported exerting potent neuroprotective effects which may be related to anti-inflammation. In the present study, the anti-inflammatory effects of IMM-H004 were investigated in lipopolysaccharide (LPS)-treated BV2 microglia. Our observations indicated that treatment with IMM-H004 significantly inhibited BV2 microglia activation, protected PC12 cells and primary neurons against indirect toxicity mediated by exposure to conditioned medium (CM) from LPS-treated BV2 cells. Additionally, IMM-H004 significantly suppressed the release of TNF-α, IL-1β and NO, and suppressed the expression of pro-inflammatory mediators and cytokines such as iNOS, COX-2, and IL-6 in LPS-stimulated BV2 microglia. The nuclear translocation of NF-κB and the phosphorylation level of JNK and p38 MAPK pathways were also inhibited by IMM-H004 in LPS-treated BV2 microglia. Moreover, IMM-H004 also was a strong selective OH scavenger whose effect was similar with vitamin C. Overall, our findings suggested that IMM-H004 might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation. PMID:24878446

  14. Citrus bergamia Juice Extract Attenuates β-Amyloid-Induced Pro-Inflammatory Activation of THP-1 Cells Through MAPK and AP-1 Pathways.

    PubMed

    Currò, Monica; Risitano, Roberto; Ferlazzo, Nadia; Cirmi, Santa; Gangemi, Chiara; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

    2016-01-01

    Flavonoids have been shown to be effective in protecting against age-related cognitive and motor decline in both in vitro and in vivo models. Recently, a flavonoid-rich extract of Citrus bergamia juice (BJe) has been shown to display anti-oxidant and anti-inflammatory properties against LPS-induced activation of human THP-1 monocytes. In the light of these observations, we wondered whether BJe may be beneficial against neuroinflammatory processes, such as those observed in Alzheimer's disease. To this aim we used THP-1 monocytes to investigate the mechanisms underlying the beneficial potential of BJe against amyloid-beta1-42 (Aβ1-42) -mediated inflammation. Exposure of THP-1 cells to Aβ1-42 significantly induced the expression and secretion of IL-6 and IL-1β in THP-1 cells and increased the phosphorylation of ERK 1/2 as well as p46 and p54 members of JNK family. Moreover, Aβ1-42 raises AP-1 DNA binding activity in THP-1-treated cells. Interestingly, all these effects were reduced in the presence of BJe. Our data indicate that BJe may effectively counteract the pro-inflammatory activation of monocytes/microglial cells exposed to amyloid fibrils, suggesting a promising role as a natural drug against neuroinflammatory processes. PMID:26853104

  15. Arctigenin but not arctiin acts as the major effective constituent of Arctium lappa L. fruit for attenuating colonic inflammatory response induced by dextran sulfate sodium in mice.

    PubMed

    Wu, Xin; Yang, Yan; Dou, Yannong; Ye, Jun; Bian, Difei; Wei, Zhifeng; Tong, Bei; Kong, Lingyi; Xia, Yufeng; Dai, Yue

    2014-12-01

    The crude powder of the fruit of Arctium lappa L. (ALF) has previously been reported to attenuate experimental colitis in mice. But, its main effective ingredient and underlying mechanisms remain to be identified. In this study, ALF was extracted with ethanol, and then successively fractionated into petroleum ether, ethyl acetate, n-butanol and water fraction. Experimental colitis was induced by dextran sulfate sodium (DSS) in mice. Among the four fractions of ALF, the ethyl acetate fraction showed the most significant inhibition of DSS-induced colitis in mice. The comparative studies of arctigenin and arctiin (the two main ingredients of ethyl acetate fraction) indicated that arctigenin rather than arctiin could reduce the loss of body weight, disease activity index and histological damage in the colon. Arctigenin markedly recovered the loss of intestinal epithelial cells (E-cadherin-positive cells) and decreased the infiltration of neutrophils (MPO-positive cells) and macrophages (CD68-positive cells). Arctigenin could down-regulate the expressions of TNF-α, IL-6, MIP-2, MCP-1, MAdCAM-1, ICAM-1 and VCAM-1 at both protein and mRNA levels in colonic tissues. Also, it markedly decreased the MDA level, but increased SOD activity and the GSH level. Of note, the efficacy of arctigenin was comparable or even superior to that of the positive control mesalazine. Moreover, it significantly suppressed the phosphorylation of MAPKs and the activation of NF-κB, including phosphorylation of IκBα and p65, p65 translocation and DNA binding activity. In conclusion, arctigenin but not arctiin is the main active ingredient of ALF for attenuating colitis via down-regulating the activation of MAPK and NF-κB pathways. PMID:25284342

  16. Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-κB pathways.

    PubMed

    Zheng, Jifang; Zhao, Tingting; Yuan, Yan; Hu, Nan; Tang, Xiaoqing

    2015-12-01

    As an endogenous gaseous mediator, H2S exerts anti-oxidative, anti-inflammatory and cytoprotective effects in kidneys. This study was designed to investigate the protective effect of H2S against uranium-induced nephrotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H2S formation was explored in kidneys. The levels of endogenous H2S and H2S-producing enzymes (CBS and CSE) were measured in renal homogenates from rats intoxicated by an intraperitoneally (i.p.) injection of uranyl acetate at a single dose of 2.5, 5 or 10 mg/kg. In rats injected i.p. with uranyl acetate (5 mg/kg) or NaHS (an H2S donor, 28 or 56 μmol/kg) alone or in combination, we determined biochemical parameters and histopathological alteration to assess kidney function, examined oxidative stress markers, and investigated Nrf2 and NF-κB pathways in kidney homogenates. The results suggest that uranium intoxication in rats decreased endogenous H2S generation as well as CBS and CSE protein expression. NaHS administration in uranium-intoxicated rats ameliorated the renal biochemical indices and histopathological effects, lowered MDA accumulation, and restored GSH level and anti-oxidative enzymes activities like SOD, CAT, GPx and GST. NaHS treatment in uranium-intoxicated rats activated uranium-inhibited protein expression and nuclear translocation of transcription factor Nrf2, which increased protein expression of downstream target-Nrf2 genes HO-1, NQO-1, GCLC, and TXNRD-1. NaHS administration in uranium-intoxicated rats inhibited uranium-induced nuclear translocation and phosphorylation of transcription factor κB/p65, which decreased protein expression of target-p65 inflammatory genes TNF-α, iNOS, and COX-2. Taken together, these data implicate that H2S can afford protection to rat kidneys against uranium-induced adverse effects through induction of antioxidant defense by activating Nrf2 pathway and reduction of inflammatory response by suppressing NF-κB pathway. PMID

  17. Turkish Scorzonera Species Extracts Attenuate Cytokine Secretion via Inhibition of NF-κB Activation, Showing Anti-Inflammatory Effect in Vitro.

    PubMed

    Bahadır Acikara, Özlem; Hošek, Jan; Babula, Petr; Cvačka, Josef; Budešínský, Miloš; Dračinský, Martin; Saltan İşcan, Gülçin; Kadlecová, Daniela; Ballová, Ludmila; Šmejkal, Karel

    2015-01-01

    Scorzonera species are used in different folk medicines to combat many diseases, including the illnesses connected with inflammation. Previous experiments showed anti-inflammatory activity of Scorzonera extracts in vivo. S. latifolia, S. cana var. jacquiniana, S. tomentosa, S. mollis ssp. szowitsii, S. eriophora, S. incisa, S. cinerea, and S. parviflora extracts were, therefore, evaluated for their inhibitory activities of TNF-α and IL-1β production, and NF-κB nuclear translocation in THP-1 macrophages. The HPLC analysis was carried out to elucidate and to compare the composition of these extracts. Major compounds of the tested extracts have been isolated using different chromatographic techniques and further tested for their inhibitory activities on TNF-α and IL-1β production. Several extracts showed promising anti-inflammatory activity in these in vitro tests. Results of HPLC analysis revealed chlorogenic acid as a compound present in all tested extracts. Hyperoside, quercetin-3-O-β-d-glucoside and rutin were also present in varying amount in some Scorzonera species analyzed. Furthermore, eight phenolics which were identified as quercetin-3-O-β-d-glucoside (1), hyperoside (2), hydrangenol-8-O-glucoside (3), swertisin (4), 7-methylisoorientin (5), 4,5-O-dicaffeoyl-quinic acid (6), 3,5-di-O-caffeoyl-quinic acid (7), and chlorogenic acid (8) have been isolated as major phenolic compounds of the tested extracts and, together with eight terpenoids (9-16) previously obtained from different Scorzonera species, have been tested for the inhibition of TNF-α production, unfortunately with no activity comparable with standard. PMID:26729082

  18. An extract of chokeberry attenuates weight gain and modulates insulin, adipogenic and inflammatory signalling pathways in epididymal adipose tissue of rats fed a fructose-rich diet.

    PubMed

    Qin, Bolin; Anderson, Richard A

    2012-08-01

    Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-α and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3β. The protein and gene expression of adiponectin and Pparγ mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1β, Il6 and Tnfα were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation. PMID:22142480

  19. Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-κB signaling pathway in experimental traumatic brain injury

    PubMed Central

    FENG, YAN; CUI, YING; GAO, JUN-LING; LI, MING-HANG; LI, RAN; JIANG, XIAO-HUA; TIAN, YAN-XIA; WANG, KAI-JIE; CUI, CHANG-MENG; CUI, JIAN-ZHONG

    2016-01-01

    Previous research has demonstrated that traumatic brain injury (TBI) activates autophagy and a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of this cascade. In the present study, we investigated the hypothesis that resveratrol (RV), a natural polyphenolic compound with potent multifaceted properties, alleviates brain damage mediated by TLR4 following TBI. Adult male Sprague Dawley rats, subjected to controlled cortical impact (CCI) injury, were intraperitoneally injected with RV (100 mg/kg, daily for 3 days) after the onset of TBI. The results demonstrated that RV significantly reduced brain edema, motor deficit, neuronal loss and improved spatial cognitive function. Double immunolabeling demonstrated that RV decreased microtubule-associated protein 1 light chain 3 (LC3), TLR4-positive cells co-labeled with the hippocampal neurons, and RV also significantly reduced the number of TLR4-positive neuron-specific nuclear protein (NeuN) cells following TBI. Western blot analysis revealed that RV significantly reduced the protein expression of the autophagy marker proteins, LC3II and Beclin1, in the hippocampus compared with that in the TBI group. Furthermore, the levels of TLR4 and its known downstream signaling molecules, nuclear factor-κB (NF-κB), and the inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were also decreased after RV treatment. Our results suggest that RV reduces neuronal autophagy and inflammatory reactions in a rat model of TBI. Thus, we suggest that the neuroprotective effect of RV is associated with the TLR4/NF-κB signaling pathway. PMID:26936125

  20. 5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response

    PubMed Central

    Miao, Yi-Feng; Wu, Hui; Yang, Shao-Feng; Dai, Jiong; Qiu, Yong-Ming; Tao, Zhen-Yi; Zhang, Xiao-Hua

    2015-01-01

    Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP), a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH) may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO) model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9), interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and Toll-like receptor (TLR) protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL-) positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia. PMID:25873763

  1. Anti-platelet drugs attenuate the expansion of circulating CD14highCD16+ monocytes under pro-inflammatory conditions

    PubMed Central

    Layne, Kerry; Di Giosia, Paolo; Ferro, Albert; Passacquale, Gabriella

    2016-01-01

    Aims Levels of circulating CD14highCD16+ monocytes increase in atherosclerotic patients and are predictive of future cardiovascular events. Platelet activation has been identified as a crucial determinant in the acquisition of a CD16+ phenotype by classical CD14highCD16− cells. We tested the hypothesis that anti-platelet drugs modulate the phenotype of circulating monocytes. Methods and results Sixty healthy subjects undergoing influenza immunization were randomly assigned to either no treatment or anti-platelet therapy, namely aspirin 300 mg or 75 mg daily, or clopidogrel (300 mg loading dose followed by 75 mg), for 48 h post-immunization (n = 15/group). Monocyte subsets, high-sensitivity C-reactive protein, pro-inflammatory cytokines, and P-selectin were measured at baseline and post-immunization. The CD14highCD16+ monocyte cell count rose by 67.3% [interquartile range (IQR): 35.7/169.2; P = 0.0002 vs. baseline] in untreated participants. All anti-platelet regimes counteracted expansion of this monocytic subpopulation. Although no statistical differences were noted among the three treatments, aspirin 300 mg was the most efficacious compared with the untreated group (−12.5% change from baseline; IQR: −28.7/18.31; P = 0.001 vs. untreated). Similarly, the rise in P-selectin (17%; IQR: −5.0/39.7; P = 0.03 vs. baseline) observed in untreated participants was abolished by all treatments, with aspirin 300 mg exerting the strongest effect (−30.7%; IQR: −58.4/−0.03; P = 0.007 vs. untreated). Changes in P-selectin levels directly correlated with changes in CD14highCD16+ cell count (r = 0.5; P = 0.0002). There was a similar increase among groups in high-sensitivity C-reactive protein (P < 0.03 vs. baseline levels). Conclusions Anti-platelet drugs exert an immunomodulatory action by counteracting CD14highCD16+ monocyte increase under pro-inflammatory conditions, with this effect being dependent on the amplitude of P-selectin reduction. PMID:27118470

  2. (-)-Hydroxycitric acid attenuates endoplasmic reticulum stress-mediated alterations in 3T3-L1 adipocytes by protecting mitochondria and downregulating inflammatory markers.

    PubMed

    Nisha, V M; Priyanka, A; Anusree, S S; Raghu, K G

    2014-11-01

    Endoplasmic reticulum (ER) stress is an emerging potential therapeutic target for metabolic syndrome due to its role in synthesis, secretion, and folding of proteins. It leads to an increased production of reactive oxygen species (ROS) which, along with mitochondrial dysfunction and reduced antioxidant defense, causes chronic cell injury. The present investigation aims to observe the alterations in adipocytes due to ER stress and the protective effect of hydroxycitric acid (HCA), a bioactive from Garcinia species, to develop the same as a nutraceutical. ER stress was induced in mature 3T3-L1 adipocytes by treating them with tunicamycin (2μg/ml) for 18 h. Alterations in cell viability, innate antioxidant system (superoxide dismutase, glutathione peroxidase, and glutathione reductase), mitochondria (membrane potential, biogenesis, and transition pore opening), and inflammatory cytokines (tumor necrosis factor, monocyte chemoattractant protein, interferon-γ, interleukin (IL)-10, IL-6, and IL-1β) during ER stress, and co-treatment with HCA were analyzed. Endocrine function of adipocytes was also assessed by measuring adiponectin and leptin secretion levels. HCA protected the cells from ER stress by improving the antioxidant status and mitochondrial functions. The results validate nutraceutical properties of the edible bioactive, commonly used for culinary purpose. A more detailed study on the mechanism of action of HCA is required for developing it as a therapeutic agent for metabolic syndrome. PMID:25175938

  3. Superpulsed (Ga-As, 904 nm) low-level laser therapy (LLLT) attenuates inflammatory response and enhances healing of burn wounds.

    PubMed

    Gupta, Asheesh; Keshri, Gaurav K; Yadav, Anju; Gola, Shefali; Chauhan, Satish; Salhan, Ashok K; Bala Singh, Shashi

    2015-06-01

    Low-level laser therapy (LLLT) using superpulsed near-infrared light can penetrate deeper in the injured tissue and could allow non-pharmacological treatment for chronic wound healing. This study investigated the effects of superpulsed laser (Ga-As 904 nm, 200 ns pulse width; 100 Hz; 0.7 mW mean output power; 0.4 mW/cm(2) average irradiance; 0.2 J/cm(2) total fluence) on the healing of burn wounds in rats, and further explored the probable associated mechanisms of action. Irradiated group exhibited enhanced DNA, total protein, hydroxyproline and hexosamine contents compared to the control and silver sulfadiazine (reference care) treated groups. LLLT exhibited decreased TNF-α level and NF-kB, and up-regulated protein levels of VEGF, FGFR-1, HSP-60, HSP-90, HIF-1α and matrix metalloproteinases-2 and 9 compared to the controls. In conclusion, LLLT using superpulsed 904 nm laser reduced the inflammatory response and was able to enhance cellular proliferation, collagen deposition and wound contraction in the repair process of burn wounds. Photomicrographs showing no, absence inflammation and faster wound contraction in LLLT superpulsed (904 nm) laser treated burn wounds as compared to the non-irradiated control and silver sulfadiazine (SSD) ointment (reference care) treated wounds. PMID:25207838

  4. The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-kappaB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection.

    PubMed

    Wessler, Silja; Muenzner, Petra; Meyer, Thomas F; Naumann, Michael

    2005-05-01

    Neisseria gonorrhoeae (Ngo) is a Gram-negative pathogenic bacterium responsible for an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions between Ngo and the mucosal epithelium, which induce a local inflammatory response. Here we analyzed the molecular mechanism involved in the Ngo-induced induction of the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and IL-8. We identified the immediate early response transcription factor nuclear factor kappaB (NF-kappaB) as a key molecule for the induction of cytokine release. Ngo-induced activation of direct upstream signaling molecules was demonstrated for IkappaB kinase alpha and beta (IKKalpha and IKKbeta) by phosphorylation of IkappaBalpha as a substrate and IKK autophosphorylation. Using dominant negative cDNAs encoding kinase-dead IKKalpha, IKKbeta, and NF-kappaB-inducing kinase (NIK), Ngo-induced NF-kappaB activity was significantly inhibited. Curcumin, the yellow pigment derived from Curcuma longa, inhibited IKKalpha, IKKbeta and NIK, indicating its strong potential to block NF-kappaB-mediated cytokine release and the innate immune response. In addition to the inhibition of Ngo-induced signaling, curcumin treatment of cells completely abolished the adherence of bacteria to cells in late infection, underlining the high potential of curcumin as an anti-microbial compound without cytotoxic side effects. PMID:15927892

  5. Intracellular expression of inflammatory proteins S100A8 and S100A9 leads to epithelial-mesenchymal transition and attenuated aggressivity of breast cancer cells.

    PubMed

    Cormier, Kevin; Harquail, Jason; Ouellette, Rodney J; Tessier, Philippe A; Guerrette, Roxann; Robichaud, Gilles A

    2014-01-01

    S100 inflammatory proteins have been previously shown to modulate breast cancer processes. More specifically, genome-wide transcriptome studies associate S100A8 and S100A9 members to breast cancer progression and malignancy. Findings have shown that S100A8 and S100A9 can signal and regulate cancer cell behavior through both extracellular and intracellular-initiated cascades. However, functional studies exploring the effects of S100 proteins are often contradictory leaving ambiguity and a paucity of data relating to the specific function of S100A8 and S100A9 in breast cancer progression. In this study we sought to better define the functions of intracellular expressed S100A8 and S100A9 on key signaling and cellular processes driving breast cancer malignancy. We observed that extracellular treatments of the MCF7 breast cancer cell line with S100A8 and S100A9 proteins induces cell proliferation. In contrast, intracellular recombinant expression of S100A8 and S100A9 led to growth suppression. Furthermore our analysis revealed that intracellular-expressed S100A8 and S100A9 promote an epithelial-like phenotype through the induction of key markers, such as Ecadherin, integrin alpha-5 and Zona Occludens 1 (ZO-1). Concomitantly, S100A8 and S100A9 negatively regulate the activity of the promalignant Focal Adhesion Kinase-1 (FAK) signaling cascade leading to changes in cell adhesion and invasion properties. Our results uncover important differences in intracellular versus extracellular initiated S100A8 and S100A9 signaling cascades and their effects on mammary epithelial growth. Importantly, S100A8 and S100A9 appear to suppress breast cancer malignancy through an increase in mesenchymal to epithelial transitioning. Our findings shed insight into S100 protein involvement in breast cancer invasiveness and metastasis and clarify some of the controversies relating to these proteins in breast cancer processes. PMID:24041228

  6. miR-146a Attenuates Inflammatory Pathways Mediated by TLR4/NF-κB and TNFα to Protect Primary Human Retinal Microvascular Endothelial Cells Grown in High Glucose

    PubMed Central

    Ye, Eun-Ah; Steinle, Jena J.

    2016-01-01

    Pathological mechanisms underlying diabetic retinopathy are still not completely understood. Increased understanding of potential cellular pathways responsive to hyperglycemia is essential to develop novel therapeutic strategies for diabetic retinopathy. A growing body of evidence shows that microRNA (miRNA) play important roles in pathological mechanisms involved in diabetic retinopathy, as well as possessing potential as novel therapeutic targets. The hypothesis of this study was that miR-146a plays a key role in attenuating hyperglycemia-induced inflammatory pathways through reduced TLR4/NF-κB and TNFα signaling in primary human retinal microvascular endothelial cells (REC). We cultured human REC in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC with miRNA mimic (hsa-miR-146a-5p). Our results demonstrate that miR-146a expression was decreased in human REC cultured in high glucose. Overexpression of miR-146a using mimics reduced the levels of TLR4/NF-κB and TNFα in REC cultured in high glucose. Both MyD88-dependent and -independent signaling were decreased by miR-146a overexpression in REC in high glucose conditions. The results suggest that miR-146a is a potential therapeutic target for reducing inflammation in REC through inhibition of TLR4/NF-κB and TNFα. Our study will contribute to understanding of diabetic retinal pathology, as well as providing important clues to develop therapeutics for clinical applications. PMID:26997759

  7. miR-146a Attenuates Inflammatory Pathways Mediated by TLR4/NF-κB and TNFα to Protect Primary Human Retinal Microvascular Endothelial Cells Grown in High Glucose.

    PubMed

    Ye, Eun-Ah; Steinle, Jena J

    2016-01-01

    Pathological mechanisms underlying diabetic retinopathy are still not completely understood. Increased understanding of potential cellular pathways responsive to hyperglycemia is essential to develop novel therapeutic strategies for diabetic retinopathy. A growing body of evidence shows that microRNA (miRNA) play important roles in pathological mechanisms involved in diabetic retinopathy, as well as possessing potential as novel therapeutic targets. The hypothesis of this study was that miR-146a plays a key role in attenuating hyperglycemia-induced inflammatory pathways through reduced TLR4/NF-κB and TNFα signaling in primary human retinal microvascular endothelial cells (REC). We cultured human REC in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC with miRNA mimic (hsa-miR-146a-5p). Our results demonstrate that miR-146a expression was decreased in human REC cultured in high glucose. Overexpression of miR-146a using mimics reduced the levels of TLR4/NF-κB and TNFα in REC cultured in high glucose. Both MyD88-dependent and -independent signaling were decreased by miR-146a overexpression in REC in high glucose conditions. The results suggest that miR-146a is a potential therapeutic target for reducing inflammation in REC through inhibition of TLR4/NF-κB and TNFα. Our study will contribute to understanding of diabetic retinal pathology, as well as providing important clues to develop therapeutics for clinical applications. PMID:26997759

  8. Reducing the Dietary Omega-6:Omega-3 Utilizing α-Linolenic Acid; Not a Sufficient Therapy for Attenuating High-Fat-Diet-Induced Obesity Development Nor Related Detrimental Metabolic and Adipose Tissue Inflammatory Outcomes

    PubMed Central

    Enos, Reilly T.; Velázquez, Kandy T.; McClellan, Jamie L.; Cranford, Taryn L.; Walla, Michael D.; Murphy, E. Angela

    2014-01-01

    Aims To examine the effect of manipulating the omega-6:omega-3 (1∶1, 5∶1, 10∶1, and 20∶1) utilizing only α-linolenic and linoleic acid within a clinically-relevant high-fat diet (HFD) composed of up to seven sources of fat and designed to be similar to the standard American diet (MUFA∶PUFA of 2∶1, 12% and 40% of calories from saturated and total fat, respectively) on body composition, macrophage polarization, inflammation, and metabolic dysfunction in mice. Methods Diets were administered for 20 weeks. Body composition and metabolism (HOMA index and lipid profile) were examined monthly. GC-MS was utilized to determine the eicosapentaenoic acid (EPA):arachidonic acid (AA) and the docosahexaenoic acid (DHA):AA in AT phospholipids. Adipose tissue (AT) mRNA expression of chemokines (MCP-1, Fetuin-A, CXCL14), marker genes for M1 and M2 macrophages (CD11c and CD206, respectively) and inflammatory markers (TNF-α, IL-6, IL-1β, TLR-2, TLR-4, IL-10, GPR120) were measured along with activation of NFκB, JNK, and STAT-3. Macrophage infiltration into AT was examined using F4/80 immunohistochemistry. Results Any therapeutic benefit produced by reducing the omega-6:omega-3 was evident only when comparing the 1∶1 to 20∶1 HFD; the 1∶1 HFD resulted in a lower TC:HDL-C and decreased AT CXCL14 gene expression and AT macrophage infiltration, which was linked to a higher EPA:AA and DHA:AA in AT phospholipids. However, despite these effects, and independent of the omega-6:omega-3, all HFDs, in general, led to similar levels of adiposity, insulin resistance, and AT inflammation. Conclusion Reducing the omega-6:omega-3 using α-linolenic acid is not an effective therapy for attenuating obesity and type II diabetes mellitus development. PMID:24733548

  9. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of infla

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In an effort to attain earlier diagnoses in children with hemophagocytic lymphohistiocytosis (HLH), the International Histiocyte Society has now broadened their diagnostic criteria to no longer differentiate primary (HLH) and secondary hemophagocytic lymphohistiocytosis (SHLH). Five of the following...

  10. PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

    PubMed Central

    Lee, Dong-Sung; Jang, Jae-Hyuk; Ko, Wonmin; Kim, Kyoung-Su; Sohn, Jae Hak; Kang, Myeong-Suk; Ahn, Jong Seog; Kim, Youn-Chul; Oh, Hyuncheol

    2013-01-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1–3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1. PMID:23612372

  11. Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

    PubMed

    Shao, Anwen; Wu, Haijian; Hong, Yuan; Tu, Sheng; Sun, Xuejun; Wu, Qun; Zhao, Qiong; Zhang, Jianmin; Sheng, Jifang

    2016-07-01

    Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH, involved to anti-oxidative and anti-apoptotic effect. We have previously reported that HS could attenuate neuronal apoptosis as well as vasospasm. However, the underlying mechanism of HS on inflammation in SAH-induced EBI remains unclear. In this study, we explored the influence of HS on nuclear factor-κB (NF-κB) pathway and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome at early stage after SAH, by injecting HS intraperitoneally to SAH rats. One hundred and twenty-nine SD rats were randomly divided into four groups: sham group, SAH group, SAH+vehicle group, and SAH+HS group. SAH model was conducted using endovascular perforation method; all rats were sacrificed at 24 h after SAH. Protein level of pIκBα, cytosolic and nuclear p65, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-1β (IL-1β), and cleaved caspase-3 were measured by western blot. mRNA level of IL-1β, interleukin-6 (IL-6), tumor necrosis factor-c (TNF-α) were evaluated by RT-PCR. Cellular injury and death was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining, respectively. Our results showed that pIκBα, nuclear p65, NLRP3, ASC, caspase-1, IL-1β, cleaved caspase-3 proteins, as well as the mRNA of IL-1β, IL-6, and TNF-ɑ increased at 24 h after SAH, while cytosolic p65 decreased. TUNEL and Nissl staining presented severe cellular injury at 24 h post-SAH. However, after HS administration, the changes mentioned above were reversed. In conclusion, HS may inhibit inflammation in EBI and improve

  12. Activated protein C attenuates acute lung injury and apoptosis in a hyperoxic animal model.

    PubMed

    Husari, Ahmad W; Khayat, Aline; Awdeh, Haitham; Hatoum, Hadi; Nasser, Michel; Mroueh, Salman M; Zaatari, Ghazi; El-Sabban, Marwan; Dbaibo, Ghassan S

    2010-05-01

    Evidence suggests that activated protein C (APC) attenuates acute lung injury (ALI) through antithrombotic and anti-inflammatory mechanisms. The aim of this study was to determine the effects of APC on ALI in adult rats exposed to hyperoxic environment. Rats were divided into control, hyperoxia, hyperoxia + APC, and APC. Hyperoxia and hyperoxia + APC were exposed to 1, 3, and 5 days of hyperoxia. Hyperoxia + APC and APC were injected with APC (5 mg/kg, i.p.) every 12 h. Control and hyperoxia received isotonic sodium chloride solution injection. Measurement of wet to dry ratio and albumin leak demonstrated significant improvement in hyperoxia + APC when compared with hyperoxia. Apoptosis, as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, was significantly reduced in hyperoxia + APC when compared with hyperoxia. Histological evaluation of lung sections showed significant reduction in inflammation, edema, and in the number of marginating neutrophils in hyperoxia + APC as compared with hyperoxia. Transcriptional expression of lung inflammatory mediators demonstrated a time-dependent surge in the levels TNF-alpha, IL-1beta, and IL-6 in response to hyperoxia that was attenuated with APC administration in the presence of hyperoxia. In this rat model, APC attenuates lung injury and the expression of inflammatory mediators in ALI secondary to hyperoxia. PMID:19851127

  13. Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Excavatolide B Isolated from the Culture-Type Formosan Gorgonian Briareum excavatum.

    PubMed

    Lin, Yen-You; Lin, Sung-Chun; Feng, Chien-Wei; Chen, Pei-Chin; Su, Yin-Di; Li, Chi-Min; Yang, San-Nan; Jean, Yen-Hsuan; Sung, Ping-Jyun; Duh, Chang-Yih; Wen, Zhi-Hong

    2015-05-01

    In recent years, several marine-derived compounds have been clinically evaluated. Diterpenes are secondary metabolites from soft coral that exhibit anti-inflammatory, anti-tumor and cytotoxic activities. In the present study, we isolated a natural diterpene product, excavatolide B, from cultured Formosan gorgonian Briareum excavatum and investigated its anti-inflammatory activities. We found that excavatolide B significantly inhibited the mRNA expression of the proinflammatory mediators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-challenged murine macrophages (RAW 264.7). We also examined the anti-inflammatory and anti-nociceptive effects of excavatolide B on intraplantar carrageenan-induced inflammatory responses. Excavatolide B was found to significantly attenuate carrageenan-induced nociceptive behaviors, mechanical allodynia, thermal hyperalgesia, weight bearing deficits and paw edema. In addition, excavatolide B inhibited iNOS, as well as the infiltration of immune cells in carrageenan-induced inflammatory paw tissue. PMID:25923315

  14. Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Excavatolide B Isolated from the Culture-Type Formosan Gorgonian Briareum excavatum

    PubMed Central

    Lin, Yen-You; Lin, Sung-Chun; Feng, Chien-Wei; Chen, Pei-Chin; Su, Yin-Di; Li, Chi-Min; Yang, San-Nan; Jean, Yen-Hsuan; Sung, Ping-Jyun; Duh, Chang-Yih; Wen, Zhi-Hong

    2015-01-01

    In recent years, several marine-derived compounds have been clinically evaluated. Diterpenes are secondary metabolites from soft coral that exhibit anti-inflammatory, anti-tumor and cytotoxic activities. In the present study, we isolated a natural diterpene product, excavatolide B, from cultured Formosan gorgonian Briareum excavatum and investigated its anti-inflammatory activities. We found that excavatolide B significantly inhibited the mRNA expression of the proinflammatory mediators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-challenged murine macrophages (RAW 264.7). We also examined the anti-inflammatory and anti-nociceptive effects of excavatolide B on intraplantar carrageenan-induced inflammatory responses. Excavatolide B was found to significantly attenuate carrageenan-induced nociceptive behaviors, mechanical allodynia, thermal hyperalgesia, weight bearing deficits and paw edema. In addition, excavatolide B inhibited iNOS, as well as the infiltration of immune cells in carrageenan-induced inflammatory paw tissue. PMID:25923315

  15. Chronic ozone exposure alters the secondary metabolite profile, antioxidant potential, anti-inflammatory property, and quality of red pepper fruit from Capsicum baccatum.

    PubMed

    Bortolin, Rafael Calixto; Caregnato, Fernanda Freitas; Divan Junior, Armando Molina; Zanotto-Filho, Alfeu; Moresco, Karla Suzana; de Oliveira Rios, Alessandro; de Oliveira Salvi, Aguisson; Ortmann, Caroline Flach; de Carvalho, Pâmela; Reginatto, Flávio Henrique; Gelain, Daniel Pens; Fonseca Moreira, José Cláudio

    2016-07-01

    Tropospheric ozone (O3) background concentrations have increased since pre-industrial times, reaching phytotoxic concentrations in many regions globally. However, the effect of high O3 concentrations on quality of fruit and vegetables remains unknown. Here, we evaluated whether O3 pollution alters the quality of Capsicum baccatum peppers by changing the secondary compound profiles and biological activity of the fruit. C. baccatum pepper plants were exposed to ozone for 62 days in an open-top chamber at a mean O3 concentration of 171.6µg/m(3). Capsaicin levels decreased by 50% in the pericarp, but remained unchanged in the seeds. In contrast, the total carotenoid content increased by 52.8% in the pericarp. The content of total phenolic compounds increased by 17% in the pericarp. The total antioxidant potential decreased by 87% in seeds of O3-treated plants. The seeds contributed more than the pericarp to the total radical-trapping antioxidant potential and total antioxidant reactivity. O3 treatment impaired the ferric-reducing antioxidant power of the seeds and reduced NO(•)-scavenging activity in the pericarp. However, O3 treatment increased ferrous ion-chelating activity and hydroxyl radical-scavenging activity in the pericarp. Our results confirm that O3 alters the secondary metabolite profile of C. baccatum pepper fruits and, consequently, their biological activity profile. PMID:26970882

  16. Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3α, Mip-3β, and Secondary Lymphoid Organ Chemokine

    PubMed Central

    Iwasaki, Akiko; Kelsall, Brian L.

    2000-01-01

    We describe the anatomical localization of three distinct dendritic cell (DC) subsets in the murine Peyer's patch (PP) and explore the role of chemokines in their recruitment. By two-color in situ immunofluorescence, CD11b+ myeloid DCs were determined to be present in the subepithelial dome (SED) region, whereas CD8α+ lymphoid DCs are present in the T cell–rich interfollicular region (IFR). DCs that lack expression of CD8α or CD11b (double negative) are present in both the SED and IFR. By in situ hybridization, macrophage inflammatory protein (MIP)-3α mRNA was dramatically expressed only by the follicle-associated epithelium overlying the SED, while its receptor, CCR6, was concentrated in the SED. In contrast, CCR7 was expressed predominantly in the IFR. Consistent with these findings, reverse transcriptase polymerase chain reaction analysis and in vitro chemotaxis assays using freshly isolated DCs revealed that CCR6 was functionally expressed only by DC subsets present in the SED, while all subsets expressed functional CCR7. Moreover, none of the splenic DC subsets migrated toward MIP-3α. These data support a distinct role for MIP-3α/CCR6 in recruitment of CD11b+ DCs toward the mucosal surfaces and for MIP-3β/CCR7 in attraction of CD8α+ DCs to the T cell regions. Finally, we demonstrated that all DC subsets expressed an immature phenotype when freshly isolated and maintained expression of subset markers upon maturation in vitro. In contrast, CCR7 expression by myeloid PP DCs was enhanced with maturation in vitro. In addition, this subset disappeared from the SED and appeared in the IFR after microbial stimulation in vivo, suggesting that immature myeloid SED DCs capture antigens and migrate to IFR to initiate T cell responses after mucosal microbial infections. PMID:10770804

  17. Taurine and inflammatory diseases.

    PubMed

    Marcinkiewicz, Janusz; Kontny, Ewa

    2014-01-01

    Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in humans and plays an important role in several essential biological processes such as bile acid conjugation, maintenance of calcium homeostasis, osmoregulation and membrane stabilization. Moreover, attenuation of apoptosis and its antioxidant activity seem to be crucial for the cytoprotective effects of taurine. Although these properties are not tissue specific, taurine reaches particularly high concentrations in tissues exposed to elevated levels of oxidants (e.g., inflammatory cells). It suggests that taurine may play an important role in inflammation associated with oxidative stress. Indeed, at the site of inflammation, taurine is known to react with and detoxify hypochlorous acid generated by the neutrophil myeloperoxidase (MPO)-halide system. This reaction results in the formation of less toxic taurine chloramine (TauCl). Both haloamines, TauCl and taurine bromamine (TauBr), the product of taurine reaction with hypobromous acid (HOBr), exert antimicrobial and anti-inflammatory properties. In contrast to a well-documented regulatory role of taurine and taurine haloamines (TauCl, TauBr) in acute inflammation, their role in the pathogenesis of inflammatory diseases is not clear. This review summarizes our current knowledge concerning the role of taurine, TauCl and TauBr in the pathogenesis of inflammatory diseases initiated or propagated by MPO-derived oxidants. The aim of this paper is to show links between inflammation, neutrophils, MPO, oxidative stress and taurine. We will discuss the possible contribution of taurine and taurine haloamines to the pathogenesis of inflammatory diseases, especially in the best studied example of rheumatoid arthritis. PMID:22810731

  18. Rotary antenna attenuator

    NASA Technical Reports Server (NTRS)

    Dickinson, R. M.; Hardy, J. C.

    1969-01-01

    Radio frequency attenuator, having negligible insertion loss at minimum attenuation, can be used for making precise antenna gain measurements. It is small in size compared to a rotary-vane attenuator.

  19. Obstructive inflammatory tracheal pseudomembrane.

    PubMed

    Crespo-Lessmann, Astrid; Torrego-Fernández, Alfons

    2013-09-01

    Pathologies acquired after the establishment of an artificial airway include stenosis, granulomas and the formation of pseudomembranes, to name a few. The most common form of presentation in adults is circumferential stenosis, which often requires therapeutic endoscopic measures to achieve resolution. This Case Report describes the case of an obstructive inflammatory tracheal pseudomembrane in the shape of a tracheal septum secondary to repeated intubations that was resolved with conservative treatment. The clinical presentation of this entity generally includes the appearance of respiratory infection and/or atelectasis after the withdrawal of the orotracheal tube as a consequence of the accumulation of secretions between the tracheal wall and the pseudomembrane. Inflammatory pseudomembranes can resolve spontaneously with the help of glucocorticoids, although on occasion they require an invasive endotracheal procedure depending on the evolution. PMID:23419993

  20. Single Chain Recombinant HLA-DQ2.5/peptide Molecules Block α2-gliadin-Specific Pathogenic CD4+ T Cell Proliferation and Attenuate Production of Inflammatory Cytokines: A Potential Therapy for Celiac Disease

    PubMed Central

    Huan, J; Meza-Romero, R; Mooney, J L; Vandenbark, A A; Offner, H; Burrows, G G

    2010-01-01

    Celiac disease (CD) is a disorder of the small intestine caused by intolerance to wheat gluten and related proteins in barley and rye. CD4+ T cells play a central role in CD, recognizing and binding complexes of HLA-DQ2.5 bearing gluten peptides that have survived digestion and that are deamidated by tissue transglutaminase (TG2), propagating a cascade of inflammatory processes that damage and eventually destroy the villous tissue structures of the small intestine. Here we present data showing that recombinant DQ2.5-derived molecules bearing covalently tethered α2-gliadin-61-71 peptide have a remarkable ability to block antigen-specific T cell proliferation and inhibited pro-inflammatory cytokine secretion in human DQ2.5-restricted α2-gliadin specific T cell clones obtained from patients with celiac disease. The results from our in vitro studies suggest that HLA-DQ2.5 derived molecules could significantly inhibit and perhaps reverse the intestinal pathology caused by T cell mediated inflammation and the associated production of proinflammatory cytokines. PMID:20736999

  1. DC attenuation meter

    DOEpatents

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  2. LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells.

    PubMed

    Xu, Hong; He, Luling; Liu, Changle; Tang, Lan; Xu, Yonghu; Xiong, Mengqi; Yang, Mei; Fan, Yongfang; Hu, Fangfang; Liu, Xingzi; Ding, Lu; Gao, Yun; Xu, Changshui; Li, Guilin; Liu, Shuangmei; Wu, Bing; Zou, Lifang; Liang, Shangdong

    2016-06-01

    Diabetic neuropathy (DNP) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. High glucose and elevated free fatty acids (FFAs) have been recently recognized as major causes of nervous system damage in diabetes. Our previous study has indicated extracellular stimuli, such as high glucose and/or FFA stress, may activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway and induce a p38 MAPK-dependent sensitization of the P2X7 receptor and release of inflammatory factors in PC12 cells, while the mechanisms underlying remain to be elucidated. Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes, including activation of a series of pathway signalings. Here, we showed combined high D-glucose and FFAs (HGHF) induced an increment of lncRNA-NONRATT021972 (NONCODE ID, nc021972) in PC12 cells. Nc021972 small interference RNA (siRNA) alleviated HGHF-induced activation of p38 MAPK, expression of the P2X7 receptor, and [Ca(2+)]i increment upon P2X7 receptor activation. Further experiments showed that there existed a crosstalk between nc021972 and the p38 MAPK signaling pathway. Inhibition of p38 MAPK signaling decreased nc021972-induced expression of the P2X7 receptor and [Ca(2+)]i increment upon P2X7 receptor activation. Also, nc021972 siRNA inhibited HGHF-induced PC12 release of TNF-α and IL-6 and rescued decreased cell viability mediated by the P2X7 receptor. Therefore, inhibition of nc021972 may serve as a novel therapeutic strategy for diabetes complicated with nervous inflammatory diseases. PMID:26865268

  3. Attenuation of Vaccinia Virus.

    PubMed

    Yakubitskiy, S N; Kolosova, I V; Maksyutov, R A; Shchelkunov, S N

    2015-01-01

    Since 1980, in the post-smallpox vaccination era the human population has become increasingly susceptible compared to a generation ago to not only the variola (smallpox) virus, but also other zoonotic orthopoxviruses. The need for safer vaccines against orthopoxviruses is even greater now. The Lister vaccine strain (LIVP) of vaccinia virus was used as a parental virus for generating a recombinant 1421ABJCN clone defective in five virulence genes encoding hemagglutinin (A56R), the IFN-γ-binding protein (B8R), thymidine kinase (J2R), the complement-binding protein (C3L), and the Bcl-2-like inhibitor of apoptosis (N1L). We found that disruption of these loci does not affect replication in mammalian cell cultures. The isogenic recombinant strain 1421ABJCN exhibits a reduced inflammatory response and attenuated neurovirulence relative to LIVP. Virus titers of 1421ABJCN were 3 lg lower versus the parent VACV LIVP when administered by the intracerebral route in new-born mice. In a subcutaneous mouse model, 1421ABJCN displayed levels of VACV-neutralizing antibodies comparable to those of LIVP and conferred protective immunity against lethal challenge by the ectromelia virus. The VACV mutant holds promise as a safe live vaccine strain for preventing smallpox and other orthopoxvirus infections. PMID:26798498

  4. Neoadjuvant chemotherapy shows similar response in patients with inflammatory or locally advanced breast cancer when compared with operable breast cancer: a secondary analysis of the GeparTrio trial data.

    PubMed

    Costa, Serban Dan; Loibl, Sibylle; Kaufmann, Manfred; Zahm, Dirk-Michael; Hilfrich, Jörn; Huober, Jens; Eidtmann, Holger; du Bois, Andreas; Blohmer, Jens-Uwe; Ataseven, Beyhan; Weiss, Erich; Tesch, Hans; Gerber, Bernd; Baumann, Klaus H; Thomssen, Christoph; Breitbach, Georg Peter; Ibishi, Shaip; Jackisch, Christian; Mehta, Keyur; von Minckwitz, Gunter

    2010-01-01

    PURPOSE Neoadjuvant chemotherapy followed by mastectomy is the treatment of choice in patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC), but it is considered less effective in these diseases than in operable breast cancer (OBC). We report a prospective comparison of the GeparTrio trial of patients with IBC (cT4 days) or LABC (cT4a-c or cN3; stage IIIB or IIIC) and patients with OBC (cT2-3). PATIENTS AND METHODS Participants were stratified by stage and were randomly assigned to six or eight cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) or to two cycles of TAC followed by four cycles of vinorelbine/capecitabine. We present results of a secondary aim of the study, which was to compare pathologic complete response (pCR; ie, no remaining invasive/noninvasive tumor in breast and lymph nodes) in different stage groups. Results A total of 287 patients with IBC (n = 93) or LABC (n = 194) and 1,777 patients with OBC were entered onto the trial. At baseline, parameters were as follows for the three types of cancer, respectively: median tumor sizes: 8.0 cm, 7.0 cm, and 4.0 cm (P < .001); multiple lesions: 31.2%, 27.3%, and 19.6% (P < .001); nodal involvement: 86.6%, 71.2%, and 51.6% (P < .001); grade 3: 44.4%, 30.4%, and 39.9% (P = .178); lobular-invasive type: 7.5%, 17.5%, and 13.3% (P = .673); negative hormone receptor status: 38.0%, 20.0%, and 36.4% (P = .008); and positive human growth factor receptor 2 status: 45.1%, 38.9%, and 35.7% (P = .158). Response rates for IBC, LABC, and OBC, respectively, were 8.6%, 11.3%, and 17.7% for pCR (P = .002); 71.0%, 69.6%, and 83.4% for overall response by physical or sonographic examination (P < .001); and 12.9%, 33.0%, and 69.9% for breast conservation (P < .001). All P values were for IBC and LABC versus OBC. However, tumor stage itself was not an independent predictor for pCR in multivariable analysis (odds ratio, 1.51; 95% CI, 0.88 to 2.59; P = .13). CONCLUSION No evidence of a

  5. Radiometer calibration procedure and beacon attenuation estimation reference level

    NASA Technical Reports Server (NTRS)

    Crane, Robert K.

    1994-01-01

    The primary objectives are to compare radiometer attenuation with beacon attenuation and to compare sky temperature estimates with calculations using simultaneous meteorological data. Secondary objectives are: (1) noise diode and reference load measurements and (2) to adjust for outside temperature and component temperature changes.

  6. Pressure surge attenuator

    DOEpatents

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  7. Tracer attenuation in groundwater

    NASA Astrophysics Data System (ADS)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  8. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition

    SciTech Connect

    Kim, Seok-Joo; Lee, Sun-Mee

    2012-01-01

    Alcoholic fatty liver is susceptible to secondary stresses such as ischemia/reperfusion (I/R). Baicalin is an active component extracted from Scutellaria baicalensis, which is widely used in herbal preparations for treatment of hepatic diseases and inflammatory disorders. This study evaluated the potential beneficial effect of baicalin on I/R injury in alcoholic fatty liver. Rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Baicalin (200 mg/kg) was intraperitoneally administered 24 and 1 h before ischemia. After reperfusion, baicalin attenuated the increases in serum alanine aminotransferase activity, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in alcoholic fatty liver. The increased levels of TNF-α and IL-6 mRNA expression and inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions increased after reperfusion, which were higher in ethanol-fed animals, were attenuated by baicalin. In ethanol-fed animals, baicalin attenuated the increases in toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expressions and the nuclear translocation of NF-κB after reperfusion. In conclusion, our findings suggest that baicalin ameliorates I/R-induced hepatocellular damage by suppressing TLR4-mediated inflammatory responses in alcoholic fatty liver. -- Highlights: ► Baicalin attenuates hepatic I/R-induced inflammation in alcoholic fatty liver. ► Baicalin downregulates TLR4, MyD88 expression during I/R in alcoholic fatty liver. ► Baicalin attenuates NF-κB nuclear translocation during I/R in alcoholic fatty liver.

  9. Inflammatory glaucoma

    PubMed Central

    Bodh, Sonam A.; Kumar, Vasu; Raina, Usha K.; Ghosh, B.; Thakar, Meenakshi

    2011-01-01

    Glaucoma is seen in about 20% of the patients with uveitis. Anterior uveitis may be acute, subacute, or chronic. The mechanisms by which iridocyclitis leads to obstruction of aqueous outflow include acute, usually reversible forms (e.g., accumulation of inflammatory elements in the intertrabecular spaces, edema of the trabecular lamellae, or angle closure due to ciliary body swelling) and chronic forms (e.g., scar formation or membrane overgrowth in the anterior chamber angle). Careful history and follow-up helps distinguish steroid-induced glaucoma from uveitic glaucoma. Treatment of combined iridocyclitis and glaucoma involves steroidal and nonsteroidal antiinflammatory agents and antiglaucoma drugs. However, glaucoma drugs can often have an unpredictable effect on intraocular pressure (IOP) in the setting of uveitis. Surgical intervention is required in case of medical failure. Method of Literature Search: Literature on the Medline database was searched using the PubMed interface. PMID:21713239

  10. 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a Potent Inhibitor of Bacterial Phosphopantetheinyl Transferase That Attenuates Secondary Metabolism and Thwarts Bacterial Growth

    PubMed Central

    2015-01-01

    4′-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus, and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli. Additionally, we highlight the in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor. PMID:24450337

  11. Variable laser attenuator

    DOEpatents

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  12. Variable laser attenuator

    DOEpatents

    Foltyn, S.R.

    1987-05-29

    The disclosure relates to low loss, high power variable attenuators comprising one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength. 9 figs.

  13. Secondary parkinsonism

    MedlinePlus

    Parkinsonism - secondary; Atypical Parkinson disease ... to be less responsive to medical therapy than Parkinson disease. ... Unlike Parkinson disease, some types of secondary parkinsonism may stabilize or even improve if the underlying cause is treated. ...

  14. Secondary parkinsonism

    MedlinePlus

    Parkinsonism - secondary; Atypical Parkinson disease ... to be less responsive to medical therapy than Parkinson disease. ... Unlike Parkinson disease, some types of secondary parkinsonism may stabilize or even improve if the underlying cause is treated. Brain ...

  15. Inflammatory Choroidal Neovascularization

    PubMed Central

    Neri, Piergiorgi; Lettieri, Marta; Fortuna, Cinzia; Manoni, Mara; Giovannini, Alfonso

    2009-01-01

    Purpose and Methods: Choroidal neovascularization (CNV) can be a severe sight-threatening sequela, which can be secondary to both infectious and noninfectious uveitis. This review summarizes the different diseases associated with CNV, highlighting new treatment modalities and the possible strategies, which could be applied for the therapy of this occurrence. Results: Since CNV can often originate from posterior pole lesions and can be hard to identify, an accurate examination is mandatory in order to identify the correct diagnosis. In the majority of cases, fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) enable the determination of the clinical characteristics of the CNV. An infectious disease should be looked for to include a suitable therapy when available. The treatment strategy for CNV secondary to noninfectious uveal inflammations should be directed at controlling the inflammatory process. Systemic corticosteroids with or without immunosuppressive agents are indicated even when the CNV occurs with apparently inactive uveitis: Chronic subclinical inflammation can be the basis for the pathogenesis of CNV. Additional therapies aimed directly at the neovascular process, such as the intravitreal anti-Vascular Endothelial Growth Factor (VEGF) agents, are recommended particularly when the therapy shows an insufficient response. Conclusion: CNV secondary to uveitis is a severe sequela leading to significant visual impairment. ICGA is mandatory in order to obtain relevant information about the choroidal status. Several therapeutic options have been considered, but no guidelines are provided at the moment. Moreover, the current data are still only based on case reports or small series. For such reasons, further trials are mandatory to validate the preliminary available results. PMID:20404991

  16. Silibinin attenuates allergic airway inflammation in mice

    SciTech Connect

    Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu; Piao, Hong Mei; Li, Liang chang; Li, Guang Zhao; Lin, Zhen Hua; Yan, Guang Hai

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.

  17. Activation of peripheral KCNQ channels attenuates inflammatory pain

    PubMed Central

    2014-01-01

    Background Refractory chronic pain dramatically reduces the quality of life of patients. Existing drugs cannot fully achieve effective chronic pain control because of their lower efficacy and/or accompanying side effects. Voltage-gated potassium channels (KCNQ) openers have demonstrated their analgesic effect in preclinical and clinical studies, and are thus considered to be a potential therapeutic target as analgesics. However, these drugs exhibit a narrow therapeutic window due to their imposed central nerve system (CNS) side effects. To clarify the analgesic effect by peripheral KCNQ channel activation, we investigated whether the analgesic effect of the KCNQ channel opener, retigabine, is inhibited by intracerebroventricular (i.c.v.) administration of the KCNQ channel blocker, 10, 10-bis (4-Pyridinylmethyl)-9(10H) -anthracenone dihydrochloride (XE-991) in rats. Results Oral administration (p.o.) of retigabine showed an anticonvulsant effect on maximal electronic seizures and an analgesic effect on complete Freund’s adjuvant-induced thermal hyperalgesia. However, impaired motor coordination and reduced exploratory behavior were also observed at the analgesic doses of retigabine. Administration (i.c.v.) of XE-991 reversed the retigabine-induced anticonvulsant effect, impaired motor coordination and reduced exploratory behavior but not the analgesic effect. Moreover, intraplantar administration of retigabine or an additional KCNQ channel opener, N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243), inhibited formalin-induced nociceptive behavior. Conclusions Our findings suggest that the peripheral sensory neuron is the main target for KCNQ channel openers to induce analgesia. Therefore, peripheral KCNQ channel openers that do not penetrate the CNS may be suitable analgesic drugs as they would prevent CNS side effects. PMID:24555569

  18. Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits

    PubMed Central

    Corser-Jensen, Chelsea E.; Goodell, Dayton J.; Freund, Ronald K.; Serbedzija, Predrag; Murphy, Robert C.; Farias, Santiago E.; Dell'Acqua, Mark L.; Frey, Lauren C.; Serkova, Natalie; Heidenreich, Kim A.

    2014-01-01

    Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11 weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arms water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits. PMID:24681156

  19. Landing gear noise attenuation

    NASA Technical Reports Server (NTRS)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  20. RADIO FREQUENCY ATTENUATOR

    DOEpatents

    Giordano, S.

    1963-11-12

    A high peak power level r-f attenuator that is readily and easily insertable along a coaxial cable having an inner conductor and an outer annular conductor without breaking the ends thereof is presented. Spaced first and second flares in the outer conductor face each other with a slidable cylindrical outer conductor portion therebetween. Dielectric means, such as water, contact the cable between the flares to attenuate the radio-frequency energy received thereby. The cylindrical outer conductor portion is slidable to adjust the voltage standing wave ratio to a low level, and one of the flares is slidable to adjust the attenuation level. An integral dielectric container is also provided. (AFC)

  1. [Secondary hypertension].

    PubMed

    Yoshida, Yuichi; Shibata, Hirotaka

    2015-11-01

    Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice. PMID:26619670

  2. [Secondary diabetes].

    PubMed

    Nomiyama, Takashi; Yanase, Toshihiko

    2015-12-01

    Secondary diabetes is diabetes that results as a consequence of another medication, endocrine disease or hereditary disease. Secondary diabetes is very broad and diverted category among diabetes. Clinically, pancreatic diabetes is one of the most popular secondary diabetes, which provides insulin deficiency following pancreatic diseases, such as pancreatitis and pancreatic cancer. Among endocrine diseases, Cushing's syndrome and acromegaly are typical endocrine disorders causing secondary diabetes. They mainly induce insulin resistance in early stage, however, insulin deficiency is also observed in advanced stage. Steroid is the most popular drug-induced secondary diabetes. Importantly, not only oral administered steroid but also cutaneous and inhalation steroid could induce hyperglycemia. Major hereditary diabetes are MODY and mitochondrial diabetes. Concerning secondary diabetes, careful medical examination is required. PMID:26666145

  3. Attenuator And Conditioner

    DOEpatents

    Anderson, Gene R.; Armendariz, Marcelino G.; Carson, Richard F.; Bryan, Robert P.; Duckett, III, Edwin B.; Kemme, Shanalyn Adair; McCormick, Frederick B.; Peterson, David W.

    2006-04-04

    An apparatus and method of attenuating and/or conditioning optical energy for an optical transmitter, receiver or transceiver module is disclosed. An apparatus for attenuating the optical output of an optoelectronic connector including: a mounting surface; an array of optoelectronic devices having at least a first end; an array of optical elements having at least a first end; the first end of the array of optical elements optically aligned with the first end of the array of optoelectronic devices; an optical path extending from the first end of the array of optoelectronic devices and ending at a second end of the array of optical elements; and an attenuator in the optical path for attenuating the optical energy emitted from the array of optoelectronic devices. Alternatively, a conditioner may be adapted in the optical path for conditioning the optical energy emitted from the array of optoelectronic devices.

  4. Fiber Optic Attenuators

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Mike Buzzetti designed a fiber optic attenuator while working at Jet Propulsion Laboratory, intended for use in NASA's Deep Space Network. Buzzetti subsequently patented and received an exclusive license to commercialize the device, and founded Nanometer Technologies to produce it. The attenuator functions without introducing measurable back-reflection or insertion loss, and is relatively insensitive to vibration and changes in temperature. Applications include cable television, telephone networks, other signal distribution networks, and laboratory instrumentation.

  5. Secondary Syphilitic Lesions

    PubMed Central

    Baughn, Robert E.; Musher, Daniel M.

    2005-01-01

    An important theme that emerges from all early historical accounts is that in addition to the decreased virulence of Treponema pallidum, the incidence of secondary syphilis has decreased drastically over the past three centuries. Even in the early 20th century, most syphilologists were of the opinion that the disease had undergone changes in its manifestations and that they were dealing with an attenuated form of the spirochete. Such opinions were based primarily on the observations that violent cutaneous reactions and fatalities associated with the secondary stage had become extremely rare. The rate of primary and secondary syphilis in the United States increased in 2002 for the second consecutive year. After a decade-long decline that led to an all-time low in 2000, the recent trend is attributable, to a large extent, by a increase in reported syphilis cases among men, particularly homosexual and bisexual men having sex with men. The present review addresses the clinical and diagnostic criteria for the recognition of secondary syphilis, the clinical course and manifestations of the disease if allowed to proceed past the primary stage of disease in untreated individuals, and the treatment for this stage of the disease. PMID:15653827

  6. Inhibition of Inflammatory Arthritis Using Fullerene Nanomaterials

    PubMed Central

    Dellinger, Anthony L.; Cunin, Pierre; Lee, David; Kung, Andrew L.; Brooks, D. Bradford; Zhou, Zhiguo; Nigrovic, Peter A.; Kepley, Christopher L.

    2015-01-01

    Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis. PMID:25879437

  7. A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo

    PubMed Central

    Pan, Yong; Li, Jianling; Zhang, Yali; Ye, Faqing; Yang, Shulin; Zhang, Hui; Li, Xiaokun; Liang, Guang

    2011-01-01

    Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases. PMID:21931698

  8. Radiofrequency attenuator and method

    DOEpatents

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-01-20

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  9. Radiofrequency attenuator and method

    DOEpatents

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-11-10

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3 C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  10. Seismic attenuation in Florida

    SciTech Connect

    Bellini, J.J.; Bartolini, T.J.; Lord, K.M.; Smith, D.L. . Dept. of Geology)

    1993-03-01

    Seismic signals recorded by the expanded distribution of earthquake seismograph stations throughout Florida and data from a comprehensive review of record archives from stations GAI contribute to an initial seismic attenuation model for the Florida Plateau. Based on calculations of surface particle velocity, a pattern of attenuation exists that appears to deviate from that established for the remainder of the southeastern US. Most values suggest greater seismic attenuation within the Florida Plateau. However, a separate pattern may exist for those signals arising from the Gulf of Mexico. These results have important implications for seismic hazard assessments in Florida and may be indicative of the unique lithospheric identity of the Florida basement as an exotic terrane.

  11. Ibuprofen administration attenuates serum TNF-{alpha} levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

    SciTech Connect

    Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina; Berson, Alain; Letteron, Philippe; Larosche, Isabelle; Descatoire, Veronique; Feldmann, Gerard; Robin, Marie-Anne |; Pessayre, Dominique |

    2008-09-15

    Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-{alpha} (TNF-{alpha}), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 {mu}g/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-{alpha}. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-{alpha} secretion) and infliximab (trapping TNF-{alpha}) likewise attenuated the Jo2-mediated increase in TNF-{alpha}, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-{alpha} secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-{alpha} secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.

  12. Tritium Attenuation by Distillation

    SciTech Connect

    Wittman, N.E.

    2001-07-31

    The objective of this study was to determine how a 100 Area distillation system could be used to reduce to a satisfactory low value the tritium content of the dilute moderator produced in the 100 Area stills, and whether such a tritium attenuator would have sufficient capacity to process all this material before it is sent to the 400 Area for reprocessing.

  13. Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain.

    PubMed

    Kim, Shi Hyoung; Park, Jae Gwang; Sung, Gi-Ho; Yang, Sungjae; Yang, Woo Seok; Kim, Eunji; Kim, Jun Ho; Ha, Van Thai; Kim, Han Gyung; Yi, Young-Su; Kim, Ji Hye; Baek, Kwang-Soo; Sung, Nak Yoon; Lee, Mi-nam; Kim, Jong-Hoon; Cho, Jae Youl

    2015-07-01

    Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing. PMID:25917334

  14. Inflammatory demyelinating neuropathies.

    PubMed

    Muley, Suraj Ashok; Parry, Gareth J

    2009-05-01

    Early and effective treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is important to minimize axonal degeneration that occurs secondary to demyelination. The disease course is invariably chronic, so long-term treatment is often required, and adverse effects and costs are important considerations in devising a treatment plan. CIDP responds to prednisone, but long-term treatment can result in significant adverse effects. Azathioprine, mycophenolate mofetil, and cyclosporine can be used as steroid-sparing agents and may facilitate more rapid and successful tapering of prednisone. Intravenous immunoglobulin (IVIg) and plasma exchange are also effective in the treatment of CIDP and can be used in patients who are unresponsive to prednisone or develop steroid-related adverse effects. IVIg may also be used as a first-line treatment, but its cost can be a limiting factor. A few uncontrolled studies have suggested that pulsed weekly methylprednisolone is both effective and well tolerated in the long-term treatment of CIDP. Treatments based on rituximab or cyclophosphamide have also been used in resistant disease. Variants of CIDP have been described on the basis of their association with specific antibodies or immunoglobulins and their response to specific immunomodulatory treatments. Multifocal motor neuropathy with conduction block responds to IVIg in the majority of patients. However, weakness may slowly worsen over time, and some patients become unresponsive. Anecdotal reports suggest that rituximab may be useful in patients who develop progressive disease. Placebo-controlled trials in anti-myelin-associated glycoprotein neuropathy suggest that rituximab is effective and, with a combination of prednisone and cyclophosphamide, numbness and strength may improve. Other treatments that may be effective include plasma exchange and IVIg. Treatment is generally started with prednisone, IVIg, or plasma exchange. Rituximab and cyclophosphamide are used only

  15. Anti-Inflammatory Iridoids of Botanical Origin

    PubMed Central

    Viljoen, A; Mncwangi, N; Vermaak, I

    2012-01-01

    Inflammation is a manifestation of a wide range of disorders which include; arthritis, atherosclerosis, Alzheimer’s disease, inflammatory bowel syndrome, physical injury and infection amongst many others. Common treatment modalities are usually non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, paracetamol, indomethacin and ibuprofen as well as corticosteroids such as prednisone. These however, may be associated with a host of side effects due to non-selectivity for cyclooxygenase (COX) enzymes involved in inflammation and those with selectivity may be highly priced. Thus, there is a continuing search for safe and effective anti-inflammatory molecules from natural sources. Research has confirmed that iridoids exhibit promising anti-inflammatory activity which may be beneficial in the treatment of inflammation. Iridoids are secondary metabolites present in various plants, especially in species belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae families. Many of these ethnobotanicals have an illustrious history of traditional use alluding to their use to treat inflammation. Although iridoids exhibit a wide range of pharmacological activities such as cardiovascular, hepatoprotection, hypoglycaemic, antimutagenic, antispasmodic, anti-tumour, antiviral, immunomodulation and purgative effects this review will acutely focus on their anti-inflammatory properties. The paper aims to present a summary for the most prominent iridoid-containing plants for which anti-inflammatory activity has been demonstrated in vitro and / or in vivo. PMID:22414102

  16. A compact rotary vane attenuator

    NASA Technical Reports Server (NTRS)

    Nixon, D. L.; Otosh, T. Y.; Stelzried, C. T.

    1969-01-01

    Rotary vane attenuator, when used as a front end attenuator, introduces an insertion loss that is proportional to the angle of rotation. New technique allows the construction of a shortened compact unit suitable for most installations.

  17. Hydrogen Sulfide Attenuates the Recruitment of CD11b+Gr-1+ Myeloid Cells and Regulates Bax/Bcl-2 Signaling in Myocardial Ischemia Injury

    PubMed Central

    Zhang, Youen; Li, Hua; Zhao, Gang; Sun, Aijun; Zong, Nobel C.; Li, Zhaofeng; Zhu, Hongming; Zou, Yunzeng; Yang, Xiangdong; Ge, Junbo

    2014-01-01

    Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b+Gr-1+ myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b+Gr-1+ myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling. PMID:24758901

  18. Optical Evaluation of a Refractive Secondary Concentrator

    NASA Technical Reports Server (NTRS)

    Jaworske, Donald A.; Wong, Wayne A.; Skowronski, Timothy J.

    1999-01-01

    Refractive secondary concentrators are being considered for solar thermal applications because of their ability to archive maximum efficiency through the use of total internal reflection for the concentration and distribution of solar energy. A prototype refractive secondary concentrator was built based on ray tracing analysis to demonstrate this collection and distribution concept. The design included a conical secondary concentrator and a faceted extractor. The objective of this effort was to functionally evaluate the performance of the refractive secondary concentrator/extractor prototype and to compare the results with modeling. Most of the light was found to exit the refractive secondary concentrator through the extractor. In addition, the degree of attenuation encountered by the light as it passed through the refractive secondary concentrator was of interest. Quantifying optical output and validating the modeling will provide further understanding of the efficiency of the prototype and will provide insight for additional design and materials selection activities.

  19. Fluid dynamic bowtie attenuators

    NASA Astrophysics Data System (ADS)

    Szczykutowicz, Timothy P.; Hermus, James

    2015-03-01

    Fluence field modulated CT allows for improvements in image quality and dose reduction. To date, only 1-D modulators have been proposed, the extension to 2-D modulation is difficult with solid-metal attenuation-based modulators. This work proposes to use liquids and gas to attenuate the x-ray beam which can be arrayed allowing for 2-D fluence modulation. The thickness of liquid and the pressure for a given path length of gas were determined that provided the same attenuation as 30 cm of soft tissue at 80, 100, 120, and 140 kV. Gaseous Xenon and liquid Iodine, Zinc Chloride, and Cerium Chloride were studied. Additionally, we performed some proof-of-concept experiments in which (1) a single cell of liquid was connected to a reservoir which allowed the liquid thickness to be modulated and (2) a 96 cell array was constructed in which the liquid thickness in each cell was adjusted manually. Liquid thickness varied as a function of kV and chemical composition, with Zinc Chloride allowing for the smallest thickness; 1.8, 2.25, 3, and 3.6 cm compensated for 30 cm of soft tissue at 80, 100, 120, and 140 kV respectively. The 96 cell Iodine attenuator allowed for a reduction in both dynamic range to the detector and scatter to primary ratio. Successful modulation of a single cell was performed at 0, 90, and 130 degrees using a simple piston/actuator. The thickness of liquids and the Xenon gas pressure seem logistically implementable within the constraints of CBCT and diagnostic CT systems.

  20. Downhole pressure attenuation apparatus

    SciTech Connect

    Ricles, T.D.; Barton, J.A.

    1992-02-18

    This patent describes a process for preventing damage to tool strings and other downhole equipment in a well caused by pressures produced during detonation of one or more downhole explosive devices. It comprises adding to a tool string at least one pressure attenuating apparatus for attenuating the peak pressure wave and quasi-static pressure pulse produced by the explosive devices, the pressure attenuating apparatus including an initially closed relief vent including tubing means supporting a plurality of charge port assemblies each including an explosive filled shaped charge and a prestressed disc, the shaped charges interconnected by a detonating cord, the amount of explosive in each shaped charge being sufficient to rupture its associated disc without damaging surrounding tubular bodies in the well, and a vent chamber defined by the tubing means and providing a liquid free volume, and opening the relief vent substantially contemporaneously with downhole explosive device detonation by detonating the shaped charges to rupture the discs of the charge port assemblies.

  1. Secondary Products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In spite of their name, "secondary" products are essential for plant survival. They are required for basic cell functions as well as communicating the plant's presence to the surrounding environment and defense against pests as defined in the broad sense (i.e., diseases, nematodes, insects and plan...

  2. Flexible graphene based microwave attenuators.

    PubMed

    Byun, Kisik; Ju Park, Yong; Ahn, Jong-Hyun; Min, Byung-Wook

    2015-02-01

    We demonstrate flexible 3 dB and 6 dB microwave attenuators using multilayer graphene grown by the chemical vapor deposition method. On the basis of the characterized results of multilayer graphene and graphene-Au ohmic contacts, the graphene attenuators are designed and measured. The flexible graphene-based attenuators have 3 dB and 6 dB attenuation with a return loss of less than -15 dB at higher than 5 GHz. The devices have shown durability in a bending cycling test of 100 times. The circuit model of the attenuator based on the characterized results matches the experimental results well. PMID:25590144

  3. Control algorithms for dynamic attenuators

    SciTech Connect

    Hsieh, Scott S.; Pelc, Norbert J.

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  4. Ultrasonic attenuation in pearlitic steel.

    PubMed

    Du, Hualong; Turner, Joseph A

    2014-03-01

    Expressions for the attenuation coefficients of longitudinal and transverse ultrasonic waves are developed for steel with pearlitic microstructure. This type of lamellar duplex microstructure influences attenuation because of the lamellar spacing. In addition, longitudinal attenuation measurements were conducted using an unfocused transducer with 10 MHz central frequency on the cross section of a quenched railroad wheel sample. The dependence of longitudinal attenuation on the pearlite microstructure is observed from the changes of longitudinal attenuation from the quenched tread surface to deeper locations. The results show that the attenuation value is lowest and relatively constant within the quench depth, then increases linearly. The experimental results demonstrate a reasonable agreement with results from the theoretical model. Ultrasonic attenuation provides an important non-destructive method to evaluate duplex microstructure within grains which can be implemented for quality control in conjunction with other manufacturing processes. PMID:24268679

  5. Curcumin in inflammatory diseases.

    PubMed

    Shehzad, Adeeb; Rehman, Gauhar; Lee, Young Sup

    2013-01-01

    Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future. PMID:23281076

  6. Secondary osteoporosis.

    PubMed

    Sheu, Angela; Diamond, Terry

    2016-06-01

    Secondary osteoporosis is less common than primary osteoporosis. It may be suspected in patients who present with a fragility fracture despite having no risk factors for osteoporosis. In addition, secondary osteoporosis should be considered if the bone density Z-score is -2.5 or less. Consider the fracture site and presence of other clinical clues to guide investigations for an underlying cause. The tests to use are those that are indicated for the suspected cause. Baseline investigations include tests for bone and mineral metabolism (calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone), liver and kidney function, full blood count and thyroid-stimulating hormone. More detailed testing may be required in patients with severe osteoporosis. PMID:27346916

  7. Secondary osteoporosis

    PubMed Central

    Sheu, Angela; Diamond, Terry

    2016-01-01

    SUMMARY Secondary osteoporosis is less common than primary osteoporosis. It may be suspected in patients who present with a fragility fracture despite having no risk factors for osteoporosis. In addition, secondary osteoporosis should be considered if the bone density Z-score is –2.5 or less. Consider the fracture site and presence of other clinical clues to guide investigations for an underlying cause. The tests to use are those that are indicated for the suspected cause. Baseline investigations include tests for bone and mineral metabolism (calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone), liver and kidney function, full blood count and thyroid-stimulating hormone. More detailed testing may be required in patients with severe osteoporosis. PMID:27346916

  8. Anti-Inflammatory Effects of Progesterone in Lipopolysaccharide-Stimulated BV-2 Microglia

    PubMed Central

    Lei, Beilei; Mace, Brian; Dawson, Hana N.; Warner, David S.; Laskowitz, Daniel T.; James, Michael L.

    2014-01-01

    Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone’s effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury. PMID:25080336

  9. AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY

    PubMed Central

    Hook, Michelle A.; Washburn, Stephanie N.; Moreno, Georgina; Woller, Sarah A.; Puga, Denise; Lee, Kuan H.; Grau, James W.

    2010-01-01

    Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 hrs later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 hrs after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function. PMID:20974246

  10. Digitally Controlled Beam Attenuator

    NASA Astrophysics Data System (ADS)

    Peppler, W. W.; Kudva, B.; Dobbins, J. T.; Lee, C. S.; Van Lysel, M. S.; Hasegawa, B. H.; Mistretta, C. A.

    1982-12-01

    In digital fluorographic techniques the video camera must accommodate a wide dynamic range due to the large variation in the subject thickness within the field of view. Typically exposure factors and the optical aperture are selected such that the maximum video signal is obtained in the most transmissive region of the subject. Consequently, it has been shown that the signal-to-noise ratio is severely reduced in the dark regions. We have developed a prototype digital beam attenuator (DBA) which will alleviate this and some related problems in digital fluorography. The prototype DBA consists of a 6x6 array of pistons which are individually controlled. A membrane containing an attenuating solu-tion of (CeC13) in water and the piston matrix are placed between the x-ray tube and the subject. Under digital control the pistons are moved into the attenuating material in order to adjust the beam intensity over each of the 36 cells. The DBA control unit which digitizes the image during patient positioning will direct the pistons under hydraulic control to produce a uniform x-ray field exiting the subject. The pistons were designed to produce very little structural background in the image. In subtraction studies any structure would be cancelled. For non-subtraction studies such as cine-cardiology we are considering higher cell densities (eg. 64x64). Due to the narrow range of transmission provided by the DBA, in such studies ultra-high contrast films could be used to produce a high resolution quasi-subtraction display. Additional benefits of the DBA are: 1) reduced dose to the bright image areas when the dark areas are properly exposed. 2) improved scatter and glare to primary ratios, leading to improved contrast in the dark areas.

  11. Radiation Imaging and Attenuation

    NASA Astrophysics Data System (ADS)

    Davison, Candace; Yocum, Douglas

    2008-03-01

    X-ray and neutron images are used to demonstrate materials' different radiation attenuation properties. This leads to discussion of applications in medicine, industry and research. The Penn State Radiation Science and Engineering Center (RSEC) uses neutron radioscopy to image the inside of a working hydrogen fuel cell. This is one of the many educational activities that are conducted when students visit the RSEC. To encourage pre-college students to apply these principles and learn more about nuclear technology, we are sponsoring a design competition. For more information visit www.rsec.psu.edu

  12. Anti-inflammatory iridoids of botanical origin.

    PubMed

    Viljoen, A; Mncwangi, N; Vermaak, I

    2012-01-01

    Inflammation is a manifestation of a wide range of disorders which include; arthritis, atherosclerosis, Alzheimer's disease, inflammatory bowel syndrome, physical injury and infection amongst many others. Common treatment modalities are usually nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, paracetamol, indomethacin and ibuprofen as well as corticosteroids such as prednisone. These however, may be associated with a host of side effects due to non-selectivity for cyclooxygenase (COX) enzymes involved in inflammation and those with selectivity may be highly priced. Thus, there is a continuing search for safe and effective antiinflammatory molecules from natural sources. Research has confirmed that iridoids exhibit promising anti-inflammatory activity which may be beneficial in the treatment of inflammation. Iridoids are secondary metabolites present in various plants, especially in species belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae families. Many of these ethnobotanicals have an illustrious history of traditional use alluding to their use to treat inflammation. Although iridoids exhibit a wide range of pharmacological activities such as cardiovascular, hepatoprotection, hypoglycaemic, antimutagenic, antispasmodic, anti-tumour, antiviral, immunomodulation and purgative effects this review will acutely focus on their anti-inflammatory properties. The paper aims to present a summary for the most prominent iridoid-containing plants for which anti-inflammatory activity has been demonstrated in vitro and / or in vivo. PMID:22414102

  13. Intermittent fasting attenuates inflammasome activity in ischemic stroke.

    PubMed

    Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

    2014-07-01

    Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. PMID:24805069

  14. Bioactive secondary metabolites of a marine Bacillus sp. inhibit superoxide generation and elastase release in human neutrophils by blocking formyl peptide receptor 1.

    PubMed

    Yang, Shun-Chin; Lin, Chwan-Fwu; Chang, Wen-Yi; Kuo, Jimmy; Huang, Yin-Ting; Chung, Pei-Jen; Hwang, Tsong-Long

    2013-01-01

    It is well known that overwhelming neutrophil activation is closely related to acute and chronic inflammatory injuries. Formyl peptide receptor 1 (FPR1) plays an important role in activation of neutrophils and may represent a potent therapeutic target in inflammatory diseases. In the present study, we demonstrated that IA-LBI07-1 (IA), an extract of bioactive secondary metabolites from a marine Bacillus sp., has anti-inflammatory effects in human neutrophils. IA significantly inhibited superoxide generation and elastase release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated neutrophils, but failed to suppress the cell responses activated by non-FPR1 agonists. IA did not alter superoxide production and elastase activity in cell-free systems. IA also attenuated the downstream signaling from FPR1, such as the Ca2+, MAP kinases and AKT pathways. In addition, IA inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analogue of FMLP, to FPR1 in human neutrophils and FPR1-transfected HEK293 cells. Taken together, these results show that the anti-inflammatory effects of IA in human neutrophils are through the inhibition of FPR1. Also, our data suggest that IA may have therapeutic potential to decrease tissue damage induced by human neutrophils. PMID:23736784

  15. Primary and secondary neoplasms of the spleen

    PubMed Central

    Azar, S.; Al-Hawary, M.M.; Francis, I.R.

    2010-01-01

    Abstract With the exception of lymphoma involving the spleen, other primary and secondary neoplasms are rare and infrequently encountered. Primary malignant neoplasms involving the spleen are lymphoma and angiosarcoma. Primary benign neoplasms involving the spleen include hemangioma, lymphangioma, littoral cell angioma and splenic cyst and solid lesions such as hamartoma and inflammatory pseudotumor. PMID:20713317

  16. Chopping-Wheel Optical Attenuator

    NASA Technical Reports Server (NTRS)

    Leviton, Douglas B.

    1988-01-01

    Star-shaped rotating chopping wheel provides adjustable time-averaged attenuation of narrow beam of light without changing length of optical path or spectral distribution of light. Duty cycle or attenuation factor of chopped beam controlled by adjusting radius at which beam intersects wheel. Attenuation factor independent of wavelength. Useful in systems in which chopping frequency above frequency-response limits of photodetectors receiving chopped light. Used in systems using synchronous detection with lock-in amplifiers.

  17. Ultrasonic Attenuation in Zircaloy-4

    SciTech Connect

    Gomez, M.P.; Banchik, A.D.; Lopez Pumarega, M.I.; Ruzzante, J.E.

    2005-04-09

    In this work the relationship between Zircaloy-4 grain size and ultrasonic attenuation behavior was studied for longitudinal waves in the frequency range of 10-90 MHz. The attenuation was analyzed as a function of frequency for samples with different mechanical and heat treatments having recrystallized and Widmanstatten structures with different grain size. The attenuation behavior was analyzed by different scattering models, depending on grain size, wavelength and frequency.

  18. LINE-ABOVE-GROUND ATTENUATOR

    DOEpatents

    Wilds, R.B.; Ames, J.R.

    1957-09-24

    The line-above-ground attenuator provides a continuously variable microwave attenuator for a coaxial line that is capable of high attenuation and low insertion loss. The device consists of a short section of the line-above- ground plane type transmission lime, a pair of identical rectangular slabs of lossy material like polytron, whose longitudinal axes are parallel to and indentically spaced away from either side of the line, and a geared mechanism to adjust amd maintain this spaced relationship. This device permits optimum fineness and accuracy of attenuator control which heretofore has been difficult to achieve.

  19. Vinpocetine attenuates lipid accumulation and atherosclerosis formation

    SciTech Connect

    Cai, Yujun; Li, Jian-Dong; Yan, Chen

    2013-05-10

    Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.

  20. Pelvic Inflammatory Disease

    MedlinePlus

    Pelvic inflammatory disease (PID) is an infection and inflammation of the uterus, ovaries, and other female reproductive organs. It causes scarring ... United States. Gonorrhea and chlamydia, two sexually transmitted diseases, are the most common causes of PID. Other ...

  1. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  2. Marine Diterpenoids as Potential Anti-Inflammatory Agents.

    PubMed

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E; Fernandez, Patricia L

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

  3. Marine Diterpenoids as Potential Anti-Inflammatory Agents

    PubMed Central

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E.; Fernandez, Patricia L.

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

  4. Macrophage Depletion Attenuates Extracellular Matrix Deposition and Ductular Reaction in a Mouse Model of Chronic Cholangiopathies.

    PubMed

    Best, Jan; Verhulst, Stefaan; Syn, Wing-Kin; Lagaisse, Kimberly; van Hul, Noemi; Heindryckx, Femke; Sowa, Jan-Peter; Peeters, Liesbeth; Van Vlierberghe, Hans; Leclercq, Isabelle A; Canbay, Ali; Dollé, Laurent; van Grunsven, Leo A

    2016-01-01

    Chronic cholangiopathies, such as primary and secondary sclerosing cholangitis, are progressive disease entities, associated with periportal accumulation of inflammatory cells, encompassing monocytes and macrophages, peribiliary extracellular matrix (ECM) deposition and ductular reaction (DR). This study aimed to elucidate the relevance of macrophages in the progression of chronic cholangiopathies through macrophage depletion in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse model. One group of mice received a single i.p. injection of Clodronate encapsulated liposomes (CLOLipo) at day 7 of a 14 day DDC treatment, while control animals were co-treated with PBSLipo instead. Mice were sacrificed after 7 or respectively 14 days of treatment for immunohistochemical assessment of macrophage recruitment (F4/80), ECM deposition (Sirius Red, Laminin) and DR (CK19). Macrophage depletion during a 14 day DDC treatment resulted in a significant inhibition of ECM deposition. Porto-lobular migration patterns of laminin-rich ECM and ductular structures were significantly attenuated and a progression of DR was effectively inhibited by macrophage depletion. CLOLipo co-treatment resulted in a confined DR to portal regions without amorphous cell clusters. This study suggests that therapeutic options selectively directed towards macrophages might represent a feasible treatment for chronic cholestatic liver diseases. PMID:27618307

  5. An attenuated philosophical gentleman.

    PubMed

    Christie, John R R

    2014-06-20

    Dr. Joseph Black had at one time, a house near us to the west. He was a striking and beautiful person; tall, very thin, and cadaverously pale; his hair carefully powdered, though there was little of it except what was collected in a long thin queue; his eyes dark, clear and large, like deep pools of pure water. He wore black speckless clothes, silk stockings, silver buckles, and either a slim green umbrella, or a genteel brown cane. The general frame and air were feeble and slender. The wildest boy respected Black. No lad could be irreverent toward a man so pale, so gentle, so elegant and so illustrious. So he glided, like a spirit, through our rather mischievous sportiveness, unharmed. He died seated, with a bowl of milk upon his knee, of which his ceasing to be did not spill a drop; a departure which it seemed, after the event, might have been foretold of this attenuated philosophical gentleman. PMID:24921110

  6. Fiber optic attenuator

    NASA Technical Reports Server (NTRS)

    Buzzetti, Mike F. (Inventor)

    1994-01-01

    A fiber optic attenuator of the invention is a mandrel structure through which a bundle of optical fibers is wrapped around in a complete circle. The mandrel structure includes a flexible cylindrical sheath through which the bundle passes. A set screw on the mandrel structure impacts one side of the sheath against two posts on the opposite side of the sheath. By rotating the screw, the sheath is deformed to extend partially between the two posts, bending the fiber optic bundle to a small radius controlled by rotating the set screw. Bending the fiber optic bundle to a small radius causes light in each optical fiber to be lost in the cladding, the amount depending upon the radius about which the bundle is bent.

  7. The agaricoglyceride of royal sun medicinal mushroom, Agaricus brasiliensis (higher basidiomycetes) is anti-inflammatory and reverses diabetic glycemia in the liver of mice.

    PubMed

    Yu, Haitao; Han, Chunchao; Sun, Yan; Qi, Xiaodan; Shi, Yan; Gao, Xu; Zhang, Chunjing

    2013-01-01

    The agaricoglyceride is a new fungal secondary metabolite that constitutes esters of chlorinated 4-hydroxy benzoic acid and glycerol. The objective of this study was to explore whether the administration of agaricoglyceride could correct hepatic glycemic metabolism dysfunction by attenuating inflammation in the liver. The effects of agaricoglycerides on tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor-α, interleukin-17, insulin secretion, adiponectin, leptin, hepatic glycogen, nuclear factor-κB activation, and total antioxidant activity were studied respectively. We demonstrated that administration of agaricoglycerides alleviated glycemic metabolism dysfunction, inflammation, and oxidative stress in mice. These data indicate that agaricoglyceride supplementation could restrain metabolic dysfunction through suppressing the nuclear factor-κB pathway as well as decreasing the levels of inflammatory cytokines and total antioxidant activities. PMID:23796217

  8. Amyloid Goiter Secondary to Ulcerative Colitis

    PubMed Central

    Aydin, Bunyamin; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  9. Amyloid Goiter Secondary to Ulcerative Colitis.

    PubMed

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  10. Range Restriction and Attenuation Corrections.

    ERIC Educational Resources Information Center

    Mumford, Michael D.; Mendoza, Jorge L.

    The present paper reviews the techniques commonly used to correct an observed correlation coefficient for the simultaneous influence of attenuation and range restriction effects. It is noted that the procedure which is currently in use may be somewhat biased because it treats range restriction and attenuation as independent restrictive influences.…

  11. Suicide Risk: Amplifiers and Attenuators.

    ERIC Educational Resources Information Center

    Plutchik, Robert; Van Praag, Herman M.

    1994-01-01

    Attempts to integrate findings on correlates of suicide and violent risk in terms of a theory called a two-stage model of countervailing forces, which assumes that the strength of aggressive impulses is modified by amplifiers and attenuators. The vectorial interaction of amplifiers and attenuators creates an unstable equilibrium making prediction…

  12. Adjustable Optical-Fiber Attenuator

    NASA Technical Reports Server (NTRS)

    Buzzetti, Mike F.

    1994-01-01

    Adjustable fiber-optic attenuator utilizes bending loss to reduce strength of light transmitted along it. Attenuator functions without introducing measurable back-reflection or insertion loss. Relatively insensitive to vibration and changes in temperature. Potential applications include cable television, telephone networks, other signal-distribution networks, and laboratory instrumentation.

  13. Mesenchymal stem cells and inflammatory lung diseases.

    PubMed

    Iyer, S S; Co, C; Rojas, M

    2009-03-01

    Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn's disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury. PMID:19352305

  14. Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!

    PubMed Central

    Kodan, P; Chakrapani, M; Shetty, M; Pavan, R; Bhat, P

    2015-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper inflammatory condition, if not recognized and treated in time. A high index of suspicion can help identify the condition early. This condition can occur in the primary or secondary form. Secondary HLH or hemophagocytic syndrome (HPS) secondary to infections is an important clinical entity especially in tropical world. In this article, we share our experience with this entity and make an attempt to explore literature about ravenous macrophages which occurs secondary to infections. It is a series of six cases of HLH secondary to infectious disease in our center in a coastal city in South India over last one year with follow up. PMID:25766345

  15. Idiopathic Inflammatory Myopathies

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2012-01-01

    The idiopathic inflammatory myopathies are a group of rare disorders including polymyositis (PM), dermatomyositis (DM), and autoimmune necrotizing myopathies (NMs). The idiopathic inflammatory myopathies share many similarities. They present acutely, subacutely, or chronically with marked proximal and symmetric muscle weakness, except for associated distal and asymmetric weakness in inclusion body myositis. The idiopathic inflammatory myopathies also share a variable degree of creatine kinase (CK) elevation and a nonspecifically abnormal electromyogram demonstrating an irritative myopathy. The muscle pathology demonstrates inflammatory exudates of variable distribution within the muscle fascicle. Despite these similarities, the idiopathic inflammatory myopathies are a heterogeneous group. The overlap syndrome (OS) refers to the association of PM, DM, or NM with connective tissue disease, such as scleroderma or systemic lupus erythematosus. In addition to elevated antinuclear antibodies (ANA), patients with OS may be weaker in the proximal arms than the legs mimicking the pattern seen in some muscular dystrophies. In this review, we focus on DM, PM, and NM and examine current and promising therapies. PMID:23117947

  16. Intertrigo and secondary skin infections.

    PubMed

    Kalra, Monica G; Higgins, Kim E; Kinney, Bruce S

    2014-04-01

    Intertrigo is a superficial inflammatory dermatitis occurring on two closely opposed skin surfaces as a result of moisture, friction, and lack of ventilation. Bodily secretions, including perspiration, urine, and feces, often exacerbate skin inflammation. Physical examination of skin folds reveals regions of erythema with peripheral scaling. Excessive friction and inflammation can cause skin breakdown and create an entry point for secondary fungal and bacterial infections, such as Candida, group A beta-hemolytic streptococcus, and Corynebacterium minutissimum. Candidal intertrigo is commonly diagnosed clinically, based on the characteristic appearance of satellite lesions. Diagnosis may be confirmed using a potassium hydroxide preparation. Resistant cases require oral fluconazole therapy. Bacterial superinfections may be identified with bacterial culture or Wood lamp examination. Fungal lesions are treated with topical nystatin, clotrimazole, ketoconazole, oxiconazole, or econazole. Secondary streptococcal infections are treated with topical mupirocin or oral penicillin. Corynebacterium infections are treated with oral erythromycin. PMID:24695603

  17. R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice

    PubMed Central

    Schmitz, Katja; de Bruin, Natasja; Bishay, Philipp; Männich, Julia; Häussler, Annett; Altmann, Christine; Ferreirós, Nerea; Lötsch, Jörn; Ultsch, Alfred; Parnham, Michael J; Geisslinger, Gerd; Tegeder, Irmgard

    2014-01-01

    R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T cells, CTLA4+ inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial. PMID:25269445

  18. Chikusetsusaponin V attenuates lipopolysaccharide-induced liver injury in mice.

    PubMed

    Dai, Yan Wen; Zhang, Chang Cheng; Zhao, Hai Xia; Wan, Jing Zhi; Deng, Li Li; Zhou, Zhi Yong; Dun, Yao Yan; Liu, Chao Qi; Yuan, Ding; Wang, Ting

    2016-06-01

    Chikusetsusaponin V (CsV), a saponin from Panax japonicus, has been reported to inhibit inflammatory responses in lipopolysaccharide (LPS)-induced macrophage cells. However, whether CsV could alleviate LPS-induced liver injury in vivo and the potential mechanisms involved remain unclear. In the present study, we investigated the anti-inflammatory effects of CsV on LPS-induced acute liver injury in mice and further explored the potential mechanisms involved. Our results showed that CsV significantly attenuated elevation of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and improved liver histopathological changes in LPS-induced mice. In addition, CsV decreased serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β in LPS challenged mice. Furthermore, CsV inhibited nuclear factor kappa B (NF-κB) activation by downregulating phosphorylated NF-κB, IκB-α, ERK, c-Jun N-terminal kinase (JNK) and p38 levels in the liver tissue, which ultimately decreased nucleus NF-κB protein level. In conclusion, our data suggested that CsV could be a promising drug for preventing LPS challenged liver injury since it attenuated LPS-induced inflammatory responses, partly via inhibiting NF-κB and MAPK signaling pathways. PMID:26981791

  19. Development and Characterization of attenuated Mutant Candidate Vaccines for Control of Paratuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mycobacterium avium subsp. paratuberculosis (Map) is the causative pathogen of Johne’s disease, a chronic inflammatory wasting disease in ruminants. The disease has been difficult to control because of the lack of an effective vaccine. To develop a live attenuated vaccine for Map, as well as for the...

  20. Anti-inflammatory treatment.

    PubMed

    Fistarol, Susanna K; Itin, Peter H

    2011-01-01

    Inflammatory mucosal disorders are treated conventionally with potent or superpotent topical corticosteroids. For more than 20 years, topical cyclosporine has been used in the management of oral mucous membrane affections. Recently other topically applied calcineurin inhibitors, namely tacrolimus and pimecrolimus, expanded the armamentarium for the treatment of inflammatory mucosal diseases. This chapter places its main emphasis on the efficacy and safety of topical calcineurin inhibitors in the management of different oral and genital conditions, including anogenital lichen sclerosus (LS), oral and genital lichen planus, plasma cell balanitis and vulvitis, mucous membrane pemphigoid and pemphigus vulgaris, all conditions having usually a protracted course, requiring long-lasting treatment. There is current evidence for the effectiveness of both pimecrolimus and tacrolimus in the topical treatment of inflammatory oral mucosal diseases and genital dermatoses, especially oral lichen planus and genital LS. PMID:21325840

  1. Inflammatory Bowel Disease.

    PubMed

    2016-01-01

    Inflammation response plays an important role in host survival, and it also leads to acute and chronic inflammatory diseases such as rheumatoid arthritis, bowel diseases, allergic rhinitis, asthma, atopic dermatitis and various neurodegenerative diseases. During the course of inflammation, the ROS level increases. In addition to ROS, several inflammatory mediators produced at the site lead to numerous cell-mediated damages. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal disorder resulting from a dysfunctional epithelial, innate and adaptive immune response to intestinal microorganisms. The methods involving indomethacin-induced enterocolitis in rats with macroscopic changes of IBD, myeloperoxidase assay, microscopic (histologic) characters and biochemical parameters are discussed. PMID:26939275

  2. Evolution of Inflammatory Diseases

    PubMed Central

    Okin, Daniel

    2013-01-01

    The association of inflammation with modern human diseases (e.g. obesity, cardiovascular disease, type 2 diabetes mellitus, cancer) remains an unsolved mystery of current biology and medicine. Inflammation is a protective response to noxious stimuli that unavoidably occurs at a cost to normal tissue function. This fundamental tradeoff between the cost and benefit of the inflammatory response has been optimized over evolutionary time for specific environmental conditions. Rapid change of the human environment due to niche construction outpaces genetic adaptation through natural selection, leading increasingly to a mismatch between the modern environment and selected traits. Consequently, multiple tradeoffs that affect human physiology are not optimized to the modern environment, leading to increased disease susceptibility. Here we examine the inflammatory response from an evolutionary perspective. We discuss unique aspects of the inflammatory response and its evolutionary history that can help explain the association between inflammation and modern human diseases. PMID:22975004

  3. Macrophage Inflammatory Assay

    PubMed Central

    Ylostalo, Joni H.

    2016-01-01

    Macrophages represent a widely distributed and functionally diverse population of innate myeloid cells involved in inflammatory response to pathogens, tissue homeostasis and tissue repair (Murray and Wynn, 2011). Macrophages can be broadly grouped into two subpopulations with opposing activites: M1 or pro-inflammatory macrophages that promote T-helper type 1 (Th1) cell immunity and tissue damage, and M2 or anti-inflammatory/alternatively activated macrophages implicated in Th2 response and resolution of inflammation. Here we describe a rapid assay we used previously to monitor changes in pro-inflammatory and anti-inflammatory cytokine production by lipopolysaccharide (LPS)-activated macrophages in response to therapeutic paracrine factors produced by adult stem cells (Bartosh et al., 2010; Ylostalo et al., 2012; Bartosh et al., 2013). The assay can be adapted appropriately to test macrophage response to other agents as well that will be referred to herein as ‘test reagents’ or ‘test compounds’. In this protocol, the mouse macrophage cell line J774A.1 is expanded as an adherent monolayer on petri dishes allowing for the cells to be harvested easily without enzymes or cell scrapers that can damage the cells. The macropahges are then stimulated in suspension with LPS and seeded into 12-well cell culture plates containing the test reagents. After 16–18 h, the medium conditioned by the macrophages is harvested and the cytokine profile in the medium determined with enzyme-linked immunosorbent assays (ELISA). We routinely measure levels of the pro-inflammtory cytokine TNF-alpha and the anti-inflammatory cytokine interleukin-10 (IL-10).

  4. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  5. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-04-01

    Wave-induced variations of pore pressure in a partially-saturated reservoir result in oscillatory liquid flow. The viscous losses during this flow are responsible for wave attenuation. The same viscous effects determine the changes in the dynamic bulk modulus of the system versus frequency. These changes are necessarily linked to attenuation via the causality condition. We analytically quantify the frequency dependence of the bulk modulus of a partially saturated rock by assuming that saturation is patchy and then link these changes to the inverse quality factor. As a result, the P-wave attenuation is quantitatively linked to saturation and thus can serve as a saturation indicator.

  6. Inflammatory nodules following soft tissue filler use: a review of causative agents, pathology and treatment options.

    PubMed

    Ledon, Jennifer A; Savas, Jessica A; Yang, Steven; Franca, Katlein; Camacho, Ivan; Nouri, Keyvan

    2013-10-01

    Nodule development is a common complication following the use of fillers for soft tissue augmentation and is commonly categorized as inflammatory or non-inflammatory in nature. Inflammatory nodules may appear anywhere from days to years after treatment, whereas non-inflammatory nodules are typically seen immediately following implantation and are usually secondary to improper placement of the filler. Although inflammatory nodules are more common with permanent fillers such as silicone, inflammatory nodule development following administration of temporary fillers such as hyaluronic acid and collagen has also been reported. Treated many times with corticosteroids due to their anti-inflammatory properties, inflammatory nodules may be secondary to infection or biofilm formation, warranting the use of alternative agents. Appropriate and prompt diagnosis is important in avoiding delay of treatment or long-term complications for the patient. This paper addresses the etiology, development, and studied treatment options available for inflammatory nodules secondary to each of the major classes of fillers. With this knowledge, practitioners may expeditiously recognize and manage this common side effect and thus maximize functional and aesthetic benefit. PMID:24037757

  7. Diarrhea in chronic inflammatory bowel diseases.

    PubMed

    Wenzl, Heimo H

    2012-09-01

    Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea. PMID:22917170

  8. Reduced Acute Inflammatory Responses to Microgel Conformal Coatings

    PubMed Central

    Bridges, Amanda W.; Singh, Neetu; Burns, Kellie L.; Babensee, Julia E.; Lyon, L. Andrew; García, Andrés J.

    2008-01-01

    Implantation of synthetic materials into the body elicits inflammatory host responses that limit medical device integration and biological performance. This inflammatory cascade involves protein adsorption, leukocyte recruitment and activation, cytokine release, and fibrous encapsulation of the implant. We present a coating strategy based on thin films of poly(N-isopropylacrylamide) hydrogel microparticles (i.e. microgels) cross-linked with poly(ethylene glycol) diacrylate. These particles were grafted onto a clinically relevant polymeric material to generate conformal coatings that significantly reduced in vitro fibrinogen adsorption and primary human monocytes/macrophage adhesion and spreading. These microgel coatings also reduced leukocyte adhesion and expression of pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) in response to materials implanted acutely in the murine intraperitoneal space. These microgel coatings can be applied to biomedical implants as a protective coating to attenuate biofouling, leukocyte adhesion and activation, and adverse host responses for biomedical and biotechnological applications. PMID:18804859

  9. Hesperetin derivatives: Synthesis and anti-inflammatory activity.

    PubMed

    Wang, Qian-Qian; Shi, Jing-Bo; Chen, Chen; Huang, Cheng; Tang, Wen-Jian; Li, Jun

    2016-03-01

    Sixteen novel hesperetin derivatives containing Mannich base moiety were designed and synthesized and their anti-inflammatory activities were evaluated by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in mouse RAW264.7 macrophages. Compounds 3a-3k showed better hydrophilic, while compounds 3l-3p with aromatic groups was hydrophobic. The anti-inflammatory activity of title compounds was correlated with logP values, among them, compounds 3c, 3e and 3i with minus logP values exhibited best anti-inflammatory activity through decreasing both IL-6 and TNF-α. Furthermore, the expression of LPS-induced notch1 and inos was reduced by compounds 3c, 3e, and 3i, and compound 3e attenuated LPS-induced inos protein levels in a dose-dependent manner. PMID:26848111

  10. Prostacyclin: An Inflammatory Paradox

    PubMed Central

    Stitham, Jeremiah; Midgett, Charles; Martin, Kathleen A.; Hwa, John

    2011-01-01

    Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI2) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI2) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI2) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression (“pro-inflammatory”), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression (“anti-inflammatory”). The emerging role of prostacyclin (PGI2) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments. PMID:21687516

  11. Mesenteric inflammatory myofibroblastic tumors

    PubMed Central

    Chaudhary, Poras

    2015-01-01

    Inflammatory myofibroblastic tumors (IMTs), also known as inflammatory pseudotumors and inflammatory fibrosarcomas, are uncommon mesenchymal tumors composed of myofibroblastic spindle cells admixed with lymphocytes, plasma cells and eosinophils. Once thought to be reactive, these lesions are now considered to be neoplastic. These tumors can occur throughout the body, most commonly in the lung, mesentery and omentum. Patients commonly present with painless abdominal mass or with intestinal obstruction. IMTs may be multicentric, have a high local recurrence rate and may metastasize in rare cases. The lesions show wide variability in their histologic features and cellularity, and marked inflammatory infiltration, predominantly of plasmatocytes and lymphocytes, and occasionally neutrophils and eosinophils. Anaplastic lymphoma kinase (ALK) rearrangements and/or ALK1 and p80 immunoreactivity are reported in 33-67% of the tumors. Owing to the rarity of these lesions, there are no specific imaging findings that distinguish IMTs from other mesenteric masses. Complete surgical resection is the treatment of choice. Local recurrence rates are high, and re-excision is the preferred therapy for local recurrences. ALK-positive tumors show good response to ALK inhibitors. Current knowledge and comprehensive review of the available literature on IMTs is herein presented. PMID:25608706

  12. Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

    PubMed Central

    Chmiel, James F.; Konstan, Michael W.; Elborn, J. Stuart

    2013-01-01

    Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed. PMID:23880054

  13. Antibiotic and anti-inflammatory therapies for cystic fibrosis.

    PubMed

    Chmiel, James F; Konstan, Michael W; Elborn, J Stuart

    2013-10-01

    Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed. PMID:23880054

  14. Method for detecting moisture in soils using secondary cosmic radiation

    DOEpatents

    Condreva, Kenneth

    2003-12-16

    Water content in a soil is determined by measuring the attenuation of secondary background cosmic radiation as this radiation propagates through a layer of soil and water. By measuring the attenuation of secondary cosmic radiation in the range of 5 MeV-15 MeV it is possible to obtain a relative measure of the water content in a soil layer above a suitable radiation detector and thus establish when and how much irrigation is needed. The electronic circuitry is designed so that a battery pack can be used to supply power.

  15. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

    PubMed

    Zhang, Qun; Yuan, Lin; Zhang, Qingrui; Gao, Yan; Liu, Guangheng; Xiu, Meng; Wei, Xiang; Wang, Zhen; Liu, Dexiang

    2015-09-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia-induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IκB-alpha and phosphorylation of p65 NF-κB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia-stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-ĸB, ERK and JNK MAPK signaling pathways. PMID:26225925

  16. Large bowel obstruction secondary to adhesive bands.

    PubMed

    El-Masry, Nabil S; Geevarghese, Ruben

    2015-01-01

    Large bowel obstruction (LBO) is most commonly due to malignancy, volvulus, hernia, diverticular disease and inflammatory bowel disease. LBO due to adhesions is unusual. A literature review was conducted which revealed that only a few such cases have been reported. We report two cases of LBO secondary to adhesions in patients, one with and one without a past abdominal surgical history. We highlight that while rare, the aetiology of LBO secondary to adhesions must be considered in the differential diagnosis in patients presenting with obstructive symptoms. PMID:25650387

  17. Chronic Inflammatory Demyelinating Polyneuropathy

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

  18. Inflammatory pseudotumor of spleen

    PubMed Central

    Rajabi, Parvin; Noorollahi, Hasan; Hani, Mohsen; Bagheri, Marzie

    2014-01-01

    Inflammatory pseudotumor (IPT) is an uncommon tumor and its occurrence in spleen is rare. This tumor is composed of proliferation of spindle cells of unknown origin and etiology that mimic other tumors at clinical and histological evaluation. The most surmising etiology is Epstein Barr virus (EBV) and the most suspected origin is myofibroblasts, hence its synonym is “inflammatory myofibroblastic tumor.” The clinical appearance of tumor is related to its location but the most ones are abdominal pain, fever and weight loss. Surgical removal for this lesion is treatment of choice and there is few reported case with recurrence and metastasis. Herein we report a 63-year-old female patient with and abdominal discomfort that primary paraclinical investigations had been showed splenic mass and therefore surgical treatment was performed for her. Microscopic examination suggest some different diagnosis such as IPT, thus immunohistochemical staining was perform to confirm the diagnosis and rule out the others. PMID:24592376

  19. Inflammatory mechanisms of endometritis.

    PubMed

    Woodward, E M; Troedsson, M H T

    2015-07-01

    Transient post breeding endometritis is a normal physiological reaction in the mare, as it is believed that an inflammatory response is necessary for the effective removal of contaminating bacteria and excess spermatozoa introduced into the uterus. While most mares can clear endometritis within a reasonable amount of time, persistent endometritis caused by either bacteria or spermatozoa can threaten the success of a pregnancy. A subpopulation of mares is susceptible to persistent endometritis, and these mares are a concern in equine reproductive medicine. Research has identified several factors that contribute to susceptibility; however, the exact mechanisms of the progression of the disease are still being elucidated. Current research focuses on endometrial gene expression during endometritis in an attempt to understand the timing of specific inflammatory processes involved with the development of susceptibility to persistent endometritis. With an increased understanding of the mechanisms involved with the disease, current treatments can be improved upon, and new treatments can be developed to target affected pathways. PMID:25537084

  20. The long-acting β2-adrenoceptor agonist olodaterol attenuates pulmonary inflammation

    PubMed Central

    Wex, Eva; Kollak, Ines; Duechs, Matthias J; Naline, Emmanuel; Wollin, Lutz; Devillier, Philippe

    2015-01-01

    Background and Purpose β2-adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β2-adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions. Experimental Approach Olodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-α release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated. Key Results Olodaterol dose-dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration. Conclusions and Implications This is the first evidence for the anti-inflammatory efficacy of a β2-adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting β2-adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days. PMID:25824824

  1. Keratoconus: an inflammatory disorder?

    PubMed Central

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-01-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

  2. Keratoconus: an inflammatory disorder?

    PubMed

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-07-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

  3. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway.

    PubMed

    Liu, Xiaojie; Mei, Zhigang; Qian, Jingping; Zeng, Yongbao; Wang, Mingzhi

    2013-12-01

    Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen), has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment (intravenous injection) reduced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissue. Pretreatment with puerarin (intravenous injection) attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) activation and nuclear factor kappa B (NF-κB) inhibition. These observations were inhibited by the alpha7 nicotinic acetylcholine receptor (α7nAchR) antagonist α-bungarotoxin (α-BGT). In addition, puerarin pretreatment increased the expression of α7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory response. Our results also indicated that the anti-inflammatory effect of puerarin may partly be mediated through the activation of the cholinergic anti-inflammatory pathway. PMID:25206641

  4. Coagulation parameters in inflammatory bowel disease

    PubMed Central

    Dolapcioglu, Can; Soylu, Aliye; Kendir, Tulin; Ince, Ali Tuzun; Dolapcioglu, Hatice; Purisa, Sevim; Bolukbas, Cengiz; Sokmen, Haci Mehmet; Dalay, Remzi; Ovunc, Oya

    2014-01-01

    Thromboembolic events represent a major cause of morbidity and mortality in patients with inflammatory bowel disease and they may occur both at the gastrointestinal tract and at extraintestinal sites. This study aimed to examine the alterations in coagulation parameters involved at different steps of hemostasis in patients with Crohn’s disease and ulcerative colitis, in comparison with healthy individuals. Fifty-one patients with inflammatory bowel disease and 26 healthy controls were included in this study. Plasma levels of PT, APTT, AT III, plasminogen, fibrinogen, D-dimer, factor V, factor VIII, protein C, protein S, and APCR were measured and factor V Leiden mutation was examined in both patients and controls. Two patients with ulcerative colitis had a history of previous thromboembolic event. Inflammatory bowel disease was associated with significantly higher levels of fibrinogen, PT, factor V, factor VIII, plasminogen and thrombocyte. Protein S, fibrinogen, plasminogen and thrombocyte levels were associated with disease activity, depending on the type of the disease (Crohn’s disease or ulcerative colitis). The coagulation abnormalities detected in this study seems to be a secondary phenomena resulting from the disease process, which is more likely to be associated with a multitude of factors rather than a single abnormality. PMID:24995109

  5. [Ultrasonographic diagnosis of inflammatory neuropathies].

    PubMed

    Sugimoto, Takamichi; Ochi, Kazuhide; Hosomi, Naohisa; Matsumoto, Masayasu

    2014-03-01

    Ultrasonographic nerve enlargement has primarily been reported in patients with inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, Guillain-Barre syndrome, vasculitic neuropathy and leprosy. Nerve ultrasonography is a promising diagnostic supportive tool for inflammatory neuropathies. The ultrasonographic findings that are currently useful are 1) nerve enlargement primarily suggests the existence of inflammatory or demyelinating neuropathies and 2) for patients with CIDP or demyelinating Charcot-Marie-Tooth disease, the pattern of nerve enlargement is noted, and this pattern is useful for discriminating between these diseases. More precise evidence of ultrasonographic findings for inflammatory neuropathies should be established in the future. PMID:24607946

  6. Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice.

    PubMed

    Siljehav, Veronica; Shvarev, Yuri; Herlenius, Eric

    2014-11-01

    Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R(-/-) mice (P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R(-/-) preparations (P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R(-/-) mice. Moreover, during severe hypoxic stress EP3R(-/-) mice had an increased gasping duration (P < 0.01) as well as number of gasps (P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R(-/-) mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia (P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R(-/-) mice (P < 0.05). In vitro, EP3R(-/-) brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium (P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates. PMID:25213632

  7. Peripheral Brain Derived Neurotrophic Factor Precursor Regulates Pain as an Inflammatory Mediator.

    PubMed

    Luo, Cong; Zhong, Xiao-Lin; Zhou, Fiona H; Li, Jia-Yi; Zhou, Pei; Xu, Jun-Mei; Song, Bo; Li, Chang-Qi; Zhou, Xin-Fu; Dai, Ru-Ping

    2016-01-01

    The precursor of brain derived neurotrophic factor (proBDNF), the unprocessed BDNF gene product, binds to its receptors and exerts the opposing biologic functions of mature BDNF. proBDNF is expressed in the peripheral tissues but the functions of peripheral proBDNF remain elusive. Here we showed that proBDNF and its predominant receptor, p75 pan-neurotrophin receptor were upregulated in the nerve fibers and inflammatory cells in the local tissue in inflammatory pain. Neutralization of proBDNF by polyclonal antibody attenuated pain in different models of inflammatory pain. Unilateral intra-plantar supplementation of proBDNF by injecting exogenous proBDNF or ectopic overexpression resulted in pain hypersensitivity and induced spinal phosphorylated extracellular signal-regulated kinase activation. Exogenous proBDNF injection induced the infiltration of inflammatory cells and the activation of proinflammatory cytokines, suggesting that inflammatory reaction contributed to the pro-algesic effect of proBDNF. Finally, we generated monoclonal anti-proBDNF antibody that could biologically block proBDNF. Administration of monoclonal Ab-proBDNF attenuated various types of inflammatory pain and surgical pain. Thus, peripheral proBDNF is a potential pain mediator and anti-proBDNF pretreatment may alleviate the development of inflammatory pain. PMID:27251195

  8. Peripheral Brain Derived Neurotrophic Factor Precursor Regulates Pain as an Inflammatory Mediator

    PubMed Central

    Luo, Cong; Zhong, Xiao-Lin; Zhou, Fiona H.; Li, Jia-yi; Zhou, Pei; Xu, Jun-Mei; Song, Bo; Li, Chang-Qi; Zhou, Xin-Fu; Dai, Ru-Ping

    2016-01-01

    The precursor of brain derived neurotrophic factor (proBDNF), the unprocessed BDNF gene product, binds to its receptors and exerts the opposing biologic functions of mature BDNF. proBDNF is expressed in the peripheral tissues but the functions of peripheral proBDNF remain elusive. Here we showed that proBDNF and its predominant receptor, p75 pan-neurotrophin receptor were upregulated in the nerve fibers and inflammatory cells in the local tissue in inflammatory pain. Neutralization of proBDNF by polyclonal antibody attenuated pain in different models of inflammatory pain. Unilateral intra-plantar supplementation of proBDNF by injecting exogenous proBDNF or ectopic overexpression resulted in pain hypersensitivity and induced spinal phosphorylated extracellular signal-regulated kinase activation. Exogenous proBDNF injection induced the infiltration of inflammatory cells and the activation of proinflammatory cytokines, suggesting that inflammatory reaction contributed to the pro-algesic effect of proBDNF. Finally, we generated monoclonal anti-proBDNF antibody that could biologically block proBDNF. Administration of monoclonal Ab-proBDNF attenuated various types of inflammatory pain and surgical pain. Thus, peripheral proBDNF is a potential pain mediator and anti-proBDNF pretreatment may alleviate the development of inflammatory pain. PMID:27251195

  9. Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

    PubMed Central

    Hanes, William M; Olofsson, Peder S; Kwan, Kevin; Hudson, LaQueta K; Chavan, Sangeeta S; Pavlov, Valentin A; Tracey, Kevin J

    2015-01-01

    Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach. PMID:26322849

  10. Dietary L-arginine supplementation modulates lipopolysaccharide-induced systemic inflammatory response in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was conducted to evaluate whether dietary supplementation with L-arginine (Arg) could attenuate lipopolysaccharide (LPS)-induced systemic inflammatory response through LPS/TLR-4 signaling pathway in broilers. The experiment was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatm...

  11. Vitamin D and inflammatory diseases

    PubMed Central

    Yin, Kai; Agrawal, Devendra K

    2014-01-01

    Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed. PMID:24971027

  12. B-1a Lymphocytes Attenuate Insulin Resistance

    PubMed Central

    Shen, Lei; Chng, MH; Alonso, Michael N.; Yuan, Robert

    2015-01-01

    Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell–derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell–deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell–activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell–depleting, B-1a cell–sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance. PMID:25249575

  13. Vinpocetine attenuates lipid accumulation and atherosclerosis formation.

    PubMed

    Cai, Yujun; Li, Jian-Dong; Yan, Chen

    2013-05-10

    Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis. PMID:23583194

  14. Vinpocetine Attenuates Lipid Accumulation and Atherosclerosis Formation

    PubMed Central

    Cai, Yujun; Li, Jian-Dong; Yan, Chen

    2013-01-01

    Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis PMID:23583194

  15. Sound attenuation in magnetorheological fluids

    NASA Astrophysics Data System (ADS)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  16. Sphingosine Kinases Are Not Required for Inflammatory Responses in Macrophages*

    PubMed Central

    Xiong, Yuquan; Lee, Hyeuk Jong; Mariko, Boubacar; Lu, Yi-Chien; Dannenberg, Andrew J.; Haka, Abigail S.; Maxfield, Frederick R.; Camerer, Eric; Proia, Richard L.; Hla, Timothy

    2013-01-01

    Sphingosine kinases (Sphks), which catalyze the formation of sphingosine 1-phosphate (S1P) from sphingosine, have been implicated as essential intracellular messengers in inflammatory responses. Specifically, intracellular Sphk1-derived S1P was reported to be required for NFκB induction during inflammatory cytokine action. To examine the role of intracellular S1P in the inflammatory response of innate immune cells, we derived murine macrophages that lack both Sphk1 and Sphk2 (MΦ Sphk dKO). Compared with WT counterparts, MΦ Sphk dKO cells showed marked suppression of intracellular S1P levels whereas sphingosine and ceramide levels were strongly up-regulated. Cellular proliferation and apoptosis were similar in MΦ Sphk dKO cells compared with WT counterparts. Treatment of WT and MΦ Sphk dKO with inflammatory mediators TNFα or Escherichia coli LPS resulted in similar NFκB activation and cytokine expression. Furthermore, LPS-induced inflammatory responses, mortality, and thioglycolate-induced macrophage recruitment to the peritoneum were indistinguishable between MΦ Sphk dKO and littermate control mice. Interestingly, autophagic markers were constitutively induced in bone marrow-derived macrophages from Sphk dKO mice. Treatment with exogenous sphingosine further enhanced intracellular sphingolipid levels and autophagosomes. Inhibition of autophagy resulted in caspase-dependent cell death. Together, these data suggest that attenuation of Sphk activity, particularly Sphk2, leads to increased intracellular sphingolipids and autophagy in macrophages. PMID:24081141

  17. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

    PubMed

    Liu, Yunen; Tan, Dehong; Shi, Lin; Liu, Xinwei; Zhang, Yubiao; Tong, Changci; Song, Dequn; Hou, Mingxiao

    2015-01-01

    We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE. PMID:26133371

  18. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury

    PubMed Central

    Liu, Yunen; Tan, Dehong; Shi, Lin; Liu, Xinwei; Zhang, Yubiao; Tong, Changci; Song, Dequn; Hou, Mingxiao

    2015-01-01

    We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE. PMID:26133371

  19. Extra intestinal manifestations and complications in inflammatory bowel disease.

    PubMed

    Marineaţă, Anca; Rezuş, Elena; Mihai, Cătălina; Prelipcean, Cristina Cijevschi

    2014-01-01

    Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), doesn't affect only the intestinal tract, but also involve other organs such as: eyes, skin, joints, liver and biliary tracts, kidneys, lungs, vascular system. It is difficult to differentiate the true extraintestinal manifestations from secondary extraintestinal complications. The pathogenetic autoimmune mechanisms include genetic susceptibility, antigenic display of autoantigen, aberrant self-recognition and immunopathogenetic autoantibodies against organ-specific cellular antigens shared by colon and extra-colonic organs. An important role is owned by microbes due to molecular mimicry. This paper reviews the frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. PMID:25076688

  20. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-04-01

    In this report we will show results of seismic and well log derived attenuation attributes from a deep water Gulf of Mexico data set. This data was contributed by Burlington Resources and Seitel Inc. The data consists of ten square kilometers of 3D seismic data and three well penetrations. We have computed anomalous seismic absorption attributes on the seismic data and have computed Q from the well log curves. The results show a good correlation between the anomalous absorption (attenuation) attributes and the presence of gas as indicated by well logs.

  1. Anti-Inflammatory Property of Plantago major Leaf Extract Reduces the Inflammatory Reaction in Experimental Acetaminophen-Induced Liver Injury.

    PubMed

    Hussan, Farida; Mansor, Adila Sofea; Hassan, Siti Nazihahasma; Tengku Nor Effendy Kamaruddin, Tg Nurul Tasnim; Budin, Siti Balkis; Othman, Faizah

    2015-01-01

    Hepatic injury induces inflammatory process and cell necrosis. Plantago major is traditionally used for various diseases. This study aimed to determine the anti-inflammatory property of P. major leaf extracts on inflammatory reaction following acetaminophen (APAP) hepatotoxicity. Thirty male Sprague-Dawley rats were divided into 5 groups, namely, normal control (C), APAP, aqueous (APAP + AQ), methanol (APAP + MT), and ethanol (APAP + ET) extract treated groups. All APAP groups received oral APAP (2 g/kg) at day 0. Then, 1000 mg/kg dose of P. major extracts was given for six days. The levels of liver transaminases were measured at day 1 and day 7 after APAP induction. At day 7, the blood and liver tissue were collected to determine plasma cytokines and tissue 11β-HSD type 1 enzyme. The in vitro anti-inflammatory activities of methanol, ethanol, and aqueous extracts were 26.74 ± 1.6%, 21.69 ± 2.81%, and 12.23 ± 3.15%, respectively. The ALT and AST levels were significantly higher in the APAP groups at day 1 whereas the enzyme levels of all groups showed no significant difference at day 7. The extracts treatment significantly reduced the proinflammatory cytokine levels and significantly increased the 11β-HSD type 1 enzyme activity (p < 0.05). In conclusion, the P. major extracts attenuate the inflammatory reaction following APAP-induced liver injury. PMID:26300946

  2. Chronic inflammatory systemic diseases

    PubMed Central

    Straub, Rainer H.; Schradin, Carsten

    2016-01-01

    It has been recognized that during chronic inflammatory systemic diseases (CIDs) maladaptations of the immune, nervous, endocrine and reproductive system occur. Maladaptation leads to disease sequelae in CIDs. The ultimate reason of disease sequelae in CIDs remained unclear because clinicians do not consider bodily energy trade-offs and evolutionary medicine. We review the evolution of physiological supersystems, fitness consequences of genes involved in CIDs during different life-history stages, environmental factors of CIDs, energy trade-offs during inflammatory episodes and the non-specificity of CIDs. Incorporating bodily energy regulation into evolutionary medicine builds a framework to better understand pathophysiology of CIDs by considering that genes and networks used are positively selected if they serve acute, highly energy-consuming inflammation. It is predicted that genes that protect energy stores are positively selected (as immune memory). This could explain why energy-demanding inflammatory episodes like infectious diseases must be terminated within 3–8 weeks to be adaptive, and otherwise become maladaptive. Considering energy regulation as an evolved adaptive trait explains why many known sequelae of different CIDs must be uniform. These are, e.g. sickness behavior/fatigue/depressive symptoms, sleep disturbance, anorexia, malnutrition, muscle wasting—cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal (HPG) axis, hypertension, bone loss and hypercoagulability. Considering evolved energy trade-offs helps us to understand how an energy imbalance can lead to the disease sequelae of CIDs. In the future, clinicians must translate this knowledge into early diagnosis and symptomatic treatment in CIDs. PMID:26817483

  3. Neuroprotective effects of activated protein C on intrauterine inflammation-induced neonatal white matter injury are associated with the downregulation of fibrinogen-like protein 2/fibroleukin prothrombinase and the inhibition of pro-inflammatory cytokine expression

    PubMed Central

    JIN, SHENG-JUAN; LIU, YAN; DENG, SHI-HUA; LIAO, LI-HONG; LIN, TU-LIAN; NING, QIN; LUO, XIAO-PING

    2015-01-01

    Maternal intrauterine inflammation or infection is an important risk factor for neonatal cerebral white matter injury (WMI) and future neurological deficits. Activated protein C (APC), a natural anticoagulant, has been shown to exhibit anti-inflammatory, anti-apoptotic, profibrinolytic and cytoprotective activities. Recent studies have demonstrated that the novel prothrombinase, fibrinogen-like protein 2 (fgl2), contributes to the pathogenesis of a number of inflammatory diseases through the generation of fibrin. Thus, we hypothesized that APC may regulate coagulant and inflammatory processes and improve brain injury in an experimental rat model of intrauterine inflammation-induced WMI. The animal model was established by the administration of an intraperitoneal injection of lipopolysaccharide (LPS) to pregnant Sprague-Dawley rats on embryonic day (E)17 and E18. APC was administered intraperitoneally 30 min after the second LPS injection. The expression of fgl2 and the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression in the placentas and fetal brains was determined on E19. Nerve cell death, the brain water content and protease-activated receptor 1 (PAR1) and nuclear factor κB (NF-κB) p65 expression was detected in the fetal brains. WMI in the neonatal rat brains was evaluated by hematoxylin and eosin (H&E) staining and immunohistochemistry for myelin basic protein (MBP). The results revealed that APC markedly reduced the LPS-induced increase in fgl2 expression and fibrin deposition, as well as the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in the placentas and fetal brains. In addition, APC attenuated cerebral apoptosis and brain edema, downregulated PAR1 and NF-κB p65 expression in the fetal brains, and improved hypomyelination and structural disturbances in the periventricular area of the neonatal rat brains. Our observations provide evidence that APC attenuates fetal

  4. [Inflammatory myopathies. New concepts].

    PubMed

    López Longo, Francisco Javier

    2008-03-01

    Myopathies are diseases characterized by the primary affection of skeletal muscle. In general they present with muscle weakness, pain, contracture, paresthesias, rigidity, or fatigue. They can be hereditary, such as muscle dystrophies, congenital, myotonic, metabolic, and myasthenic, or acquired. Among the latter ones we include idiopathic inflammatory myopathies (IIM), toxic, endocrine, or infectious myopathies and myasthenia gravis. There is a current acceptance of considerable clinical and histopathological overlap among some muscle dystrophies and some IIM. However, the molecular profile is different and characteristic in each myopathy and the study into the patterns of expression of genes in the muscle can be useful in their differential diagnosis, including that of IIM. PMID:21794553

  5. Anti-inflammatory Activity.

    PubMed

    2016-01-01

    Inflammation is the body's first response to infection or injury and is critical for both innate and adaptive immunity. It can be considered as part of the complex biological response of vascular tissues to harmful stimuli such as pathogens, damaged cells, or irritants. The search for natural compounds and phytoconstituents that are able to interfere with these mechanisms by preventing a prolonged inflammation could be useful for human health. Here, the anti-inflammatory properties of plant-based drugs are put together with both in vitro and acute (carrageenan, egg albumin and croton oil) and chronic (cotton pellet) in vivo models. PMID:26939273

  6. Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response.

    PubMed

    Hansel, Gisele; Tonon, André Comiran; Guella, Felipe Lhywinskh; Pettenuzzo, Letícia Ferreira; Duarte, Thiago; Duarte, Marta Maria Medeiros Frescura; Oses, Jean Pierre; Achaval, Matilde; Souza, Diogo Onofre

    2015-12-01

    Stroke is the major cause of death and the most frequent cause of disability in the adult population worldwide. Guanosine plays an important neuroprotective role in several cerebral ischemic models and is involved in the modulation of oxidative responses and glutamatergic parameters. Because the excessive reactive oxygen species produced during an ischemic event can trigger an inflammatory response, the purpose of this study was to evaluate the hypothesis that guanosine is neuroprotective against focal cerebral ischemia, inhibits microglia/macrophages activation, and mediates an inflammatory response ameliorating the neural damage. Permanent focal cerebral ischemia was induced in adult rats, and guanosine was administered immediately, 1, 3, and 6 h after surgery. Twenty-four hours after ischemia, the asymmetry scores were evaluated by the cylinder test; neuronal damage was evaluated by Fluoro-Jade C (FJC) staining and propidium iodide (PI) incorporation; microglia and immune cells were evaluated by anti-Iba-1 antibody; and inflammatory parameters such as interleukins (IL): IL-1, IL-6, IL-10; tumor necrosis factors alpha (TNF-α); and interferon-gamma (INF-γ) were evaluated in the brain tissue and cerebrospinal fluid. The ischemic event increased the levels of Iba-1-positive cells and pro-inflammatory cytokines and decreased IL-10 levels (an anti-inflammatory cytokine) in the lesion periphery. The guanosine treatment attenuated the changes in these inflammatory parameters and also reduced the infarct volume, PI incorporation, and number of FJC-positive cells, improving the functional recovery. Thus, guanosine may have been a promising therapeutic agent for the treatment of ischemic brain injury by reduction of inflammatory process triggered in an ischemic event. PMID:25394382

  7. The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury

    PubMed Central

    Collino, Massimo; Pini, Alessandro; Mastroianni, Rosanna; Benetti, Elisa; Lanzi, Cecilia; Bani, Daniele; Chini, Jacopo; Manoni, Marco; Fantozzi, Roberto; Masini, Emanuela

    2012-01-01

    Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1–1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E2 and tumour-necrosis-factor-α production. The robust increase in oxidative stress and inflammatory markers was blunted by K5-N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5-N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects. PMID:22248092

  8. Plasma-parameter measurements using neutral-particle-beam attenuation

    SciTech Connect

    Foote, J H; Molvik, A W; Turner, W C

    1982-07-07

    Intense and energetic neutral-particle-beam injection used for fueling or heating magnetically confined, controlled-fusion experimental plasmas can also provide diagnostic measurements of the plasmas. The attenuation of an atomic beam (mainly from charge-exchange and ionization interactions) when passing through a plasma gives the plasma line density. Orthogonal arrays of highly collimated detectors of the secondary-electron-emission type have been used in magnetic-mirror experiments to measure neutral-beam attenuation along chords through the plasma volume at different radial and axial positions. The radial array is used to infer the radial plasma-density profile; the axial array, to infer the axial plasma-density profile and the ion angular distribution at the plasma midplane.

  9. NATURAL ATTENUATION OF CHLORINATED SOLVENTS

    EPA Science Inventory

    The protocol will simply describe in detail, with references and illustrations, the approach currently used by staff of the SPRD to evaluate natural attenuation of chlorinated solvents in ground water. Staff of SPRD, and staff of the Air Force Center for environmental excellence...

  10. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-07-01

    In fully-saturated rock and at ultrasonic frequencies, the microscopic squirt flow induced between the stiff and soft parts of the pore space by an elastic wave is responsible for velocity-frequency dispersion and attenuation. In the seismic frequency range, it is the macroscopic cross-flow between the stiffer and softer parts of the rock. We use the latter hypothesis to introduce simple approximate equations for velocity-frequency dispersion and attenuation in a fully water saturated reservoir. The equations are based on the assumption that in heterogeneous rock and at a very low frequency, the effective elastic modulus of the fully-saturated rock can be estimated by applying a fluid substitution procedure to the averaged (upscaled) dry frame whose effective porosity is the mean porosity and the effective elastic modulus is the Backus-average (geometric mean) of the individual dry-frame elastic moduli of parts of the rock. At a higher frequency, the effective elastic modulus of the saturated rock is the Backus-average of the individual fully-saturated-rock elastic moduli of parts of the rock. The difference between the effective elastic modulus calculated separately by these two methods determines the velocity-frequency dispersion. The corresponding attenuation is calculated from this dispersion by using (e.g.) the standard linear solid attenuation model.

  11. Other noninfectious inflammatory disorders.

    PubMed

    Rovira, Álex; Auger, Cristina; Rovira, Antoni

    2016-01-01

    Idiopathic inflammatory-demyelinating diseases (IIDDs) represent a broad spectrum of central nervous system (CNS) disorders, including monophasic, multiphasic, and progressive disorders that range from highly localized forms to multifocal or diffuse variants. In addition to the classic multiple sclerosis (MS) phenotypes, several MS variants have been described, which can be differentiated on the basis of severity, clinical course, and lesion distribution. Other forms of IIDD are now recognized as distinct entities and not MS variants, such as acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. The CNS can also be affected by a variety of inflammatory diseases. These include primary angiitis of the CNS (PACNS), a rare disorder specifically targeting the CNS vasculature, and various systemic conditions which, among other organs and systems, can also affect the CNS, such as systemic vasculitis and sarcoidosis. The diagnosis of PACNS is difficult, as this condition may be confused with reversible cerebral vasoconstriction syndrome (RCVS), a term comprising a group of conditions characterized by prolonged but reversible vasoconstriction of the cerebral arteries. Magnetic resonance imaging of the brain and spine is the radiologic technique of choice for diagnosing these disorders, and, together with the clinical and laboratory findings, enables a prompt and accurate diagnosis. PMID:27432677

  12. Idiopathic Inflammatory Myopathies

    PubMed Central

    Barohn, Richard J.; Amato, Anthony

    2014-01-01

    The idiopathic inflammatory myopathies (IIM) consist of rare heterogenous autoimmune disorders that present with marked proximal and symmetric muscle weakness, except for distal and asymmetric weakness in inclusion body myositis (IBM). Besides frequent creatine kinase (CK) elevation, the electromyogram confirms the presence of an irritative myopathy. Extramuscular involvement affects a significant number of cases with interstitial lung disease (ILD), cutaneous in dermatomyositis (DM), systemic or joint manifestations and increased risk of malignancy especially in DM. Myositis specific autoantibodies influence phenotype of the IIM. Jo-1 antibodies are frequently associated with ILD and the newly described HMG-CoA reductase antibodies are characteristic of autoimmune necrotizing myopathy (NM). Muscle pathology ranges from inflammatory exudates of variable distribution, to intact muscle fiber invasion, necrosis, phagocytosis and in the case of IBM rimmed vacuoles and protein deposits. Despite many similarities, the IIM are a quite heterogeneous from the histopathological and pathogenetic standpoints in addition to some clinical and treatment-response difference. The field has witnessed significant advances in our understanding of pathophysiology and treatment of these rare disorders. In this review, we focus on DM, polymyositis (PM) and NM and examine current and promising therapies. The reader interested in more details on IBM is referred to the corresponding chapter in this issue. PMID:25037081

  13. Endogenous endophthalmitis secondary to erysipelas.

    PubMed

    Costa, José F; Marques, João Pedro; Marques, Marco; Quadrado, Maria João

    2015-01-01

    A 64-year-old woman with chronic right arm lymphoedema presented with progressive and painful vision loss in the right eye following diagnosis of erysipelas in the ipsilateral arm. Visual acuity was light perception. Biomicroscopy revealed marked conjunctival injection, decreased corneal transparency and an inflammatory mass in the anterior chamber, which precluded fundoscopy. The ocular ultrasonography features were consistent with acute endophthalmitis, and the patient was admitted to the hospital. A systemic evaluation, including complete physical examination, echocardiography and blood tests, ruled out other sources of infection besides the cutaneous site. Blood cultures were positive for group A Streptococcus. A diagnosis of unilateral acute endophthalmitis due to group A Streptococcus bacteraemia secondary to erysipelas was made and successfully treated with optimal medical care, including prompt intravitreal and systemic antibiotic administration. Despite resolution of the infectious process, visual acuity did not improve. PMID:26123459

  14. Stormwater Attenuation by Green Roofs

    NASA Astrophysics Data System (ADS)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.

    2014-12-01

    Innovative municipal stormwater management technologies are urgently required in urban centers. Inadequate stormwater management can lead to excessive flooding, channel erosion, decreased stream baseflows, and degraded water quality. A major source of urban stormwater is unused roof space. Green roofs can be used as a stormwater management tool to reduce roof generated stormwater and generally improve the quality of runoff. With recent legislation in some North American cities, including Toronto, requiring the installation of green roofs on large buildings, research on the effectiveness of green roofs for stormwater management is important. This study aims to assess the hydrologic response of an extensive sedum green roof in London, Ontario, with emphasis on the response to large precipitation events that stress municipal stormwater infrastructure. A green roof rapidly reaches field capacity during large storm events and can show significantly different behavior before and after field capacity. At field capacity a green roof has no capillary storage left for retention of stormwater, but may still be an effective tool to attenuate peak runoff rates by transport through the green roof substrate. The attenuation of green roofs after field capacity is linked to gravity storage, where gravity storage is the water that is temporarily stored and can drain freely over time after field capacity has been established. Stormwater attenuation of a modular experimental green roof is determined from water balance calculations at 1-minute intervals. Data is used to evaluate green roof attenuation and the impact of field capacity on peak flow rates and gravity storage. In addition, a numerical model is used to simulate event based stormwater attenuation. This model is based off of the Richards equation and supporting theory of multiphase flow through porous media.

  15. [Biomarkers for chronic inflammatory diseases].

    PubMed

    Holzinger, D; Föll, D

    2015-12-01

    Inflammatory disorders of childhood, such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) are a challenge for laboratory diagnostics. Firstly, the classical inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) often inadequately reflect disease activity but on the other hand there are few specific biomarkers that can be helpful in managing these diseases. Acute phase proteins reflect the systemic inflammatory response insufficiently as their increase is only the indirect result of local inflammatory processes. Modern inflammation diagnostics aim to reflect these local processes and to allow precise monitoring of disease activity. Experimental biomarkers, such as S100 proteins can detect subclinical inflammatory activity. In addition, established laboratory parameters exist for JIA [antinuclear antibodies (ANA), rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP)] and for chronic IBD (fecal calprotectin) that are useful in the treatment of these diseases. PMID:26608264

  16. [Advances in the treatment of secondary osteoporosis].

    PubMed

    Galindo Zavala, R; Núñez Cuadros, E; Díaz Cordovés-Rego, G; Urda Cardona, A L

    2014-12-01

    Osteoporosis is being increasingly recognised in paediatric practice as a consequence of the increasing life expectancy of children who suffer from chronic diseases and other factors. There are many non-pharmacological measures that can improve children' bone health, for example, avoiding inflammatory activity and osteotoxic treatments; increasing sun exposure and weight-bearing exercise, and maintaining an adequate nutritional status. Vitamin D and calcium supplements have been proposed as a measure to increase bone mass, but their effect and therapeutic indications are not completely clear. On the other hand, bisphosphonates are currently the only pharmacological alternative for the patients with infantile secondary osteoporosis. However, more studies are required on the therapeutic indications, posology, and long term secondary effects of biphosphonates. The aim of this article is to analyze the scientific evidence of the effectiveness of the therapeutic alternatives for childhood secondary osteoporosis and their safety in children. PMID:25441207

  17. Raf-kinase inhibitor protein attenuates microglia inflammation in an in vitro model of intracerebral hemorrhage.

    PubMed

    Wang, J; Du, J; Miao, C; Lian, H

    2016-01-01

    Microglia mediated neuroinflammation plays a crucial role in intracerebral hemorrhage (ICH). Raf kinase inhibitor protein (RKIP), a member of the phosphatidylethanolamine-binding protein (PEBP) family, is a negative regulator of inflammatory responses. However, the expression and anti-inflammatory effects of RKIP in microglia after ICH have not been reported. Therefore, in the current study, we investigated the effects of RKIP on inflammatory responses in erythrocyte lysate-treated BV2 microglia. Furthermore, we analyzed the detailed molecular mechanisms underlying the anti-inflammatory effects of RKIP in microglia. Our results showed that the expression level of RKIP was significantly decreased by erythrocyte lysate treatment in BV2 microglia. Overexpression of RKIP inhibited the production of pro-inflammatory molecules. In addition, overexpression of RKIP attenuated neuronal cell death induced by activated microglia. Moreover, RKIP suppressed the activation of NF-κB signaling pathway in erythrocyte lysis-treated BV2 cells. In conclusion, these data suggest that overexpression of RKIP attenuated microglia inflammation through inhibiting the NF-κB signaling pathway in erythrocyte lysis-treated BV2 cells. The present study provides evidence that RKIP may be used as an effective molecular target for the treatment of ICH. PMID:27262809

  18. Defensins as anti-inflammatory compounds and mucosal adjuvants

    PubMed Central

    Kohlgraf, Karl G; Pingel, Lindsey C; Dietrich, Deborah E; Brogden, Kim A

    2010-01-01

    Human neutrophil peptide α-defensins and human β-defensins are small, well-characterized peptides with broad antimicrobial activities. In mixtures with microbial antigens, defensins attenuate proinflammatory cytokine responses by dendritic cells in culture, attenuate proinflammatory cytokine responses in the nasal fluids of exposed mice and enhance antibody responses in the serum of vaccinated mice. Although the exact mechanisms are unknown, defensins first start by binding to microbial antigens and adhesins, often attenuating toxic or inflammatory-inducing capacities. Binding is not generic; it appears to be both defensin-specific and antigen-specific with high affinities. Binding of defensins to antigens may, in turn, alter the interaction of antigens with epithelial cells and antigen-presenting cells attenuating the production of proinflammatory cytokines. The binding of defensins to antigens may also facilitate the delivery of bound antigen to antigen-presenting cells in some cases via specific receptors. These interactions enhance the immunogenicity of the bound antigen in an adjuvant-like fashion. Future research will determine the extent to which defensins can suppress early events in inflammation and enhance systemic antibody responses, a very recent and exciting concept that could be exploited to develop therapeutics to prevent or treat a variety of oral mucosal infections, particularly where inflammation plays a role in the pathogenesis of disease and its long-term sequelae. PMID:20020832

  19. Ferrite attenuator modulation improves antenna performance

    NASA Technical Reports Server (NTRS)

    Hooks, J. C.; Larson, S. G.; Shorkley, F. H.; Williams, B. T.

    1970-01-01

    Ferrite attenuator inserted into appropriate waveguide reduces the gain of the antenna element which is causing interference. Modulating the ferrite attenuator to change the antenna gain at the receive frequency permits ground tracking until the antenna is no longer needed.

  20. Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches.

    PubMed

    Szychlinska, M A; Leonardi, R; Al-Qahtani, M; Mobasheri, A; Musumeci, G

    2016-06-01

    Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief. PMID:27118399

  1. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

    SciTech Connect

    Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong; Cui, Wei; Chen, Wensheng; Zhu, Guo-Qing; Qin, Da-Nian; Kang, Yu-Ming

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  2. Escin attenuates acute lung injury induced by endotoxin in mice.

    PubMed

    Xin, Wenyu; Zhang, Leiming; Fan, Huaying; Jiang, Na; Wang, Tian; Fu, Fenghua

    2011-01-18

    Endotoxin causes multiple organ dysfunctions, including acute lung injury (ALI). The current therapeutic strategies for endotoxemia are designed to neutralize one or more of the inflammatory mediators. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and anti-edematous effects. The aim of this study was to evaluate the effect of escin on ALI induced by endotoxin in mice. ALI was induced by injection of lipopolysaccharide (LPS) intravenously. The mice were given dexamethasone or escin before injection of LPS. The mortality rate was recorded. Tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and nitric oxide (NO) were measured. Pulmonary superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, glutathione (GSH), malondialdehyde (MDA) contents, and myeloperoxidase (MPO) activity were also determined. The expression of glucocorticoid receptor (GR) level was detected by Western blotting. Pretreatment with escin could decrease the mortality rate, attenuate lung injury resulted from LPS, down-regulate the level of the inflammation mediators, including NO, TNF-α, and IL-1β, enhance the endogenous antioxidant capacity, and up-regulating the GR expression in lung. The results suggest that escin may have potent protective effect on the LPS-induced ALI by inhibiting of the inflammatory response, and its mechanism involves in up-regulating the GR and enhancing the endogenous antioxidant capacity. PMID:21040784

  3. Skin gangrene as an extraintestinal manifestation of inflammatory bowel disease*

    PubMed Central

    Komatsu, Yumi Cristina; Capareli, Gabriela Cunha; Boin, Maria Fernanda Feitosa de Camargo; Lellis, Rute; de Freitas, Thaís Helena Proença; Simone, Karine

    2014-01-01

    Inflammatory bowel diseases can commonly present many cutaneous lesions which can contribute to the diagnosis of the disease or its activity. The most frequent cutaneous or mucocutaneous manifestations suggesting ulcerative rectocolitis activity are erythema nodosum (3-10%), pyoderma gangrenosum (5-12%) and aphthous stomatitis (4%). Other reactive skin manifestations related to immunological mechanisms associated with the inflammatory bowel disease are: Sweet's syndrome, arthritis-dermatitis syndrome associated with inflammatory bowel disease and leukocytoclastic vasculitis. We describe the case of a young man with diagnosis of ulcerative rectocolitis, which presented an extensive cutaneous gangrene secondary to microvascular thrombosis. The case represents a dermatologic rarity and should be recognized as a cutaneous manifestation related to the hypercoagulability state observed in the disease's activity. PMID:25387503

  4. Skin gangrene as an extraintestinal manifestation of inflammatory bowel disease.

    PubMed

    Komatsu, Yumi Cristina; Capareli, Gabriela Cunha; Boin, Maria Fernanda Feitosa de Camargo; Lellis, Rute; Freitas, Thaís Helena Proença de; Simone, Karine

    2014-01-01

    Inflammatory bowel diseases can commonly present many cutaneous lesions which can contribute to the diagnosis of the disease or its activity. The most frequent cutaneous or mucocutaneous manifestations suggesting ulcerative rectocolitis activity are erythema nodosum (3-10%), pyoderma gangrenosum (5-12%) and aphthous stomatitis (4%). Other reactive skin manifestations related to immunological mechanisms associated with the inflammatory bowel disease are: Sweet's syndrome, arthritis-dermatitis syndrome associated with inflammatory bowel disease and leukocytoclastic vasculitis. We describe the case of a young man with diagnosis of ulcerative rectocolitis, which presented an extensive cutaneous gangrene secondary to microvascular thrombosis. The case represents a dermatologic rarity and should be recognized as a cutaneous manifestation related to the hypercoagulability state observed in the disease's activity. PMID:25387503

  5. Attenuated Rabies Virus Activates, while Pathogenic Rabies Virus Evades, the Host Innate Immune Responses in the Central Nervous System

    PubMed Central

    Wang, Zhi W.; Sarmento, Luciana; Wang, Yuhuan; Li, Xia-qing; Dhingra, Vikas; Tseggai, Tesfai; Jiang, Baoming; Fu, Zhen F.

    2005-01-01

    Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-α/β) signaling pathways and inflammatory chemokines. For the IFN-α/β signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2′-5′-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses. PMID:16160183

  6. Inflammatory bowel disease.

    PubMed

    Szigethy, Eva; McLafferty, Laura; Goyal, Alka

    2010-04-01

    This article reviews the etiology, clinical characteristics, and treatment of inflammatory bowel disease (IBD) and associated psychological sequelae in children and adolescents with this lifelong disease. Pediatric-onset IBD, consisting of Crohn's disease and ulcerative colitis, has significant medical morbidity and in many young persons is also associated with psychological and psychosocial challenges. Depression and anxiety are particularly prevalent and have a multifaceted etiology, including IBD-related factors such as cytokines and steroids used to treat IBD and psychosocial stress. A growing number of empirically supported interventions, such as cognitive behavioral therapy, hypnosis, and educational resources, help youth and their parents cope with IBD as well as the psychological and psychosocial sequelae. While there is convincing evidence that such interventions can help improve anxiety, depression, and health-related quality of life, their effects on IBD severity and course await further study. PMID:20478501

  7. Inflammatory bowel disease.

    PubMed

    Szigethy, Eva; McLafferty, Laura; Goyal, Alka

    2011-08-01

    This article reviews the etiology, clinical characteristics, and treatment of inflammatory bowel disease (IBD) and associated psychological sequelae in children and adolescents with this lifelong disease. Pediatric-onset IBD, consisting of Crohn's disease and ulcerative colitis, has significant medical morbidity and in many young persons is also associated with psychological and psychosocial challenges. Depression and anxiety are particularly prevalent and have a multifaceted etiology, including IBD-related factors such as cytokines and steroids used to treat IBD and psychosocial stress. A growing number of empirically supported interventions, such as cognitive behavioral therapy, hypnosis, and educational resources, help youth and their parents cope with IBD as well as the psychological and psychosocial sequelae. While there is convincing evidence that such interventions can help improve anxiety, depression, and health-related quality of life, their effects on IBD severity and course await further study. PMID:21855713

  8. Inflammatory Bowel Disease

    PubMed Central

    Kaser, Arthur; Zeissig, Sebastian; Blumberg, Richard S.

    2015-01-01

    Insights into inflammatory bowel disease (IBD) are advancing rapidly owing to immunologic investigations of a plethora of animal models of intestinal inflammation, ground-breaking advances in the interrogation of diseases that are inherited as complex genetic traits, and the development of culture-independent methods to define the composition of the intestinal microbiota. These advances are bringing a deeper understanding to the genetically determined interplay between the commensal microbiota, intestinal epithelial cells, and the immune system and the manner in which this interplay might be modified by relevant environmental factors in the pathogenesis of IBD. This review examines these interactions and, where possible, potential lessons from IBD-directed, biologic therapies that may allow for elucidation of pathways that are central to disease pathogenesis in humans. PMID:20192811

  9. Inflammatory pathways in spondyloarthritis.

    PubMed

    Hreggvidsdottir, Hulda S; Noordenbos, Troy; Baeten, Dominique L

    2014-01-01

    Spondyloarthritis is the second most common form of chronic inflammatory arthritis and a unique hallmark of the disease is pathologic new bone formation. Several cytokine pathways have been genetically associated with ankylosing spondylitis (AS), the prototypic subtype of SpA, and additional evidence from human and animal studies support a role of these pathways in the disease. TNF has a key role in SpA as blockade significantly reduces inflammation and destruction, however the treatment does not halt new bone formation. New insights into the TNF pathway were recently obtained from an animal model specifically overexpressing the transmembrane form of TNF. This model leads to axial and peripheral new bone formation which is not seen in soluble TNF overexpression models, indicating different pathogenic roles of soluble and transmembrane TNF in arthritis development. Besides TNF, the IL-23/IL-17 axis is emerging as an important inflammatory pathway in SpA, as a SNP in the IL-23R locus has been associated with developing AS, mice overexpressing IL-23 develop SpA-like features and IL-17 blockade has been shown to be efficacious for AS patients in a phase II trial. In this review, we focus on the cytokine pathways that have recently been genetically associated with SpA, i.e. TNF, IL-1, IL-6 and IL-23/IL-17. We review the current genetic, experimental and human in vivo data available and discuss how these different pathways are involved in the pathophysiology of SpA. Additionally, we discuss how these pathways relate to the pathogenic new bone formation in SpA. PMID:23969080

  10. Autoantibodies in inflammatory arthritis.

    PubMed

    Conigliaro, P; Chimenti, M S; Triggianese, P; Sunzini, F; Novelli, L; Perricone, C; Perricone, R

    2016-07-01

    Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides. PMID:26970491

  11. Ultrasonography and computed tomography of inflammatory abdominal wall lesions

    SciTech Connect

    Yeh, H.C.; Rabinowitz, J.G.

    1982-09-01

    Twenty-four patients with inflammatory lesions of the abdominal wall were examined by ultrasonography. Nine of these patients underwent computed tomographic (CT) scanning as well. Both ultrasonography and CT clearly delineated the exact location and extent of abdominal wall abscesses. Abscesses were easily differentiated from cellulitis or phlegmon with ultrasound. The peritoneal line was more clearly delineated on ultrasonograms than on CT scans; abscesses were also more distinct on the ultrasonograms because of their low echogenicity compared with the surrounding structures. Gas bubbles, fat density with specific low attenuation values, and underlying inflamed bowel loops in obese patients with Crohn's disease were better delineated by CT.

  12. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    SciTech Connect

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  13. Coenzyme Q10 Ameliorates Pain and Cartilage Degradation in a Rat Model of Osteoarthritis by Regulating Nitric Oxide and Inflammatory Cytokines

    PubMed Central

    Jeong, Jeong Hee; Yang, Eun Ji; Jhun, Joo Yeon; Park, Mi Kyoung; Jung, Young Ok; Min, Jun Ki; Kim, Ho Youn; Park, Sung Hwan; Cho, Mi-La

    2013-01-01

    Objective To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). Materials and Methods OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. Results Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. Conclusion CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis. PMID:23894457

  14. Neuropathy secondary to drugs

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000700.htm Neuropathy secondary to drugs To use the sharing features on this page, please enable JavaScript. Neuropathy secondary to drugs is a loss of sensation ...

  15. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-01-01

    In Section 1 of this first report we will describe the work we are doing to collect and analyze rock physics data for the purpose of modeling seismic attenuation from other measurable quantities such as porosity, water saturation, clay content and net stress. This work and other empirical methods to be presented later, will form the basis for ''Q pseudo-well modeling'' that is a key part of this project. In Section 2 of this report, we will show the fundamentals of a new method to extract Q, dispersion, and attenuation from field seismic data. The method is called Gabor-Morlet time-frequency decomposition. This technique has a number of advantages including greater stability and better time resolution than spectral ratio methods.

  16. Chlorine signal attenuation in concrete.

    PubMed

    Naqvi, A A; Maslehuddin, M; ur-Rehman, Khateeb; Al-Amoudi, O S B

    2015-11-01

    The intensity of prompt gamma-ray was measured at various depths from chlorine-contaminated silica fume (SF) concrete slab concrete specimens using portable neutron generator-based prompt gamma-ray setup. The intensity of 6.11MeV chloride gamma-rays was measured from the chloride contaminated slab at distance of 15.25, 20.25, 25.25, 30.25 and 35.25cm from neutron target in a SF cement concrete slab specimens. Due to attenuation of thermal neutron flux and emitted gamma-ray intensity in SF cement concrete at various depths, the measured intensity of chlorine gamma-rays decreases non-linearly with increasing depth in concrete. A good agreement was noted between the experimental results and the results of Monte Carlo simulation. This study has provided useful experimental data for evaluating the chloride contamination in the SF concrete utilizing gamma-ray attenuation method. PMID:26218450

  17. Secondary extinction in Pavlovian fear conditioning

    PubMed Central

    Vurbic, Drina; Bouton, Mark E.

    2011-01-01

    Pavlov (1927/1960) reported that following the conditioning of several stimuli, extinction of one conditioned stimulus (CS) attenuated responding to others that had not undergone direct extinction. However, this secondary extinction effect has not been widely replicated in the contemporary literature. In three conditioned suppression experiments with rats, we further explored the phenomenon. In Experiment 1, we asked whether secondary extinction is more likely to occur with target CSs that have themselves undergone some prior extinction. A robust secondary extinction effect was obtained with a nonextinguished target CS. Experiment 2 showed that extinction of one CS was sufficient to reduce renewal of a second CS when it was tested in a neutral (nonextinction) context. In Experiment 3, secondary extinction was observed in groups that initially received intermixed conditioning trials with the target and nontarget CSs, but not in groups that received conditioning of the two CSs in separate sessions. The results are consistent with the hypothesis that CSs must be associated with a common temporal context during conditioning for secondary extinction to occur. PMID:21286897

  18. Teaching with Secondary Data.

    ERIC Educational Resources Information Center

    Sobol, Jeff

    1981-01-01

    Presents a general overview of the use of secondary data in teaching sociology on the college level. Topics discussed include potential for additional applications, sources which constitute secondary data, reasons for using secondary data in the classroom, information about computing, and potential problems. (Author/DB)

  19. Vitamin D in inflammatory diseases

    PubMed Central

    Wöbke, Thea K.; Sorg, Bernd L.; Steinhilber, Dieter

    2014-01-01

    Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq. PMID:25071589

  20. Hormonal control of inflammatory responses

    PubMed Central

    Farsky, Sandra P.

    1993-01-01

    Almost any stage of inflammatory and immunological responses is affected by hormone actions. This provides the basis for the suggestion that hormones act as modulators of the host reaction against trauma and infection. Specific hormone receptors are detected in the reactive structures in inflamed areas and binding of hormone molecules to such receptors results in the generation of signals that influence cell functions relevant for the development of inflammatory responses. Diversity of hormonal functions accounts for recognized pro- and anti-inflammatory effects exerted by these substances. Most hormone systems are capable of influencing inflammatory events. Insulin and glucocorticoids, however, exert direct regulatory effects at concentrations usually found in plasma. Insulin is endowed with facilitatory actions on vascular reactivity to inflammatory mediators and inflammatory cell functions. Increased concentrations of circulating glucocorticoids at the early stages of inflammation results in downregulation of inflammatory responses. Oestrogens markedly reduce the response to injury in a variety of experimental models. Glucagon and thyroid hormones exert indirect anti-inflammatory effects mediated by the activity of the adrenal cortex. Accordingly, inflammation is not only merely a local response, but a hormone-controlled process. PMID:18475521

  1. Modeling transmission and scatter for photon beam attenuators.

    PubMed

    Ahnesjö, A; Weber, L; Nilsson, P

    1995-11-01

    The development of treatment planning methods in radiation therapy requires dose calculation methods that are both accurate and general enough to provide a dose per unit monitor setting for a broad variety of fields and beam modifiers. The purpose of this work was to develop models for calculation of scatter and transmission for photon beam attenuators such as compensating filters, wedges, and block trays. The attenuation of the beam is calculated using a spectrum of the beam, and a correction factor based on attenuation measurements. Small angle coherent scatter and electron binding effects on scattering cross sections are considered by use of a correction factor. Quality changes in beam penetrability and energy fluence to dose conversion are modeled by use of the calculated primary beam spectrum after passage through the attenuator. The beam spectra are derived by the depth dose effective method, i.e., by minimizing the difference between measured and calculated depth dose distributions, where the calculated distributions are derived by superposing data from a database for monoenergetic photons. The attenuator scatter is integrated over the area viewed from the calculation point of view using first scatter theory. Calculations are simplified by replacing the energy and angular-dependent cross-section formulas with the forward scatter constant r2(0) and a set of parametrized correction functions. The set of corrections include functions for the Compton energy loss, scatter attenuation, and secondary bremsstrahlung production. The effect of charged particle contamination is bypassed by avoiding use of dmax for absolute dose calibrations. The results of the model are compared with scatter measurements in air for copper and lead filters and with dose to a water phantom for lead filters for 4 and 18 MV. For attenuated beams, downstream of the buildup region, the calculated results agree with measurements on the 1.5% level. The accuracy was slightly less in situations

  2. Lipid Bodies in Inflammatory Cells

    PubMed Central

    Melo, Rossana C. N.; D’Avila, Heloisa; Wan, Hsiao-Ching; Bozza, Patrícia T.; Dvorak, Ann M.; Weller, Peter F.

    2011-01-01

    Lipid bodies (LBs), also known as lipid droplets, have increasingly been recognized as functionally active organelles linked to diverse biological functions and human diseases. These organelles are actively formed in vivo within cells from the immune system, such as macrophages, neutrophils, and eosinophils, in response to different inflammatory conditions and are sites for synthesis and storage of inflammatory mediators. In this review, the authors discuss structural and functional aspects of LBs and current imaging techniques to visualize these organelles in cells engaged in inflammatory processes, including infectious diseases. The dynamic morphological aspects of LBs in leukocytes as inducible, newly formable organelles, elicitable in response to stimuli that lead to cellular activation, contribute to the evolving understanding of LBs as organelles that are critical regulators of different inflammatory diseases, key markers of leukocyte activation, and attractive targets for novel anti-inflammatory therapies. PMID:21430261

  3. Review of Anti-Inflammatory Herbal Medicines

    PubMed Central

    Ghasemian, Mona; Owlia, Sina; Owlia, Mohammad Bagher

    2016-01-01

    Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as a complementary medicine. Inflammation is a pathologic condition that includes a wide range of diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, and etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis, evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the treatment of inflammation is not a one-dimensional remedy, this review tries to reach a multidimensional therapeutic approach to inflammation with the help of herbal medicine and modification in lifestyle. PMID:27247570

  4. Review of Anti-Inflammatory Herbal Medicines.

    PubMed

    Ghasemian, Mona; Owlia, Sina; Owlia, Mohammad Bagher

    2016-01-01

    Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as a complementary medicine. Inflammation is a pathologic condition that includes a wide range of diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, and etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis, evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the treatment of inflammation is not a one-dimensional remedy, this review tries to reach a multidimensional therapeutic approach to inflammation with the help of herbal medicine and modification in lifestyle. PMID:27247570

  5. Prior voluntary wheel running attenuates neuropathic pain.

    PubMed

    Grace, Peter M; Fabisiak, Timothy J; Green-Fulgham, Suzanne M; Anderson, Nathan D; Strand, Keith A; Kwilasz, Andrew J; Galer, Erika L; Walker, Frederick Rohan; Greenwood, Benjamin N; Maier, Steven F; Fleshner, Monika; Watkins, Linda R

    2016-09-01

    Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1β production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1β, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain. PMID:27355182

  6. Effect of Negative Pressure Therapy on the Inflammatory Response of the Intestinal Microenvironment in a Porcine Septic Model

    PubMed Central

    Norbury, Kenneth C.; Moyer, Mary Pat

    2015-01-01

    In a swine model of ischemia/reperfusion injury coupled with sepsis, we have previously shown attenuation of secondary organ injury and decreased mortality with negative pressure therapy (NPT). We hypothesized that NPT modulates the intestinal microenvironment by mediating the innate immune system. Sepsis was induced in 12 anesthetized female pigs. Group 1 (n = 6) was decompressed at 12 hrs after injury (T12) and treated with standard of care (SOC), and group 2 (n = 6) with NPT for up to T48. Immunoparalysis was evident as lymphocytopenia at T24 in both groups; however, survival was improved in the NPT group versus SOC (Odds ratio = 4.0). The SOC group showed significant reduction in lymphocyte numbers compared to NPT group by T48 (p < 0.05). The capacity of peritoneal fluid to stimulate a robust reactive oxygen species response in vitro was greater for the NPT group, peaking at T24 for both M1 (p = 0.0197) and M2 macrophages (p = 0.085). Plasma elicited little if any effect which was confirmed by microarray analysis. In this septic swine model NPT appeared to modulate the intestinal microenvironment, facilitating an early robust, yet transient, host defense mediated by M1 and M2 macrophages. NPT may help overcome immunoparalysis that occurs during inflammatory response to septic injury. PMID:26294849

  7. Natural and enhanced attenuation of metals

    SciTech Connect

    Rouse, J.V.; Pyrih, R.Z.

    1996-12-31

    The ability of natural earthen materials to attenuate the movement of contamination can be quantified in relatively simple geochemical experiments. In addition, the ability of subsurface material to attenuate potential contaminants can be enhanced through modifications to geochemical parameters such as pH or redox conditions. Such enhanced geochemical attenuation has been demonstrated at a number of sites to be a cost-effective alternative to conventional pump and treat operations. This paper describes the natural attenuation reactions which occur in the subsurface, and the way to quantify such attenuation. It also introduces the concept of enhanced geochemical attenuation, wherein naturally-occurring geochemical reactions can be used to achieve in situ fixation. The paper presents examples where such natural and enhanced attenuation have been implemented as a part of an overall remedy.

  8. The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells.

    PubMed

    Gray, Andrea; Marrero-Berrios, Ileana; Weinberg, Jonathan; Manchikalapati, Devasena; SchianodiCola, Joseph; Schloss, Rene S; Yarmush, Joel

    2016-04-01

    Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist

  9. Secondary power systems

    SciTech Connect

    Not Available

    1985-01-01

    In aeronautical engineering secondary power systems have long played second fiddle to the airframe, the engine, and indeed, the avionics. This collection of papers is thus timely, and its publication by the Institution of Mechanical Engineers appropriate, as secondary power systems in modern aircraft present challenging mechanical engineering problems. In military aircraft demands for electrical and hydraulic power and high pressure air have grown over the past two decades. To these basic needs are added requirements for emergency power, ground power, and independent engine starting. Additionally increased reliability and maintainability is demanded from all secondary power systems. Complete contents: What is a secondary power system. Modern technology secondary power systems for next generation military aircraft; Integrated power units; Secondary power system gearbox; Starting the system - air turbine starters; Auxiliary and emergency power system; Secondary hydraulic power generation; Advanced technology electrical power generation equipment.

  10. Canine chronic inflammatory rhinitis.

    PubMed

    Windsor, Rebecca C; Johnson, Lynelle R

    2006-05-01

    Chronic inflammatory rhinitis is commonly found in dogs with chronic nasal disease and is characterized by lymphoplasmacytic infiltrates in the nasal mucosa in the absence of an obvious etiologic process. The pathogenesis of lymphoplasmacytic rhinitis remains unknown. Animals respond poorly to antibiotics, oral glucocorticoids, and antihistamines, making primary infectious, immune-mediated, or allergic etiologies unlikely. Aberrant immune response to inhaled organisms or allergens may induce inflammation in some animals. Common clinical signs include nasal discharge, sneezing, coughing, epistaxis, and stertor. Diagnosis is made by performing a thorough history, physical examination, radiography or advanced imaging (via computed tomography or magnetic resonance imaging), rhinoscopy, and nasal mucosal biopsy to rule out primary etiologies of nasal discharge. Treatment strategies have included various antibiotics, antihistamines, oral and inhalant steroids, nonsteroidal antiinflammatories, and antifungal medications. Some dogs may respond partially to doxycycline or azithromycin, although it is unclear whether response is related to antimicrobial or antiinflammatory properties of these drugs. Hydration of the nasal cavity through nasal drops or aerosols may limit nasal discharge, and some animals may improve with inhalant (but rarely oral) glucocorticoids. PMID:16711613

  11. Inflammatory bowel disease: Pathogenesis

    PubMed Central

    Zhang, Yi-Zhen; Li, Yong-Yu

    2014-01-01

    Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. It has been a worldwide health-care problem with a continually increasing incidence. It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar genetic predispositions. However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD. Meanwhile, the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD, as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation. Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms, including the innate and adaptive immunity, and the interactions between genetic factors and microbial and environmental cues. In this review, we provide an update on the major advances that have occurred in above areas. PMID:24415861

  12. Idiopathic inflammatory myositis.

    PubMed

    Tieu, Joanna; Lundberg, Ingrid E; Limaye, Vidya

    2016-02-01

    Knowledge on idiopathic inflammatory myopathy (IIM) has evolved with the identification of myositis-associated and myositis-specific antibodies, development of histopathological classification and the recognition of how these correlate with clinical phenotype and response to therapy. In this paper, we outline key advances in diagnosis and histopathology, including the more recent identification of antibodies associated with immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Ongoing longitudinal observational cohorts allow further classification of these patients with IIM, their predicted clinical course and response to specific therapies. Registries have been developed worldwide for this purpose. A challenging aspect in IIM, a multisystem disease with multiple clinical subtypes, has been defining disease status and clinically relevant improvement. Tools for assessing activity and damage are now recognised to be important in determining disease activity and guiding therapeutic decision-making. The International Myositis Assessment and Clinical Studies (IMACS) group has developed such tools for use in research and clinical settings. There is limited evidence for specific treatment strategies in IIM. With significant development in the understanding of IIM and improved classification, longitudinal observational cohorts and trials using validated outcome measures are necessary, to provide important information for evidence-based care in the clinical setting. PMID:27421222

  13. MicroRNA 26a inhibits HMGB1 expression and attenuates cardiac ischemia-reperfusion injury.

    PubMed

    Yao, Li; Lv, Xin; Wang, Xiaohua

    2016-05-01

    Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. MicroRNA 26a (Mir-26a) plays important roles in cellular differentiation, cell growth, cell apoptosis and metastasis. Mir-26a has been demonstrated to modulate regulatory T cells expansion and attenuates renal IR injury. However, the role of Mir-26a in the cardiac IR injury has never been investigated. In our study, hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 hours and then transplanted into syngeneic recipients. The results demonstrate a crucial role for Mir-26a in inhibiting high mobility group box-1 (HMGB1) expression and attenuating cardiac IR injury. Mir-26a overexpression results in attenuated cardiac IR injury and inhibited HMGB1 expression. Mir-26a also inhibits inflammatory cells infiltration and cytokines expression. Furthermore, the attenuated cardiac IR injury induced by Mir-26a was abrogated by additional administration of recombinant HMGB1 (rHMGB1). In conclusion, Mir-26a plays a protective role in cardiomyocyte IR injury and this is associated with inhibited HMGB1 expression. PMID:26320674

  14. Secondary systemic amyloidosis

    MedlinePlus

    ... occurs as a result of chronic infection or chronic inflammatory disease. Primary amyloidosis means there is no disease that is causing the condition. Systemic means that the disease affects the entire body. Causes ... fibrosis Familial Mediterranean fever Hairy cell ...

  15. Passion fruit peel extract attenuates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Chilakapati, Shanmuga Reddy; Serasanambati, Mamatha; Manikonda, Pavan Kumar; Chilakapati, Damodar Reddy; Watson, Ronald Ross

    2014-08-01

    Idiopathic pulmonary fibrosis is a progressive fatal lung disease characterized by excessive collagen deposition, with no effective treatments. We investigated the efficacy of natural products with high anti-inflammatory activity, such as passion fruit peel extract (PFPE), in a mouse model of bleomycin-induced pulmonary fibrosis (PF). C57BL/6J mice were subjected to a single intratracheal instillation of bleomycin to induce PF. Daily PFPE treatment significantly reduced loss of body mass and mortality rate in mice compared with those treated with bleomycin. While bleomycin-induced PF resulted in elevated total numbers of inflammatory cells, macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid on both days 7 and 21, PFPE administration significantly attenuated these phenomena compared with bleomycin group. On day 7, the decreased superoxide dismutase and myeloperoxidase activities observed in the bleomycin group were significantly restored with PFPE treatment. On day 21, enhanced hydroxyproline deposition in the bleomycin group was also suppressed by PFPE administration. PFPE treatment significantly attenuated extensive inflammatory cell infiltration and accumulation of collagen in lung tissue sections of bleomycin-induced mice on days 7 and 21, respectively. Our results indicate that administration of PFPE decreased bleomycin-induced PF because of anti-inflammatory and antioxidant activities. PMID:24933624

  16. Intrathecal curcumin attenuates pain hypersensitivity and decreases spinal neuroinflammation in rat model of monoarthritis.

    PubMed

    Chen, Jun-Jie; Dai, Lin; Zhao, Lin-Xia; Zhu, Xiang; Cao, Su; Gao, Yong-Jing

    2015-01-01

    Curcumin is a major component of turmeric and reportedly has anti-inflammatory and anti-oxidant effects. Neuroinflammation has been recognized to play an important role in the pathogenesis of various diseases in the central nervous system. Here we investigated the anti-nociceptive and anti-neuroinflammatory effect of curcumin on arthritic pain in rats. We found that repeated oral treatment with curcumin, either before or after complete Freund's adjuvant (CFA) injection, dose-dependently attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, but had no effect on joint edema. Repeated intrathecal injection of curcumin reversed CFA-induced pain hypersensitivity. Furthermore, such a curcumin treatment reduced CFA-induced activation of glial cells and production of inflammatory mediators [interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and monocyte inflammatory protein-1 (MIP-1α)] in the spinal cord. Curcumin also decreased lipopolysaccharide-induced production of IL-1β, tumor necrosis factor-α, MCP-1, and MIP-1α in cultured astrocytes and microglia. Our results suggest that intrathecal curcumin attenuates arthritic pain by inhibiting glial activation and the production of inflammatory mediators in the spinal cord, suggesting a new application of curcumin for the treatment of arthritic pain. PMID:25988362

  17. Attenuation of Lipopolysaccharide-Induced Lung Vascular Stiffening by Lipoxin Reduces Lung Inflammation

    PubMed Central

    Meng, Fanyong; Mambetsariev, Isa; Tian, Yufeng; Beckham, Yvonne; Meliton, Angelo; Leff, Alan; Gardel, Margaret L.; Allen, Michael J.; Birukov, Konstantin G.

    2015-01-01

    Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action. PMID:24992633

  18. Withaferin A attenuates lipopolysaccharide-induced acute lung injury in neonatal rats.

    PubMed

    Gao, S; Li, H; Zhou, X-Q; You, J-B; Tu, D-N; Xia, G; Jiang, J-X; Xin, C

    2015-01-01

    Withaferin A (WFA) is an active compound from Withania somnifera and has been reported to exhibit a variety of pharmacological activities such as anti—inflammatory, immunomodulatory and anti—tumor properties. In the present study, we investigated the potential protective role of WFA on acute lung injury in neonatal rats induced by lipopolysaccharide (LPS). We found that WFA significantly attenuated the pathological changes of lungs induced by LPS injection. Administration with WFA obviously decreased pulmonary neutrophil infiltration accompanied with decreased MPO concentrations. WFA also reduced the expression of pro—inflammatory cytokines including MIP—2, TNF—α, IL—1β and IL—6. Meanwhile, the expression levels of anti—inflammatory mediators such as TGF—β1 and IL—10 were significantly increased following WFA administration. Moreover, WFA protected LPS—treated rats from oxidative damage via up—regulation of TBARS and H2O2 concentrations and down—regulation of ROS contents. Taken together, the present study demonstrated that WFA administration attenuated LPS—induced lung injury through inhibition of inflammatory responses and oxidative stress. PMID:26255139

  19. Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling.

    PubMed

    Ma, Lei; Jia, Ji; Liu, Xiangyu; Bai, Fuhai; Wang, Qiang; Xiong, Lize

    2015-02-27

    Inhibition of microglial activation is effective in treating various neurological disorders. Activation of microglial cannabinoid CB2 receptor induces anti-inflammatory effects, and the mechanism, however, is still elusive. Microglia could be activated into the classic activated state (M1 state) or the alternative activated state (M2 state), the former is cytotoxic, and the latter is neurotrophic. In this study, we used lipopolysaccharide (LPS) plus interferon-γ (IFNγ) to activate N9 microglia and hypothesized the pretreatment with cannabinoid CB2 receptor agonist AM1241 attenuates microglial activation by shifting microglial M1 to M2 state. We found that pretreatment with 5 μM AM1241 at 1 h before microglia were exposed to LPS plus IFNγ decreased the expression of inducible nitric oxide synthase (iNOS) and the release of pro-inflammatory factors, increased the expression of arginase 1 (Arg-1) and the release of anti-inflammatory and neurotrophic factors in microglia. However, these effects induced by AM1241 pretreatment were significantly reversed in the presence of 10 μM cannabinoid CB2 receptor antagonist AM630 or 10 μM protein kinase C (PKC) inhibitor chelerythrine. These findings indicated that AM1241 pretreatment attenuates microglial activation by shifting M1 to M2 activated state via CB2 receptor, and the AM1241-induced anti-inflammatory effects may be mediated by PKC. PMID:25637536

  20. Saikosaponin-d attenuates ventilator-induced lung injury in rats

    PubMed Central

    Wang, Hong-Wei; Liu, Ming; Zhong, Tai-Di; Fang, Xiang-Ming

    2015-01-01

    Saikosaponin-d is one of the main bioactive components in the traditional Chinese medicine Bupleurum falcatum L and possesses anti-inflammatory and immune-modulatory properties. The current study aimed to investigate the protective effects of saikosaponin-d on ventilator-induced lung injury (VILI) in rats. We found that saikosaponin-d treatment significantly attenuated the pathological changes of lungs induced by mechanical ventilation. Administration of saikosaponin-d reduced the pulmonary neutrophil infiltration as well as the MPO concentrations. Saikosaponin-d also decreased the expression of pro-inflammatory cytokines including MIP-2, IL-6 and TNF-α. Meanwhile, the expression of anti-inflammatory mediators, such as TGF-β1 and IL-10, was obviously elevated after saikosaponin-d administration. Saikosaponin-d remarkably reduced the oxidative stress and apoptosis rate in lung tissues. On the molecular level, saikosaponin-d treatment obviously downregulated the expression of caspases-3 and the pro-apoptotic protein bax, and promoted the expression level of anti-apoptotic protein bcl-2. Collectively, our study demonstrated that saikosaponin-d may attenuate ventilator induced lung injury through inhibition of inflammatory responses, oxidative stress and apoptosis. PMID:26628997

  1. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-04-01

    In this report we will show some new Q related seismic attributes on the Burlington-Seitel data set. One example will be called Energy Absorption Attribute (EAA) and is based on a spectral analysis. The EAA algorithm is designed to detect a sudden increase in the rate of exponential decay in the relatively higher frequency portion of the spectrum. In addition we will show results from a hybrid attribute that combines attenuation with relative acoustic impedance to give a better indication of commercial gas saturation.

  2. Zingiber mioga (Thunb.) Roscoe attenuates allergic asthma induced by ovalbumin challenge.

    PubMed

    Shin, Na-Rae; Shin, In-Sik; Jeon, Chan-Mi; Hong, Ju-Mi; Kwon, Ok-Kyoung; Kim, Hui-Seong; Oh, Sei-Ryang; Hahn, Kyu-Woung; Ahn, Kyung-Seop

    2015-09-01

    Zingiber mioga (Thunb.) Roscoe (ZM) is a traditional medicine, used to treat inflammatory diseases. The present study aimed to evaluate the inhibitory effects of ZM on the inflammatory response in lipopolysaccharide (LPS)‑stimulated RAW264.7 murine macrophage cells and in a mouse model of ovalbumin (OVA)‑induced allergic asthma. Mice received OVA sensitization on day 0 and 14, and were challenged with OVA between days 21 and 23. ZM was administered to the mice at a dose of 30 mg/kg, 1 h prior to OVA challenge. In LPS‑stimulated RAW264.7 cells, ZM significantly decreased nitric oxide (NO) and tumor necrosis factor (TNF)‑α production in a concentration‑dependent manner, and mRNA expression of inducible NO synthase (iNOS), TNF‑α and matrix metalloproteinase (MMP)‑9 was reduced. In addition, treatment with ZM decreased the inflammatory cell count in bronchoalveolar lavage fluid from the mice, and reduced the expression of interleukin (IL)‑4, IL‑5, IL‑13, eotaxin and immunoglobulin E. ZM also reduced airway hyperresponsiveness in OVA‑challenged mice, and attenuated the infiltration of inflammatory cells and mucus production in the airways, with a decrease in the expression of iNOS and MMP‑9 in lung tissue. In conclusion, the results of the present study indicate that ZM effectively inhibits inflammatory responses. Therefore, it may be that ZM has potential as a therapeutic agent for use in inflammatory diseases. PMID:26063513

  3. Imaging Rayleigh wave attenuation with USArray

    NASA Astrophysics Data System (ADS)

    Bao, Xueyang; Dalton, Colleen A.; Jin, Ge; Gaherty, James B.; Shen, Yang

    2016-04-01

    The EarthScope USArray provides an opportunity to obtain detailed images of the continental upper mantle at an unprecedented scale. The majority of mantle models derived from USArray data to date contain spatial variations in seismic-wave speed; however, in many cases these data sets do not by themselves allow a non-unique interpretation. Joint interpretation of seismic attenuation and velocity models can improve upon the interpretations based only on velocity and provide important constraints on the temperature, composition, melt content, and volatile content of the mantle. The surface-wave amplitudes that constrain upper-mantle attenuation are sensitive to factors in addition to attenuation, including the earthquake source exc