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Sample records for peripheral lipopolysaccharide induce

  1. Equine colostral carbohydrates reduce lipopolysaccharide-induced inflammatory responses in equine peripheral blood mononuclear cells.

    PubMed

    Vendrig, J C; Coffeng, L E; Fink-Gremmels, J

    2012-12-01

    Increasing evidence suggests that reactions to lipopolysaccharide (LPS), particularly in the gut, can be partly or completely mitigated by colostrum- and milk-derived oligosaccharides. Confirmation of this hypothesis could lead to the development of new therapeutic concepts. To demonstrate the influence of equine colostral carbohydrates on the inflammatory response in an in vitro model with equine peripheral blood mononuclear cells (PBMCs). Carbohydrates were extracted from mare colostrum, and then evaluated for their influence on LPS-induced inflammatory responses in PBMCs isolated from the same mares, mRNA expression of tumour necrosis factor-alpha, interleukin-6 and interleukin-10 was measured as well as the protein levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10). Equine colostral carbohydrates significantly reduced LPS-induced TNF-alpha protein at both times measured and significantly reduced LPS-induced TNF-alpha, IL-6 and IL-10 mRNA expression by PBMCs. Moreover, cell viability significantly increased in the presence of high concentrations of colostral carbohydrates. Carbohydrates derived from equine colostrum reduce LPS-induced inflammatory responses of equine PBMCs. Colostrum and milk-derived carbohydrates are promising candidates for new concepts in preventive and regenerative medicine.

  2. Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat.

    PubMed

    Bhatt, S; Bhatt, R S; Zalcman, S S; Siegel, A

    2009-11-10

    Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide (LPS) challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60 to 300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an Anti-tumor necrosis factor-alpha (TNFalpha) antibody but not with an anti- interleukin-1 (IL-1) antibody demonstrated that the effects of LPS were mediated through TNF-alpha rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE(2) or 5-HT(1A) receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-alpha antibody into the medial hypothalamus were ineffective. Microinjections of -Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) benzamide monohydrochloride (p-MPPI) into lateral hypothalamus (to test for anatomical specificity) had no effect upon

  3. Lipopolysaccharide Stimulates Butyric Acid-Induced Apoptosis in Human Peripheral Blood Mononuclear Cells

    PubMed Central

    Kurita-Ochiai, Tomoko; Fukushima, Kazuo; Ochiai, Kuniyasu

    1999-01-01

    We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3+-T-cell apoptosis followed by similar levels of both CD4+- and CD8+-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3+ PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4+ and CD8+ cells. PMID:9864191

  4. Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Filipov, Nikolay M

    2016-04-01

    Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature.

  5. Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration

    PubMed Central

    Krishna, Saritha; Dodd, Celia A.; Filipov, Nikolay M.

    2016-01-01

    Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature. PMID:26802725

  6. Lipopolysaccharide induces visceral hypersensitivity: role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor in rats.

    PubMed

    Nozu, Tsukasa; Miyagishi, Saori; Nozu, Rintaro; Takakusaki, Kaoru; Okumura, Toshikatsu

    2017-01-01

    Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility. Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs. LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 µg/kg) blocked this effect. Additionally, IL-1β (10 µg/kg, sc) or IL-6 (10 µg/kg, sc) induced visceral allodynia. Astressin (200 µg/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin2-B (200 µg/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 µg/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 µg/kg, ip) abolished it. LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.

  7. Characterization of basal and lipopolysaccharide-induced microRNA expression in equine peripheral blood mononuclear cells using Next-Generation Sequencing

    PubMed Central

    Buechner-Maxwell, Virginia A.; Witonsky, Sharon G.; Pleasant, R. Scott; Werre, Stephen R.; Ahmed, S. Ansar

    2017-01-01

    The innate immune response to lipopolysaccharide contributes substantially to the morbidity and mortality of gram-negative sepsis. Horses and humans share an exquisite sensitivity to lipopolysaccharide and thus the horse may provide valuable comparative insights into this aspect of the inflammatory response. MicroRNAs, small non-coding RNA molecules acting as post-transcriptional regulators of gene expression, have key roles in toll-like receptor signaling regulation but have not been studied in this context in horses. The central hypothesis of this study was that lipopolysaccharide induces differential microRNA expression in equine peripheral blood mononuclear cells in a manner comparable to humans. Illumina Next Generation Sequencing was used to characterize the basal microRNA transcriptome in isolated peripheral blood mononuclear cells from healthy adult horses, and to evaluate LPS-induced changes in microRNA expression in cells cultured for up to four hours. Selected expression changes were validated using quantitative reverse-transcriptase PCR. Only miR-155 was significantly upregulated by LPS, changing in parallel with supernatant tumor necrosis factor-α concentration. Eight additional microRNAs, including miR-146a and miR-146b, showed significant expression change with time in culture without a clear LPS effect. Target predictions indicated a number of potential immunity-associated targets for miR-155 in the horse, including SOCS1, TAB2 and elements of the PI3K signaling pathway, suggesting that it is likely to influence the acute inflammatory response to LPS. Gene alignment showed extensive conservation of the miR-155 precursor gene and associated promoter regions between horses and humans. The basal and LPS-stimulated microRNA expression pattern characterized here were similar to those described in human leukocytes. As well as providing a resource for further research into the roles of microRNAs in immune responses in horses, this will facilitate inter

  8. Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation.

    PubMed

    Harden, Lois M; Rummel, Christoph; Laburn, Helen P; Damm, Jelena; Wiegand, Florian; Poole, Stephen; Gerstberger, Rüdiger; Roth, Joachim

    2014-07-01

    Although peripherally released interleukin (IL)-10 has a critical regulatory role in limiting fever in mild-to-moderate forms of inflammation, its role in regulating the more complex thermoregulatory manifestations of hypothermia and fever noted during severe inflammation is less clear. Using cytokine antagonism, we therefore investigated the involvement of peripherally released IL-10 in mediating hypothermia, fever and inflammation induced by intraperitoneal (IP) administration of a large dose of lipopolysaccharide (LPS). Male Wistar rats (200-250 g) were anaesthetized and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were randomly assigned to receive IL-10 antiserum (IL-10AS) or normal sheep serum IP, 4 h before receiving an IP injection of LPS (10 mg/kg) or phosphate-buffered saline (PBS). Inflammatory responses were measured in plasma and tissue samples (spleen, liver and brain) at 90 min and 6 h after the IP injection of LPS or PBS. Administration of LPS induced an initial period of hypothermia (~90 min) after which fever developed. Pre-treating rats with IL-10AS abolished the LPS-induced increase in plasma IL-10 levels, attenuated the hypothermia and increased the amplitude of the fever. Moreover, IL-10AS pre-treatment augmented the LPS-induced increase in plasma levels of tumor necrosis factor-alpha (90 min and 6 h), IL-1β (90 min), prostaglandin E2 (90 min) and IL-6 (6 h), in the periphery, but not the hypothalamus, over the duration of hypothermia and fever. Via its action on the synthesis of inflammatory mediators in the spleen and liver, endogenous IL-10 plays a crucial regulatory role in mediating hypothermia and fever during severe aspectic (LPS-induced) systemic inflammation.

  9. Lipopolysaccharide potentiates hyperthermia-induced seizures

    PubMed Central

    Eun, Baik-Lin; Abraham, Jayne; Mlsna, Lauren; Kim, Min Jung; Koh, Sookyong

    2015-01-01

    Background Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain. Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children. Methods The innate immune activator lipopolysaccharide (LPS) was administered to postnatal day 14 rat (200 μg/kg) and mouse (100 μg/kg) pups 2–2.5 h prior to hyperthermic seizures (HT) induced by hair dryer or heat lamp. To determine whether simulation of infection enhances neuronal excitability, latency to seizure onset, threshold temperature and total number of seizures were quantified. Behavioral seizures were correlated with electroencephalographic changes in rat pups. Seizure-induced proinflammatory cytokine production was assessed in blood samples at various time points after HT. Seizure-induced microglia activation in the hippocampus was quantified using Cx3cr1GFP/+ mice. Results Lipopolysaccharide priming increased susceptibility of rats and mice to hyperthemic seizures and enhanced seizure-induced proinflammatory cytokine production and microglial activation. Conclusions Peripheral inflammation appears to work synergistically with hyperthermia to potentiate seizures and to exacerbate seizure-induced immune responses. By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS. PMID:26357586

  10. Lipopolysaccharide potentiates hyperthermia-induced seizures.

    PubMed

    Eun, Baik-Lin; Abraham, Jayne; Mlsna, Lauren; Kim, Min Jung; Koh, Sookyong

    2015-08-01

    Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain. Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children. The innate immune activator lipopolysaccharide (LPS) was administered to postnatal day 14 rat (200 μg/kg) and mouse (100 μg/kg) pups 2-2.5 h prior to hyperthermic seizures (HT) induced by hair dryer or heat lamp. To determine whether simulation of infection enhances neuronal excitability, latency to seizure onset, threshold temperature and total number of seizures were quantified. Behavioral seizures were correlated with electroencephalographic changes in rat pups. Seizure-induced proinflammatory cytokine production was assessed in blood samples at various time points after HT. Seizure-induced microglia activation in the hippocampus was quantified using Cx3cr1(GFP/+) mice. Lipopolysaccharide priming increased susceptibility of rats and mice to hyperthemic seizures and enhanced seizure-induced proinflammatory cytokine production and microglial activation. Peripheral inflammation appears to work synergistically with hyperthermia to potentiate seizures and to exacerbate seizure-induced immune responses. By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.

  11. Peripheral tumors alter neuroinflammatory responses to lipopolysaccharide in female rats.

    PubMed

    Pyter, Leah M; El Mouatassim Bih, Sarah; Sattar, Husain; Prendergast, Brian J

    2014-03-13

    Cancer is associated with an increased prevalence of depression. Peripheral tumors induce inflammatory cytokine production in the brain and depressive-like behaviors. Mounting evidence indicates that cytokines are part of a pathway by which peripheral inflammation causes depression. Neuroinflammatory responses to immune challenges can be exacerbated (primed) by prior immunological activation associated with aging, early-life infection, and drug exposure. This experiment tested the hypothesis that peripheral tumors likewise induce neuroinflammatory sensitization or priming. Female rats with chemically-induced mammary carcinomas were injected with either saline or lipopolysaccharide (LPS, 250μg/kg; i.p.), and expression of mRNAs involved in the pathway linking inflammation and depression (interleukin-1beta [Il-1β], CD11b, IκBα, indolamine 2,3-deoxygenase [Ido]) was quantified by qPCR in the hippocampus, hypothalamus, and frontal cortex, 4 or 24h post-treatment. In the absence of LPS, hippocampal Il-1β and CD11b mRNA expression were elevated in tumor-bearing rats, whereas Ido expression was reduced. Moreover, in saline-treated rats basal hypothalamic Il-1β and CD11b expression were positively correlated with tumor weight; heavier tumors, in turn, were characterized by more inflammatory, necrotic, and granulation tissue. Tumors exacerbated CNS proinflammatory gene expression in response to LPS: CD11b was greater in hippocampus and frontal cortex of tumor-bearing relative to tumor-free rats, IκBα was greater in hippocampus, and Ido was greater in hypothalamus. Greater neuroinflammatory responses in tumor-bearing rats were accompanied by attenuated body weight gain post-LPS. The data indicate that neuroinflammatory pathways are potentiated, or primed, in tumor-bearing rats, which may exacerbate future negative behavioral consequences.

  12. Inhibitory activity of the white wine compounds, tyrosol and caffeic acid, on lipopolysaccharide-induced tumor necrosis factor-alpha release in human peripheral blood mononuclear cells.

    PubMed

    Giovannini, L; Migliori, M; Filippi, C; Origlia, N; Panichi, V; Falchi, M; Bertelli, A A E; Bertelli, A

    2002-01-01

    The objective of this study was to assess whether tyrosol and caffeic acid are able to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release. TNF is one of the most important cytokines involved in inflammatory reactions. The results show that both tyrosol and caffeic acid are able to inhibit LPS-induced TNF-alpha release from human monocytes, even at low doses. Their mechanisms of action are discussed and we conclude that high doses of the two compounds are not required to achieve effective inhibition of inflammatory reactions due to TNF-alpha release.

  13. Protective Effect of Yinhua Miyanling Tablet on Lipopolysaccharide-Induced Inflammation through Suppression of NLRP3/Caspase-1 Inflammasome in Human Peripheral Blood Mononuclear Cells

    PubMed Central

    Sai, Jingying; Zheng, Jingtong; Liu, Chuangui; Lu, Yanjiao; Wang, Guoqiang; Wang, Ting; Guan, Xuewa; Chen, Fang; Fang, Keyong; Zhang, Chao; Lu, Junying; Zhang, Xiaotian; Zhu, Hailin

    2016-01-01

    Yinhua Miyanling Tablet (YMT), the Chinese formula, has long been administrated in clinical practice for the treatment of acute pyelonephritis and acute urocystitis. In the current study, we aimed to investigate the anti-inflammatory effect of YMT in vitro and to evaluate the association between anti-inflammation and innate immune response. Human peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll density gradient centrifugation and then were stimulated by Lipopolysaccharide (LPS). The differential gene expression of inflammation-related genes after drug administration was assessed using PCR array, and the protein levels of differential genes were measured by ELISA and Western blot. The result showed that YMT significantly inhibited the expression of NLRP3, Caspase-1, and the downstream cytokine IL-1β and suppressed the production of inflammatory mediators TNF-α, IL-6, IL-10, and MCP-1 in a dose-dependent manner compared to the LPS group (P < 0.01). The finding indicated that YMT exhibited anti-inflammatory effect in vitro by suppressing the NLRP3/Caspase-1 inflammasome, and that may have therapeutic potential for the treatment of inflammatory diseases. PMID:27795729

  14. Lactic acid stimulates interleukin-23 production by peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide.

    PubMed

    Witkin, Steven S; Alvi, Shaheen; Bongiovanni, Ann Marie; Linhares, Iara M; Ledger, William J

    2011-03-01

    Lactic acid is the predominant acid present in the vagina. We evaluated the consequences of lactic acid, at physiological levels present in the vagina, on cytokine responses of peripheral blood mononuclear cells (PBMCs) obtained from 10 individuals in the presence or absence of bacterial lipopolysaccharide. Preincubation of PBMCs in 15 mM lactic acid before the addition of lipopolysaccharide resulted in a 246% mean increase in interleukin-23 (IL-23) secretion over that released in the presence of lipopolysaccharide alone (P=0.0068). The lipopolysaccharide-induced production of tumor necrosis factor-α, IL-6, IL-10 and IL-12 was unaffected by lactic acid. IL-23 stimulation was not observed if the lactic acid was neutralized before its addition to the culture medium or if hydrochloric acid was substituted for lactic acid. In the absence of lipopolysaccharide, lactic acid did not stimulate the production of IL-23 or any of the other cytokines. The increase in IL-23 production was proportional to the lactic acid concentration over a 15-60 mM range. We conclude that at body sites characterized by lactic acid accumulation, such as in the human vagina, exposure to gram-negative bacteria results in selective IL-23 production, leading to a subsequent preferential stimulation of the Th17 T lymphocyte pathway. © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  15. Early life peripheral lipopolysaccharide challenge reprograms catecholaminergic neurons

    PubMed Central

    Ong, Lin Kooi; Fuller, Erin A.; Sominsky, Luba; Hodgson, Deborah M.; Dunkley, Peter R.; Dickson, Phillip W.

    2017-01-01

    Neonatal immune challenge with the bacterial mimetic lipopolysaccharide has the capacity to generate long-term changes in the brain. Neonatal rats were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg) on postnatal day (PND) 3 and again on PND 5. The activation state of tyrosine hydroxylase (TH) was measured in the locus coeruleus, ventral tegmental area and substantia nigra on PND 85. In the locus coeruleus there was an approximately four-fold increase in TH activity. This was accompanied by a significant increase in TH protein together with increased phosphorylation of all three serine residues in the N-terminal region of TH. In the ventral tegmental area, a significant increase in TH activity and increased phosphorylation of the serine 40 residue was seen. Neonatal lipopolysaccharide had no effect on TH activation in the substantia nigra. These results indicate the capacity of a neonatal immune challenge to generate long-term changes in the activation state of TH, in particular in the locus coeruleus. Overall, the current results demonstrate the enduring outcomes of a neonatal immune challenge on specific brain catecholaminergic regions associated with catecholamine synthesis. This highlights a novel mechanism for long-term physiological and behavioural alterations induced by this model. PMID:28071709

  16. On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death.

    PubMed

    Kell, Douglas B; Pretorius, Etheresia

    2015-11-01

    We have recently highlighted (and added to) the considerable evidence that blood can contain dormant bacteria. By definition, such bacteria may be resuscitated (and thus proliferate). This may occur under conditions that lead to or exacerbate chronic, inflammatory diseases that are normally considered to lack a microbial component. Bacterial cell wall components, such as the endotoxin lipopolysaccharide (LPS) of Gram-negative strains, are well known as potent inflammatory agents, but should normally be cleared. Thus, their continuing production and replenishment from dormant bacterial reservoirs provides an easy explanation for the continuing, low-grade inflammation (and inflammatory cytokine production) that is characteristic of many such diseases. Although experimental conditions and determinants have varied considerably between investigators, we summarise the evidence that in a great many circumstances LPS can play a central role in all of these processes, including in particular cell death processes that permit translocation between the gut, blood and other tissues. Such localised cell death processes might also contribute strongly to the specific diseases of interest. The bacterial requirement for free iron explains the strong co-existence in these diseases of iron dysregulation, LPS production, and inflammation. Overall this analysis provides an integrative picture, with significant predictive power, that is able to link these processes via the centrality of a dormant blood microbiome that can resuscitate and shed cell wall components.

  17. Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

    PubMed

    Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

    2007-04-30

    Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

  18. Amygdaloid signature of peripheral immune activation by bacterial lipopolysaccharide or staphylococcal enterotoxin B.

    PubMed

    Prager, Geraldine; Hadamitzky, Martin; Engler, Andrea; Doenlen, Raphael; Wirth, Timo; Pacheco-López, Gustavo; Krügel, Ute; Schedlowski, Manfred; Engler, Harald

    2013-03-01

    Activated immune cells produce soluble mediators that not only coordinate local and systemic immune responses but also act on the brain to initiate behavioral, neuroendocrine and metabolic adaptations. Earlier studies have shown that the amygdala, a group of nuclei located in the medial temporal lobe, is engaged in the central processing of afferent signals from the peripheral immune system. Here, we compared amygdaloid responses to lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB), two prototypic bacterial products that elicit distinct immune responses. Intraperitoneal administration of LPS (0.1 mg/kg) or SEB (1 mg/kg) in adult rats induced substantial increases in amygdaloid neuronal activity as measured by intracerebral electroencephalography and c-fos gene expression. Amygdaloid neuronal activation was accompanied by an increase in anxiety-related behavior in the elevated plus-maze test. However, only treatment with LPS, but not SEB, enhanced amygdaloid IL-1β and TNF-α mRNA expression. This supports the view of the immune system as a sensory organ that recognizes invading pathogens and rapidly relays this information to the brain, independent of the nature of the immune response induced. The observation that neuronal and behavioral responses to peripheral immune challenges are not necessarily accompanied by increased brain cytokine expression suggests that cytokines are not the only factors driving sickness-related responses in the CNS.

  19. Methylprednisolone Stiffens Aortas in Lipopolysaccharide-Induced Chronic Inflammation in Rats

    PubMed Central

    Ko, Ya-Hui; Tsai, Ming-Shian; Lee, Po-Huang; Liang, Jin-Tung; Chang, Kuo-Chu

    2013-01-01

    Introduction Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid) on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats. Methods Chronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg−1 day−1 lipopolysaccharide) for either 2 or 4 weeks. Arterial wave transit time (τ) was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra. Results Long-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs) in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO), which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp). However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp. However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content. Conclusion Methylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs. PMID:23874978

  20. Epigenetic Alterations Induced by Bacterial Lipopolysaccharides.

    PubMed

    Chiariotti, Lorenzo; Coretti, Lorena; Pero, Raffaela; Lembo, Francesca

    2016-01-01

    Lipopolysaccharide (LPS) is one of the principal bacterial products known to elicit inflammation. Cells of myeloid lineage such as monocytes and macrophages, but also epithelial cells give rise to an inflammatory response upon LPS stimulation. This phenomenon implies reprogramming of cell specific gene expression that can occur through different mechanisms including epigenetic modifications. Given their intrinsic nature, epigenetic modifications may be involved both in the acute response to LPS and in the establishment of a preconditioned genomic state (epigenomic memory) that may potentially influence the host response to further contacts with microorganisms. Information has accumulated during the last years aimed at elucidating the epigenetic mechanisms which underlie the cellular LPS response. These findings, summarized in this chapter, will hopefully be a good basis for a definition of the complete cascade of LPS-induced epigenetic events and their biological significance in different cell types.

  1. Peripherally induced oromandibular dystonia

    PubMed Central

    Sankhla, C.; Lai, E.; Jankovic, J.

    1998-01-01

    OBJECTIVES—Oromandibular dystonia (OMD) is a focal dystonia manifested by involuntary muscle contractions producing repetitive, patterned mouth, jaw, and tongue movements. Dystonia is usually idiopathic (primary), but in some cases it follows peripheral injury. Peripherally induced cervical and limb dystonia is well recognised, and the aim of this study was to characterise peripherally induced OMD.
METHODS—The following inclusion criteria were used for peripherally induced OMD: (1) the onset of the dystonia was within a few days or months (up to 1 year) after the injury; (2) the trauma was well documented by the patient's history or a review of their medical and dental records; and (3) the onset of dystonia was anatomically related to the site of injury (facial and oral).
RESULTS—Twenty seven patients were identified in the database with OMD, temporally and anatomically related to prior injury or surgery. No additional precipitant other than trauma could be detected. None of the patients had any litigation pending. The mean age at onset was 50.11 (SD 14.15) (range 23-74) years and there was a 2:1 female preponderance. Mean latency between the initial trauma and the onset of OMD was 65 days (range 1 day-1 year). Ten (37%) patients had some evidence of predisposing factors such as family history of movement disorders, prior exposure to neuroleptic drugs, and associated dystonia affecting other regions or essential tremor. When compared with 21 patients with primary OMD, there was no difference for age at onset, female preponderance, and phenomenology. The frequency of dystonic writer's cramp, spasmodic dysphonia, bruxism, essential tremor, and family history of movement disorder, however, was lower in the post-traumatic group (p<0.05). In both groups the response to botulinum toxin treatment was superior to medical therapy (p<0.005). Surgical intervention for temporomandibular disorders was more frequent in the post-traumatic group and was associated with

  2. Lipopolysaccharide induced conversion of recombinant prion protein

    PubMed Central

    Saleem, Fozia; Bjorndahl, Trent C; Ladner, Carol L; Perez-Pineiro, Rolando; Ametaj, Burim N; Wishart, David S

    2014-01-01

    The conformational conversion of the cellular prion protein (PrPC) to the β-rich infectious isoform PrPSc is considered a critical and central feature in prion pathology. Although PrPSc is the critical component of the infectious agent, as proposed in the “protein-only” prion hypothesis, cellular components have been identified as important cofactors in triggering and enhancing the conversion of PrPC to proteinase K resistant PrPSc. A number of in vitro systems using various chemical and/or physical agents such as guanidine hydrochloride, urea, SDS, high temperature, and low pH, have been developed that cause PrPC conversion, their amplification, and amyloid fibril formation often under non-physiological conditions. In our ongoing efforts to look for endogenous and exogenous chemical mediators that might initiate, influence, or result in the natural conversion of PrPC to PrPSc, we discovered that lipopolysaccharide (LPS), a component of gram-negative bacterial membranes interacts with recombinant prion proteins and induces conversion to an isoform richer in β sheet at near physiological conditions as long as the LPS concentration remains above the critical micelle concentration (CMC). More significant was the LPS mediated conversion that was observed even at sub-molar ratios of LPS to recombinant ShPrP (90–232). PMID:24819168

  3. Brain CB₁ receptor expression following lipopolysaccharide-induced inflammation.

    PubMed

    Hu, H; Ho, W; Mackie, K; Pittman, Q J; Sharkey, K A

    2012-12-27

    Cannabinoid 1 receptors (CB(1)) are highly expressed on presynaptic terminals in the brain where they are importantly involved in the control of neurotransmitter release. Alteration of CB(1) expression is associated with a variety of neurological and psychiatric disorders. There is now compelling evidence that peripheral inflammatory disorders are associated with depression and cognitive impairments. These can be modeled in rodents with peripheral administration of lipopolysaccharide (LPS), but central effects of this treatment remain to be fully elucidated. As a reduction in endocannabinoid tone is thought to contribute to depression, we asked whether the expression of CB(1) in the CNS is altered following LPS treatment. CD1 mice received LPS (0.1-1mg/kg, ip) and 6h later activated microglial cells were observed only in circumventricular organs and only at the higher dose. At 24h, activated microglial cells were identified in other brain regions, including the hippocampus, a structure implicated in some mood disorders. Immunohistochemistry and real-time polymerase chain reaction (PCR) were utilized to evaluate the change of CB(1) expression 24h after inflammation. LPS induced an increase of CB(1) mRNA in the hippocampus and brainstem. Subsequent immunohistochemical analysis revealed reduced CB(1) in the hippocampus, especially in CA3 pyramidal layer. Analysis of co-localization with markers of excitatory and inhibitory terminals indicated that the decrease in CB(1) expression was restricted to glutamatergic terminals. Despite widespread microglial activation, these results suggest that peripheral LPS treatment leads to limited changes in CB(1) expression in the brain.

  4. Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation.

    PubMed

    Reisenauer, Chris J; Bhatt, Dhaval P; Mitteness, Dane J; Slanczka, Evan R; Gienger, Heidi M; Watt, John A; Rosenberger, Thad A

    2011-04-01

    Glyceryl triacetate (GTA), a compound effective at increasing circulating and tissue levels of acetate was used to treat rats subjected to a continual 28 day intra-ventricular infusion of bacterial lipopolysaccharide (LPS). This model produces a neuroinflammatory injury characterized by global neuroglial activation and a decrease in choline acetyltransferase immunoreactivity in the basal forebrain. During the LPS infusion, rats were given a daily treatment of either water or GTA at a dose of 6 g/kg by oral gavage. In parallel experiments, free-CoA and acetyl-CoA levels were measured in microwave fixed brains and flash frozen heart, liver, kidney and muscle following a single oral dose of GTA. We found that a single oral dose of GTA significantly increased plasma acetate levels by 15 min and remained elevated for up to 4 h. At 30 min the acetyl-CoA levels in microwave-fixed brain and flash frozen heart and liver were increased at least 2.2-fold. The concentrations of brain acetyl-CoA was significantly increased between 30 and 45 min following treatment and remained elevated for up to 4 h. The concentration of free-CoA in brain was significantly decreased compared to controls at 240 min. Immunohistochemical and morphological analysis demonstrated that a daily treatment with GTA significantly reduced the percentage of reactive glial fibrillary acidic protein-positive astrocytes and activated CD11b-positive microglia by 40-50% in rats subjected to LPS-induced neuroinflammation. Further, in rats subjected to neuroinflammation, GTA significantly increased the number of choline acetyltransferase (ChAT)-positive cells by 40% in the basal forebrain compared to untreated controls. These data suggest that acetate supplementation increases intermediary short chain acetyl-CoA metabolism and that treatment is potentially anti-inflammatory and neuroprotective with regards to attenuating neuroglial activation and increasing ChAT immunoreactivity in this model.

  5. Beryllium Alters Lipopolysaccharide-Mediated Intracellular Phosphorylation and Cytokine Release in Human Peripheral Blood Mononuclear Cells

    PubMed Central

    Silva, Shannon; Ganguly, Kumkum; Fresquez, Theresa M.; Gupta, Goutam; McCleskey, T. Mark; Chaudhary, Anu

    2013-01-01

    Beryllium exposure in susceptible individuals leads to the development of chronic beryllium disease, a lung disorder marked by release of inflammatory cytokine and granuloma formation. We have previously reported that beryllium induces an immune response even in blood mononuclear cells from healthy individuals. In this study, we investigate the effects of beryllium on lipopolysaccharide - mediated cytokine release in blood mononuclear and dendritic cells from healthy individuals. We find that in vitro treatment of beryllium sulfate inhibits the secretion of lipopolysaccharide-mediated interleukin 10, while the release of interleukin 1β is enhanced. Additionally, not all lipopolysaccharide - mediated responses are altered, as interleukin 6 release in unaffected upon beryllium treatment. Beryllium sulfate treated cells show altered phosphotyrosine levels upon lipopolysaccharide stimulation. Significantly, beryllium inhibits the phosphorylation of signal transducer and activator of transducer 3, induced by lipopolysaccharide. Finally, inhibitors of phosphoinositide-3 kinase mimic the effects of beryllium in inhibition of interleukin 10 release, while they have no effect on interleukin 1β secretion. This study strongly suggests that prior exposures to beryllium could alter host immune responses to bacterial infections in healthy individuals, by altering intracellular signaling. PMID:19894180

  6. Cerium dioxide nanoparticles do not modulate the lipopolysaccharide-induced inflammatory response in human monocytes

    PubMed Central

    Hussain, Salik; Al-Nsour, Faris; Rice, Annette B; Marshburn, Jamie; Ji, Zhaoxia; Zink, Jeffery I; Yingling, Brenda; Walker, Nigel J; Garantziotis, Stavros

    2012-01-01

    Background Cerium dioxide (CeO2) nanoparticles have potential therapeutic applications and are widely used for industrial purposes. However, the effects of these nanoparticles on primary human cells are largely unknown. The ability of nanoparticles to exacerbate pre-existing inflammatory disorders is not well documented for engineered nanoparticles, and is certainly lacking for CeO2 nanoparticles. We investigated the inflammation-modulating effects of CeO2 nanoparticles at noncytotoxic concentrations in human peripheral blood monocytes. Methods CD14+ cells were isolated from peripheral blood samples of human volunteers. Cells were exposed to either 0.5 or 1 μg/mL of CeO2 nanoparticles over a period of 24 or 48 hours with or without lipopolysaccharide (10 ng/mL) prestimulation. Modulation of the inflammatory response was studied by measuring secreted tumor necrosis factor-alpha, interleukin-1beta, macrophage chemotactic protein-1, interferon-gamma, and interferon gamma-induced protein 10. Results CeO2 nanoparticle suspensions were thoroughly characterized using dynamic light scattering analysis (194 nm hydrodynamic diameter), zeta potential analysis (−14 mV), and transmission electron microscopy (irregular-shaped particles). Transmission electron microscopy of CD14+ cells exposed to CeO2 nanoparticles revealed that these nanoparticles were efficiently internalized by monocytes and were found either in vesicles or free in the cytoplasm. However, no significant differences in secreted cytokine profiles were observed between CeO2 nanoparticle-treated cells and control cells at noncytotoxic doses. No significant effects of CeO2 nanoparticle exposure subsequent to lipopolysaccharide priming was observed on cytokine secretion. Moreover, no significant difference in lipopolysaccharide-induced cytokine production was observed after exposure to CeO2 nanoparticles followed by lipopolysaccharide exposure. Conclusion CeO2 nanoparticles at noncytotoxic concentrations neither

  7. Enzymatic Activities of Bovine Peripheral Blood Leukocytes and Milk Polymorphonuclear Neutrophils during Intramammary Inflammation Caused by Lipopolysaccharide

    PubMed Central

    Prin-Mathieu, C.; Le Roux, Y.; Faure, G. C.; Laurent, F.; Béné, M. C.; Moussaoui, F.

    2002-01-01

    Leukocytes are recruited from peripheral blood into milk as part of the inflammatory response to mastitis. However, excessive accumulation of inflammatory cells alters the quality of milk and the proteases produced by polymorphonuclear neutrophils (PMNs) and macrophages may lead to mammary tissue damage. To investigate PMN recruitment and the kinetics of their intracytoplasmic enzymes in inflammation, we generated mastitis in six cows by intramammary infusion of lipopolysaccharide (LPS). Clinical signs of acute mastitis were observed in all of the cows, and normal status was resumed by 316 h. Intracytoplasmic elastase, collagenase, and cathepsin activities were measured within live cells by flow cytometry in peripheral blood leukocytes and milk PMNs before and during the inflammatory process (at 10 time points between 4 and 316 h). The proportion of immature PMNs was appreciated by CD33 surface labeling measured in flow cytometry. Leukopenia was observed in the peripheral blood 4 h postinfusion, concomitant to an increase in somatic cell counts in milk. CD33+ PMNs were preferentially recruited from the peripheral blood to milk. Enzymatic activities were detected in PMNs, lymphocytes, and monocytes at levels depending on the cell type, sample nature, and time of collection. Milk PMNs had lower enzymatic activities than peripheral blood PMNs. This study showed that milk PMNs recruited during LPS-induced experimental mastitis have an immature phenotype and significantly lower enzymatic activities than peripheral blood PMNs. This suggests that CD33, an adhesion molecule, may be involved in the egress from blood to milk and that the enzymatic contents of PMNs are partly used during this process. PMID:12093678

  8. Proteomic changes in chicken plasma induced by Salmonella typhimurium lipopolysaccharides

    USDA-ARS?s Scientific Manuscript database

    Lipopolysaccharides (LPS) are cell wall components of gram-negative bacteria that cause inflammation and sickness through genetic and proteomic activation. The objective of our study was to identify the proteomic changes in plasma associated with inflammation induced by LPS treatment. Five-week-old ...

  9. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    SciTech Connect

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2014-08-08

    Highlights: • Knockout of SIRT2 attenuates lipopolysaccharide-induced iNOS expression. • Lipopolysaccharide-induced NO production is decreased in SIRT2 KO macrophage. • SIRT2 deficiency suppresses lipopolysaccharide-induced ROS production in macrophage. • M1-macrophage related factors are decreased in SIRT2 deficient cells. • SIRT2 deficiency decreases lipopolysaccharide-induced activation of NFκB. - Abstract: Introduction: SIRT2 is a NAD(+)-dependent deacetylases and associated with numerous processes such as infection, carcinogenesis, DNA damage and cell cycle regulation. However, the role of SIRT2 in inflammatory process in macrophage remains unclear. Materials and methods: In the present study, we have evaluated the regulatory effects of SIRT2 in lipopolysaccharide (LPS)-stimulated macrophages isolated from SIRT2 knockout (KO) and wild type (WT) mice or Raw264.7 macrophage cells. As inflammatory parameters, expression of inducible nitric oxide synthase (iNOS), the productions of nitric oxide, reactive oxygen species (ROS) and M1-macrophage-related factors were evaluated. We also examined the effects of SIRT2 on activation of nuclear factor-kappaB (NFκB) signaling. Results: SIRT2 deficiency inhibits LPS-induced iNOS mRNA and protein expression in bone marrow derived macrophages. SIRT2-siRNA transfection also suppressed LPS-induced iNOS expression in Raw264.7 macrophage cells. Bone marrow derived macrophages isolated from SIRT2 KO mice produced lower nitric oxide and expressed lower levels of M1-macrophage related markers including iNOS and CD86 in response to LPS than WT mice. Decrease of SIRT2 reduced the LPS-induced reactive oxygen species production. Deficiency of SIRT2 resulted in inhibition of NFκB activation through reducing the phosphorylation and degradation of IκBα. The phosphorylation and nuclear translocation of p65 was significantly decreased in SIRT2-deficient macrophages after LPS stimulation. Discussion: Our data suggested that

  10. Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain.

    PubMed

    Schnydrig, Sabine; Korner, Lukas; Landweer, Svenja; Ernst, Beat; Walker, Gaby; Otten, Uwe; Kunz, Dieter

    2007-12-11

    Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.

  11. Evidence that the anorexia induced by lipopolysaccharide is mediated by the 5-HT2C receptor.

    PubMed

    von Meyenburg, Claudia; Langhans, Wolfgang; Hrupka, Brian J

    2003-01-01

    Rats consistently reduce their food intake following injections of bacterial lipopolysaccharides (LPS). Because inhibition of serotonergic (5-HT) activity by 8-OH-DPAT (5-HT(1A) activation) attenuates LPS-induced anorexia, we conducted a series of studies to examine whether other 5-HT-receptors are involved in the mediation of peripheral LPS-induced anorexia. In all experiments, rats were injected with LPS (100 microg/kg body weight [BW] ip) at lights out (hour 0). Antagonists were administered peripherally at hour 4, shortly after the onset of anorexia, which presumably follows the enhanced cytokine production after LPS. Food intake was then recorded during the subsequent 2 h or longer. 5-HT receptor antagonists cyanopindolol and SB 224289 (5-HT(1B)), ketanserin (5-HT(2A)), RS-102221 (5-HT(2C)), and metoclopramide (5-HT(3)) failed to attenuate LPS-induced anorexia. In contrast, both ritanserin (5-HT(2A/C)-receptor antagonist) (0.5 mg/kg BW) and SB 242084 (5-HT(2C)) (0.3 mg/kg BW) attenuated LPS-induced anorexia at doses that did not alter food intake in non-LPS-treated rats (all P<.01). Our results suggest that at least part of the anorexia following peripheral LPS administration is mediated through an enhanced 5-HT-ergic activity and the 5-HT(2C) receptor.

  12. Protection against Lipopolysaccharide-Induced Death by Fluoroquinolones

    PubMed Central

    Khan, Anis A.; Slifer, Teri R.; Araujo, Fausto G.; Suzuki, Yasuhiro; Remington, Jack S.

    2000-01-01

    Because fluoroquinolones have an immunomodulatory effect on cytokine production by lipopolysaccharide (LPS)-treated human monocytes, we examined the effect of fluoroquinolones on the survival of mice injected with a lethal dose of LPS. Trovafloxacin (100 mg/kg), ciprofloxacin (250 mg/kg), and tosufloxacin (100 mg/kg) protected 75% (P = 0.0001), 25% (P = 0.002), and 50% (P = 0.002), respectively, of mice against death. The fluoroquinolones significantly reduced serum levels of interleukin-6 and tumor necrosis factor alpha in LPS-treated mice. The protective effects of fluoroquinolones in LPS-induced shock in mice may also occur in humans. PMID:11036044

  13. Lipopolysaccharide-Induced Toxic Shock Syndrome in Rabbits.

    PubMed

    Stach, Christopher S; Schlievert, Patrick M

    2016-01-01

    Enhancement of susceptibility to lipopolysaccharide (LPS; endotoxin) is a defining characteristic of Staphylococcus aureus superantigens. At the time of this publication, there are 24 identified staphylococcal superantigens (SAgs), some of which have yet to be fully characterized. Testing the capacity of superantigens to potentiate LPS sensitivity is essential to characterize the role of these proteins in disease development. Here we describe how to perform studies of the enhancement of LPS-induced toxic shock syndrome in rabbits. This protocol also provides information on a second important activity of superantigens: the production of fever.

  14. Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge.

    PubMed

    Salazar, Alexander; Gonzalez-Rivera, Bryan L; Redus, Laney; Parrott, Jennifer M; O'Connor, Jason C

    2012-08-01

    Upregulation of indoleamine 2,3-dioxygenase (IDO) by proinflammatory cytokines has been implicated as a biological mediator of inflammation-related mood disorders. Clinical reports on this neuro-immune interaction remain correlative, while mechanism-centered preclinical experiments have focused on a relatively narrow, and somewhat controversial, survey of depression-like behaviors that include the forced swim and tail suspension tests. Here, we sought to determine whether peripheral immune challenge with Escherichia coli, lipopolysaccharides (LPS) precipitates the development of translationally relevant depression-like behaviors and to investigate the role of IDO in mediating these LPS-induced behaviors. Intraperitoneal injection of C57BL/6J mice with LPS resulted in a robust, but transient, reduction in exploratory locomotor activity (eLMA) that returned to near baseline levels by 24h. Sucrose preference, a preclinical correlate of anhedonia, was diminished by more than 20% in LPS-treated compared to saline-treated control mice, and LPS induced a significant increase in anxiety-like behavior at 24h that was independent eLMA. Pretreatment of mice with an IDO inhibitor, 1-methyltryptophan (1MT), ablated the anxiogenic effects of LPS, while having no impact on sickness associated changes in body weight or eLMA. Additionally, 1MT pretreatment attenuated the LPS-induced reduction in sucrose preference, which was also confirmed in IDO-1 null mice. Interestingly, acute systemic administration of l-kynurenine, the enzymatic product of IDO, precipitated an anhedonic and anxiogenic effect in naïve mice without effect on eLMA. In a preclinical model, these data implicate IDO as a pivotal mediator of LPS-induced depression- and anxiety-like behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Dexmedetomidine Attenuates Lipopolysaccharide Induced MCP-1 Expression in Primary Astrocyte.

    PubMed

    Liu, Huan; Davis, Jacques R J; Wu, Zhi-Lin; Faez Abdelgawad, Amro

    2017-01-01

    Background. Neuroinflammation which presents as a possible mechanism of delirium is associated with MCP-1, an important proinflammatory factor which is expressed on astrocytes. It is known that dexmedetomidine (DEX) possesses potent anti-inflammatory properties. This study aimed to investigate the potential effects of DEX on the production of MCP-1 in lipopolysaccharide-stimulated astrocytes. Materials and Methods. Astrocytes were treated with LPS (10 ng/ml, 50 ng/ml, 100 ng/ml, and 1000 ng/ml), DEX (500 ng/mL), LPS (100 ng/ml), and DEX (10, 100, and 500 ng/mL) for a duration of three hours; expression levels of MCP-1 were measured by real-time PCR. The double immunofluorescence staining protocol was utilized to determine the expression of α2-adrenoceptors (α2AR) and glial fibrillary acidic protein (GFAP) on astrocytes. Results. Expressions of MCP-1 mRNA in astrocytes were induced dose-dependently by LPS. Administration of DEX significantly inhibited the expression of MCP-1 mRNA (P < 0.001). Double immunofluorescence assay showed that α2AR colocalize with GFAP, which indicates the expression of α2-adrenoceptors in astrocytes. Conclusions. DEX is a potent suppressor of MCP-1 in astrocytes induced with lipopolysaccharide through α2A-adrenergic receptors, which potentially explains its beneficial effects in the treatment of delirium by attenuating neuroinflammation.

  16. Dexmedetomidine Attenuates Lipopolysaccharide Induced MCP-1 Expression in Primary Astrocyte

    PubMed Central

    Liu, Huan; Faez Abdelgawad, Amro

    2017-01-01

    Background. Neuroinflammation which presents as a possible mechanism of delirium is associated with MCP-1, an important proinflammatory factor which is expressed on astrocytes. It is known that dexmedetomidine (DEX) possesses potent anti-inflammatory properties. This study aimed to investigate the potential effects of DEX on the production of MCP-1 in lipopolysaccharide-stimulated astrocytes. Materials and Methods. Astrocytes were treated with LPS (10 ng/ml, 50 ng/ml, 100 ng/ml, and 1000 ng/ml), DEX (500 ng/mL), LPS (100 ng/ml), and DEX (10, 100, and 500 ng/mL) for a duration of three hours; expression levels of MCP-1 were measured by real-time PCR. The double immunofluorescence staining protocol was utilized to determine the expression of α2-adrenoceptors (α2AR) and glial fibrillary acidic protein (GFAP) on astrocytes. Results. Expressions of MCP-1 mRNA in astrocytes were induced dose-dependently by LPS. Administration of DEX significantly inhibited the expression of MCP-1 mRNA (P < 0.001). Double immunofluorescence assay showed that α2AR colocalize with GFAP, which indicates the expression of α2-adrenoceptors in astrocytes. Conclusions. DEX is a potent suppressor of MCP-1 in astrocytes induced with lipopolysaccharide through α2A-adrenergic receptors, which potentially explains its beneficial effects in the treatment of delirium by attenuating neuroinflammation. PMID:28286770

  17. Galangin dampens mice lipopolysaccharide-induced acute lung injury.

    PubMed

    Shu, Yu-Sheng; Tao, Wei; Miao, Qian-Bing; Lu, Shi-Chun; Zhu, Ya-Bing

    2014-10-01

    Galangin, an active ingredient of Alpinia galangal, has been shown to possess anti-inflammatory and antioxidant activities. Inflammation and oxidative stress are known to play vital effect in the pathogenesis of acute lung injury (ALI). In this study, we determined whether galangin exerts lung protection in lipopolysaccharide (LPS)-induced ALI. Male BALB/c mice were randomized to receive galangin or vehicle intraperitoneal injection 3 h after LPS challenge. Samples were harvested 24 h post LPS administration. Galangin administration decreased biochemical parameters of oxidative stress and inflammation, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of galangin were associated with inhibition of nuclear factor (NF)-κB and upregulation of heme oxygenase (HO)-1. Galangin reduces LPS-induced ALI by inhibition of inflammation and oxidative stress.

  18. Roscovitine protects murine Leydig cells from lipopolysaccharide-induced inflammation.

    PubMed

    Xie, Tiancheng; Hu, Guanghui; Dong, Binbin; Yan, Yangye; Liu, Min; Yao, Xudong; Zheng, Junhua; Xu, Yunfei

    2017-05-01

    Roscovitine is a cyclin-dependent kinase inhibitor, which has been previously investigated for its anticancer effects. It has also been confirmed that roscovitine can downregulate the expression of myeloid cell leukemia-1 protein to inhibit inflammation. In the present study, roscovitine was used to treat inflammation in lipopolysaccharide (LPS)-induced model mice. At the cellular level, Leydig cells isolated from mouse testis were assessed for inflammatory factors. It was revealed that roscovitine successfully reduced inflammation-associated injury induced by LPS pretreatment. At the molecular level, roscovitine was found to exert this effect through promotion of adenosine monophosphate-activated protein kinase phosphorylation. To the best of our knowledge, the present study was the first to suggest that roscovitine has a protective role in Leydig cells through its anti-inflammatory action.

  19. Chemotherapy-induced peripheral neuropathy.

    PubMed

    Fehrenbacher, Jill C

    2015-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents, there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy.

  20. Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide

    PubMed Central

    Richwine, Amy F.; Sparkman, Nathan L.; Dilger, Ryan N.; Buchanan, Jessica B.; Johnson, Rodney W.

    2010-01-01

    Interleukin (IL)-10 is important for regulating inflammation but whether it protects against infection-related deficits in cognitive function is unknown. Therefore, the current study evaluated sickness behavior, hippocampal-dependent matching-to-place performance and several inflammatory cytokines and neurotrophins in wild type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after i.p. injection of lipopolysaccharide (LPS). Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Treatment with LPS increased IL-1β, IL-6, and tumor necrosis factor alpha (TNFα) mRNA in all brain areas examined including the hippocampus, in both IL-10+/+ and IL-10−/− mice but the increase was largest in IL-10−/− mice. Plasma IL-1β, IL-6 and TNFα were also higher in IL-10−/− mice compared to IL-10+/+ mice after LPS. Consistent with increased inflammatory cytokines in IL-10−/− mice after LPS treatment, were a more lengthy sickness behavior syndrome and a more prominent reduction in hippocampal levels of nerve growth factor mRNA; brain-derived neurotrophic factor mRNA was reduced similarly in both genotypes after LPS. In a test of hippocampal-dependent learning and memory that required mice to integrate new information with previously learned information and switch strategies to master a task, IL-10−/− mice were found to be less efficient after LPS than were similarly treated wild type mice. LPS did not affect morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus in either genotype. Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection. PMID:19272439

  1. Alpinetin inhibits lipopolysaccharide-induced acute kidney injury in mice.

    PubMed

    Huang, Yi; Zhou, Li-shan; Yan, Li; Ren, Juan; Zhou, Dai-xing; Li, Shu-Sheng

    2015-10-01

    Alpinetin, a novel plant flavonoid isolated from Alpinia katsumadai Hayata, has been demonstrated to have anti-inflammatory and antioxidant effects. However, the effects of alpinetin on lipopolysaccharide (LPS)-induced acute kidney injury have not been reported. In the present study, we investigated the protective effects and the underlying mechanism of alpinetin against LPS-induced acute kidney injury in mice. The results showed that alpinetin inhibited LPS-induced kidney histopathologic changes, blood urea nitrogen (BUN) and creatinine levels. Alpinetin also inhibited LPS-induced ROS, MDA, and inflammatory cytokines TNF-α, IL-6 and IL-1β production in kidney tissues. Meanwhile, Western blot analysis showed that alpinetin suppressed LPS-induced TLR4 expression and NF-κB activation in kidney tissues. In addition, alpinetin was found to up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner. In conclusion, alpinetin protected LPS-induced kidney injury through activating Nrf2 and inhibiting TLR4 expression.

  2. Prevention of lipopolysaccharide-induced mouse lethality by resveratrol.

    PubMed

    Sebai, Hichem; Sani, Mamane; Ghanem-Boughanmi, Néziha; Aouani, Ezzedine

    2010-06-01

    The present study was undertaken to determine whether subacute treatment with resveratrol (RVT) protects mice against lipopolysaccharide (LPS)-induced oxidative stress and mortality as well as the mechanism involved in such protection. Mice were divided into three groups: control, LPS and LPS+RVT. Animals were pre-treated with RVT during 7 days. The survival rate was monitored over 48 h after LPS administration. Survival animals were sacrificed, their kidney, liver and brain homogenized for malondialdehyde (MDA), catalase (CAT) activity, free iron and nitric oxide (NO) determination. Plasma was also processed for transaminases, creatinine, urea, NO and iron measurement. Pre-treatment with resveratrol greatly improved the survival rate of LPS-treated mice. Resveratrol counteracted LPS-induced tissue lipoperoxidation and catalase activity depletion. The polyphenol abrogated LPS-induced liver and kidney dysfunction as increased creatinine and urea as well as transaminases activities. In addition, pre-treatment with resveratrol abrogated LPS-induced tissues and plasma NO elevation and iron sequestration from plasma to tissue compartment. These data suggest that resveratrol prevents LPS-induced lethality and that its mode of action may involve differential iron deposition via iron shuttling proteins. Copyright 2010 Elsevier Ltd. All rights reserved.

  3. Neutrophil adherence induced by lipopolysaccharide in vitro. Role of plasma component interaction with lipopolysaccharide.

    PubMed Central

    Worthen, G S; Avdi, N; Vukajlovich, S; Tobias, P S

    1992-01-01

    Endotoxemia results in neutrophil localization within a number of microcirculatory beds, reflecting in part an adhesive interaction between neutrophils and the vascular endothelial cell. In previous studies, endotoxin or lipopolysaccharide (LPS) treatment of rabbits resulted in neutrophil sequestration at LPS concentrations well below those effective at increasing neutrophil adherence in vitro. We hypothesized that LPS-induced neutrophil adherence involved a plasma component. In the absence of plasma, high concentrations of LPS (10 micrograms/ml) were required to increase human neutrophil adherence to endothelial cells in vitro. With the inclusion of as little as 1% plasma or serum, however, the LPS dose-response curve was markedly shifted, resulting in increments in adherence at 10 ng/ml, and the time course of enhanced adherence was accelerated. Pretreatment studies suggested that the effect of LPS was on the neutrophil rather than the endothelial cell. Immunoprecipitation of 0111:B4 LPS paralleled the loss of functional activity, suggesting that LPS was an integral part of the active complex, rather than altering a plasma component to make it active. The incubation of plasma with LPS decreased the apparent molecular mass of LPS from 500-1,000 kD to approximately 100 kD. The disaggregated 0111:B4 LPS eluted in the range of albumin and was able to increase adherence in the absence of additional plasma. Plasma depleted of lipoproteins or heat treated retained activity, suggesting that the interaction of LPS with HDL or complement did not account for the observed findings. An LPS-binding protein isolated from rabbit serum enhanced the adherence-inducing effects of both 0111:B4 and Re595 LPS. Furthermore, the activity of rabbit serum was abolished after incubation with an antibody directed against this LPS-binding protein (LBP). An antibody directed against CD14, the putative receptor of the LPS-LBP complex, prevented the adhesive response to LPS. These data suggest

  4. Theophylline potentiates lipopolysaccharide-induced NO production in cultured astrocytes.

    PubMed

    Ogawa, Mizue; Takano, Katsura; Kawabe, Kenji; Moriyama, Mitsuaki; Ihara, Hideshi; Nakamura, Yoichi

    2014-01-01

    Elucidation of the functions of astrocytes is important for understanding of the pathogenic mechanism of various neurodegenerative diseases. Theophylline is a common drug for bronchial asthma and occasionally develops side-effects, such as acute encephalopathy; although the pathogenic mechanism of the side-effects is unknown. The lipopolysaccharide (LPS)-induced nitricoxide (NO) production is generally used for an index of the activation of astrocyte in vitro. In this study, in order to elucidate the effect of theophylline on the astrocytic functions, we examined the LPS-induced NO production and the expression of iNOS in cultured rat cortex astrocytes.Theophylline alone could not induce the NO production; however, NO production induced by LPS was enhanced by theophylline in a dose-dependent manner; and by isobutylmethylxanthine, a phosphodiesterase inhibitor. The theophylline enhancement of LPS-induced NO production was further increased by dibutyryl cyclic AMP, a membrane-permeable cAMP analog; and by forskolin, an adenylate cyclase activator. When the cells were preincubated with Rp-8-Br-cAMP, an inhibitor of protein kinase A, the theophylline enhancement of LPS-induced NO production was decreased. The extent of iNOS protein expression induced by LPS was also enhanced by theophylline.It is likely that phosphodiesterase inhibition is a major action mechanism for the theophylline enhancement of LPS-induced NO production in astrocytes. Theophylline-induced acute encephalopathy might be due to the hyper-activation of astrocytes via cAMP signaling to produce excess amount of NO.

  5. Bitter gourd suppresses lipopolysaccharide-induced inflammatory responses.

    PubMed

    Kobori, Masuko; Nakayama, Hirosuke; Fukushima, Kenji; Ohnishi-Kameyama, Mayumi; Ono, Hiroshi; Fukushima, Tatsunobu; Akimoto, Yukari; Masumoto, Saeko; Yukizaki, Chizuko; Hoshi, Yoshikazu; Deguchi, Tomoaki; Yoshida, Mitsuru

    2008-06-11

    Bitter gourd ( Momordica charantia L.) is a popular tropical vegetable in Asian countries. Previously it was shown that bitter gourd placenta extract suppressed lipopolysaccharide (LPS)-induced TNFalpha production in RAW 264.7 macrophage-like cells. Here it is shown that the butanol-soluble fraction of bitter gourd placenta extract strongly suppresses LPS-induced TNFalpha production in RAW 264.7 cells. Gene expression analysis using a fibrous DNA microarray showed that the bitter gourd butanol fraction suppressed expression of various LPS-induced inflammatory genes, such as those for TNF, IL1alpha, IL1beta, G1p2, and Ccl5. The butanol fraction significantly suppressed NFkappaB DNA binding activity and phosphorylation of p38, JNK, and ERK MAPKs. Components in the active fraction from bitter gourd were identified as 1-alpha-linolenoyl-lysophosphatidylcholine (LPC), 2-alpha-linolenoyl-LPC, 1-lynoleoyl-LPC, and 2-linoleoyl-LPC. Purified 1-alpha-linolenoyl-LPC and 1-linoleoyl-LPC suppressed the LPS-induced TNFalpha production of RAW 264.7 cells at a concentration of 10 microg/mL.

  6. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

  7. Interleukin-1 in Lipopolysaccharide Induced Chorioamnionitis in the Fetal Sheep

    PubMed Central

    Berry, Clare A.; Nitsos, Ilias; Hillman, Noah H.; Pillow, J. Jane; Polglase, Graeme R.; Kramer, Boris W.; Kemp, Matthew W.; Newnham, John P.; Jobe, Alan H.; Kallapur, Suhas G.

    2011-01-01

    We tested the hypothesis that interleukin 1 (IL-1) mediates intra-amniotic lipopolysaccharide (LPS)-induced chorioamnionitis in preterm fetal sheep. Time-mated Merino ewes with singleton fetuses received IL-1α, LPS, or saline (control) by intra-amniotic injection 1 to 2 days before operative delivery at 124 ± 1 days gestational age (N = 5-9/group; term = 150 days). Recombinant human IL-1 receptor antagonist (rhIL-1ra) was given into the amniotic fluid 3 hours before intra-amniotic LPS or saline to block IL-1 signaling. Inflammation in the chorioamnion was determined by histology, cytokine messenger RNA (mRNA), protein expression, and by quantitation of activated inflammatory cells. Intra-amniotic IL-1 and LPS both induced chorioamnionitis. However, IL-1 blockade with IL-1ra did not decrease intra-amniotic LPS-induced increases in pro-inflammatory cytokine mRNAs, numbers of inflammatory cells, myeloperoxidase, or monocyte chemotactic protein-1-expressing cells in the chorioamnion. We conclude that IL-1 and LPS both can cause chorioamnionitis, but IL-1 is not an important mediator of LPS-induced chorioamnionitis in fetal sheep. PMID:21493953

  8. Preventive Effects of Carnosine on Lipopolysaccharide-induced Lung Injury

    PubMed Central

    Tanaka, Ken-Ichiro; Sugizaki, Toshifumi; Kanda, Yuki; Tamura, Fumiya; Niino, Tomomi; Kawahara, Masahiro

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is a potentially devastating form of acute lung injury, which involves neutrophilic inflammation and pulmonary cell death. Reactive oxygen species (ROS) play important roles in ARDS development. New compounds for inhibiting the onset and progression of ARDS are required. Carnosine (β-alanyl-L-histidine) is a small di-peptide with numerous activities, including antioxidant effects, metal chelation, proton buffering capacity and the inhibition of protein carbonylation and glycoxidation. We have examined the preventive effects of carnosine on tissue injury, oedema and inflammation in a murine model for ARDS. Oral administration of carnosine suppressed lipopolysaccharide (LPS)-induced vascular permeability, tissue injury and inflammation in the lung. In vivo imaging analysis revealed that LPS administration increased the level of ROS and that this increase was inhibited by carnosine administration. Carnosine also suppressed LPS-induced neutrophilic inflammation (evaluated by activation of myeloperoxidase in the lung and increased extracellular DNA in bronchoalveolar lavage fluid). Furthermore, carnosine administration suppressed the LPS-induced endoplasmic reticulum stress response in vivo. These results suggest that the oral administration of carnosine suppresses LPS-induced lung injury via carnosine’s ROS-reducing activity. Therefore, carnosine may be beneficial for suppressing the onset and progression of ARDS. PMID:28205623

  9. Systematic Analysis of the Cytokine and Anhedonia Response to Peripheral Lipopolysaccharide Administration in Rats

    PubMed Central

    Bouwknecht, Jan A.; De Haes, Patrick; Hellings, Niels; Meert, Theo F.

    2016-01-01

    Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans. PMID:27504457

  10. Systematic Analysis of the Cytokine and Anhedonia Response to Peripheral Lipopolysaccharide Administration in Rats.

    PubMed

    Biesmans, Steven; Matthews, Liam J R; Bouwknecht, Jan A; De Haes, Patrick; Hellings, Niels; Meert, Theo F; Nuydens, Rony; Ver Donck, Luc

    2016-01-01

    Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans.

  11. Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans, Candida albicans, and lipopolysaccharide.

    PubMed Central

    Levitz, S M; Tabuni, A; Nong, S H; Golenbock, D T

    1996-01-01

    Deactivation of mononuclear phagocytes is critical to limit the inflammatory response but can be detrimental in the face of progressive infection. We compared the effects of the deactivating cytokine interleukin 10 (IL-10) on human peripheral blood mononuclear cell (PBMC) responses to lipopolysaccharide (LPS), Cryptococcus neoformans, and Candida albicans. IL-10 effected dose-dependent inhibition of tumor necrosis factor alpha (TNF-alpha) release in PBMC stimulated by LPS and C. neoformans, with significant inhibition seen with 0.1 U/ml and greater than 90% inhibition noted with 10 U/ml. In contrast, even at doses as high as 100 U/ml, IL-10 inhibited TNF-alpha release in response to C. albicans by only 50%. IL-10 profoundly inhibited release of IL-1beta from PBMC stimulated by all three stimuli. TNF-alpha mRNA and release was inhibited even if IL-10 was added up to 8 h after cryptococcal stimulation. In contrast, inhibition of IL-1 beta mRNA was of lesser magnitude and occurred only when IL-10 was added within 2 h of cryptococcal stimulation. IL-10 inhibited translocation of NF-kappaB in response to LPS but not the fungal stimuli. All three stimuli induced IL-10 production in PBMC, although over 10-fold less IL-10 was released in response to C. neoformans compared with LPS and C. albicans. Thus, while IL-10 has deactivating effects on PBMC responses to all three stimuli, disparate stimulus- and response-specific patterns of deactivation are seen. Inhibition by IL-10 of proinflammatory cytokine release appears to occur at the level of gene transcription for TNF-alpha and both transcriptionally and posttranscriptionally for IL-1beta. PMID:8641805

  12. Lipopolysaccharide induced acute red eye and corneal ulcers.

    PubMed

    Schultz, C L; Morck, D W; McKay, S G; Olson, M E; Buret, A

    1997-01-01

    Using a new animal model, the aims of this study were to assess the role played by purified lipopolysaccharide (LPS) and neutrophils in the pathogenesis of acute red-eye reactions (ARE) and corneal ulcers. In addition, IL-1 alpha was assessed for its implications in the formation of corneal ulcers. Following corneal abrasion, eyes of rabbits underwent single or double exposures to various doses of LPS from Pseudomonas aeruginosa or Serratia marcescens. This protocol induced ARE symptoms, and their severity depended on the dosage, number of LPS exposures, and type of LPS used (LPS from S. marcescens showing highest virulence). Corneal ulcers were induced by delivering a high dose of Serratia LPS (100 micrograms) followed by a low dose (10 micrograms). Histopathological examination revealed that both ARE and corneal ulceration were associated with prominent neutrophil infiltration. In addition, many lymphocytes and other monocytic cells infiltrated ulcerated ocular tissue. Tear fluids obtained from ulcerated eyes contained high concentrations of a protein recognized by anti-rabbit IL-1 alpha antibodies as demonstrated by immunoblotting studies. The results indicate that LPS can induce ARE and corneal ulceration in the absence of any live bacteria. Moreover, the findings implicate the accumulation of neutrophils and IL-1 alpha-related proteins in the pathogenesis of ARE and corneal ulcers.

  13. Lipopolysaccharide induces autotaxin expression in human monocytic THP-1 cells

    SciTech Connect

    Li Song; Zhang Junjie

    2009-01-09

    Autotaxin (ATX) is a secreted enzyme with lysophospholipase D (lysoPLD) activity, which converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive phospholipid involved in numerous biological activities, including cell proliferation, differentiation, and migration. In the present study, we found that bacterial lipopolysaccharide (LPS), a well-known initiator of the inflammatory response, induced ATX expression in monocytic THP-1 cells. The activation of PKR, JNK, and p38 MAPK was required for the ATX induction. The LPS-induced ATX in THP-1 cells was characterized as the {beta} isoform. In the presence of LPC, ATX could promote the migrations of THP-1 and Jurkat cells, which was inhibited by pertussis toxin (PTX), an inhibitor of Gi-mediated LPA receptor signaling. In summary, LPS induces ATX expression in THP-1 cells via a PKR, JNK and p38 MAPK-mediated mechanism, and the ATX induction is likely to enhance immune cell migration in proinflammatory response by regulating LPA levels in the microenvironment.

  14. Maturation Phenotype of Peripheral Blood Monocyte/Macrophage After Stimulation with Lipopolysaccharides in Irritable Bowel Syndrome.

    PubMed

    Rodríguez-Fandiño, Oscar A; Hernández-Ruiz, Joselín; López-Vidal, Yolanda; Charúa-Guindic, Luis; Escobedo, Galileo; Schmulson, Max J

    2017-04-30

    Abnormal immune regulation and increased intestinal permeability augmenting the passage of bacterial molecules that can activate immune cells, such as monocytes/macrophages, have been reported in irritable bowel syndrome (IBS). The aim was to compare the maturation phenotype of monocytes/macrophages (CD14+) from IBS patients and controls in the presence or absence of Escherichia coli lipopolysaccharides (LPS), in vitro. Mononuclear cells were isolated from peripheral blood of 20 Rome II-IBS patients and 19 controls and cultured with or without LPS for 72 hours. The maturation phenotype was examined by flow cytometry as follows: M1-Early (CD11c(+)CD206(-)), M2-Advanced (CD11c(-)CD206(+)CX3CR1(+)); expression of membrane markers was reported as mean fluorescence intensity (MFI). The Mann-Whitney test was used and significance was set at P < 0.05. In CD14+ cells, CD11c expression decreased with vs without LPS both in IBS (MFI: 8766.0 ± 730.2 vs 12 920.0 ± 949.2, P < 0.001) and controls (8233.0 ± 613.9 vs 13 750.0 ± 743.3, P < 0.001). M1-Early cells without LPS, showed lower CD11c expression in IBS than controls (MFI: 11 540.0 ± 537.5 vs 13 860.0 ± 893.7, P = 0.040), while both groups showed less CD11c in response to LPS (P < 0.01). Furthermore, the percentage of "Intermediate" (CD11c(+)CD206(+)CX3CR1(+)) cells without LPS, was higher in IBS than controls (IBS = 9.5 ± 1.5% vs C = 4.9 ± 1.4%, P < 0.001). Finally, fractalkine receptor (CX3CR1) expression on M2-Advanced cells was increased when treated with LPS in controls but not in IBS (P < 0.001). The initial phase of monocyte/macrophage maturation appears to be more advanced in IBS compared to controls. However, the decreased CX3CR1 in patients with IBS, compared to controls, when stimulated with LPS suggests a state of immune activation in IBS.

  15. Maturation Phenotype of Peripheral Blood Monocyte/Macrophage After Stimulation with Lipopolysaccharides in Irritable Bowel Syndrome

    PubMed Central

    Rodríguez-Fandiño, Oscar A; Hernández-Ruiz, Joselín; López-Vidal, Yolanda; Charúa-Guindic, Luis; Escobedo, Galileo; Schmulson, Max J

    2017-01-01

    Background/Aims Abnormal immune regulation and increased intestinal permeability augmenting the passage of bacterial molecules that can activate immune cells, such as monocytes/macrophages, have been reported in irritable bowel syndrome (IBS). The aim was to compare the maturation phenotype of monocytes/macrophages (CD14+) from IBS patients and controls in the presence or absence of Escherichia coli lipopolysaccharides (LPS), in vitro. Methods Mononuclear cells were isolated from peripheral blood of 20 Rome II-IBS patients and 19 controls and cultured with or without LPS for 72 hours. The maturation phenotype was examined by flow cytometry as follows: M1-Early (CD11c+CD206−), M2-Advanced (CD11c−CD206+CX3CR1+); expression of membrane markers was reported as mean fluorescence intensity (MFI). The Mann-Whitney test was used and significance was set at P < 0.05. Results In CD14+ cells, CD11c expression decreased with vs without LPS both in IBS (MFI: 8766.0 ± 730.2 vs 12 920.0 ± 949.2, P < 0.001) and controls (8233.0 ± 613.9 vs 13 750.0 ± 743.3, P < 0.001). M1-Early cells without LPS, showed lower CD11c expression in IBS than controls (MFI: 11 540.0 ± 537.5 vs 13 860.0 ± 893.7, P = 0.040), while both groups showed less CD11c in response to LPS (P < 0.01). Furthermore, the percentage of “Intermediate” (CD11c+CD206+CX3CR1+) cells without LPS, was higher in IBS than controls (IBS = 9.5 ± 1.5% vs C = 4.9 ± 1.4%, P < 0.001). Finally, fractalkine receptor (CX3CR1) expression on M2-Advanced cells was increased when treated with LPS in controls but not in IBS (P < 0.001). Conclusions The initial phase of monocyte/macrophage maturation appears to be more advanced in IBS compared to controls. However, the decreased CX3CR1 in patients with IBS, compared to controls, when stimulated with LPS suggests a state of immune activation in IBS. PMID:28044051

  16. Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity.

    PubMed

    Zhao, Wei-Xing; Zhang, Jun-Han; Cao, Jiang-Bei; Wang, Wei; Wang, Dong-Xin; Zhang, Xiao-Ying; Yu, Jun; Zhang, Yong-Yi; Zhang, You-Zhi; Mi, Wei-Dong

    2017-01-21

    Considerable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. Increasing evidence suggests that acetaminophen (APAP) has unappreciated antioxidant and anti-inflammatory properties. However, the impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. The objective of this study is to explore whether APAP could have neuroprotective effects on lipopolysaccharide (LPS)-induced cognitive impairment in mice. A mouse model of LPS-induced cognitive impairment was established to evaluate the neuroprotective effects of APAP against LPS-induced cognitive impairment. Adult C57BL/6 mice were treated with APAP half an hour prior to intracerebroventricular microinjection of LPS and every day thereafter, until the end of the study period. The Morris water maze was used to assess cognitive function from postinjection days 1 to 3. Animal behavioural tests as well as pathological and biochemical assays were performed to evaluate LPS-induced hippocampal damage and the neuroprotective effect of APAP. Mice treated with LPS exhibited impaired performance in the Morris water maze without changing spontaneous locomotor activity, which was ameliorated by treatment with APAP. APAP suppressed the accumulation of pro-inflammatory cytokines and microglial activation induced by LPS in the hippocampus. In addition, APAP increased SOD activity, reduced MDA levels, modulated glycogen synthase kinase 3β (GSK3β) activity and elevated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, APAP significantly decreased the Bax/Bcl-2 ratio and neuron apoptosis in the hippocampus of LPS-treated mice. Our results suggest that APAP may possess a neuroprotective effect against LPS-induced cognitive impairment and inflammatory and oxidative stress via mechanisms involving its antioxidant and

  17. Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment.

    PubMed

    Vasconcelos, Andrea R; Yshii, Lidia M; Viel, Tania A; Buck, Hudson S; Mattson, Mark P; Scavone, Cristoforo; Kawamoto, Elisa M

    2014-05-06

    Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels. Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

  18. Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment

    PubMed Central

    2014-01-01

    Background Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Methods Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Results Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels. Conclusions Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection. PMID:24886300

  19. Lipopolysaccharide induces a fibrotic-like phenotype in endothelial cells.

    PubMed

    Echeverría, César; Montorfano, Ignacio; Sarmiento, Daniela; Becerra, Alvaro; Nuñez-Villena, Felipe; Figueroa, Xavier F; Cabello-Verrugio, Claudio; Elorza, Alvaro A; Riedel, Claudia; Simon, Felipe

    2013-06-01

    Endothelial dysfunction is crucial in endotoxaemia-derived sepsis syndrome pathogenesis. It is well accepted that lipopolysaccharide (LPS) induces endothelial dysfunction through immune system activation. However, LPS can also directly generate actions in endothelial cells (ECs) in the absence of participation by immune cells. Although interactions between LPS and ECs evoke endothelial death, a significant portion of ECs are resistant to LPS challenge. However, the mechanism that confers endothelial resistance to LPS is not known. LPS-resistant ECs exhibit a fibroblast-like morphology, suggesting that these ECs enter a fibrotic programme in response to LPS. Thus, our aim was to investigate whether LPS is able to induce endothelial fibrosis in the absence of immune cells and explore the underlying mechanism. Using primary cultures of ECs and culturing intact blood vessels, we demonstrated that LPS is a crucial factor to induce endothelial fibrosis. We demonstrated that LPS was able and sufficient to promote endothelial fibrosis, in the absence of immune cells through an activin receptor-like kinase 5 (ALK5) activity-dependent mechanism. LPS-challenged ECs showed an up-regulation of both fibroblast-specific protein expression and extracellular matrix proteins secretion, as well as a down-regulation of endothelial markers. These results demonstrate that LPS is a crucial factor in inducing endothelial fibrosis in the absence of immune cells through an ALK5-dependent mechanism. It is noteworthy that LPS-induced endothelial fibrosis perpetuates endothelial dysfunction as a maladaptive process rather than a survival mechanism for protection against LPS. These findings are useful in improving current treatment against endotoxaemia-derived sepsis syndrome and other inflammatory diseases.

  20. Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation.

    PubMed

    He, Hua; Chen, Fei; Ni, Wensi; Li, Jianhui; Zhang, Yongjun

    2014-07-01

    Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased numbers of alveoli and increased airspace. BPD, frequently suffered by very low birth weight infants, has been closely associated with intrauterine infection. However, the underlying mechanisms of BPD remain unclear. In the present study, it was identified that administration of intra-amniotic lipopolysaccharide (LPS) to pregnant rats on embryonal day 16.5 (E16.5) induced significant alveolarization arrest similar to that of BPD in neonatal pups, and theophylline injected subcutaneously into the newborns improved the pathological changes. To further investigate the underlying mechanism of the morphogenesis amelioration of theophylline, cytokine antibody arrays were performed with the lung lysates of neonatal rats. The results indicated that LPS upregulated a series of pro-inflammatory cytokines and theophylline significantly attenuated the expression levels of pro-inflammatory cytokines tumor necrosis factor‑α, macrophage inflammatory protein (MIP)-1α and MIP-2, and markedly elevated the production of tumor growth factor (TGF)-β family members TGF-β1, TGF-β2 and TGF-β3, which are anti‑inflammatory cytokines. Accordingly, it was hypothesized that theophylline may protect against BPD and improve chorioamnionitis‑induced alveolar arrest by regulating the balance between pro‑and anti-inflammatory cytokine expression.

  1. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Itoh, Takefumi; Obata, Hiroaki; Murakami, Shinsuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi; Nagaya, Noritoshi

    2007-08-01

    Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

  2. Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors

    PubMed Central

    2013-01-01

    Background Activation of the tryptophan degrading enzyme indoleamine-2,3-dioxygenase 1 (IDO1) is associated with the development of behavioral signs of depression. Systemic immune challenge induces IDO1 in both the periphery and the brain, leading to increased circulating and brain concentrations of kynurenines. However, whether IDO1 activity within the brain is necessary for the manifestation of depression-like behavior of mice following a central immune challenge remains to be elucidated. Methods We investigated the role of brain IDO1 in mediating depression-like behavior of mice in response to intracerebroventricular injection of saline or lipopolysaccharide (LPS, 10 ng). Results LPS increased the duration of immobility in the tail suspension test and decreased preference for a sucrose solution. These effects were associated with an activation of central but not peripheral IDO1, as LPS increased brain kynurenine but had no effect on plasma concentrations of kynurenine. Interestingly, genetic deletion or pharmacological inhibition of IDO1, using 1-methyl-tryptophan, abrogated the reduction in sucrose preference induced by intracerebroventricular LPS. 1-Methyl-tryptophan also blocked the LPS-induced increase in duration of immobility during the tail suspension test. Conclusions These data indicate that activation of brain IDO1 is sufficient to induce depression-like behaviors of mice in response to central LPS. PMID:23866724

  3. Lipopolysaccharide-induced hemolysis: Evidence for direct membrane interactions

    PubMed Central

    Brauckmann, Stephan; Effenberger-Neidnicht, Katharina; de Groot, Herbert; Nagel, Michael; Mayer, Christian; Peters, Jürgen; Hartmann, Matthias

    2016-01-01

    While hemolysis in patients with sepsis is associated with increased mortality its mechanisms are unknown and Toll-like receptor (TLR)-4 mediated effects, complement-mediated hemolysis, or direct cell membrane effects are all conceivable mechanisms. In this study, we tested the hypotheses that toxic lipopolysaccharide (LPS) as well as non-toxic RS-LPS evokes hemolysis (1) by direct membrane effects, and (2) independent of the complement system and TLR-4 activation. We found, that incubation with LPS resulted in a marked time and concentration dependent increase of free hemoglobin concentration and LDH activity in whole blood and washed red cells. Red cell integrity was diminished as shown by decreased osmotic resistance, formation of schistocytes and rolls, and a decrease in red cell membrane stiffness. Non-toxic RS-LPS inhibited the LPS-evoked increase in TNF-α concentration demonstrating its TLR-4 antagonism, but augmented LPS-induced increase in supernatant hemoglobin concentration and membrane disturbances. Removal of plasma components in washed red cell assays failed to attenuate hemolysis. In summary, this study demonstrates direct physicochemical interactions of LPS with red cell membranes resulting in hemolysis under in vitro conditions. It might thus be hypothesized, that not all effects of LPS are mediated by TLR and may explain LPS toxicity in cells missing TLR. PMID:27759044

  4. Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency

    PubMed Central

    Huang, Ho-Shiang; Ma, Ming-Chieh

    2015-01-01

    N-methyl-D-aspartate (NMDA) receptor activation in rat kidney reduces renal perfusion and ultrafiltration. Hypoperfusion-induced ischemia is the most frequent cause of functional insufficiency in the endotoxemic kidney. Here, we used non-hypotensive rat model of lipopolysaccharide-induced endotoxemia to examine whether NMDA receptor hyperfunction contributes to acute kidney injury. Lipopolysaccharide-induced renal damage via increased enzymuria and hemodynamic impairments were ameliorated by co-treatment with the NMDA receptor blocker, MK-801. The NMDA receptor NR1 subunit in the rat kidney mainly co-localized with serine racemase, an enzyme responsible for synthesizing the NMDA receptor co-agonist, D-serine. The NMDA receptor hyperfunction in lipopolysaccharide-treated kidneys was demonstrated by NR1 and serine racemase upregulation, particularly in renal tubules, and by increased D-serine levels. Lipopolysaccharide also induced cell damage in cultured tubular cell lines and primary rat proximal tubular cells. This damage was mitigated by MK-801 and by small interfering RNA targeting NR1. Lipopolysaccharide increased cytokine release in tubular cell lines via toll-like receptor 4. The release of interleukin-1β from these cells are the most abundant. An interleukin-1 receptor antagonist not only attenuated cell death but also abolished lipopolysaccharide-induced NR1 and serine racemase upregulation and increases in D-serine secretion, suggesting that interleukin-1β-mediated NMDA receptor hyperfunction participates in lipopolysaccharide-induced tubular damage. The results of this study indicate NMDA receptor hyperfunction via cytokine effect participates in lipopolysaccharide-induced renal insufficiency. Blockade of NMDA receptors may represent a promising therapeutic strategy for the treatment of sepsis-associated renal failure. PMID:26133372

  5. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

    SciTech Connect

    El-Agamy, Dina S.

    2011-06-01

    The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells

  6. Electric stimulation of the vagus nerve reduced mouse neuroinflammation induced by lipopolysaccharide.

    PubMed

    Meneses, G; Bautista, M; Florentino, A; Díaz, G; Acero, G; Besedovsky, H; Meneses, D; Fleury, A; Del Rey, A; Gevorkian, G; Fragoso, G; Sciutto, E

    2016-01-01

    Neuroinflammation (NI) is a key feature in the pathogenesis and progression of infectious and non-infectious neuropathologies, and its amelioration usually improves the patient outcome. Peripheral inflammation may promote NI through microglia and astrocytes activation, an increased expression of inflammatory mediators and vascular permeability that may lead to neurodegeneration. Several anti-inflammatory strategies have been proposed to control peripheral inflammation. Among them, electrical stimulation of the vagus nerve (VNS) recently emerged as an alternative to effectively attenuate peripheral inflammation in a variety of pathological conditions with few side effects. Considering that NI underlies several neurologic pathologies we explored herein the possibility that electrically VNS can also exert anti-inflammatory effects in the brain. NI was experimentally induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS) in C57BL/6 male mice; VNS with constant voltage (5 Hz, 0.75 mA, 2 ms) was applied for 30 s, 48 or 72 h after lipopolysaccharide injection. Twenty four hours later, pro-inflammatory cytokines (IL-1β, IL-6, TNFα) levels were measured by ELISA in brain and spleen extracts and total brain cells were isolated and microglia and macrophage proliferation and activation was assessed by flow cytometry. The level of ionized calcium binding adaptor molecule (Iba-1) and glial fibrillary acidic protein (GFAP) were estimated in whole brain extracts and in histologic slides by Western blot and immunohistochemistry, respectively. VNS significantly reduced the central levels of pro-inflammatory cytokines and the percentage of microglia (CD11b/CD45(low)) and macrophages (CD11b/CD45(high)), 24 h after the electrical stimulus in LPS stimulated mice. A significantly reduced level of Iba-1 expression was also observed in whole brain extracts and in the hippocampus, suggesting a reduction in activated microglia. VNS is a feasible therapeutic tool

  7. Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

    PubMed Central

    Brown, A P; Schultze, A E; Holdan, W L; Buchweitz, J P; Roth, R A; Ganey, P E

    1996-01-01

    After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury. Images Figure 1. Figure 2. A Figure 2. B Figure 3. Figure 4. A Figure 4. B Figure 5. Figure 6. PMID:8793352

  8. Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses

    PubMed Central

    Ashbrook, M J; McDonough, K L; Pituch, J J; Christopherson, P L; Cornell, T T; Selewski, D T; Shanley, T P; Blatt, N B

    2015-01-01

    Citrate, a central component of cellular metabolism, is a widely used anti-coagulant due to its ability to chelate calcium. Adenosine triphosphate (ATP)-citrate lyase, which metabolizes citrate, has been shown to be essential for inflammation, but the ability of exogenous citrate to impact inflammatory signalling cascades remains largely unknown. We hypothesized that citrate would modulate inflammatory responses as both a cellular metabolite and calcium chelator, and tested this hypothesis by determining how clinically relevant levels of citrate modulate monocyte proinflammatory responses to lipopolysaccharide (LPS) in a human acute monocytic leukaemia cell line (THP-1). In normal medium (0·4 mM calcium), citrate inhibited LPS-induced tumour necrosis factor (TNF)-α and interleukin (IL)-8 transcripts, whereas in medium supplemented with calcium (1·4 mM), TNF-α and IL-8 levels increased and appeared independent of calcium chelation. Using an IL-8–luciferase plasmid construct, the same increased response was observed in the activation of the IL-8 promoter region, suggesting transcriptional regulation. Tricarballylic acid, an inhibitor of ATP-citrate lyase, blocked the ability of citrate to augment TNF-α, linking citrate's augmentation effect with its metabolism by ATP-citrate lyase. In the presence of citrate, increased histone acetylation was observed in the TNF-α and IL-8 promoter regions of THP-1 cells. We observed that citrate can both augment and inhibit proinflammatory cytokine production via modulation of inflammatory gene transactivation. These findings suggest that citrate anti-coagulation may alter immune function through complex interactions with the inflammatory response. PMID:25619261

  9. Influence of feeding status on neuronal activity in the hypothalamus during lipopolysaccharide-induced anorexia in rats.

    PubMed

    Gautron, L; Mingam, R; Moranis, A; Combe, C; Layé, S

    2005-01-01

    Fasting attenuates disease-associated anorexia, but the mechanisms underlying this effect are not well understood. In the present study, we investigated the extent to which a 48 h fast alters hypothalamic neuronal activity in response to the anorectic effects of lipopolysaccharide in rats. Male rats were fed ad libitum or fasted, and were injected with i.p. saline or lipopolysaccharide (250 microg/kg). Immunohistochemistry for Fos protein was used to visualize neuronal activity in response to lipopolysaccharide within selected hypothalamic feeding regulatory nuclei. Additionally, food intake, body weight, plasma interleukin-1 and leptin levels, and the expression of mRNA for appetite-related neuropeptides (neuropeptide Y, proopiomelanocortin and cocaine-amphetamine-regulated transcript) were measured in a time-related manner. Our data show that the pattern of lipopolysaccharide-induced Fos expression was similar in most hypothalamic nuclei whatever the feeding status. However, we observed that fasting significantly reduced lipopolysaccharide-induced Fos expression in the paraventricular nucleus, in association with an attenuated lipopolysaccharide-induced anorexia and body weight loss. Moreover, lipopolysaccharide reduced fasting-induced Fos expression in the perifornical area of the lateral hypothalamus. Lipopolysaccharide-induced circulating levels of interleukin-1 were similar across feeding status. Finally, fasting, but not lipopolysaccharide, affected circulating level of leptin and appetite-related neuropeptides expression in the arcuate nucleus. Together, our data show that fasting modulates lipopolysaccharide-induced anorexia and body weight loss in association with neural changes in specific hypothalamic nuclei.

  10. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats.

    PubMed

    Al-Harbi, Naif O; Imam, Faisal; Nadeem, Ahmed; Al-Harbi, Mohammed M; Korashy, Hesham M; Sayed-Ahmed, Mohammed M; Hafez, Mohamed M; Al-Shabanah, Othman A; Nagi, Mahmoud N; Bahashwan, Saleh

    2015-01-01

    Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20 μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p < 0.01) and MPO activity (p < 0.001), whereas marked decrease in glutathione (GSH) content (p < 0.001), glutathione reductase (GR) (p < 0.001) and glutathione peroxidase (p < 0.01) activity. These changes were significantly (p < 0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100 mg/kg, respectively). Riboflavin (100 mg/kg, p.o.) showed similar protective effects as dexamethasone (1 mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p < 0.001) and levels of CAT mRNA expression was decreased significantly (p < 0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p < 0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.

  11. The effects of Nigella sativa on sickness behavior induced by lipopolysaccharide in male Wistar rats

    PubMed Central

    Norouzi, Fatemeh; Abareshi, Azam; Anaeigoudari, Akbar; Shafei, Mohammad Naser; Gholamnezhad, Zahra; Saeedjalali, Mohsen; Mohebbati, Reza; Hosseini, Mahmoud

    2016-01-01

    Objective: Neuroimmune factors contribute on the pathogenesis of sickness behaviors. Nigella sativa (NS) has anti-inflammatory, anti-anxiety and anti-depressive effects. In the present study, the effect of NS hydro-alcoholic extract on sickness behavior induced by lipopolysaccharide (LPS) was investigated. Materials and Methods: The rats were divided into five groups (n=10 in each): (1) control (saline), (2) LPS (1 mg/kg, administered two hours before behavioral tests), (3-5) LPS-Nigella sativa 100 , 200 and 400 mg/kg (LPS-NS 100, LPS-NS 200 and LPS-NS 400, respectively). Open- field (OF), elevated plus maze (EPM) and forced swimming test (FST) were performed. Results: In OF, LPS reduced the peripheral crossing, peripheral distance, total crossing and total distance compared to control (p<0.01- p<0.001). The central crossing, central distance and central time in LPS-NS 100, LPS-NS200 and LPS-NS 400 groups were higher than LPS (p<0.01- p<0.001). In EPM, LPS decreased the open arm entries, open arm time and closed arm entries while increased the closed time compared to control (p<0.001). Pretreatment by NS extract reversed the effects of LPS (p<0.05- p<0.001). In FST, LPS increased the immobility time while, decreased the climbing and active times compared to control (p<0.05- p<0.001). In LPS-NS 100, LPS-NS 200 and LPS-NS 400 groups the immobility time was less while, the active and climbing times were more than those of LPS (p<0.05- p<0.001). Conclusion: The results of the present study showed that the hydro-alcoholic extract of NS reduced the LPS-induced sickness behaviors in rats. Further investigations are required for better understanding the responsible compound (s) and the underlying mechanism(s). PMID:27247927

  12. Supra-therapeutic plasma concentrations of haloperidol induce moderate inhibition of lipopolysaccharide-induced interleukin-8 release in human monocytes

    PubMed Central

    2016-01-01

    Background The clinical use of antipsychotics and mood-stabilizing drugs with proven efficacy is largely determined by the occurrence of treatment-emergent adverse events and routine clinical chemistry and haematology data, which together define the safety and tolerability profile of these psychopharmaceuticals. Whereas the effects of mood-stabilizing drugs on functional properties of blood cells have been poorly investigated, the effects of antipsychotics have received more attention. Such studies have yielded conflicting results. This study examined the effects of the mood-stabilizing drugs carbamazepine and valproic acid and of the antipsychotic drugs olanzapine, risperidone and haloperidol on the production of the pro-inflammatory chemokine interleukin-8 (IL-8), which is released from human monocytes when activated by Gram-negative lipopolysaccharide (LPS). Methods Peripheral human whole blood was diluted with Roswell Park Memorial Institute (RPMI) cell culture medium and stimulated with LPS. Accumulating IL-8 was quantified in the supernatant with an adapted enzyme-linked immunosorbent assay (ELISA) and the results correlated to the number of monocytes at venipuncture. Results At supra-therapeutic concentrations of 100 µM, haloperidol inhibited the LPS-induced release of IL-8 in peripheral human monocytes moderately, whereas olanzapine, risperidone, carbamazepine and valproic acid showed no such effect. Conclusions The results suggest that these mood-stabilizing drugs and antipsychotics are endowed with clinically favorable inertness rather than pro-inflammatory properties. PMID:27867948

  13. Modulation of lipopolysaccharide-induced oxidative stress by capsaicin.

    PubMed

    Abdel-Salam, Omar M E; Abdel-Rahman, Rehab Fawzy; Sleem, Amany A; Farrag, Abdel Razik

    2012-08-01

    This study investigated the effect of capsaicin (the active principle of hot red pepper and a sensory excitotoxin) on oxidative stress after systemic administration of the endotoxin lipopolysaccharide (100 μg/kg, i.p.) in rats. Capsaicin (15, 150 or 1,500 μg/kg; 10, 100 or 400 μg/mL) was given via intragastric (i.g.) or intraperitoneal (i.p.) routes at time of endotoxin administration. Rats were killed 4 h later. Malondialdehyde (MDA) and reduced glutathione (GSH) were measured in brain, liver, and lungs. Alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase (ALP), nitric oxide, and glucose were measured in serum. In addition, histopathological examination of liver tissue was performed. In LPS-treated rats, hepatic GSH increased significantly by 40.8% after i.p. capsaicin at 1,500 μg/kg. Liver MDA increased significantly by 32.9% after the administration of i.g. capsaicin at 1,500 μg/kg and by 27.8 and 37.6% after the administration of i.p. capsaicin at 150 and 1,500 μg/kg, respectively. In lung tissue, both MDA and GSH were decreased by capsaicin administration. MDA decreased by 19-20.8% after i.g. capsaicin and by 17.5-23.2% after i.p. capsaicin (150-1,500 μg/kg), respectively. GSH decreased by 39.3-64.3% and by 35.7-41.1% after i.g. or i.p. capsaicin (150-1,500 μg/kg), respectively. Brain GSH increased significantly after the highest dose of i.g. or i.p. capsaicin (by 20.6 and 15.9%, respectively). The increase in serum ALT and ALP after endotoxin administration was decreased by oral or i.p. capsaicin. Serum nitric oxide showed marked increase after LPS injection, but was markedly decreased after capsaicin (1,500 μg/kg, i.p.). Serum glucose increased markedly after the administration of LPS, and was normalized by capsaicin treatment. It is suggested that in the presence of mild systemic inflammation, acute capsaicin administration might alter oxidative status in some tissues and exert an anti-inflammatory effect

  14. Lipopolysaccharide-induced lethality and cytokine production in aged mice.

    PubMed Central

    Tateda, K; Matsumoto, T; Miyazaki, S; Yamaguchi, K

    1996-01-01

    This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS-induced

  15. Enrofloxacin in therapeutic doses alters cytokine production by porcine PBMCs induced by lipopolysaccharide.

    PubMed

    Pomorska-Mól, Małgorzata; Czyżewska-Dors, Ewelina; Kwit, Krzysztof; Pejsak, Zygmunt

    2017-07-01

    The effect of enrofloxacin on cytokine secretion by porcine peripheral blood mononuclear cells (PBMCs) was studied. Twenty 8-20-week-old pigs were randomly divided into two groups: control (C, n = 10) and experimental (E, n = 10) were used. Pigs from group E received enrofloxacin at therapeutic dose for 5 consecutive days. Blood samples were collected at 0 (before antibiotic administration), 2, 4 (during antibiotic therapy) 6, 9, 14 21, 35, 49, and 63 d of study (after treatment). PBMCs of pigs from both groups were incubated with or without lipopolysaccharide (LPS). Ex vivo production on interleukin (IL)-4, IL-6, IL-10, INF-γ, and TNF-α were analyzed using ELISA assay. Intramuscular administration of enrofloxacin to healthy pigs for 5 consecutive days induced a transitory reduction of the ex vivo response of PBMCs to LPS in terms of IL-6 and TNF-α secretion. The level of IL-6 returned to day 0 level shortly after end of treatment, while the TNF-α production remained reduced 10 d after the end of treatment. Our results indicate that enrofloxacin given in vivo in therapeutic doses has an immunomodulatory effect through its capacity to inhibit ex vivo secretion of IL-6 and TNF-α by porcine PBMC after LPS stimulation.

  16. Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation*

    PubMed Central

    Grabner, Gernot F.; Eichmann, Thomas O.; Wagner, Bernhard; Gao, Yuanqing; Farzi, Aitak; Taschler, Ulrike; Radner, Franz P. W.; Schweiger, Martina; Lass, Achim; Holzer, Peter; Zinser, Erwin; Tschöp, Matthias H.; Yi, Chun-Xia; Zimmermann, Robert

    2016-01-01

    Monoglyceride lipase (MGL) is required for efficient hydrolysis of the endocannabinoid 2-arachidonoylglyerol (2-AG) in the brain generating arachidonic acid (AA) and glycerol. This metabolic function makes MGL an interesting target for the treatment of neuroinflammation, since 2-AG exhibits anti-inflammatory properties and AA is a precursor for pro-inflammatory prostaglandins. Astrocytes are an important source of AA and 2-AG, and highly express MGL. In the present study, we dissected the distinct contribution of MGL in astrocytes on brain 2-AG and AA metabolism by generating a mouse model with genetic deletion of MGL specifically in astrocytes (MKOGFAP). MKOGFAP mice exhibit moderately increased 2-AG and reduced AA levels in brain. Minor accumulation of 2-AG in the brain of MKOGFAP mice does not cause cannabinoid receptor desensitization as previously observed in mice globally lacking MGL. Importantly, MKOGFAP mice exhibit reduced brain prostaglandin E2 and pro-inflammatory cytokine levels upon peripheral lipopolysaccharide (LPS) administration. These observations indicate that MGL-mediated degradation of 2-AG in astrocytes provides AA for prostaglandin synthesis promoting LPS-induced neuroinflammation. The beneficial effect of astrocyte-specific MGL-deficiency is not fully abrogated by the inverse cannabinoid receptor 1 agonist SR141716 (Rimonabant) suggesting that the anti-inflammatory effects are rather caused by reduced prostaglandin synthesis than by activation of cannabinoid receptors. In conclusion, our data demonstrate that MGL in astrocytes is an important regulator of 2-AG levels, AA availability, and neuroinflammation. PMID:26565024

  17. Iloprost improves endothelial barrier function in lipopolysaccharide-induced lung injury.

    PubMed

    Birukova, Anna A; Wu, Tinghuai; Tian, Yufeng; Meliton, Angelo; Sarich, Nicolene; Tian, Xinyong; Leff, Alan; Birukov, Konstantin G

    2013-01-01

    The protective effects of prostacyclin and its stable analogue iloprost are mediated by elevation of intracellular cyclic AMP (cAMP) leading to enhancement of the peripheral actin cytoskeleton and cell-cell adhesive structures. This study tested the hypothesis that iloprost may exhibit protective effects against lung injury and endothelial barrier dysfunction induced by bacterial wall lipopolysaccharide (LPS). Endothelial barrier dysfunction was assessed by measurements of transendothelial permeability, morphologically and by analysis of LPS-activated inflammatory signalling. In vivo, C57BL/6J mice were challenged with LPS with or without iloprost or 8-bromoadenosine-3',5'-cyclic monophosphate (Br-cAMP) treatment. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count and Evans blue extravasation. Iloprost and Br-cAMP attenuated the disruption of the endothelial monolayer, and suppressed the activation of p38 mitogen-activated protein kinase (MAPK), the nuclear factor (NF)-κB pathway, Rho signalling, intercellular adhesion molecular (ICAM)-1 expression and neutrophil migration after LPS challenge. In vivo, iloprost was effective against LPS-induced protein and neutrophil accumulation in bronchoalveolar lavage fluid, and reduced myeloperoxidase activation, ICAM-1 expression and Evans blue extravasation in the lungs. Inhibition of Rac activity abolished the barrier-protective and anti-inflammatory effects of iloprost and Br-cAMP. Iloprost-induced elevation of intracellular cAMP triggers Rac signalling, which attenuates LPS-induced NF-κB and p38 MAPK inflammatory pathways and the Rho-dependent mechanism of endothelial permeability.

  18. Glucocorticoid inhibition of leptin- and lipopolysaccharide-induced interleukin-6 production in obesity.

    PubMed

    Huang, Chun-Jung; Acevedo, Edmund O; Mari, David C; Randazzo, Christopher; Shibata, Yoshimi

    2014-01-01

    Obesity is considered a chronic inflammatory condition that enhances the risk of numerous inflammatory diseases, including diabetes and cardiovascular disease. Glucocorticoids (GCs) and synthetic therapeutic GCs are anti-inflammatory agents, but the exact functions of GCs in obesity-related inflammation are unknown. Therefore, the objective of this study was to examine the inhibitory effect of an exogenous GC (dexamethasone, DEX) on leptin- and lipopolysaccharide (LPS)-induced IL-6 production by peripheral blood mononuclear cells (PBMCs) ex vivo in obese subjects compared to normal-weight subjects. Blood samples were drawn from 14 obese (BMI>30 kg/m(2)) and 14 normal-weight (BMI<25 kg/m(2)) subjects. Plasma cortisol, TNF-α and IL-6 levels, and insulin resistance (HOMA-IR) were quantified. Subjects' PBMCs (1×10(6) cells/mL) were isolated and cultured with leptin (18.75 and 250 ng/mL) or LPS (10ng/mL) in the presence of DEX (0, 10(-8), 10(-7), and 10(-6) M), a synthetic GC, for 24 h; IL-6 levels and GC sensitivity (IC50) were assessed in the cultured supernatants. No differences in the plasma cortisol levels were found between the two groups. We found that obese subjects showed greater leptin- and LPS-induced IL-6 production compared to normal-weight subjects. The suppressive effect of DEX on leptin- and LPS-induced IL-6 production (IC50) was not different between the two groups. However, the IC50 of DEX for LPS-induced was correlated with BMI, waist circumference, and hip circumference. These findings suggest that reduced GC sensitivity may be an important mechanism in the up-regulation of selected obese inflammation. Published by Elsevier Inc.

  19. The alteration of copper homeostasis in inflammation induced by lipopolysaccharides.

    PubMed

    Han, Ming; Lin, Zhexuan; Zhang, Yuan

    2013-08-01

    Significant changes of copper homeostasis were triggered by lipopolysaccharides, which result in systemic inflammatory response and contribute to hepatic injury. Administration of lipopolysaccharides resulted in the increase of plasma "free" copper and total copper concentrations, whereas, the decrease of "free" copper and total copper contents in liver tissue. Copper-associated proteins were detected and showed a down-regulation of X-linked inhibitor of apoptosis protein, and up-regulation of copper metabolism domain containing 1 and copper transporter 1. The alteration of these proteins would lower the apoptotic threshold. Meanwhile, the increasing of circulation copper might cause oxidative injury through Fenton reaction and contribute to tissue injury. Our findings underscored the possibility that these changes in systemic copper homeostasis might provide a novel insight of the characteristic of the acute phase of inflammatory response and the underlying influence on tissue injury.

  20. Roles of interleukin-1 and tumor necrosis factor in lipopolysaccharide-induced hypoglycemia.

    PubMed Central

    Vogel, S N; Henricson, B E; Neta, R

    1991-01-01

    In this study, hypoglycemia induced by injection of lipopolysaccharide (LPS) or the recombinant cytokine interleukin-1 alpha or tumor necrosis factor alpha (administered alone or in combination) was compared. LPS-induced hypoglycemia was reversed significantly by recombinant interleukin-1 receptor antagonist. PMID:1828792

  1. Intraperitoneal administration of fetuin-A attenuates D-galactosamine/lipopolysaccharide-induced liver failure in mouse.

    PubMed

    Zhang, Pan; Shen, Hong; Huang, Jinlin; Wang, Haichao; Zhang, Baoxin; Zhou, Rongrong; Zhong, Baiyun; Fan, Xuegong

    2014-08-01

    Fulminant hepatic failure (FHF) is a devastating syndrome, which sometimes results in death or liver transplantation, in which inflammation would aggravate the development of fetuin-A which would act as an anti-inflammatory factor and may be an available approach to attenuate FHF. The purpose of this study was to investigate the effects of fetuin-A on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced liver failure in mice. A mouse model of FHF induced by D-GalN/LPS was established and fetuin-A was injected intraperitoneally prior to D-GalN/LPS treatment. At different time points after D-GalN/LPS intervention, serum TNF-α and IL-6 levels were measured by ELISA. Fetuin-A mRNA and protein expression in liver tissues was assessed by RT-PCR, Western blotting and immunohistochemical staining. Besides, an observation of liver tissue injury, the apoptosis of hepatocytes, was analyzed by TUNEL assay. Expression of fetuin-A mRNA and protein in liver tissue were significantly and gradually decreased after D-GalN/LPS administration. A pre-intervention of exogenous fetuin-A significantly improved the liver function, decreased TNF-α and IL-6 expression in peripheral blood, and liver tissue inhibited hepatocyte apoptosis responded to D-GalN/LPS induction so as to decrease the mortality rates of FHF mouse. Meanwhile, fetuin-A was negatively correlated with the hepatic pathological score and TNF-α protein staining in FHF mouse. An intraperitoneal injection of fetuin-A attenuates D-GalN/LPS-induced FHF in mice. Fetuin-A might be a protective agent of liver damage partly through inhibiting liver inflammatory response and hepatocyte apoptosis.

  2. Synergistic effect of DDT and its metabolites in lipopolysaccharide-mediated TNF-α production is inhibited by progesterone in peripheral blood mononuclear cells.

    PubMed

    Dominguez-Lopez, Pablo; Diaz-Cueto, Laura; Aguilar-Rojas, Arturo; Arechavaleta-Velasco, Fabian

    2017-02-26

    Increased TNF-α levels have been associated with adverse pregnancy outcomes. Lipopolysaccharide (LPS), 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) induce TNF-α release in peripheral blood mononuclear cells (PBMC). Conversely, progesterone (P4) inhibits TNF-α secretion. Pregnant women in malaria endemic areas may be co-exposure to these compounds. Thus, this study was to investigate the synergistic effect of LPS and these pesticides in PBMC and to assess P4 influence on this synergy. Cultured PBMC were exposed to each pesticide in the presence of LPS, P4, or their combination. TNF-α was measured by ELISA. All pesticides enhanced TNF-α synthesis in PBMC. Co-exposure with LPS synergizes TNF-α production, which is blocked by progesterone. These results indicate that these organochlorines act synergistically with LPS to induce TNF-α secretion in PBMC. This effect is blocked by P4.

  3. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide.

    PubMed

    Konsman, J P; Veeneman, J; Combe, C; Poole, S; Luheshi, G N; Dantzer, R

    2008-12-01

    Although receptors for the pro-inflammatory cytokine interleukin-1 have long been known to be expressed in the brain, their role in fever and behavioural depression observed during the acute phase response (APR) to tissue infection remains unclear. This may in part be due to the fact that interleukin-1 in the brain is bioactive only several hours after peripheral administration of bacterial lipopolysaccharide (LPS). To study the role of cerebral interleukin-1 action in temperature and behavioural changes, and activation of brain structures during the APR, interleukin-1 receptor antagonist (IL-1ra; 100 microg) was infused into the lateral brain ventricle 4 h after intraperitoneal (i.p.) LPS injection (250 microg/kg) in rats. I.p. LPS administration induced interleukin-1beta (IL-1beta) production in systemic circulation as well as in brain circumventricular organs and the choroid plexus. Intracerebroventricular (i.c.v.) infusion of IL-1ra 4 h after i.p. LPS injection attenuated the reduction in social interaction, a cardinal sign of behavioural depression during sickness, and c-Fos expression in the amygdala and bed nucleus of the stria terminalis. However, LPS-induced fever, rises in plasma corticosterone, body weight loss and c-Fos expression in the hypothalamus and caudal brainstem were not altered by i.c.v. infusion of IL-1ra. These findings, together with our previous observations showing that i.c.v. infused IL-1ra diffuses throughout perivascular spaces, where macrophages express interleukin-1 receptors, can be interpreted to suggest that circulating or locally produced brain IL-1beta acts on these cells to bring about behavioural depression and activation of limbic structures during the APR after peripheral LPS administration.

  4. The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide - induced depression like behavior in rats

    PubMed Central

    Hosseini, Mahmoud; Zakeri, Samaneh; Khoshdast, Sadieh; Yousefian, Fatemeh T.; Rastegar, Monireh; Vafaee, Farzaneh; Kahdouee, Shamsi; Ghorbani, Fatemeh; Rakhshandeh, Hassan; Kazemi, S. Abolfazl

    2012-01-01

    Background: Neuroimmune factors have been proposed as contributors to the pathogenesis of depression. Beside other therapeutic effects including neuroprotective, antioxidant, anticonvulsant and analgesic effects, Nigella sativa and its main ingredient, thymoquinone (TQ), have been shown to have anti-inflammatory effects. In the present study, the effects of Nigella sativa hydro-alcoholic extract and thymoquinone was investigated on lipopolysaccharide- induced depression like behavior in rats. Materials and Methods: 50 male Wistar rats were divided into 5 groups: Group 1 (control group) received saline instead of NS extract, thymoquinone or lipopolysaccharide. The animals in group 2 (lipopolysaccharide (LPS)) were treated by saline instead of NS extract and were injected LPS (100μg/kg, ip) 2 hours before conducting each forced swimming test. Groups 3 (LPS + NS 200) and 4 (LPS + NS 400) were treated by 200 and 400 mg/kg of NS (ip), respectively, from the day before starting the experiments and before each forced swimming test. These animals were also injected LPS 2hours before conducting each swimming test. The animals in group 5 received TQ instead of NS extract. Forced swimming test was performed 3 times for all groups (in alternative days), and immobility time was recorded. Finally, the animals were placed in an open- field apparatus, and the crossing number on peripheral and central areas was observed. Results: The immobility time in the LPS group was higher than that in the control group in all 3 times (P<0.001). The animals in LPS + NS 200, LPS + NS 400 and LPS + TQ had lower immobility times in comparison with LPS groups (P<0.01, and P<0.01). In the open- field test, the crossing number of peripheral in the LPS group was higher than that of the control one (P<0.01) while the animals of LPS + NS 200, LPS + NS 400 and LPS + TQ groups had lower crossing number of peripheral compared with the LPS group (P <0.05, and P<0.001). Furthermore, in the LPS group, the

  5. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

    PubMed Central

    Starobova, Hana; Vetter, Irina

    2017-01-01

    Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches. PMID:28620280

  6. Modulation by gamithromycin and ketoprofen of in vitro and in vivo porcine lipopolysaccharide-induced inflammation.

    PubMed

    Wyns, Heidi; Meyer, Evelyne; Plessers, Elke; Watteyn, Anneleen; van Bergen, Thomas; Schauvliege, Stijn; De Baere, Siegrid; Devreese, Mathias; De Backer, Patrick; Croubels, Siska

    2015-12-15

    The immunomodulatory properties of gamithromycin (GAM), ketoprofen (KETO) and their combination (GAM-KETO) were investigated after both in vitro and in vivo lipopolysaccharide (LPS)-induced inflammation. The influence of these drugs was measured on the production of prostaglandin E2 (PGE2) and the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in both LPS-stimulated porcine peripheral blood mononuclear cells (PBMCs) and LPS-challenged pigs. Additionally, effects on the production of acute phase proteins (APPs), including pig major acute phase protein (pig-MAP) and C-reactive protein (CRP), as well as on the development of fever, pulmonary symptoms and sickness behaviour were investigated. Dexamethasone was included as a positive control in the in vitro research. Following an 18h-incubation period with 1.25μg/mL LPS, the levels of TNF-α, IL-1β and IL-6 (p<0.05) measured in the PBMC supernatants were significantly increased. Incubation with a high concentration of both GAM and KETO significantly reduced the in vitro levels of all three cytokines. Maximal plasma concentrations of TNF-α and IL-6 were observed at 1h and 2.5h following LPS challenge in pigs, respectively. Neither GAM, nor KETO nor the combination GAM-KETO was able to inhibit the in vivo LPS-induced cytokine production. Furthermore, none of the drugs influenced the subsequent APPs production. In contrast, administration of KETO significantly reduced PGE2 production both in vitro and in vivo (p<0.05 and p<0.001, respectively) and prevented the development of fever and severe symptoms, including dyspnoea, anorexia, vomiting and lateral decubitus.

  7. Hypoxia augments lipopolysaccharide-induced cytokine expression in periodontal ligament cells.

    PubMed

    Jian, Congxiang; Li, Chenjun; Ren, Yu; He, Yong; Li, Yunming; Feng, Xiaodan; Zhang, Gang; Tan, Yinghui

    2014-10-01

    Periodontitis is a chronic inflammatory disease characterized by the destruction of tooth supporting tissues. Hypoxia, the mainly changes of the plateau environment, can induce severe periodontitis by animal experiments. There is, however, very little information on hypoxia and lipopolysaccharide (LPS) induced cytokine expression in periodontal ligament (PDL) cells. In this article, we characterized hypoxia or P. gingivalis lipopolysaccharide (Pg LPS) induced tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 expression by human periodontal ligament (hPDL) cells. We found that hypoxia augmented Pg LPS induced TNF-α, IL-1β, and IL-6 expression in hPDL cells. We also demonstrated that nuclear factor kappa B pathway was involved in hypoxia augmenting Pg LPS induced cytokine expression in hPDL cells. Thus, our results suggest that the hypoxic environment may enhance the immune function of hPDL cells that is induced by Pg LPS.

  8. Fungal cell wall agents suppress the innate inflammatory cytokine responses of human peripheral blood mononuclear cells challenged with lipopolysaccharide in vitro.

    PubMed

    Stopinšek, Sanja; Ihan, Alojz; Wraber, Branka; Terčelj, Marjeta; Salobir, Barbara; Rylander, Ragnar; Simčič, Saša

    2011-08-01

    Exposure to high levels of fungi might lead to diseases, such as airway inflammation, hypersensitivity pneumonitis and allergy. To comprehend the mechanisms behind the exposure to fungi and a disease, we examined the in vitro innate inflammatory cytokine response of human peripheral blood mononuclear cells (PBMC) challenged by fungal cell wall agents (FCWAs), i.e., soluble and particulate (1→3)-β-D-glucan-curdlan (BGS and BGP), zymosan (ZYM) and chitosan (CHT) in the absence or presence of lipopolysaccharide (LPS). We also studied FCWA effects on the mRNA expression of dectin-1, TLR2, TLR4 and mannose receptor (MR) by real-time RT-PCR. Our results demonstrated that BGP strongly induced the secretion of TNF-α, IL-6, IL-10 and IL-12; BGS, ZYM and CHT were weaker, but still significant cytokine inducers. We showed that BGS significantly augmented the LPS-induced in vitro secretion of TNF-α. On the other hand, BGP, ZYM and CHT suppressed the LPS-induced production of all cytokines. At the mRNA level, the dectin-1, TLR2 and TLR4 expressions were significantly reduced by all FCWAs in the absence of LPS and even more in the presence of LPS. While we demonstrated that the innate inflammatory cytokine response of PBMC induced by CHT was mediated by MR, the MR mRNA expression was significantly reduced by CHT. On the contrary, BGS significantly enhanced the MR mRNA expression. In conclusion, a long-term and massive exposure to LPS and FCWA (e.g., organic dust) may cause an important disruption of normal immune response and allow development and/or persistence of various immunopathological events. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice

    PubMed Central

    Zhu, Xiaobin; He, Lianying; McCluskey, Lynnette Phillips

    2013-01-01

    A fundamental role of the taste system is to discriminate between nutritive and toxic foods. However, it is unknown whether bacterial pathogens that might contaminate food and water modulate the transmission of taste input to the brain. We hypothesized that exogenous, bacterially-derived lipopolysaccharide (LPS), modulates neural responses to taste stimuli. Neurophysiological responses from the chorda tympani nerve, which innervates taste cells on the anterior tongue, were unchanged by acute exposure to LPS. Instead, neural responses to sucrose were selectively inhibited in mice that drank LPS during a single overnight period. Decreased sucrose sensitivity appeared 7 days after LPS ingestion, in parallel with decreased lingual expression of Tas1r2 and Tas1r3 transcripts, which are translated to T1R2+T1R3 subunits forming the sweet taste receptor. Tas1r2 and Tas1r3 mRNA expression levels and neural responses to sucrose were restored by 14 days after LPS consumption. Ingestion of LPS, rather than contact with taste receptor cells, appears to be necessary to suppress sucrose responses. Furthermore, mice lacking the Toll-like receptor (TLR) 4 for LPS were resistant to neurophysiological changes following LPS consumption. These findings demonstrate that ingestion of LPS during a single period specifically and transiently inhibits neural responses to sucrose. We suggest that LPS drinking initiates TLR4-dependent hormonal signals that downregulate sweet taste receptor genes in taste buds. Delayed inhibition of sweet taste signaling may influence food selection and the complex interplay between gastrointestinal bacteria and obesity. PMID:24215981

  10. Ingestion of bacterial lipopolysaccharide inhibits peripheral taste responses to sucrose in mice.

    PubMed

    Zhu, X; He, L; McCluskey, L P

    2014-01-31

    A fundamental role of the taste system is to discriminate between nutritive and toxic foods. However, it is unknown whether bacterial pathogens that might contaminate food and water modulate the transmission of taste input to the brain. We hypothesized that exogenous, bacterially-derived lipopolysaccharide (LPS), modulates neural responses to taste stimuli. Neurophysiological responses from the chorda tympani nerve, which innervates taste cells on the anterior tongue, were unchanged by acute exposure to LPS. Instead, neural responses to sucrose were selectively inhibited in mice that drank LPS during a single overnight period. Decreased sucrose sensitivity appeared 7days after LPS ingestion, in parallel with decreased lingual expression of Tas1r2 and Tas1r3 transcripts, which are translated to T1R2+T1R3 subunits forming the sweet taste receptor. Tas1r2 and Tas1r3 mRNA expression levels and neural responses to sucrose were restored by 14 days after LPS consumption. Ingestion of LPS, rather than contact with taste receptor cells, appears to be necessary to suppress sucrose responses. Furthermore, mice lacking the Toll-like receptor (TLR) 4 for LPS were resistant to neurophysiological changes following LPS consumption. These findings demonstrate that ingestion of LPS during a single period specifically and transiently inhibits neural responses to sucrose. We suggest that LPS drinking initiates TLR4-dependent hormonal signals that downregulate sweet taste receptor genes in taste buds. Delayed inhibition of sweet taste signaling may influence food selection and the complex interplay between gastrointestinal bacteria and obesity. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Effect of lipopolysaccharide on indices of peripheral and hepatic metabolism in lactating cows.

    PubMed

    Waldron, M R; Nishida, T; Nonnecke, B J; Overton, T R

    2003-11-01

    Four multiparous lactating cows (175 to 220 d in milk [DIM]) were used in a 4 x 4 Latin square design to assess the effects of four doses (0.0, 0.5, 1.0, and 1.5 microg/kg of body weight) of lipopolysaccharide (LPS; Escherichia coli 0111:B4) on performance and plasma metabolite and hormone concentrations. In addition, effects of immune activation on in vitro hepatic metabolic capacity were evaluated in 12 multiparous lactating cows (150 to 220 DIM) infused with 0 (n = 6), 1.0 (n = 4) or 2.0 (n = 2) microg of LPS/kg. Milk production and DMI decreased linearly with LPS dose for 24 h after LPS infusion. Overall mean plasma tumor necrosis factor-alpha, insulin, glucagon, and cortisol concentrations increased linearly with LPS dose, and plasma beta-hydroxybutyrate decreased linearly by dose after LPS infusion. Infusion of LPS decreased the insulin:glucagon molar ratio, but did not affect plasma concentrations of growth hormone, insulin-like growth factor-1, leptin, or L-(+)-lactate. Plasma concentrations of glucose tended to increase initially and subsequently decrease, and there was a quadratic tendency for increased plasma nonesterified fatty acid concentrations after LPS administration. In vitro hepatic capacity for conversion of [1-(14)C]L-(+)-lactate and [1-(14)C]palmitate, but not [1-(14)C]propionate or [1-(14)C]L-alanine, to CO2 increased after LPS administration. Hepatic capacity to convert [1-(14)C]propionate to glucose tended to increase, but neither esterification nor the conversion of palmitate to acid soluble products was altered by LPS. The LPS infusion resulted in significant changes of endocrine mediators responsible for regulation of energy metabolism of lactating cows and tended to alter subsequent in vitro hepatic metabolic capacity.

  12. Alpha-lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice

    EPA Science Inventory

    Abstract: Hypothermia is a key symptom of sepsis and the mechanism(s) leading to hypothermia during sepsis is largely unknown. To investigate a potential mechanism and find an effective treatment for hypothermia in sepsis, we induced hypothermia in mice by lipopolysaccharide (LP...

  13. Lipopolysaccharide from Xanthomonas campestris induces defense-related gene expression in Brassica campestris.

    PubMed

    Newman, M A; Daniels, M J; Dow, J M

    1995-01-01

    Purified lipopolysaccharide (LPS) from Xanthomonas campestris pv. campestris induced accumulation of transcript for beta-1,3-glucanase in turnip at concentrations of 1 micrograms/ml. The lipid A-inner core structure was required for activity but the O-antigen had no role. We suggest that release of LPS in planta triggers expression of at least some defense-related genes.

  14. Alpha-lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice

    EPA Science Inventory

    Abstract: Hypothermia is a key symptom of sepsis and the mechanism(s) leading to hypothermia during sepsis is largely unknown. To investigate a potential mechanism and find an effective treatment for hypothermia in sepsis, we induced hypothermia in mice by lipopolysaccharide (LP...

  15. Garlic (Allium sativum) Extracts Inhibits Lipopolysaccharide-Induced Toll-Like Receptor 4 Dimerization

    USDA-ARS?s Scientific Manuscript database

    Garlic has been used as a folk medicine for a long history. Numerous studies demonstrated that garlic extracts and its sulfur-containing compounds inhibit nuclear factor-kappa B (NF-kB) activation induced by various receptor agonist including lipopolysaccharide (LPS). These effects suggest that garl...

  16. Serum myoglobin, but not lipopolysaccharides, is predictive of AMPH-induced striatal neurotoxicity.

    PubMed

    Levi, Mark S; Patton, Ralph E; Hanig, Joseph P; Tranter, Karen M; George, Nysia I; James, Laura P; Davis, Kelly J; Bowyer, John F

    2013-07-01

    Determinants of amphetamine (AMPH)-induced neurotoxicity are poorly understood. The role of lipopolysaccharides (LPS) and organ injury in AMPH-induced neurotoxicity was examined in adult male Sprague-Dawley rats that were give AMPH and became hyperthermic during the exposure. Environmentally-induced hyperthermia (EIH) in the rat was compared to AMPH to determine whether AMPH-induced increases in LPS and peripheral toxicities were solely attributable to hyperthermia. Muscle, liver, and kidney function were determined biochemically at 3h or 1 day after AMPH or EIH exposure and histopathology at 1 day after treatment. Circulating levels of LPS were monitored (via limulus amoebocyte coagulation assay) during AMPH or EIH exposure. Blood LPS levels were detected in 40-50% of the AMPH and EIH rats, but the presence of LPS in the serum had no effect on organ damage or striatal dopamine depletions (neurotoxicity). In both CR and NCTR rats, serum bound urea nitrogen and creatinine levels increased at 3h after EIH or AMPH (2- to 3-fold above control) but subsided by 1 day. Alanine transaminase was increased (indicating liver dysfunction) by both AMPH and EIH at 3 h (2- to 10-fold above control) in CR rats, but the levels were not significantly different between the control and AMPH groups in NCTR animals. Mild liver necrosis was detected in 1 of 7 rats examined in the AMPH group and in 1 of 5 rats examined in the EIH group (only NCTR rats were examined). Serum myoglobin increased (indicating muscle damage) in both CR and NCTR rats at 3h and was more pronounced with AMPH (≈5-fold above control) than EIH. Our results indicate that: (1) "free" blood borne LPS often increases with EIH and AMPH but may not be necessary for striatal neurotoxicity and CNS immune responses; (2) liver or kidney dysfunction may result from muscle damage; however, it is not sufficient nor necessary to produce, but may exacerbate, neurotoxicity; (3) AMPH-induced serum myoglobin release is a potential

  17. An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance.

    PubMed Central

    Henricson, B E; Neta, R; Vogel, S N

    1991-01-01

    In this report, administration of a recombinant interleukin-1 receptor antagonist protein to mice was found to inhibit induction of colony-stimulating factor as well as induction of early endotoxin tolerance by lipopolysaccharide. These findings provide direct evidence that interleukin-1 is an intermediate in these two lipopolysaccharide-induced phenomena. PMID:1825485

  18. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death.

    PubMed Central

    Laubach, V E; Shesely, E G; Smithies, O; Sherman, P A

    1995-01-01

    Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNOS) is thought to be important in the pathogenesis of septic shock. To further our understanding of the role of iNOS in normal biology and in a variety of inflammatory disorders, including septic shock, we have used gene targeting to generate a mouse strain that lacks iNOS. Mice lacking iNOS were indistinguishable from wild-type mice in appearance and histology. Upon treatment with lipopolysaccharide and interferon gamma, peritoneal macrophages from the mutant mice did not produce nitric oxide measured as nitrite in the culture medium. In addition, lysates of these cells did not contain iNOS protein by immunoblot analysis or iNOS enzyme activity. In a Northern analysis of total RNA, no iNOS transcript of the correct size was detected. No increases in serum nitrite plus nitrate levels were observed in homozygous mutant mice treated with a lethal dose of lipopolysaccharide, but the mutant mice exhibited no significant survival advantage over wild-type mice. These results show that lack of iNOS activity does not prevent mortality in this murine model for septic shock. Images Fig. 2 Fig. 3 PMID:7479866

  19. Pentraxin-3 modulates lipopolysaccharide-induced inflammatory response and attenuates liver injury.

    PubMed

    Perea, Luis; Coll, Mar; Sanjurjo, Lucia; Blaya, Delia; Taghdouini, Adil El; Rodrigo-Torres, Daniel; Altamirano, José; Graupera, Isabel; Aguilar-Bravo, Beatriz; Llopis, Marta; Vallverdú, Julia; Caballeria, Joan; van Grunsven, Leo A; Sarrias, Maria-Rosa; Ginès, Pere; Sancho-Bru, Pau

    2017-09-01

    Acute-on-chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute-phase proteins such as Pentraxin-3 (PTX3) are released; however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. The role of PTX3 was evaluated in cultured human cells, liver tissue slices, and mice with acute-on-chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis. PTX3 expression was up-regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells were the main cell types expressing PTX3 in liver injury. Ex vivo and in vivo studies showed that PTX3 treatment attenuated LPS-induced liver injury, inflammation, and cell recruitment. Mechanistically, PTX3 mediated the hepatic stellate cell wound-healing response. Moreover, PTX3 modulated LPS-induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TIR domain-containing adapter-inducing interferon-dependent response and favoring a macrophage interleukin-10-like phenotype. Additionally, hepatic and plasma PTX3 levels were increased in patients with alcoholic hepatitis, a prototypic acute-on-chronic condition; and its expression correlated with disease severity scores, endotoxemia, infections, and short-term mortality, thus suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury. Experimental and human evidence suggests that, in addition to being a potential biomarker for alcoholic hepatitis, PTX3 participates in the wound-healing response and attenuates LPS-induced liver injury and inflammation; therefore, administration of PTX3 could be a promising therapeutic strategy in acute-on-chronic conditions, particularly those

  20. The opioid antagonist, β-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice.

    PubMed

    Davis, Randall L; Stevens, Craig W; Thomas Curtis, J

    2017-05-01

    Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (β-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered β-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered β-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. β-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by β-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of β-FNA is warranted.

  1. Proteomic Changes in Chicken Plasma Induced by Salmonella typhimurium Lipopolysaccharides

    PubMed Central

    Packialakshmi, Balamurugan; Liyanage, Rohana; Lay, Jackson O.; Makkar, Sarbjeet K.; Rath, Narayan C.

    2016-01-01

    Lipopolysaccharides (LPS) are cell wall components of Gram-negative bacteria that produce inflammation and sickness in higher animals. The objective was to identify plasma proteomic changes in an avian model of inflammation. Chickens were treated with either saline or LPS, and blood was collected at 24 hours postinjection. The pooled plasma samples were depleted of high-abundant proteins and analyzed by matrix-assisted laser desorption ionization (MALDI)-time-of-flight mass spectrometry and liquid chromatography–tandem mass spectrometry (LC–MS/MS). MALDI analyses showed an increase in fibrinogen beta-derived peptide and a decrease in apolipoprotein-AII-derived peptide in LPS samples. Label-free quantitation of LC–MS/MS spectra revealed an increase in the levels of α1-acid glycoprotein, a chemokine CCLI10, and cathelicidin-2, but a decrease in an interferon-stimulated gene-12-2 protein in the LPS group. These differentially expressed proteins are associated with immunomodulation, cytokine changes, and defense mechanisms, which may be useful as candidate biomarkers of infection and inflammation. PMID:27053921

  2. Protective effect of mangiferin against lipopolysaccharide-induced depressive and anxiety-like behaviour in mice.

    PubMed

    Jangra, Ashok; Lukhi, Manish M; Sulakhiya, Kunjbihari; Baruah, Chandana C; Lahkar, Mangala

    2014-10-05

    Numerous studies have demonstrated that inflammation, oxidative stress and altered level of neurotrophins are involved in the pathogenesis of depressive illness. Mangiferin, a C-glucosylxanthone is abundant in the stem and bark of Mangifera indica L. The compound has been shown to possess antioxidant, anti-inflammatory and immunomodulatory activities. The present study was performed to investigate the effect of mangiferin pretreatment on lipopolysaccharide-induced increased proinflammatory cytokines, oxidative stress and neurobehavioural abnormalities. Mice were challenged with lipopolysaccharide (0.83 mg/kg, i.p.) after 14 days of mangiferin (20 and 40 mg/kg, p.o.) pretreatment. Mangiferin pretreatment significantly ameliorated the anxiety-like behaviour as evident from the results of an elevated plus maze, light-dark box and open field test. Mangiferin pretreatment also improved the anhedonic behaviour as revealed by sucrose preference test and increased social interaction time. It also prevented the lipopolysaccharide-evoked depressive-like effect by reducing the immobility time in forced swim and tail suspension test. Lipopolysaccharide-induced elevated oxidative stress was decreased with mangiferin pretreatment due to its potential to increase reduced glutathione concentration, Superoxide dismutase and catalase activity and decrease lipid peroxidation and nitrite level in the hippocampus as well as in the prefrontal cortex. Mangiferin pretreatment also attenuated neuroinflammation by reducing the interleukin-1 beta (IL-1β) level in hippocampus and prefrontal cortex. In conclusion, our results demonstrated that mangiferin possessed antidepressant and anti-anxiety properties due to its ability to attenuate IL-1β level and oxidative stress evoked by intraperitoneal administration of lipopolysaccharide. Mangiferin may be a potential therapeutic agent for the treatment of depressive and anxiety illness.

  3. Intravenous Lidocaine Infusion to Treat Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Papapetrou, Peter; Kumar, Aashish J; Muppuri, Rudram; Chakrabortty, Shushovan

    2015-11-01

    Chemotherapy-induced peripheral neuropathy is a debilitating side effect of chemotherapy, which manifests as paresthesias, dysesthesias, and numbness in the hands and feet. Numerous chemoprotective agents and treatments have been used with limited success to treat chemotherapy-induced peripheral neuropathy. We report a case in which a patient presenting with chemotherapy-induced peripheral neuropathy received an IV lidocaine infusion over the course of 60 minutes with complete symptomatic pain relief for a prolonged period of 2 weeks.

  4. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

    PubMed Central

    O’Connor, J.C.; Lawson, M.A.; André, C.; Moreau, M.; Lestage, J.; Castanon, N.; Kelley, K.W.; Dantzer, R.

    2009-01-01

    Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase(IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naïve mice dose-dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway. PMID:18195714

  5. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    SciTech Connect

    Foley, K.M.; Woodruff, J.M.; Ellis, F.T.; Posner, J.B.

    1980-04-01

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

  6. Effects of D-003 on Lipopolysaccharides-induced Osteonecrosis in Rabbits.

    PubMed

    Noa, Miriam; Valle, M; Mendoza, Sarahí; Mas, Rosa; Mendoza, Nilda

    2011-09-01

    D-003, a mixture of high molecular weight acids, inhibits cholesterol synthesis prior to mevalonate and prevents osteoporosis induced by ovariectomy in rats, and both osteoporosis and osteonecrosis induced by corticoids in rats. The aim of this study was to investigate effects of D-003 on lipopolysaccharides-induced osteonecrosis in rabbits. Animals were randomized into 5 groups: a sham and four groups injected with lipopolysaccharides: one treated orally with vehicle and three with D-003 (5, 25 and 200 mg/kg, respectively) during four weeks. We assessed the effects of treatments on the incidence of osteonecrosis (number of animals with osteonecrosis lesions/animals per group), the mean numbers and areas of osteonecrosis per animal and on the mean sizes of the bone marrow fat cells. The incidence of osteonecrosis in the groups of D-003 25 and 200 mg/kg was significantly lower than in the positive controls. The reduction of osteonecrosis increased with the doses, but significant dose-dependence relationship was not achieved. D-003 significantly and dose-dependently decreased the number of osteonecrosis lesions per animal as compared to the positive controls. Likewise, the mean osteonecrosis areas in the proximal femoral and humeral bones were significantly decreased by D-003. The injection of lipopolysaccharides significantly increased the average size of bone marrow fat cells as compared to the negative controls, and such increase was significantly and markedly reduced with D-003. It is concluded that D-003 reduced the incidence, number and percent areas of osteonecrosis lesions, and the size of bone marrow fat cells, a marker of adipogenesis, in rabbits with lipopolysaccharides-induced ostenonecrosis.

  7. Peripheral nerve morphogenesis induced by scaffold micropatterning

    PubMed Central

    Memon, Danish; Boneschi, Filippo Martinelli; Madaghiele, Marta; Brambilla, Paola; Del Carro, Ubaldo; Taveggia, Carla; Riva, Nilo; Trimarco, Amelia; Lopez, Ignazio D.; Comi, Giancarlo; Pluchino, Stefano; Martino, Gianvito; Sannino, Alessandro; Quattrini, Angelo

    2014-01-01

    Several bioengineering approaches have been proposed for peripheral nervous system repair, with limited results and still open questions about the underlying molecular mechanisms. We assessed the biological processes that occur after the implantation of collagen scaffold with a peculiar porous microstructure of the wall in a rat sciatic nerve transection model compared to commercial collagen conduits and nerve crush injury using functional, histological and genome wide analyses. We demonstrated that within 60 days, our conduit had been completely substituted by a normal nerve. Gene expression analysis documented a precise sequential regulation of known genes involved in angiogenesis, Schwann cells/axons interactions and myelination, together with a selective modulation of key biological pathways for nerve morphogenesis induced by porous matrices. These data suggest that the scaffold’s microstructure profoundly influences cell behaviors and creates an instructive micro-environment to enhance nerve morphogenesis that can be exploited to improve recovery and understand the molecular differences between repair and regeneration. PMID:24559639

  8. Role of Notch signaling during lipopolysaccharide-induced preterm labor.

    PubMed

    Agrawal, Varkha; Jaiswal, Mukesh K; Pamarthy, Sahithi; Katara, Gajendra K; Kulshrestha, Arpita; Gilman-Sachs, Alice; Hirsch, Emmet; Beaman, Kenneth D

    2016-08-01

    Notch signaling pathways exert effects throughout pregnancy and are activated in response to TLR ligands. To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta-like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed. Preterm labor was initiated on gestation d 14.5 by 1 of 2 methods: 1) inflammation-induced preterm labor: intrauterine injection of LPS (a TLR4 agonist) and 2) hormonally induced preterm labor: subcutaneous injection of mifepristone. Delta-like protein-1, Notch1, and hairy and enhancer of split-1 were elevated significantly, and Numb was decreased in the uterus and placenta of inflammation-induced preterm labor mice but remained unchanged in hormonally induced preterm labor compared with their respective controls. F4/80(+) macrophage polarization was skewed in the uterus of inflammation-induced preterm labor toward M1-positive (CD11c(+)) and double-positive [CD11c(+) (M1) and CD206(+) (M2)] cells. This process is dependent on activation of Notch signaling, as shown by suppression of M1 and M2 macrophage-associated cytokines in decidual macrophages in response to γ-secretase inhibitor (an inhibitor of Notch receptor processing) treatment ex vivo. γ-Secretase inhibitor treatment also diminished the LPS-induced secretion of proinflammatory cytokines and chemokines in decidual and placental cells cultured ex vivo. Furthermore, treatment with recombinant Delta-like protein-1 ligand enhanced the LPS-induced proinflammatory response. Notch ligands (Jagged 1 and 2 and Delta-like protein-4) and vascular endothelial growth factor and its receptor involved in angiogenesis were reduced significantly in the uterus and placenta during inflammation-induced preterm labor. These results suggest that up-regulation of Notch-related inflammation and down-regulation of angiogenesis factors may be associated with inflammation-induced preterm labor but not with

  9. Patchouli alcohol dampens lipopolysaccharide induced mastitis in mice.

    PubMed

    Li, Yong-Ping; Yuan, Shi-Fang; Cai, Guo-Hong; Wang, Hui; Wang, Ling; Yu, Lei; Ling, Rui; Yun, Jun

    2014-10-01

    Patchouli alcohol (PA), a tricyclic sesquiterpene isolated from Pogostemonis Herba, has been known to exhibit antioxidant, anti-inflammatory, and other important therapeutic activities. The aim of this study was to investigate the effects of PA on LPS-induced mastitis in vivo and the possible mechanism. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. Mice were pretreated with dexamethasone or PA 1 h before and 12 h after induction of LPS. The myeloperoxidase activity and inflammatory cytokines production in mammary tissues were determined. The effects of PA on NF-κB signal pathways were analyzed by Western blotting. The results showed that PA inhibited the LPS-induced TNF-α, IL-6, and IL-1β production in a dose manner. It was also observed that PA attenuated mammary histopathologic changes. Furthermore, Western blot analysis showed that PA could inhibit the phosphorylation of NF-κB and IκB induced by LPS. These results indicate that PA inhibits NF-κB signaling pathways to attenuate inflammatory injury induced by LPS. PA may be a potent therapeutic reagent for the prevention of mastitis.

  10. ATF-2 regulates lipopolysaccharide-induced transcription in macrophage cells.

    PubMed

    Hirose, Noriyuki; Maekawa, Toshio; Shinagawa, Toshie; Ishii, Shunsuke

    2009-07-17

    The transcription factor ATF-2, a member of the ATF/CREB family, is a target of p38 that are involved in stress-induced apoptosis and in Toll-like receptor (TLR)-mediated signaling. Phosphorylation of ATF-2 at Thr-71 was enhanced by treating of RAW264.7 macrophage cells with either LPS, MALP-2, or CpG-ODN. LPS treatment enhanced the trans-activation capacity of ATF-2. Among multiple LPS-induced genes, the LPS-induced expression of Socs-3 was significantly reduced by the treatment of RAW264.7 cells with an Atf-2 siRNA. Transcription from the Socs-3 promoter was synergistically stimulated by ATF-2 and LPS, whereas it was suppressed by Atf-2 siRNA. Histone deacetylase 1 (HDAC1) interacted with ATF-2 after LPS treatment, but not before treatment. Treatment of RAW264.7 cells with trichostatin A, an inhibitor of HDAC, suppressed the LPS-induced Socs-3 expression, suggesting that HDAC1 positively regulates the LPS-induced transcription of Socs-3. Thus, ATF-2 plays an important role in TLR-mediated transcriptional control in macrophage cells.

  11. Lactobacillus acidophilus modulates inflammatory activity by regulating the TLR4 and NF-κB expression in porcine peripheral blood mononuclear cells after lipopolysaccharide challenge.

    PubMed

    Lee, Sang In; Kim, Hyun Soo; Koo, Jin Mo; Kim, In Ho

    2016-02-28

    A total of forty weaned pigs ((Landrace × Yorkshire) × Duroc) were used to evaluate the effects of Lactobacillus acidophilus on inflammatory activity after lipopolysaccharide (LPS) challenge. Experimental treatments were as follows: (T1) control diet+saline challenge; (T2) control diet with 0·1% L. acidophilus+saline challenge; (T3) control diet+LPS challenge; and (T4) control diet with 0·1% L. acidophilus+LPS challenge. On d-14, piglets were challenged with saline (T1 and T2) or LPS (T3 and T4). Blood samples were obtained at 0, 2, 4, 6 and 12 h after being challenged and analysed for immune cell cytokine production and gene expression pattern. The L. acidophilus treatment increased the average daily weight gain (ADWG) and average daily feed intake (ADFI) compared with the control diet. With the control diet, the LPS challenge (T3) increased the number of immune cells and expression of TNF-α and IL-6 compared with the saline challenge (T1). Whereas with the saline challenge L. acidophilus treatment (T2) increased the number of leucocytes and CD4 compared with the control diet (T1), with the LPS challenge L. acidophilus treatment (T4) decreased the number of leucocytes, lymphocytes, CD4+ and CD8+ and expression of TNF-α and IL-6 compared with the control diet (T3). L. acidophilus treatment decreased the expression of TRL4 and NF-κB in peripheral blood mononuclear cells (PBMC) after LPS challenge, which leads to inhibition of TNF-α, IFN-γ, IL-6, IL-8 and IL1B1 and to induction of IL-4 and IL-10. We suggested that L. acidophilus improved ADWG and ADFI and protected against LPS-induced inflammatory responses by regulating TLR4 and NF-κB expression in porcine PBMC.

  12. Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14.

    PubMed

    Huang, Jing-Rong; Wu, Chia-Chuan; Hou, Rolis Chien-Wei; Jeng, Kee-Ching

    2008-01-01

    Bromelain has been reported to have anti-inflammatory and immunomodulatory effects. However, the anti-inflammatory mechanism of bromelain is unclear. Therefore, we investigated the effect of bromelain on cytokine production from lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) and monocytic leukemia THP-1 cells. The result showed that bromelain (50-100 microg/ml) significantly and reversibly reduced tumor necrosis factor (TNF)-alpha interleukin- (IL)-1beta and IL-6 from LPS-induced PBMC and THP-1 cells. This effect was correlated with reduced LPS-induced TNF-alpha mRNA and NF-kappaB activity in THP-1 cells. In addition, bromelain dose-dependently inhibited LPS-induced prostaglandin E(2), thromboxane B(2) and COX-2 mRNA but not COX-1 mRNA. Importantly, bromelain degraded TNF-alpha and IL-1beta molecules, reduced the expression of surface marker CD14 but not Toll-like receptor 4 from THP-1 cells. Taken together, the results suggest that the suppression of signaling pathways by bromelain's proteolytic activity may contribute to the anti-inflammatory activity of bromelain.

  13. Nardosinone Suppresses RANKL-Induced Osteoclastogenesis and Attenuates Lipopolysaccharide-Induced Alveolar Bone Resorption

    PubMed Central

    Niu, Chenguang; Xiao, Fei; Yuan, Keyong; Hu, XuChen; Lin, Wenzhen; Ma, Rui; Zhang, Xiaoling; Huang, Zhengwei

    2017-01-01

    Periodontitis is a chronic inflammatory disease that damages the integrity of the tooth-supporting tissues, known as the periodontium, and comprising the gingiva, periodontal ligament and alveolar bone. In this study, the effects of nardosinone (Nd) on bone were tested in a model of lipopolysaccharide (LPS)-induced alveolar bone loss, and the associated mechanisms were elucidated. Nd effectively suppressed LPS-induced alveolar bone loss and reduced osteoclast (OC) numbers in vivo. Nd suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated OC differentiation, bone resorption, and F-actin ring formation in a dose-dependent manner. Further investigation revealed that Nd suppressed osteoclastogenesis by suppressing the ERK and JNK signaling pathways, scavenging reactive oxygen species, and suppressing the activation of PLCγ2 that consequently affects the expression and/or activity of the OC-specific transcription factors, c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). In addition, Nd significantly reduced the expression of OC-specific markers in mouse bone marrow-derived pre-OCs, including c-Fos, cathepsin K (Ctsk), VATPase d2, and Nfatc1. Collectively, these findings suggest that Nd has beneficial effects on bone, and the suppression of OC number implies that the effect is exerted directly on osteoclastogenesis. PMID:28955231

  14. Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain.

    PubMed

    Roughton, Karolina; Andreasson, Ulf; Blomgren, Klas; Kalm, Marie

    2013-01-01

    Radiotherapy is an effective treatment strategy in the treatment of brain tumors, but it is also a major cause of long-term complications, especially in survivors of pediatric brain tumors. Cognitive decline caused by cranial radiotherapy is thought, at least partly, to depend on injury to stem and progenitor cells in the dentate gyrus of the hippocampus. This study investigated the effects of lipopolysaccharide (LPS)-induced inflammation at the time of irradiation (IR) in the growing mouse brain. A single injection of LPS (0.3 mg/kg) was administered 24 h prior to cranial IR of 14-day-old male mice. LPS pretreatment increased the levels of the chemokine CCL2 and the cytokine IL-1β in the brain by 440 and 560%, respectively, compared to IR alone. IR disrupted hippocampal neurogenesis and the growth of the dentate gyrus, and the mice pretreated with LPS displayed an even more pronounced lack of growth than the vehicle-treated group 2 months after IR. The density of microglia was not affected, but LPS-pretreated mice displayed 48% fewer bromodeoxyuridine-positive cells and 43% fewer doublecortin-positive cells in the granule cell layer 2 months after IR compared with the vehicle-treated group. In conclusion, an ongoing inflammation in the brain at the time of IR further enhanced the IR-induced loss of neurogenesis, and may aggravate future cognitive deficits in patients treated with cranial radiotherapy.

  15. Effect of Capparis spinosa Linn. extract on lipopolysaccharide-induced cognitive impairment in rats.

    PubMed

    Goel, Ashish; Digvijaya; Garg, Arun; Kumar, Ashok

    2016-02-01

    Cognitive disorders in mankind are not uncommon. Apart from neurodegenerative diseases such as Alzheimer's (AD), various stresses also affect cognitive functions. Plants are known to be potential source of compounds that ameliorate several diseases including cognitive impairment. Here, we evaluated effect of aqueous extract of caper (Capparis spinosa) buds on lipopolysaccharide-induced cognitive impairment in rats using two different oral doses i.e. 10 (pre-treatment) and 30 mg/rat(post-treatment) through assessment of behavioural (Morris Water maze test and Y maze test), biochemical (Cholinesterase assay) and histopathological (H&E staining) parameters. Lipopolysaccharide (from E. coli) administration resulted in an increased neurodegeneration and time taken to reach the platform (in Morris water maze). The increased neurodegeneration in CA1 region of hippocampus was significantly reduced in animals which received caper bud extract; they showed marked reduction in time taken to reach the platform at both the dose levels. The experiment demonstrated that caper bud extract exhibits potential protective effect against learning and memory damage induced by chronic administration of lipopolysaccharide (175 μg/kg) for 7 days. The results suggest that the caper bud extract could be explored for its use in the treatment of cognitive disorders.

  16. [Immune-regulating effect of phenibut under lipopolysaccharide-induced immune stress conditions].

    PubMed

    Samotrueva, M A; Tiurenkov, I N; Teplyĭ, D L; Kuleshevskaia, N R; Khlebtsova, E V

    2010-05-01

    The immunoregulating effect of phenibut has been demonstrated on the model of immune stress caused by the injection of lipopolysaccharide from Pseudomonas aeruginosa. The degree of expression of the specific (in a delayed-type hypersensitivity reaction and passive hemagglutination) and nonspecific (phagocytic activity of neutrophils) links of immunomodulation was studied. The formation of lipopolysaccharide (LPS) induced immune stress is characterized by the increase of the indicated parameters of immunity. It is found that phenibut (under intraabdominal injection of 25 mg/kg within 5 days) removes the manifestations of hyperreactivity of the cellular link of immunity, and also restores the amount of phagocytic cells, which is evidence of the immunomodulating properties of the drug under conditions of hyperimmunization.

  17. Bortezomib-induced peripheral neurotoxicity: an update.

    PubMed

    Argyriou, Andreas A; Cavaletti, Guido; Bruna, Jordi; Kyritsis, Athanasios P; Kalofonos, Haralabos P

    2014-09-01

    This review paper provides a critical exploration of updates concerning the spectrum of characteristics and treatment options of bortezomib-induced peripheral neuropathy (BIPN). Emphasis is given on pathogenesis issues. Although the mechanism underlying BIPN still remains elusive, it is increasingly acknowledged that the inhibition of proteasome activity in dorsal root ganglia and peripheral nerves, the mitochondrial-mediated disruption of Ca⁺⁺ intracellular homeostasis and the disregulation in nuclear factor κB and brain-derived neurotrophic factor play a significant pathogenic role. Assessment of BIPN is based on comprehensive grading scales, using a combination of "subjective" and "objective" parameters, which turn out to be ambiguously interpreted, thus leading to both under- and misreporting of its true incidence and severity. BIPN is clinically defined as a typical example of a dose-dependent, distally attenuated painful, sensory neuronopathy. Patients pre-treated with neurotoxic regimens and those with pre-existing neuropathy are more likely to develop severe neurotoxicity. To date, there is no effective pharmacological treatment to prevent BIPN, and therefore, interventions remain merely symptomatic to focus on the alleviation of neuropathic pain. Hence, strict adherence to the dose reduction and schedule change algorithm is recommended in order to prevent treatment-emergent BIPN and allow the continuation of treatment. Further studies in animal models and humans, including experimental, clinical, neurophysiological and pharmacogenetic approaches, are needed to allow the identification of the true spectrum of BIPN pathogenesis and characteristics. It is expected that such comprehensive approaches would be the starting point for the development of early preventive and therapeutic interventions against BIPN.

  18. Human peripheral blood eosinophils induce angiogenesis.

    PubMed

    Puxeddu, Ilaria; Alian, Akram; Piliponsky, Adrian Martin; Ribatti, Domenico; Panet, Amos; Levi-Schaffer, Francesca

    2005-03-01

    Eosinophils play a crucial role in allergic reactions and asthma. They are also involved in responses against parasites, in autoimmune and neoplastic diseases, and in fibroses. There is increasing evidence that angiogenesis plays an important role in these processes. Since eosinophils are known to produce angiogenic mediators, we have hypothesized a direct contribution of these cells to angiogenesis. The effect of human peripheral blood eosinophil sonicates on rat aortic endothelial cell proliferation (in vitro), rat aorta sprouting (ex vivo) and angiogenesis in the chick embryo chorioallantoic membrane (in vivo) have been investigated. To determine whether eosinophil-derived vascular endothelial growth factor influences the eosinophil pro-angiogenic activity, eosinophil sonicates were incubated with anti-vascular endothelial growth factor antibodies and then added to the chorioallantoic membrane. Vascular endothelial growth factor mRNA expression and vascular endothelial growth factor receptor density on the endothelial cells were also evaluated. Eosinophils were found to enhance endothelial cell proliferation and to induce a strong angiogenic response both in the aorta rings and in the chorioallantoic membrane assays. Pre-incubation of eosinophil sonicates with anti-vascular endothelial growth factor antibodies partially reduced the angiogenic response of these cells in the chorioallantoic membrane. Eosinophils also increased vascular endothelial growth factor mRNA production on endothelial cells. Eosinophils are able to induce angiogenesis and this effect is partially mediated by their pre-formed vascular endothelial growth factor. This strongly suggests an important role of eosinophils in angiogenesis-associated diseases such as asthma.

  19. Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-alpha and dopamine transporter expression.

    PubMed

    Lai, Yu-Ting; Tsai, Yen-Ping N; Cherng, Chianfang G; Ke, Jing-Jer; Ho, Ming-Che; Tsai, Chia-Wen; Yu, Lung

    2009-04-01

    Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion. This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying mechanisms. An LPS injection (1 mg/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of MA (10 mg/kg each) at 2-h intervals] diminished the MA-induced DA depletion in mouse striatum. Such an LPS-associated effect was independent of MA-produced hyperthermia. TNF-alpha, IL-1beta, IL-6 expressions were all elevated in striatal tissues following a systemic injection with LPS, indicating that peripheral LPS treatment affected striatal pro-inflammatory cytokine expression. Striatal TNF-alpha expression was dramatically increased at 72 and 96 h after the MA treatment, while such TNF-alpha elevation was abolished by the LPS pretreatment protocol. Moreover, MA-produced activation of nuclear NFkappaB, a transcription factor following TNF-alpha activation, in striatum was abolished by the LPS (1 mg/kg) pretreatment. Furthermore, thalidomide, a TNF-alpha antagonist, treatment abolished the LPS pretreatment-associated protective effects. Pretreatment with mouse recombinant TNF-alpha in striatum diminished the MA-produced DA depletion. Finally, single LPS treatment caused a rapid down-regulation of dopamine transporter (DAT) in striatum. Taken together, we conclude that peripheral LPS treatment protects nigrostriatal DA neurons against MA-induced toxicity, in part, by reversing elevated TNF-alpha expression and subsequent signaling cascade and causing a rapid DAT down-regulation in striatum.

  20. Glucocorticoid-induced leucine zipper overexpression inhibits lipopolysaccharide-induced retinal inflammation in rats.

    PubMed

    Gu, Ruiping; Lei, Boya; Shu, Qinmeng; Li, Gang; Xu, Gezhi

    2017-02-24

    Glucocorticoid-induced leucine zipper (GILZ) mediates several effects of glucocorticoids and has important anti-inflammatory properties. Here, we explored the role of GILZ in inhibiting retinal inflammation. Endotoxin-induced uveitis (EIU) was established in rats by intravitreal injection of lipopolysaccharide (LPS). GILZ levels decreased in the EIU retina at 4 h after LPS injection and slowly recovered within 24 h. Retinal GILZ was downregulated by recombinant lentivirus-delivered short-hairpin RNA targeting GILZ (shRNA-GILZ-rLV) and upregulated by recombinant lentivirus-mediated GILZ overexpression (Oe-GILZ-rLV). GILZ silencing attenuated the anti-inflammatory effects of intravitreal injection of triamcinolone acetonide (TA) in the EIU retina, as demonstrated by increased retinal interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1and intercellular cell adhesion molecule-1 expression at 18 h after TA injection. A Bio-Plex cytokine assay and western blotting demonstrated that GILZ overexpression inhibited the effects of LPS, downregulating retinal IL-1β, MCP-1, MIP-1α, and IL-17 and inhibiting LPS-induced activation of the retinal toll-like receptor 4-myeloid differentiation factor 88 signaling pathway. At 48 and 72 h after LPS injection, the clinical score of inflammation was significantly lower in Oe-GILZ-rLV-transfected eyes than in blank-rLV-transfected eyes. Histological examination showed a 67.85% reduction of infiltrating inflammatory cells in the anterior chamber and a 58.97% reduction in vitreous cavity of Oe-GILZ-rLV transfected eyes at 48 h after LPS injection. Taken together, our results suggest that GILZ is a novel therapeutic target for the treatment of retinal inflammatory diseases.

  1. Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy.

    PubMed

    Li, Yan; Zhang, Haijun; Zhang, Hongmei; Kosturakis, Alyssa K; Jawad, Abdul Basit; Dougherty, Patrick M

    2014-07-01

    This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy. Copyright © 2014 American Pain

  2. Lipopolysaccharide-induced experimental immune activation does not impair memory functions in humans.

    PubMed

    Grigoleit, Jan-Sebastian; Oberbeck, J Reiner; Lichte, Philipp; Kobbe, Philipp; Wolf, Oliver T; Montag, Thomas; del Rey, Adriana; Gizewski, Elke R; Engler, Harald; Schedlowski, Manfred

    2010-11-01

    Systemic immune activation occurring together with release of peripheral cytokines can affect behavior and the functioning of the central nervous system (CNS). However, it remains unknown whether and to what extent cognitive functions like memory and attention are affected during transient immune activation. We employed a human endotoxemia model and standardized neuropsychological tests to assess the cognitive effects of an experimental inflammation in two groups of 12 healthy young men before and after intravenous injection of lipopolysaccharide (LPS, Escherichia coli, 0.4 ng/kg) or physiological saline. Endotoxin administration caused a profound transient physiological response with elevations in body temperature, number of circulating neutrophils, and increases in plasma cytokine levels [interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α], and concentrations of norepinephrine, ACTH and cortisol. However, these changes in immune and neuroendocrine parameters were not associated with alterations of memory performance, selective attention or executive functions. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour

    PubMed Central

    Sykes, Lynne; Herbert, Bronwen R; MacIntyre, David A; Hunte, Emma; Ponnampalam, Sathana; Johnson, Mark R; Teoh, Tiong G; Bennett, Phillip R

    2013-01-01

    We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J2 (15dPGJ2) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ2 is an agonist of the second prostaglandin D2 receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ2 in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1β, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ2 is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour. PMID:23374103

  4. Lipopolysaccharide-induced hypothermia and hypotension are associated with inflammatory signaling that is triggered outside the brain.

    PubMed

    Al-Saffar, Hiba; Lewis, Kevin; Liu, Elaine; Schober, Alexandra; Corrigan, Joshua J; Shibata, Keita; Steiner, Alexandre A

    2013-02-01

    Little is known about the neuroimmune mechanisms responsible for the switch from fever to hypothermia observed in severe forms of systemic inflammation. We evaluated whether bacterial lipopolysaccharide (LPS) acting directly on the brain could promote a fever-hypothermia switch as well as the hypotension that is often associated with hypothermia in models of systemic inflammation. At an ambient temperature of 22°C, freely moving rats received intracerebroventricular (i.c.v.) injections of LPS at doses ranging from 0.5 to 25μg. Despite the use of such high doses, the prevailing thermal response was fever. To investigate if a hypothermic response could be hidden within the prevailing febrile response, rats were pretreated with a cyclooxygenase-2 inhibitor (SC-236, 3.5mg/kg i.v.) known to block fever, but this strategy also failed to reveal any consistent hypothermic response following i.c.v. LPS. At the doses tested, i.c.v. LPS was similarly ineffective at inducing hypotension. Additional doses of LPS did not need to be tested because the 25-μg dose was already sufficient to induce both hypothermia and hypotension when administered peripherally (intra-arterially). An empirical 3D model of the interplay among body temperature, arterial pressure and heart rate following intra-arterial LPS reinforced the strong association of hypothermia with hypotension and, at the same time, exposed a bell-shaped relationship between heart rate and body temperature. In summary, the present study demonstrates that hypothermia and hypotension are triggered exclusively by LPS acting outside the brain and provides an integrated model of the thermal and cardiovascular responses to peripheral LPS.

  5. Effect of methanolic extract of Asparagus racemosus Willd. on lipopolysaccharide induced-oxidative stress in rats.

    PubMed

    Ahmad, Mohammad Parwez; Hussain, Arshad; Siddiqui, Hefazat Hussain; Wahab, Shadma; Adak, Manoranjan

    2015-03-01

    Lipopolysaccharide (LPS) induced oxidative stress and impairment of normal physiological function generally categorized by increased anxiety and reduced mobility. Therefore, the present study was to find out the effect Methanolic extract of Asparagus racemosus (MEAR ) in lipopolysaccharide (LPS)-induced oxidative stress in rats . LPS-induced oxidative stress in rats was measured by locomotor activity by photoactometer test, anxiety with elevated plus maze test and also studied the oxidative stress markers, nitric oxide and cytokines. The obtained data shows that LPS markedly exhausted (p<0.001) brain- reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) significantly increased (p<0.001) the level of malondialdehyde (MDA), nitric oxide and the activity of cytokines in the brain. MEAR supplementation resulted in normalization of brain GSH and CAT and SOD and decreases in the levels of MDA with reduction of nitric oxide and cytokines in the brain. The action of the extract at dose of 200 mg/kg was almost similar to the standard drug, quercetin (100mg/kg, p.o.). These present study conclude that MEAR administration significantly (P<0.05) reduced LPS- induced oxidative-stress and intensely suggest that Asparagus racemosus Willd. is a functionally newer type of cerebroprotective agent.

  6. Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.

    PubMed

    Du, Shi-lin; Yuan, Xue; Zhan, Sun; Tang, Luo-jia; Tong, Chao-yang

    2015-03-13

    Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.

  7. Metformin Suppresses Lipopolysaccharide (LPS)-induced Inflammatory Response in Murine Macrophages via Activating Transcription Factor-3 (ATF-3) Induction*

    PubMed Central

    Kim, Juyoung; Kwak, Hyun Jeong; Cha, Ji-Young; Jeong, Yun-Seung; Rhee, Sang Dahl; Kim, Kwang Rok; Cheon, Hyae Gyeong

    2014-01-01

    Metformin, a well known antidiabetic agent that improves peripheral insulin sensitivity, also elicits anti-inflammatory actions, but its mechanism is unclear. Here, we investigated the mechanism responsible for the anti-inflammatory effect of metformin action in lipopolysaccharide (LPS)-stimulated murine macrophages. Metformin inhibited LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF-3), a transcription factor and member of the cAMP-responsive element-binding protein family. ATF-3 knockdown abolished the inhibitory effects of metformin on LPS-induced proinflammatory cytokine production accompanied with reversal of metformin-induced suppression of mitogen-activated protein kinase (MAPK) phosphorylation. Conversely, AMP-activated protein kinase (AMPK) phosphorylation and NF-κB suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-κB enrichments on the promoters of IL-6 and TNF-α were replaced by ATF-3 upon metformin treatment. AMPK knockdown blunted all the effects of metformin (ATF-3 induction, proinflammatory cytokine inhibition, and MAPK inactivation), suggesting that AMPK activation by metformin is required for and precedes ATF-3 induction. Oral administration of metformin to either mice with LPS-induced endotoxemia or ob/ob mice lowered the plasma and tissue levels of TNF-α and IL-6 and increased ATF-3 expression in spleen and lungs. These results suggest that metformin exhibits anti-inflammatory action in macrophages at least in part via pathways involving AMPK activation and ATF-3 induction. PMID:24973221

  8. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction.

    PubMed

    Kim, Juyoung; Kwak, Hyun Jeong; Cha, Ji-Young; Jeong, Yun-Seung; Rhee, Sang Dahl; Kim, Kwang Rok; Cheon, Hyae Gyeong

    2014-08-15

    Metformin, a well known antidiabetic agent that improves peripheral insulin sensitivity, also elicits anti-inflammatory actions, but its mechanism is unclear. Here, we investigated the mechanism responsible for the anti-inflammatory effect of metformin action in lipopolysaccharide (LPS)-stimulated murine macrophages. Metformin inhibited LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF-3), a transcription factor and member of the cAMP-responsive element-binding protein family. ATF-3 knockdown abolished the inhibitory effects of metformin on LPS-induced proinflammatory cytokine production accompanied with reversal of metformin-induced suppression of mitogen-activated protein kinase (MAPK) phosphorylation. Conversely, AMP-activated protein kinase (AMPK) phosphorylation and NF-κB suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-κB enrichments on the promoters of IL-6 and TNF-α were replaced by ATF-3 upon metformin treatment. AMPK knockdown blunted all the effects of metformin (ATF-3 induction, proinflammatory cytokine inhibition, and MAPK inactivation), suggesting that AMPK activation by metformin is required for and precedes ATF-3 induction. Oral administration of metformin to either mice with LPS-induced endotoxemia or ob/ob mice lowered the plasma and tissue levels of TNF-α and IL-6 and increased ATF-3 expression in spleen and lungs. These results suggest that metformin exhibits anti-inflammatory action in macrophages at least in part via pathways involving AMPK activation and ATF-3 induction. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. n-Butanol extract from Folium isatidis inhibits lipopolysaccharide-induced inflammatory cytokine production in macrophages and protects mice against lipopolysaccharide-induced endotoxic shock

    PubMed Central

    Jiang, Lili; Lu, Yili; Jin, Jiahui; Dong, Lili; Xu, Fengli; Chen, Shuangshuang; Wang, Zhanyue; Liang, Guang; Shan, Xiaoou

    2015-01-01

    Sepsis, which is caused by severe infection, is an important cause of mortality, but effective clinical treatment against sepsis is extremely limited. As the main component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) plays a major role in inflammatory responses. Studies have shown beneficial pharmacological effects for Folium isatidis. The present study further illuminated the effects of n-butanol extract from Folium isatidis in LPS-induced septic shock and identified the main active chemical components. Our study showed that pretreatment with n-butanol extract from Folium isatidis not only significantly inhibited LPS-induced tumor necrosis factor-α and interleukin-6 production but also markedly and dose dependently enhanced the recruitment of MyD88, the phosphorylation of extracellular signal-regulated kinase, and the degradation of IκB-α. Additionally, the extract exhibited dramatic protective effects against lung injury and death in mice with septic shock. Eight main active compounds were identified, including organic acids, glycoside, indolinones, and flavonoids. These findings provide a perspective on the respiratory protection offered by n-butanol extract from Folium isatidis in LPS-induced sepsis and outline a novel therapeutic strategy for the treatment of sepsis. PMID:26491261

  10. Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice.

    PubMed

    Feng, Xiaosheng; Jia, Aiqing

    2014-08-01

    Carvacrol, the major component of Plectranthus amboinicus, has been known to exhibit anti-inflammatory activities. The aim of this study was to investigate the effects of carvacrol on lipopolysaccharide (LPS)-induced endotoxemia and acute lung injury (ALI) in mice. Mice were injected intraperitoneally (i.p.) with LPS and the mortality of mice for 7 days were observed twice a day. Meanwhile, the protective effect of carvacrol (20, 40 or 80 mg/kg) on LPS-induced endotoxemia were detected. Using an experimental model of LPS-induced ALI, we examined the effect of carvacrol in resolving lung injury. The results showed that carvacrol could improve survival during lethal endotoxemia and attenuate LPS-induced ALI in mice. The anti-inflammatory mechanisms of carvacrol may be due to its ability to inhibit NF-κB and MAPKs signaling pathways, thereby inhibiting inflammatory cytokines TNF-α, IL-6 and IL-1β production.

  11. Identification and Characterization of Lipopolysaccharide Induced TNFα Factor from Blunt Snout Bream, Megalobrama amblycephala

    PubMed Central

    Lv, Yina; Xiang, Xinying; Jiang, Yuhong; Tang, Leilei; Zhou, Yi; Zhong, Huan; Xiao, Jun; Yan, Jinpeng

    2017-01-01

    Lipopolysaccharide induced TNFα factor (LITAF) is an important transcription factor responsible for regulation of tumor necrosis factor α. In this study, a novel litaf gene (designated as Malitaf) was identified and characterized from blunt snout bream, Megalobrama amblycephala. The full-length cDNA of Malitaf was of 956 bp, encoding a polypeptide of 161 amino acids with high similarity to other known LITAFs. A phylogenetic tree also showed that Malitaf significantly clustered with those of other teleost, indicating that Malitaf was a new member of fish LITAF family. The putative maLITAF protein possessed a highly conserved LITAF domain with two CXXC motifs. The mRNA transcripts of Malitaf were detected in all examined tissues of healthy M. amblycephala, including kidney, head kidney, muscle, liver, spleen, gill, and heart, and with the highest expression in immune organs: spleen and head kidney. The expression level of Malitaf in spleen was rapidly up-regulated and peaked (1.29-fold, p < 0.05) at 2 h after lipopolysaccharide (LPS) stimulation. Followed the stimulation of Malitaf, Matnfα transcriptional level was also transiently induced to a high level (51.74-fold, p < 0.001) at 4 h after LPS stimulation. Taken together, we have identified a putative fish LITAF ortholog, which was a constitutive and inducible immune response gene involved in M. amblycephala innate immunity during the course of a pathogenic infection. PMID:28212275

  12. Circulating leptin mediates lipopolysaccharide-induced anorexia and fever in rats.

    PubMed

    Sachot, Christelle; Poole, Stephen; Luheshi, Giamal N

    2004-11-15

    Anorexia and fever are important features of the host's response to inflammation that can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and the appetite suppressant leptin. Previous studies have demonstrated that LPS induces leptin synthesis and secretion in the periphery, and that the action of leptin on appetite suppression and fever are dependent on brain interleukin (IL)-1beta. However, the role of leptin as a neuroimmune mediator of LPS-induced inflammation has not been fully elucidated. To address this issue, we neutralized circulating leptin using a leptin antiserum (LAS) and determined how this neutralization affected LPS-induced anorexia, fever and hypothalamic IL-1beta. Adult male rats were separated into four treatment groups, namely LPS + normal sheep serum (NSS), LPS + LAS, saline + LAS and saline + NSS. Intraperitoneal injection of LPS (100 microg kg(-1)) induced a significant reduction in food intake and body weight, which were significantly reversed in the presence of LAS (1 ml kg(-1)), 8 and 24 h after treatment. In addition, LPS-induced fever was significantly attenuated by LAS over the duration of the fever response (8 h). Lipopolysaccharide induced an increase of circulating IL-6, another potential circulating pyrogen, which was not affected by neutralization of leptin at 2 h. Interleukin-1beta mRNA at 1 and 8 h, and IL-1 receptor antagonist (ra) at 2 h were significantly upregulated in the hypothalamus of LPS-treated animals. The induction of these cytokines was attenuated in the presence of LAS. These results are the first to demonstrate that leptin is a circulating mediator of LPS-induced anorexia and fever, probably through a hypothalamic IL-1beta-dependent mechanism.

  13. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide

    PubMed Central

    2012-01-01

    Background The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated, Methods Four HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristics Results The in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-κB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-κB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. Conclusions Our results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC. PMID:22938142

  14. Fish Oil Prevents Lipopolysaccharide-Induced Depressive-Like Behavior by Inhibiting Neuroinflammation.

    PubMed

    Shi, Zhe; Ren, Huixia; Huang, Zhijian; Peng, Yu; He, Baixuan; Yao, Xiaoli; Yuan, Ti-Fei; Su, Huanxing

    2016-11-04

    Depression is associated with somatic immune changes, and neuroinflammation is now recognized as hallmark for depressive disorders. N-3 (or omega-3) polyunsaturated fatty acids (PUFAs) are well known to suppress neuroinflammation, reduce oxidative stress, and protect neuron from injury. We pretreated animals with fish oil and induced acute depression-like behaviors with systemic lipopolysaccharide (LPS) injection. The levels of cytokines and stress hormones were determined from plasma and different brain areas. The results showed that fish oil treatment prevent LPS-induce depressive behavior by suppression of neuroinflammation. LPS induced acute neuroinflammation in different brain regions, which were prevented in fish oil fed mice. However, neither LPS administration nor fish oil treatment has strong effect on stress hormone secretion in the hypothalamus and adrenal. Fish oil might provide a useful therapy against inflammation-associated depression.

  15. Requirement for tyrosine phosphorylation in lipopolysaccharide-induced murine B-cell proliferation.

    PubMed Central

    Dearden-Badet, M T; Revillard, J P

    1993-01-01

    Bacterial lipopolysaccharide (LPS) induces a strong B-cell proliferative response with subsequent differentiation, through a complex signal transduction pathway. This process is known to be mediated through protein kinase C (PKC) translocation without Ca2+ mobilization. Here, we show that B-cell proliferative responses induced by five different LPS preparations, as well as by F(ab')2 anti-IgM antibodies, are inhibited by the tyrosine kinase inhibitors, genistein and herbimycin A. In contrast, B-cell proliferation induced by the combination of phorbol 12-myristate 13-acetate (PMA) plus ionomycin was not influenced by treatment with either herbimycin A or genistein. These data indicate that tyrosine phosphorylation is required to initiate B-cell proliferation by LPS. PMID:8307617

  16. Paeonol suppresses lipopolysaccharide-induced inflammatory cytokines in macrophage cells and protects mice from lethal endotoxin shock.

    PubMed

    Chen, Na; Liu, Dianfeng; Soromou, Lanan Wassy; Sun, Jingjing; Zhong, Weiting; Guo, Weixiao; Huo, Meixia; Li, Hongyu; Guan, Shuang; Chen, Zhenwen; Feng, Haihua

    2014-06-01

    Paeonol (2'-hydroxy-4'-methoxyacetophenone) is the main phenolic compound of the radix of Paeonia suffruticosa which has been used as traditional Chinese medicine. In this study, we primarily investigated the anti-inflammatory effects and the underlying mechanisms of paeonol in RAW macrophage cells; and based on these effects, we assessed the protective effects of paeonol on lipopolysaccharide-induced endotoxemia in mice. The in vitro study showed that paeonol regulated the production of TNF-α, IL-1β, IL-6, and IL-10 via inactivation of IκBα, ERK1/2, JNK, and p38 MAPK. In mouse model of lipopolysaccharide-induced endotoxemia, pro- and anti-inflammatory cytokines are significantly regulated, and thus the survival rates of lipolysaccharide-challenged mice are improved by paeonol (150, 200, or 250 mg/kg). Therefore, paeonol has a beneficial activity against lipopolysaccharide-induced inflammation in RAW 264.7 cell and mouse models.

  17. Chemotherapy-Induced Peripheral Neuropathy: Current Status and Progress

    PubMed Central

    Brewer, Jamie R; Morrison, Gladys; Dolan, M. Eileen; Fleming, Gini F

    2015-01-01

    As there are increasing numbers of cancer survivors, more attention is being paid to the long term unwanted effects patients may experience as a result of their treatment and the impact these side effects can have on their quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxicities from chemotherapy. In this review we will briefly review the clinical presentation, evaluation and management of chemotherapy-induced peripheral neuropathy, with a focus on CIPN related to platinum and taxane agents. We will then discuss current clinical models of peripheral neuropathy and ongoing research to better understand CIPN and develop potential treatment options. PMID:26556766

  18. Protective effects of melatonin on lipopolysaccharide-induced mastitis in mice.

    PubMed

    Shao, Guoxi; Tian, Yinggang; Wang, Haiyu; Liu, Fangning; Xie, Guanghong

    2015-12-01

    Melatonin, a secretory product of the pineal gland, has been reported to have antioxidant and anti-inflammatory effects. However, the protective effects of melatonin on lipopolysaccharide (LPS)-induced mastitis have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of melatonin on LPS-induced mastitis both in vivo and in vitro. In vivo, our results showed that melatonin attenuated LPS-induced mammary histopathologic changes and myeloperoxidase (MPO) activity. Melatonin also inhibited LPS-induced inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) production in mammary tissues. In vitro, melatonin was found to inhibit LPS-induced TNF-α and IL-6 production in mouse mammary epithelial cells. Melatonin also suppressed LPS-induced Toll-like receptor 4 (TLR4) expression and nuclear factor-kappaB (NF-κB) activation in a dose-dependent manner. In addition, melatonin was found to up-regulate the expression of PPAR-γ. Inhibition of PPAR-γ by GW9662 reduced the anti-inflammatory effects of melatonin. In conclusion, we found that melatonin, for the first time, had protective effects on LPS-induced mastitis in mice. The anti-inflammatory mechanism of melatonin was through activating PPAR-γ which subsequently inhibited LPS-induced inflammatory responses.

  19. Activation of α2 adrenoceptor attenuates lipopolysaccharide-induced hepatic injury.

    PubMed

    Chen, Jing-Hui; Yu, Gao-Feng; Jin, Shang-Yi; Zhang, Wen-Hua; Lei, Dong-Xu; Zhou, Shao-Li; Song, Xing-Rong

    2015-01-01

    Sepsis induces hepatic injury but whether alpha-2 adrenoceptor (α2-AR) modulates the severity of sepsis-induced liver damage remains unclear. The present study used lipopolysaccharide (LPS) to induce hepatic injury and applied α2-AR agonist dexmedetomidine (DEX) and/or antagonist yohimbine to investigate the contribution of α2-AR in LPS-induced liver injury. Our results showed that LPS resulted in histological and functional abnormality of liver tissue (ALT and AST transaminases, lactate), higher mortality, an increase in proinflammatory cytokines (IL-1β, IL-6 & TNF-α), as well as a change in oxidative stress (MDA, SOD). Activation of α2-AR by dexmedetomidine (DEX) attenuated LPS-induced deleterious effects on the liver and block of α2-AR by yohimbine aggravated LPS-induced liver damage. Our data suggest that α2-AR plays an important role in sepsis-induced liver damage and activation of α2-AR with DEX could be a novel therapeutic avenue to protect the liver against sepsis-induced injury.

  20. Folic acid supplementation during pregnancy protects against lipopolysaccharide-induced neural tube defects in mice.

    PubMed

    Zhao, Mei; Chen, Yuan-Hua; Chen, Xue; Dong, Xu-Ting; Zhou, Jun; Wang, Hua; Wu, Shu-Xian; Zhang, Cheng; Xu, De-Xiang

    2014-01-13

    Folic acid is a water-soluble B-complex vitamin. Increasing evidence demonstrates that physiological supply of folic acid during pregnancy prevents folic acid deficiency-related neural tube defects (NTDs). Previous studies showed that maternal lipopolysaccharide (LPS) exposure caused NTDs in rodents. The aim of this study was to investigate the effects of high-dose folic acid supplementation during pregnancy on LPS-induced NTDs. Pregnant mice were intraperitoneally injected with LPS (20 μg/kg/d) from gestational day (GD) 8 to GD12. As expected, a five-day LPS injection resulted in 19.96% of fetuses with NTDs. Interestingly, supplementation with folic acid (3mg/kg/d) during pregnancy significantly alleviated LPS-induced NTDs. Additionally, folic acid significantly attenuated LPS-induced fetal growth restriction and skeletal malformations. Additional experiment showed that folic acid attenuated LPS-induced glutathione (GSH) depletion in maternal liver and placentas. Moreover, folic acid significantly attenuated LPS-induced expression of placental MyD88. Additionally, folic acid inhibited LPS-induced c-Jun NH2-terminal kinase (JNK) phosphorylation and nuclear factor kappa B (NF-κB) activation in placentas. Correspondingly, folic acid significantly attenuated LPS-induced tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in placentas, maternal serum and amniotic fluid. In conclusion, supplementation with high-dose folic acid during pregnancy protects against LPS-induced NTDs through its anti-inflammatory and anti-oxidative effects.

  1. Lipopolysaccharide Induces Human Pulmonary Micro-Vascular Endothelial Apoptosis via the YAP Signaling Pathway

    PubMed Central

    Yi, Lei; Huang, Xiaoqin; Guo, Feng; Zhou, Zengding; Chang, Mengling; Tang, Jiajun; Huan, Jingning

    2016-01-01

    Gram-negative bacterial lipopolysaccharide (LPS) induces a pathologic increase in lung vascular leakage under septic conditions. LPS-induced human pulmonary micro-vascular endothelial cell (HPMEC) apoptosis launches and aggravates micro-vascular hyper-permeability and acute lung injury (ALI). Previous studies show that the activation of intrinsic apoptotic pathway is vital for LPS-induced EC apoptosis. Yes-associated protein (YAP) has been reported to positively regulate intrinsic apoptotic pathway in tumor cells apoptosis. However, the potential role of YAP protein in LPS-induced HPMEC apoptosis has not been determined. In this study, we found that LPS-induced activation and nuclear accumulation of YAP accelerated HPMECs apoptosis. LPS-induced YAP translocation from cytoplasm to nucleus by the increased phosphorylation on Y357 resulted in the interaction between YAP and transcription factor P73. Furthermore, inhibition of YAP by small interfering RNA (siRNA) not only suppressed the LPS-induced HPMEC apoptosis but also regulated P73-mediated up-regulation of BAX and down-regulation of BCL-2. Taken together, our results demonstrated that activation of the YAP/P73/(BAX and BCL-2)/caspase-3 signaling pathway played a critical role in LPS-induced HPMEC apoptosis. Inhibition of the YAP might be a potential therapeutic strategy for lung injury under sepsis. PMID:27807512

  2. Follistatin-like protein 1 suppressed pro-inflammatory cytokines expression during neuroinflammation induced by lipopolysaccharide.

    PubMed

    Cheng, Kai-Yuan; Liu, Yi; Han, Ying-Guang; Li, Jing-Kun; Jia, Jia-Lin; Chen, Bin; Yao, Zhi-Xiao; Nie, Lin; Cheng, Lei

    2017-04-01

    Follistain-like protein 1 (FSTL1), has been recently demonstrated to be involved in the embryo development of nervous system and glioblastoma. However, the role of FSTL1 in neuroinflammation remains unexplored. In this study, the expression of FSTL1 in astrocytes was verified and its role was studied in neuroinflammation induced by in vivo intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) or LPS treatment to astrocytes in vitro. FSTL1 was significantly induced after ICV LPS injection or LPS treatment. FSTL1 suppressed upregulation of pro-inflammatory cytokines in astrocytes after LPS treatment. Moreover, FSTL1 downregulated expression of pro-inflammatory cytokines through suppressing MAPK/p-ERK1/2 pathway in astrocytes. Our results suggest that FSTL1 may play an anti-inflammatory role in neuroinflammation mediated by astrocytes.

  3. CXCL10/IP-10 Neutralization Can Ameliorate Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats

    PubMed Central

    Lang, Shan; Li, Libing; Wang, Xuning; Sun, Junping; Xue, Xinying; Xiao, Yongjiu; Zhang, Mingyue; Ao, Ting; Wang, Jianxin

    2017-01-01

    The role of C-X-C motif chemokine 10 (CXCL10), a pro-inflammatory factor, in the development of acute respiratory distress syndrome (ARDS) remains unclear. In this study, we explored the role of CXCL10 and the effect of CXCL10 neutralization in lipopolysaccharide (LPS)-induced ARDS in rats. The expression of CXCL10 and its receptor chemokine receptor 3(CXCR3) increased after LPS induction. Moreover, neutralization of CXCL10 ameliorated the severity of ARDS by reducing pulmonary edema, inhibiting the release of inflammatory mediators (IFN-γ, IL-6 and ICAM-1) and limiting inflammatory cells (neutrophils, macrophages, CD8+ T cells) influx into the lung, with a reduction in CXCR3 expression in neutrophils and macrophages. Therefore, CXCL10 could be a potential therapeutic target in LPS-induced ARDS. PMID:28046003

  4. The intracerebroventricular injection of rimonabant inhibits systemic lipopolysaccharide-induced lung inflammation.

    PubMed

    Johnson, Arnold; Neumann, Paul H; Peng, Jianya; James, Janey; Russo, Vincenzo; MacDonald, Hunter; Gertzberg, Nancy; Feleder, Carlos

    2015-09-15

    We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

  5. Interferon-induced guanylate-binding proteins promote cytosolic lipopolysaccharide detection by caspase-11.

    PubMed

    Meunier, Etienne; Broz, Petr

    2015-01-01

    Lipopolysaccharide (LPS) from gram-negative bacteria is a classical pathogen-associated molecular pattern and a strong inducer of immune responses. While the detection of LPS on the cell surface and in the endosome by Toll-like receptor 4 (TLR4) has been studied for some time, it has only recently been discovered that LPS can also be sensed in the cytosol of cells by a noncanonical inflammasome pathway, resulting in the activation of the cysteine protease caspase-11. Intriguingly, activation of this pathway requires the production of interferons (IFNs) and the induction of a class of IFN-induced GTPases called guanylate-binding proteins (GBPs), which have previously been linked to cell-autonomous killing of intracellular microbes. In this study, we review the recent advances in our understanding of cytosolic LPS sensing and the function of mammalian GBPs.

  6. Murine P-glycoprotein Deficiency Alters Intestinal Injury Repair and Blunts Lipopolysaccharide-Induced Radioprotection

    PubMed Central

    Staley, Elizabeth M.; Yarbrough, Vanisha R.; Schoeb, Trenton R.; Daft, Joseph G.; Tanner, Scott M.; Steverson, Dennis; Lorenz, Robin G.

    2012-01-01

    P-glycoprotein (P-gp) has been reported to increase stem cell proliferation and regulate apoptosis. Absence of P-gp results in decreased repair of intestinal epithelial cells after chemical injury. To further explore the mechanisms involved in the effects of P-gp on intestinal injury and repair, we used the well-characterized radiation injury model. In this model, injury repair is mediated by production of prostaglandins (PGE2) and lipopolysaccharide (LPS) has been shown to confer radioprotection. B6.mdr1a−/− mice and wild-type controls were subjected to 12 Gy total body X-ray irradiation and surviving crypts in the proximal jejunum and distal colon were evaluated 3.5 days after irradiation. B6.mdr1a−/−mice exhibited normal baseline stem cell proliferation and COX dependent crypt regeneration after irradiation. However, radiation induced apoptosis was increased and LPS-induced radioprotection was blunted in the C57BL6.mdr1a−/−distal colon, compared to B6 wild-type controls. The LPS treatment induced gene expression of the radioprotective cytokine IL-1α, in B6 wild-type controls but not in B6.mdr1a−/− animals. Lipopolysaccharid-induced radioprotection was absent in IL-1R1−/− animals, indicating a role for IL-1α in radioprotection, and demonstrating that P-gp deficiency interferes with IL-1α gene expression in response to systemic exposure to LPS. PMID:22780103

  7. Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex

    PubMed Central

    Garcia-Oscos, Francisco; Peña, David; Housini, Mohammad; Cheng, Derek; Lopez, Diego; Borland, Michael S.; Salgado-Delgado, Roberto; Salgado, Humberto; D’Mello, Santosh; Kilgard, Michael P.; Rose-John, Stefan; Atzori, Marco

    2016-01-01

    The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (single acute injections of lipopolysaccharide, LPS, 10 mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-signaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic α7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or – in wild-type animals – upon application sgp130Fc. Similar results were obtained by activating the “anti-inflammatory reflex” – a neural circuit regulating peripheral immune response – by stimulation of the vagal nerve or through peripheral administration of the α7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-signaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depression. PMID:25128387

  8. Lipopolysaccharide aggravated DOI-induced Tourette syndrome: elaboration for recurrence of Tourette syndrome.

    PubMed

    Hongyan, Long; Zhenyang, Si; Chunyan, Wang; Qingqing, Pan

    2017-08-09

    Tourette syndrome (TS) is a neurological disorder characterized by highest familial recurrence rate among neuropsychiatric diseases with complicated inheritance. Recurrence of Tourette syndrome was frequently observed in clinical. Unexpectedly, the mechanism of recurrence of Tourette syndrome was failure to elucidate. Here, we first shown that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome. The TS model in rats was induced by DOI (the selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl) -2- aminopropane). The rats were randomly divided into 4 groups:(1)Control;(2) Control + LPS; (2)TS; (3)TS + LPS. The results demonstrated that the LPS treatment significantly increased stereotypic score and autonomic activity. LPS treatment also significantly increased inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and striatum. Also, highly expressed TLR4, MyD88, P-NF-κBp65, P-IκBα in TS rats were increased respectively by LPS treatment as indicted in western blot analysis and immunohistochemistry analysis. Thus, it was supposed that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome and its mechanism was related to TLR/NF-κB pathway.

  9. Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis.

    PubMed

    Zhang, Peng; Zhang, Meisheng; Wan, Mengqi; Huang, Xiaoliu; Jiang, Yan; Xu, Siying; Luo, Mansheng

    2017-04-01

    Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1β were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1β (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

  10. Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.

    PubMed

    Shen, Yongbin; Sun, Zhanfeng; Guo, Xiaotong

    2015-01-15

    Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-α, IL-6 and IL-1β production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-α, IL-6 and IL-1β production in alveolar macrophages. LPS-induced NF-κB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, this is the first to demonstrate that citral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-γ, thereby inhibiting LPS-induced inflammatory response. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Lipopolysaccharide stimulation of trophoblasts induces corticotropin-releasing hormone expression through MyD88.

    PubMed

    Uh, Andy; Nicholson, Richard C; Gonzalez, Gustavo V; Simmons, Charles F; Gombart, Adrian; Smith, Roger; Equils, Ozlem

    2008-09-01

    We hypothesized that intrauterine infection may lead to placental corticotrophin-releasing hormone (CRH) expression via Toll-like receptor signaling. To test this hypothesis JEG3 cells were stimulated with lipopolysaccharide (LPS), chlamydial heat shock protein 60, and interleukin (IL)-1. CRH expression was assessed by reverse transcription polymerase chain reaction (RT-PCR). The signaling mechanisms that were involved were examined in transient transfection experiments with beta-galactosidase, CRH-luciferase, cyclic adenosine monophosphate (AMP) response element-luciferase, dominant-negative (DN)-myeloid differentiation primary response gene (MyD88) and DN-toll-IL-1-receptor domain containing adapter inducing interferon (TRIF) vectors. Luciferase activity was determined by luciferase assay. Beta-galactosidase assay was performed to determine transfection efficiency. LPS, chlamydial heat shock protein 60, and IL-1 stimulation led to CRH expression in the JEG3 cells. LPS-induced CRH expression was not due to the autocrine effect of LPS-induced IL-1 because the supernatant from LPS-conditioned JEG3 cells did not induce CRH expression in the naïve cells. DN-MyD88, but not DN-TRIF, blocked the LPS-induced CRH expression. The cAMP response element did not play a role in LPS-induced CRH expression. Toll-like receptor signaling 4 may induce placental CRH expression through MyD88.

  12. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Xia, Mi-Zhen; Wang, Hua; Zhao, Hui; Xu, De-Xiang; Yu, De-Xin

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. 6-Hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: involvement of nitric oxide and mitochondria.

    PubMed

    Gupta, Sonam; Goswami, Poonam; Biswas, Joyshree; Joshi, Neeraj; Sharma, Sharad; Nath, C; Singh, Sarika

    2015-01-15

    The present study was conducted to investigate the effect of the neurotoxins 6-hydroxydopamine and lipopolysaccharide on astrocytes. Rat astrocyte C6 cells were treated with different concentration of 6-hydroxydopamine (6-OHDA)/lipopolysaccharides (LPS) for 24 h. Both neurotoxins significantly decreased the viability of astrocytes, augmented the expression of inducible nitric oxide synthase (iNOS) and the astrocyte marker--glial fibrillar acidic protein. A significantly decreased mitochondrial dehydrogenase activity, mitochondrial membrane potential, augmented reactive oxygen species (ROS) level, caspase-3 mRNA level, chromatin condensation and DNA damage was observed in 6-OHDA/LPS treated astroglial cells. 6-OHDA/LPS treatment also caused the significantly increased expression of iNOS and nitrite level. Findings showed that 6-OHDA/LPS treatment caused mitochondrial dysfunction mediated death of astrocytes, which significantly involve the nitric oxide. Since we have observed significantly increased level of iNOS along with mitochondrial impairment and apoptotic cell death in astrocytes, therefore to validate the role of iNOS, the cells were co-treated with iNOS inhibitor aminoguanidine (AG, 100 μM). Co-treatment of AG significantly attenuated the 6-OHDA/LPS induced cell death, mitochondrial activity, augmented ROS level, chromatin condensation and DNA damage. GFAP and caspase-3 expression were also inhibited with co-treatment of AG, although the extent of inhibition was different in both experimental sets. In conclusion, the findings showed that iNOS mediated increased level of nitric oxide acts as a key regulatory molecule in 6-OHDA/LPS induced mitochondrial dysfunction, DNA damage and apoptotic death of astrocytes.

  14. Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice.

    PubMed

    Martin, Stephen A; Dantzer, Robert; Kelley, Keith W; Woods, Jeffrey A

    2014-01-01

    Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate-intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running (VWR) would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4- and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (VWR) or no wheel (standard) for 30 (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective standard control groups. VWR had no effect on LPS-induced anorexia, weight loss, increased immobility in the tail suspension test and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and 24 h (aged mice) after injection of LPS, mRNA transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. Prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences in young adult and aged mice. © 2013 S. Karger AG, Basel.

  15. [Different expression of cytokines induced by Actinobacillus actinomycetemcomitans lipopolysaccharide in monocytes/macrophages from different organs of rabbits].

    PubMed

    Huang, Min; Li, Hou-xuan; Luo, Lan; Chen, Shuai; Li, Yan-fen; Yan, Fu-hua

    2013-03-01

    To investigate the expression of cytokines induced by Actinobacillus actinomycetemcomitans lipopolysaccharide (Aa-LPS) in monocytes/macrophages from different organs of rabbits. The peripheral mononuclear cells (Mo), alveolar macrophages (AM), peritoneal macrophages (PM) and Kupffer cells (KC) from five New Zealand rabbits were isolated respectively. Then the cells from different organs were stimulated with Escherichia coli (Ec)-LPS or Aa-LPS at the dose of 1 mg/L. After culture for 24 hours, the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)6, IL-1β, IL-8 mRNA and protein were determined by real-time PCR and enzyme-linked immunosorbent assay respectively. The monocytes/macrophages challenged by Ec-LPS or Aa-LPS expressed more cytokines both in mRNA and protein levels compared with the controls (P < 0.05). Among them, AM displayed the highest respond when encount with Aa-LPS, with the TNF-α, IL-6, IL-1β, IL-8 mRNA relative levels were (0.4719 ± 0.0171), (2.7895 ± 0.0669), (5.1527 ± 0.1190), (3.6785 ± 0.1836) and the proteins concentrations were (82.2 ± 5.4), (40.2 ± 2.0), (50 308.3 ± 445.0), (35 305.3 ± 1480.9) ng/L respectively. And the inducibility of Aa-LPS was stronger than that of Ec-LPS (P < 0.05). Meanwhile the cells from different organs showed discrepant response when exposed to Aa-LPS (P < 0.05). The results showed their abilities to secrete cytokines were in the sequence of AM > Mo > KC > PM. Aa-LPS influenced the expression of cytokines in monocytes/macrophages from different organs of rabbits.

  16. Voluntary Wheel Running Does not Affect Lipopolysaccharide-Induced Depressive-Like Behavior in Young Adult and Aged Mice

    PubMed Central

    Martin, Stephen A.; Dantzer, Robert; Kelley, Keith W.; Woods, Jeffrey A.

    2014-01-01

    Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4-month-old and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (Voluntary Wheel Running, VWR) or no wheel (Standard) for 30 days (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective Standard control groups. VWR had no effect on LPS-induced anorexia, weight-loss, increased immobility in the tail suspension test, and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and twenty-four (aged mice) hours after injection of LPS transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. These results indicate that prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences. PMID:24281669

  17. Vitexin alleviates lipopolysaccharide-induced islet cell injury by inhibiting HMGB1 release

    PubMed Central

    Wang, Feifei; Yin, Jiajing; Ma, Yujin; Jiang, Hongwei; Li, Yanbo

    2017-01-01

    Diabetes mellitus (DM) is a chronic metabolic disease, where the predominant pathogenesis is pancreatic β-cells dysfunction or injury. It has been well established that inflammation leads to a gradual exhaustion of pancreatic β-cell function with decreased β-cell mass likely resulting from pancreatic β-cells apoptosis or death. Vitexin, a major bioactive flavonoid compound in plants has numerous pharmacological properties, including antioxidant, anti-inflammatory and antimyeloperoxidase. Whether vitexin can protect pancreatic β-cells against lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and apoptosis has received little attention. The present study investigated the potential effects of vitexin on LPS-induced pancreatic β-cell injury and apoptosis. It was revealed that apoptosis and damage induced by LPS in islet tissue of rats and INS-1 cells was significantly decreased in response to vitexin treatment. In addition, pretreatment with vitexin decreased the levels of the pro-inflammatory cytokines tumor necrosis factor-α and high mobility group box 1 (HMGB1) in LPS-induced rats. Further experiments demonstrated that vitexin pretreatment suppressed the activation of P38 mitogen-activated protein kinase signaling pathways in LPS-induced INS-1 cells. In conclusion, the results indicated that vitexin prevented LPS-induced islet tissue damage in rats, and INS-1 cells injury and apoptosis by inhibiting HMGB1 release. Therefore, the present study provided clear evidence indicating that vitexin may be a viable therapeutic strategy for the treatment of DM. PMID:28098903

  18. Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System.

    PubMed

    Jin, Yang; Peng, Jian; Wang, Xiaona; Zhang, Dong; Wang, Tianyin

    2017-01-11

    Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 μg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (α7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect.

  19. Bacterial lipopolysaccharide induces osteoclast formation in RAW 264.7 macrophage cells

    SciTech Connect

    Islam, Shamima; Hassan, Ferdaus; Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Koide, Naoki; Naiki, Yoshikazu; Mori, Isamu; Yoshida, Tomoaki; Yokochi, Takashi . E-mail: yokochi@aichi-med-u.ac.jp

    2007-08-24

    Lipopolysaccharide (LPS) is a potent bone resorbing factor. The effect of LPS on osteoclast formation was examined by using murine RAW 264.7 macrophage cells. LPS-induced the formation of multinucleated giant cells (MGC) in RAW 264.7 cells 3 days after the exposure. MGCs were positive for tartrate-resistant acid phosphatase (TRAP) activity. Further, MGC formed resorption pits on calcium-phosphate thin film that is a substrate for osteoclasts. Therefore, LPS was suggested to induce osteoclast formation in RAW 264.7 cells. LPS-induced osteoclast formation was abolished by anti-tumor necrosis factor (TNF)-{alpha} antibody, but not antibodies to macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-{kappa}B ligand (RANKL). TNF-{alpha} might play a critical role in LPS-induced osteoclast formation in RAW 264.7 cells. Inhibitors of NF-{kappa}B and stress activated protein kinase (SAPK/JNK) prevented the LPS-induced osteoclast formation. The detailed mechanism of LPS-induced osteoclast formation is discussed.

  20. Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/d-galactosamine-induced liver injury.

    PubMed

    Morita, Tatsuya; Jinno, Keiko; Kawagishi, Hirokazu; Arimoto, Yasushi; Suganuma, Hiroyuki; Inakuma, Takahiro; Sugiyama, Kimio

    2003-03-12

    To evaluate the hepatoprotective activity of spices, 21 different spices were fed to rats with liver damage caused by lipopolysaccharide (LPS) plus d-galactosamine (D-GalN). As assessed by plasma aminotranferase activities, nutmeg showed the most potent hepatoprotective activity. Bioassay-guided isolation of the active compound from nutmeg was carried out in mice by a single oral administration of the respective fractions. Myristicin, one of the major essential oils of nutmeg, was found to possess extraordinarily potent hepatoprotective activity. Myristicin markedly suppressed LPS/D-GalN-induced enhancement of serum TNF-alpha concentrations and hepatic DNA fragmentation in mice. These findings suggest that the hepatoprotective activity of myristicin might be, at least in part, due to the inhibition of TNF-alpha release from macrophages. However, further studies are needed to elucidate the hepatoprotective mechanism(s) of myristicin.

  1. Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice

    SciTech Connect

    Mirrione, M.M.; Mirrione, M.M.; Konomosa, D.K.; Ioradanis, G.; Dewey, S.L.; Agzzid, A.; Heppnerd, F.L.; Tsirka, St.E.

    2010-04-01

    Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.

  2. Antidepressants prevent hierarchy destabilization induced by lipopolysaccharide administration in mice: a neurobiological approach to depression.

    PubMed

    Cohn, Daniel Wagner Hamada; Kinoshita, Denise; Palermo-Neto, João

    2012-07-01

    In spite of the high prevalence and negative impact of depression, little is known about its pathophysiology. Basic research on depression needs new animal models in order to increase knowledge of the disease and search for new therapies. The work presented here aims to provide a neurobiologically validated model for investigating the relationships among sickness behavior, antidepressants treatment, and social dominance behavior. For this purpose, dominant individuals from dyads of male Swiss mice were treated with the bacterial endotoxin lipopolysaccharide (LPS) to induce social hierarchy destabilization. Two groups were treated with the antidepressants imipramine and fluoxetine prior to LPS administration. In these groups, antidepressant treatment prevented the occurrence of social destabilization. These results indicate that this model could be useful in providing new insights into the understanding of the brain systems involved in depression. © 2012 New York Academy of Sciences.

  3. Involvement of Prokineticin 2 and Prokineticin Receptor 1 in Lipopolysaccharide-Induced Testitis in Rats.

    PubMed

    Chen, Biao; Yu, Lili; Wang, Jiaojiao; Li, Cuiling; Zhao, Kai; Zhang, Huiping

    2016-04-01

    Prokineticin 2, a newly discovered proinflammatory peptide, has been amply evidenced to be involved in the occurrence and progress of local and systematical inflammation. Although the presence of Prokineticn 2 in mammal testis has been documented clearly, research targeting the involvement of prokineticin 2 in testicular pathology, especially testitis, is rather scarce. Employing a lipopolysaccharide-induced testitis rat model, we for the first time demonstrated the expression and upregulation of prokineticin 2 in orchitis at several levels. Our effort also addressed the differential expression patterns of prokineticin 2 and interleukin-1β, a key inflammation indicator, during testitis suggesting Prokineticn 2 serves more than a proinflammatory factor in the context of testitis. Given one of the cognate receptors of prokineticin 2, prokineticin receptor 1 (PKR1) was also significantly upregulated in orchitis as discussed in the current study, it is very likely that PK2/PKR1 signaling contribute to the development of inflammation-related testicular diseases.

  4. Lipopolysaccharide-induced multinuclear cells: increased internalization of polystyrene beads and possible signals for cell fusion.

    PubMed

    Nakanishi-Matsui, Mayumi; Yano, Shio; Futai, Masamitsu

    2013-11-01

    A murine macrophage-derived line, RAW264.7, becomes multinuclear on stimulation with lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria. These multinuclear cells internalized more polystyrene beads than mononuclear cells or osteoclasts (Nakanishi-Matsui, M., Yano, S., Matsumoto, N., and Futai, M., 2012). In this study, we analyzed the time courses of cell fusion in the presence of large beads. They were internalized into cells actively fusing to become multinuclear. However, the multinuclear cells once formed showed only low phagocytosis activity. These results suggest that formation of the multinuclear cells and bead internalization took place simultaneously. The formation of multinuclear cells was blocked by inhibitors for phosphoinositide 3-kinase, phospholipase C, calcineurin, and c-Jun N-terminal kinase. In addition, interleukin 6 and 10 also exhibited inhibitory effects. These signaling molecules and cytokines may play a crucial role in the LPS-induced multinuclear cell formation. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement.

    PubMed

    Bullón, Pedro; Román-Malo, Lourdes; Marín-Aguilar, Fabiola; Alvarez-Suarez, José Miguel; Giampieri, Francesca; Battino, Maurizio; Cordero, Mario D

    2015-01-01

    Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Lipopolysaccharide enhances glutaric acid-induced seizure susceptibility in rat pups: behavioral and electroencephalographic approach.

    PubMed

    Magni, Danieli Valnes; Souza, Mauren Assis; Oliveira, Ana Paula Ferreira; Furian, Ana Flávia; Oliveira, Mauro Schneider; Ferreira, Juliano; Santos, Adair Roberto Soares; Mello, Carlos Fernando; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2011-02-01

    Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. Considering that seizures are precipitated by common infections in children with GA-I, we investigated whether lipopolysaccharide (LPS) modifies GA-induced electrographic and neurochemical alterations in 21 days-old rats. The effect of LPS on convulsive behavior and electroencephalographic (EEG) alterations induced by GA (0.13; 0.4; 1.3 μmol/striatum) was determined in freely moving rats. After EEG recordings, we measured the levels of interleukin 1β (IL-1β) in GA-injected striatum. The injection of LPS (2mg/kg; i.p.) 6h before of GA administration, reduced the latency and increased the duration of seizures induced by GA (1.3 μmol/site). In addition, LPS administration increased IL-1β striatal levels, which positively correlated with total time in seizures. The intrastriatal injection of an IL-1β antibody (200 ng/2 μl) prevented the facilitation of GA-induced seizures by LPS. These data suggest that inflammatory processes during critical periods of development may decrease GA-induced seizure threshold. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. Melatonin Attenuates Manganese and Lipopolysaccharide-Induced Inflammatory Activation of BV2 Microglia.

    PubMed

    Park, Euteum; Chun, Hong Sung

    2017-02-01

    Melatonin, a naturally occurring neurohormone in the pineal gland, has been shown to exert antioxidant and anti-inflammatory effects. This study examined the effects of melatonin on manganese (Mn) and/or lipopolysaccharide (LPS)-induced microglial activation. Melatonin (10 μM) inhibited Mn (100 μM) and/or LPS (0.5 μg/ml)-induced phagocytotic activity of activated BV2 microglia. It also inhibited the lipid peroxidation and intracellular reduced glutathione (GSH) depletion induced by Mn and/or LPS. Melatonin effectively suppressed the upregulation of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) at both mRNA and protein levels in Mn and/or LPS-stimulated BV2 microglia. In addition, melatonin pretreatment attenuated Mn and/or LPS-induced degradation of IκB-α, nuclear translocation of nuclear factor-κB (NF-κB) and its activation, and the expressions of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in BV2 microglial cells. These results suggest that melatonin can effectively modulate phagocytosis and expression of proinflammatory mediators, and can prevent neuroinflammatory disorders accompanied by microglial activation.

  8. Cepharanthine attenuates lipopolysaccharide-induced mice mastitis by suppressing the NF-κB signaling pathway.

    PubMed

    Ershun, Zhou; Yunhe, Fu; Zhengkai, Wei; Yongguo, Cao; Naisheng, Zhang; Zhengtao, Yang

    2014-04-01

    Cepharanthine (CEP), a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effects of CEP on a mouse model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms remain to be elucidated. The purpose of the present study was to investigate the effects of CEP on LPS-induced mouse mastitis. The mouse model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. CEP was administered intraperitoneally at 1 h before and 12 h after induction of LPS. The results show that CEP significantly attenuates the infiltration of neutrophils, suppresses myeloperoxidase activity, and reduces the levels of TNF-α, IL-1β, and IL-6 in LPS-induced mouse mastitis. Furthermore, CEP inhibited the phosphorylation of NF-κB p65 subunit and the degradation of its inhibitor IκBα. All the results suggest that CEP exerts potent anti-inflammatory effects on LPS-induced mouse mastitis. Accordingly, CEP might be a potential therapeutic agent for mastitis.

  9. Protective Effect of Isorhamnetin on Lipopolysaccharide-Induced Acute Lung Injury in Mice.

    PubMed

    Yang, Bo; Li, Xiao-Ping; Ni, Yun-Feng; Du, Hong-Yin; Wang, Rong; Li, Ming-Jiang; Wang, Wen-Chen; Li, Ming-Ming; Wang, Xu-Hui; Li, Lei; Zhang, Wei-Dong; Jiang, Tao

    2016-02-01

    Isorhamnetin has been reported to have anti-inflammatory, anti-oxidative, and anti-proliferative effects. The aim of this study was to investigate the protective effect of isorhamnetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by inhibiting the expression of cyclooxygenase-2 (COX-2). The effects of isorhamnetin on LPS-induced lung pathological damage, wet/dry ratios and the total protein level in bronchoalveolar lavage fluid (BALF), inflammatory cytokine release, myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) level were examined. In addition, the COX-2 activation in lung tissues was detected by Western blot. Isorhamnetin pretreatment improved the mice survival rates. Moreover, isorhamnetin pretreatment significantly attenuated edema and the pathological changes in the lung and inhibited protein extravasation in BALF. Isorhamnetin also significantly decreased the levels of inflammatory cytokines in BALF. In addition, isorhamnetin markedly prevented LPS-induced oxidative stress. Furthermore, isorhamnetin pretreatment significantly suppressed LPS-induced activation of COX-2. Isorhamnetin has been demonstrated to protect mice from LPS-induced ALI by inhibiting the expression of COX-2.

  10. Protective effects of kaempferol on lipopolysaccharide-induced mastitis in mice.

    PubMed

    Cao, Rongfeng; Fu, Kaiqiang; Lv, Xiaopei; Li, Weishi; Zhang, Naisheng

    2014-10-01

    Kaempferol isolated from the root of Zingiberaceae plants galangal and other Chinese herbal medicines have been reported to have anti-inflammatory properties. However, the anti-inflammatory effects of kaempferol on lipopolysaccharide (LPS)-induced mastitis are unknown and their underlying molecular mechanisms remain to be explored. The aim of this study was to evaluate the effects of kaempferol on LPS-induced mouse mastitis. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. Kaempferol was injected 1 h before and 12 h after induction of LPS intraperitoneally. The present results showed that kaempferol markedly reduced infiltration of neutrophilic granulocyte, activation of myeloperoxidase (MPO), expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in a dose-dependent manner, which were increased in LPS-induced mouse mastitis. Furthermore, kaempferol suppressed the phosphorylation of nuclear factor-κB (NF-κB) p65 subunit and the degradation of its inhibitor IκBα. All results suggest that anti-inflammatory effects of kaempferol against the LPS-induced mastitis possibly through inhibition of the NF-κB signaling pathway. Kaempferol may be a potential therapeutic agent for mastitis.

  11. Mucoactive effects of naringin in lipopolysaccharide-induced acute lung injury mice and beagle dogs.

    PubMed

    Chen, Yan; Wu, Hao; Nie, Yi-chu; Li, Pei-bo; Shen, Jian-gang; Su, Wei-wei

    2014-07-01

    Our previous study has demonstrated that naringin attenuates EGF-induced MUC5AC hypersecretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. However, the volume of airway mucus is determined by two factors including the number of mucous cells and capacity of mucus secretion. The aim of the present study is to explore the mucoactive effects of naringin in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and beagle dogs. The results demonstrated that naringin of 12.4 mg/kg treatment significantly decreased LPS-induced enhancement of sputum volume and pulmonary inflammation, remarkably increased the subglottic sputum volume and solids content in sputum of lower trachea, while partially, but not fully, significantly increased the elasticity and viscosity of sputum in lower trachea of beagle dogs. Moreover, the MUC5AC content in BALF and goblet-cells in large airways of LPS-induced ALI mice were significantly attenuated by dexamethasone (5 mg/kg), ambroxol (25 mg/kg), and naringin (15, 60 mg/kg). However, the goblet-cells hyperplasia in small airways induced by LPS was only significantly inhibited by dexamethasone and naringin (60 mg/kg). In conclusion, naringin exhibits mucoactive effects through multiple targets which including reduction of goblet cells hyperplasia and mucus hypersecretion, as well as promotion of sputum excretion.

  12. Mangiferin regulates cognitive deficits and heme oxygenase-1 induced by lipopolysaccharide in mice.

    PubMed

    Fu, Yanyan; Liu, Hongzhi; Song, Chengjie; Zhang, Fang; Liu, Yi; Wu, Jian; Wen, Xiangru; Liang, Chen; Ma, Kai; Li, Lei; Zhang, Xunbao; Shao, Xiaoping; Sun, Yafeng; Du, Yang; Song, Yuanjian

    2015-12-01

    Accumulating evidence reveals that lipopolysaccharide (LPS) can induce neuroinflammation, ultimately leading to cognitive deficits. Mangiferin, a natural glucoxilxanthone, is known to possess various biological activities. The present study aimed to investigate the effects of mangiferin on LPS-induced cognitive deficits and explore the underlying mechanisms. Brain injury was induced in mice via intraperitoneal LPS injection (1mg/kg) for five consecutive days. Mangiferin was orally pretreatmented (50mg/kg) for seven days and then treatmented (50mg/kg) for five days after LPS injection. The Morris water maze was used to detect changes in cognitive function. Immunohistochemical and immunoblotting were respectively performed to measure the expression of interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the hippocampus. The results showed that mangiferin can ameliorate cognitive deficits. Moreover, mangiferin decreased LPS-induced IL-6 production and increase HO-1 in the hippocampus. Taken together, these results suggest that mangiferin attenuates LPS-induced cognitive deficits, which may be potentially linked to modulating HO-1 in the hippocampus.

  13. Protective effect of sodium cromoglycate on lipopolysaccharide-induced bronchial obstruction in asthmatics.

    PubMed

    Michel, O; Ginanni, R; Sergysels, R

    1995-11-01

    Lipopolysaccharides (LPS, the major part of endotoxins) are bacterial proinflammatory substances which can induce in asthmatic patients after inhalation a bronchial obstruction with an increase in both histamine bronchial hyperresponsiveness and blood inflammatory markers. The aim of the present study was to evaluate whether an acute inhalation of sodium cromoglycate, an anti-inflammatory and membrane-stabilizating agent, can block the LPS-induced lung function response. Using a double-blind placebo-controlled crossover method, 7 asthmatic subjects were submitted, at 4 days' interval, to a bronchial challenge test with either solvent solution or LPS (20 micrograms) preceded by inhalation of sodium cromoglycate (10 mg) or placebo. Compared to the solvent reaction, LPS induced a significant bronchial obstruction [measured by both the forced expiratory volume in 1 s (FEV1) and the airway resistances] beginning at the 60th minute and lasting more than 300 min (p < 0.01, 2-way ANOVA). On the other hand, acute pretreatment with sodium cromoglycate significantly inhibited the LPS-induced bronchial obstruction. The total lung capacity did not change significantly after LPS inhalation. Thus, this study showed that in asthmatics the LPS-induced FEV1 response is blocked by acute treatment with sodium cromoglycate. Sodium cromoglycate could be an active treatment in asthmatics exposed to house dust containing endotoxin.

  14. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death

    PubMed Central

    Kim, Hyun-Ji

    2016-01-01

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death. PMID:27030196

  15. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death.

    PubMed

    Kim, Hyun-Ji; Joo, Hong-Gu

    2016-12-30

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death.

  16. Resveratrol counteracts lipopolysaccharide-induced depressive-like behaviors via enhanced hippocampal neurogenesis

    PubMed Central

    Liu, Liang; Zhang, Qin; Cai, Yulong; Sun, Dayu; He, Xie; Wang, Lian; Yu, Dan; Li, Xin; Xiong, Xiaoyi; Xu, Haiwei; Yang, Qingwu; Fan, Xiaotang

    2016-01-01

    Radial glial-like cells (RGLs) in the adult dentate gyrus (DG) function as progenitor cells for adult hippocampal neurogenesis, a process involved in the stress-related pathophysiology and treatment efficiency of depression. Resveratrol (RSV) has been demonstrated to be a potent activator of neurogenesis. The present study investigated whether chronic RSV treatment has antidepressant potential in relation to hippocampal neurogenesis. Mice received two weeks of RSV (20 mg/kg) or dimethylsulfoxide (DMSO) treatment, followed by lipopolysaccharide (LPS; 1 mg/kg) or saline injections for 5 days. We found that RSV treatment abrogated the increased immobility in the forced swimming test and tail suspension test induced by LPS. Immunohistochemical staining revealed that RSV treatment reversed the increase in microglial activation and the inhibition in DG neurogenesis. RSV treatment also attenuated LPS-induced defects in the expanding of RGLs through promoting symmetric division. In addition, RSV ameliorated LPS-induced NF-κB activation in the hippocampus coincides with the up-regulation levels of Sirt1 and Hes1. Taken together, these data indicated that RSV-induced Sirt1 activation counteracts LPS-induced depression-like behaviors via a neurogenic mechanism. A new model to understand the role of RSV in treating depression may result from these findings. PMID:27517628

  17. Endogenous glucocorticoids inhibit myocardial inflammation induced by lipopolysaccharide: involvement of regulation of histone deacetylation.

    PubMed

    Zhang, Hai-Ning; He, Yan-Hua; Zhang, Gen-Shui; Luo, Miao-Shan; Huang, Yue; Wu, Xiao-qian; Liu, Shi-Ming; Luo, Jian-Dong; Chen, Min-Sheng

    2012-07-01

    Emerging evidence indicates that myocardial inflammation plays a key role in the pathogenesis of cardiac diseases. But the exact mechanisms for this chronic inflammatory disorder have not been elucidated. Glucocorticoids (GCs) are the most effective anti-inflammatory treatments available for many inflammatory diseases. However, it is unknown whether endogenous GCs are able to exert anti-inflammatory effect on myocardial inflammation. In this study, the potential role of endogenous GCs in the regulation of myocardial inflammation was investigated. We showed that the reduction of endogenous GC level by adrenalectomy promoted the production of basal and lipopolysaccharide (LPS)-induced proinflammatory cytokines, which could be partly reversed by supplementing with exogenous physiological level of hydrocortisone. Inhibition of GC receptor (GR) signaling pathway with GR antagonist mifepristone (RU486) or histone deacetylase inhibitor trichostatin A (TSA) also increased the levels of basal and LPS-induced proinflammatory cytokines. Moreover, blockade of GC-GR signaling pathway by adrenalectomy, RU486 or TSA enhanced LPS-induced myocardial nuclear factor-κB activation and histone acetylation but inhibited myocardial histone deacetylase expression and activity. Cardiac function studies demonstrated that blockade of the GC-GR signaling pathway aggravated inflammation-induced cardiac dysfunction. These findings indicate that endogenous GCs are able to inhibit myocardial inflammation induced by LPS. Endogenous GCs represent an important endogenous anti-inflammatory mechanism for myocardium in rats and such mechanism injury may be an important factor for pathogenesis of cardiac diseases.

  18. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    PubMed

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  19. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.

    PubMed

    Zheng, H; Xiao, W H; Bennett, G J

    2012-12-01

    Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-L-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts.

  20. Astragalus mongholicus polysaccharide inhibits lipopolysaccharide-induced production of TNF-α and interleukin-8

    PubMed Central

    Yuan, Yuan; Sun, Mei; Li, Ke-Shen

    2009-01-01

    AIM: To explore the effect of Astragalus mongholicus polysaccharide (APS) on gene expression and mitogen-activated protein kinase (MAPK) transcriptional activity in intestinal epithelial cells (IEC). METHODS: IEC were divided into control group, lipopolysaccharide (LPS) group, LPS+ 50 μg/mL APS group, LPS+ 100 μg/mL APS group, LPS+ 200 μg/mL APS group, and LPS+ 500 μg/mL APS group. Levels of mRNAs in LPS-induced inflammatory factors, tumor necrosis factor (TNF)-α and interleukin (IL)-8, were measured by reverse transcription-polymerase chain reaction. MAPK protein level was measured by Western blotting. RESULTS: The levels of TNF-α and IL-8 mRNAs were significantly higher in IEC with LPS-induced damage than in control cells. APS significantly abrogated the LPS-induced expression of the TNF-α and IL-8 genes. APS did not block the activation of extracellular signal-regulated kinase or c Jun amino-terminal kinase, but inhibited the activation of p38, suggesting that APS inhibits LPS-induced production of TNF-α and IL-8 mRNAs, possibly by suppressing the p38 signaling pathway. CONCLUSION: APS-modulated bacterial product-mediated p38 signaling represents an attractive strategy for prevention and treatment of intestinal inflammation. PMID:19653348

  1. Protective effect of β-glucan on acute lung injury induced by lipopolysaccharide in rats.

    PubMed

    Iraz, Meryem; Iraz, Mustafa; Eşrefoğlu, Mukaddes; Aydin, Mehmet Şerif

    2015-01-01

    Lipopolysaccharide (LPS)-induced endotoxemia can cause serious organ damage such as acute lung injury and death by triggering the secretion of proinflammatory cytokines and acute-phase reactants. The goal of this study was to evaluate the effects of β-glucan on inflammatory mediator levels and histopathological changes in LPS-induced endotoxemia. Forty-seven male Wistar albino rats were randomly allocated into four groups as follows: control group, LPS group (10 mg/kg LPS), LPS + β-glucan group (100 mg/kg β-glucan before LPS administration), and β-glucan group. Twelve hours after LPS administration, lung and serum samples were collected. Concentrations of IL-6, IL-8, C-reactive protein (CRP), and procalcitonin were measured in the serum at hours 0 (basal) and 12. The severity of lung damage was assessed by an appropriate histopathological scoring system. Serum levels of CRP in the LPS group at 12 h were significantly higher than in the other groups, whereas serum IL-6 levels in the LPS and LPS + β-glucan groups at 12 h were significantly decreased. The mean histopathological damage score of the LPS group was slightly higher than that of the LPS + β-glucan group. Moreover, mortality rate was significantly decreased in the LPS + β-glucan group versus the LPS group. β-glucan reduces endotoxemia-induced mortality and might be protective against endotoxemia-induced lung damage.

  2. Dietary selenium deficiency exacerbates lipopolysaccharide-induced inflammatory response in mouse mastitis models.

    PubMed

    Wei, Zhengkai; Yao, Minjun; Li, Yimeng; He, Xuexiu; Yang, Zhengtao

    2014-12-01

    Selenium (Se) is an essential micronutrient that plays a critical role in anti-inflammatory processes and antioxidant defense system. In this study, we investigated the effects of dietary selenium deficiency on lipopolysaccharide (LPS)-induced mastitis in mouse models. Se content in the liver was assessed by fluorescent atomic absorption spectrometry. Glutathione peroxidase (GPx) activity in the blood, myeloperoxidase (MPO) activity, tumor necrosis actor alpha (TNF-α), and interleukin (IL)-1β in the supernatant of the mammary tissue were determined according to the corresponding kits. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were evaluated by Western blotting. The results showed that the Se-deficient mouse model was successfully replicated, and selenium deficiency exacerbated mammary gland histopathology, increased the expressions of TNF-α and IL-1β, and facilitated the activation of iNOS and COX-2 in LPS-induced mouse mastitis. In conclusion, our studies demonstrated that selenium deficiency resulted in more severe inflammatory response in LPS-induced mouse mastitis.

  3. Dexmedetomidine attenuates acute lung injury induced by lipopolysaccharide in mouse through inhibition of MAPK pathway.

    PubMed

    Xu, Yingzhen; Zhang, Ruyi; Li, Chunli; Yin, Xue; Lv, Changjun; Wang, Yaoqi; Zhao, Wenxiang; Zhang, Xiuli

    2015-10-01

    Dexmedetomidine (Dex) is widely used for sedation in intensive care units and can be used as an adjunct to anesthetics. Previous studies have demonstrated that Dex has anti-inflammatory property. In this study, we aim to explore the potential therapeutic effects and mechanisms of Dex on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. To induce ALI, mice were intraperitoneally injected with LPS, while Dex was treated 1 h before LPS injection. The inflammation of lung tissues was evaluated by HE stain, and bronchoalveolar lavage fluid (BALF) was obtained after 6 h to measure protein concentrations. We also used an enzyme-linked immunosorbent assay to detect the secretion levels of proinflammatory cytokines in the serum. Western blotting method was adopted to observe changes in mitogen-activated protein kinases and downstream nuclear transcription factors. The results showed that pretreatment with Dex considerably reduced neutrophil infiltration and pulmonary edema, and significantly reduced protein concentrations in the BALF, as well as suppressed LPS-induced elevation of proinflammatory cytokines (TNF-α and IL-1β) in the serum. In addition, we observed that the molecular mechanism of Dex-mediated anti-inflammation is associated with decreasing phosphorylation of MKK4, MMK3/6, ERK1/2, p38MAPK, and JNK, and diminishing activation of Elk-1, c-Jun, and ATF-2. Dex could attenuate ALI induced by LPS in mice, and this effect may be mediated through the inhibition of MAPK pathway.

  4. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium.

    PubMed

    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-08-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4(+) T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses.

  5. Role of kinase suppressor of ras-1 in lipopolysaccharide-induced acute lung injury.

    PubMed

    Li, Xiang; Gulbins, Erich; Zhang, Yang

    2012-01-01

    Kinase suppressor of ras-1 (Ksr1) has been recently shown to be a central signaling molecule in the host response to Pseudomonas aeruginosa infections in the lung. Ksr1 functions to regulate the release of nitric oxide (NO)-radicals upon P. aeruginosa infections. Ksr1 also enhances Raf-1/MEK/ERK signaling and is involved in a variety of cellular responses, including cell differentiation, proliferation, and apoptosis. Here, we investigated whether Ksr1 is involved in the host immune response to lipopolysaccharide (LPS), one of the major components of gram-negative bacteria, in the lung. To this end, we induced an acute lung injury in wild type and Ksr1-deficient mice by intratracheal instillation of LPS. We found that LPS-induces acute lung injury, as characterized by cytokine expression, neutrophil infiltration and protein extrusion in wildtype mice. Ksr1-deficient mice showed a very similar reaction to LPS as the wildtype mice. In freshly isolated alveolar macrophages from wild type and Ksr1-deficient mice, LPS increased ERK activation, nuclear translocation of NFĸB and expression of inflammatory cytokines and chemokines in a similar pattern. Inhibition of Src or Raf-1 blocked LPS-induced ERK activation. Taken together, these findings indicate that Ksr1 plays a dispensable role in LPS-induced ERK activation in alveolar macrophages and does not contribute to the development of acute lung injury in the LPS model.

  6. The effects of fisetin on lipopolysaccharide-induced depressive-like behavior in mice.

    PubMed

    Yu, Xuefeng; Jiang, Xi; Zhang, Xiangming; Chen, Ziwei; Xu, Lexing; Chen, Lei; Wang, Guokang; Pan, Jianchun

    2016-10-01

    Major depressive disorder (MDD) involves a series of pathological changes including the inflammation and increased cytokine levels. Fisetin, a natural flavonoid, has anti-inflammatory and antioxidant, and also has been shown in our previous studies to exert anti-depressant-like properties. The present study aimed to investigate the effect of fisetin on lipopolysaccharide (LPS)-induced depressive-like behavior and inflammation in mice. The results suggested that the immobility time in the forced swimming test (FST) and tail suspension test (TST) were increased at 6 h, 12 h and 24 h after LPS injection (0.83 mg/kg). However, only the group of 24 h treatment did not show any effect on locomotion counts. Pretreatment with fisetin at doses of 20, 40 and 80 mg/kg (p.o.) for 7 days reversed LPS-induced alterations of the immobility time in both of these two tests. Further neurochemical assays suggested that pretreatment with fisetin reversed LPS-induced overexpression of pro-inflammatory cytokine (IL-1β, IL-6 and TNF-α) in the hippocampus and the prefrontal cortex (PFC). Moreover, higher dose of fisetin effectively antagonized iNOS mRNA expression and nitrite levels via the modulation of NF-κB in the hippocampus and PFC. Taken together, fisetin may be an effective therapeutic agent for LPS-induced depressive-like behaviors, which is due to its anti-inflammatory property.

  7. Effect of azithromycin on Prevotella intermedia lipopolysaccharide-induced production of interleukin-6 in murine macrophages.

    PubMed

    Choi, Eun-Young; Jin, Ji-Young; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

    2014-04-15

    Interleukin-6 (IL-6) is a key proinflammatory cytokine which plays a central role in the pathogenesis of periodontal disease. Host modulatory agents targeting at inhibiting IL-6, therefore, appear to be beneficial in slowing the progression of periodontal disease and potentially reducing destructive aspects of the host response. The present study was designed to investigate the effect of the macrolide antibiotic azithromycin on IL-6 generation in murine macrophages treated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. Azithromycin significantly suppressed IL-6 production as well as its mRNA expression in P. intermedia LPS-activated RAW264.7 cells. LPS-induced activation of JNK and p38 was not affected by azithromycin treatment. Azithromycin failed to prevent P. intermedia LPS from degrading IκB-α. Instead, azithromycin significantly diminished nuclear translocation and DNA binding activity of NF-κB p50 subunit induced with LPS. Azithromycin inhibited P. intermedia LPS-induced STAT1 and STAT3 phosphorylation. In addition, azithromycin up-regulated the mRNA level of SOCS1 in cells treated with LPS. In conclusion, azithromycin significantly attenuated P. intermedia LPS-induced production of IL-6 in murine macrophages via inhibition of NF-κB, STAT1 and STAT3 activation, which is possibly related to the activation of SOCS1 signaling. Further in vivo studies are required to better evaluate the potential of azithromycin in the treatment of periodontal disease.

  8. Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction.

    PubMed

    Wang, Xiao; Ge, Qin Min; Bian, Fan; Dong, Yan; Huang, Chun Mei

    2017-02-01

    Oxidative stress leads to dysfunction in pancreatic cells, causing a reduction in insulin secretion following exposure to glucose. Toll-like receptor 4 (TLR4) may be activated by exposure to lipopolysaccharide (LPS) stress. TLR4 may mediate the initiation of inflammatory and immune defense responses; however, the importance of the LPS/TLR4 interaction in apoptosis induced by oxidative stress in pancreatic β cells remains to be elucidated. The present study aimed to investigate the importance of TLR4 during LPS‑induced oxidative stress, apoptosis and dysfunction of insulin secretion in isolated islets of rats. LPS‑induced stimulation of TLR4 increased the production of reactive oxygen species and promoted apoptosis by upregulating the expression levels of caspase‑3, poly ADP ribose polymerase and altering the expression ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2 associated X protein. Additionally, the insulin secretion of islets cells was reduced. Anti‑TLR4 antibody and a knockdown of TLR4 by TLR4‑short hairpin RNA were used to inhibit TLR4 activity, which may reverse LPS‑induced events. The present study determined that in islets exposed to LPS oxidative stress, dysfunction may be partly mediated via the TLR4 pathway. Inhibition of TLR4 may prevent dysfunction of rat islets due to oxidative stress. The present study revealed that targeting the LPS/TLR4 signaling pathway and antioxidant therapy may be a novel treatment for the severely septic patients with hyperglycemia stress.

  9. Analysis of cellular senescence induced by lipopolysaccharide in pulmonary alveolar epithelial cells.

    PubMed

    Kim, Chang Oh; Huh, Ae Jung; Han, Sang Hoon; Kim, June Myung

    2012-01-01

    In this work, it was examined the possibility of lipopolysaccharide (LPS) causing cellular senescence in lung alveolar epithelial cells. Then, it was clarified how this cellular senescence phenomenon is associated with oxidative stress effect induced by LPS and whether antioxidants could inhibit reduced cellular viability by oxidant stress effect of LPS. In cell viability using cell counting kit-8, exposure to LPS decreased cellular viability and induced growth arrest in a concentration-dependent manner. The pre-apoptotic concentration of LPS was determined by caspase activation using a Caspase-Glo 3/7 luminescence assay kit. This concentration of LPS caused morphologic characteristics shown in senescent cells and elevated senescence-associated β-galactosidase activity. In addition, lysosomal content associated with senescence was increased by LPS at the pre-apoptotic concentration. However, this concentration of LPS did not shorten the telomere length. Exposure to LPS resulted in the formation of hydrogen peroxide in a concentration-dependent manner. The ability of LPS to reduce cellular viability was inhibited by the presence of glutathione. This study revealed that LPS could induce cellular senescence in lung alveloar epithelial cells, and these phenomena were closely associated with hydrogen peroxide production by LPS. Taken together, it is suggested that LPS-induced cellular senescence may play an important role in limiting the tissue repair response after sepsis.

  10. Antioxidant properties of lutein contribute to the protection against lipopolysaccharide-induced uveitis in mice

    PubMed Central

    2011-01-01

    Background Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS)-induced uveitis in mice. Methods Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse) into the footpad in the model and lutein groups on day 5 after the last drug administration. Eyes of the mice were collected 24 hours after the LPS injection for the detection of indicators using commercial kits and reverse transcription-polymerase chain reaction. Results LPS-induced uveitis was confirmed by significant pathological damage and increased the nitric oxide level in eye tissue of BALB/C mice 24 hours after the footpad injection. The elevated nitric oxide level was significantly reduced by oral administration of lutein (125 and 500 mg/kg/d for five days) before LPS injection. Moreover, lutein decreased the malondialdehyde content, increased the oxygen radical absorbance capacity level, glutathione, the vitamin C contents and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Lutein further increased expressions of copper-zinc SOD, manganese SOD and GPx mRNA. Conclusion The antioxidant properties of lutein contribute to the protection against LPS-induced uveitis, partially through the intervention of inflammation process. PMID:22040935

  11. Caffeic acid attenuates lipopolysaccharide-induced sickness behaviour and neuroinflammation in mice.

    PubMed

    Basu Mallik, Sanchari; Mudgal, Jayesh; Nampoothiri, Madhavan; Hall, Susan; Dukie, Shailendra Anoopkumar-; Grant, Gary; Rao, C Mallikarjuna; Arora, Devinder

    2016-10-06

    Accumulating data links inflammation, oxidative stress and immune system in the pathophysiology of major depressive disorders. Sickness behaviour is a set of behavioural changes that develop during infection, eventually leading to decrease in mobility and depressed behaviour. Lipopolysaccharide (LPS) induces a depression-like state in animals that mimics sickness behaviour. Caffeic acid, a naturally occurring polyphenol, possesses antioxidant and anti-inflammatory properties. The present study was designed to explore the potential of caffeic acid against LPS-induced sickness behaviour in mice. Caffeic acid (30mg/kg) and imipramine (15mg/kg) were administered orally one hour prior to LPS (1.5mg/kg) challenge. Behavioural assessment was carried out between 1 and 2h and blood samples were collected at 3h post-LPS injection. Additionally, cytokines (brain and serum) and brain oxidative stress markers were estimated. LPS increased the systemic and brain cytokine levels, altered the anti-oxidant defence and produced key signs of sickness behaviour in animals. Caffeic acid treatment significantly reduced the LPS-induced changes, including reduced expression of inflammatory markers in serum and whole brain. Caffeic acid also exerted an anti-oxidant effect, which was evident from the decreased levels of oxidative stress markers in whole brain. Our data suggests that caffeic acid can prevent the neuroinflammation-induced acute and probably the long term neurodegenerative changes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Sesamin inhibits lipopolysaccharide-induced inflammation and extracellular matrix catabolism in rat intervertebral disc.

    PubMed

    Li, Kang; Li, Yan; Xu, Bo; Mao, Lu; Zhao, Jie

    2016-09-01

    Intervertebral disc (IVD) degeneration contributes to most spinal degenerative diseases, while treatment inhibiting IVD degeneration is still in the experimental stage. Sesamin, a bioactive component extracted from sesame, has been reported to exert chondroprotective and anti-inflammatory effects. Here, we analyzed the anti-inflammatory and anti-catabolic effects of sesamin on rat IVD in vitro and ex vivo. Results show that sesamin significantly inhibits the lipopolysaccharide (LPS)-induced expression of catabolic enzymes (MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5) and inflammation factors (IL-1β, TNF-α, iNOS, NO, COX-2, PGE2) in a dose-dependent manner in vitro. It is also proven that migration of macrophages induced by LPS can be inhibited by treatment with sesamin. Organ culture experiments demonstrate that sesamin protects the IVD from LPS-induced depletion of the extracellular matrix ex vivo. Moreover, sesamin suppresses LPS-induced activation of the mitogen-activated protein kinase (MAPK) pathway through inhibiting phosphorylation of JNK, the common downstream signaling pathway of LPS and IL-1β, which may be the potential mechanism of the effects of sesamin. In light of our results, sesamin protects the IVD from inflammation and extracellular matrix catabolism, presenting positive prospects in the treatment of IVD degenerative diseases.

  13. Taraxacum officinale protects against lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Liu, Liben; Xiong, Huanzhang; Ping, Jiaqi; Ju, Yulin; Zhang, Xuemei

    2010-07-20

    Taraxacum officinale has been frequently used as a remedy for inflammatory diseases. In the present study, we investigated the in vivo protective effect of Taraxacum officinale on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Taraxacum officinale at 2.5, 5 and 10 mg/kg was orally administered once per day for 5 days consecutively, followed by 500 microg/kg LPS was instilled intranasally. The lung wet/dry weight (W/D) ratio, protein concentration and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were determined. Superoxidase dismutase (SOD) and myeloperoxidase (MPO) activities, and histological change in the lungs were examined. The levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the BALF were measured using ELISA. We found that Taraxacum officinale decreased the lung W/D ratio, protein concentration and the number of neutrophils in the BALF at 24 h after LPS challenge. Taraxacum officinale decreased LPS-induced MPO activity and increased SOD activity in the lungs. In addition, histopathological examination indicated that Taraxacum officinale attenuated tissue injury of the lungs in LPS-induced ALI. Furthermore, Taraxacum officinale also inhibited the production of inflammatory cytokines TNF-alpha and IL-6 in the BALF at 6h after LPS challenge in a dose-dependent manner. These results suggest that Taraxacum officinale protects against LPS-induced ALI in mice. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Prunella vulgaris extract and rosmarinic acid suppress lipopolysaccharide-induced alteration in human gingival fibroblasts.

    PubMed

    Zdarilová, A; Svobodová, A; Simánek, V; Ulrichová, J

    2009-04-01

    Periodontitis is a chronic disease associated with inflammation of the tooth-supporting tissues. The inflammation is initiated by a group of gram-negative anaerobic bacteria. These express a number of irritating factors including a lipopolysaccharide (LPS), which plays a key role in periodontal disease development. Plant extracts with anti-inflammatory and anti-microbial properties have been shown to inhibit bacterial plaque formation and thus prevent chronic gingivitis. In this study we tested effects of Prunella vulgaris L. extract (PVE; 5, 10, 25microg/ml) and its component rosmarinic acid (RA; 1microg/ml) on LPS-induced oxidative damage and inflammation in human gingival fibroblasts. PVE and RA reduced reactive oxygen species (ROS) production, intracellular glutathione (GSH) depletion as well as lipid peroxidation in LPS-treated cells. Treatment with PVE and RA also inhibited LPS-induced up-regulation of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and suppressed expression of inducible nitric oxide synthase (iNOS). The results indicate that PVE and RA are able to suppress LPS-induced biological changes in gingival fibroblasts. The effects of PVE and RA are presumably linked to their anti-inflammatory activities and thus use of PVE and RA may be relevant in modulating the inflammation process, including periodontal disease.

  15. Cross-linked bromelain inhibits lipopolysaccharide-induced cytokine production involving cellular signaling suppression in rats.

    PubMed

    Hou, Rolis Chien-Wei; Chen, Yuh-Shuen; Huang, Jing-Rong; Jeng, Kee-Ching G

    2006-03-22

    Bromelain has been reported to have anti-inflammatory and immunomodulatory effects. It has been cross-linked with organic acids and polysaccharides by gamma irradiation. The cross-linked (CL)-bromelain preparation resisted an acidic environment of pH 3 for 2 h and preserved 80% of its enzyme activity. Pretreatment of rats with CL-bromelain intragastrically for 7 days significantly reduced serum cytokine production induced by injected i.p. with 2.5 mg/kg of lipopolysaccharide (LPS). Bromelain significantly reduced serum glutamate-oxalacetate transaminase induced by LPS. The anti-inflammatory effect of CL-bromelain was correlated with reduced LPS-induced NF-kappaB activity and cyclooxygenase 2 (COX-2) mRNA expression in rat livers. In addition, CL-bromelain dose-dependently inhibited LPS-induced COX-2 mRNA and prostaglandin E2 (PGE2) in BV-2 microglial cells. CL-Bromelain also suppressed the LPS-activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). In conclusion, the anti-inflammatory effects of the CL-bromelain preparation in vivo and in vitro suggest its therapeutic potentials.

  16. Astragalus mongholicus polysaccharide inhibits lipopolysaccharide-induced production of TNF-alpha and interleukin-8.

    PubMed

    Yuan, Yuan; Sun, Mei; Li, Ke-Shen

    2009-08-07

    To explore the effect of Astragalus mongholicus polysaccharide (APS) on gene expression and mitogen-activated protein kinase (MAPK) transcriptional activity in intestinal epithelial cells (IEC). IEC were divided into control group, lipopolysaccharide (LPS) group, LPS+ 50 microg/mL APS group, LPS+ 100 microg/mL APS group, LPS+ 200 microg/mL APS group, and LPS+ 500 microg/mL APS group. Levels of mRNAs in LPS-induced inflammatory factors, tumor necrosis factor (TNF)-alpha and interleukin (IL)-8, were measured by reverse transcription-polymerase chain reaction. MAPK protein level was measured by Western blotting. The levels of TNF-alpha and IL-8 mRNAs were significantly higher in IEC with LPS-induced damage than in control cells. APS significantly abrogated the LPS-induced expression of the TNF-alpha and IL-8 genes. APS did not block the activation of extracellular signal-regulated kinase or c Jun amino-terminal kinase, but inhibited the activation of p38, suggesting that APS inhibits LPS-induced production of TNF-alpha and IL-8 mRNAs, possibly by suppressing the p38 signaling pathway. APS-modulated bacterial product-mediated p38 signaling represents an attractive strategy for prevention and treatment of intestinal inflammation.

  17. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium

    PubMed Central

    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-01-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4+ T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses. PMID:21631497

  18. Hypertonic saline reduces lipopolysaccharide-induced mouse brain edema through inhibiting aquaporin 4 expression

    PubMed Central

    2012-01-01

    Introduction Three percent sodium chloride (NaCl) treatment has been shown to reduce brain edema and inhibited brain aquaporin 4 (AQP4) expression in bacterial meningitis induced by Escherichia coli. Lipopolysaccharide (LPS) is the main pathogenic component of E. coli. We aimed to explore the effect of 3% NaCl in mouse brain edema induced by LPS, as well as to elucidate the potential mechanisms of action. Methods Three percent NaCl was used to treat cerebral edema induced by LPS in mice in vivo. Brain water content, IL-1β, TNFα, immunoglobulin G (IgG), AQP4 mRNA and protein were measured in brain tissues. IL-1β, 3% NaCl and calphostin C (a specific inhibitor of protein kinase C) were used to treat the primary astrocytes in vitro. AQP4 mRNA and protein were measured in astrocytes. Differences in various groups were determined by one-way analysis of variance. Results Three percent NaCl attenuated the increase of brain water content, IL-1β, TNFα, IgG, AQP4 mRNA and protein in brain tissues induced by LPS. Three percent NaCl inhibited the increase of AQP4 mRNA and protein in astrocytes induced by IL-1β in vitro. Calphostin C blocked the decrease of AQP4 mRNA and protein in astrocytes induced by 3% NaCl in vitro. Conclusions Osmotherapy with 3% NaCl ameliorated LPS-induced cerebral edema in vivo. In addition to its osmotic force, 3% NaCl exerted anti-edema effects possibly through down-regulating the expression of proinflammatory cytokines (IL-1β and TNFα) and inhibiting the expression of AQP4 induced by proinflammatory cytokines. Three percent NaCl attenuated the expression of AQP4 through activation of protein kinase C in astrocytes. PMID:23036239

  19. Soyasaponin Ab inhibits lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Lin, Jing; Cheng, Yanwen; Wang, Tao; Tang, Lihua; Sun, Yan; Lu, Xiuyun; Yu, Huimin

    2016-01-01

    Soyasaponin Ab (SA) has been reported to have anti-inflammatory effect. However, the effects of SA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. The aim of this study was to investigate the anti-inflammatory effects of SA on LPS-induced ALI and clarify the possible mechanism. The mice were stimulated with LPS to induce ALI. SA was given 1h after LPS treatment. 12h later, lung tissues were collected to assess pathological changes and edema. Bronchoalveolar lavage fluid (BALF) was collected to assess inflammatory cytokines and nitric oxide (NO) production. In vitro, mice alveolar macrophages were used to investigate the anti-inflammatory mechanism of SA. Our results showed that SA attenuated LPS-induced lung pathological changes, edema, the expression of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in lung tissues, as well as TNF-α, IL-6, IL-1β, and NO production in mice. Meanwhile, SA up-regulated the activities of superoxide dismutase (SOD) and catalase decreased by LPS in mice. SA also inhibited LPS-induced TNF-α, IL-6 and IL-1β production as well as NF-κB activation in alveolar macrophages. Furthermore, SA could activate Liver X Receptor Alpha (LXRα) and knockdown of LXRα by RNAi abrogated the anti-inflammatory effects of SA. In conclusion, the current study demonstrated that SA exhibited protective effects against LPS-induced acute lung injury and the possible mechanism was involved in activating LXRα, thereby inhibiting LPS-induced inflammatory response. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

    PubMed Central

    Shirozu, Kazuhiro; Tokuda, Kentaro; Marutani, Eizo; Lefer, David; Wang, Rui

    2014-01-01

    Abstract Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms. Antioxid. Redox Signal. 20, 204

  1. Cystathionine γ-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure.

    PubMed

    Shirozu, Kazuhiro; Tokuda, Kentaro; Marutani, Eizo; Lefer, David; Wang, Rui; Ichinose, Fumito

    2014-01-10

    Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms.

  2. Copper sulfate pentahydrate reduced epithelial cytotoxicity induced by lipopolysaccharide from enterogenic bacteria.

    PubMed

    Feyzi, Adel; Delkhosh, Aref; Nasrabadi, Hamid Tayefi; Cheraghi, Omid; Khakpour, Mansour; Barekati-Mowahed, Mazyar; Soltani, Sina; Mohammadi, Seyede Momeneh; Kazemi, Masoumeh; Hassanpour, Mehdi; Rezabakhsh, Aysa; Maleki-Dizaji, Nasrin; Rahbarghazi, Reza; Namdarian, Reza

    2017-05-01

    The over usage of multiple antibiotics contributes to the emergence of a whole range of antibiotic-resistant strains of bacteria causing enterogenic infections in poultry science. Therefore, finding an appropriate alternative natural substance carrying an antibacterial capacity would be immensely beneficial. It has been previously discovered that the different types of cupric salts, especially copper sulfate pentahydrate (CuSO4·5H2O), to carry a potent bactericidal capacity. We investigated the neutralizing effect of CuSO4·5H2O (6.25μg/ml) on the reactive oxygen species generation, and expression of MyD88, an essential adaptor protein of Toll-like receptor, and NF-κB in three intestinal epithelial cell lines exposed to 50ng/ml lipopolysaccharide. In order to find the optimal cupric sulfate concentration without enteritis-inducing toxicity, broiler chickens were initially fed with water containing 0.4, 0.5, and 1mg/l during a period of 4days. After determination of appropriate dosage, two broiler chickens and turkey flocks with enteritis were fed with cupric compound for 4days. We found that cupric sulfate can lessen the cytotoxic effect of lipopolysaccharide by reducing the reactive oxygen species content (p<0.05). Additionally, the expression of MyD88 and NF-κB was remarkably down-regulated in the presence of lipopolysaccharide and cupric sulfate. The copper sulfate in doses lower than 0.4mg/ml expressed no cytotoxic effect on the liver, kidney, and the intestinal tract while a concentration of 0.5 and 1mg/ml contributed to a moderate to severe tissue injuries. Pearson Chi-Square analysis revealed the copper cation significantly diminished the rate of mortality during 4-day feeding of broiler chicken and turkey with enteritis (p=0.000). Thus, the results briefed above all confirm the potent anti-bactericidal feature of cupric sulfate during the course of enteritis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Estradiol-mediated increases in the anorexia induced by intraperitoneal injection of bacterial lipopolysaccharide in female rats.

    PubMed

    Geary, Nori; Asarian, Lori; Sheahan, James; Langhans, Wolfgang

    2004-09-15

    Lipopolysaccharide (LPS) derived from the cell walls of gram-negative bacteria causes a robust acute phase response (APR) that includes fever, anorexia, and many other elements. Because immune system function, including some models of illness anorexia, is sexually differentiated, we investigated the sexual differentiation of the anorexia induced by intraperitoneal LPS injections in rats. Cycling female Long-Evans rats tested either during diestrus or estrus ate less following 6.25 microg/kg LPS than did intact males. Following 12.5 microg/kg LPS, females in estrus ate less than either females during diestrus or males. Similarly, a more pronounced anorexia occurred following 12.5, 25, and 50 microg/kg LPS in ovariectomized females that received cyclic estradiol treatment and were tested on the day modeling estrus than in untreated ovariectomized rats. LPS also increased the length of the rats' ovarian cycles, usually by a day, especially when injected during diestrus. As in male rats, when LPS injections were repeated in the same rats, both estradiol-treated and untreated rats failed to display any significant anorexia. The inhibitory effects of LPS on eating in intact and ovariectomized rats were expressed solely as decreases in spontaneous meal frequency, without significant alteration of spontaneous meal size. These data indicate that anorexia following peripheral LPS administration is sexually differentiated and that estradiol is sufficient to produce this response. The mechanism of the pathophysiological effect of estradiol on meal frequency appears to be different from the physiological effect of estradiol on food intake because the latter is expressed solely as a change in meal size.

  4. Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia: effect on NF-кB activation and cytokine production.

    PubMed

    Zucoloto, Amanda Z; Manchope, Marília F; Staurengo-Ferrari, Larissa; Pinho-Ribeiro, Felipe A; Zarpelon, Ana C; Saraiva, André L L; Cecílio, Nerry Tatiana; Alves-Filho, José C; Cunha, Thiago M; Menezes, Gustavo B; Cunha, Fernando Q; Casagrande, Rubia; Verri, Waldiceu A

    2017-08-15

    Probucol 4,4'- (Isopropylidenedithio)bis(2,6-di-tert-butylphenol) is a synthetic molecule clinically used for prevention and treatment of hypercholesterolemia and atherosclerosis. Recent studies have shown that the beneficial effects of probucol mainly derive from its anti-inflammatory and antioxidant properties. Gram-negative bacteria are common infectious agents and their wall components, e.g. lipopolysaccharide (LPS), are important elicitors of inflammation. LPS is sensed by tissue resident cells and it triggers a Toll-like receptor 4/MyD88-dependent signaling cascade resulting in endothelial activation, leukocyte recruitment and nociception. Therefore the present study aimed to investigate the anti-inflammatory and analgesic effects of probucol in models of LPS-induced acute inflammation. Probucol at 0.3-30mg/kg was administrated to male Swiss mice per oral 1h before intraplantar or intraperitoneal lipopolysaccharide stimulus. Probucol at 3mg/kg reduced lipopolysaccharide-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx and cytokine production in both paw skin and peritoneum exudate. Unexpectedly, probucol did not alter lipopolysaccharide-induced tissue oxidative stress at anti-inflammatory /analgesic dose. On the other hand, probucol inhibited lipopolysaccharide-induced nuclear factor kappa B (NF-кB) activation in paw tissue as well as NF-кB activity in cultured macrophages in vitro, reinforcing the inhibitory effect of probucol over the NF-кB signaling pathway. In this sense, we propose that probucol acts on resident immune cells, such as macrophages, targeting the NF-кB pathway. As a result, it prevents the amplification and persistence of the inflammatory response by attenuating NF-кB-dependent cytokine production and leukocyte recruitment explaining its analgesic effects as well. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Fluctuations in central and peripheral temperatures induced by intravenous nicotine: central and peripheral contributions

    PubMed Central

    Tang, Jeremy; Kiyatkin, Eugene A.

    2011-01-01

    Nicotine (NIC) is a highly addictive substance that interacts with different subtypes of nicotinic acetylcholine receptors widely distributed in the central and peripheral nervous systems. While the direct action of NIC on central neurons appears to be essential for its reinforcing properties, the role of peripheral actions of this drug remains a matter of controversy. In this study, we examined changes in locomotor activity and temperature fluctuations in the brain (nucleus accumbens and ventral tegmental area), temporal muscle, and skin induced by intravenous (iv) NIC at low human-relevant doses (10 and 30 μg/kg) in freely moving rats. These effects were compared to those induced by social interaction, an arousing procedure that induces behavioral activation and temperature responses via pure neural mechanism procedure, and iv injections of a peripherally acting NIC analogue, NIC pyrrolidine methiodide (NIC-PM) used at equimolar doses. We found that NIC at 30 μg/kg induces a modest locomotor activation, rapid and strong decrease in skin temperature, and weak increases in brain and muscle temperature. While these effects were qualitatively similar to those induced by social interaction, they were much weaker and showed a tendency to increase with repeated drug administrations. In contrast, NIC-PM did not affect locomotion and induced much weaker than NIC increases in brain and muscle temperatures and decreases in skin temperature; these effects showed a tendency to be weaker with repeated drug administrations. Our data indicate that NIC's actions in the brain are essential to induce locomotor activation and brain and body hyperthermic responses. However, rapid peripheral action of NIC on sensory afferents could be an important factor in triggering its central effects, contributing to neural and physiological activation following repeated drug use. PMID:21295014

  6. Pharmacologic studies on ET-26 hydrochloride in a rat model of lipopolysaccharide-induced sepsis.

    PubMed

    Wang, Bin; Jiang, Junli; Yang, Jun; Chen, Jun; Zhu, Zhaoqiong; Liu, Jin; Zhang, Wensheng

    2017-09-04

    ET-26 hydrochloride (ET-26 HCl) is a promising sedation-hypnotic compound with stable hemodynamic features that elicits virtually no adrenocortical suppression. However, whether it preserves better pharmacologic characteristics in a rat model of sepsis is not known. This study compared the survival rate, levels of corticosterone and pro-inflammatory cytokines, and histologic injury in the lungs and kidneys of rats suffering from sepsis treated with ET-26 HCl, etomidate, or normal saline (NS). Rats were given lipopolysaccharide (1mg/kg body weight, i.v.) to establish a sepsis model. Thirty minutes after lipopolysaccharide administration, ET-26 HCl, etomidate or NS were given as a bolus injection at equivalent doses. Plasma levels of corticosterone, interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α were measured 1, 2, 4, 6 and 24h after administration. Histologic injury was observed at the time of death or 24h after drug administration. The survival rate for rats in the etomidate, ET-26 HCl and NS groups was 40%, 90% and 90%, respectively. Corticosterone concentrations in the etomidate group were lower than those in the other groups 1h after administration of hypnotic compounds. Concentrations of pro-inflammatory cytokines in the ET-26 HCl group and NS group were not significantly different, but were significantly lower than those in the etomidate group. The injury scores of kidneys and lungs in the etomidate group were higher than those in ET-26 HCl and NS groups. ET-26 HCl showed virtually no suppression of corticosterone synthesis, lower concentrations of pro-inflammatory cytokines, higher survival rate, and less organ injury in rats suffering from sepsis compared with the etomidate group. It may be safer to induce anesthesia using ET-26 HCl, rather than etomidate, in patients suffering from sepsis. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Neutrophil extracellular traps induce IL-1β production by macrophages in combination with lipopolysaccharide

    PubMed Central

    Hu, Zhongshuang; Murakami, Taisuke; Tamura, Hiroshi; Reich, Johannes; Kuwahara-Arai, Kyoko; Iba, Toshiaki; Tabe, Yoko; Nagaoka, Isao

    2017-01-01

    Upon exposure to invading microorganisms, neutrophils undergo NETosis, a recently identified type of programmed cell death, and release neutrophil extracellular traps (NETs). NETs are described as an antimicrobial mechanism, based on the fact that NETs can trap microorganisms and exhibit bactericidal activity through the action of NET-associated components. In contrast, the components of NETs have been recognized as damage-associated molecular pattern molecules (DAMPs), which trigger inflammatory signals to induce cell death, inflammation and organ failure. In the present study, to clarify the effect of NETs on cytokine production by macrophages, mouse macrophage-like J774 cells were treated with NETs in combination with lipopolysaccharide (LPS) as a constituent of pathogen-associated molecular patterns. The results revealed that NETs significantly induced the production of interleukin (IL)-1β by J774 cells in the presence of LPS. Notably, the NET/LPS-induced IL-1β production was inhibited by both caspase-1 and caspase-8 inhibitors. Furthermore, nucleases and serine protease inhibitors but not anti-histone antibodies significantly inhibited the NET/LPS-induced IL-1β production. Moreover, we confirmed that caspase-1 and caspase-8 were activated by NETs/LPS, and the combination of LPS, DNA and neutrophil elastase induced IL-1β production in reconstitution experiments. These observations indicate that NETs induce the production of IL-1β by J774 macrophages in combination with LPS via the caspase-1 and caspase-8 pathways, and NET-associated DNA and serine proteases are involved in NET/LPS-induced IL-1β production as essential components. PMID:28204821

  8. The Role of IL-17 in a Lipopolysaccharide-Induced Rhinitis Model

    PubMed Central

    Bae, Jun-Sang; Kim, Ji-Hye; Kim, Eun Hee

    2017-01-01

    Purpose Lipopolysaccharide (LPS) is a cell wall component of Gram-negative bacteria and important for pro-inflammatory mediators. This study aimed to establish a rhinitis model using ovalbumin (OVA) and LPS in order to evaluate the role of interleukin (IL)-17 in the pathogenesis of an LPS-induced non-eosionophilic rhinitis model. Methods Mice were divided into 4 groups and each group consisted of 10 mice (negative control group, allergic rhinitis model group, 1-µg LPS treatment group, and 10-µg LPS treatment group). BALB/c mice were sensitized with OVA and 1 or 10 µg of LPS, and challenged intranasally with OVA. Multiple parameters of rhinitis were also evaluated to establish the LPS-induced rhinitis model. IL-17 knockout mice were used to check if the LPS-induced rhinitis model were dependent on IL-17. Eosinophil and neutrophil infiltration, and mRNA and protein expression profiles of cytokine in nasal mucosa or spleen cell culture were evaluated using molecular, biochemical, histopathological, and immunohistological methods. Results In the LPS-induced rhinitis model, neutrophil infiltration increased in the nasal mucosa, and systemic and nasal IL-17 and interferon-gamma (IFN-γ) levels also increased as compared with the OVA-induced allergic rhinitis model. These findings were LPS-dose-dependent. In IL-17 knockout mice, those phenotypes (neutrophil infiltration, IL-17, and IFN-γ) were reversed, showing IL-17 dependency of LPS-induced rhinitis. The expression of vascular endothelial growth factor (VEGF), an important mediator for inflammation and angiogenesis, decreased in IL-17 knockout mice, showing the relationship between IL-17 and VEGF. Conclusions This study established an LPS-induced rhinitis model dependent on IL-17, characterized by neutrophil infiltration and increased expression of IL-17. PMID:28102062

  9. A Fermented Whole Grain Prevents Lipopolysaccharides-Induced Dysfunction in Human Endothelial Progenitor Cells

    PubMed Central

    Gabriele, Morena; Del Prato, Stefano; Pucci, Laura

    2017-01-01

    Endogenous and exogenous signals derived by the gut microbiota such as lipopolysaccharides (LPS) orchestrate inflammatory responses contributing to development of the endothelial dysfunction associated with atherosclerosis in obesity, metabolic syndrome, and diabetes. Endothelial progenitor cells (EPCs), bone marrow derived stem cells, promote recovery of damaged endothelium playing a pivotal role in cardiovascular repair. Since healthy nutrition improves EPCs functions, we evaluated the effect of a fermented grain, Lisosan G (LG), on early EPCs exposed to LPS. The potential protective effect of LG against LPS-induced alterations was evaluated as cell viability, adhesiveness, ROS production, gene expression, and NF-kB signaling pathway activation. Our results showed that LPS treatment did not affect EPCs viability and adhesiveness but induced endothelial alterations via activation of NF-kB signaling. LG protects EPCs from inflammation as well as from LPS-induced oxidative and endoplasmic reticulum (ER) stress reducing ROS levels, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defense. Moreover, LG pretreatment prevented NF-kB translocation from the cytoplasm into the nucleus caused by LPS exposure. In human EPCs, LPS increases ROS and upregulates proinflammatory tone, proapoptotic factors, and antioxidants. LG protects EPCs exposed to LPS reducing ROS, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defenses possibly by inhibiting NF-κB nuclear translocation. PMID:28386305

  10. Establishment of hydrochloric acid/lipopolysaccharide-induced pelvic inflammatory disease model

    PubMed Central

    Oh, Yeonsu; Lee, Jaehun; Kim, Hyeon-Cheol; Hahn, Tae-Wook; Yoon, Byung-Il; Han, Jeong-Hee; Kwon, Yong-Soo; Park, Joung Jun; Koo, Deog-Bon; Rhee, Ki-Jong

    2016-01-01

    Pelvic inflammatory disease (PID), which is one of the most problematic complications experienced by women with sexually transmitted diseases, frequently causes secondary infections after reproductive abnormalities in veterinary animals. Although the uterus is self-protective, it becomes fragile during periods or pregnancy. To investigate PID, bacteria or lipopolysaccharide (LPS) extracted from gram negative bacteria has been used to induce the disease in several animal models. However, when LPS is applied to the peritoneum, it often causes systemic sepsis leading to death and the PID was not consistently demonstrated. Hydrochloric acid (HCl) has been used to induce inflammation in the lungs and stomach but not tested for reproductive organs. In this study, we developed a PID model in mice by HCl and LPS sequential intracervical (i.c.) administration. The proinflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, were detected in the mouse uterus by western blot analysis and cytokine enzyme-linked immunosorbent assay after HCl (25 mg/kg) administration i.c. followed by four LPS (50 mg/kg) treatments. Moreover, mice exhibited increased infiltration of neutrophils in the endometrium and epithelial layer. These results suggest that ic co-administration of HCl and LPS induces PID in mice. This new model may provide a consistent and reproducible PID model for future research. PMID:26726020

  11. Static magnetic field attenuates lipopolysaccharide-induced multiple organ failure: a histopathologic study in mice.

    PubMed

    Lai, Wei-Yi; Huang, Yu-Chih; Chang, Wei-Jen; Wang, Hsin-Ta; Fong, Tsorng-Harn; Lin, Che-Tong; Huang, Haw-Ming

    2015-02-01

    Previous studies demonstrated that static magnetic fields (SMF) were effective in down-regulating the expression of lipopolysaccharide (LPS)-induced inflammatory cytokines. The aim of this study was to provide histological evidence of SMF attenuating LPS-induced multiple organ failure (MOF). In this study, BALB/cByJNarl (5 weeks, weighing 20-25 g) mice were chosen as test subjects. The tested animals were challenged with 50 mg/kg LPS after they were exposed to a continuous SMF for 2 h. The survival rate and pathological changes in lungs, kidneys, and livers of the LPS- challenged mice were examined with and without SMF treatment. In addition, the effects of SMF exposure on body temperature control of the LPS-challenged mice were monitored. Our results showed that at 30 h the survival rate of LPS-challenged mice increased 3.6-fold (p < 0.05). In addition, 6 h after LPS injection, the average body temperature of SMF-exposed mice was 1.07°C lower than that of unexposed animals. Tissue biopsies demonstrated that SMF exposure reduced damage to the lungs, livers, and kidneys in the LPS-challenged mice. SMF show potential as a viable prophylactic alternative for controlling LPS-induced MOF.

  12. Static Magnetic Field Attenuates Lipopolysaccharide-Induced Inflammation in Pulp Cells by Affecting Cell Membrane Stability

    PubMed Central

    Tsao, Jeng-Ting; Lee, Lin-Wen; Lin, Che-Tong

    2015-01-01

    One of the causes of dental pulpitis is lipopolysaccharide- (LPS-) induced inflammatory response. Following pulp tissue inflammation, odontoblasts, dental pulp cells (DPCs), and dental pulp stem cells (DPSCs) will activate and repair damaged tissue to maintain homeostasis. However, when LPS infection is too serious, dental repair is impossible and disease may progress to irreversible pulpitis. Therefore, the aim of this study was to examine whether static magnetic field (SMF) can attenuate inflammatory response of dental pulp cells challenged with LPS. In methodology, dental pulp cells were isolated from extracted teeth. The population of DPSCs in the cultured DPCs was identified by phenotypes and multilineage differentiation. The effects of 0.4 T SMF on DPCs were observed through MTT assay and fluorescent anisotropy assay. Our results showed that the SMF exposure had no effect on surface markers or multilineage differentiation capability. However, SMF exposure increases cell viability by 15%. In addition, SMF increased cell membrane rigidity which is directly related to higher fluorescent anisotropy. In the LPS-challenged condition, DPCs treated with SMF demonstrated a higher tolerance to LPS-induced inflammatory response when compared to untreated controls. According to these results, we suggest that 0.4 T SMF attenuates LPS-induced inflammatory response to DPCs by changing cell membrane stability. PMID:25884030

  13. Escin inhibits lipopolysaccharide-induced inflammation in human periodontal ligament cells.

    PubMed

    Liu, Shutai; Wang, Huaizhou; Qiu, Caiqing; Zhang, Jing; Zhang, Taowen; Zhou, Wenjuan; Lu, Zhishan; Rausch-Fan, Xiaohui; Liu, Zhonghao

    2012-11-01

    Periodontitis is a chronic inflammatory disease associated with gram-negative subgingival microflora infection. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and anti-edematous effects. This study was designed to investigate the in vitro effects of escin on the inflammatory reaction of human periodontal ligament cells (hPDLs). hPDLs were stimulated with lipopolysaccharide (LPS). The cells were treated with various concentrations of escin. The viability of hPDLs was evaluated using the MTT method. The expression of Toll-like receptor 2 (TLR2) in hPDLs and the levels of IL-1β, TNF-α and IL-6 in the supernatant were measured. Escin significantly attenuated LPS-induced cytotoxicity in a concentration-dependent manner in hPDLs. Treatment with escin partly blocked the expression of TLR2. Escin also lowered the increase of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) induced by LPS. The present findings show that escin exerts a protective effect against LPS-induced inflammation in hPDLs. It was also shown that escin is a promising medicine for the treatment of periodontitis.

  14. A Fermented Whole Grain Prevents Lipopolysaccharides-Induced Dysfunction in Human Endothelial Progenitor Cells.

    PubMed

    Giusti, Laura; Gabriele, Morena; Penno, Giuseppe; Garofolo, Monia; Longo, Vincenzo; Del Prato, Stefano; Lucchesi, Daniela; Pucci, Laura

    2017-01-01

    Endogenous and exogenous signals derived by the gut microbiota such as lipopolysaccharides (LPS) orchestrate inflammatory responses contributing to development of the endothelial dysfunction associated with atherosclerosis in obesity, metabolic syndrome, and diabetes. Endothelial progenitor cells (EPCs), bone marrow derived stem cells, promote recovery of damaged endothelium playing a pivotal role in cardiovascular repair. Since healthy nutrition improves EPCs functions, we evaluated the effect of a fermented grain, Lisosan G (LG), on early EPCs exposed to LPS. The potential protective effect of LG against LPS-induced alterations was evaluated as cell viability, adhesiveness, ROS production, gene expression, and NF-kB signaling pathway activation. Our results showed that LPS treatment did not affect EPCs viability and adhesiveness but induced endothelial alterations via activation of NF-kB signaling. LG protects EPCs from inflammation as well as from LPS-induced oxidative and endoplasmic reticulum (ER) stress reducing ROS levels, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defense. Moreover, LG pretreatment prevented NF-kB translocation from the cytoplasm into the nucleus caused by LPS exposure. In human EPCs, LPS increases ROS and upregulates proinflammatory tone, proapoptotic factors, and antioxidants. LG protects EPCs exposed to LPS reducing ROS, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defenses possibly by inhibiting NF-κB nuclear translocation.

  15. Suppression of lipopolysaccharide and galactosamine-induced hepatic inflammation by red grape pomace.

    PubMed

    Nishiumi, Shin; Mukai, Rie; Ichiyanagi, Takashi; Ashida, Hitoshi

    2012-09-12

    Grape pomace is generated in the production process of wine and grape juices and is an industrial waste. This study investigated whether an intake of grape pomace was able to suppress chronic inflammation induced by lipopolysaccharide (LPS) and galactosamine (GalN) in vivo. When Sprague-Dawley rats were orally given methanolic extracts from red and white grape pomace, the extracts inhibited the LPS/GalN-evoked activation of nuclear factor-κB (NF-κB) dose-dependently, and red grape pomace exerted a stronger effect than white grape one. Next, rats were fed an AIN93 M-based diet containing 5% red grape pomace for 7 days, followed by the intraperitoneal injection of LPS and GalN. The intake of the red grape pomace-supplemented diet was found to suppress the LPS/GalN-induced activation of NF-κB and expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. These results suggest that red grape pomace may contain an abundance of effective compound(s) for anti-inflammatory action.

  16. Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice.

    PubMed

    Zhao, Lei; Chen, Yuan-Hua; Wang, Hua; Ji, Yan-Li; Ning, Huan; Wang, Su-Fang; Zhang, Cheng; Lu, Jin-Wei; Duan, Zi-Hao; Xu, De-Xiang

    2008-05-01

    Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, fetal death and growth retardation, and preterm delivery. In the present study, we showed that an ip injection with LPS daily from gestational day (gd) 8 to gd 12 resulted in the incidence of external malformations. The highest incidence of malformed fetuses was observed in fetuses from dams exposed to 20 microg/kg LPS, in which 34.9% of fetuses per litter were externally malformed. In addition, 17.4% of fetuses per litter in 30 microg/kg group and 12.5% of fetuses per litter in 10 microg/kg group were externally malformed. Importantly, external malformations were also observed in fetuses from dams exposed to only two doses of LPS (20 microg/kg, ip) on gd 8, in which 76.5% (13/17) of litters and 39.1% of fetuses per litter were affected. LPS-induced teratogenicity seemed to be associated with oxidative stress in fetal environment, measured by lipid peroxidation, nitrotyrosine residues, and glutathione (GSH) depletion in maternal liver, embryo, and placenta. alpha-Phenyl-N-t-butylnitrone (PBN, 100 mg/kg, ip), a free radical spin-trapping agent, abolished LPS-induced lipid peroxidation, nitrotyrosine residues, and GSH depletion. Consistent with its antioxidant effects, PBN decreased the incidence of external malformations. Taken together, these results suggest that reactive oxygen species might be, at least partially, involved in LPS-induced teratogenesis.

  17. Lipopolysaccharide-Induced Spatial Memory and Synaptic Plasticity Impairment Is Preventable by Captopril

    PubMed Central

    Abareshi, Azam; Anaeigoudari, Akbar; Norouzi, Fatemeh; Shafei, Mohammad Naser; Khazaei, Majid

    2016-01-01

    Introduction. Renin-angiotensin system has a role in inflammation and also is involved in many brain functions such as learning, memory, and emotion. Neuroimmune factors have been proposed as the contributors to the pathogenesis of memory impairments. In the present study, the effect of captopril on spatial memory and synaptic plasticity impairments induced by lipopolysaccharide (LPS) was investigated. Methods. The rats were divided and treated into control (saline), LPS (1 mg/kg), LPS-captopril (LPS-Capto; 50 mg/kg captopril before LPS), and captopril groups (50 mg/kg) before saline. Morris water maze was done. Long-term potentiation (LTP) from CA1 area of hippocampus was assessed by 100 Hz stimulation in the ipsilateral Schaffer collateral pathway. Results. In the LPS group, the spent time and traveled path to reach the platform were longer than those in the control, while, in the LPS-Capto group, they were shorter than those in the LPS group. Moreover, the slope and amplitude of field excitatory postsynaptic potential (fEPSP) decreased in the LPS group, as compared to the control group, whereas, in the LPS-Capto group, they increased compared to the LPS group. Conclusion. The results of the present study showed that captopril improved the LPS-induced memory and LTP impairments induced by LPS in rats. Further investigations are required in order to better understand the exact responsible mechanism(s). PMID:27830176

  18. Methyl palmitate attenuates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Kalemci, S; Zeybek, A; Intepe, Y S; Uner, A G; Acar, T; Yaylali, A; Aksun, S; Can, C; Gulaydin, A; Sütçü, R

    2013-01-01

    The study is aimed to determine the beneficial effects of methyl palmitate (MP) which has antioxidant and anti-inflammatory effects demonstrated on murine model of acute lung injury induced by lipopolysaccharide (LPS). Forty male BALB/C mice were randomly allocated into four groups (n=10, each): control group, methyl palmitate group (300 mg/kg), LPS group, and methyl palmitate -treated groups. Methyl palmitate or vehicle was given with an intraperitoneal administration 1 h before an intratracheal instillation of LPS (5 mg/kg). The severity of pulmonary injury was evaluated 6 h after LPS challenge. All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the Adnan Menderes University. Methyl palmitate pretreatment significantly attenuated LPS-induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. Methyl palmitate pretreatment also reduced the concentrations of malondialdehyde in lung tissues. This study indicates that methyl palmitate may have a protective effect against LPS-induced acute lung injury, and the potential mechanism of this action may involve the inhibition of NF-κB. activation.

  19. Vitamin C suppresses lipopolysaccharide-induced procoagulant response of human monocyte-derived macrophages.

    PubMed

    Parahuleva, M S; Jung, J; Burgazli, M; Erdogan, A; Parviz, B; Hölschermann, H

    2016-05-01

    Although vitamin C is a strong antioxidant, the epidemiologic evidence to support its role in lowering risk of cardiovascular disease is inconsistent. In order to define the role of vitamin C in vascular pathophysiology, we have investigated the effect of vitamin C on the tissue factor (TF) and Factor VII Activating Protease (FSAP) expression induced by lipopolysaccharide (LPS) in human monocyte-derived macrophages. Vitamin C at clinically relevant doses was tested to its ability to influence the LPS- and reactive oxygen species (ROS) - generating system of xanthine/xanthine oxidase (X/XO) NF-kB activity in human monocyte-derived macrophages. Vitamin C-treatment prevents LPS- and ROS-induced DNA-binding activity of NF-kB in a concentration-dependent fashion. Vitamin C also inhibited the phosphorylation and proteolytic degradation of the inhibitor protein IkBa. In parallel to regulate NF-kB activity, vitamin C reduced the expression of TF and FSAP, genes known to be induced by bacterial LPS and triggered the extrinsic coagulation cascade and linked thrombosis with inflammation. Vitamin C alters pro-inflammatory and pro-coagulatory processes via inhibition of NF-kB activation and exerts beneficial antiatherogenic effects on human monocyte-derived macrophages in addition to its anti-oxidant properties.

  20. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    SciTech Connect

    Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2013-07-05

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

  1. Characterization of uveitis induced by use of a single intravitreal injection of bacterial lipopolysaccharide in cats.

    PubMed

    Del Sole, María J; Sande, Pablo H; Felipe, Antonio E; Fernandez, Diego C; Keller Sarmiento, María I; Aba, Marcelo A; Rosenstein, Ruth E

    2008-11-01

    To investigate the use of a single intravitreal injection of bacterial lipopolysaccharide (LPS) to experimentally induce uveitis in cats. 7 young male European shorthair cats that were considered physically and ophthalmologically healthy. In each cat, LPS was injected intravitreally into 1 eye; the contralateral eye was injected with the preparation vehicle. During a period of 45 days, both eyes were evaluated by means of clinical evaluation; assessment of the integrity of the blood-aqueous humor barrier (determined via measurement of protein concentration and cell content in samples of aqueous humor); functional analysis (via electroretinography); and following euthanasia, histologic examination of the retinas. In LPS-treated eyes, several clinical signs were observed until day 45 after injection. Compared with vehicle-treated eyes, intraocular pressure was significantly lower and protein concentration and the number of infiltrating cells were significantly higher in LPS-treated eyes. Mean amplitudes of scotopic electroretinographic a- and b-waves were significantly reduced in eyes injected with LPS, compared with findings in eyes injected with vehicle. At 45 days after injection, LPS-induced alterations in photoreceptors and the middle portion of the retina were detected histologically. Results indicated that a single intravitreal injection of LPS in eyes of cats induced clinical, biochemical, functional, and histologic changes that were consistent with the main features of naturally occurring uveitis. This technique may be a useful tool in the investigation of new treatment strategies for uveitis in cats.

  2. HJP272, a novel endothelin receptor antagonist, attenuates lipopolysaccharide-induced acute lung injury in hamsters.

    PubMed

    Patel, Shikha; Liu, Xingjian; Liu, Ming; Stephani, Ralph; Patel, Hardik; Cantor, Jerome

    2014-10-01

    Previous studies from this laboratory indicate that endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in lipopolysaccharide (LPS)-induced release of neutrophils from the pulmonary microvasculature. To further test this concept, Syrian hamsters were treated with a novel endothelin receptor A (ETA) antagonist (HJP272) prior to intratracheal instillation of LPS. The effect of HJP272 on the LPS-induced inflammatory reaction was determined by measuring: (1) lung histopathological changes, (2) total neutrophils in bronchoalveolar lavage fluid (BALF), (3) expression of tumor necrosis factor receptor 1 (TNFR1) by BALF macrophages, and (4) alveolar septal cell apoptosis. Treatment with HJP272 significantly reduced each of these parameters during a 24-hr period following LPS instillation, supporting the concept that limiting the activity of ET-1 may reduce the extent of lung injury. This hypothesis was further tested by giving ET-1 prior to LPS instillation, which resulted in a marked enhancement of LPS-induced lung inflammation, as measured by BALF neutrophils and TNFR1-positive macrophages. Furthermore, the increase in neutrophils resulting from treatment with ET-1 was significantly reduced by HJP272, again demonstrating the ability of ETA receptor antagonists to limit the influx of these cells into the lung. These findings suggest a potential therapeutic role for these agents in diseases where neutrophils are a significant cause of lung injury, such as bronchopneumonia, respiratory distress syndrome, and chronic obstructive pulmonary disease.

  3. Mycoplasma membrane lipoproteins induced proinflammatory cytokines by a mechanism distinct from that of lipopolysaccharide.

    PubMed Central

    Rawadi, G; Roman-Roman, S

    1996-01-01

    To gain a clear understanding of the mechanisms by which mycoplasmas induced the expression of proinflammatory cytokines in monocytic cells, we have studied the induction of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and IL-6 by mycoplasmas in three distinct human myelomonocytic cell lines in comparison with induction by lipopolysaccharide (LPS). HL-60 cell line did not release cytokines when induced with either LPS or mycoplasmas. In contrast to LPS, mycoplasmas failed to increase the weak levels of tumor necrosis factor alpha secreted by phorbol myristate acetate-differentiated U937 cells. In addition, Northern (RNA) blot analysis of cytokine expression in these cells showed that the induction of IL-1 beta by mycoplasmas involves, unlike that by LPS, posttranscriptional events. Interestingly, in THP-1 cells, cytokine induction pathways triggered by mycoplasmas remained operational under conditions where LPS pathways were abolished, suggesting functional independence. The study of cytokine-inducing activity displayed by distinct fractions derived from a series of different mycoplasma species demonstrated that lipid membrane constituents were largely responsible for these effects. Finally, we have demonstrated that tyrosine phosphorylation is a crucial event in the mycoplasma-mediated induction of proinflammatory cytokines in either THP-1 cells or human monocytes. PMID:8550219

  4. Establishment of hydrochloric acid/lipopolysaccharide-induced pelvic inflammatory disease model.

    PubMed

    Oh, Yeonsu; Lee, Jaehun; Kim, Hyeon-Cheol; Hahn, Tae-Wook; Yoon, Byung-Il; Han, Jeong-Hee; Kwon, Yong-Soo; Park, Joung Jun; Koo, Deog-Bon; Rhee, Ki-Jong; Jung, Bae Dong

    2016-09-30

    Pelvic inflammatory disease (PID), which is one of the most problematic complications experienced by women with sexually transmitted diseases, frequently causes secondary infections after reproductive abnormalities in veterinary animals. Although the uterus is self-protective, it becomes fragile during periods or pregnancy. To investigate PID, bacteria or lipopolysaccharide (LPS) extracted from gram negative bacteria has been used to induce the disease in several animal models. However, when LPS is applied to the peritoneum, it often causes systemic sepsis leading to death and the PID was not consistently demonstrated. Hydrochloric acid (HCl) has been used to induce inflammation in the lungs and stomach but not tested for reproductive organs. In this study, we developed a PID model in mice by HCl and LPS sequential intracervical (i.c.) administration. The proinflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, were detected in the mouse uterus by western blot analysis and cytokine enzyme-linked immunosorbent assay after HCl (25 mg/kg) administration i.c. followed by four LPS (50 mg/kg) treatments. Moreover, mice exhibited increased infiltration of neutrophils in the endometrium and epithelial layer. These results suggest that ic co-administration of HCl and LPS induces PID in mice. This new model may provide a consistent and reproducible PID model for future research.

  5. Dehydroepiandrosterone inhibits lipopolysaccharide-induced nitric oxide production in BV-2 microglia.

    PubMed

    Wang, M J; Huang, H M; Chen, H L; Kuo, J S; Jeng, K C

    2001-05-01

    Levels of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEAS) decline during aging and reach even lower levels in Alzheimer's disease (AD). DHEA is known to exhibit a variety of functional activities in the CNS, including an increase of memory and learning, neurotrophic and neuroprotective effects, and the reduction of risk of age-related neurodegenerative disorders. However, the influence of DHEA on the immune functions of glial cells is poorly understood. In this study, we investigated the effect of DHEA on activated glia. The production of inducible nitric oxide synthase (iNOS) was studied in lipopolysaccharide (LPS)-stimulated BV-2 microglia, as a model of glial activation. The results showed that DHEA but not DHEAS significantly inhibited the production of nitrite in the LPS-stimulated BV-2 cell cultures. Pretreatment of BV-2 cells with DHEA reduced the LPS-induced iNOS mRNA and protein levels in a dose-dependent manner. The LPS-induced iNOS activity in BV-2 cells was decreased by the exposure of 100 microM DHEA. Moreover, DHEA suppressed iNOS gene expression in LPS-stimulated BV-2 cells did not require de novo synthesis of new proteins or destabilize of iNOS mRNA. Since DHEA is biosynthesized by astrocytes and neurons, our findings suggest that it might have an important regulatory function on microglia.

  6. Interleukin-13 Inhibits Lipopolysaccharide-Induced BPIFA1 Expression in Nasal Epithelial Cells

    PubMed Central

    Chen, Hui-Chen; Hsu, Hui-Ying; Wu, Lii-Tzu; Chiang-Ni, Chuan; Chen, Chih-Jung; Wu, Tsu-Fang; Kao, Min-Chuan; Chen, Yu-An; Peng, Ming-Te; Tsai, Ming-Hsui; Chen, Chuan-Mu; Lai, Chih-Ho

    2015-01-01

    Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is expressed in human nasopharyngeal and respiratory epithelium and has demonstrated antimicrobial activity. SPLUNC1 is now referred to as bactericidal/permeability-increasing fold containing family A, member 1 (BPIFA1). Reduced BPIFA1 expression is associated with bacterial colonization in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Interleukin 13 (IL-13), predominately secreted by T helper 2 (TH2) cells, has been found to contribute to airway allergies and suppress BPIFA1 expression in nasal epithelial cells. However, the molecular mechanism of IL-13 perturbation of bacterial infection and BPIFA1 expression in host airways remains unclear. In this study, we found that lipopolysaccharide (LPS)-induced BPIFA1 expression in nasal epithelial cells was mediated through the JNK/c-Jun signaling pathway and AP-1 activation. We further demonstrated that IL-13 downregulated the LPS-induced activation of phosphorylated JNK and c-Jun, followed by attenuation of BPIFA1 expression. Moreover, the immunohistochemical analysis showed that IL-13 prominently suppressed BPIFA1 expression in eosinophilic CRSwNP patients with bacterial infection. Taken together, these results suggest that IL-13 plays a critical role in attenuation of bacteria-induced BPIFA1 expression that may result in eosinophilic CRSwNP. PMID:26646664

  7. Hypoxic preconditioning attenuates lipopolysaccharide-induced oxidative stress in rat kidneys

    PubMed Central

    Yang, Chih-Ching; Ma, Ming-Chieh; Chien, Chiang-Ting; Wu, Ming-Shiou; Sun, Wan-Kuan; Chen, Chau-Fong

    2007-01-01

    Chronic hypoxic (CH) preconditioning reduces superoxide-induced renal dysfunction via the upregulation of superoxide dismutase (SOD) activity and contents. Endotoxaemia reduces renal antioxidant status. We hypothesize that CH preconditioning might protect the kidney from subsequent endotoxaemia-induced oxidative injury. Endotoxaemia was induced by intraperitoneal injection of lipopolysaccharide (LPS; 4 mg kg−1) in rats kept at sea level (SL) and rats with CH in an altitude chamber (5500 m for 15 h day−1) for 4 weeks. LPS enhanced xanthine oxidase (XO) and gp91phox (catalytic subunit of NADPH oxidase) expression associated with burst amount of superoxide production from the SL kidney surface and renal venous blood detected by lucigenin-enhanced chemiluminescence. LPS induced a morphologic-independent renal dysfunction in baseline and acute saline loading stages and increased renal IL-1β protein and urinary protein concentration in the SL rats. After 4 weeks of induction, CH significantly increased Cu/ZnSOD, MnSOD and catalase expression (16 ± 17, 128 ± 35 and 48 ± 21, respectively) in renal cortex, and depressed renal cortex XO (44 ± 16%) and renal cortex (20 ± 9%) and medulla (28 ± 11%) gp91phox when compared with SL rats. The combined effect of enhanced antioxidant proteins and depressed oxidative proteins significantly reduced LPS-enhanced superoxide production, renal XO and gp91phox expression, renal IL-1β production, and urinary protein level. CH also ameliorated LPS-induced renal dysfunction in the baseline and acute saline loading periods. We conclude that CH treatment enhances the intrarenal antioxidant/oxidative protein ratio to overcome endotoxaemia-induced reactive oxygen species formation and inflammatory cytokine release. PMID:17317755

  8. Hypothalamic neuronal histamine modulates febrile response but not anorexia induced by lipopolysaccharide.

    PubMed

    Chiba, Seiichi; Itateyama, Emi; Oka, Kyoko; Masaki, Takayuki; Sakata, Toshiie; Yoshimatsu, Hironobu

    2005-05-01

    This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats. To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.

  9. Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Zhang, Zhi-Hui; Wang, Hua; Zhao, Hui; Yu, De-Xin; Xu, De-Xiang

    2015-12-22

    Vitamin D receptor (VDR) is highly expressed in human and mouse kidneys. Nevertheless, its functions remain obscure. This study investigated the effects of vitamin D3 (VitD3) pretreatment on renal inflammation during lipopolysaccharide (LPS)-induced acute kidney injury. Mice were intraperitoneally injected with LPS. In VitD3 + LPS group, mice were pretreated with VitD3 (25 μg/kg) at 48, 24 and 1 h before LPS injection. As expected, an obvious reduction of renal function and pathological damage was observed in LPS-treated mice. VitD3 pretreatment significantly alleviated LPS-induced reduction of renal function and pathological damage. Moreover, VitD3 pretreatment attenuated LPS-induced renal inflammatory cytokines, chemokines and adhesion molecules. In addition, pretreatment with 1,25(OH)2D3, the active form of VitD3, alleviated LPS-induced up-regulation of inflammatory cytokines and chemokines in human HK-2 cells, a renal tubular epithelial cell line, in a VDR-dependent manner. Further analysis showed that VitD3, which activated renal VDR, specifically repressed LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit in the renal tubules. LPS, which activated renal NF-κB, reciprocally suppressed renal VDR and its target gene. Moreover, VitD3 reinforced the physical interaction between renal VDR and NF-κB p65 subunit. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity during LPS-induced acute kidney injury.

  10. Chemotherapy-induced peripheral neuropathy: Current status and progress.

    PubMed

    Brewer, Jamie R; Morrison, Gladys; Dolan, M Eileen; Fleming, Gini F

    2016-01-01

    As there are increasing numbers of cancer survivors, more attention is being paid to the long term unwanted effects patients may experience as a result of their treatment and the impact these side effects can have on their quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxicities from chemotherapy. In this review we will briefly review the clinical presentation, evaluation and management of chemotherapy-induced peripheral neuropathy, with a focus on CIPN related to platinum and taxane agents. We will then discuss current clinical models of peripheral neuropathy and ongoing research to better understand CIPN and develop potential treatment options. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures

    PubMed Central

    Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-01-01

    Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation. PMID:26729090

  12. Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures.

    PubMed

    Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-12-28

    Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson's disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation.

  13. The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells.

    PubMed

    Han, Chaoqun; Ding, Zhen; Shi, Huiying; Qian, Wei; Hou, Xiaohua; Lin, Rong

    2016-01-01

    Dysfunction of autophagy has been associated with loss of intestinal homeostasis. Lipopolysaccharide (LPS) from Gram-negative bacteria is known to be a major initiator of intestinal epithelial cell (IEC) autophagy. Although probiotics have been recognized to be involved in many therapeutic properties and participate in host defense responses, the molecular mechanisms by which probiotics exert these positive effects remain unknown. This study assessed the effect of probiotics on LPS-induced physical barrier dysfunction and the underlying mechanism of probiotic action in IECs with a focus on autophagy. A LPS-induced autophagic model was established in rat IEC18 cells wherein cells were treated with culture medium supernatants of Bifidobacteria following LPS intervention at indicated times. Autophagosomes in IEC18 cells were visualized by confocal microscopy after transfection with a tandem GFP-mCherry-LC3 construct and also by transmission electron microscopy. Autophagy-associated protein levels were analyzed by western blot and transepithelial electrical resistance (TEER) was measured using an epithelial voltohmmeter. Probiotic treatment could effectively inhibit LPS-induced autophagy, as evidenced by the decreased ratio of microtubule-associated light chain 3 (LC3)-II/LC3-I, fewer autophagic vacuoles, and reduced punctate distribution of GFP-mCherry-LC3. In addition, probiotics prevented chloroquine (CQ) inhibition of autophagic flux and autophagolysosomal fusion as indicated by a failure to recruit LAMP1 and cathepsin D to lysosomes. Interestingly, ATG16L1 knockdown did not inhibit the effect of probiotics on LPS-induced autophagy. Furthermore, the diminished barrier function could be prevented by probiotics. We provide evidence that autophagy mediation by probiotics may be involved in enteroprotection against LPS-induced intestinal epithelial toxicity, and could serve as a novel mechanism through which probiotics promote and maintain gut homeostasis. © 2016 The

  14. Interleukin-1β induces in vivo tolerance to lipopolysaccharide in mice

    PubMed Central

    ALVES-ROSA, F; VULCANO, M; BEIGIER-BOMPADRE, M; FERNÁNDEZ, G; PALERMO, M; ISTURIZ, M A

    2002-01-01

    Endotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent anti-inflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1β (IL-1β) and tumour necrosis factor alpha (TNF-α), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1β were tolerant to LPS-induced shock. However, TNF-α was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1β increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1β that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1β is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1β can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the down-regulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects. PMID:12041508

  15. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

    PubMed Central

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G.; Fan, Lir-Wan

    2011-01-01

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5 mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5 mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for ninety-six hours. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. PMID:21669234

  16. Microgravity inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression in macrophage cells.

    PubMed

    Wang, Chongzhen; Luo, Haiying; Zhu, Linnan; Yang, Fan; Chu, Zhulang; Tian, Hongling; Feng, Meifu; Zhao, Yong; Shang, Peng

    2014-01-01

    Microgravity environments in space can cause major abnormalities in human physiology, including decreased immunity. The underlying mechanisms of microgravity-induced inflammatory defects in macrophages are unclear. RAW264.7 cells and primary mouse macrophages were used in the present study. Lipopolysaccharide (LPS)-induced cytokine expression in mouse macrophages was detected under either simulated microgravity or 1g control. Freshly isolated primary mouse macrophages and RAW264.7 cells were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1g control conditions. The cytokine expression was determined by real-time PCR and ELISA assays. Western blots were used to investigate the related intracellular signals. LPS-induced tumor necrosis factor-α (TNF-α) expression, but not interleukin-1β expression, in mouse macrophages was significantly suppressed under simulated microgravity. The molecular mechanism studies showed that LPS-induced intracellular signal transduction including phosphorylation of IKK and JNK and nuclear translocation of NF-κB in macrophages was identical under normal gravity and simulated microgravity. Furthermore, TNF-α mRNA stability did not decrease under simulated microgravity. Finally, we found that heat shock factor-1 (HSF1), a known repressor of TNF-α promoter, was markedly activated under simulated microgravity. Short-term treatment with microgravity caused significantly decreased TNF-α production. Microgravity-activated HSF1 may contribute to the decreased TNF-α expression in macrophages directly caused by microgravity, while the LPS-induced NF-κB pathway is resistant to microgravity.

  17. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats.

    PubMed

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G; Fan, Lir-Wan

    2011-10-10

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Trans-10, cis-12 conjugated linoleic acid and the PPAR-γ agonist rosiglitazone attenuate lipopolysaccharide-induced TNF-α production by bovine immune cells.

    PubMed

    Perdomo, M C; Santos, J E; Badinga, L

    2011-10-01

    Lipopolysaccharide (LPS) modulates innate immunity through alteration of cytokine production by immune cells. The objective of this study was to examine the effect of exogenous conjugated linoleic acid (CLA) and PPAR-γ agonist, rosiglitazone, on LPS-induced tumor necrosis factor α (TNF-α) production by cultured whole blood from prepubertal Holstein heifers (mean age, 5.5 mo). Compared with unstimulated cells, addition of LPS (10 μg/mL) to the culture medium increased (P<0.03) peripheral blood mononuclear cell proliferation≤2.5-fold. Coincubation with interferon γ (5 ng/mL) further stimulated (P<0.01) the lymphoproliferative response to LPS. Lipopolysaccharide increased (P<0.01) TNF-α concentration in cultured whole blood in a dose- and time-dependent manner. The greatest TNF-α stimulation occurred after 12 h of exposure to 1 μg/mL LPS. Coincubation with trans-10, cis-12 CLA isomer (100 μM) or rosiglitazone (10 μM), a PPAR-γ agonist, decreased (P<0.01) LPS-induced TNF-α production by 13% and 29%, respectively. Linoleic acid and cis-9, trans-11 CLA isomer had no detectable effects on LPS-induced TNF-α production in cultured bovine blood. The PPAR-γ agonist-induced TNF-α attenuation was reversed when blood was treated with both rosiglitazone and GW9662, a selective PPAR-γ antagonist. Addition of rosiglitazone to the culture medium tended to reduce nuclear factor-κ Bp65 concentration in nuclear and cytosolic extracts isolated from cultured peripheral blood mononuclear cells. Results show that LPS is a potent inducer of TNF-α production in bovine blood cells and that trans-10, cis-12 CLA and PPAR-γ agonists may attenuate the pro-inflammatory response induced by LPS in growing dairy heifers. Additional studies are needed to fully characterize the involvement of nuclear factor-κ B in LPS signaling in bovine blood cells.

  19. Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice.

    PubMed

    Tao, Weiwei; Wang, Hanqing; Su, Qiang; Chen, Yanyan; Xue, Wenda; Xia, Baomei; Duan, Jinao; Chen, Gang

    2016-04-30

    The present study was designed to detect the anti-depressant effects of paeonol and the possible mechanisms in the lipopolysaccharide-induced depressive-like behavior. Open-field test(OFT), tail suspension test(TST) and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that LPS significantly decreased the levels of 5-HT and NE in the hippocampus. LPS also reduced open-field activity, as well as increased immobility duration in FST and TST. Paeonol administration could effectively reverse the alterations in the concentrations of 5-HT, NE and reduce the IL-6 and TNF-α levels. Moreover, paeonol effectively downregulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal. In conclusion, paeonol administration exhibited significant antidepressant-like effects in mice with LPS-induced depression.

  20. Lipopolysaccharide-induced epididymitis disrupts epididymal beta-defensin expression and inhibits sperm motility in rats.

    PubMed

    Cao, Dongmei; Li, Yidong; Yang, Rui; Wang, Yan; Zhou, Yuchuan; Diao, Hua; Zhao, Yue; Zhang, Yonglian; Lu, Jian

    2010-12-01

    Although more than 40 beta-defensins have been identified in rat epididymis, little is known about their regulation or their relation to male infertility caused by inflammation. Using a rat model of epididymitis induced by lipopolysaccharide (LPS), we examined expression of SPAG11E (also known as Bin1b), a caput epididymis-specific beta-defensin in rat. Unlike the expression of other beta-defensins in various epithelial cells with upregulated expression after LPS stimulation, expression of SPAG11E was significantly decreased by LPS at the mRNA and protein levels. LPS treatment also significantly decreased both sperm binding to SPAG11E and sperm motility, and supplementation of the spermatozoa with recombinant SPAG11E in vitro remarkably increased both SPAG11E binding and motility of sperm. To clarify whether decreased expression is a common pattern of epididymal beta-defensins after LPS stimulation, we examined the expression of another 12 epididymal beta-defensins expressed in the caput epididymis. For nine of these beta-defensins, expression was decreased, but for the other three, expression remained unaffected. These findings demonstrate that LPS-induced epididymitis can decrease the expression of epididymal beta-defensins and that disruption of SPAG11E expression is involved in the impairment of sperm motility.

  1. Cannabidiol (CBD) Enhances Lipopolysaccharide (LPS)-Induced Pulmonary Inflammation in C57BL/6 Mice

    PubMed Central

    Karmaus, Peer W. F.; Wagner, James G.; Harkema, Jack R.; Kaminski, Norbert E.; Kaplan, Barbara L.F.

    2012-01-01

    Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL) 6 and 23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function. PMID:23173851

  2. Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock▿ †

    PubMed Central

    Sekine, Hiroki; Mimura, Junsei; Oshima, Motohiko; Okawa, Hiromi; Kanno, Jun; Igarashi, Katsuhide; Gonzalez, Frank J.; Ikuta, Togo; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki

    2009-01-01

    Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1β (IL-1β). Since the enhanced IL-1β secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1β secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-κB but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders. PMID:19822660

  3. Systemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide.

    PubMed

    Hirose, Keiko; Li, Song-Zhe; Ohlemiller, Kevin K; Ransohoff, Richard M

    2014-08-01

    Aminoglycoside antibiotics are highly effective agents against gram-negative bacterial infections, but they cause adverse effects on hearing and balance dysfunction as a result of toxicity to hair cells of the cochlea and vestibular organs. While ototoxicity has been comprehensively studied, the contributions of the immune system, which controls the host response to infection, have not been studied in antibiotic ototoxicity. Recently, it has been shown that an inflammatory response is induced by hair cell injury. In this study, we found that lipopolysaccharide (LPS), an important component of bacterial endotoxin, when given in combination with kanamycin and furosemide, augmented the inflammatory response to hair cell injury and exacerbated hearing loss and hair cell injury. LPS injected into the peritoneum of experimental mice induced a brisk cochlear inflammatory response with recruitment of mononuclear phagocytes into the spiral ligament, even in the absence of ototoxic agents. While LPS alone did not affect hearing, animals that received LPS prior to ototoxic agents had worse hearing loss compared to those that did not receive LPS pretreatment. The poorer hearing outcome in LPS-treated mice did not correlate to changes in endocochlear potential. However, LPS-treated mice demonstrated an increased number of CCR2(+) inflammatory monocytes in the inner ear when compared with mice treated with ototoxic agents alone. We conclude that LPS and its associated inflammatory response are harmful to the inner ear when coupled with ototoxic medications and that the immune system may contribute to the final hearing outcome in subjects treated with ototoxic agents.

  4. Modulation of Pseudomonas aeruginosa lipopolysaccharide-induced lung inflammation by chronic iron overload in rat.

    PubMed

    Lê, Bá Vuong; Khorsi-Cauet, Hafida; Bach, Véronique; Gay-Quéheillard, Jérôme

    2012-03-01

    Iron constitutes a critical nutrient source for bacterial growth, so iron overload is a risk factor for bacterial infections. This study aimed at investigating the role of iron overload in modulating bacterial endotoxin-induced lung inflammation. Weaning male Wistar rats were intraperitoneally injected with saline or iron sucrose [15 mg kg(-1) body weight (bw), 3 times per week, 4 weeks]. They were then intratracheally injected with Pseudomonas aeruginosa lipopolysaccharide (LPS) (5 μg kg(-1) bw) or saline. Inflammatory indices were evaluated 4 or 18 h post-LPS/saline injection. At 4 h, LPS-treated groups revealed significant increases in the majority of inflammatory parameters (LPS-binding protein (LBP), immune cell recruitment, inflammatory cytokine synthesis, myeloperoxidase activity, and alteration of alveolar-capillary permeability), as compared with control groups. At 18 h, these parameters reduced strongly with the exception for LBP content and interleukin (IL)-10. In parallel, iron acted as a modulator of immune cell recruitment; LBP, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant 3, and IL-10 synthesis; and alveolar-capillary permeability. Therefore, P. aeruginosa LPS may only act as an acute lung inflammatory molecule, and iron overload may modulate lung inflammation by enhancing different inflammatory parameters. Thus, therapy for iron overload may be a novel and efficacious approach for the prevention and treatment of bacterial lung inflammations.

  5. Biochanin A inhibits lipopolysaccharide-induced inflammatory cytokines and mediators production in BV2 microglia.

    PubMed

    Zhang, Yang; Chen, Wei-An

    2015-01-01

    Biochanin A, one of the major isoflavonoids in red clover or cabbage, has been reported to have anti-inflammatory effects. However, the molecular mechanism underlying the anti-inflammatory effects of biochanin A has not been completely elucidated. The aim of this study was to investigate the anti-inflammatory effect and mechanism on lipopolysaccharide (LPS)-stimulated BV2 microglia. The results showed that biochanin A suppressed LPS-induced inflammatory mediators nitric oxide, prostaglandin E2 and inflammatory cytokines TNF-α and IL-1β production. LPS-induced NF-κB activation was also inhibited by biochanin A. In addition, biochanin A up-regulated the expression of PPAR-γ and the anti-inflammatory effects of biochanin A can be abolished by PPAR-γ antagonist GW9662. These results suggest that biochanin A exerts an anti-inflammatory property by activating PPAR-γ, thereby attenuating NF-κB activation and the release of pro-inflammatory mediators.

  6. Protective Effects of Luteolin on Lipopolysaccharide-Induced Acute Renal Injury in Mice

    PubMed Central

    Xin, Shao-bin; Yan, Hao; Ma, Jing; Sun, Qiang; Shen, Li

    2016-01-01

    Background Sepsis can cause serious acute kidney injury in bacterium-infected patients, especially in intensive care patients. Luteolin, a bioactive flavonoid, has renal protection and anti-inflammatory effects. This study aimed to investigate the effect and underlying mechanism of luteolin in attenuating lipopolysaccharide (LPS)-induced renal injury. Material/Methods ICR mice were treated with LPS (25 mg/kg) with or without luteolin pre-treatment (40 mg/kg for three days). The renal function, histological changes, degree of oxidative stress, and tubular apoptosis in these mice were examined. The effects of luteolin on LPS-induced expression of renal tumor necrosis factor-α (TNF-α), NF-κB, MCP-1, ICAM-1, and cleaved caspase-3 were evaluated. Results LPS resulted in rapid renal damage of mice, increased level of blood urea nitrogen (BUN), and serum creatinine (Scr), tubular necrosis, and increased oxidative stress, whereas luteolin pre-treatment could attenuate this renal damage and improve the renal functions significantly. Treatment with LPS increased TNF-α, NF-κB, IL-1β, cleaved caspase-3, MCP-1, and ICAM-1 expression, while these disturbed expressions were reversed by luteolin pre-treatment. Conclusions These results indicate that luteolin ameliorates LPS-mediated nephrotoxicity via improving renal oxidant status, decreasing NF-κB activation and inflammatory and apoptosis factors, and then disturbing the expression of apoptosis-related proteins. PMID:28029146

  7. Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

    PubMed

    Karmaus, Peer W F; Wagner, James G; Harkema, Jack R; Kaminski, Norbert E; Kaplan, Barbara L F

    2013-01-01

    Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL)-5 and -23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function.

  8. Lipopolysaccharide-induced multinuclear cells: Increased internalization of polystyrene beads and possible signals for cell fusion

    SciTech Connect

    Nakanishi-Matsui, Mayumi Yano, Shio; Futai, Masamitsu

    2013-11-01

    Highlights: •LPS induces multinuclear cells from murine macrophage-derived RAW264.7 cells. •Large beads are internalized by cells actively fusing to become multinuclear. •The multinuclear cell formation is inhibited by anti-inflammatory cytokine, IL10. •Signal transduction for cell fusion is different from that for inflammation. -- Abstract: A murine macrophage-derived line, RAW264.7, becomes multinuclear on stimulation with lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria. These multinuclear cells internalized more polystyrene beads than mononuclear cells or osteoclasts (Nakanishi-Matsui, M., Yano, S., Matsumoto, N., and Futai, M., 2012). In this study, we analyzed the time courses of cell fusion in the presence of large beads. They were internalized into cells actively fusing to become multinuclear. However, the multinuclear cells once formed showed only low phagocytosis activity. These results suggest that formation of the multinuclear cells and bead internalization took place simultaneously. The formation of multinuclear cells was blocked by inhibitors for phosphoinositide 3-kinase, phospholipase C, calcineurin, and c-Jun N-terminal kinase. In addition, interleukin 6 and 10 also exhibited inhibitory effects. These signaling molecules and cytokines may play a crucial role in the LPS-induced multinuclear cell formation.

  9. Protective Effect of Dihydromyricetin Against Lipopolysaccharide-Induced Acute Kidney Injury in a Rat Model.

    PubMed

    Wang, Jun-Tao; Jiao, Peng; Zhou, Yun; Liu, Qian

    2016-02-11

    BACKGROUND The present study investigated the effect of dihydromyricetin (DHM) on lipopolysaccharide (LPS)-induced acute kidney injury in a rat model. MATERIAL AND METHODS Kidney injury was induced in male Sprague-Dawley rats by injection of LPS through the tail vein. The rats were treated with 5 µg/kg body weight DHM within 12 h of the LPS administration. The urine of the rats was collected over a period of 48 h for determination of calcium and creatinine concentrations. Blood urea nitrogen in the serum was analyzed using a BC-2800 Vet Animal Auto Biochemistry Analyzer. On day 3 after treatment, the rats were sacrificed to extract the kidneys. RESULTS Treatment of the endotoxemia rats with DHM caused a significant (P<0.05) decrease in the level of kidney injury molecule‑1 and blood urea nitrogen. DHM treatment significantly (P<0.05) decreased the level of calcium in the kidney tissues compared to those of the untreated endotoxemia rats. The level of malonaldehyde (MDA) in the kidney tissues was significantly reduced in the endotoxemia rats by DHM treatment. The results from immunohistochemistry reveled a significant decrease in the expression of osteopontin (OPN) and CD44 levels. The endotoxemia rats showed significantly higher levels of TUNEL-positive stained nuclei compared to the normal controls. However, treatment of the endotoxemia rats with DHM resulted in a significant decrease in the population of TUNEL-positive cells. CONCLUSIONS DHM may be a promising candidate for the treatment of acute kidney injury.

  10. Cerium oxide nanoparticles inhibit lipopolysaccharide induced MAP kinase/NF-kB mediated severe sepsis.

    PubMed

    Selvaraj, Vellaisamy; Nepal, Niraj; Rogers, Steven; Manne, Nandini D P K; Arvapalli, Ravikumar; Rice, Kevin M; Asano, Shinichi; Fankenhanel, Erin; Ma, J Y; Shokuhfar, Tolou; Maheshwari, Mani; Blough, Eric R

    2015-09-01

    The life threatening disease of sepsis is associated with high mortality. Septic patient survivability with currently available treatments has failed to improve. The purpose of this study was to evaluate whether lipopolysaccharide (LPS) induced sepsis mortality and associated hepatic dysfunction can be prevented by cerium oxide nanoparticles (CeO2NPs) treatment in male Sprague Dawley rats. Here we provide the information about the methods processing of raw data related to our study published in Biomaterials (Selvaraj et al., Biomaterials, 2015, In press) and Data in Brief (Selvaraj et al., Data in Brief, 2015, In Press). The data present here provides confirmation of cerium oxide nanoparticle treatments ability to prevent the LPS induced sepsis associated changes in physiological, blood cell count, inflammatory protein and growth factors in vivo. In vitro assays investigation the treated of macrophages cells with different concentrations of cerium oxide nanoparticle demonstrate that concentration of cerium oxide nanoparticles below 1 µg/ml did not significantly influence cell survival as determined by the MTT assay.

  11. Eupatorium lindleyanum DC. flavonoids fraction attenuates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Chu, Chunjun; Yao, Shi; Chen, Jinglei; Wei, Xiaochen; Xia, Long; Chen, Daofeng; Zhang, Jian

    2016-10-01

    Eupatorium lindleyanum DC., "Ye-Ma-Zhui" called by local residents in China, showed anti-inflammatory activity and is used to treat tracheitis. We had isolated and identified the flavonoids, diterpenoids and sesquiterpenes compounds from the herb. In the present study, we evaluated the protective effects of the flavonoids fraction of E. lindleyanum (EUP-FLA) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanisms of action. EUP-FLA could significantly decrease lung wet-to-dry weight (W/D) ratio, nitric oxide (NO) and protein concentration in BALF, lower myeloperoxidase (MPO) activity, increase superoxide dismutase (SOD) activity and down-regulate the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Additionally, EUP-FLA attenuated lung histopathological changes and significantly reduced complement deposition with decreasing the levels of Complement 3 (C3) and Complement 3c (C3c) in serum. These results demonstrated that EUP-FLA may attenuate LPS-induced ALI via reducing productions of pro-inflammatory mediators, decreasing the level of complement and affecting the NO, SOD and MPO activity.

  12. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Tsurumaki, Hiroaki; Mogi, Chihiro; Aoki-Saito, Haruka; Tobo, Masayuki; Kamide, Yosuke; Yatomi, Masakiyo; Sato, Koichi; Dobashi, Kunio; Ishizuka, Tamotsu; Hisada, Takeshi; Yamada, Masanobu; Okajima, Fumikazu

    2015-01-01

    Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production. PMID:26690120

  13. Role of circulating Fibroblast Growth Factor-2 in lipopolysaccharide-induced acute kidney injury in mice

    PubMed Central

    Mattison, Parnell C.; Soler-García, Ángel A.; Das, Jharna R.; Jerebtsova, Marina; Perazzo, Sofia; Tang, Pingtao; Ray, Patricio E.

    2011-01-01

    Background Fibroblast Growth Factor (FGF-2) is an angiogenic growth factor involved in renal growth and regeneration. Previous studies in rodents showed that single intrarenal injections of FGF-2 improved the outcome of acute kidney injury (AKI). Septic children usually show elevated plasma levels of FGF-2, and are at risk of developing AKI. However, the role of circulating FGF-2 in the pathogenesis of AKI is not well understood. Methods Here, we developed a mouse model to determine how FGF-2 released into the circulation modulates the outcome of AKI induced by lipopolysaccharide (LPS). Young FVB/N mice were infected with adenoviruses carrying a secreted form of human FGF-2 or control LacZ vectors. Subsequently, when the circulating levels of FGF-2 were similar to those seen in septic children, mice were injected with a non-lethal dose of LPS or control buffer. Results All mice injected with LPS developed hypotension and AKI, and recovered after five days. FGF-2 did not improve the outcome of AKI, and induced more significant renal proliferative and apoptotic changes during the recovery phase. Conclusions These findings suggest that circulating FGF-2 may not necessarily prevent the development or improve the outcome of AKI. Moreover, the renal accumulation of FGF-2 might cause further renal damage. PMID:21959768

  14. Deletion of ovarian hormones induces a sickness behavior in rats comparable to the effect of lipopolysaccharide.

    PubMed

    Azizi-Malekabadi, Hamid; Hosseini, Mahmoud; Pourganji, Masoume; Zabihi, Hoda; Saeedjalali, Mohsen; Anaeigoudari, Akbar

    2015-01-01

    Neuroimmune factors have been proposed as the contributors to the pathogenesis of sickness behaviors. The effects of female gonadal hormones on both neuroinflammation and depression have also been well considered. In the present study, the capability of deletion of ovarian hormones to induce sickness-like behaviors in rats was compared with the effect lipopolysaccharide (LPS). The groups were including Sham, OVX, Sham-LPS, and OVX-LPS. The Sham-LPS and OVX-LPS groups were treated with LPS (250 μg/kg) two hours before conducting the behavioral tests. In the forced swimming (FST), the immobility times in both OVX and Sham-LPS groups were higher than that of Sham (P < 0.001). In open-field (OP) test, the central crossing number by OVX and Sham-LPS groups were lower than Sham (P < 0.001) while there were no significant differences between OVX-LPS and OVX groups. In elevated plus maze (EPM), the percent of entries to the open arm by both OVX and Sham-LPS groups was lower than that of Sham group (P < 0.001). The results of present study showed that deletion of ovarian hormones induced sickness behaviors in rats which were comparable to the effects of LPS. Moreover, further investigations are required in order to better understand the mechanism(s) involved.

  15. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury.

    PubMed

    Tsurumaki, Hiroaki; Mogi, Chihiro; Aoki-Saito, Haruka; Tobo, Masayuki; Kamide, Yosuke; Yatomi, Masakiyo; Sato, Koichi; Dobashi, Kunio; Ishizuka, Tamotsu; Hisada, Takeshi; Yamada, Masanobu; Okajima, Fumikazu

    2015-12-04

    Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production.

  16. Hepcidin protects against lipopolysaccharide-induced liver injury in a mouse model of obstructive jaundice.

    PubMed

    Huang, Ying-Hsien; Yang, Ya-Ling; Tiao, Mao-Meng; Kuo, Ho-Chang; Huang, Li-Tung; Chuang, Jiin-Haur

    2012-06-01

    Obstructive jaundice (OJ) increases the risk of liver injury and sepsis, leading to increased mortality. Cholestatic liver injury is associated with a downregulation of hepcidin expression levels. In fact, hepcidin has an important antimicrobial effect, especially against Escherichia coli. It is unknown whether supplementing recombinant hepcidin is effective in alleviating cholestasis-induced liver injury and mortality in mice with superimposed sepsis. A mouse model of cholestasis was developed using extrahepatic bile duct ligation for 3 days. In addition, sepsis due to E. coli 0111:B4 lipopolysaccharide (LPS) was induced in the model. The serum levels of total bilirubin, AST, ALT, and LDH and the mRNA levels of IL-1β, TNF-α, and MCP-1 in the liver were significantly higher in the OJ mice receiving LPS than in the sham-operated mice receiving LPS. Compared to the OJ mice receiving LPS, the hepcidin-pretreated OJ mice receiving LPS showed a significant decrease in the above mentioned parameters, as well as a reversal in the downregulation of LC3B-II and upregulation of cleaved caspase-3; this, in turn, led to significantly decreased lethality in 24h. In conclusion, these results indicate that hepcidin pretreatment significantly reduced hepatic proinflammatory cytokine expression and liver injury, leading to reduced early lethality in OJ mice receiving LPS. Enhanced autophagy and reduced apoptosis may account for the protective effects of hepcidin.

  17. Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes.

    PubMed

    Grisouard, Jean; Bouillet, Elisa; Timper, Katharina; Radimerski, Tanja; Dembinski, Kaethi; Frey, Daniel M; Peterli, Ralph; Zulewski, Henryk; Keller, Ulrich; Müller, Beat; Christ-Crain, Mirjam

    2012-02-01

    High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold (P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level (P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.

  18. Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis.

    PubMed

    Tominari, Tsukasa; Hirata, Michiko; Matsumoto, Chiho; Inada, Masaki; Miyaura, Chisato

    2012-01-01

    Nobiletin, a polymethoxy flavonoid (PMF), inhibits systemic bone resorption and maintains bone mass in estrogen-deficient ovariectomized mice. This study examined the anti-inflammatory effects of PMFs, nobiletin, and tangeretin on lipopolysaccharide (LPS)-induced bone resorption. Nobiletin and tangeretin suppressed LPS-induced osteoclast formation and bone resorption and suppressed the receptor activator of NFκB ligand-induced osteoclastogenesis in RAW264.7 macrophages. Nobiletin clearly restored the alveolar bone mass in a mouse experimental model for periodontitis by inhibiting LPS-induced bone resorption. PMFs may therefore provide a new therapeutic approach for periodontal bone loss.

  19. Use of mice tolerant to lipopolysaccharide to demonstrate requirement of cooperation between macrophages and lymphocytes to generate lipopolysaccharide-induced colony-stimulating factor in vivo.

    PubMed Central

    Williams, Z; Hertogs, C F; Pluznik, D H

    1983-01-01

    Injection of lipopolysaccharide (LPS) into mice was followed by a rapid elevation of colony-stimulating factor (CSF) in the serum. A second, challenging injection of LPS given 3 to 4 days later failed to induce elevated levels of CSF in the serum. Such mice tolerant to LPS were used as an experimental tool to identify the CSF-producing cells which respond to LPS. We observed that generation of LPS-induced CSF in mice tolerant to LPS could be restored by an intraperitoneal injection of spleen cells 24 h before the challenging injection of LPS. Depletion of the adherent cells from the spleen cells reduced the ability of the splenic lymphocytes to restore the capacity of the mice tolerant to LPS to generate serum CSF. Reconstitution of the splenic lymphocytes with 5% thioglycolate-elicited peritoneal macrophages, however, reestablished the restorative capacity of these cells, whereas almost no restoration was observed after direct injection of elicited peritoneal macrophages. These data suggest that the spleen cells are active in generating CSF, provided that macrophages are present and can interact with the splenic lymphocytes to generate LPS-induced CSF in the serum. PMID:6602767

  20. A novel role of kukoamine B: Inhibition of the inflammatory response in the livers of lipopolysaccharide-induced septic mice via its unique property of combining with lipopolysaccharide

    PubMed Central

    QIN, WEI-TING; WANG, XU; SHEN, WEI-CHANG; SUN, BING-WEI

    2015-01-01

    Kukoamine B (KB), derived from the traditional Chinese herb cortex Lycii, exerts anti-inflammatory effects due to its potent affinity with lipopolysaccharide (LPS) and CpG DNA; however, little is known regarding whether the in vivo administration of KB can effectively inhibit inflammation in septic mice. The present study thus aimed to investigate the inhibitory effects of KB on the inflammatory response in the livers of LPS-induced septic mice. KB treatment in the LPS-induced septic mice significantly decreased the plasma level of LPS. In addition, KB protected against liver injury, as confirmed by improved histology and decreased aminotransferase levels in the serum. Further experiments revealed that KB attenuated liver myeloperoxidase activity and reduced the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. These effects were accompanied by decreases in the levels of tumor necrosis factor α and interleukin-1β in the liver tissue. In parallel, the activity of nuclear factor-κ-gene binding (NF-κB) in the livers of LPS-induced septic mice was markedly inhibited with KB treatment. In combination, these results demonstrate that KB inhibits inflammation in septic mice by reducing the concentrations of plasma LPS, decreasing leukocyte sequestration and interfering with NF-κB activation, and, therefore, suppressing the pro-adhesive phenotype of endothelial cells. PMID:25667619

  1. Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro

    PubMed Central

    Reisinger, Nicole; Schaumberger, Simone; Nagl, Veronika; Hessenberger, Sabine; Schatzmayr, Gerd

    2014-01-01

    The pathogenesis of laminitis is not completely identified and the role of endotoxins (lipopolysaccharides, LPS) in this process remains unclear. Phytogenic substances, like milk thistle (MT) and silymarin, are known for their anti-inflammatory and antioxidant properties and might therefore have the potential to counteract endotoxin induced effects on the hoof lamellar tissue. The aim of our study was to investigate the influence of endotoxins on lamellar tissue integrity and to test if MT and silymarin are capable of inhibiting LPS-induced effects in an in vitro/ex vivo model. In preliminary tests, LPS neutralization efficiency of these phytogenics was determined in an in vitro neutralization assay. Furthermore, tissue explants gained from hooves of slaughter horses were tested for lamellar separation after incubation with different concentrations of LPS. By combined incubation of explants with LPS and either Polymyxin B (PMB; positive control), MT or silymarin, the influence of these substances on LPS-induced effects was assessed. In the in vitro neutralization assay, MT and silymarin reduced LPS concentrations by 64% and 75%, respectively, in comparison PMB reduced 98% of the LPS concentration. In hoof explants, LPS led to a concentration dependent separation. Accordantly, separation force was significantly decreased by 10 µg/mL LPS. PMB, MT and silymarin could significantly improve tissue integrity of explants incubated with 10 µg/mL LPS. This study showed that LPS had a negative influence on the structure of hoof explants in vitro. MT and silymarin reduced endotoxin activity and inhibited LPS-induced effects on the lamellar tissue. Hence, MT and silymarin might be used to support the prevention of laminitis and should be further evaluated for this application. PMID:25290524

  2. Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: detrimental role of Na(+)-Ca(2+) exchanger.

    PubMed

    Magi, Simona; Nasti, Annamaria Assunta; Gratteri, Santo; Castaldo, Pasqualina; Bompadre, Stefano; Amoroso, Salvatore; Lariccia, Vincenzo

    2015-01-05

    Several molecular pathways involved in the development of cardiac hypertrophy are triggered by perturbation of intracellular Ca(2+) homeostasis. Within the heart, Na(+)/Ca(2+) exchanger 1 (NCX1) is one of the main determinant in controlling Ca(2+) homeostasis. In cardiac hypertrophy and heart failure NCX1 expression and activity have been reported to be altered. It has been shown that chronic bacterial infections (sepsis, endocarditis, and myocarditis) can promote cardiac hypertrophy. Bacterial stressors, such as the Gram-negative endotoxin lipopolysaccharide (LPS), can directly or indirectly affect intracellular Ca(2+) homeostasis in the heart and induce the development of cardiac hypertrophy. The present study aimed at evaluating the potential link between the signal pathways activated in LPS-exposed myocytes and NCX1. In the whole rat heart, LPS perfusion induced an early hypertrophy response during which NCX1 expression significantly increased. Notably, all these changes were completely prevented by the NCX inhibitor SN-6. We further dissect the role of NCX1 in the LPS-induced hypertrophic response in an in vitro cardiac model based on two H9c2 cardiomyoblast clones, namely H9c2-WT (lacking endogenous NCX1 expression) and H9c2-NCX1 (stably transfected with a functional NCX1). H9c2-NCX1 were more susceptible than H9c2-WT to develop a hypertrophic phenotype, and they displayed a significant increase in NCX1 expression and function after LPS treatment. SN-6 completely counteracted both hypertrophic response and exchanger alterations induced by LPS in H9c2-NCX1 cells, but it had no effects on H9c2-WT. Collectively, our results suggest that NCX1 plays a critical role in promoting myocardial hypertrophy triggered by LPS. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Protective effects of Lactobacillus plantarum NDC 75017 against lipopolysaccharide-induced liver injury in mice.

    PubMed

    Peng, Xinyan; Jiang, Yujun

    2014-10-01

    This study investigated the protective effect of Lactobacillus plantarum NDC 75017 (L. plantarum NDC 75017) against acute liver injury induced by lipopolysaccharide (LPS). Thirty male mice were randomly divided into the control, LPS, and LPS + L. plantarum NDC 75017 groups. In the LPS + L. plantarum group, the mice were orally pretreated with L. plantarum NDC 75017 for 15 days. At 16 days, the mice in the LPS and LPS + L. plantarum NDC 75017 groups were intraperitoneally injected with LPS at 4 mg/kg body weight, whereas the control mice were treated with an equal amount of saline. After 8 h, the serum alanine transaminase (ALT), aspartate aminotransferase (AST), and histology changes were examined. The oxidative stress markers and pro-inflammatory cytokines in the liver were also examined. Meanwhile, the expression of nuclear factor κB (NF-κB) mRNA and toll-like receptor 4 (TLR4) in the liver was determined by qRT-PCR. The LPS group showed an increase in ALT and AST, whereas the LPS + L. plantarum NDC 75017 group showed a significant decrease. In addition, pretreatment with L. plantarum NDC 75017 can attenuate LPS-induced oxidative stress and inflammatory response. Furthermore, the increase of hepatic NF-κB and TLR4 mRNA induced by LPS was significantly downregulated by the pretreatment with L. plantarum NDC 75017. These data show that pretreatment with L. plantarum NDC 75017 protects against LPS-induced oxidative stress and inflammatory injury in the liver of mice, which may be attributed to the inhibition of the TLR4-NF-κB pathway.

  4. Ruminal lipopolysaccharide concentration and inflammatory response during grain-induced subacute ruminal acidosis in dairy cows.

    PubMed

    Gozho, G N; Krause, D O; Plaizier, J C

    2007-02-01

    The effects of grain-induced subacute ruminal acidosis (SARA) in lactating dairy cows on free ruminal lipopolysaccharide (LPS) and indicators of inflammation were determined. Four mid lactation dairy cows were divided into 2 groups of 2 cows and used in a repeated switchover design. During each period, SARA was induced in 2 animals for 5 subsequent days by replacing 25% of their total mixed ration (dry matter basis) with a concentrate made of 50% wheat and 50% barley. The other 2 cows acted as controls and were fed a total mixed ration diet in which 44% of dry matter was concentrate. On average, inducing SARA did not affect milk composition, increased the duration of rumen pH below 5.6 from 187 to 309 min/d, and increased free ruminal LPS concentration from 24,547 endotoxin units (EU)/mL to 128,825 EU/mL. Averaged across treatments, milk fat yield and milk protein yield were 0.66 and 1.00 kg/d, respectively. Rumen pH and milk fat data suggest that control cows also experienced ruminal acidosis, albeit a milder form of this disease than SARA cows. Serum LPS concentration in both control and SARA cows was less than the detection limit of <0.01 EU/mL for the assay. Induction of SARA elevated serum amyloid A concentration from 286.8 to 498.8 mug/mL, but did not affect other markers of inflammation including haptoglobin, fibrinogen, serum copper, or white blood cells. These results suggest that grain-induced SARA in mid lactation dairy cows increases the lysis of gram-negative bacteria and activates an inflammatory response.

  5. Role of polysaccharide and lipid in lipopolysaccharide induced prion protein conversion

    PubMed Central

    LeVatte, Marcia; Wishart, David S.

    2016-01-01

    ABSTRACT Conversion of native cellular prion protein (PrPc) from an α-helical structure to a toxic and infectious β-sheet structure (PrPSc) is a critical step in the development of prion disease. There are some indications that the formation of PrPSc is preceded by a β-sheet rich PrP (PrPβ) form which is non-infectious, but is an intermediate in the formation of infectious PrPSc. Furthermore the presence of lipid cofactors is thought to be critical in the formation of both intermediate-PrPβ and lethal, infectious PrPSc. We previously discovered that the endotoxin, lipopolysaccharide (LPS), interacts with recombinant PrPc and induces rapid conformational change to a β-sheet rich structure. This LPS induced PrPβ structure exhibits PrPSc-like features including proteinase K (PK) resistance and the capacity to form large oligomers and rod-like fibrils. LPS is a large, complex molecule with lipid, polysaccharide, 2-keto-3-deoxyoctonate (Kdo) and glucosamine components. To learn more about which LPS chemical constituents are critical for binding PrPc and inducing β-sheet conversion we systematically investigated which chemical components of LPS either bind or induce PrP conversion to PrPβ. We analyzed this PrP conversion using resolution enhanced native acidic gel electrophoresis (RENAGE), tryptophan fluorescence, circular dichroism, electron microscopy and PK resistance. Our results indicate that a minimal version of LPS (called detoxified and partially de-acylated LPS or dLPS) containing a portion of the polysaccharide and a portion of the lipid component is sufficient for PrP conversion. Lipid components, alone, and saccharide components, alone, are insufficient for conversion. PMID:27906600

  6. Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis.

    PubMed

    Lu, Hongyan; Poirier, Christophe; Cook, Todd; Traktuev, Dmitry O; Merfeld-Clauss, Stephanie; Lease, Benjamin; Petrache, Irina; March, Keith L; Bogatcheva, Natalia V

    2015-02-21

    Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS. To assess the effect of ASC-CM on ARDS indices, intravenous delivery of ASC and ASC-CM to C57Bl/6 mice was carried out 4 h after LPS oropharyngeal aspiration; Evans Blue Dye (EBD) was injected intravenously 1 h prior to animal sacrifice (48 h post-LPS). Lungs were either fixed for histopathology, or used to extract bronchoalveolar lavage fluid (BALF) or EBD. To assess the effect of ASC-CM on endothelial barrier function and apoptosis, human pulmonary artery endothelial cells were treated with ASC-CM for 48-72 h. ASC-CM markedly reduced LPS-induced histopathologic changes of lung, protein extravasation into BALF, and suppressed the secretion of proinflammatory cytokines TNFα and IL6. White Blood Cells (WBC) from BALF of LPS-challenged mice receiving ASC-CM had decreased reactive oxygen species (ROS) generation compared to WBC from LPS-challenged mice receiving control media injection. Treatment of pulmonary endothelial monolayers with ASC-CM significantly suppressed H2O2-induced leakage of FITC dextran and changes in transendothelial resistance, as well as gap formation in endothelial monolayer. ASC-CM exposure reduced the percentage of endothelial cells expressing ICAM-1, and suppressed TNFα-induced expression of E-selectin and cleavage of caspase-3. ASC-CM reduced the endothelial level of pro-apoptotic protein Bim, but did not affect the level of Bcl-2, Bad, or Bad phosphorylation. Factors secreted by ASC efficiently reduce ARDS indices, endothelial barrier hyperpermeability, and activation of pro-inflammatory and pro-apoptotic pathways in endothelium.

  7. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: role of autophagy.

    PubMed

    Turdi, Subat; Han, Xuefeng; Huff, Anna F; Roe, Nathan D; Hu, Nan; Gao, Feng; Ren, Jun

    2012-09-15

    Lipopolysaccharide (LPS) from gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complications in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis, and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity, and carbonyl formation. A Kaplan-Meier curve was constructed for survival after LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice after LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O(2)(-), and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury after LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by the antioxidant N-acetylcysteine and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy.

  8. Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-03-01

    The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose

  9. DHA suppresses Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.

    PubMed

    Choi, Eun-Young; Jin, Ji-Young; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

    2014-04-14

    Several reports have indicated that dietary intake of DHA is associated with lower prevalence of periodontitis. In the present study, we investigated the effect of DHA on the production of proinflammatory mediators in murine macrophage-like RAW264.7 cells stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. LPS was isolated from lyophilised P. intermedia ATCC 25,611 cells using the standard hot-phenol-water protocol. Culture supernatants were collected and assayed for NO, IL-1β and IL-6. Real-time PCR analysis was carried out to detect the expression of inducible NO synthase (iNOS), IL-1β, IL-6 and haeme oxygenase-1 (HO-1) mRNA. Immunoblot analysis was carried out to quantify the expression of iNOS and HO-1 protein and concentrations of signalling proteins. DNA-binding activities of NF-κB subunits were determined using an ELISA-based assay kit. DHA significantly attenuated the production of NO, IL-1β and IL-6 at both gene transcription and translation levels in P. intermedia LPS-activated RAW264.7 cells. DHA induced the expression of HO-1 in cells treated with P. intermedia LPS. Selective inhibition of HO-1 activity by tin protoporphyrin IX significantly mitigated the inhibitory effects of DHA on LPS-induced NO production. DHA significantly attenuated the phosphorylation of c-Jun N-terminal kinase induced by LPS. In addition, DHA suppressed the transcriptional activity of NF-κB by regulating the nuclear translocation and DNA-binding activity of NF-κB p50 subunit and inhibited the phosphorylation of signal transducer and activator of transcription 1. Further in vivo studies are needed to better evaluate the potential of DHA in humans as a therapeutic agent to treat periodontal disease.

  10. Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

    PubMed Central

    Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

    2012-01-01

    Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

  11. Bacterial lipopolysaccharides induce in vitro degradation of cartilage matrix through chondrocyte activation.

    PubMed Central

    Jasin, H E

    1983-01-01

    The present studies demonstrate that bacterial lipopolysaccharides (LPS) induce cartilage matrix degradation in live explants in organ culture. Quintuplicate bovine nasal fibrocartilage explants cultured for 8 d with three different purified LPS preparations derived from Escherichia coli and Salmonella typhosa at concentrations ranging from 1.0 to 25.0 micrograms/ml resulted in matrix proteoglycan depletion of 33.3 +/- 5.8 to 92.5 +/- 2.0% (medium control depletion 17.7 +/- 0.7 to 32.4 +/- 1.4%). Matrix degradation depended on the presence of live chondrocytes because frozen-thawed explants incubated with LPS failed to show any proteoglycan release. Moreover, the addition of Polymyxin B (25 micrograms/ml) to live explants incubated with LPS abolished matrix release, whereas Polymyxin B had no effect on the matrix-degrading activity provided by blood mononuclear cell factors. A highly purified Lipid A preparation induced matrix degradation at a concentration of 0.01 micrograms/ml. Cartilage matrix collagen and proteoglycan depletion also occurred with porcine articular cartilage explants (collagen release: 18.3 +/- 3.5%, medium control: 2.1 +/- 0.5%; proteoglycan release: 79.0 +/- 5.9%, medium control: 28.8 +/- 4.8%). Histochemical analysis of the cultured explants confirmed the results described above. Gel chromatography of the proteoglycans released in culture indicated that LPS induced significant degradation of the high molecular weight chondroitin sulfate-containing aggregates. These findings suggest that bacterial products may induce cartilage damage by direct stimulation of chondrocytes. This pathogenic mechanism may play a role in joint damage in septic arthritis and in arthropathies resulting from the presence of bacterial products derived from the gastrointestinal tract. Images PMID:6358260

  12. Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide

    SciTech Connect

    Huang, Chunrong; Zheng, Haichong; He, Wanmei; Lu, Guifang; Li, Xia; Deng, Yubin; Zeng, Mian

    2016-05-20

    Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activated the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI. -- Graphical abstract: Ghrelin ameliorates the human alveolar epithelial A549 cells apoptosis induced by lipopolysaccharide partly through activating the PI3K/Akt and ERK pathway. Display Omitted -- Highlights: •It has been observed that LPS insult significantly increased apoptosis in A549 cells. •Both Akt and ERK signaling are critical adapter molecules to mediate the ghrelin-mediated proliferative effect. •Ghrelin may have a therapeutic effect in the prevention of LPS-induced apoptosis.

  13. CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.

    PubMed

    Lee, Dong Hun; Park, Mi Hee; Hwang, Chul Ju; Hwang, Jae Yeon; Yoon, Hae Suk; Yoon, Do Young; Hong, Jin Tae

    2016-05-01

    C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.

  14. Milk thistle extract and silymarin inhibit lipopolysaccharide induced lamellar separation of hoof explants in vitro.

    PubMed

    Reisinger, Nicole; Schaumberger, Simone; Nagl, Veronika; Hessenberger, Sabine; Schatzmayr, Gerd

    2014-10-06

    The pathogenesis of laminitis is not completely identified and the role of endotoxins (lipopolysaccharides, LPS) in this process remains unclear. Phytogenic substances, like milk thistle (MT) and silymarin, are known for their anti-inflammatory and antioxidant properties and might therefore have the potential to counteract endotoxin induced effects on the hoof lamellar tissue. The aim of our study was to investigate the influence of endotoxins on lamellar tissue integrity and to test if MT and silymarin are capable of inhibiting LPS-induced effects in an in vitro/ex vivo model. In preliminary tests, LPS neutralization efficiency of these phytogenics was determined in an in vitro neutralization assay. Furthermore, tissue explants gained from hooves of slaughter horses were tested for lamellar separation after incubation with different concentrations of LPS. By combined incubation of explants with LPS and either Polymyxin B (PMB; positive control), MT or silymarin, the influence of these substances on LPS-induced effects was assessed. In the in vitro neutralization assay, MT and silymarin reduced LPS concentrations by 64% and 75%, respectively, in comparison PMB reduced 98% of the LPS concentration. In hoof explants, LPS led to a concentration dependent separation. Accordantly, separation force was significantly decreased by 10 µg/mL LPS. PMB, MT and silymarin could significantly improve tissue integrity of explants incubated with 10 µg/mL LPS. This study showed that LPS had a negative influence on the structure of hoof explants in vitro. MT and silymarin reduced endotoxin activity and inhibited LPS-induced effects on the lamellar tissue. Hence, MT and silymarin might be used to support the prevention of laminitis and should be further evaluated for this application.

  15. Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death.

    PubMed

    Liu, Yaming; Verma, Vikas K; Malhi, Harmeet; Gores, Greg J; Kamath, Patrick S; Sanyal, Arun; Chalasani, Naga; Gao, Bin; Shah, Vijay H

    2017-09-01

    Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration-dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage-derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.

  16. Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity

    SciTech Connect

    Nakanishi-Matsui, Mayumi; Yano, Shio; Matsumoto, Naomi; Futai, Masamitsu

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer LPS induces multinuclear cells from murine macrophage-derived RAW264.7 cells. Black-Right-Pointing-Pointer The multinuclear cells are formed through cell-cell fusion in the presence of Ca{sup 2+}. Black-Right-Pointing-Pointer The multinuclear cells do not express osteoclast-specific enzymes. Black-Right-Pointing-Pointer They internalized more and larger beads than mononuclear cells and osteoclasts. -- Abstract: Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, induces strong proinflammatory responses, including the release of cytokines and nitric oxide from macrophage. In this study, we found that a murine macrophage-derived line, RAW264.7, became multinuclear through cell-cell fusion after incubation with highly purified LPS or synthetic lipid A in the presence of Ca{sup 2+}. The same cell line is known to differentiate into multinuclear osteoclast, which expresses a specific proton pumping ATPase together with osteoclast markers on stimulation by the extracellular domain of receptor activator of nuclear factor {kappa}B ligand (Toyomura, T., Murata, Y., Yamamoto, A., Oka, T., Sun-Wada, G.-H., Wada, Y. and Futai, M., 2003). The LPS-induced multinuclear cells did not express osteoclast-specific enzymes including tartrate-resistant acid phosphatase and cathepsin K. During multinuclear cell formation, the cells internalized more and larger polystyrene beads (diameter 6-15 {mu}m) than mononuclear cells and osteoclasts. The internalized beads were located in lysosome-marker positive organelles, which were probably phagolysosomes. The LPS-induced multinuclear cell could be a good model system to study phagocytosis of large foreign bodies.

  17. IL-37 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption in vivo.

    PubMed

    Saeed, Jafari; Kitaura, Hideki; Kimura, Keisuke; Ishida, Masahiko; Sugisawa, Haruki; Ochi, Yumiko; Kishikawa, Akiko; Takano-Yamamoto, Teruko

    2016-07-01

    IL-37 is a newly defined member of the IL-1 cytokine family. It has been reported that IL-37 inhibited innate immunity and inflammatory responses in autoimmune diseases and tumors. IL-37 also inhibited Lipopolysaccharide (LPS)-induced immunological reaction. LPS is a bacterial cell wall component that is capable of inducing osteoclast formation and pathological bone resorption. However, there is no study to investigate the effect of IL-37 on LPS-induced osteoclast formation and bone resorption. The purpose of this study is to investigate the effect of IL-37 in LPS-induced osteoclast formation and bone resorption. LPS was administrated with or without IL-37 by subcutaneous injection on mice calvariae. The number of osteoclasts, the level of tartrate-resistant acid phosphatase (TRAP) and cathepsin K mRNA, the ratio of the bone resorption pits and the level of C-terminal telopeptide fragments of type I collagen cross-Links as a marker of bone resorption in mice administrated both LPS and IL-37 were lower than that in mice administrated LPS alone. Real-time RT-PCR was performed to analyze osteoclast related cytokines RANKL, TNF-α and IL-1β mRNA levels in vivo. RANKL, TNF-α and IL-1β mRNAs were increased in the LPS alone administrated mice as compared with PBS administrated groups. On the other hand, RANKL, TNF-α and IL-1β mRNAs were inhibited in the IL-37 and LPS administrated mice as compared with LPS alone administrated group. In vitro analysis, there was no effect of IL-37 in RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation and cell viability from bone marrow macrophages as osteoclast precursor and LPS-induced RANKL expression from stromal cells. These results indicated that IL-37 inhibited LPS-induced osteoclast formation and bone resorption via inhibition of LPS-induced osteoclast related cytokines, but might not directly inhibit osteoclast formation on osteoclast precursor and RANKL expression on stromal cells. Copyright © 2016

  18. Influence of Capsaicin on Inflammatory Cytokines Induced by Lipopolysaccharide in Myoblast Cells Under In vitro Environment

    PubMed Central

    Shang, Ke; Amna, Touseef; Amina, Musarat; Al-Musayeib, Nawal M.; Al-Deyab, Salem S.; Hwang, Inho

    2017-01-01

    Background: ellular damage initiated by reactive oxygen species (ROS) is the main cause of numerous severe diseases and therefore for this reason, the natural antioxidants have note worthy significance in human health. Capsaicin possesses noteworthy analgesic and anti-inflammatory properties. It also possesses healing effects for treatment of arthritis, diabetic neuropathy, gastric lesions, and cardiac excitability that is why it is incorporated in creams and gels. Objective: The present study was carried out to estimate the in vitro antioxidant and ROS scavenging activities of capsaicin against muscle precursor cells. Till date, no investigation has been carried out to study the effect of capsaicin on myoblasts. Materials and methods: Herein, the cytotoxicity was induced by endotoxin lipopolysaccharide (LPS) to analyze the effect of capsaicin on LPS induced inflammation and apoptosis on muscle cells. To find out the toxicity of endotoxin, myoblasts were exposed to different concentrations of LPS, viability and morphology was checkedby the means of CCK-8 test and microscopy, respectively. Apoptotic cell death was examined by fluorescence staining. Additionally, LPS-induced apoptosis was determined by mRNAexpression of calpain, caspase-3 and tumor necrosisfactor alpha (TNF-α), and were quantified by qRT-PCR. Results: The outcome of the presentstudy demonstrated that LPS stimulation generatestoxicity in dose-dependent manner. Pre-treatmentof myoblasts with capsaicin can considerably alleviate LPS-induced inflammation. Conclusion: In conclusion, this study indicates that dietetic supplementation of capsicum may help to alleviate/reduce the inflammatory effects and is therefore potent source of natural antioxidant agent which can be utilized to control muscle related diseases, such as myotube atrophy. SUMMARY In the present study cytotoxicity was induced by LPS to analyze the effect of capsaicin on LPS induced inflammation and apoptosis on muscle cells.The results of

  19. Comparative in vitro stimulation with lipopolysaccharide to study TNFalpha gene expression in fresh whole blood, fresh and frozen peripheral blood mononuclear cells.

    PubMed

    Chen, Jiwang; Bruns, Anke H; Donnelly, Helen K; Wunderink, Richard G

    2010-05-31

    In vitro stimulation with fresh and frozen peripheral blood mononuclear cells (PBMCs) or fresh whole blood has been widely used in animal studies and clinical trials to study the immunological features of a number of human diseases. The objective of this study was to determine the difference in response to stimulation of fresh PBMCs, frozen PBMCs, and fresh whole blood by change of TNFalpha gene expression levels after 4-hour in vitro lipopolysaccharide (LPS) stimulation. Our results demonstrate that TNFalpha gene expression significantly increases in both fresh PBMCs and fresh whole blood when 1 microg/ml or 10 microg/ml LPS was used but only after stimulation with 10 microg/ml LPS in frozen PBMCs. Mean fold change of TNFalpha gene expression levels after 1 microg/ml LPS stimulation was significantly higher using fresh whole blood (51.01+/-7.91) as compared to fresh PBMCs (8.92+/-2.16) or frozen PBMCs (3.04+/-0.55) (p

  20. [Chemotherapy-induced peripheral neuropathy and neuropathic pain].

    PubMed

    Schuler, U; Heller, S

    2017-03-14

    The perception of the media is that chemotherapy is mainly associated with nausea, vomiting and hair loss. In the longer term the development of peripheral neuropathy, i.e. chemotherapy-induced peripheral neuropathy (CIPN) is often more important for patients. The CIPN represents a side effect of many antineoplastic substances with severe functional impairment and its prevention and treatment is an important task. In addition to many interventions, which have been shown to be ineffective, physiotherapeutic measures and possibly the prophylactic application of cold are helpful for prevention. Randomized studies on the treatment of painful CIPN provided positive data for duloxetine and to a lesser extent for venlafaxine.

  1. [Chemotherapy-induced peripheral neuropathy: characteristics, diagnosis and treatment].

    PubMed

    Istenes, Ildikó; Nagy, Zsolt; Demeter, Judit

    2016-06-06

    Longer remissions and better overall survival rates can be achieved with the introduction of new, effective treatments and targeted therapies in the past 1-2 decades, however, the incidence of side effects is also increasing parallelly. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially debilitating side effect due to peripheral somatic or autonomic nerve dysfunction. CIPN becomes increasingly important, as it affects patients' quality of life, and it is very often a dose limiting factor with the potential for reduced treatment efficacy. The pathomechanism, diagnosis, prevention and treatment possibilities are described in this review with special attention to the different groups of drugs.

  2. Protective effects of leucine against lipopolysaccharide-induced inflammatory response in Labeo rohita fingerlings.

    PubMed

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

    2016-05-01

    The present study investigated the protective effects of leucine against lipopolysaccharide (LPS)-induced inflammatory responses in Labeo rohita (rohu) in vivo and in vitro. Primary hepatocytes, isolated from the hepatopancreas, were exposed to different concentrations of LPS for 24 h to induce an inflammatory response, and the protective effects of leucine against LPS-induced inflammation were studied. Finally, we investigated the efficiency of dietary leucine supplementation in attenuating an immune challenge induced by LPS in vivo. Exposure of cells to 10-25 μg mL(-1) of LPS for 24 h resulted in a significant production of nitric oxide and release of lactate dehydrogenase to the medium, whereas cell viability and protein content were reduced (p < 0.05). LPS exposure (10 μg mL(-1)) increased mRNA levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-8 in vitro (p < 0.05). However, pretreatment with leucine prevented the LPS-induced upregulation of TNF-α, IL-1β and IL-8 mRNAs by downregulating TLR4, MyD88, NF-κBp65, and MAPKp38 mRNA expression. Interestingly, mRNA expression of the anti-inflammatory cytokine, IL-10, which was increased by LPS treatment, was further enhanced (p < 0.05) by leucine pretreatment. The enhanced expression of IL-10 might inhibit the production of other pro-inflammatory cytokines. It was found that leucine pretreatment attenuated the excessive activation of LPS-induced TLR4-MyD88 signaling as manifested by lower level of TLR4, MyD88, MAPKp38, NF-κBp65 and increased level of IκB-α protein in leucine pre-treatment group. In vivo experiments demonstrated that leucine pre-supplementation could protect fish against LPS-induced inflammation through an attenuation of TLR4-MyD88 signaling pathway. Taken together, we propose that leucine pre-supplementation decreases LPS-induced immune damage in rohu by enhancing the expression of IL-10 and by regulating the TLR4-MyD88 signaling pathways.

  3. Acute Glucagon Induces Postprandial Peripheral Insulin Resistance

    PubMed Central

    Patarrão, Rita S.; Lautt, W. Wayne; Macedo, M. Paula

    2015-01-01

    Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions. PMID:25961284

  4. Acute glucagon induces postprandial peripheral insulin resistance.

    PubMed

    Patarrão, Rita S; Lautt, W Wayne; Macedo, M Paula

    2015-01-01

    Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions.

  5. Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

    PubMed

    Yu, Peng-Jiu; Li, Jing-Rong; Zhu, Zheng-Guang; Kong, Huan-Yu; Jin, Hong; Zhang, Jun-Yan; Tian, Yuan-Xin; Li, Zhong-Huang; Wu, Xiao-Yun; Zhang, Jia-Jie; Wu, Shu-Guang

    2013-06-15

    Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. The role of lipopolysaccharide injected systemically in the reactivation of collagen-induced arthritis in mice

    PubMed Central

    Yoshino, Shin; Ohsawa, Motoyasu

    2000-01-01

    We investigated the role of bacterial lipopolysaccharide (LPS) in the reactivation of autoimmune disease by using collagen-induced arthritis (CIA) in mice in which autoimmunity to the joint cartilage component type II collagen (CII) was involved.CIA was induced by immunization with CII emulsified with complete Freund's adjuvant at the base of the tail (day 0) followed by a booster injection on day 21. Varying doses of LPS from E. coli were i.p. injected on day 50.Arthritis began to develop on day 25 after immunization with CII and reached a peak on day 35. Thereafter, arthritis subsided gradually but moderate joint inflammation was still observed on day 50. An i.p. injection of LPS on day 50 markedly reactivated arthritis on a dose-related fashion. Histologically, on day 55, there were marked oedema of synovium which had proliferated by the day of LPS injection, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. The reactivation of CIA by LPS was associated with increases in anti-CII IgG and IgG2a antibodies as well as various cytokines including IL-12, IFN-γ, IL-1β, and TNF-α. LPS from S. enteritidis, S. typhimurium, and K. neumoniae and its component, lipid A from E. coli also reactivated the disease. Polymyxin B sulphate suppressed LPS- or lipid A-induced reactivation of CIA.These results suggest that LPS may play an important role in the reactivation of autoimmune joint inflammatory diseases such as rheumatoid arthritis in humans. PMID:10742285

  7. Clausena anisata-mediated protection against lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Jeon, Chan-Mi; Shin, In-Sik; Shin, Na-Rae; Hong, Ju-Mi; Kwon, Ok-Kyoung; Kim, Jung-Hee; Oh, Sei-Ryang; Bach, Tran-The; Hai, Do-Van; Quang, Bui-Hong; Choi, Sang-Ho; Lee, Joongku; Myung, Pyung-Keun; Ahn, Kyung-Seop

    2016-04-01

    Clausena anisata (Willd.) Hook.f. ex Benth. (CA), which is widely used in traditional medicine, reportedly exerts antitumor, anti-inflammatory and other important therapeutic effects. The aim of the present study was to investigate the potential therapeutic effects of CA in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and in LPS-stimulated RAW 264.7 cells. Male C57BL/6 mice were administered treatments for 3 days by oral gavage. On day 3, the mice were instilled intranasally with LPS or PBS followed 3 h later by oral CA (30 mg/kg) or vehicle administration. In vitro, CA decreased nitric oxide (NO) production and pro-inflammatory cytokines, such as interleukin (IL)-6 and prostaglandin E2 (PGE2), in LPS-stimulated RAW 264.7 cells. CA also reduced the expression of pro-inflammatory mediators, such as cyclooxygenase-2. In vivo, CA administration significantly reduced inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF) and suppressed pro-inflammatory cytokine levels, including tumor necrosis factor-α (TNF-α), IL-6, and IL-1β, as well as reactive oxygen species production in the BALF. CA also effectively reduced airway inflammation in mouse lung tissue of an LPS-induced ALI mouse model, in addition to decreasing inhibitor κB (IκB) and nuclear factor-κB (NF-κB) p65 phosphorylation. Taken together, the findings demonstrated that CA inhibited inflammatory responses in a mouse model of LPS-induced ALI and in LPS-stimulated RAW 264.7 cells. Thus, CA is a potential candidate for development as an adjunctive treatment for inflammatory disorders, such as ALI.

  8. Boron Induces Lymphocyte Proliferation and Modulates the Priming Effects of Lipopolysaccharide on Macrophages.

    PubMed

    Routray, Indusmita; Ali, Shakir

    2016-01-01

    Chemical mediators of inflammation (CMI) are important in host defense against infection. The reduced capacity of host to induce the secretion of these mediators following infection is one of the factors in host susceptibility to infection. Boron, which has been suggested for its role in infection, is reported in this study to increase lymphocyte proliferation and the secretion of CMI by the lipopolysaccharide (LPS)-stimulated peritoneal macrophages in BALB/c mice. Boron was administered to mice orally as borax at different doses for 10 consecutive days, followed by the stimulation of animals with ovalbumin and isolation of splenocytes for proliferation assay. The lymphocyte subsets were determined by flow cytometry in spleen cell suspension. The mediators of inflammation, TNF-α, IL-6, IL-1β and nitric oxide (NO), were measured in culture supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and ILs were measured by ELISA. NO was determined by Griess test. The expression of inducible nitric oxide synthase (iNOS) in macrophages was studied by confocal microscopy. Results showed a significant increase in T and B cell populations, as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further stimulated the secretion of TNF-α, IL-6, IL-1β, NO and the expression of iNOS by the LPS-primed macrophages. The effect was dose dependent and most significant at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that boron at physiological concentration induces lymphocyte proliferation and increases the synthesis and secretion of pro-inflammatory mediators by the LPS-primed macrophages, more specifically the M1 macrophages, possibly acting through Toll-like receptor. The study implicates boron as a regulator of the immune and inflammatory reactions and macrophage polarization, thus playing an important role in augmenting host defense against infection, with possible role in cancer and other diseases.

  9. Boron Induces Lymphocyte Proliferation and Modulates the Priming Effects of Lipopolysaccharide on Macrophages

    PubMed Central

    Routray, Indusmita; Ali, Shakir

    2016-01-01

    Chemical mediators of inflammation (CMI) are important in host defense against infection. The reduced capacity of host to induce the secretion of these mediators following infection is one of the factors in host susceptibility to infection. Boron, which has been suggested for its role in infection, is reported in this study to increase lymphocyte proliferation and the secretion of CMI by the lipopolysaccharide (LPS)-stimulated peritoneal macrophages in BALB/c mice. Boron was administered to mice orally as borax at different doses for 10 consecutive days, followed by the stimulation of animals with ovalbumin and isolation of splenocytes for proliferation assay. The lymphocyte subsets were determined by flow cytometry in spleen cell suspension. The mediators of inflammation, TNF-α, IL-6, IL-1β and nitric oxide (NO), were measured in culture supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and ILs were measured by ELISA. NO was determined by Griess test. The expression of inducible nitric oxide synthase (iNOS) in macrophages was studied by confocal microscopy. Results showed a significant increase in T and B cell populations, as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further stimulated the secretion of TNF-α, IL-6, IL-1β, NO and the expression of iNOS by the LPS-primed macrophages. The effect was dose dependent and most significant at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that boron at physiological concentration induces lymphocyte proliferation and increases the synthesis and secretion of pro-inflammatory mediators by the LPS-primed macrophages, more specifically the M1 macrophages, possibly acting through Toll-like receptor. The study implicates boron as a regulator of the immune and inflammatory reactions and macrophage polarization, thus playing an important role in augmenting host defense against infection, with possible role in cancer and other diseases. PMID:26934748

  10. Differential inhibition of lipopolysaccharide-induced granulocyte aggregation and prostanoid production by emoxypin.

    PubMed

    Kubatiev, A; Turgiev, A; Smirnov, L; Pomoynetsky, V; Dumaev, K

    1990-01-01

    Emoxypin is known to be an effective membrane-stabilizing 3-oxy-pyridine derivative. We attempted to evaluate its influence on lipopolysaccharide (LPS)-induced granulocyte aggregation and prostanoid production. Granulocytes isolated from rabbit venous blood by dextran sedimentation and Pezcoll gradient centrifugation were stirred in the aggregometer cuvette with emoxypin (5mM), indomethacin (50 microM) or their solvents at 37 degrees C for 2 min. Then S. typhimurium LPS (200 micrograms/ml) was added and the aggregation was traced for 5 min. Thromboxane B2 (TxB2), prostaglandins (PG) E, F2 alpha and 13,14-dihydro-15-keto-PGF2 alpha were determined in supernatants radioimmunochemically. Indomethacin did not affect the pattern of aggregation, whereas emoxypin virtually precluded the response. Granulocytes incubated with LPS produced by the 15th sec and 5th min 1.3 and 2.5 times as much TxB2 respectively as did the intact cells (p less than 0.01). LPS had no effect on PGE production. Fifteen-sec contact of granulocytes with LPS had no significant influence on the formation of PGF2 alpha and its 13,14-dihydro-15-keto metabolite. The amount of PGF2 alpha released into the medium by the end of the 5th min of incubation with LPS was 1.5 times higher than in the control (p less than 0.05); the level of 13,14-dihydro-15-keto-PGF2 alpha was decreased 1.6 times (p less than 0.01). Emoxypin abolished totally LPS-induced TxB2 and PGF2 alpha production. We conclude that aggregation and eicosanoid production are independent manifestations of LPS-induced rabbit granulocyte activation.

  11. Movement-evoked hyperalgesia induced by lipopolysaccharides is not suppressed by glucocorticoids

    PubMed Central

    Kovács, Katalin J.; Papic, Jonathan C.; Larson, Alice A.

    2008-01-01

    Systemic exposure to lipopolysaccharides (LPS) produces a variety of effects, including movement-evoked hyperalgesia that can be measured using the grip force assay in mice. Because both lethality and enhanced sensitivity to cutaneous pain following exposure to endotoxins have each been attributed to inflammatory mediators, we explored the possibility that LPS-induced movement-evoked hyperalgesia is also sensitive to manipulations of glucocorticoids that regulate these other LPS responses. We found that the hyperalgesic effect of LPS (5 mg/kg s.c.) in mice that were adrenalectomized did not differ from that in control mice that were sham-operated, even though mortality after LPS was potentiated by adrenalectomy. The development of tolerance to the movement-evoked hyperalgesic effect of LPS also did not differ between adrenalectomized and sham-operated control mice. In addition, mifepristone (25 mg/kg s.c.), a glucocorticoid antagonist, did not attenuate the hyperalgesic effect of LPS (2 mg/kg s.c.), yet this dose of mifepristone was sufficient to enhance the incidence of lethality induced by LPS. Enhancement of glucocorticoid activity by two injections of dexamethasone (1 mg/kg s.c.) had no effect on the degree of hyperalgesia in mice injected with LPS (5 mg/kg s.c.), yet this dose of dexamethasone was sufficient to attenuate the incidence of mortality induced by LPS in adrenalectomized mice. Finally, morphine (10 mg/kg i.p.) reversed the decrease in grip force caused by LPS (5 mg/kg i.p.), supporting the interpretation that decreases in grip force produced by LPS reflect muscle hyperalgesia that is not sensitive to glucocorticoids. PMID:17686584

  12. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation.

    PubMed

    Lee, Jae Woong; Lee, Yong Kyung; Yuk, Dong Yeon; Choi, Dong Young; Ban, Sang Bae; Oh, Ki Wan; Hong, Jin Tae

    2008-08-29

    Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Abeta) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD. In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting. Intraperitoneal injection of LPS, (250 microg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 microg/kg, 3 or 7 times) resulted in an accumulation of Abeta1-42 in the hippocampus and cerebralcortex of mice brains through increased beta- and gamma-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Abeta1-42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5-50 microM) also suppressed LPS (1 microg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro. This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

  13. The effect of dexmedetomidine post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide.

    PubMed

    Xie, Cuiying; Wang, Zhenhong; Tang, Jiajia; Shi, Zhiqian; He, Zhenzhou

    2015-01-01

    To explore the effect of dexmedetomidine (DEX) post-treatment on the inflammatory response of astrocyte induced by lipopolysaccharide (LPS). The astrocytes of neonatal mice were primarily cultured in vitro. After purification and identification, the cells were divided into five groups: group C: control group; group L: astrocytes were treated with 1 μg/ml LPS for 24 h; group D1, D2, and D3: astrocytes were pretreated with 1 μg/ml for 24 h LPS, and then cultured with low (0.1 μM), medium (1 μM), high (10 μM) concentration of DEX for 30 min, respectively. The cell survival rate was detected by cell counting kit. The expressions of inducible nitric oxide synthase (iNOS) mRNA, tumor necrosis gactor-α (TNF-α) mRNA, and interleukin-1β (IL-1β) mRNA were measured by RT-PCR in cell lysis solution of every group. The concentration of nitric oxide (NO) was detected by Griess method. The concentrations of IL-1β and TNF-α were measured, respectively, by enzyme-linked immuno sorbent assay. Compared with the group C, the expressions of iNOS mRNA, TNF-α mRNA, and IL-1βm RNA were significantly up-regulated, the release of NO, TNF-α, and IL-1β was significantly increased in group L (P < 0.05). Compared with group L, mRNA levels of inflammation-related factors and release of inflammatory factors were significantly down-regulated in group D2 and D3 (P < 0.05). There was no statistical difference between group D1 and group L. Pre-treatment with medium and high concentration of DEX can inhibit the LPS-induced inflammatory response of astrocyte.

  14. Inhibition of neddylation represses lipopolysaccharide-induced proinflammatory cytokine production in macrophage cells.

    PubMed

    Chang, Fang-Mei; Reyna, Sara M; Granados, Jose C; Wei, Sung-Jen; Innis-Whitehouse, Wendy; Maffi, Shivani K; Rodriguez, Edward; Slaga, Thomas J; Short, John D

    2012-10-12

    Cullin-RING E3 ligases (CRLs) are a class of ubiquitin ligases that control the proteasomal degradation of numerous target proteins, including IκB, and the activity of these CRLs are positively regulated by conjugation of a Nedd8 polypeptide onto Cullin proteins in a process called neddylation. CRL-mediated degradation of IκB, which normally interacts with and retains NF-κB in the cytoplasm, permits nuclear translocation and transactivation of the NF-κB transcription factor. Neddylation occurs through a multistep enzymatic process involving Nedd8 activating enzymes, and recent studies have shown that the pharmacological agent, MLN4924, can potently inhibit Nedd8 activating enzymes, thereby preventing neddylation of Cullin proteins and preventing the degradation of CRL target proteins. In macrophages, regulation of NF-κB signaling functions as a primary pathway by which infectious agents such as lipopolysaccharides (LPSs) cause the up-regulation of proinflammatory cytokines. Here we have analyzed the effects of MLN4924, and compared the effects of MLN4924 with a known anti-inflammatory agent (dexamethasone), on certain proinflammatory cytokines (TNF-α and IL-6) and the NF-κB signaling pathway in LPS-stimulated macrophages. We also used siRNA to block neddylation to assess the role of this molecular process during LPS-induced cytokine responsiveness. Our results demonstrate that blocking neddylation, either pharmacologically or using siRNA, abrogates the increase in certain proinflammatory cytokines secreted from macrophages in response to LPS. In addition, we have shown that MLN4924 and dexamethasone inhibit LPS-induced cytokine up-regulation at the transcriptional level, albeit through different molecular mechanisms. Thus, neddylation represents a novel molecular process in macrophages that can be targeted to prevent and/or treat the LPS-induced up-regulation of proinflammatory cytokines and the disease processes associated with their up-regulation.

  15. 1,25-Dihydroxyvitamin D3 inhibits lipopolysaccharide-induced immune activation in human endothelial cells

    PubMed Central

    Equils, O; Naiki, Y; Shapiro, A M; Michelsen, K; Lu, D; Adams, J; Jordan, S

    2006-01-01

    In addition to its well-known role in mineral and skeletal homeostasis, 1,25-dihydroxyvitamin D3[1,25-(OH)2, D3] regulates the differentiation, growth and function of a broad range of immune system cells, including monocytes, dendritic cells, T and B lymphocytes. Vascular endothelial cells play a major role in the innate immune activation during infections, sepsis and transplant rejection; however, currently there are no data on the effect of 1,25-(OH)2 D3 on microbial antigen-induced endothelial cell activation. Here we show that 1,25-(OH)2 D3 pretreatment of human microvessel endothelial cells (HMEC) inhibited the enteric Gram-negative bacterial lipopolysaccharide (LPS) activation of transcription factor NF-κB and interleukin (IL)-6, IL-8 and regulated upon activation normal T cell exposed and secreted (RANTES) release. The effect of 1,25-(OH)2 D3 was not due to increased cell death or inhibition of endothelial cell proliferation. 1,25-(OH)2 D3 pretreatment of HMEC did not block MyD88-independent LPS-induced interferon (IFN)-β promoter activation. 1,25-(OH)2 D3 pretreatment of HMEC did not modulate Toll-like receptor 4 (TLR4) or MD-2 expression. These data suggest that 1,25-(OH)2 D3 may play a role in LPS-induced immune activation of endothelial cells during Gram-negative bacterial infections, and a suggest a potential role for 1,25-(OH)2 D3 and its analogues as an adjuvant in the treatment of Gram-negative sepsis. PMID:16367934

  16. 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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    PubMed Central

    Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y.

    2016-01-01

    Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity. PMID:27428953

  18. Hepatoprotective effects of erythropoietin on D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice.

    PubMed

    Yang, Xue-Fei; He, Yi; Li, Hai-Yuan; Liu, Xin; Chen, Huan; Liu, Jian-Bang; Ji, Wen-Jun; Wang, Bing; Chen, Li-Na

    2014-07-01

    Fulminant hepatic failure is a severe clinical syndrome associated with a high rate of patient mortality. Recent studies have shown that in addition to its hematopoietic effect, erythropoietin (EPO) has multiple protective effects and exhibits antiapoptotic, antioxidant and anti-inflammatory activities. The present study aimed to determine the hepatoprotective effect of EPO and to elucidate the underlying mechanisms using a D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced model of acute liver injury. Experimental groups of mice were administered with various doses of EPO (1,000, 3,000 or 10,000 U/kg, intraperitoneal) once per day for 3 days, prior to injection with D-GalN (700 mg/kg)/LPS (10 µg/kg). Mice were sacrificed 8 h after treatment with D‑GalN/LPS. Liver function and histopathology, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) activities and EPO receptor (EPOR) and phosphatidylinositol 3-kinase (PI3K) mRNA expression were evaluated. D-GalN/LPS administration markedly induced liver injury, as evidenced by elevated levels of serum aminotransferases, as well as histopathological changes. Compared with the D-GalN/LPS group, pretreatment with EPO significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase and MDA, and increased the activities of SOD and GSH-Px. Furthermore, the protective effects of EPO were paralleled by an upregulation in the mRNA expression of EPOR and PI3K. These data suggest that EPO can ameliorate D-GalN/LPS-induced acute liver injury by reducing oxidative stress and upregulating the mRNA expression of EPOR and PI3K.

  19. Celastrol enhances cell viability and inhibits amyloid-β production induced by lipopolysaccharide in vitro.

    PubMed

    Zhao, Yan; Zhao, Hailin; Lobo, Niyati; Guo, Xiangyang; Gentleman, Steve M; Ma, Daqing

    2014-01-01

    Neuroinflammation is a notable hallmark of Alzheimer's disease pathogenesis and can markedly exacerbate amyloid pathology. Celastrol, a pentacyclic-triterpene, has been found to possess anti-inflammatory properties. The purpose of this study was to characterize the effects of celastrol on cell viability and amyloid-β (Aβ) peptide production induced by lipopolysaccharide (LPS) administration in H4 human neuroglioma cells stably transfected to overexpress human full length APP (H4-APP). H4-APP cells were exposed to 1, 10, and 100 nM of celastrol in the presence of 0.1 μg/ml or 100 μg/ml of LPS for 24 hours. The effects of celastrol were determined using MTT cell viability assay, immunohistochemistry, western blot, and ELISA. Cell viability tests revealed that a dose-dependent death of H4-APP cells following administration of LPS. Moreover, celastrol significantly reduced (p < 0.05) cell death induced by LPS compared to LPS alone. Furthermore, the administration of celastrol was associated with a significant reduction in LPS-stimulated Aβ production compared to LPS alone. Western blot and immunofluorescence analysis showed that exposure to celastrol increased HSP-70 and Bcl-2 expression but decreased NFκB activity, phosphorylated glycogen synthase kinase-3β (GSK-3β) at tyrosine 216 and cyclooxygenase-2 (COX-2) expression, Aβ accumulation together with a reduction of superoxide and hydrogen peroxide generation. HSP-70 siRNA abolished celastrol mediated cytoprotection. This study demonstrates that celastrol reduced both LPS-induced cell death and Aβ production in vitro through increasing HSP-70 and Bcl-2 expression and reducing NFκB, COX-2, and GSK-3β expression and oxidative stress.

  20. Brucella abortus Induces the Premature Death of Human Neutrophils through the Action of Its Lipopolysaccharide.

    PubMed

    Barquero-Calvo, Elías; Mora-Cartín, Ricardo; Arce-Gorvel, Vilma; de Diego, Juana L; Chacón-Díaz, Carlos; Chaves-Olarte, Esteban; Guzmán-Verri, Caterina; Buret, Andre G; Gorvel, Jean-Pierre; Moreno, Edgardo

    2015-05-01

    Most bacterial infections induce the activation of polymorphonuclear neutrophils (PMNs), enhance their microbicidal function, and promote the survival of these leukocytes for protracted periods of time. Brucella abortus is a stealthy pathogen that evades innate immunity, barely activates PMNs, and resists the killing mechanisms of these phagocytes. Intriguing clinical signs observed during brucellosis are the low numbers of Brucella infected PMNs in the target organs and neutropenia in a proportion of the patients; features that deserve further attention. Here we demonstrate that B. abortus prematurely kills human PMNs in a dose-dependent and cell-specific manner. Death of PMNs is concomitant with the intracellular Brucella lipopolysaccharide (Br-LPS) release within vacuoles. This molecule and its lipid A reproduce the premature cell death of PMNs, a phenomenon associated to the low production of proinflammatory cytokines. Blocking of CD14 but not TLR4 prevents the Br-LPS-induced cell death. The PMNs cell death departs from necrosis, NETosis and classical apoptosis. The mechanism of PMN cell death is linked to the activation of NADPH-oxidase and a modest but steadily increase of ROS mediators. These effectors generate DNA damage, recruitments of check point kinase 1, caspases 5 and to minor extent of caspase 4, RIP1 and Ca++ release. The production of IL-1β by PMNs was barely stimulated by B. abortus infection or Br-LPS treatment. Likewise, inhibition of caspase 1 did not hamper the Br-LPS induced PMN cell death, suggesting that the inflammasome pathway was not involved. Although activation of caspases 8 and 9 was observed, they did not seem to participate in the initial triggering mechanisms, since inhibition of these caspases scarcely blocked PMN cell death. These findings suggest a mechanism for neutropenia in chronic brucellosis and reveal a novel Brucella-host cross-talk through which B. abortus is able to hinder the innate function of PMN.

  1. Brucella abortus Induces the Premature Death of Human Neutrophils through the Action of Its Lipopolysaccharide

    PubMed Central

    Barquero-Calvo, Elías; Mora-Cartín, Ricardo; Arce-Gorvel, Vilma; de Diego, Juana L.; Chacón-Díaz, Carlos; Chaves-Olarte, Esteban; Guzmán-Verri, Caterina; Buret, Andre G.; Gorvel, Jean-Pierre; Moreno, Edgardo

    2015-01-01

    Most bacterial infections induce the activation of polymorphonuclear neutrophils (PMNs), enhance their microbicidal function, and promote the survival of these leukocytes for protracted periods of time. Brucella abortus is a stealthy pathogen that evades innate immunity, barely activates PMNs, and resists the killing mechanisms of these phagocytes. Intriguing clinical signs observed during brucellosis are the low numbers of Brucella infected PMNs in the target organs and neutropenia in a proportion of the patients; features that deserve further attention. Here we demonstrate that B. abortus prematurely kills human PMNs in a dose-dependent and cell-specific manner. Death of PMNs is concomitant with the intracellular Brucella lipopolysaccharide (Br-LPS) release within vacuoles. This molecule and its lipid A reproduce the premature cell death of PMNs, a phenomenon associated to the low production of proinflammatory cytokines. Blocking of CD14 but not TLR4 prevents the Br-LPS-induced cell death. The PMNs cell death departs from necrosis, NETosis and classical apoptosis. The mechanism of PMN cell death is linked to the activation of NADPH-oxidase and a modest but steadily increase of ROS mediators. These effectors generate DNA damage, recruitments of check point kinase 1, caspases 5 and to minor extent of caspase 4, RIP1 and Ca++ release. The production of IL-1β by PMNs was barely stimulated by B. abortus infection or Br-LPS treatment. Likewise, inhibition of caspase 1 did not hamper the Br-LPS induced PMN cell death, suggesting that the inflammasome pathway was not involved. Although activation of caspases 8 and 9 was observed, they did not seem to participate in the initial triggering mechanisms, since inhibition of these caspases scarcely blocked PMN cell death. These findings suggest a mechanism for neutropenia in chronic brucellosis and reveal a novel Brucella-host cross-talk through which B. abortus is able to hinder the innate function of PMN. PMID:25946018

  2. ENDOTHELIAL CELL TOLERANCE TO LIPOPOLYSACCHARIDE CHALLENGE IS INDUCED BY MONOPHOSPHORYL LIPID A

    PubMed Central

    Stark, Ryan J.; Choi, Hyehun; Koch, Stephen R.; Fensterheim, Benjamin A.; Lamb, Fred S.; Sherwood, Edward R.

    2015-01-01

    Prior exposure to lipopolysaccharide (LPS) produces a reduced or “tolerant” inflammatory response to subsequent challenges with LPS, however the potent pro-inflammatory effects of LPS limit its clinical benefit. The adjuvant Monophosphoryl lipid A (MPLA) is a weak toll-like receptor 4 (TLR4) agonist that induces negligible inflammation but retains potent immunomodulatory properties. We postulated that pre-treatment with MPLA would inhibit the inflammatory response of endothelial cells to secondary LPS challenge. Human umbilical vein endothelial cells (HUVECs), were exposed to MPLA (10 µg/ml), LPS (100 ng/ml) or vehicle control. HUVECs were then washed and maintained in culture for 24 hours before being challenged with LPS (100 ng/ml). Supernatants were collected and examined for cytokine production in the presence or absence of siRNA inhibitors of critical TLR4 signaling proteins. Pretreatment with MPLA attenuated IL-6 production to secondary LPS challenge to a similar degree as LPS. The application of MyD88 siRNA dramatically reduced MPLA-induced tolerance while TRIF siRNA had no effect. The tolerant phenotype in endothelial cells was associated with reduced IKK, p38 and JNK phosphorylation and enhanced IRAK-M expression for LPS primed HUVECs, but less so in MPLA primed cells. Instead, MPLA-primed HUVECs demonstrated enhanced ERK phosphorylation. In contrast to leukocytes in which tolerance is largely TRIF-dependent, MyD88 signaling mediated endotoxin tolerance in endothelial cells. Most importantly, MPLA, a vaccine adjuvant with a wide therapeutic window, induced tolerance to LPS in endothelial cells. PMID:26669797

  3. Ouabain attenuates the oxidative stress induced by lipopolysaccharides in the cerebellum of rats.

    PubMed

    Garcia, Israel José Pereira; Kinoshita, Paula Fernanda; de Oliveira Braga, Italo; Parreira, Gabriela Machado; Mignaco, Julio Alberto; Scavone, Cristoforo; Barbosa, Leandro Augusto; de Lima Santos, Hérica

    2017-08-31

    Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol and gangliosides were analyzed in Wistar rats after intraperitoneal injection of ouabain(1.8 µg/kg), LPS(200 µg/kg) or saline. Oxidative parameters were also evaluated, including the activities of superoxide dismutase, catalase and glutathione peroxidase, the levels of glutathione and lipid peroxidation, as well as Na,K-ATPase activity and the level of glutamate transporter EAAT4. Administration of LPS resulted in increased oxidative stress, as evidenced by an increase in lipid peroxidation levels, glutathione peroxidase activity, decreased catalase activity and reduced glutathione levels. All changes recorded were attenuated by pretreatment with ouabain. Administration of ouabain plus LPS enhanced the total ganglioside content and EAAT4 levels, but failed to alter the Na,K-ATPase activity. Our data suggest a neuroprotective effect of ouabain against LPS-induced oxidative stress by promoting membrane lipid remodeling and increasing the expression of glutamate transporter EAAT4. Our results emphasize that the observed oxidative stress is not correlated with Na,K-ATPase, but with a possible ouabain-mediated effect on cellular signaling. The relevance of our results extends beyond LPS-induced changes in oxidative parameters, as nanomolar doses of ouabain might prove useful in neurodegenerative models. Further study of other cardenolides and related molecules, as well as the development of new molecules derived from ouabain, could also prove useful in the fight against the oxidative and/or general cell stress triggered by neuronal pathologies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. Effect of ciprofloxacin/dexamethasone versus ciprofloxacin/hydrocortisone on lipopolysaccharide-induced experimental otitis media.

    PubMed

    Dattaray, Piali; Pudrith, Charles; Nyc, Mary Ann; Martin, Dusan; Kim, You Hyun; Jahng, Patrick; Chung, You Sun; Wall, G Michael; Jung, Timothy

    2011-08-01

    The purpose of this study is to compare the effect of topical ciprofloxacin/dexamethasone versus topical ciprofloxacin/hydrocortisone on the outcome of lipopolysaccharide (LPS)–induced otitis media with effusion in chinchillas. A randomized experimental animal study. Jerry L. Pettis Veteran's Medical Center. Otitis media with effusion was induced in 5 groups of chinchillas, 6 per group, by injecting 0.3 mL (1 mg/mL) of Salmonella enteric LPS into the superior bullae of each chinchilla with a venting needle in place. Each group was treated with 0.2 mL of test substance at –2, 24, 48, and 72 hours relative to the 0-hour LPS induction. Group 1 was treated with vehicle control. Groups 2 to 5 received 0.3% ciprofloxacin with either 0.1% dexamethasone (group 2), 1% dexamethasone (group 3), 0.1% hydrocortisone (group 4), or 1% hydrocortisone (group 5). The outcome of each treatment was measured by the amount of middle ear effusion present and mucosal thickness at 120 hours posttreatment. Ciprofloxacin/dexamethasone 1% significantly (P = .0150) reduced middle ear effusion compared with control. Ciprofloxacin/dexamethasone 1% significantly reduced the mucosal thickness when compared with vehicle control (P = .0005), ciprofloxacin/dexamethasone 0.1% (P = .0240), and ciprofloxacin/hydrocortisone 0.1% (P = 1.00). Results also showed a dose-response effect between the ciprofloxacin/dexamethasone concentrations. This study demonstrated that treatment with a combination of topical ciprofloxacin and corticosteroid decreased the middle ear effusion when compared with the control group and that ciprofloxacin/dexamethasone suspension reduced the severity of LPS-induced experimental otitis media more than ciprofloxacin/hydrocortisone did.

  5. An Analog of the Antimicrobial Peptide CopA5 Inhibits Lipopolysaccharide-Induced Macrophage Activation.

    PubMed

    Yoon, I Na; Hong, Ji; Zhang, Peng; Hwang, Jae Sam; Kim, Ho

    2017-02-28

    We previously reported that the CopA3 peptide (LLCIALRKK, D-form) originally isolated from the Korean dung beetle has antimicrobial and immunosuppressive effects. However, the high cost of producing the synthetic peptide, especially the D-form, has limited the development of CopA3 for therapeutic purposes. Here, we investigated whether the CopA3 deletion derivative, CopA5, which is composed of only five amino acids (LLCIA) and has the L-form structure, could inhibit the lipopolysaccharide (LPS)-induced activation of macrophages. Peritoneal exudate macrophages (PEM) were isolated from mice and exposed to LPS in the presence or absence of CopA5, and biomarkers of macrophage activation were measured. Our results revealed that LPS-induced nitric oxide (NO) production, tumor necrosis factor (TNF)-α secretion, and phagocytic activity of PEM were significantly inhibited by CopA5 treatment. Similar to CopA3, the structurally modified CopA5 peptide had no cell toxicity (as assessed by measurement of cell viability loss and apoptosis) in PEM. Moreover, the LPS-induced upregulation of the activating phosphorylation of signal transducer and activator of transcription 1 (STAT1) was markedly inhibited by CopA5 treatment. These results suggest that, similar to CopA3, CopA5 inhibits macrophage activation by inhibiting STAT1 phosphorylation and blocking the release of NO and TNF-α. CopA5 may therefore prove therapeutically useful in the realm of immune suppression.

  6. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment

    PubMed Central

    Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H.; Ehrlich, Barbara E.

    2012-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.—Mo, M., Erdelyi, I., Szigeti-Buck, K., Benbow, J. H., Ehrlich, B. E. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. PMID:22889832

  7. Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons.

    PubMed

    Hossain-Ibrahim, M K; Rezajooi, K; MacNally, J K; Mason, M R J; Lieberman, A R; Anderson, P N

    2006-01-24

    Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS) was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 (a microglia and macrophage marker). Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. Application of LPS induced a gradient of inflammation through the full depth of the motor cortex and promoted c-Jun and SCG10 expression for up to 2 weeks, and GAP-43 upregulation for 3 days by many corticospinal neurons, but had very limited effects on neuronal ATF3 expression. However, many glial cells in the subcortical white matter upregulated ATF3. LPS did not promote sprouting of anterogradely labelled corticospinal axons, which did not grow into or beyond a cervical lesion site. Inflammation produced by topical application of LPS promoted increased expression of some growth-associated genes in the cell bodies of corticospinal neurons, but was insufficient to promote regeneration of the corticospinal tract.

  8. Chemical Profiles and Protective Effect of Hedyotis diffusa Willd in Lipopolysaccharide-Induced Renal Inflammation Mice

    PubMed Central

    Ye, Jian-Hong; Liu, Meng-Hua; Zhang, Xu-Lin; He, Jing-Yu

    2015-01-01

    Protective effect of Hedyotis diffusa (H. diffusa) Willd against lipopolysaccharide (LPS)-induced renal inflammation was evaluated by the productions of cytokines and chemokine, and the bioactive constituents of H. diffusa were detected by the ultra-fast liquid chromatography -diode array detector-quadrupole-time of flight mass spectrometry (UFLC-DAD-Q-TOF-MS/MS) method. As the results showed, water extract of H. diffusa (equal to 5.0 g/kg body weight) obviously protected renal tissues, significantly suppressed the productions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1, as well as significantly promoted the production of IL-10 in serum and renal tissues. According the chemical profiles of H. diffusa, flavonoids, iridoid glycosides and anthraquinones were greatly detected in serum from H. diffusa extract treatment mice. Two main chemotypes, including eight flavonoids and four iridoid glycosides were found in renal tissues from H. diffusa extract treatment mice. The results demonstrated that water extract of H. diffusa had protective effect on renal inflammation, which possibly resulted from the bioactive constituents consisting of flavonoids, iridoids and anthraquinones. PMID:26580602

  9. [Joint effects of apoptosis induced by microcystins and bacterial lipopolysaccharides on grass carp (Ctenopharyngodon idellus) lymphocytes].

    PubMed

    Fang, Wen-Di; Zhang, Hang-Jun; Wu, Yu-Huan

    2014-02-01

    In this study, grass carp (Ctenopharyngodon idellus) lymphocytes were used as the vitro test object to demonstrate the joint effects of microcystins (MC-LR) and bacterial lipopolysaccharides (LPS) on fish immune system. The results showed that MC-LR and LPS in the single and combined exposure groups could both induce grass carp lymphocytes apoptosis with typical ladder-like DNA electrophoresis characteristics. However, comparing the apoptosis rate of the combined and single exposure groups, it was suggested that bacterial LPS could cooperate with MC-LR causing a higher rate of fish lymphocytes apoptosis (2.1 and 3.3-fold of that for the single exposure group I (MC-LR) and II (LPS), respectively), and there existed a significant dose-response relationship. The MC-LR cooperating with bacterial LPS decreased the activity of glutathione S-transferase (GST), increased the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), resulted in DNA damage and cell arrest in G0 phase, which inhibited cell proliferation and accelerated apoptosis. It was proved that MC-LR exacerbated fish immunotoxicity by collaborating with LPS, which had a serious adverse effect on aquaculture industry.

  10. Protective effects of radix Rosa laevigata against Propionibacterium acnes and lipopolysaccharide-induced liver injury.

    PubMed

    He, Rong-Rong; Yao, Xin-Sheng; Yao, Nan; Wang, Min; Dai, Yi; Gao, Hao; Yu, Yang; Kurihara, Hiroshi

    2009-05-01

    We investigated the effects of an extract of Radix Rosa laevigata (R. R. laevigata) on Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS)-induced acute liver injury. The plasma alanine aminotransferase (ALT) activity was significantly elevated by an intravenous injection of heat-killed P. acnes at a dose of 0.4 mg/mouse and then with LPS at 0.1 microg/mouse after 5 d. However, the elevated ALT activity was significantly reduced by the administered of R. R. laevigata (125 and 500 mg/kg/d) for 7 d before the LPS injection. In addition, the extract treatment reduced the number of liver mononuclear cells (MNCs), and malondialdehyde (MDA) and nitric oxide (NO) contents, but improved the liver oxygen radical absorbance capacity (ORAC) and mitochondrial membrane potential. Moreover, the chemical profile of R. R. laevigata was performed by high-performance liquid chromatography (HPLC) and the main peaks were identified as a series of polyphenol compounds which had been confirmed as the significantly active components by their anti-oxidative and NO inhibitory effects. These results suggest that the extract of R. R. laevigata offered good efficacy for preventing liver injury.

  11. Inducible expression of an antibiotic peptide gene in lipopolysaccharide-challenged tracheal epithelial cells.

    PubMed Central

    Diamond, G; Russell, J P; Bevins, C L

    1996-01-01

    Mammals continually confront microbes at mucosal surfaces. A current model suggests that epithelial cells contribute to defense at these sites, in part through the production of broad-spectrum antibiotic peptides. Previous studies have shown that invertebrates can mount a host defense response characterized by the induction in epithelia] cells of a variety of antibiotic proteins and peptides when they are challenged with microorganisms, bacterial cell wall/membrane components, or traumatic injury [Boman, H.G. & Hultmark, D. (1987) Annu. Rev. Microbiol. 41, 103-126J. However, factors that govern the expression of similar defense molecules in mammalian epithelial cells are poorly understood. Here, a 13-fold induction of the endogenous gene encoding tracheal antimicrobial peptide was found to characterize a host response of tracheal epithelia] cells (TECs) exposed to bacterial lipopolysaccharide (LPS). Northern blot data indicated that TECs express CD14, a well-characterized LPS-binding protein known to mediate many LPS responses. A monoclonal antibody to CD14 blocked the observed tracheal antimicrobial peptide induction by LPS under serum-free conditions. Together the data support that CD14 of epithelial cell origin mediates the LPS induction of an antibiotic peptide gene in TECs, providing evidence for the active participation of epithelial cells in the host's local defense response to bacteria. Furthermore, the data allude to a conservation of this host response in evolution and suggest that a similar inducible pathway of host defense is prevalent at mucosal surfaces of mammals. Images Fig. 1 Fig. 2 Fig. 3 PMID:8643545

  12. Therapeutic Effect of the Tuber of Alisma orientale on Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Kwun, Min Jung; Choi, Jun-Yong; Ahn, Kyung-Seop; Oh, Sei-Ryang; Lee, Yong Gyu; Christman, John W.; Sadikot, Ruxana T.

    2013-01-01

    Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI). Ethanol extract of the tuber of A. orientale (EEAO) was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t.) spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF-κB/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis. PMID:23983806

  13. Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis.

    PubMed

    Morton, Alison J; Campbell, Nigel B; Gayle, J'mai M; Redding, W Rich; Blikslager, Anthony T

    2005-04-01

    Synovitis in horses is frequently treated by administration of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase isoforms (COX-1 and COX-2). Constitutively expressed COX-1 is involved in physiologic functions such as maintenance of gastric mucosal integrity, whereas COX-2 is up-regulated at sites of inflammation. Thus, COX-2 inhibitors reduce inflammation with reduced gastrointestinal side effects as compared to non-selective COX inhibitors. The objective of the present study was to compare the anti-inflammatory effects of the preferential COX-2 inhibitor etodolac with the non-selective COX inhibitor phenylbutazone in horses with lipopolysaccharide (LPS)-induced synovitis. Three groups of horses (n=6) received no treatment, phenylbutazone (4.4 mg/kg, IV, q12h), or etodolac (23 mg/kg, IV, q12h), respectively, 2-h following injection of LPS into one middle carpal joint. Synovial fluid was analyzed for white blood cell (WBC) count, and TXB2 and PGE2 levels. Phenylbutazone and etodolac significantly reduced WBC count 6 and 24-h following injection of LPS compared to untreated horses. In addition, both drugs significantly reduced PGE2 levels (P<0.05) 6-h following LPS injection, whereas the probable COX-1 prostanoid TXB2 was significantly reduced by phenylbutazone (P<0.05), but not etodolac. Etodolac may serve as a more selective anti-inflammatory agent than phenylbutazone for treatment of equine synovitis.

  14. Lipopolysaccharide-Induced Ionized Hypocalcemia and Acute Kidney Injury in Carotid Chemo/Baro-Denervated Rats.

    PubMed

    Fernández, R; Cortés, P; Del Rio, R; Acuña-Castillo, C; Reyes, E P

    2015-01-01

    The acute kidney injury (AKI) observed during sepsis is due to an uncontrolled release of inflammatory mediators. Septic patients develop electrolytic disturbances and one of the most important is ionized hypocalcemia. AKI adversely affects the function of other organs and hypocalcemia is associated with cardiovascular and respiratory dysfunctions. Since carotid body chemoreceptors modulate the systemic inflammatory response during sepsis syndromes, we used pentobarbitone-anesthetized male Sprague-Dawley rats in control condition (SHAM surgery) and after bilateral carotid neurotomy (carotid chemo/baro-denervated, BCN). We evaluate serum creatinine (CRE), serum neutrophil gelatinase-associated lipocaline (NGAL), ionized calcium (iCa) and cardiac Troponin I (cTnI) 90 min after the IP administration of 15 mg/kg lipopolysaccharide (LPS) or saline. In the SHAM group, LPS failed to induce significant changes CRE, NGAL, or iCa, and increased cTnI. Conversely, in the BCN group LPS increased CRE and NGAL, decreased iCa, and enhanced the increase of cTnI. Our results suggest that carotid chemo/baro-receptors might contribute to the regulation of both renal function and calcemia during sepsis. In addition, results imply that the carotid chemo-baroreceptors serve as an immunosensory organ.

  15. Lipopolysaccharide-induced memory impairment in rats is preventable using 7-nitroindazole.

    PubMed

    Anaeigoudari, Akbar; Shafei, Mohammad Naser; Soukhtanloo, Mohammad; Sadeghnia, Hamid Reza; Reisi, Parham; Beheshti, Farimah; Mohebbati, Reza; Mousavi, Seyed Mojtaba; Hosseini, Mahmoud

    2015-09-01

    Inflammation and oxidative stress have important roles in memory impairment. The effect of 7-nitroindazole (7NI) on lipopolysaccharide (LPS)-induced memory impairment was investigated. Rats were used, divided into four groups that were treated as follows: (1) control (saline); (2) LPS; (3) 7NI-LPS; and (4) 7NI before passive avoidance (PA). In the LPS group, the latency for entering the dark compartment was shorter than in the controls (p < 0.01 and p < 0.001); while in the 7NI-LPS group, it was longer than in the LPS group (p < 0.01 and p < 0.001). Malondialdehyde (MDA) and nitric oxide (NO) metabolite concentrations in the brain tissues of the LPS group were higher than in the controls (p < 0.001 and p < 0.05); while in the 7NI-LPS group, they were lower than in the LPS group (p < 0.001 and p < 0.05, respectively). The thiol content in the brain of the LPS group was lower than in the controls (p < 0.001); while in the 7NI-LPS group, it was higher than in the LPS group (p < 0.001). It is suggested that brain tissue oxidative damage and NO elevation have a role in the deleterious effects of LPS on memory retention that are preventable using 7NI.

  16. Protective effect of daidzin against D-galactosamine and lipopolysaccharide-induced hepatic failure in mice.

    PubMed

    Kim, Sung-Hwa; Heo, Jeong-Haing; Kim, Yeong Shik; Kang, Sam Sik; Choi, Jae Sue; Lee, Sun-Mee

    2009-05-01

    This study examined the effects of daidzin, a major isoflavone from Puerariae Radix, on D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver failure. Mice were given an intraperitoneal injection of daidzin (25, 50, 100 and 200 mg/kg) 1 h before receiving an injection of D-GalN (700 mg/kg)/LPS (10 microg/kg). Daidzin markedly reduced the elevated serum aminotransferase activity and the levels of lipid peroxidation and tumor necrosis factor-alpha. The glutathione content was lower in the D-GalN/LPS group, which was attenuated by daidzin. The daidzin pretreatment attenuated the swollen mitochondria observed in the d-GalN/LPS group. Daidzin attenuated the apoptosis of hepatocytes, which was confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and a caspase-3 assay. Overall, these results suggest that the liver protection of daidzin is due to reduced oxidative stress and its antiapoptotic activity.

  17. Lipopolysaccharide-Induced Lung Injury Is Independent of Serum Vitamin D Concentration

    PubMed Central

    Klaff, Lindy S.; Gill, Sean E.; Wisse, Brent E.; Mittelsteadt, Kristen; Matute-Bello, Gustavo; Chen, Peter; Altemeier, William A.

    2012-01-01

    Vitamin D deficiency is increasing in incidence around the world. Vitamin D, a fat-soluble vitamin, has documented effects on the innate and adaptive immune system, including macrophage and T regulatory (Treg) cell function. Since Treg cells are important in acute lung injury resolution, we hypothesized that vitamin D deficiency increases the severity of injury and delays injury resolution in lipopolysaccharide (LPS) induced acute lung injury. Vitamin D deficient mice were generated, using C57BL/6 mice, through diet modification and limited exposure to ultraviolet light. At 8 weeks of age, vitamin D deficient and sufficient mice received 2.5 g/kg of LPS or saline intratracheal. At 1 day, 3 days and 10 days, mice were anesthetized and lung elastance measured. Mice were euthanized and bronchoalveolar lavage fluid, lungs and serum were collected. Ex vivo neutrophil chemotaxis was evaluated, using neutrophils from vitamin D sufficient and deficient mice exposed to the chemoattractants, KC/CXCL1 and C5a, and to bronchoalveolar lavage fluid from LPS-exposed mice. We found no difference in the degree of lung injury. Leukocytes were mildly decreased in the bronchoalveolar fluid of vitamin D deficient mice at 1 day. Ex-vivo, neutrophils from vitamin D deficient mice showed impaired chemotaxis to KC but not to C5a. Vitamin D deficiency modestly impairs neutrophil chemotaxis; however, it does not affect lung injury or its resolution in an LPS model of acute lung injury. PMID:23185294

  18. Viola yedoensis liposoluble fraction ameliorates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Li, Wen; Xie, Jun-Yun; Li, Hong; Zhang, Yun-Yi; Cao, Jie; Cheng, Zhi-Hong; Chen, Dao-Feng

    2012-01-01

    Viola yedoensis is a component of traditional Chinese herb medicine for inflammatory diseases. Chemical constituents of V. yedoensis have been shown to possess antibacterial, anti-HIV, and anticoagulant effects in experimental research; however, their anti-inflammatory properties remain to be demonstrated. In this study, a mouse model of lipopolysaccharide (LPS)-induced acute lung injury was used to investigate the effect of petroleum ether fraction of V. yedoensis (PEVY) on inflammation in vivo. After being shown to have anti-complementary activity in vitro, PEVY was orally administered to the mice at doses of 2, 4, and 8 mg/kg. Treatment with PEVY significantly decreased the wet-to-dry weight ratio of the lung, total cells, red blood cells, protein concentration, and myeloperoxidase activity in bronchoalveolar lavage fluid. PEVY markedly attenuated lung injury with improved lung morphology and reduced complement deposition. In addition, PEVY suppressed the expression of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6. Taken together, PEVY protects the lung from acute injury, potentially via inhibiting the activation of the complement system and excessive production of proinflammatory mediators.

  19. Prenylated Flavonoids from Cudrania tricuspidata Suppress Lipopolysaccharide-Induced Neuroinflammatory Activities in BV2 Microglial Cells

    PubMed Central

    Kim, Dong-Cheol; Yoon, Chi-Su; Quang, Tran Hong; Ko, Wonmin; Kim, Jong-Su; Oh, Hyuncheol; Kim, Youn-Chul

    2016-01-01

    In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE2 in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE2 in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation. PMID:26907256

  20. The effect of hydrogen sulfide donors on lipopolysaccharide-induced formation of inflammatory mediators in macrophages.

    PubMed

    Whiteman, Matthew; Li, Ling; Rose, Peter; Tan, Choon-Hong; Parkinson, David B; Moore, Philip K

    2010-05-15

    The role of hydrogen sulfide (H(2)S) in inflammation is controversial, with both pro- and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H(2)S, which give a rapid bolus of H(2)S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H(2)S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H(2)S donor (GYY4137) on the release of pro- and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1beta, IL-6, TNF-alpha, nitric oxide (*NO), and PGE(2) but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kappaB/ATF-2/HSP-27-dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1beta, IL-6, NO, PGE(2) and TNF-alpha. This study clearly shows that the effects of H(2)S on the inflammatory process are complex and dependent not only on H(2)S concentration but also on the rate of H(2)S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro- versus antiinflammatory role of H(2)S.

  1. Lipopolysaccharides induce changes in the visceral pigmentation of Eupemphix nattereri (Anura: Leiuperidae).

    PubMed

    Franco-Belussi, Lilian; de Oliveira, Classius

    2011-10-01

    Amphibians have an extracutaneous pigmentary system composed of melanin-containing cells in various tissues and organs. The functional role of these pigment cells in visceral organs has not yet been determined, although several hypotheses have been proposed. Our aim was to describe the visceral pigmentation in the frog Eupemphix nattereri under conditions of endotoxemia induced experimentally with lipopolysaccharides (LPS) from Escherichia coli and to analyze the pigmentation on the organs' surface. We used 60 adult males of E. nattereri and analyzed the visceral pigmentation 2 (LPS 2h), 6 (LPS 6h), 12 (LPS 12h), 24 (LPS 24h) or 48 h (LPS 48 h) after the LPS inoculation. We observed pigmentation on the surface of several abdominal organs. The highest degree of pigmentation was found only on the testes of the animals in the LPS 2h, LPS 6h and LPS 12h groups. The pigmentation decreased in the animals of the LPS 24h and LPS 48 h groups. The LPS administration produced no changes in the pigmentation of the cardio-respiratory and digestive systems. Thus, the cells appear to have responded to LPS intoxication, producing a rapid increase of pigmentation on the surface of the testes and a subsequent decrease in the pigmentation. These changes are most likely related to the bactericidal role of melanin, which neutralizes the effects of LPS.

  2. Plasma and tissue disposition of florfenicol in Escherichia coli lipopolysaccharide-induced endotoxaemic sheep.

    PubMed

    Pérez-Fernández, Rubén; Cazanga, Victoria; Jeldres, Jessie Ana; Silva, Pedro P; Riquelme, José; Quiroz, Fernando; Palma, Cristina; Carretta, Maria D; Burgos, Rafael A

    2017-05-01

    1. The purpose of this study was to understand the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on florfenicol (FFC) and FFC-amine (FFC-a) plasma and tissue concentrations. 2. Ten Suffolk Down sheep, 60.5 ± 4.7 kg, were distributed into two experimental groups: group 1 (LPS) treated with three intravenous doses of 1 μg/kg bw of LPS at 24, 16, and 0.75 h (45 min) before FFC treatment; group 2 (Control) was treated with saline solution (SS) in parallel to group 1. An IM dose of 20 mg FFC/kg was administered at 0.75 h after the last injection of LPS or SS. Blood and tissue samples were taken after FFC administration. 3. The plasma AUC0-4 h values of FFC were higher (p = 0.0313) in sheep treated with LPS (21.8 ± 2.0 μg·min/mL) compared with the control group (12.8 ± 2.3 μg·min/mL). Lipopolysaccharide injections increased FFC concentrations in kidneys, spleen, and brain. Low levels of plasma FFC-a were observed in control sheep (Cmax = 0.14 ± 0.01 μg/mL) with a metabolite ratio (MR) of 4.0 ± 0.87%. While in the LPS group, Cmax increased slightly (0.25 ± 0.01 μg/mL), and MR decreased to 2.8 ± 0.17%. 4. The changes observed in the plasma and tissue concentrations of FFC were attributed to the pathophysiological effects of LPS on renal hemodynamics that modified tissue distribution and reduced elimination of the drug.

  3. Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice

    PubMed Central

    Xu, Yang; Ito, Toshihiro; Fushimi, Soichiro; Takahashi, Sakuma; Itakura, Junya; Kimura, Ryojiro; Sato, Miwa; Mino, Megumi; Yoshimura, Akihiko; Matsukawa, Akihiro

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. Methods Wild-type (WT) mice and Spred-2−/− mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2−/− mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. Results LPS-induced acute lung inflammation was significantly exacerbated in Spred-2−/− mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2−/− mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. Conclusions The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the

  4. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

    PubMed

    Krukowski, Karen; Ma, Jiacheng; Golonzhka, Olga; Laumet, Geoffroy O; Gutti, Tanuja; van Duzer, John H; Mazitschek, Ralph; Jarpe, Matthew B; Heijnen, Cobi J; Kavelaars, Annemieke

    2017-03-04

    Chemotherapy-induced peripheral neuropathy is one of the most common doselimiting side-effects of cancer treatment. Currently, there is no FDA-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of á-tubulin-dependent intracellular mitochondrial transport. Here we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 versus other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased á-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intra-epidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in DRG and nerve, and restoration of intra-epidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

  5. Lipopolysaccharide-Induced Middle Ear Inflammation Disrupts the cochlear Intra-Strial Fluid–Blood Barrier through Down-Regulation of Tight Junction Proteins

    PubMed Central

    Zhang, Jinhui; Chen, Songlin; Hou, Zhiqiang; Cai, Jing; Dong, Mingmin; Shi, Xiaorui

    2015-01-01

    Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid–blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid–blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid–blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC-albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid

  6. Lipopolysaccharide-induced middle ear inflammation disrupts the cochlear intra-strial fluid-blood barrier through down-regulation of tight junction proteins.

    PubMed

    Zhang, Jinhui; Chen, Songlin; Hou, Zhiqiang; Cai, Jing; Dong, Mingmin; Shi, Xiaorui

    2015-01-01

    Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid-blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid-blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid-blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC-albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid-blood barrier

  7. Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy

    PubMed Central

    Komatsu, Masaaki; Wheeler, Heather E.; Chung, Suyoun; Low, Siew-Kee; Wing, Claudia; Delaney, Shannon M.; Gorsic, Lidija K.; Takahashi, Atsushi; Kubo, Michiaki; Kroetz, Deanna L.; Zhang, Wei; Nakamura, Yusuke; Dolan, M. Eileen

    2015-01-01

    Purpose Paclitaxel is used worldwide in the treatment of breast, lung, ovarian and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCLs) and Asian patients. Methods GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare to a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human induced pluripotent stem cells were used for functional validation of candidate genes. Results SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10−6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphological changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05) including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphological characteristics. Conclusion We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. PMID:26015512

  8. Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.

    PubMed

    Komatsu, Masaaki; Wheeler, Heather E; Chung, Suyoun; Low, Siew-Kee; Wing, Claudia; Delaney, Shannon M; Gorsic, Lidija K; Takahashi, Atsushi; Kubo, Michiaki; Kroetz, Deanna L; Zhang, Wei; Nakamura, Yusuke; Dolan, M Eileen

    2015-10-01

    Paclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients. GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes. SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10(-6)). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics. We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. ©2015 American Association for Cancer Research.

  9. Bioactive compounds from liverworts: Inhibition of lipopolysaccharide-induced inducible NOS mRNA in RAW 264.7 cells by herbertenoids and cuparenoids.

    PubMed

    Harinantenaina, Liva; Quang, Dang Ngoc; Nishizawa, Takashi; Hashimoto, Toshihiro; Kohchi, Chie; Soma, Gen-Ichiro; Asakawa, Yoshinori

    2007-08-01

    The inhibition of lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) by herbertenoids and cuparenoids isolated from liverworts in RAW 264.7 macrophages was evaluated. Among compounds tested, herbertenediol, cuparenediol, 1,2-diacetoxyherbertene and 2-hydroxy-4-methoxycuparene exhibited significant activity. For 2-hydroxy-4-methoxycuparene, chosen as representative compound, the strong inhibitory activity was related to the inhibition on LPS-induced iNOS mRNA. The structure-activity relationship will be discussed.

  10. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury

    PubMed Central

    Yao, Lu; Chen, Weina; Song, Kyoungsub; Han, Chang; Gandhi, Chandrashekhar R.; Lim, Kyu; Wu, Tong

    2017-01-01

    The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand for peroxisome proliferator-activated receptor-gamma [PPAR-γ]). To evaluate the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue injury, we generated transgenic mice with targeted expression of 15-PGDH in the liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In cultured Kupffer cells, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from hepatocytes is able to activate PPAR-γ and inhibit inflammatory cytokine production in Kupffer cells and that this paracrine mechanism

  11. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

    PubMed Central

    Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

    2015-01-01

    Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PMID:26198449

  12. Effect of induced transverse chromatic aberration on peripheral vision.

    PubMed

    Winter, Simon; Fathi, Mohammad Taghi; Venkataraman, Abinaya Priya; Rosén, Robert; Seidemann, Anne; Esser, Gregor; Lundström, Linda; Unsbo, Peter

    2015-10-01

    Transverse chromatic aberration (TCA) is one of the largest optical errors affecting the peripheral image quality in the human eye. However, the effect of chromatic aberrations on our peripheral vision is largely unknown. This study investigates the effect of prism-induced horizontal TCA on vision, in the central as well as in the 20° nasal visual field, for four subjects. Additionally, the magnitude of induced TCA (in minutes of arc) was measured subjectively in the fovea with a Vernier alignment method. During all measurements, the monochromatic optical errors of the eye were compensated for by adaptive optics. The average reduction in foveal grating resolution was about 0.032 ± 0.005  logMAR/arcmin of TCA (mean ± std). For peripheral grating detection, the reduction was 0.057 ± 0.012  logMAR/arcmin. This means that the prismatic effect of highly dispersive spectacles may reduce the ability to detect objects in the peripheral visual field.

  13. Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

    PubMed

    Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

    2017-05-01

    Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m(2), and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

  14. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia.

    PubMed

    von Meyenburg, Claudia; Langhans, Wolfgang; Hrupka, Brian J

    2003-03-01

    We examined the role of serotonin (5-HT) and the 5-HT(1A) and 5-HT(2C) receptors in the anorectic effects of centrally administered lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), and leptin. Food intake was measured in rats after intracerebroventricular (ICV) injections of LPS (20 ng), IL-1 beta (10 ng), or leptin (1 microg) at lights out, followed by intraperitoneal (IP) injections of either the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) (125 microg/kg) or the 5-HT(2C) receptor antagonist SB 242084 (0.3 mg/kg) at the onset of anorexia. SB 242084 significantly attenuated the food intake reduction caused by all compounds (all P<.01). IP 8-OH-DPAT attenuated ICV IL-1 beta-induced anorexia (P<.01). We also tested the involvement of the median raphe 5-HT(1A) receptors in peripheral LPS- and IL-1 beta-induced anorexia. Rats were injected intraperitoneally with either LPS (100 microg/kg) or IL-1 beta (2 microg/kg) at lights out, and 8-OH-DPAT (4 nmol) was administered directly into the median raphe nucleus at the onset of anorexia. Median raphe injections of 8-OH-DPAT significantly attenuated both IL-1 beta- and LPS-induced anorexia (both P<.01). These results implicate the 5-HT(2C) receptors in the mediation of central LPS-, IL-1 beta-, and leptin-induced anorexia. Our results also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and IL-1 beta.

  15. Analysis of Ionomic Profiles of Canine Hairs Exposed to Lipopolysaccharide (LPS)-Induced Stress.

    PubMed

    So, Kyoung-Min; Lee, Yoonseok; Bok, Jin Duck; Kim, Eun Bae; Chung, Myung Il

    2016-08-01

    The purpose of this study was to provide a new insight on the response of canines to stress exposure; the ionomic profiles of canine hair (2.8 ± 0.3 years, 15.17 ± 2.1 kg) (n = 10) was determined before and after lipopolysaccharide (LPS) injections. LPS was intramuscularly injected to induce inflammatory stress responses which were confirmed by observing increases in the level of serum cortisol, aldosterone, and inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The hair contents of 17 elements were obtained by applying analytical procedures using the inductively coupled plasma mass spectrometry (ICP-MS). The following elements: sodium(Na) and potassium(K) among macro-elements, iron(Fe) and manganese(Mn) among micro-elements, and aluminum(Al), nickel(Ni), and lead(Pb) for toxic elements, showed significant increased levels with the immunological stress. The degree of increase in toxic elements was remarkable with the stress exposure. A forty-five-fold increase seen in Al accumulation with the stress exposure was noteworthy. Although mercury(Hg) and cadmium(Cd) showed decreased levels with the stress exposure, the degree was negligible compared to the level of increase. Correlation pattern between the elements was changed with the immunological stress. Toxic elements became more correlated with macro- or micro-elements than with toxic elements themselves after the stress exposure. Principal component analysis (PCA) showed that LPS challenge shifted the overall hair mineral profiles to a consistent direction changing Al and K up, even in animals with different hair mineral profiles before LPS treatment. In conclusion, the multivariate data processing and study of element distribution patterns provided new information about the ionomic response of the canine hairs to immunological stress, i.e., the ionomic profiles of canine hairs is strongly affected by the stress induced by LPS injections.

  16. Zinc Prevents Sickness Behavior Induced by Lipopolysaccharides after a Stress Challenge in Rats

    PubMed Central

    Kirsten, Thiago B.; Galvão, Marcella C.; Reis-Silva, Thiago M.; Queiroz-Hazarbassanov, Nicolle; Bernardi, Maria M.

    2015-01-01

    Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations. PMID:25775356

  17. Iron oxide nanoparticles modulate lipopolysaccharide-induced inflammatory responses in primary human monocytes

    PubMed Central

    Grosse, Susann; Stenvik, Jørgen; Nilsen, Asbjørn M

    2016-01-01

    Co-stimulation of the immune system to more than one agent concomitantly is very common in real life, and considering the increasing use of engineered nanoparticles and nanomaterials, it is highly relevant to assess the ability of these materials to modulate key innate immune responses, which has not yet been studied in detail. We investigated the immunomodulatory effects of 10 nm and 30 nm iron oxide nanoparticles (IONPs) on primary human monocytes in the presence and absence of Toll-like receptor 4 agonist lipopolysaccharide (LPS). Prior to the cell studies, we characterized the physicochemical properties of the nanoparticles in cell culture medium and ensured that the nanoparticles were free from biological contamination. Cellular uptake of the IONPs in monocytes was assessed using transmission electron microscopy. Using enzyme-linked immunosorbent assay, we found that the IONPs per se did not induce the production of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. However, the IONPs had the ability to suppress LPS-induced nuclear factor kappa B activation and production of proinflammatory cytokines in primary human monocytes in an LPS and a particle dose-dependent manner. Using confocal microscopy and fluorescently labeled LPS, we showed that the effects correlated with impaired LPS internalization by monocytes in the presence of IONPs, which could be partly explained by LPS adsorption onto the nanoparticle surface. Additionally, the results from particle pretreatment experiments indicate that other cellular mechanisms might also play a role in the observed effects, which warrants further studies to elucidate the additional mechanisms underlying the capacity of IONPs to alter the reactivity of monocytes to LPS and to mount an appropriate cellular response. PMID:27695322

  18. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats.

    PubMed

    Zhao, Z G; Zhang, L L; Niu, C Y; Zhang, J

    2014-02-01

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  19. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    PubMed Central

    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J.

    2014-01-01

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis. PMID:24519128

  20. Effect of Inulin on Proteome Changes Induced by Pathogenic Lipopolysaccharide in Human Colon.

    PubMed

    Guarino, Michele Pier Luca; Altomare, Annamaria; Barera, Simone; Locato, Vittoria; Cocca, Silvia; Franchin, Cinzia; Arrigoni, Giorgio; Vannini, Candida; Grossi, Sarah; Campomenosi, Paola; Pasqualetti, Valentina; Bracale, Marcella; Alloni, Rossana; De Gara, Laura; Cicala, Michele

    2017-01-01

    In the present study, the protective role of inulin against lipopolysaccharide (LPS)-induced oxidative stress was evaluated on human colonic mucosa using a proteomic approach. Human colonic mucosa and submucosa were sealed between two chambers, with the luminal side facing upwards and overlaid with Krebs (control), LPS or LPS+ inulin IQ solution. The solutions on the submucosal side (undernatants) were collected following 30 min of mucosal exposure. iTRAQ based analysis was used to analyze the total soluble proteomes from human colonic mucosa and submucosa treated with different undernatants. Human colonic muscle strips were exposed to the undernatants to evaluate the response to acetylcholine. Inulin exposure was able to counteract, in human colonic mucosa, the LPS-dependent alteration of some proteins involved in the intestinal contraction (myosin light chain kinase (MLCK), myosin regulatory subunit (MYL)), to reduce the up-regulation of two proteins involved in the radical-mediated oxidative stress (the DNA-apurinic or apyrimidinic site) lyase) APEX1 and the T-complex protein 1 subunit eta (CCT7) and to entail a higher level of some detoxification enzymes (the metallothionein-2 MT2A, the glutathione-S-transferase K GSTk, and two UDP- glucuronosyltransferases UGT2B4, UGT2B17). Inulin exposure was also able to prevent the LPS-dependent intestinal muscle strips contraction impairment and the mucosa glutathione level alterations. Exposure of colonic mucosa to inulin seems to prevent LPS-induced alteration in expression of some key proteins, which promote intestinal motility and inflammation, reducing the radical-mediated oxidative stress.

  1. Protein Phosphatase 2A in Lipopolysaccharide-Induced Cyclooxygenase-2 Expression in Murine Lymphatic Endothelial Cells

    PubMed Central

    Chuang, Yu-Fan; Chen, Mei-Chieh; Huang, Shiu-Wen; Hsu, Ya-Fen; Ou, George; Tsai, Yu-Jou; Hsu, Ming-Jen

    2015-01-01

    The lymphatic endothelium plays an important role in the maintenance of tissue fluid homeostasis. It also participates in the pathogenesis of several inflammatory diseases. However, little is known about the underlying mechanisms by which lymphatic endothelial cell responds to inflammatory stimuli. In this study, we explored the mechanisms by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in murine lymphatic endothelial cells (SV-LECs). LPS caused increases in cox-2 mRNA and protein levels, as well as in COX-2 promoter luciferase activity in SV-LECs. These actions were associated with protein phosphatase 2A (PP2A), apoptosis signal-regulating kinase 1 (ASK1), JNK1/2 and p38MAPK activation, and NF-κB subunit p65 and C/EBPβ phosphorylation. PP2A-ASK1 signaling blockade reduced LPS-induced JNK1/2, p38MAPK, p65 and C/EBPβ phosphorylation. Transfection with PP2A siRNA reduced LPS’s effects on p65 and C/EBPβ binding to the COX-2 promoter region. Transfected with the NF-κB or C/EBPβ site deletion of COX-2 reporter construct also abrogated LPS’s enhancing effect on COX-2 promoter luciferase activity in SV-LECs. Taken together, the induction of COX-2 in SV-LECs exposed to LPS may involve PP2A-ASK1-JNK and/or p38MAPK-NF-κB and/or C/EBPβ cascade. PMID:26317424

  2. Iron oxide nanoparticles modulate lipopolysaccharide-induced inflammatory responses in primary human monocytes.

    PubMed

    Grosse, Susann; Stenvik, Jørgen; Nilsen, Asbjørn M

    Co-stimulation of the immune system to more than one agent concomitantly is very common in real life, and considering the increasing use of engineered nanoparticles and nanomaterials, it is highly relevant to assess the ability of these materials to modulate key innate immune responses, which has not yet been studied in detail. We investigated the immunomodulatory effects of 10 nm and 30 nm iron oxide nanoparticles (IONPs) on primary human monocytes in the presence and absence of Toll-like receptor 4 agonist lipopolysaccharide (LPS). Prior to the cell studies, we characterized the physicochemical properties of the nanoparticles in cell culture medium and ensured that the nanoparticles were free from biological contamination. Cellular uptake of the IONPs in monocytes was assessed using transmission electron microscopy. Using enzyme-linked immunosorbent assay, we found that the IONPs per se did not induce the production of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. However, the IONPs had the ability to suppress LPS-induced nuclear factor kappa B activation and production of proinflammatory cytokines in primary human monocytes in an LPS and a particle dose-dependent manner. Using confocal microscopy and fluorescently labeled LPS, we showed that the effects correlated with impaired LPS internalization by monocytes in the presence of IONPs, which could be partly explained by LPS adsorption onto the nanoparticle surface. Additionally, the results from particle pretreatment experiments indicate that other cellular mechanisms might also play a role in the observed effects, which warrants further studies to elucidate the additional mechanisms underlying the capacity of IONPs to alter the reactivity of monocytes to LPS and to mount an appropriate cellular response.

  3. Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats.

    PubMed

    Murtishaw, Andrew S; Heaney, Chelcie F; Bolton, Monica M; Sabbagh, Jonathan J; Langhardt, Michael A; Kinney, Jefferson W

    2016-02-01

    Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 μL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and β-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.

  4. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  5. Bacterial lipopolysaccharides, phorbol myristate acetate, and zymosan induce the myristoylation of specific macrophage proteins.

    PubMed Central

    Aderem, A A; Keum, M M; Pure, E; Cohn, Z A

    1986-01-01

    We demonstrate stimulus-dependent incorporation of exogenously added [3H]myristic acid into specific macrophage proteins. In control unstimulated cells an 18-kDa protein is the major acylated species. In cells incubated with bacterial lipopolysaccharide (LPS), or its monoacyl glucosamine phosphate derivative, fatty acid is incorporated into proteins with molecular mass of 68 kDa and a doublet of approximately 42-45 kDa. Phorbol 12-myristate 13-acetate (PMA) or a phagocytic stimulus (zymosan) promotes the acylation of a similar array of proteins. However, PMA and zymosan also promote the myristoylation of unique proteins of 92 and 50 kDa. The fatty acid associated with each of the acylated proteins is myristic acid. The myristate is probably linked to the proteins through amide bonds, since it is not released by treatment with hydroxylamine. Palmitate and arachidonate are not incorporated into proteins in the same manner. Temporal analysis revealed that LPS-induced proteins are myristoylated by 30 min, while the 50-kDa protein myristoylated in response to PMA is labeled later. Most myristoylated proteins appear to be associated with the membrane fraction. Macrophages from C3H/HeJ mice, which do not respond to LPS, do not show any LPS-dependent protein acylation. Interestingly, zymosan and PMA induce the myristoylation of the 50-kDa protein in C3H/HeJ macrophages, but not the acylation of the 68-kDa and 42-kDa doublet species. We suggest that myristoylation of specific proteins is an intermediary in the capacity of LPS, PMA, and zymosan to alter macrophage functions such as arachidonic acid metabolism. Images PMID:3461461

  6. Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing NF-κB signaling pathway

    PubMed Central

    Dang, Yalong; Mu, Yalin; Wang, Kun; Xu, Ke; Yang, Jing; Zhu, Yu; Luo, Bin

    2016-01-01

    Objective To investigate the effects of papaverine (PAP) on lipopolysaccharide (LPS)-induced microglial activation and its possible mechanisms. Materials and methods BV2 microglial cells were first pretreated with PAP (0, 0.4, 2, 10, and 50 μg/mL) and then received LPS stimulation. Transcription and production of proinflammatory factors (IL1β, TNFα, iNOS, and COX-2) were used to evaluate microglial activation. The transcriptional changes undergone by M1/M2a/M2b markers were used to evaluate phenotype transformation of BV2 cells. Immunofluorescent staining and Western blot were used to detect the location and expression of P65 and p-IKK in the presence or absence of PAP pretreatment. Results Pretreatment with PAP significantly inhibited the expression of IL1β and TNFα, and suppressed the transcription of M1/M2b markers Il1rn, Socs3, Nos2 and Ptgs2, but upregulated the transcription of M2a markers (Arg1 and Mrc1) in a dose-dependent manner. In addition, PAP pretreatment significantly decreased the expression of p-IKK and inhibited the nuclear translocation of P65 after LPS stimulation. Conclusion PAP not only suppressed the LPS-induced microglial activity by inhibiting transcription/production of proinflammatory factors, but also promoted the transformation of activated BV2 cells from cytotoxic phenotypes (M1/M2b) to a neuroprotective phenotype (M2a). These effects were probably mediated by NF-κB signaling pathway. Thus, it would be a promising candidate for the treatment of neurodegenerative diseases. PMID:27013863

  7. Docosahexaenoic acid ester of phloridzin inhibit lipopolysaccharide-induced inflammation in THP-1 differentiated macrophages.

    PubMed

    Sekhon-Loodu, Satvir; Ziaullah; Rupasinghe, H P Vasantha

    2015-03-01

    Phloridzin or phlorizin (PZ) is a predominant phenolic compound found in apple and also used in various natural health products. Phloridzin shows poor absorption and cellular uptake due to its hydrophilic nature. The aim was to investigate and compare the effect of docosahexaenoic acid (DHA) ester of PZ (PZ-DHA) and its parent compounds (phloridzin and DHA), phloretin (the aglycone of PZ) and cyclooxygenase inhibitory drugs (diclofenac and nimesulide) on production of pro-inflammatory biomarkers in inflammation-induced macrophages by lipopolysaccharide (LPS)-stimulation. Human THP-1 monocytes were seeded in 24-well plates (5×10(5)/well) and treated with phorbol 12-myristate 13-acetate (PMA, 0.1μg/mL) for 48h to induce macrophage differentiation. After 48h, the differentiated macrophages were washed with Hank's buffer and treated with various concentrations of test compounds for 4h, followed by the LPS-stimulation (18h). Pre-exposure of PZ-DHA ester was more effective in reducing tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) protein levels compared to DHA and nimesulide. However, diclofenac was the most effective in reducing prostaglandin (PGE2) level by depicting a dose-dependent response. However, PZ-DHA ester and DHA were the most effective in inhibiting the activation of nuclear factor-kappa B (NF-κB) among other test compounds. Our results suggest that PZ-DHA ester might possess potential therapeutic activity to treat inflammation related disorders such as type 2 diabetes, asthma, atherosclerosis and inflammatory bowel disease.

  8. Mas receptor deficiency exacerbates lipopolysaccharide-induced cerebral and systemic inflammation in mice.

    PubMed

    Oliveira-Lima, Onésia C; Pinto, Mauro C X; Duchene, Johan; Qadri, Fatimunnisa; Souza, Laura L; Alenina, Natalia; Bader, Michael; Santos, Robson A S; Carvalho-Tavares, Juliana

    2015-12-01

    Beyond the classical actions of the renin-angiotensin system on the regulation of cardiovascular homeostasis, several studies have shown its involvement in acute and chronic inflammation. The G protein-coupled receptor Mas is a functional binding site for the angiotensin-(1-7); however, its role in the immune system has not been fully elucidated. In this study, we evaluated the effect of genetic deletion of Mas receptor in lipopolysaccharide (LPS)-induced systemic and cerebral inflammation in mice. Inflammatory response was triggered in Mas deficient (Mas(-/-)) and C57BL/6 wild-type (WT) mice (8-12 weeks-old) by intraperitoneal injection of LPS (5 mg/kg). Mas(-/-) mice presented more intense hypothermia compared to WT mice 24 h after LPS injection. Systemically, the bone marrow of Mas(-/-) mice contained a lower number of neutrophils and monocytes 3 h and 24 h after LPS injection, respectively. The plasma levels of inflammatory mediators KC, MCP-1 and IL-10 were higher in Mas(-/-) mice 24 h after LPS injection in comparison to WT. In the brain, Mas(-/-) animals had a significant increase in the number of adherent leukocytes to the brain microvasculature compared to WT mice, as well as, increased number of monocytes and neutrophils recruited to the pia-mater. The elevated number of adherent leukocytes on brain microvasculature in Mas(-/-) mice was associated with increased expression of CD11b - the alpha-subunit of the Mac-1 integrin - in bone marrow neutrophils 3h after LPS injection, and with increased brain levels of chemoattractants KC, MIP-2 and MCP-1, 24 h later. In conclusion, we demonstrated that Mas receptor deficiency results in exacerbated inflammation in LPS-challenged mice, which suggest a potential role for the Mas receptor as a regulator of systemic and brain inflammatory response induced by LPS. Copyright © 2015 Elsevier GmbH. All rights reserved.

  9. Lipopolysaccharide-induced cytokine cascade and lethality in LT alpha/TNF alpha-deficient mice.

    PubMed Central

    Amiot, F.; Fitting, C.; Tracey, K. J.; Cavaillon, J. M.; Dautry, F.

    1997-01-01

    BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is often considered the main proinflammatory cytokine induced by lipopolysaccharide (LPS) and consequently the critical mediator of the lethality associated with septic shock. MATERIALS AND METHODS: We used mice carrying a deletion of both the lymphotoxin alpha (LT-alpha) and TNF-alpha genes to assess the role of TNF in the cytokine cascade and lethality induced by LPS. RESULTS: Initial production of IL-1 alpha, IL-1 beta, IL-6, and IL-10 is comparable in wild-type and mutant mice. However, at later times, expression of IL-1 alpha, IL-1 beta, and IL-10 is prolonged, whereas that of IL-6 decreases in mutant mice. Expression of IFN-gamma is almost completely abrogated in mutants, which is in agreement with a more significant alteration of the late phase of the cytokine cascade. We measured similar LD50 (600 micrograms) for the intravenous injection of LPS in mice of the three genotypes (+/+, +/-, -/-), demonstrating that the absence of TNF does not confer long-term protection from lethality. However, death occurred much more slowly in mutant mice, who were protected more efficiently from death by CNI 1493, an inhibitor of proinflammatory cytokine production, than were wild-type mice. DISCUSSION: Thus, while TNF-alpha is not required for the induction of these cytokines by LPS, it modulates the kinetics of their expression. The lethality studies simultaneously confirm a role for TNF as a mediator of early lethality and establish that, in the absence of these cytokines, other mediators take over, resulting in the absence of long-term protection from LPS toxicity. Images FIG. 1 FIG. 2 PMID:9440119

  10. Effect of Inulin on Proteome Changes Induced by Pathogenic Lipopolysaccharide in Human Colon

    PubMed Central

    Guarino, Michele Pier Luca; Barera, Simone; Locato, Vittoria; Cocca, Silvia; Franchin, Cinzia; Arrigoni, Giorgio; Vannini, Candida; Grossi, Sarah; Campomenosi, Paola; Pasqualetti, Valentina; Bracale, Marcella; Alloni, Rossana; De Gara, Laura; Cicala, Michele

    2017-01-01

    In the present study, the protective role of inulin against lipopolysaccharide (LPS)-induced oxidative stress was evaluated on human colonic mucosa using a proteomic approach. Human colonic mucosa and submucosa were sealed between two chambers, with the luminal side facing upwards and overlaid with Krebs (control), LPS or LPS+ inulin IQ solution. The solutions on the submucosal side (undernatants) were collected following 30 min of mucosal exposure. iTRAQ based analysis was used to analyze the total soluble proteomes from human colonic mucosa and submucosa treated with different undernatants. Human colonic muscle strips were exposed to the undernatants to evaluate the response to acetylcholine. Inulin exposure was able to counteract, in human colonic mucosa, the LPS-dependent alteration of some proteins involved in the intestinal contraction (myosin light chain kinase (MLCK), myosin regulatory subunit (MYL)), to reduce the up-regulation of two proteins involved in the radical-mediated oxidative stress (the DNA-apurinic or apyrimidinic site) lyase) APEX1 and the T-complex protein 1 subunit eta (CCT7) and to entail a higher level of some detoxification enzymes (the metallothionein-2 MT2A, the glutathione–S-transferase K GSTk, and two UDP- glucuronosyltransferases UGT2B4, UGT2B17). Inulin exposure was also able to prevent the LPS-dependent intestinal muscle strips contraction impairment and the mucosa glutathione level alterations. Exposure of colonic mucosa to inulin seems to prevent LPS-induced alteration in expression of some key proteins, which promote intestinal motility and inflammation, reducing the radical-mediated oxidative stress. PMID:28068390

  11. Red Blood Cell Supernatant Potentiates LPS-Induced Proinflammatory Cytokine Response From Peripheral Blood Mononuclear Cells

    PubMed Central

    Nydam, Trevor L.; Clarke, Jason H.; Banerjee, Anirban; Silliman, Christopher C.; McCarter, Martin D.

    2009-01-01

    Allogeneic blood transfusion has an immunomodulatory capacity on its recipients through accumulation of immunologically active substances with blood storage, and prestorage leukoreduction reduces many of these mediators. We investigated lipopolysaccharide (LPS)-induced cytokine response of peripheral blood mononuclear cells (PBMCs) exposed to packed red blood cell (PRBC) supernatants from leukoreduced (LR) or non-leukoreduced (NLR) units with variable duration of storage. PRBC units were collected with or without leukoreduction on Day 0 before routine storage. The plasma fraction (supernatant) was isolated from LR and NLR units after 1 day (D1) or 42 days (D42) of storage and exposed to PBMCs versus control media for 24 h, then with LPS for an additional 24 h. Cell supernatants were analyzed for IL-1β, IL-6, IL-8, IL-10, and TNF-α by cytokine bead array. IL-1β, TNF-α, and IL-6 were significantly elevated in PRBC groups versus control. D42 NLR PRBC supernatant significantly increased secretion of IL-1β and IL-6 compared to D1 NLR PRBC supernatant. LR significantly attenuated the cytokine response of IL-1β. Thus, PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs. This response is accentuated with storage duration and partially attenuated with leukoreduction. These findings may partially explain the immune activation seen clinically after blood transfusion. PMID:19441884

  12. Hericium erinaceum induces maturation of dendritic cells derived from human peripheral blood monocytes.

    PubMed

    Kim, Sun Kyung; Son, Chang Gue; Yun, Cheol-Heui; Han, Seung Hyun

    2010-01-01

    Hericium erinaceum, a medicinal mushroom, has long been used as a therapeutic due to its immuno-regulating potentials eliciting anticarcinogenic and antimicrobial efficacies. Since maturation of dendritic cells (DC) is an important process in the initiation and regulation of immune responses, the ability of water-soluble components from H. erinaceum (WEHE) to regulate DC maturation was investigated. Immature DC were prepared by differentiating human peripheral blood CD14-positive cells with GM-CSF and IL-4. DC were stimulated with WEHE at 2-20 microg/mL for 48 h and subjected to flow cytometric analysis to determine the expression of indicative maturation markers. The endocytic capacity of WEHE-stimulated DC was examined by a Dextran-FITC uptake assay. An enzyme-linked immunosorbent assay was performed to examine the secretion of TNF-alpha and IL-12p40. DC stimulated with WEHE showed representative features upon DC maturation: enhanced expression of CD80, CD83 and CD86, and both MHC class I and II molecules, decreased endocytic capacity of DC, increased expression of CD205, and decreased expression of CD206. However, interestingly, WEHE could not induce the production of TNF-alpha and IL-12p40, whereas lipopolysaccharide substantially increased the production of both cytokines. Collectively, these results suggest that H. erinaceum induces the maturation of human DC, which might reinforce the host innate immune system.

  13. B Vitamin Complex and Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Schloss, Janet; Colosimo, Maree

    2017-10-05

    The purpose of this mini review is to evaluate the literature on B vitamins and chemotherapy-induced peripheral neuropathy. One hundred and five journal articles were evaluated and nine manuscripts were included. There was one in vitro, one was an animal and seven were human studies. The in vitro study was a safety study on vitamin B6 and oxaliplatin which was not directly related to CIPN. The animal study evaluated vitamin B3 on paclitaxel administration with positive results. The human studies varied using a vitamin B complex, vitamin B12 only and vitamin B6. Chemotherapy-induced peripheral neuropathy (CIPN) continues to plague patients and the medical fraternity. Currently, there are still no conclusive protective or treatment options. B vitamins have been found to play a role in CIPN prevention, but further studies are required to ascertain possible protection and treatment options.

  14. Genetic advances uncover mechanisms of chemotherapy-induced peripheral neuropathy.

    PubMed

    Chua, K C; Kroetz, D L

    2017-04-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity experienced in 30-40% of patients undergoing treatment with various chemotherapeutics, including taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and thalidomide. Importantly, CIPN significantly affects a patient's quality of life. Recent genetic association studies are enhancing our understanding of CIPN pathophysiology and serve as a foundation for identification of genetic biomarkers to predict toxicity risk and for the development of novel strategies for prevention and treatment.

  15. Serotonin induces peripheral mechanical antihyperalgesic effects in mice.

    PubMed

    Diniz, Danielle A; Petrocchi, Júlia Alvarenga; Navarro, Larissa Caldeira; Souza, Tâmara Cristina; Castor, Marina G M; Perez, Andrea C; Duarte, Igor D G; Romero, Thiago R L

    2015-11-15

    The role of serotonin (5-HT) in nociception will vary according to the subtypes of receptors activated. When administered peripherally, it induces pain in humans and in rats by activation of 5-HT1, 5-HT2 and 5-HT3 receptors. In addition, endogenous 5-HT produced in situ, is involved in the nociceptive response induced by formalin in rat's paw inflammation, possibly via 5-HT3 receptors. Moreover, it has been shown that 5-HT released in the dorsal horn of the spinal cord by stimulation of the periaqueductal gray causes activation of inhibitory interneurons, resulting in inhibition of spinal neurons. In the present study we evaluated the effect of serotonin and its receptors at peripheral antinociception. The mice paw pressure test was used in animals that had increased sensitivity by an intraplantar injection of PGE2 (2 µg). We used selective antagonists of serotonin receptors (isamoltan 5-HT1B, BRL 15572 5-HT1D, ketanserin 5-HT2A, ondansetron 5-HT3 and SB-269970 5-HT7). Administration of serotonin into the right hind paw (62.5, 125, 250 and 500 ng and 1 µg) produced a dose-dependent peripheral mechanical antihyperalgesic effect of serotonin in mice. Selective antagonists for 5-HT1B, 5-HT2A, 5-HT3 receptors at doses of 0.1, 1 and 10 µg, reversed the antihyperalgesic effect induced by 250 ng serotonin. In contrast, selective antagonists for 5-HT1D and 5-HT7 receptors were unable to reverse the antihyperalgesic effect induced by serotonin. These results demonstrated for the first time, the peripheral mechanical antihyperalgesic effect of serotonin, and participation of 5-HT1B, 5-HT2A and 5-HT3 receptors in this event.

  16. Effect of Ambroxol and Beclomethasone on Lipopolysaccharide-Induced Nitrosative Stress in Bronchial Epithelial Cells.

    PubMed

    Ricciardolo, Fabio L M; Sorbello, Valentina; Benedetto, Sabrina; Paleari, Davide

    2015-01-01

    Nitrosative stress is involved in different airway diseases. Lipopolysaccharide (LPS) induces neutrophil-related cytokine release and nitrosative stress in human bronchial epithelial (BEAS-2B) cells alone or with human polymorphonuclear neutrophils (PMNs). Ambroxol protects against oxidative stress, and beclomethasone dipropionate is an anti-inflammatory drug. We evaluated the ability of ambroxol and/or beclomethasone dipropionate to inhibit LPS-induced expression/release of RANTES, IL-8, inducible NO synthase (iNOS), myeloperoxidase (MPO) and 3-nitrotyrosine (3-NT: nitrosative stress biomarker) in BEAS-2B ± PMNs stimulated with LPS (1 μg/ml). The effect of ambroxol and/or beclomethasone dipropionate on IL-8, RANTES and iNOS levels was assessed by Western blot analysis; IL-8, MPO and 3-NT levels were measured by ELISA. Cell viability was assessed by the trypan blue exclusion test. In BEAS-2B alone, LPS (at 12 h) increased RANTES/iNOS expression and IL-8 levels (p < 0.001). Ambroxol suppressed LPS-induced RANTES expression and IL-8 release (p < 0.001), whilst inhibiting iNOS expression (p < 0.05). Beclomethasone dipropionate had no effect on RANTES but halved iNOS expression and IL-8 release. Coculture of BEAS-2B with PMNs stimulated IL-8, MPO and 3-NT production (p < 0.001), potentiated by LPS (p < 0.001). Ambroxol and beclomethasone dipropionate inhibited LPS-stimulated IL-8, MPO and 3-NT release (p < 0.05). Ambroxol/beclomethasone dipropionate combination potentiated the inhibition of IL-8 and 3-NT production in BEAS-2B with PMNs (p < 0.05 and p < 0.01, respectively). Ambroxol and/or beclomethasone dipropionate inhibited nitrosative stress and the release of neutrophilic inflammatory products in vitro. The additive effect of ambroxol and beclomethasone dipropionate on IL-8 and 3-NT inhibition suggests new therapeutic options in the treatment of neutrophil-related respiratory diseases such as chronic obstructive pulmonary disease and respiratory infections.

  17. Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers.

    PubMed

    Sparkman, Nathan L; Buchanan, Jessica B; Heyen, Jonathan R R; Chen, Jing; Beverly, James L; Johnson, Rodney W

    2006-10-18

    Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6(+/+)) and IL-6 knock-out (IL-6(-/-)) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6(+/+) mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6(-/-) mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1beta and tumor necrosis factor alpha (TNFalpha), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1beta and TNFalpha mRNA in neuronal layers of the hippocampus were determined in IL-6(+/+) and IL-6(-/-) mice after injection of LPS. Plasma IL-1beta and TNFalpha and c-Fos immunoreactivity in the NTS were increased similarly in IL-6(+/+) and IL-6(-/-) mice after LPS, indicating high circulating levels of IL-1beta and TNFalpha and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1beta and TNFalpha mRNA that was evident in hippocampal tissue of IL-6(+/+) mice was greatly attenuated or entirely absent in IL-6(-/-) mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.

  18. MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta.

    PubMed

    Ogimoto, Kayoko; Harris, Marvin K; Wisse, Brent E

    2006-09-01

    Systemic inflammatory signals can disrupt the physiological regulation of energy balance, causing anorexia and weight loss. In the current studies, we investigated whether MyD88, the primary, but not exclusive, intracellular signal transduction pathway for Toll-like receptor 4 and IL-1 receptor I, is necessary for anorexia and weight loss to occur in response to stimuli that activate these key innate immune receptors. Our findings demonstrate that the absence of MyD88 signaling confers complete protection against anorexia induced by either lipopolysaccharide (LPS) (20 h food intake in MyD88-/- mice 5.4 +/- 0.3 vs. 3.3 +/- 0.4 g in MyD88+/+ control mice, P < 0.001) or IL-1 beta (20 h food intake in MyD88-/- mice 4.9 +/- 0.5 vs. 4.0 +/- 0.3 g in MyD88+/+ control mice, P < 0.001). However, absent MyD88 signaling does not prevent these inflammatory mediators from causing weight loss (LPS, -0.4 +/- 0.1 g; IL1 beta, -0.1 +/- 0.1 g, both P < 0.01 vs. vehicle-injected MyD88-/- mice, +0.4 +/- 0.2 g). Furthermore, LPS-induced weight loss occurs in the absence of adipsia, fever, or hypothalamus-pituitary-adrenal axis activation in MyD88-deficient mice. In addition, the peripheral inflammatory response to LPS is surprisingly intact in mice lacking MyD88. Together, these observations indicate that LPS reduces food intake via a mechanism that is dissociated from its effect on peripheral cytokine production, and whereas the presence of circulating proinflammatory cytokines per se is insufficient to cause anorexia in the absence of MyD88 signaling, it may contribute to LPS-induced weight loss.

  19. Hepatoprotective effect of Hovenia dulcis THUNB. on experimental liver injuries induced by carbon tetrachloride or D-galactosamine/lipopolysaccharide.

    PubMed

    Hase, K; Ohsugi, M; Xiong, Q; Basnet, P; Kadota, S; Namba, T

    1997-04-01

    The hepatoprotective effects of the fruits of Hovenia dulcis THUNB. on chemically or immunologically induced experimental liver injury models were examined. The methanol extract showed significant hepatoprotective activity against CCl4-toxicity in rats and D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. The methanol extract also significantly protected against CCl4-toxicity in primary cultured rat hepatocytes. Hepatoprotective activity-guided fractionation and chemical analysis led to the isolation of an active constituent, (+)-ampelopsin (1) from the methanol extract.

  20. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats.

    PubMed

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2017-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)‑induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial‑dependent apoptosis. It was revealed that LPS‑challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet‑to‑dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS‑induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS‑induced mitochondrial‑dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick‑end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl‑2 downregulation). Furthermore, DEX treatment markedly attenuated LPS‑induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS‑induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis.

  1. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats

    PubMed Central

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2016-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)-induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. It was revealed that LPS-challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet-to-dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS-induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS-induced mitochondrial-dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl-2 downregulation). Furthermore, DEX treatment markedly attenuated LPS-induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS-induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. PMID:27959438

  2. Epidural analgesia with morphine or buprenorphine in ponies with lipopolysaccharide (LPS)-induced carpal synovitis

    PubMed Central

    Freitas, Gabrielle C.; Carregaro, Adriano B.; Gehrcke, Martielo I.; De La Côrte, Flávio D.; Lara, Valéria M.; Pozzobon, Ricardo; Brass, Karin E.

    2011-01-01

    This study evaluated the analgesia effects of the epidural administration of 0.1 mg/kg bodyweight (BW) of morphine or 5 μg/kg BW of buprenorphine in ponies with radiocarpal joint synovitis. Six ponies were submitted to 3 epidural treatments: the control group (C) received 0.15 mL/kg BW of a 0.9% sodium chloride (NaCl) solution; group M was administered 0.1 mg/kg BW of morphine; and group B was administered 5 μg/kg BW of buprenorphine, both diluted in 0.9% NaCl to a total volume of 0.15 mL/kg BW administered epidurally at 10 s/mL. The synovitis model was induced by injecting 0.5 ng of lipopolysaccharide (LPS) in the left or right radiocarpal joint. An epidural catheter was later introduced in the lumbosacral space and advanced up to the thoracolumbar level. The treatment started 6 h after synovitis induction. Lameness, maximum angle of carpal flexion, heart rate, systolic arterial pressure, respiratory rate, temperature, and intestinal motility were evaluated before LPS injection (baseline), 6 h after LPS injection (time 0), and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after treatments. Although the model of synovitis produced clear clinical signs of inflammation, the lameness scores in group C were different from the baseline for only up to 12 h. Both morphine and buprenorphine showed a reduction in the degree of lameness starting at 0.5 and 6 h, respectively. Reduced intestinal motility was observed at 0.5 h in group M and at 0.5 to 1 h in group B. Epidural morphine was a more effective analgesic that lasted for more than 12 h and without side effects. It was concluded that morphine would be a valuable analgesic option to alleviate joint pain in the thoracic limbs in ponies. PMID:21731186

  3. Lipopolysaccharide-induced biliary factors enhance invasion of Salmonella enteritidis in a rat model.

    PubMed

    Islam, A F; Moss, N D; Dai, Y; Smith, M S; Collins, A M; Jackson, G D

    2000-01-01

    In this study, the role of the hepatobiliary system in the early pathogenesis of Salmonella enteritidis infection was investigated in a rat model. Intravenous (i.v.) challenge with lipopolysaccharide (LPS) has previously been shown to enhance the translocation of normal gut flora. We first confirmed that LPS can similarly promote the invasion of S. enteritidis. Oral infection of outbred Australian Albino Wistar rats with 10(6) to 10(7) CFU of S. enteritidis led to widespread tissue invasion after days. If animals were similarly challenged after intravenous administration of S. enteritidis LPS (3 to 900 microg/kg of body weight), significant invasion of the livers and mesenteric lymph nodes (MLN) occurred within 24 h, with invasion of the liver increasing in a dose-dependent fashion (P < 0.01). If bile was prevented from reaching the intestine by bile duct ligation or cannulation, bacterial invasion of the liver and MLN was almost totally abrogated (P < 0.001). As i.v. challenge with LPS could induce the delivery of inflammatory mediators into the bile, biliary tumor necrosis factor alpha (TNF-alpha) concentrations were measured by bioassay. Biliary concentrations of TNF-alpha rose shortly after LPS challenge, peaked with a mean concentration of 27.0 ng/ml at around 1 h postchallenge, and returned to baseline levels (3.1 ng/ml) after 2.5 h. Although TNF-alpha cannot be directly implicated in the invasion process, we conclude that the invasiveness of the enteric pathogen S. enteritidis is enhanced by the presence of LPS in the blood and that this enhanced invasion is at least in part a consequence of the delivery of inflammatory mediators to the gastrointestinal tract by the hepatobiliary system.

  4. Lipopolysaccharide-Induced Biliary Factors Enhance Invasion of Salmonella enteritidis in a Rat Model

    PubMed Central

    Islam, Abul F. M. W.; Moss, Nathan D.; Dai, Yung; Smith, Murray S. R.; Collins, Andrew M.; Jackson, Graham D. F.

    2000-01-01

    In this study, the role of the hepatobiliary system in the early pathogenesis of Salmonella enteritidis infection was investigated in a rat model. Intravenous (i.v.) challenge with lipopolysaccharide (LPS) has previously been shown to enhance the translocation of normal gut flora. We first confirmed that LPS can similarly promote the invasion of S. enteritidis. Oral infection of outbred Australian Albino Wistar rats with 106 to 107 CFU of S. enteritidis led to widespread tissue invasion after days. If animals were similarly challenged after intravenous administration of S. enteritidis LPS (3 to 900 μg/kg of body weight), significant invasion of the livers and mesenteric lymph nodes (MLN) occurred within 24 h, with invasion of the liver increasing in a dose-dependent fashion (P < 0.01). If bile was prevented from reaching the intestine by bile duct ligation or cannulation, bacterial invasion of the liver and MLN was almost totally abrogated (P < 0.001). As i.v. challenge with LPS could induce the delivery of inflammatory mediators into the bile, biliary tumor necrosis factor alpha (TNF-α) concentrations were measured by bioassay. Biliary concentrations of TNF-α rose shortly after LPS challenge, peaked with a mean concentration of 27.0 ng/ml at around 1 h postchallenge, and returned to baseline levels (3.1 ng/ml) after 2.5 h. Although TNF-α cannot be directly implicated in the invasion process, we conclude that the invasiveness of the enteric pathogen S. enteritidis is enhanced by the presence of LPS in the blood and that this enhanced invasion is at least in part a consequence of the delivery of inflammatory mediators to the gastrointestinal tract by the hepatobiliary system. PMID:10603360

  5. Epidural analgesia with morphine or buprenorphine in ponies with lipopolysaccharide (LPS)-induced carpal synovitis.

    PubMed

    Freitas, Gabrielle C; Carregaro, Adriano B; Gehrcke, Martielo I; De La Côrte, Flávio D; Lara, Valéria M; Pozzobon, Ricardo; Brass, Karin E

    2011-04-01

    This study evaluated the analgesia effects of the epidural administration of 0.1 mg/kg bodyweight (BW) of morphine or 5 μg/kg BW of buprenorphine in ponies with radiocarpal joint synovitis. Six ponies were submitted to 3 epidural treatments: the control group (C) received 0.15 mL/kg BW of a 0.9% sodium chloride (NaCl) solution; group M was administered 0.1 mg/kg BW of morphine; and group B was administered 5 μg/kg BW of buprenorphine, both diluted in 0.9% NaCl to a total volume of 0.15 mL/kg BW administered epidurally at 10 s/mL. The synovitis model was induced by injecting 0.5 ng of lipopolysaccharide (LPS) in the left or right radiocarpal joint. An epidural catheter was later introduced in the lumbosacral space and advanced up to the thoracolumbar level. The treatment started 6 h after synovitis induction. Lameness, maximum angle of carpal flexion, heart rate, systolic arterial pressure, respiratory rate, temperature, and intestinal motility were evaluated before LPS injection (baseline), 6 h after LPS injection (time 0), and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after treatments. Although the model of synovitis produced clear clinical signs of inflammation, the lameness scores in group C were different from the baseline for only up to 12 h. Both morphine and buprenorphine showed a reduction in the degree of lameness starting at 0.5 and 6 h, respectively. Reduced intestinal motility was observed at 0.5 h in group M and at 0.5 to 1 h in group B. Epidural morphine was a more effective analgesic that lasted for more than 12 h and without side effects. It was concluded that morphine would be a valuable analgesic option to alleviate joint pain in the thoracic limbs in ponies.

  6. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

    PubMed Central

    SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

    2014-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

  7. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS.

    PubMed

    Sepehr, Reyhaneh; Audi, Said H; Maleki, Sepideh; Staniszewski, Kevin; Eis, Annie L; Konduri, Girija G; Ranji, Mahsa

    2013-07-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure.

  8. Metformin Alleviates Lipopolysaccharide-induced Acute Lung Injury through Suppressing Toll-like Receptor 4 Signaling.

    PubMed

    Vaez, Haleh; Najafi, Moslem; Toutounchi, Negisa Seyed; Barar, Jaleh; Barzegari, Abolfazl; Garjani, Alireza

    2016-12-01

    Signaling AMP-activated protein kinase (AMPK), an energy sensing enzyme, has been implicated in controlling inflammation. In this study we investigated whether activation of AMPK by metformin could protect the lung from lipopolysaccharide (LPS)-induced acute injury by inhibitingng TLR4 pathway. Male Wistar rats were randomly divided into 3 groups (n=6): control group received normal saline (0.5 mL), LPS group received LPS (0.5 mg/kg), and metformin-treated group received LPS and metformin (100 mg/kg). Nine hours later nuclear factor-κB (NF-κB), phosphorylated, and non-phosphorylated AMPK using western blot, and the rate of TLR4 mRNA expression using real-time PCR were assessed in the lung tissue. To evaluate neutrophil infiltration, the myeloperoxidase (MPO) activity was measured. The severity of the lung damage was assessed by histological examinations. It was found that the ratio of p-AMPKα to AMPKα was significantly upregulated by 22% (p<0.05) in the lungs obtained from the metformin group. In LPS-treated rats, we observed a high expression of TLR4 in the tissue along with increased levels of MyD88, NF-κB, and TNFα. Metformin considerably reduced all these parameters. Histological examinations revealed that metformin remarkably attenuated congestion and inflammatory cellular infiltration into the alveolar walls and also decreased MPO activity by 37% (p<0.05). We conclude that metformin could protect the lung tissue against LPS-evoked TLR4 activation and the protective effect can be related to the activation of AMPK.

  9. Saccharomyces boulardii inhibits lipopolysaccharide-induced activation of human dendritic cells and T cell proliferation

    PubMed Central

    Thomas, S; Przesdzing, I; Metzke, D; Schmitz, J; Radbruch, A; Baumgart, D C

    2009-01-01

    Saccharomyces boulardii (Sb) is a probiotic yeast preparation that has demonstrated efficacy in inflammatory and infectious disorders of the gastrointestinal tract in controlled clinical trials. Although patients clearly benefit from treatment with Sb, little is known on how Sb unfolds its anti-inflammatory properties in humans. Dendritic cells (DC) balance tolerance and immunity and are involved critically in the control of T cell activation. Thus, they are believed to have a pivotal role in the initiation and perpetuation of chronic inflammatory disorders, not only in the gut. We therefore decided to investigate if Sb modulates DC function. Culture of primary (native, non-monocyte-derived) human myeloid CD1c+CD11c+CD123– DC (mDC) in the presence of Sb culture supernatant (active component molecular weight < 3 kDa, as evaluated by membrane partition chromatography) reduced significantly expression of the co-stimulatory molecules CD40 and CD80 (P < 0·01) and the DC mobilization marker CC-chemokine receptor CCR7 (CD197) (P < 0·001) induced by the prototypical microbial antigen lipopolysaccharide (LPS). Moreover, secretion of key proinflammatory cytokines such as tumour necrosis factor-α and interleukin (IL)-6 were notably reduced, while the secretion of anti-inflammatory IL-10 increased. Finally, Sb supernatant inhibited the proliferation of naive T cells in a mixed lymphocyte reaction with mDC. In summary, our data suggest that Sb may exhibit part of its anti-inflammatory potential through modulation of DC phenotype, function and migration by inhibition of their immune response to bacterial microbial surrogate antigens such as LPS. PMID:19161443

  10. Lipopolysaccharide-Induced Dynamic Lipid Membrane Reorganization: Tubules, Perforations, and Stacks

    PubMed Central

    Adams, Peter G.; Lamoureux, Loreen; Swingle, Kirstie L.; Mukundan, Harshini; Montaño, Gabriel A.

    2014-01-01

    Lipopolysaccharide (LPS) is a unique lipoglycan, with two major physiological roles: 1), as a major structural component of the outer membrane of Gram-negative bacteria and 2), as a highly potent mammalian toxin when released from cells into solution (endotoxin). LPS is an amphiphile that spontaneously inserts into the outer leaflet of lipid bilayers to bury its hydrophobic lipidic domain, leaving the hydrophilic polysaccharide chain exposed to the exterior polar solvent. Divalent cations have long been known to neutralize and stabilize LPS in the outer membrane, whereas LPS in the presence of monovalent cations forms highly mobile negatively-charged aggregates. Yet, much of our understanding of LPS and its interactions with the cell membrane does not take into account its amphiphilic biochemistry and charge polarization. Herein, we report fluorescence microscopy and atomic force microscopy analysis of the interaction between LPS and fluid-phase supported lipid bilayer assemblies (sLBAs), as model membranes. Depending on cation availability, LPS induces three remarkably different effects on simple sLBAs. Net-negative LPS-Na+ leads to the formation of 100-μm-long flexible lipid tubules from surface-associated lipid vesicles and the destabilization of the sLBA resulting in micron-size hole formation. Neutral LPS-Ca2+ gives rise to 100-μm-wide single- or multilamellar planar sheets of lipid and LPS formed from surface-associated lipid vesicles. Our findings have important implications about the physical interactions between LPS and lipids and demonstrate that sLBAs can be useful platforms to study the interactions of amphiphilic virulence factors with cell membranes. Additionally, our study supports the general phenomenon that lipids with highly charged or bulky headgroups can promote highly curved membrane architectures due to electrostatic and/or steric repulsions. PMID:24896118

  11. Poly(Adp-ribose) synthetase inhibition prevents lipopolysaccharide-induced peroxynitrite mediated damage in diaphragm.

    PubMed

    Ozdülger, Ali; Cinel, Ismail; Unlü, Ali; Cinel, Leyla; Mavioglu, Ilhan; Tamer, Lülüfer; Atik, Ugur; Oral, Ugur

    2002-07-01

    Although the precise mechanism by which sepsis causes impairment of respiratory muscle contractility has not been fully elucidated, oxygen-derived free radicals are thought to play an important role. In our experimental study, the effects of poly(ADP-ribose) synthetase (PARS) inhibition on the diaphragmatic Ca(2+)-ATPase, malondialdehyde (MDA), and 3-nitrotyrosine (3-NT) levels and additionally histopathology of the diaphragm in lipopolysaccharide (LPS)-induced endotoxemia are investigated.Thirty-two male Wistar rats, weighing between 180-200 g were randomly divided into four groups. The first group (control; n=8) received saline solution and the second (LPS group; n=8) 10 mgkg(-1) LPS i.p. 3-Aminobenzamide (3-AB) as a PARS inhibitor; was given to the third group (C+3-AB, n=8) 20 min before administration of saline solution while the fourth group (LPS+3-AB, n=8) received 3-AB 20 min before LPS injection. Six hours later, under ketamin/xylasine anesthesia diapraghmatic specimens were obtained and the rats were decapitated. Diaphragmatic specimens were divided into four parts, three for biochemical analyses and one for histopathologic assessment. In the LPS group, tissue Ca(2+)-ATPase levels were found to be decreased and tissue MDA and 3-NT levels were found to be increased (P<0.05). In the LPS+3-AB group, 3-AB pretreatment inhibited the increase in MDA and 3-NT levels and Ca(2+)-ATPase activity remained similar to those in the control group (P<0.05). Histopathologic examination of diaphragm showed edema between muscle fibers only in LPS group. PARS inhibition with 3-AB prevented not only lipid peroxidation but also the decrease of Ca(2+)-ATPase activity in endotoxemia. These results highlights the importance of nitric oxide (NO)-peroxynitrite (ONOO(-))-PARS pathway in preventing free radical mediated injury. PARS inhibitors should further be investigated as a new thearapetic alternative in sepsis treatment.

  12. The Effect of Hydrogen Sulfide Donors on Lipopolysaccharide-Induced Formation of Inflammatory Mediators in Macrophages

    PubMed Central

    Whiteman, Matthew; Li, Ling; Rose, Peter; Tan, Choon-Hong; Parkinson, David B.

    2010-01-01

    Abstract The role of hydrogen sulfide (H2S) in inflammation is controversial, with both pro- and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H2S, which give a rapid bolus of H2S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H2S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H2S donor (GYY4137) on the release of pro- and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1β, IL-6, TNF-α, nitric oxide (•NO), and PGE2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-κB/ATF-2/HSP-27–dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1β, IL-6, NO, PGE2 and TNF-α. This study clearly shows that the effects of H2S on the inflammatory process are complex and dependent not only on H2S concentration but also on the rate of H2S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro- versus antiinflammatory role of H2S. Antioxid. Redox Signal. 12, 1147–1154. PMID:19769459

  13. Activation of decidual invariant natural killer T cells promotes lipopolysaccharide-induced preterm birth.

    PubMed

    Li, Liping; Yang, Jing; Jiang, Yao; Tu, Jiaoqin; Schust, Danny J

    2015-04-01

    Invariant natural killer T (iNKT) cells are crucial for host defense against a variety of microbial pathogens, but the underlying mechanisms of iNKT cells activation by microbes are not fully explained. In this study, we investigated the molecular mechanisms of iNKT cell activation in lipopolysaccharide (LPS)-stimulated preterm birth using an adoptive transfer system and diverse neutralizing antibodies (Abs) and inhibitors. We found that adoptive transfer of decidual iNKT cells to LPS-stimulated iNKT cell deficient Jα18(-/-) mice that lack invariant Vα14Jα281T cell receptor (TCR) expression significantly decreased the time to delivery and increased the percentage of decidual iNKT cells. Neutralizing Abs against Toll-like receptor 4 (TLR-4), CD1d, interleukin (IL)-12 and IL-18, and inhibitors blocking the activation of nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK) p38 and extracellular signal-regulated kinase (ERK) significantly reduced in vivo percentages of decidual iNKT cells, their intracellular interferon (IFN)-γ production and surface CD69 expression. In vitro, in the presence of the same Abs and inhibitors used as in vivo, decidual iNKT cells co-cultured with LPS-pulsed dendritic cells (DCs) showed significantly decreased extracellular and intracellular IFN-γ secretion and surface CD69 expression. Our data demonstrate that the activation of decidual iNKT cells plays an important role in inflammation-induced preterm birth. Activation of decidual iNKT cells also requires TLR4-mediated NF-κB, MAPK p38 and ERK pathways, the proinflammatory cytokines IL-12 and IL-18, and endogenous glycolipid antigens presented by CD1d.

  14. Bis(bibenzyls) from liverworts inhibit lipopolysaccharide-induced inducible NOS in RAW 264.7 cells: a study of structure-activity relationships and molecular mechanism.

    PubMed

    Harinantenaina, Liva; Quang, Dang Ngoc; Takeshi, Nishizawa; Hashimoto, Toshihiro; Kohchi, Chie; Soma, Gen-Ichiro; Asakawa, Yoshinori

    2005-12-01

    The inhibition of lipopolysaccharide-induced NOS by 19 bis(bibenzyls) isolated from liverworts in RAW 264.7 macrophages was evaluated. The presence of phenolic hydroxyls and saturation at 7,8 and/or 7'/8' are required for inhibition of NO production. Among the compounds tested, marchantin A was the most potent, and its inhibitory activity was consistent with the inhibition of LPS-induced iNOS mRNA.

  15. Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

    PubMed

    Mohammadi, Fatemeh; Rahimian, Reza; Fakhraei, Nahid; Rezayat, Seyed Mahdi; Javadi-Paydar, Mehrak; Dehpour, Ahmad R; Afshari, Khashayar; Ejtemaei Mehr, Shahram

    2016-08-01

    Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  16. Organ-specific protection against lipopolysaccharide-induced vascular leak is dependent on the endothelial protein C receptor.

    PubMed

    von Drygalski, Annette; Furlan-Freguia, Christian; Ruf, Wolfram; Griffin, John H; Mosnier, Laurent O

    2013-04-01

    To study the role of the endothelial protein C receptor (EPCR) in the modulation of susceptibility to inflammation-induced vascular leak in vivo. Genetically modified mice with low, <10% EPCR expression (EPCR(low)) and control mice were challenged with lipopolysaccharides in a mouse model of endotoxemia. Infrared fluorescence and quantification of albumin-bound Evans Blue in tissues and intravascular plasma volumes were used to assess plasma extravasation. Pair-wise analysis of EPCR(low) and control mice matched for sex, age, and weight allowed determination of EPCR-dependent vascular leak. Kidney, lung, and brain were the organs with highest discriminative increased Evans Blue accumulation in EPCR(low) versus control mice in response to lipopolysaccharides. Histology of kidney and lung confirmed the EPCR-specific pathology. In addition to severe kidney injury in response to lipopolysaccharides, EPCR(low) and anti-EPCR-treated wild-type mice suffered from enhanced albuminuria and profound renal hemorrhage versus controls. Intravascular volume loss at the same extent of weight loss in EPCR(low) mice compared with control mice provided proof that plasma leak was the predominant cause of Evans Blue tissue accumulation. This study demonstrates an important protective role for EPCR in vivo against vascular leakage during inflammation and suggests that EPCR-dependent vascular protection is organ-specific.

  17. Vincristine-induced peripheral neuropathy in pediatric cancer patients

    PubMed Central

    Mora, Erika; Smith, Ellen M Lavoie; Donohoe, Clare; Hertz, Daniel L

    2016-01-01

    Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment. PMID:27904761

  18. Concomitant lipopolysaccharide-induced transfer of blood-derived components including immunoglobulins into milk.

    PubMed

    Lehmann, M; Wellnitz, O; Bruckmaier, R M

    2013-02-01

    During a mammary immune response, the integrity of the blood-milk barrier is negatively affected and becomes leaky. The aim of the present study was to demonstrate the blood origin, and to investigate changes in the concentration, of various constituents including immunoglobulins in blood and milk during the early phase of lipopolysaccharide (LPS)-induced mastitis. Five lactating dairy cows received continuous β-hydroxybutyrate (BHBA) clamp infusions to maintain elevated BHBA blood concentrations (1.5 to 2.0 mmol/L) from 48 h before and 8h after LPS administration. One udder quarter was infused with 200 μg of Escherichia coli LPS. A second quarter served as control. Milk and blood samples were taken hourly for 8h postchallenge (PC). The somatic cell count in LPS-challenged quarters was increased from 4h PC to the end of the experiment compared with control quarters. In LPS-challenged quarters, l-lactate, BHBA, lactate dehydrogenase (LDH), IgG(1), and IgG(2) were increased at 3h PC and remained elevated until the end of experiment (8h PC) compared with control quarters. In addition, the optical density values in milk in a nonquantitative ELISA for antibodies directed against bluetongue virus (used as a measure of nonspecific antibody transfer; all animals were vaccinated) increased and, thus, indicates an increase in these antibodies in response to LPS treatment. l-Lactate concentration also increased in blood 2h PC and in the milk of control quarters during the experiment from 3h PC. A second experiment was conducted in vitro to investigate a possible contribution from destructed milk cells to l-lactate concentration and activity of LDH in milk. Aliquots of milk samples (n=8) were frozen (-20°C) or disrupted with ultrasound, respectively. Freeze thawing and ultrasound treatment increased LDH in milk samples, but had no effect on l-lactate concentrations. Results suggest that intramammary infusion of LPS induces a systemic response, as evidenced by an elevation

  19. The effects of a novel botanical agent on lipopolysaccharide-induced alveolar bone loss in rats.

    PubMed

    Lee, Bo-Ah; Lee, Hwa-Sun; Jung, Young-Suk; Kim, Se-Won; Lee, Yong-Wook; Chang, Sun-Hwa; Chung, Hyun-Ju; Kim, Ok-Su; Kim, Young-Joon

    2013-08-01

    The development of host-modulatory agents with low risk of adverse effects has been needed to treat periodontitis, a chronic inflammatory disease. A botanical mixture of extracts from two natural substances, Panax notoginseng and Rehmannia glutinosa Libosch, was developed as a novel botanical agent synthesized with anti-inflammatory effect. The aim of this study is to evaluate the effects of the botanical mixture on the release of inflammatory cytokines and its inhibitory effect on lipopolysaccharide (LPS)-induced alveolar bone loss (ABL) in a rat model. Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2yl)-5(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay using human gingival fibroblast (hGF) and human periodontal ligament (hPDL) cells. Human acute monocytic leukemia cell line and hGF cells were cultured to assay tumor necrosis factor (TNF)-α and interleukin (IL)-6, respectively. Microcomputed tomography analysis and immunofluoresence analysis were performed to evaluate the efficacy of the botanical mixture to inhibit the destruction of alveolar bone and connective tissue in a rat model. The botanical mixture is cytotoxic at concentrations exceeding 2.5 mg/mL (P <0.05). Based on the results from cytotoxicity assay, it can be determined that the pharmacologic ranges of the botanical mixture to be used in all subsequent in vitro and in vivo experiments. The botanical mixture reduced the release of TNF-α and IL-6 from human monocytic cells and hGF cells in a dose-dependent manner (P <0.05). The administration of the botanical mixture significantly reduced the alveolar bone loss in a rat model (P <0.05). In groups treated with the botanical mixture, matrix metalloproteinase (MMP)-9 was detected along the alveolar bone crest (ABC), but not around the gingival connective tissue, while in the group with LPS-induced ABL, pronounced expression of MMP-9 around the ABC, periodontal ligament, and gingival connective tissue was found. The botanical mixture

  20. [Role of endogenous hydrogen sulfide in pulmonary hypertension induced by lipopolysaccharide].

    PubMed

    Huang, Xin-Li; Zhou, Xiao-Hong; Wei, Peng; Zhang, Xiao-Jing; Meng, Xiang-Yan; Xian, Xiao-Hui

    2008-04-25

    The purpose of the present study was to explore the role of endogenous hydrogen sulfide (H2S) in pulmonary arterial hypertension induced by endotoxin. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group (0.5 mL/kg body weight of normal saline, i.v.), lipopolysaccharide (LPS)-treated group (5 mg/kg body weight of LPS, i.v.), LPS + NaHS (5 mg/kg body weight of LPS, i.v., and 28 μmol/kg body weight of NaHS, i.p.) and LPS + PPG group (5 mg/kg body weight of LPS, i.v., and 30 μmol/kg body weight of PPG, i.p.). Rats were anesthetized with 20% urethane (1 g/kg body weight, i.p.). A polyethylene catheter was inserted into the pulmonary artery through the right external jugular vein to measure the mean pulmonary arterial pressure (mPAP) for 7 h, and then the pulmonary artery was isolated rapidly by the method described previously. Pulmonary arterial activity was detected. H2S concentration and cystathionine γ-lyase (CSE) activity in pulmonary artery tissues were determined by biochemical method. CSE mRNA expression was detected by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with control, LPS significantly increased mPAP [(1.82±0.29) kPa vs (1.43±0.26) kPa, P<0.01], decreased H2S production [(26.33±7.84) vs (42.92±8.73) pmol/g wet tissue per minute, P<0.01), and reduced endothelium-dependent relaxation response [(75.72±7.22)% vs (86.40±4.40) %, P<0.01) induced by ACh (1×10(-6) mol/L). These effects were partly reversed by co-administration of NaHS and enhanced by co-administration of PPG. Both CSE activity and CSE mRNA expression were consistent with H2S production. It is suggested that the inhibitory effect of LPS on endothelium-dependent relaxation results in pulmonary hypertension, which might be mediated through H(2)S.

  1. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy.

    PubMed

    Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

    2015-11-01

    Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy. © FASEB.

  2. Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth.

    PubMed

    Bariani, María Victoria; Correa, Fernando; Leishman, Emma; Domínguez Rubio, Ana Paula; Arias, Andreína; Stern, Aníbal; Bradshaw, Heather B; Franchi, Ana María

    2017-08-01

    Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice? Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling. Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor. An in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation. Time of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot. In vivo treatment of 15-day

  3. autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function.

    PubMed

    Vo, Phuong A; Lad, Bhavini; Tomlinson, James A P; Francis, Stephanie; Ahluwalia, Amrita

    2005-02-25

    Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is responsible for sepsis-induced hypotension and plays a major contributory role in the ensuing multiorgan failure. The present study aimed to elucidate the role of endothelial NO in lipopolysaccharide (LPS)-induced iNOS expression, in isolated rat aortic rings. Exposure to LPS (1 mug/ml, 5 h) resulted in a reversal of phenylephrine precontracted tone in aortic rings (70.7 +/- 3.2%). This relaxation was associated with iNOS expression and NF-kappaB activation. Positive immunoreactivity for iNOS protein was localized in medial and adventitial layers of LPS-treated aortic rings. Removal of the endothelium rendered aortic rings resistant to LPS-induced relaxation (8.9 +/- 4.5%). Western blotting of these rings demonstrated an absence of iNOS expression. However, treatment of endothelium-denuded rings with the NO donor, diethylamine-NONOate (0.1 mum), restored LPS-induced relaxation (61.6 +/- 6.6%) and iNOS expression to levels comparable with arteries with intact endothelium. Blockade of endothelial NOS (eNOS) activation using geldanamycin and radicicol, inhibitors of heat shock protein 90, in endothelium-intact arteries suppressed both LPS-induced relaxation and LPS-induced iNOS expression (9.0 +/- 8.0% and 2.0 +/- 6.2%, respectively). Moreover, LPS treatment (12.5 mg/kg, intravenous, 15 h) of wild-type mice resulted in profound elevation of plasma [NO(x)] measurements that were reduced by approximately 50% in eNOS knock-out animals. Furthermore, LPS-induced changes in vascular reactivity and iNOS expression evident in wild-type tissues were profoundly suppressed in tissues taken from eNOS knockout animals. Together, these data suggest that eNOS-derived NO, in part via activation of NF-kappaB, regulates iNOS-induction by LPS. This study provides the first demonstration of a proinflammatory role of vascular eNOS in sepsis.

  4. Serratia marcescens Induces Apoptotic Cell Death in Host Immune Cells via a Lipopolysaccharide- and Flagella-dependent Mechanism*

    PubMed Central

    Ishii, Kenichi; Adachi, Tatsuo; Imamura, Katsutoshi; Takano, Shinya; Usui, Kimihito; Suzuki, Kazushi; Hamamoto, Hiroshi; Watanabe, Takeshi; Sekimizu, Kazuhisa

    2012-01-01

    Injection of Serratia marcescens into the blood (hemolymph) of the silkworm, Bombyx mori, induced the activation of c-Jun NH2-terminal kinase (JNK), followed by caspase activation and apoptosis of blood cells (hemocytes). This process impaired the innate immune response in which pathogen cell wall components, such as glucan, stimulate hemocytes, leading to the activation of insect cytokine paralytic peptide. S. marcescens induced apoptotic cell death of silkworm hemocytes and mouse peritoneal macrophages in vitro. We searched for S. marcescens transposon mutants with attenuated ability to induce apoptosis of silkworm hemocytes. Among the genes identified, disruption mutants of wecA (a gene involved in lipopolysaccharide O-antigen synthesis), and flhD and fliR (essential genes in flagella synthesis) showed reduced motility and impaired induction of mouse macrophage cell death. These findings suggest that S. marcescens induces apoptosis of host immune cells via lipopolysaccharide- and flagella-dependent motility, leading to the suppression of host innate immunity. PMID:22859304

  5. Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity.

    PubMed

    Yilmaz, Eser; Hough, Karen A; Gebhart, Gerald F; Williams, Brian A; Gold, Michael S

    2014-01-01

    The benzodiazepine midazolam has been reported to facilitate the actions of spinally administrated local anesthetics. Interestingly, despite the lack of convincing evidence for the presence of γ-aminobutyric acid type A (GABAA) receptors along peripheral nerve axons, midazolam also has been shown to have analgesic efficacy when applied alone to peripheral nerves.These observations suggest midazolam-induced nerve block is due to another site of action. Furthermore, because of evidence indicating that midazolam has equal potency at the benzodiazepine site on the GABAA receptor and the 18-kd translocator protein (TSPO), it is possible that at least the nerve-blocking actions of midazolam are mediated by this alternative site of action. We used the benzodiazepine receptor antagonist flumazenil, and the TSPO antagonist PK11195, with midazolam on rat sciatic nerves and isolated sensory neurons to determine if either receptor mediates midazolam-induced nerve block and/or neurotoxicity. Midazolam (300 μM)-induced block of nerve conduction was reversed by PK11195 (3 μM), but not flumazenil (30 μM). Midazolam-induced neurotoxicity was blocked by neither PK11195 nor flumazenil. Midazolam also causes the release of Ca from internal stores in sensory neurons, and there was a small but significant attenuation of midazolam-induced neurotoxicity by the Ca chelator, BAPTA. BAPTA (30 μM) significantly attenuated midazolam-induced nerve block. Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity.

  6. Inhibition by rebamipide of cytokine-induced or lipopolysaccharide-induced chemokine synthesis in human corneal fibroblasts.

    PubMed

    Fukuda, Ken; Ishida, Waka; Tanaka, Hiroshi; Harada, Yosuke; Fukushima, Atsuki

    2014-12-01

    The dry-eye drug rebamipide has mucin secretagogue activity in and anti-inflammatory effects on corneal epithelial cells. Corneal stromal fibroblasts (transdifferentiated keratocytes) function as immune modulators in the pathogenesis of chronic ocular allergic inflammation and in innate immune responses at the ocular surface. The possible anti-inflammatory effects of rebamipide on human corneal stromal fibroblasts were examined. Serum-deprived cells were incubated for 1 h with rebamipide and then for various times in the additional absence or presence of cytokines or bacterial lipopolysaccharide (LPS). The release of chemokines into culture supernatants was determined with ELISAs. The intracellular abundance of chemokine mRNAs was quantitated by reverse transcription and real-time PCR analysis. Degradation of the nuclear factor κB (NFκB) inhibitor IκBα was detected by immunoblot analysis. Rebamipide suppressed the release of interleukin (IL)-8 and the upregulation of IL-8 mRNA induced by tumour necrosis factor α (TNF-α) or LPS in corneal fibroblasts. It also inhibited eotaxin-1 (CCL-11) expression at the protein and mRNA levels induced by the combination of TNF-α and IL-4. In addition, rebamipide attenuated the degradation of IκBα induced by TNF-α or LPS. Rebamipide inhibited the synthesis of chemokines by corneal fibroblasts in association with suppression of NFκB signalling. Rebamipide may therefore prove effective for the treatment of corneal stromal inflammation associated with allergy or bacterial infection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  7. Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat.

    PubMed

    Sweitzer, S M; Pahl, J L; DeLeo, J A

    2006-06-12

    The development of painful peripheral neuropathy is a dose-limiting side effect of numerous cancer chemotherapeutic agents. The present study utilized a rodent model of vincristine-induced neuropathy to determine whether a glial modulating agent, propentofylline, could attenuate vincristine-induced mechanical allodynia. Intravenous vincristine administered on days 1 through 5 and days 8 through 11 produced mechanical allodynia using 2 and 12 g von Frey filaments. Lumbar spinal cord from animals on day 15 expressed mild bilateral microglial and astrocytic activation as compared to saline-treated animals. Daily intraperitoneal propentofylline at 10 mg/kg attenuated mechanical allodynia induced by vincristine administration. In addition, propentofylline was found to decrease spinal microglial and astrocytic activation on day 15. These data suggest that central glial cells may play an important role in the development of painful neuropathy following vincristine administration.

  8. Modulation of lipopolysaccharide-induced pro-inflammatory mediators by an extract of Glycyrrhiza glabra and its phytoconstituents.

    PubMed

    Thiyagarajan, P; Chandrasekaran, C V; Deepak, H B; Agarwal, Amit

    2011-08-01

    To evaluate the inhibitory property of de-glycyrrhizinated extract of Glycyrrhiza glabra root and its phytoconstituents (glabridin, isoliquiritigenin and glycyrrhizin) on LPS-induced production of pro-inflammatory mediators. Inhibitory effect of G. glabra extract and its phytoconstituents were studied on lipopolysaccharide (LPS)-induced nitric oxide (NO), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) levels in J774A.1 murine macrophages. G. glabra and isoliquiritigenin significantly inhibited LPS stimulated NO, IL-1 beta and IL-6 production. Glabridin showed significant inhibition of NO and IL-1 beta release, but failed to attenuate IL-6 levels at the tested concentrations. In addition, glycyrrhizin did not exhibit inhibitory response towards any of the LPS-induced pro-inflammatory mediators at the tested concentrations. From the results we speculate that the inhibitory effect of G. glabra extract on LPS-induced pro-inflammatory mediators is influenced by glabridin and isoliquiritigenin and is not contributed by glycyrrhizin.

  9. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN)

    PubMed Central

    Han, Yaqin; Smith, Maree T.

    2013-01-01

    Chemotherapy induced peripheral neuropathy (CIPN) is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a “stocking and glove” distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of CIPN. New insights on the pathobiology of CIPN gained using these models are discussed in this review. These include mitochondrial dysfunction and oxidative stress that are implicated as key mechanisms in the development of CIPN. Associated structural changes in peripheral nerves include neuronopathy, axonopathy and/or myelinopathy, especially intra-epidermal nerve fiber (IENF) degeneration. In patients with CIPN, loss of heat sensitivity is a hallmark symptom due to preferential damage to myelinated primary afferent sensory nerve fibers in the presence or absence of demyelination. The pathobiology of CIPN is complex as cancer chemotherapy treatment regimens frequently involve drug combinations. Adding to this complexity, there are also subtle differences in the pathobiological consequences of commonly used cancer chemotherapy drugs, viz platinum compounds, taxanes, vincristine, bortezomib, thalidomide and ixabepilone, on peripheral nerves. PMID:24385965

  10. Rodent models of chemotherapy-induced peripheral neuropathy.

    PubMed

    Höke, Ahmet; Ray, Mitali

    2014-01-01

    Peripheral neuropathy is a common and dose-limiting side effect of many chemotherapeutic drugs. These include platinum compounds, taxanes, vinca alkaloids, proteasome inhibitors, and others such as thalidomide and suramin. Although many rodent models have been developed using either mice or rats, there is limited consistency in the dose or mode of delivery of the drug; the sex, age, and genetic background of the animal used in the study; and the outcome measures used in evaluation of the peripheral neuropathy. Behavioral assays are commonly used to evaluate evoked sensory responses but are unlikely to be a good representation of the spontaneous sensory paresthesias that the patients experience. Electrophysiologic tests evaluate the integrity of large myelinated populations and are useful in drugs that cause either demyelination or degeneration of large myelinated axons but are insensitive to degeneration of unmyelinated axons in early stages of neuropathy. Histopathologic tools offer an unbiased way to evaluate the degree of axonal degeneration or changes in neuronal cell body but are often time consuming and require processing of the tissue after the study is completed. Nevertheless, use of drug doses and mode of delivery that are relevant to the clinical protocols and use of outcome measures that are both sensitive and objective in evaluation of the length-dependent distal axonal degeneration seen in most chemotherapy-induced peripheral neuropathies may improve the translational utility of these rodent models.

  11. A Mouse Model of Fatigue Induced by Peripheral Irradiation.

    PubMed

    Wolff, Brian S; Renner, Michael A; Springer, Danielle A; Saligan, Leorey N

    2017-03-17

    Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue.

  12. Effects of immunological challenge induced by lipopolysaccharide on skeletal muscle fiber type conversion of piglets.

    PubMed

    Jia, A F; Feng, J H; Zhang, M H; Chang, Y; Li, Z Y; Hu, C H; Zhen, L; Zhang, S S; Peng, Q Q

    2015-11-01

    The objective of this study was to investigate the effects of immunological challenge on the skeletal muscle fiber type conversion of piglets. Sixteen Large White weaned barrows (28 ± 3 d, 8.22 ± 0.89 kg BW) were allotted by weight and litter to 2 groups: the control group and the lipopolysaccharide (LPS) group. Saline (control) or LPS was injected intravenously via a jugular catheter on d 1, 3, 5, 7, 9, 11, 13, and 15 at an initial dosage of 80 μg/kg BW, which was increased by 30% at each subsequent injection. Blood samples were collected via the jugular catheter 3 h after the LPS challenge on d -1, 1, 5, 9, and 13. Muscle tissue samples were collected from the LM after exsanguination on d 15. The LPS challenge increased the plasma IL-6, tumor necrosis factor-α (TNF-α), cortisol, IL-1β, and haptoglobin concentrations on d 1 and 5 ( < 0.01) and increased the plasma IL-6 ( < 0.05), TNF-α ( < 0.05), and haptoglobin ( < 0.01) levels on d 9. Compared with that of the control group, the ADG of the LPS group decreased by 40.00% ( < 0.01), 29.52% ( < 0.05), and 19.30% ( < 0.05), and the ADFI decreased by 25.09% ( < 0.01), 23.15% ( < 0.05), and 19.47% ( < 0.05) during d 1 to 4, d 5 to 8, and d 9 to 15, respectively. In the LM of LPS-challenged piglets, myosin heavy chain 1 (MyHC1) mRNA and protein expression tended to be reduced ( = 0.08, 0.09), whereas mRNA, mRNA, and MyHC2 protein expression increased ( < 0.05). The LPS challenge reduced succinic dehydrogenase (SDH) activity ( < 0.05) and increased lactate dehydrogenase (LDH) activity ( < 0.05) in the LM of piglets. Compared with those in the control group, transcriptional peroxisome proliferator-activated receptor coactivator-α () mRNA ( < 0.05), calcineurin (CaN) mRNA, and protein expression were reduced ( < 0.05), and PGC-α protein expression tended to be reduced ( = 0.08) in the LM of LPS-challenged piglets. These results show that immunological challenge induced by LPS resulted in a shift from type I to

  13. Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice

    SciTech Connect

    Arteel, Gavin E. Guo, Luping; Schlierf, Thomas; Beier, Juliane I.; Kaiser, J. Phillip; Chen, Theresa S.; Liu, Marsha; Conklin, Daniel J.; Miller, Heather L.; Montfort, Claudia von; States, J. Christopher

    2008-01-15

    Exposure to arsenic via drinking water is a serious health concern in the US. Whereas studies have identified arsenic alone as an independent risk factor for liver disease, concentrations of arsenic required to damage this organ are generally higher than found in the US water supply. The purpose of the current study was to test the hypothesis that arsenic (at subhepatotoxic doses) may also sensitize the liver to a second hepatotoxin. To test this hypothesis, the effect of chronic exposure to arsenic on liver damage caused by acute lipopolysaccharide (LPS) was determined in mice. Male C57Bl/6J mice (4-6 weeks) were exposed to arsenic (49 ppm as sodium arsenite in drinking water). After 7 months of exposure, animals were injected with LPS (10 mg/kg i.p.) and sacrificed 24 h later. Arsenic alone caused no overt hepatotoxicity, as determined by plasma enzymes and histology. In contrast, arsenic exposure dramatically enhanced liver damage caused by LPS, increasing the number and size of necroinflammatory foci. This effect of arsenic was coupled with increases in indices of oxidative stress (4-HNE adducts, depletion of GSH and methionine pools). The number of apoptotic (TUNEL) hepatocytes was similar in the LPS and arsenic/LPS groups. In contrast, arsenic pre-exposure blunted the increase in proliferating (PCNA) hepatocytes caused by LPS; this change in the balance between cell death and proliferation was coupled with a robust loss of liver weight in the arsenic/LPS compared to the LPS alone group. The impairment of proliferation after LPS caused by arsenic was also coupled with alterations in the expression of key mediators of cell cycle progression (p27, p21, CDK6 and Cyclin D1). Taken together, these results suggest that arsenic, at doses that are not overtly hepatotoxic per se, significantly enhances LPS-induced liver injury. These results further suggest that arsenic levels in the drinking water may be a risk modifier for the development of chronic liver diseases.

  14. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse.

    PubMed

    Li, Ling; Bhatia, Madhav; Zhu, Yi Zhun; Zhu, Yi Chun; Ramnath, Raina Devi; Wang, Zhong Jing; Anuar, Farhana Binte Mohammed; Whiteman, Matthew; Salto-Tellez, Manuel; Moore, Philip K

    2005-07-01

    Hydrogen sulfide (H2S) is synthesized in the body from L-cysteine by several enzymes including cystathionine-gamma-lyase (CSE). To date, there is little information about the potential role of H2S in inflammation. We have now investigated the part played by H2S in endotoxin-induced inflammation in the mouse. E. coli lipopolysaccharide (LPS) administration produced a dose (10 and 20 mg/kg ip)- and time (6 and 24 h)-dependent increase in plasma H2S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H2S concentration from 34.1 +/- 0.7 microM to 40.9 +/- 0.6 microM (n=6, P<0.05) while H2S formation from added L-cysteine was increased in both liver and kidney. CSE gene expression was also increased in both liver (94.2+/-2.7%, n=6, P<0.05) and kidney (77.5+/-3.2%, n=6, P<0.05). LPS injection also elevated lung (148.2+/-2.6%, n=6, P<0.05) and kidney (78.8+/-8.2%, n=6, P<0.05) myeloperoxidase (MPO, a marker of tissue neutrophil infiltration) activity alongside histological evidence of lung, liver, and kidney tissue inflammatory damage. Plasma nitrate/nitrite (NOx) concentration was additionally elevated in a time- and dose-dependent manner in LPS-injected animals. To examine directly the possible proinflammatory effect of H2S, mice were administered sodium hydrosulfide (H2S donor drug, 14 micromol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF-alpha concentration (4.6+/-1.4 ng/ml, n=6). In contrast, DL-propargylglycine (CSE inhibitor, 50 mg/kg ip), exhibited marked anti-inflammatory activity as evidenced by reduced lung and liver MPO activity, and ameliorated lung and liver tissue damage. In separate experiments, we also detected significantly higher (150.5+/-43.7 microM c.f. 43.8+/-5.1 microM, n=5, P<0.05) plasma H2S levels in humans with septic shock. These findings suggest that H2S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of

  15. Effects of 47C allele (rs4880) of the SOD2 gene in the production of intracellular reactive species in peripheral blood mononuclear cells with and without lipopolysaccharides induction.

    PubMed

    Paludo, F J O; Bristot, I J; Alho, C S; Gelain, D P; Moreira, J C F

    2014-02-01

    Challenging of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharides (LPS) has been shown to activate monocytes and macrophages, leading to the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Manganese superoxide dismutase (MnSOD) is an important enzyme that may play a central role in the response to oxidative stress. 47C> T SNP of the SOD2 gene, the -9Val MnSOD is less efficient than the -9Ala version. We have previously characterized the cellular redox status of human PBMCs expressing either -9Ala (CC) or -9Val (TT) SOD2 and analyzed the responses of these cells to oxidative stress induced by LPS. Due to the observed alterations in the activities of these antioxidant enzymes, we decided to investigate their immunocontent and analyze the production of intracellular oxidants, as well as any resulting DNA damage. PBMCs were isolated from the blood of 30 healthy human volunteers (15 volunteers per allele). We then analyzed levels of nitrite, DNA damage by comet assay, TNF-α, carboxymethyl lysine and nitrotyrosine and assessed production of intracellular reactive species by the DCFH-DA-based assay and western blots were used to analyze protein levels. Our results show that there occurs an increase in nitric oxide production in both allele groups after challenge with LPS. A significant increase in DNA damage was observed in PBMCs after an 8-h LPS challenge. Cells expressing the SOD2 47C allele quickly adapt to a more intense metabolism by upregulating cellular detoxification mechanisms. However, when these cells are stressed over a long period, they accumulate a large quantity of toxic metabolic byproducts.

  16. Chemotherapy-induced Peripheral Neuropathy | Division of Cancer Prevention

    Cancer.gov

    It usually starts in the hands and/or feet and creeps up the arms and legs. Sometimes it feels like a tingling or numbness. Other times, it’s more of a shooting and/or burning pain or sensitivity to temperature. It can include sharp, stabbing pain, and it can make it difficult to perform normal day-to-day tasks like buttoning a shirt, sorting coins in a purse, or walking. An estimated 30 to 40 percent of cancer patients treated with chemotherapy experience these symptoms, a condition called chemotherapy-induced peripheral neuropathy (CIPN). |

  17. [Metronidazole-induced reversible cerebellar lesions and peripheral neuropathy].

    PubMed

    Toumi, S; Hammouda, M; Essid, A; Medimagh, L; Slamia, L Ben; Laouani-Kechrid, C

    2009-12-01

    Metronidazole is a widely prescribed treatment for amoebic and anaerobic germ infections. Its neurologic toxicity is rare but can be serious. We report the case of a 27-year-old male patient, treated with metronidazole for a cerebral abscess. He presented with a cerebellar syndrome and peripheral neuropathy at a cumulative metronidazole dose of 60g. The MRI aspect of the cerebellar lesions in addition to their reversibility after treatment cessation led to the diagnosis of metronidazole induced neurologic toxicity. The occurrence of neurologic disorders in patients treated with metronidazole must suggest drug toxicity and lead to cessation of treatment.

  18. Lipopolysaccharides of Pectobacterium atrosepticum and Pseudomonas corrugata induce different defence response patterns in tobacco, tomato, and potato.

    PubMed

    Desender, S; Klarzynski, O; Potin, P; Barzic, M-R; Andrivon, D; Val, F

    2006-09-01

    Lipopolysaccharides (LPS), ubiquitous cell surface components of Gram-negative bacteria, are directly implicated in plant/pathogen interactions. However, their perception by the plant, the subsequent signal transduction in both compatible and incompatible interactions, as well as the defence reactions induced in compatible interactions are as yet poorly understood. We focused on biochemical and physiological reactions induced in cell suspensions of three Solanaceae species (tobacco, tomato, and potato) by purified lipopolysaccharides from PECTOBACTERIUM ATROSEPTICUM (PA), a pathogen of potato, and PSEUDOMONAS CORRUGATA (PSC), a pathogen of tomato. LPS PA and LPS PSC caused a significant acidification of potato, tomato, and tobacco extracellular media, whereas laminarin (a linear beta-1,3 oligosaccharide elicitor) induced an alkalinisation in tobacco and tomato, but not in potato cell suspensions. None of the two LPS induced the formation of active oxygen species in any of the hosts, while laminarin induced H (2)O (2) production in cells of tobacco but not of tomato and potato. In tomato cells, LPS PA and LPS PSC induced a strong but transitory stimulation of lipoxygenase activity, whereas laminarin induced a stable or slightly increasing LOX activity over the first 24 h of contact. In tobacco, LOX activity was not triggered by either LPS, but significantly increased following treatment with laminarin. In potato, neither LPS nor laminarin induced LOX activity, in contrast with concentrated culture filtrate of PHYTOPHTHORA INFESTANS (CCF). These results demonstrate that LPS, as well as laminarin, are perceived in different ways by SOLANACEAE species, and possibly cultivars. They also suggest that defence responses modulated by LPS depend on plant genotypes rather than on the type of interaction.

  19. Lipopolysaccharide Induces a Significant Increase in Expression of Iron Regulatory Hormone Hepcidin in the Cortex and Substantia Nigra in Rat Brain

    PubMed Central

    Wang, Qin; Du, Fang; Qian, Zhong-Ming; Ge, Xiao Hu; Zhu, Li; Yung, Wing Ho; Yang, Lei; Ke, Ya

    2008-01-01

    Hepcidin plays an essential role in maintaining normal iron homeostasis outside the brain. This recently discovered iron regulation hormone is predominantly expressed in the liver, and regulated by iron and hypoxia. As an antimicrobial peptide, this hormone is also elevated during infections and inflammation. In this study we investigated the expression of hepcidin mRNA and protein in different brain regions, including the cortex, hippocampus, striatum, and substantia nigra, and the effects of lipopolysaccharide (LPS) on the expression of hepcidin using quantitative real-time RT-PCR and immunofluorescence analysis. Our data provided further evidence for the existence of hepcidin in all the regions we examined. We also demonstrated for the first time that LPS administration by iv injection can regulate the expression of hepcidin mRNA and protein not only in peripheral organs such as the liver, but also in the brain. LPS induced a significant increase in the expression of hepcidin mRNA and protein in the cortex and substantia nigra, but not in the hippocampus and striatum, indicating a regionally specific regulation of LPS on hepcidin in the brain. The relevant mechanisms and the functions of hepcidin in the brain remain to be elucidated. PMID:18450970

  20. Protective effect of Salvia miltiorrhiza and Carthamus tinctorius extract against lipopolysaccharide-induced liver injury

    PubMed Central

    Gao, Li-Na; Yan, Kuo; Cui, Yuan-Lu; Fan, Guan-Wei; Wang, Yue-Fei

    2015-01-01

    AIM: To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo. METHODS: C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline, Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection (DHI), 0.75 and 3 g/kg mixed extract] or reduced glutathione for injection (RGI, 300 mg/kg) for 30 min before exposure to lipopolysaccharide (LPS, 16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h, the mice were sacrificed by ether anaesthesia, and serum and liver samples were collected. Histological analysis (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining were performed. Alanine transferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), glutathione-S-transferase (GST), malondialdehyde (MDA), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and caspase-3 levels were measured. Bax, Bcl-2, P-IκBα, IκBα, P-NF-κB p65, and NF-κB p65 protein levels were determined by Western blot. TNF-α, IL-6, caspase-3, Bax and Bcl-2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Hematoxylin-eosin staining and TUNEL results suggested that DHI (3 g/kg) treatment alleviated inflammatory and apoptotic (P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT (72.53 ± 2.83 for 3 g/kg, P < 0.01), AST (76.97 ± 5.00 for 3 g/kg, P < 0.01), TBil (1.17 ± 0.10 for 3 g/kg, P < 0.01), MDA (0.81 ± 0.36 for 3 g/kg, P < 0.01), and GST (358.86 ± 12.09 for 3 g/kg, P < 0.01). Moreover, DHI (3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α (340.55 ± 10.18 for 3 g/kg, P < 0.01), IL-6 (261.34 ± 10.18 for 3 g/kg, P < 0.01), and enzyme activity of caspase-3 (0.93 ± 0.029 for 3 g/kg, P < 0.01). The LPS-induced mRNA expression of TNF-α, IL-6

  1. Protective effect of Salvia miltiorrhiza and Carthamus tinctorius extract against lipopolysaccharide-induced liver injury.

    PubMed

    Gao, Li-Na; Yan, Kuo; Cui, Yuan-Lu; Fan, Guan-Wei; Wang, Yue-Fei

    2015-08-14

    To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo. C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline, Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection (DHI), 0.75 and 3 g/kg mixed extract] or reduced glutathione for injection (RGI, 300 mg/kg) for 30 min before exposure to lipopolysaccharide (LPS, 16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h, the mice were sacrificed by ether anaesthesia, and serum and liver samples were collected. Histological analysis (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining were performed. Alanine transferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), glutathione-S-transferase (GST), malondialdehyde (MDA), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and caspase-3 levels were measured. Bax, Bcl-2, P-IκBα, IκBα, P-NF-κB p65, and NF-κB p65 protein levels were determined by Western blot. TNF-α, IL-6, caspase-3, Bax and Bcl-2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). Hematoxylin-eosin staining and TUNEL results suggested that DHI (3 g/kg) treatment alleviated inflammatory and apoptotic (P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT (72.53 ± 2.83 for 3 g/kg, P < 0.01), AST (76.97 ± 5.00 for 3 g/kg, P < 0.01), TBil (1.17 ± 0.10 for 3 g/kg, P < 0.01), MDA (0.81 ± 0.36 for 3 g/kg, P < 0.01), and GST (358.86 ± 12.09 for 3 g/kg, P < 0.01). Moreover, DHI (3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α (340.55 ± 10.18 for 3 g/kg, P < 0.01), IL-6 (261.34 ± 10.18 for 3 g/kg, P < 0.01), and enzyme activity of caspase-3 (0.93 ± 0.029 for 3 g/kg, P < 0.01). The LPS-induced mRNA expression of TNF-α, IL-6 and caspase-3 was also

  2. Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation.

    PubMed

    André, Caroline; Dinel, Anne-Laure; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie

    2014-10-01

    Obesity is associated with a high prevalence of mood symptoms and cognitive dysfunctions that emerges as significant risk factors for important health complications such as cardiovascular diseases and type 2 diabetes. It is therefore important to identify the dynamic of development and the pathophysiological mechanisms underlying these neuropsychiatric symptoms. Obesity is also associated with peripheral low-grade inflammation and increased susceptibility to immune-mediated diseases. Excessive production of proinflammatory cytokines and the resulting activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been shown to promote neurobehavioral complications, particularly depression. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations and the increased susceptibility to immune-mediated diseases displayed by obese patients, particularly through brain IDO activation. To answer these questions, we used C57Bl/6 mice exposed to standard diet or western diet (WD; consisting of palatable energy-dense food) since weaning and for 20 weeks. We then measured inflammatory and behavioral responses to a systemic immune challenge with lipopolysaccharide (LPS) in experimental conditions known to alter cognitive and emotional behaviors independently of any motor impairment. We first showed that in absence of LPS, 9 weeks of WD is sufficient to impair spatial recognition memory (in the Y-maze). On the other hand, 18 weeks of WD increased anxiety-like behavior (in the elevated plus-maze), but did not affect depressive-like behavior (in the tail-suspension and forced-swim tests). However, 20 weeks of WD altered LPS-induced depressive-like behavior compared to LPS-treated lean mice and exacerbated hippocampal and hypothalamic proinflammatory cytokine expression and brain IDO activation. Taken together, these results show that WD exposure alters cognition and anxiety in unstimulated

  3. Inhibitory effects of Cnidium monnieri fruit extract on pulmonary inflammation in mice induced by cigarette smoke condensate and lipopolysaccharide.

    PubMed

    Kwak, Ho-Geun; Lim, Heung-Bin

    2014-09-01

    The aim of this study was to investigate the inhibitory effect of Cnidium monnieri fruit (CM) extracts on pulmonary inflammation induced in mice by cigarette smoke condensate (CSC) and lipopolysaccharide (LPS). Pulmonary inflammation was induced by intratracheal instillation of LPS and CSC five times within 12 days. CM extract was administered orally at a dose of 50 or 200 mg·kg(-1). The number of inflammatory cells in the bronchoalveolar lavage fluid was counted using a fluorescence activated cell sorter. Inflammatory mediator levels were determined by enzyme-linked immunosorbent assay. The administration of LPS and CSC exacerbated airway hyper-responsiveness (AHR) and induced an accumulation of inflammatory cells and mediators, and led to histological changes. However, these responses are modulated by treatment with CM, and the treatment with CM extract produces similar or more extensive results than the treatment with cyclosporin A (CSA). CM extract may have an inhibitory effect on pulmonary inflammation related with chronic obstructive pulmonary disease.

  4. Chemotherapy-induced peripheral neuropathy: a review of recent findings.

    PubMed

    Kim, Peggy Y; Johnson, Carrie E

    2017-10-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently chronic condition characterized by pain and decreased function. Given the growing number of cancer survivors and an increasing recognition of opioid therapy limitations, there is a need for critical analysis of the literature in directing an informed and thoughtful approach for the management of painful CIPN. A PubMed search for 'chemotherapy-induced peripheral neuropathy AND pain' identifies 259 publications between 1 January 2016 and 31 March 2017. Based on review of this literature, we aim to present a clinically relevant update of painful CIPN. Notably, the use of duloxetine as a first-line agent in treatment of CIPN is confirmed. Moreover, clinical trials focus on nonpharmacologic strategies for managing painful CIPN. Despite the volume of recent publications, there are limited preventive or therapeutic strategies for CIPN supported by high-level evidence. Duloxetine remains the only pharmacologic agent with demonstrated benefit; its clinical use should be routinely considered. Moving forward, nonopioid analgesic therapies will likely play an increasing role in CIPN treatment, but further research is necessary to confirm their utility. Promising therapies include vitamin B12 supplementation, physical therapy, and various forms of neuromodulation.

  5. Systemic adalimumab induces peripheral corneal infiltrates: a case report.

    PubMed

    Matet, Alexandre; Daruich, Alejandra; Beydoun, Talal; Cosnes, Jacques; Bourges, Jean-Louis

    2015-06-06

    Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. A 34 year-old Caucasian woman with Crohn's disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. Paradoxical immune reactions associated with tumor necrosis factor-alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy.

  6. Chemotherapy-induced peripheral neurotoxicity: a critical analysis.

    PubMed

    Park, Susanna B; Goldstein, David; Krishnan, Arun V; Lin, Cindy S-Y; Friedlander, Michael L; Cassidy, James; Koltzenburg, Martin; Kiernan, Matthew C

    2013-01-01

    With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies. © 2013 American Cancer Society, Inc.

  7. Functional characterization of tumor necrosis factor superfamily 15 (TNFSF15) induced by lipopolysaccharides and Eimeria infection.

    PubMed

    Park, Soon S; Lillehoj, Hyun S; Hong, Yeong Ho; Lee, Sung Hyen

    2007-01-01

    A full-length cDNA encoding chicken tumor necrosis factor superfamily 15 (TNFSF15) was isolated and its functional role was investigated. TNFSF15 transcripts were primarily expressed in spleen, liver, intestinal intraepithelial lymphocytes (IEL), peripheral blood lymphocytes and bursa. In vitro infection of HTC macrophages with three species of Eimeria sporozoites induced TNFSF15 gene expression. In vivo experiments revealed that TNFSF15 gene was highly increased following primary infections with Eimeria acervulina or Eimeria maxima. In contrast, no consistent changes in transcript levels were seen following primary infection with Eimeria tenella, or following secondary infection with any of the three Eimeria species. Following infection with E. acervulina and E. maxima, TNFSF15 transcripts were primarily expressed in intestinal CD4(+) and TCR2(+) IEL, respectively. A dose-dependent cytotoxic effect of recombinant TNFSF15 protein was observed on HTC and LSCC-RP9 tumor cells. These results indicate that TNFSF15 plays an important role in local inflammatory response to Eimeria.

  8. Systemic sclerosis induces pronounced peripheral vascular dysfunction characterized by blunted peripheral vasoreactivity and endothelial dysfunction

    PubMed Central

    Frech, Tracy; Walker, Ashley E.; Barrett-O’Keefe, Zachary; Hopkins, Paul N.; Richardson, Russell S.; Wray, D. Walter; Donato, Anthony J.

    2016-01-01

    Systemic sclerosis (SSc) vasculopathy can result in a digital ulcer (DU) and/or pulmonary arterial hypertension (PAH). We hypothesized that bedside brachial artery flow-mediated dilation (FMD) testing with duplex ultrasound could be used in SSc patients to identify features of patients at risk for DU or PAH. Thirty-eight SSc patients were compared to 52 age-matched healthy controls from the VAMC Utah Vascular Research Laboratory. Peripheral hemodynamics, arterial structure, and endothelial function were assessed by duplex ultrasound. A blood pressure cuff was applied to the forearm and 5-min ischemia was induced. Post-occlusion, brachial artery vascular reactivity (peak hyperemia/area under the curve [AUC]), shear rate, and endothelial function (FMD) were measured. SSc patients had smaller brachial artery diameters (p<0.001) and less reactive hyperemia (p<0.001), peak shear rate (p= 0.03), and brachial artery FMD (p<0.001) compared with healthy controls. Brachial artery FMD was lower (p<0.05) in SSc patients with DU. Tertile analysis suggested the 2 lower FMD tertiles (<5.40 %) had a 40–50 % chance of presenting with DU while the SSc patients with highest FMD tertile (>5.40 %) had less than 15 % chance of DU. All brachial artery FMD measurements were similar between SSc patients with and without PAH (all p>0.05). Compared to healthy controls, SSc patients had significantly smaller brachial artery diameter and blunted peripheral vascular reactivity and endothelial function. SSc patients with DU have even greater impairments in endothelial function compared to those without DU. FMD testing has clinical utility to identify SSc patients at risk for DU. PMID:25511849

  9. Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin.

    PubMed

    Yasuhara, Rika; Miyamoto, Yoichi; Takami, Masamichi; Imamura, Takahisa; Potempa, Jan; Yoshimura, Kentaro; Kamijo, Ryutaro

    2009-04-01

    Porphyromonas gingivalis is one of the major pathogens of periodontitis, a condition characterized by excessive alveolar bone resorption by osteoclasts. The bacterium produces cysteine proteases called gingipains, which are classified according to their cleavage-site specificity into Kgps (lysine-specific gingipains) and Rgps (arginine-specific gingipains). In the present study we examined the effects of gingipains on osteoclast differentiation. In co-cultures of mouse bone-marrow cells and osteoblasts, formation of multinucleated osteoclasts induced by 1alpha,25(OH)(2)D(3) (1alpha,25-dihydroxyvitamin D(3)) was augmented by Kgp but not by RgpB. A physiological concentration (0.1 nM) of 1alpha,25(OH)(2)D(3) induced the osteoclast formation in the presence of 100 nM Kgp to an extent comparable with that induced by 10 nM 1alpha,25(OH)(2)D(3). Kgp also enhanced osteoclastogenesis induced by various microbial components, including lipopolysaccharide. Combined use of Kgp and 1alpha,25(OH)(2)D(3) or lipopolysaccharide also increased the number of resorption pits developed on dentin slices, indicating that the osteoclasts formed in the presence of Kgp possess bone-resorbing activity. The enhanced osteoclastogenesis by Kgp was correlated with a depletion of osteoprotegerin in co-culture medium and was proteolytic-activity-dependent, since benzyloxycarbonyl-L-phenylalanyl-L-lysylacycloxyketone, an inhibitor of Kgp, completely abolished osteoclastogenesis induced by Kgp. Kgp digested osteoprotegerin, since its recombinant protein was susceptible to degradation by Kgp in the presence of serum. As a result, Kgp did not augment osteoclastogenesis in co-cultures of osteoprotegerin-deficient osteoblasts and bone-marrow cells. In addition, enhanced osteoclastogenesis by Kgp was abolished by an excess amount of recombinant osteoprotegerin. These findings suggest that degradation of osteoprotegerin is one of the mechanisms underlying promotion of osteoclastogenesis by Kgp.

  10. Cordycepin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production via activating amp-activated protein kinase (AMPK) signaling.

    PubMed

    Zhang, Jian-Li; Xu, Ying; Shen, Jie

    2014-07-08

    Tumor necrosis factor (TNF)-α is elevated during the acute phase of Kawasaki disease (KD), which damages vascular endothelial cells to cause systemic vasculitis. In the current study, we investigated the potential role of cordycepin on TNFα expression in both lipopolysaccharide (LPS)-stimulated macrophages and ex vivo cultured peripheral blood mononuclear cells (PBMCs) of KD patients. We found that cordycepin significantly suppressed LPS-induced TNFα expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, cordycepin alleviated TNFα production in KD patients' PBMCs. PBMCs from healthy controls had a much lower level of basal TNF-α content than that of KD patients. LPS-induced TNF-α production in healthy controls' PBMCs was also inhibited by cordycepin. For the mechanism study, we discovered that cordycepin activated AMP-activated protein kinase (AMPK) signaling in both KD patients' PBMCs and LPS-stimulated macrophages, which mediated cordycepin-induced inhibition against TNFα production. AMPK inhibition by its inhibitor (compound C) or by siRNA depletion alleviated cordycepin's effect on TNFα production. Further, we found that cordycepin inhibited reactive oxygen species (ROS) production and nuclear factor kappa B (NF-κB) activation in LPS-stimulate RAW 264.7 cells or healthy controls' PBMCs. PBMCs of KD patients showed higher basal level of ROS and NF-κB activation, which was also inhibited by cordycepin co-treatment. In conclusion, our data showed that cordycepin inhibited TNFα production, which was associated with AMPK activation as well as ROS and NF-κB inhibition. The results of this study should have significant translational relevance in managing this devastating disease.

  11. Lipopolysaccharide of Aggregatibacter actinomycetemcomitans induces the expression of chemokines MCP-1, MIP-1α, and IP-10 via similar but distinct signaling pathways in murine macrophages.

    PubMed

    Park, Ok-Jin; Cho, Min-Kyung; Yun, Cheol-Heui; Han, Seung Hyun

    2015-09-01

    Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium frequently isolated from lesions of patients with localized aggressive periodontitis. Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, stimulates innate immune cells via Toll-like receptor 4 (TLR4) to initiate inflammatory responses. In this study, we purified LPS from A. actinomycetemcomitans (AaLPS) and investigated its ability to induce the expression of chemokines, which play an important role in recruitment of leukocytes to the infection site. AaLPS induced the expression of chemokines, MCP-1, MIP-1α, and IP-10 in murine macrophages, leading to the infiltration of peripheral blood mononuclear cells in a transwell system. Although TLR4 was essential for the induction of all these chemokines by AaLPS, MCP-1 and MIP-1α expressions were MyD88-dependent, but IP-10 expression was MyD88-independent, as determined using macrophages from mice deficient in TLR4 or MyD88. Furthermore, the activation of ERK and JNK were necessary for the expression of MCP-1 and MIP-1α, whereas p38 MAP kinase and JNK activations were required for IP-10 expression. In addition, IFN-β/STAT1 signaling was exclusively involved in IP-10 expression but not in MCP-1 or MIP-1α expression. AaLPS also activated the transcription factors, NF-κB, AP-1, NF-IL6, and ISRE, all of which are involved in chemokine gene expression. These results suggest that AaLPS induces the expression of chemokines MCP-1, MIP-1α, and IP-10 through TLR4 in murine macrophages. Further, the induction of MCP-1 and MIP-1α requires MyD88, ERK, and JNK, whereas the induction of IP-10 requires JNK, p38 MAP kinase, and IFN-β/STAT1.

  12. Lipopolysaccharide-induced inhibition of transcription of tlr4 in vitro is reversed by dexamethasone and correlates with presence of conserved NFκB binding sites

    SciTech Connect

    Bonin, Camila P.; Baccarin, Raquel Y.A.; Nostell, Katarina; Nahum, Laila A.; Fossum, Caroline; Camargo, Maristela M. de

    2013-03-08

    Highlights: ► Chimpanzees, horses and humans have regions of similarity on TLR4 and MD2 promoters. ► Rodents have few regions of similarity on TLR4 promoter when compared to primates. ► Conserved NFkB binding sites were found in the promoters of TLR4 and MD2. ► LPS-induced inhibition of TLR4 transcription is reversed by dexamethasone. ► LPS-induced transcription of MD2 is inhibited by dexamethasone. -- Abstract: Engagement of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) is a master trigger of the deleterious effects of septic shock. Horses and humans are considered the most sensitive species to septic shock, but the mechanisms explaining these phenomena remain elusive. Analysis of tlr4 promoters revealed high similarity among LPS-sensitive species (human, chimpanzee, and horse) and low similarity with LPS-resistant species (mouse and rat). Four conserved nuclear factor kappa B (NFκB) binding sites were found in the tlr4 promoter and two in the md2 promoter sequences that are likely to be targets for dexamethasone regulation. In vitro treatment of equine peripheral blood mononuclear cells (eqPBMC) with LPS decreased transcripts of tlr4 and increased transcription of md2 (myeloid differentiation factor 2) and cd14 (cluster of differentiation 14). Treatment with dexamethasone rescued transcription of tlr4 after LPS inhibition. LPS-induced transcription of md2 was inhibited in the presence of dexamethasone. Dexamethasone alone did not affect transcription of tlr4 and md2.

  13. The isozyme selective phosphodiesterase-4 inhibitor, ABI-4, attenuates the effects of lipopolysaccharide in human cells and rodent models of peripheral and CNS inflammation.

    PubMed

    Hedde, Joseph R; Hanks, Ashley N; Schmidt, Christopher J; Hughes, Zoë A

    2017-08-01

    Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50∼14nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in blood and brain of mice. In a rat model of endotoxin induced uveitis, ABI-4 (0.03-0.3mg/kg) demonstrated steroid-like efficacy in preventing leucocyte infiltration of the aqueous humor when administered 4h after LPS. LPS (0.32mg/kg×5days) caused a 30% upregulation of translocator protein (TSPO) binding which was prevented by co-administration of ABI-4 (0.32mg/kg). In a paradigm to assess motivation, LPS (0.32mg/kg) reduced the number of rewards received, whereas the effect was significantly blunted in mice dosed with ABI-4 (P<0.05) or in PDE4B-/- mice. PDE4B was also shown to modulate brain and plasma levels of TNF-α and IL-1β in aged mice. Aged mice dosed chronically with ABI-4 (0.32mg/kg) as well as aged PDE4B-/- mice, had significantly lower levels of TNF-α and IL-1β in brain and plasma relative to vehicle treated or PDE4+/+ mice. Together these data demonstrate that the PDE4D sparing, PDE4 inhibitor, ABI-4 retains potency and efficacy in exerting anti-inflammatory effects. This mechanism warrants further investigation in human disorders involving neuroinflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Heat shock protein 72 protects insulin-secreting beta cells from lipopolysaccharide-induced endoplasmic reticulum stress.

    PubMed

    Hagiwara, Satoshi; Iwasaka, Hideo; Shingu, Chihiro; Matsumoto, Shigekiyo; Hasegawa, Akira; Asai, Nobuhiko; Noguchi, Takayuki

    2009-12-01

    Hyperthermia-induced activation of stress response proteins allows cells to withstand metabolic insults. In this study we set out to determine whether insulin secretion by pancreatic beta cells was affected by the acute inflammatory response, systemic inflammation-induced hyperglycaemia, and whole-body hyperthermia. Given that systemic-inflammation induces ER stress, we further examined whether hyperthermia can attenuate the extent of LPS-induced ER stress. Rats were randomised and divided into three treatment groups. Control rats received a 0.9% NaCl solution. Rats in the lipopolysaccharide (LPS) group received 7.5 mg of LPS/kg. Rats in the whole-body hyperthermia (WBH) + LPS group were exposed to 42 degrees C for 15 min, followed by injection with 7.5 mg of LPS/kg after 48 h. Glucose-potentiated insulin release and extent of ER stress were measured in beta cells. LPS inhibited glucose-induced insulin release from islet cells and induced the expression of Bip/GRP78, XBP-1, and CHOP transcripts. The inhibition of glucose-induced insulin release and induction of ER stress proteins by LPS was attenuated by WBH. Our findings suggest that LPS-induced systemic inflammation decreased insulin release due to the effects of ER stress proteins on insulin secretion. Furthermore, the induction of ER stress proteins was prevented by pretreating rats with WBH. This may suggest that inhibiting the induction of ER stress proteins through WBH can restore insulin release in various disease states.

  15. Lipopolysaccharide-binding protein and leptin are associated with stress-induced interleukin-6 cytokine expression ex vivo in obesity.

    PubMed

    Huang, Chun-Jung; Stewart, Jennifer K; Shibata, Yoshimi; Slusher, Aaron L; Acevedo, Edmund O

    2015-05-01

    Obesity is associated with enhanced inflammation and mental stress, but limited information has addressed the potential additive effect of psychological stress on obesity-associated inflammation. This study examined whether obese subjects would elicit a greater host immune response (IL-6 mRNA and cytokine) to lipopolysaccharide (LPS) in response to mental stress. Blood samples for LPS-stimulated IL-6 mRNA and cytokine were collected prior to and following mental stress. Results showed that obese subjects elicited a greater LPS-induced IL-6 along with its mRNA expression following mental stress compared to normal-weight subjects. Stress-induced IL-6 cytokine response to LPS was correlated with the baseline levels of plasma LPS binding protein (LBP) and leptin. These findings are consistent with the idea that endogenous inflammatory agents (e.g., LBP and leptin), often elevated with obesity, enhance inflammatory responses to psychological stress. © 2014 Society for Psychophysiological Research.

  16. Effect of Tridax procumbens on liver antioxidant defense system during lipopolysaccharide-induced hepatitis in D-galactosamine sensitised rats.

    PubMed

    Ravikumar, Vilwanathan; Shivashangari, Kanchi Subramanian; Devaki, Thiruvengadam

    2005-01-01

    The present study was carried out to assess the effect of chloroform insoluble fraction of ethanolic extract of Tridax procumbens (TP) against D-Galactosamine/Lipopolysaccharide (D-GalN/LPS)-induced hepatitis in rats. Induction of rats with D-GalN/LPS (300 mg/kg body weight/30 microg/kg body weight) led to a marked increase in lipid peroxidation as measured by thiobarbituric acid reactive substances (TBARS) in liver. Further there was a decline in the activities of enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione s-transferase and the levels of non-enzymic antioxidants namely reduced glutathione, vitamin C and vitamin E. These biochemical alterations were normalised upon pretreatment with TP extract. Thus, the above results suggest that TP (300 mg/kg body weight orally for 10 days) is very effective in allievating the D-GalN/LPS-induced oxidative stress suggesting its antioxidant property.

  17. Inhibition of inflammatory responses by ambroxol, a mucolytic agent, in a murine model of acute lung injury induced by lipopolysaccharide.

    PubMed

    Su, Xiao; Wang, Ling; Song, Yuanlin; Bai, Chunxue

    2004-01-01

    The aim of this study is to investigate whether ambroxol inhibits inflammatory responses in a murine model of lipopolysaccharide-induced acute lung injury (ALI). Mice (n=295) were first intratracheally instilled with lipopolysaccharide (LPS) to induce ALI and then received an intraperitoneal (i.p.) injection of either normal saline (NS), ambroxol (30 or 90 mg/kg per day) or dexamethasone (2.5 or 5 mg/kg per day) for 7 days. Metabolism (n=10, each), lung morphology (n=5, each) and wet-to-dry lung weight ratio (n=10, each) were studied. The levels of tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor (TGF-beta1) and the protein concentration (n=5 or 7, each) in bronchoalveolar lavage (BAL) were measured. Mice with LPS-induced ALI that were treated with ambroxol at a dosage of 90 mg/kg per day significantly gained weight compared to the control and dexamethasone-treated groups. Ambroxol and dexamethasone significantly reduced the lung hemorrhage, edema, exudation, neutrophil infiltration and total lung injury histology score at 24 and 48 h. In addition, ambroxol and dexamethasone significantly attenuated the lung wet-to-dry weight ratio at 24 and 48 h (p<0.05). Compared to the control group, TNF-alpha, IL-6 and TGF-beta1 levels in the BAL in both ambroxol- and dexamethasone-treated groups were significantly reduced at 24 and 48 h. The protein in BAL, an index of vascular permeability, was also significantly decreased in the ambroxol- and dexamethasone-treated groups (p<0.05). Ambroxol inhibited proinflammatory cytokines, reduced lung inflammation and accelerated recovery from LPS-induced ALI.

  18. Pharmacokinetics of ceftiofur in healthy and lipopolysaccharide-induced endotoxemic newborn calves treated with single and combined therapy

    PubMed Central

    ALTAN, Feray; UNEY, Kamil; ER, Ayse; CETIN, Gul; DIK, Burak; YAZAR, Enver; ELMAS, Muammer

    2017-01-01

    The aim of this research was to compare plasma pharmacokinetics of ceftiofur sodium (CS) in healthy calves, and in calves with experimentally induced endotoxemia. Six calves received CS (2.2 mg/kg, IM) 2 hr after intravenous administration of 0.9% NaCl (Ceft group). After a washout period, the same 6 calves received CS 2 hr after intravenous injection of lipopolysaccharide (LPS+Ceft group). Another group of 6 calves received a combination of drug therapies that included CS 2 hr after administration of 0.9% NaCl (Comb group). A third group of 6 calves received the same combination therapy regimen 2 hr after intravenous injection of lipopolysaccharide (LPS+Comb group). Plasma concentrations of CS and all desfuroylceftiofur-related metabolites were determined using HPLC, and its pharmacokinetic properties were determined based on a two-compartment model. The peak concentration of CS in the LPS+Comb group occurred the earliest, and the clearance rate of CS was the highest in the Comb and LPS+Comb groups (P<0.05). The elimination half-life of CS in the LPS+Ceft group was longer than that in the Ceft and Comb groups (P<0.05). The results of this study indicate that combined therapies and endotoxemic status may alter the plasma pharmacokinetics of CS in calves. PMID:28579597

  19. Effects of tylosin, tilmicosin and tulathromycin on inflammatory mediators in bronchoalveolar lavage fluid of lipopolysaccharide-induced lung injury.

    PubMed

    Er, Ayse; Yazar, Enver

    2012-12-01

    The aim of this study was to determine the anti-inflammatory effects of macrolides through kinetic parameters in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide-induced lung injury. Rats were divided into four groups: lipopolysaccharide (LPS), LPS + tylosin, LPS + tilmicosin and LPS + tulathromycin. BALF samples were collected at sampling times. TNF, IL-1β, IL-6, IL-10 and 13,14-dihydro-15-keto-prostaglandin F2α (PGM) and C-reactive protein (CRP) were analysed. Area under the curve (AUC) and maximum plasma concentration (Cmax) values of inflammatory mediators were determined by a pharmacokinetic computer programme. When inflammatory mediator concentrations were compared between the LPS group and other groups for each sampling time, the three macrolides had no pronounced depressor effect on cytokine levels, but they depressed PGM and CRP levels. In addition, tylosin and tilmicosin decreased the AUC0-24 level of TNF, while tilmicosin decreased the AUC0-24 level of IL-10. Tylosin and tulathromycin decreased the AUC0-24 of PGM, and all three macrolides decreased the AUC0-24 of CRP. Especially tylosin and tulathromycin may have more expressed anti-inflammatory effects than tilmicosin, via depressing the production of inflammatory mediators in the lung. The AUC may be used for determining the effects of drugs on inflammation. In this study, the antiinflammatory effects of these antibiotics were evaluated with kinetic parameters as a new and different approach.

  20. IFN-τ Alleviates Lipopolysaccharide-Induced Inflammation by Suppressing NF-κB and MAPKs Pathway Activation in Mice.

    PubMed

    Wu, Haichong; Zhao, Gan; Jiang, Kangfeng; Chen, Xiuying; Rui, Guangze; Qiu, Changwei; Guo, Mengyao; Deng, Ganzhen

    2016-06-01

    IFN-τ, which is a type I interferon with low cytotoxicity, is defined as a pregnancy recognition signal in ruminants. Type I interferons have been used as anti-inflammatory agents, but their side effects limit their clinical application. The present study aimed to determine the anti-inflammatory effects of IFN-τ in a lipopolysaccharide-stimulated acute lung injury (ALI) model and in RAW264.7 cells and to confirm the mechanism of action involved. The methods used included histopathology, measuring the lung wet/dry ratio, determining the myeloperoxidase activity, ELISA, qPCR, and western blot. The results revealed that IFN-τ greatly ameliorated the infiltration of inflammatory cells and the expression of TNF-α, IL-1β, and IL-6. Further analysis revealed that IFN-τ down-regulated the expression of TLR-2 and TLR-4 mRNA and the activity of the NF-κB and MAPK pathways both in a lipopolysaccharide-induced ALI model and in RAW264.7 cells. The results demonstrated that IFN-τ suppressed the levels of pro-inflammatory cytokines by inhibiting the phosphorylation of the NF-κB and MAPK pathways. Thus, IFN-τ may be an optimal target for the treatment of inflammatory diseases.

  1. 12-oxo-phytodienoic acid, a plant-derived oxylipin, attenuates lipopolysaccharide-induced inflammation in microglia.

    PubMed

    Taki-Nakano, Nozomi; Kotera, Jun; Ohta, Hiroyuki

    2016-05-13

    Jasmonates are plant lipid-derived oxylipins that act as key signaling compounds in plant immunity, germination, and development. Although some physiological activities of natural jasmonates in mammalian cells have been investigated, their anti-inflammatory actions in mammalian cells remain unclear. Here, we investigated whether jasmonates protect mouse microglial MG5 cells against lipopolysaccharide (LPS)-induced inflammation. Among the jasmonates tested, only 12-oxo-phytodienoic acid (OPDA) suppressed LPS-induced expression of the typical inflammatory cytokines interleukin-6 and tumor necrosis factor α. In addition, only OPDA reduced LPS-induced nitric oxide production through a decrease in the level of inducible nitric oxide synthase. Further mechanistic studies showed that OPDA suppressed neuroinflammation by inhibiting nuclear factor κB and p38 mitogen-activated protein kinase signaling in LPS-activated MG5 cells. In addition, OPDA induced expression of suppressor of cytokine signaling-1 (SOCS-1), a negative regulator of inflammation, in MG5 cells. Finally, we found that the nuclear factor erythroid 2-related factor 2 signaling cascade induced by OPDA is not involved in the anti-inflammatory effects of OPDA. These results demonstrate that OPDA inhibited LPS-induced cell inflammation in mouse microglial cells via multiple pathways, including suppression of nuclear factor κB, inhibition of p38, and activation of SOCS-1 signaling.

  2. Lipopolysaccharide-induced anhedonia is abolished in male serotonin transporter knockout rats: an intracranial self-stimulation study.

    PubMed

    van Heesch, Floor; Prins, Jolanda; Konsman, Jan Pieter; Westphal, Koen G C; Olivier, Berend; Kraneveld, Aletta D; Korte, S Mechiel

    2013-03-01

    A growing body of evidence suggests that pro-inflammatory cytokines contribute to the pathogenesis of depression. Previously, it has been shown that cytokines (e.g. interferon-α therapy) induce major depression in humans. In addition, administration of the cytokine-inducer lipopolysaccharide (LPS) provokes anhedonia (i.e. the inability to experience pleasure) in rodents. Furthermore, serum pro-inflammatory cytokine levels are increased in depressed patients. Nevertheless, the etiology of cytokine-induced depression is largely unknown. Previously, it has been shown that selective serotonin re-uptake inhibitors decrease serum pro-inflammatory cytokine levels and that pro-inflammatory cytokines increase activity of the serotonin transporter (SERT). The purpose of this study was to explore the effect of partial and complete lack of the SERT in LPS-induced anhedonia assessed in the intracranial self-stimulation (ICSS) paradigm. A single intraperitoneal injection of LPS was used to induce a pro-inflammatory immune response in male serotonin transporter wild type (SERT(+/+)), heterozygous (SERT(+/-)) and knockout (SERT(-/-)) rats. Body weight and ICSS thresholds were measured daily. Although LPS reduced body weight in all genotypes, loss of body weight was less pronounced in SERT(-/-) compared to SERT(+/+) rats. Remarkably, LPS-induced anhedonia was totally abolished in SERT(-/-) rats and as expected was still present in SERT(+/+) and to a lesser extent in SERT(+/-) rats. Therefore, it is concluded that an intact SERT function is needed for pro-inflammatory cytokine-induced anhedonia and weight loss in rats.

  3. Velutin reduces lipopolysaccharide-induced proinflammatory cytokine TNFa and IL-6 production by inhibiting NF-Kappa B activation

    USDA-ARS?s Scientific Manuscript database

    Recent studies have shown that some flavonoids are modulators of proinflammatory cytokine expression. Velutin, an uncommon flavone isolated from acai (Euterpe oleraceas) berry, was tested for the effects in reducing LPS-induced TNFa and IL-6 production in RAW 264.7 peripheral macrophages and periton...

  4. Chemotherapy-induced peripheral neuropathy - epidemiology and pathogenesis.

    PubMed

    Iżycki, Dariusz; Niezgoda, Adam; Kaźmierczak, Maciej; Nowak-Markwitz, Ewa

    2016-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important neurologic complications experienced by patients receiving chemotherapy. The neuropathy often interferes with daily activities and exercise leading to severe impairment of the patient's quality of life (QoL). The evolution of most CIPNs is characterized by a gradual onset of signs/symptoms, beginning in the lower limbs and advancing proximally into a bilateral stocking and glove distribution. Patients often complain of numbness, tingling and pain in the affected areas. The symptoms become aggravated with repeated cycles of chemotherapy. When the offending agent is withheld, the symptoms generally abate, but relief is not guaranteed. The consequences of delay or discontinuation of treatment may affect overall patient survival.

  5. [Efficacy and safety of pregabalin for oxaliplatin- and paclitaxel-induced peripheral neuropathy].

    PubMed

    Nihei, Satoru; Sato, Junya; Kashiwaba, Masahiro; Itabashi, Tetsuya; Kudo, Kenzo; Takahashi, Katsuo

    2013-09-01

    This study included patients who were prescribed pregabalin, vitamin B12, amitriptyline, clonazepam, or carbamazepine to improve oxaliplatin(L-OHP)- or paclitaxel(PTX)-induced peripheral neuropathy at Iwate Medical University Hospital betwee