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Sample records for a20 protects mice

  1. A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection

    PubMed Central

    Vereecke, Lars; Mc Guire, Conor; Sze, Mozes; Schuijs, Martijn J.; Willart, Monique; Itati Ibañez, Lorena; Hammad, Hamida; Lambrecht, Bart N.; Beyaert, Rudi; Saelens, Xavier; van Loo, Geert

    2016-01-01

    A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection. PMID:26815999

  2. Oral lactoferrin protects against experimental candidiasis in mice

    PubMed Central

    Velliyagounder, Kabilan; Alsaedi, Wijdan; Alabdulmohsen, Waad; Markowitz, Kenneth; Fine, Daniel H.

    2015-01-01

    Aims To determine the role of lactoferrin in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO−/−) mice were compared to wild-type (WT) mice. We also determine the protective role of human lactoferrin in the LFKO−/− mice. Methods and Results Antibiotic treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0.3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO−/−I mice showed a 2 log (P=0.001) higher CFUs of C. albicans in the oral cavity compared to the WTI mice. LFKO−/−I mice given hLF had a 3 log (P=0.001) reduction in CFUs in the oral cavity compared to untreated LFKO−/−I mice. The severity of infection, observed by light microscopy revealed that the tongue of the LFKO−/−I mice showed more white patches compared to WTI and LFKO−/−I+hLF mice. Scanning electron microscopic observation revealed that more filiform papillae were destroyed in LFKO−/−I mice when compared to WTI or LFKO−/−I +hLF mice. Conclusions Human lactoferrin is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Significance and Impact of the Study Human lactoferrin, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral health care products against C. albicans. PMID:25319508

  3. Oral lactoferrin protects against experimental candidiasis in mice.

    PubMed

    Velliyagounder, K; Alsaedi, W; Alabdulmohsen, W; Markowitz, K; Fine, D H

    2015-01-01

    To determine the role of human lactoferrin (hLF) in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO(-/-)) mice was compared to wild-type (WT) mice. We also aim to determine the protective role of hLF in LFKO(-/-) mice. Antibiotic-treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0·3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO(-/-) I mice showed a 2 log (P = 0·001) higher CFUs of C. albicans in the oral cavity compared to the WT mice infected with C. albicans (WTI). LFKO(-/-) I mice given hLF had a 3 log (P = 0·001) reduction in CFUs in the oral cavity compared to untreated LFKO(-/-) I mice. The severity of infection, observed by light microscopy, revealed that the tongue of the LFKO(-/-) I mice showed more white patches compared to WTI and LFKO(-/-) I + hLF mice. Scanning electron microscopic observations revealed that more filiform papillae were destroyed in LFKO(-/-) I mice when compared to WTI or LFKO(-/-) I + hLF mice. Human LF is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Human LF, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral healthcare products against C. albicans. © 2014 The Society for Applied Microbiology.

  4. Broad protection against influenza infection by vectored immunoprophylaxis in mice

    PubMed Central

    Balazs, Alejandro B.; Bloom, Jesse D.; Hong, Christin M.; Rao, Dinesh S.; Baltimore, David

    2014-01-01

    Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines. PMID:23728362

  5. Protection of mice against Giardia muris infection.

    PubMed Central

    Roberts-Thomson, I C; Mitchell, G F

    1979-01-01

    Strains of mice showing relatively rapid (BALB/c) and defective (C3H/He) spontaneous elimination of Giardia muris displayed marked differences in the degree of resistance to infection induced by prior injection of trophozoites in Freund complete adjuvant. PMID:468385

  6. Suspended animation-like state protects mice from lethal hypoxia.

    PubMed

    Blackstone, Eric; Roth, Mark B

    2007-04-01

    Joseph Priestley observed the high burn rate of candles in pure oxygen and wondered if people would "live out too fast" if we were in the same environment. We hypothesize that sulfide, a natural reducer of oxygen that is made in many cell types, acts as a buffer to prevent unrestricted oxygen consumption. To test this, we administered sulfide in the form of hydrogen sulfide (H2S) to mice (Mus musculus). As we have previously shown, H2S decreases the metabolic rate of mice by approximately 90% and induces a suspended animation-like state. Mice cannot survive for longer than 20 min when exposed to 5% oxygen. However, if mice are first put into a suspended animation-like state by a 20-min pretreatment with H2S and then are exposed to low oxygen, they can survive for more than 6.5 h in 5% oxygen with no apparent detrimental effects. In addition, if mice are exposed to a 20-min pretreatment with H2S followed by 1 h at 5% oxygen, they can then survive for several hours at oxygen tensions as low as 3%. We hypothesize that prior exposure to H2S reduces oxygen demand, therefore making it possible for the mice to survive with low oxygen supply. These results suggest that H2S may be useful to prevent damage associated with hypoxia.

  7. Probiotics Protect Mice from Ovariectomy-Induced Cortical Bone Loss

    PubMed Central

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H.; Farman, Helen H.; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice. PMID:24637895

  8. Probiotics protect mice from ovariectomy-induced cortical bone loss.

    PubMed

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H; Farman, Helen H; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice.

  9. Neurochemical effects of a 20 kHz magnetic field on the central nervous system in prenatally exposed mice

    SciTech Connect

    Dimberg, Y.

    1995-09-01

    C57/B1 mice were exposed during pregnancy (gestation days 0--19) to a 20 kHz magnetic field (MF). The asymmetric sawtooth-waveform magnetic field in the exposed racks had a flux density of 15 {micro}T (peak to peak). After 19 days, the exposure was terminated, and the mice were housed individually under normal laboratory conditions. On postnatal day (PD) 1, PD21, and PD308, various neurochemical markers in the brains of the offspring were investigated and the brains weighed. No significant difference was found in the whole brain weight at PD1 or PD21 between exposed offspring and control animals. However, on PD308, a significantmore » decrease in weight of the whole brain was detected in exposed animals. No significant differences were found in the weight of cortex, hippocampus, septum, or cerebellum on nay of the sampling occasions, nor were any significant differences detected in protein-, DNA-level, nerve growth factor (NGF), acetylcholine esterase- (AChE), or 2{prime},3{prime}-cyclic nucleotide 3{prime}-phosphodiesterase- (CNP; marker for oligodendrocytes) activities on PD21 in cerebellum. Cortex showed a more complex pattern of response to MF: MF treatment resulted in a decrease in DNA level and increases in the activities of CNP, AChE, and NGF protein. On PD308, the amount of DNA was significantly reduced in MF-treated cerebellum and CNP activity was still enhanced in MF-treated cortex compared to controls. Most of the effect of MF treatment during the embryonic period were similar to those induced by ionizing radiation but much weaker. However, the duration of the exposure required to elucidate the response of different markers to MF seems to be greater and effects appear later during development compared to responses to ionizing radiation.« less

  10. Mitochondrial gene polymorphisms that protect mice from colitis.

    PubMed

    Bär, Florian; Bochmann, Wiebke; Widok, Andrea; von Medem, Kilian; Pagel, Rene; Hirose, Misa; Yu, Xinhua; Kalies, Kathrin; König, Peter; Böhm, Ruwen; Herdegen, Thomas; Reinicke, Anna T; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh; Sina, Christian

    2013-11-01

    Dysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Colitis was induced in C57BL/6J wild-type (B6.B6) and 3 strains of conplastic mice (B6.NZB, B6.NOD, and B6.AKR) by administration of dextran sodium sulfate or rectal application of trinitrobenzene sulfonate. Colon tissues were collected and analyzed by histopathology, immunohistochemical analysis, and immunoblot analysis; we also measured mucosal levels of adenosine triphosphate (ATP) and reactive oxygen species, OXPHOS complex activity, and epithelial cell proliferation and apoptosis. We identified mice with increased mucosal OXPHOS complex activities and levels of ATP. These mice developed less-severe colitis after administration of dextran sodium sulfate or trinitrobenzene sulfonate than mice with lower mucosal levels of ATP. Colon tissues from these mice also had increased enterocyte proliferation and transcription factor nuclear factor-κB activity, which have been shown to protect the mucosal barrier-defects in these processes have been associated with inflammatory bowel disease. Variants in mitochondrial DNA that increase mucosal levels of ATP protect mice from colitis. Increasing mitochondrial ATP synthesis in intestinal epithelial cells could be a therapeutic approach for UC. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  11. Recombinant raccoon pox vaccine protects mice against lethal plague

    USGS Publications Warehouse

    Osorio, J.E.; Powell, T.D.; Frank, R.S.; Moss, K.; Haanes, E.J.; Smith, S.R.; Rocke, T.E.; Stinchcomb, D.T.

    2003-01-01

    Using a raccoon poxvirus (RCN) expression system, we have developed new recombinant vaccines that can protect mice against lethal plague infection. We tested the effects of a translation enhancer (EMCV-IRES) in combination with a secretory (tPA) signal or secretory (tPA) and membrane anchoring (CHV-gG) signals on in vitro antigen expression of F1 antigen in tissue culture and the induction of antibody responses and protection against Yersinia pestis challenge in mice. The RCN vector successfully expressed the F1 protein of Y. pestis in vitro. In addition, the level of expression was increased by the insertion of the EMCV-IRES and combinations of this and the secretory signal or secretory and anchoring signals. These recombinant viruses generated protective immune responses that resulted in survival of 80% of vaccinated mice upon challenge with Y. pestis. Of the RCN-based vaccines we tested, the RCN-IRES-tPA-YpF1 recombinant construct was the most efficacious. Mice vaccinated with this construct withstood challenge with as many as 1.5 million colony forming units of Y. pestis (7.7×104 LD50). Interestingly, vaccination with F1 fused to the anchoring signal (RCN-IRES-tPA-YpF1-gG) elicited significant anti-F1 antibody titers, but failed to protect mice from plague challenge. Our studies demonstrate, in vitro and in vivo, the potential importance of the EMCV-IRES and secretory signals in vaccine design. These molecular tools provide a new approach for improving the efficacy of vaccines. In addition, these novel recombinant vaccines could have human, veterinary, and wildlife applications in the prevention of plague.

  12. Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis.

    PubMed

    Sellmann, Cathrin; Jin, Cheng Jun; Degen, Christian; De Bandt, Jean-Pascal; Bergheim, Ina

    2015-10-01

    Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies. The effect of oral Gln supplementation on the development of Western-style diet (WSD)-induced NASH in mice was assessed. Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l-Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured. Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor α and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD-fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln-fed mice compared with C mice. Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver. © 2015 American Society for Nutrition.

  13. Cathodic protection - Coating and river profile survey of a 20 year old remote onshore crude pipeline

    SciTech Connect

    Simon, P.

    1984-02-01

    This paper presents test data, evaluation and recommendations resulting from an investigative cathodic protection and coating integrity survey of a twenty year old, onshore crude oil pipeline. The pipeline discussed is 20 inches (508 mm) in diameter, 233 kilometers long and originates at a pumping facility in an inland oil field. The pipeline runs through mountainous terrain, low lying marshland and terminates at a twin 16 inch submarine crossing. The pipeline is located in Southern Kalimantan, Indonesia and is part of the Pertamina Unit IV installation. The field testing was performed by Norton Corrosion Limited (NCL) during the months ofmore » March and April, 1983 and was done concurrently with river crossing profile work by Sterling Energy and Resource Technologies, Limited. The purpose of the survey was to determine the condition of the pipeline and the condition and effectiveness of existing corrosion control measures. The pipeline had experienced an increasing number of leaks in recent years and it was necessary to know the physical condition of the line and what could be done to extend its useful life. The present and future integrity of the pipeline was critical to the clients' planning in that this particular line is the only onshore connection between the field and new refinery which was nearing completion.« less

  14. Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

    PubMed Central

    Rauch, Sabine; Gough, Portia; Kim, Hwan Keun; Schneewind, Olaf

    2014-01-01

    The risk for Staphylococcus aureus bloodstream infection (BSI) is increased in immunocompromised individuals, including patients with hematologic malignancy and/or chemotherapy. Due to the emergence of antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), staphylococcal BSI in cancer patients is associated with high mortality; however, neither a protective vaccine nor pathogen-specific immunotherapy is currently available. Here, we modeled staphylococcal BSI in leukopenic CD-1 mice that had been treated with cyclophosphamide, a drug for leukemia and lymphoma patients. Cyclophosphamide-treated mice were highly sensitive to S. aureus BSI and developed infectious lesions lacking immune cell infiltrates. Virulence factors of S. aureus that are key for disease establishment in immunocompetent hosts—α-hemolysin (Hla), iron-regulated surface determinants (IsdA and IsdB), coagulase (Coa), and von Willebrand factor binding protein (vWbp)—are dispensable for the pathogenesis of BSI in leukopenic mice. In contrast, sortase A mutants, which cannot assemble surface proteins, display delayed time to death and increased survival in this model. A vaccine with four surface antigens (ClfA, FnBPB, SdrD, and SpAKKAA), which was identified by genetic vaccinology using sortase A mutants, raised antigen-specific immune responses that protected leukopenic mice against staphylococcal BSI. PMID:25183728

  15. Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20.

    PubMed

    Han, Dan; Fang, Weirong; Zhang, Rui; Wei, Jie; Kodithuwakku, Nandani Darshika; Sha, Lan; Ma, Wenhuan; Liu, Lifang; Li, Fengwen; Li, Yunman

    2016-01-01

    Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-κB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Protective effect of cinnamic acid in endotoxin-poisoned mice.

    PubMed

    Xu, Feng; Wang, Feng; Wen, Taoqun; Sang, Wentao; He, Xinyu; Li, Ling; Zeng, Nan

    2017-12-01

    In this work, we aimed to evaluate the protective effect of cinnamic acid (CD) on lipopolysaccharide (LPS; Escherichia coli 055:B5)-induced endotoxin-poisoned mice and clarify the underlying mechanisms. The mice were administrated CD 5 d before 15 mg/kg LPS challenge. 12 hr later, thymus was separated for determination of thymus indexes. Lung and spleen tissues were collected for histologic examination and the wet/dry weight ratio of lung was calculated, and serum was acquired for tumor necrosis factor-α (TNF-α), interleukin (IL)-18, and IL-1β measurement. Moreover, the expression of NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome was determined in lung. CD increased the thymus indexes and decreased lung wet/dry weight ratio. In addition, CD improved the lung and spleen histopathological changes induced by LPS and decreased the number of neutrophils in lung tissues. CD also inhibited the pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) production in serum. Furthermore, CD suppressed the LPS-induced NLRP3, Caspase-1, and IL-1β mRNA expression in lung, as well as the expression of NLRP3 and Caspase-1 (p20) protein. CD may have protective effects in endotoxin-poisoned mice via inhibiting the activation of NLRP3 inflammasome, and can be considered as a potential therapeutic candidate for diseases involved in endotoxin poisoning such as sepsis. Copyright © 2017 John Wiley & Sons, Ltd.

  17. Methamphetamine protects against MPTP neurotoxicity in C57BL mice.

    PubMed

    Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Budai, G

    1994-01-14

    Methamphetamine (5 mg/kg) administered 30 min prior to each injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (3 x 30 mg/kg, at 24 h intervals) prevents the reduction of striatal levels of dopamine and its metabolites in C57BL mice. Methamphetamine and amphetamine inhibit the uptake of 1-methyl-4-phenylpyridinium (MPP+) by striatal synaptosomes of rats. A 30-min post-treatment with methamphetamine or amphetamine also prevents the MPTP-induced dopamine depletion, suggesting that their protective effect is related to the blockade of MPP+ uptake into dopaminergic neurons. Since amphetamine and methamphetamine are themselves neurotoxins at higher doses, this work demonstrated the protection against the actions of one neurotoxin by the administration of another.

  18. Smallpox subunit vaccine produced in planta confers protection in mice

    PubMed Central

    Golovkin, Maxim; Spitsin, Sergei; Andrianov, Vyacheslav; Smirnov, Yuriy; Xiao, Yuhong; Pogrebnyak, Natalia; Markley, Karen; Brodzik, Robert; Gleba, Yuri; Isaacs, Stuart N.; Koprowski, Hilary

    2007-01-01

    We report here the in planta production of the recombinant vaccinia virus B5 antigenic domain (pB5), an attractive component of a subunit vaccine against smallpox. The antigenic domain was expressed by using efficient transient and constitutive plant expression systems and tested by various immunization routes in two animal models. Whereas oral administration in mice or the minipig with collard-derived insoluble pB5 did not generate an anti-B5 immune response, intranasal administration of soluble pB5 led to a rise of B5-specific immunoglobulins, and parenteral immunization led to a strong anti-B5 immune response in both mice and the minipig. Mice immunized i.m. with pB5 generated an antibody response that reduced virus spread in vitro and conferred protection from challenge with a lethal dose of vaccinia virus. These results indicate the feasibility of producing safe and inexpensive subunit vaccines by using plant production systems. PMID:17428917

  19. Antisense reduction of tau in adult mice protects against seizures.

    PubMed

    DeVos, Sarah L; Goncharoff, Dustin K; Chen, Guo; Kebodeaux, Carey S; Yamada, Kaoru; Stewart, Floy R; Schuler, Dorothy R; Maloney, Susan E; Wozniak, David F; Rigo, Frank; Bennett, C Frank; Cirrito, John R; Holtzman, David M; Miller, Timothy M

    2013-07-31

    Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS--brain and spinal cord tissue, interstitial fluid, and CSF--while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.

  20. Protective Effect of Ozone against Hemiscorpius lepturus Envenomation in Mice.

    PubMed

    Naserzadeh, Parvaneh; Shahi, Farshad; Shahbazzadeh, Delavar; Ghanei, Mostafa; Ashtari, Khadijeh; Panahi, Yoones; Hosseini, Mir-Jamal; Izadi, Morteza

    2017-08-01

    Scorpion (Hemiscorpius lepturus) stings are a public health concern in Iran, particularly in south and southwestern regions of Iran. The gold standard for the treatment of a scorpion sting is anti-venom therapy. However, immunotherapy can have serious side effects, such as anaphylactic shock (which can sometimes even lead to death). The aim of the current study was to demonstrate the protective effect of ozone against toxicity induced by Hemiscorpius lepturus (H. lepturus) venom in mice. Eight hours after the injection of ozone to the experimental design groups, the male mice were decapitated and mitochondria were isolated from five different tissues (liver, kidney, heart, brain, and spinal cord) using differential ultracentrifugation. Then, assessment of mitochondrial parameters including mitochondrial reactive oxidative species (ROS) production, mitochondrial membrane potential (MMP), ATP level, and the release of cytochrome c from the mitochondria was performed. Our results showed that H. lepturus venom-induced oxidative stress is related to ROS production and MMP collapse, which is correlated with cytochrome c release and ATP depletion, indicating the predisposition to the cell death signaling. In general, ozone therapy in moderate dose can be considered as clinically effective for the treatment of H. lepturus sting as a protective and antioxidant agent. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  1. Protective effects of hydroxytyrosol on gentamicin induced nephrotoxicity in mice.

    PubMed

    Chashmi, Nooshin Ahmadian; Emadi, Sarvenaz; Khastar, Hossein

    2017-01-22

    Gentamicin (GM) is an effective and common antibiotic against severe gram-negative infections. However, its nephrotoxic action has limited the extent of its use. The aim of this study was to investigate the protective effects of hydroxytyrosol (HT) on gentamicin induced nephrotoxicity in mice. Male mice (n = 27) were randomly assigned to three groups: (1) Sham, (2) GM (100 mg/kg for 7 days) (3) GM + HT (2 mg/kg BW; gastric gavages, for 7 days). 24-h urine samples were collected on day 8 and then animal were anesthetized. The blood and kidney tissue samples were collected. Gentamicin led to increase in plasma BUN and creatinine, fractional excretion of sodium and potassium and decrease in creatinine clearance and urine flow rate. SOD and GSH levels were reduced and MDA was increased in the GM group compared with the sham group. In GM + HT group, plasma BUN and creatinine, fractional excretion of Na, creatinine clearance and urine flow rate were decreased in contrast to GM group. Increase in SOD and GSH activity and decrease in MDA compared to GM group were seen. Findings suggest that HT partly protected the kidneys from gentamicin induced nephrotoxicity and it is partly due to antioxidant effect of HT. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Tenascin C protects aorta from acute dissection in mice

    PubMed Central

    Kimura, Taizo; Shiraishi, Kozoh; Furusho, Aya; Ito, Sohei; Hirakata, Saki; Nishida, Norifumi; Yoshimura, Koichi; Imanaka-Yoshida, Kyoko; Yoshida, Toshimichi; Ikeda, Yasuhiro; Miyamoto, Takanobu; Ueno, Takafumi; Hamano, Kimikazu; Hiroe, Michiaki; Aonuma, Kazutaka; Matsuzaki, Masunori; Imaizumi, Tsutomu; Aoki, Hiroki

    2014-01-01

    Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl2 caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress. PMID:24514259

  3. Ephedrine hydrochloride protects mice from staphylococcus aureus-induced peritonitis

    PubMed Central

    He, Weigang; Ma, Jinzhu; Chen, Yijian; Jiang, Xinru; Wang, Yuli; Shi, Ting; Zhang, Qingwen; Yang, Yang; Jiang, Xin; Yin, Shulei; Zheng, Aoxiang; Lu, Jie; Zheng, Yuejuan

    2018-01-01

    Staphylococcus aureus is a Gram-positive (G+) bacterium that causes a wide range of diseases in humans and livestock. Therefore, the development of innovative and effective therapies is essential for the treatment of S. aureus-induced severe infections. Ephedrine hydrochloride (EH) is a compound derived from ephedrine and is widely used for the management of cardiovascular diseases and hypotension. The results of our previous studies demonstrated that EH has anti-inflammatory activity in macrophages and protects against endotoxic shock. However, whether EH regulates the function of dendritic cells (DCs) and the immune response in S. aureus-induced infection is unknown. In this study, the anti-inflammatory and regulatory activity of EH on DCs was evaluated. EH increased the production of anti-inflammatory cytokine IL-10 and decreased the production of proinflammatory cytokines TNF-α and IL-12 in DCs stimulated with peptidoglycan (PGN), the main cell wall component in G+ bacteria. The PI3K/Akt and p38 MAPK signaling pathways controlled EH-induced IL-10 expression and EH-inhibited TNF-α expression, respectively. The PGN-induced expression of co-stimulatory molecules CD40, CD80, CD86, and MHC class II molecule Iab was down-regulated in DCs by EH. Furthermore, EH protected the liver and kidney and increased the survival rate of mice with S. aureus-induced peritonitis. In conclusion, EH helps to keep immune homeostasis and alleviate organ damage during S. aureus-induced peritonitis. Therefore, EH may be a promising drug candidate in the treatment of S. aureus-induced severe infections and other invasive G+ bacterial infections. PMID:29636858

  4. Impaired protection against Trichinella spiralis in mice with high levels of IgE.

    PubMed

    Watanabe, Naohiro

    2014-04-01

    Helminth infection induces production of a large amount of immunoglobulin E (IgE) to nonhelminth antigens. Although such "irrelevant" IgE is a major proportion of total IgE in the host, its biological significance remains unclear. Therefore, I examined protective activity against Trichinella spiralis in mice with high levels of IgE by repeated injections of anti-dansyl IgE monoclonal antibody or Nippostrongylus brasiliensis infection. Injected anti-dansyl IgE occupied IgE receptors on mast cells in naive mice. Protective activity against T. spiralis, determined with number of muscle larvae 5weeks after infection, was impaired in mice treated with anti-dansyl IgE. The impaired protection was found in mice treated with anti-dansy IgE 7 and 14days after infection, but not 21 and 28days after infection, indicating that IgE-dependent protection operates at an early stage after infection. In the next experiments, mice were infected with N. brasiliensis 4weeks before T. spiralis infection to obtain high levels of IgE. The protective activity against T. spiralis was decreased by N. brasiliensis infection. On the other hand, protection against T. spiralis was comparable in IgE-deficient SJA/9 mice and in anti-IgE-treated BALB/c mice with or without N. brasiliensis infection, suggesting that impairment of protection is dependent on IgE. These results indicate that the high levels of irrelevant IgE are beneficial for helminths and, alternatively, that anti-helminth IgE antibodies are protective for hosts. In addition, the impaired protection was found in IgE high-responder mice but not in low-responder mice, suggesting that protection against T. spiralis is controlled by IgE responsiveness in the host. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Rodent malaria: BCG-induced protection and immunosuppression. [Mice, gamma radiation, Plasmodium berghei

    SciTech Connect

    Smrkovski, L.L.; Strickland, G.T.

    1978-10-01

    One dose of 10/sup 7/ viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10/sup 4/ thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites onlymore » if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge.« less

  6. T lymphocyte-mediated protection against Pseudomonas aeruginosa infection in granulocytopenic mice.

    PubMed Central

    Powderly, W G; Pier, G B; Markham, R B

    1986-01-01

    BALB/c mice immunized with Pseudomonas aeruginosa immunotype 1 polysaccharide develop protective T cell immunity to bacterial challenge. In vitro, T cells from immunized mice kill P. aeruginosa by production of a bactericidal lymphokine. The present study demonstrates that adoptive transfer of T cells from immunized BALB/c mice to granulocytopenic mice resulted in 97% survival on challenge with P. aeruginosa, compared with 17% survival with adoptive transfer of T cells from nonimmune BALB/c mice. This protection is specifically elicited by reexposure to the original immunizing antigen; adoptive recipients cannot withstand challenge with immunotype 3 P. aeruginosa. However, the adoptive recipients do survive simultaneous infection with both P. aeruginosa immunotypes 1 and 3. Adoptive transfer of T cells from the congenic CB.20 mice, which are unable to kill P. aeruginosa in vitro, provides only 20% protection to granulocytopenic mice. These studies indicate that transfer of specific immune T lymphocytes can significantly enhance the resistance to P. aeruginosa infection in granulocytopenic mice. PMID:2426306

  7. Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity.

    PubMed

    Bourque, Mélanie; Liu, Bin; Dluzen, Dean E; Di Paolo, Thérèse

    2007-11-01

    The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50 microg tamoxifen 24 h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5 microg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50 microg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

  8. Potential protection of vitamin C against liver-lesioned mice.

    PubMed

    Su, Min; Chen, Hongqiu; Wei, Chaohe; Chen, Ning; Wu, Wei

    2014-10-01

    Pathologically, liver injury can result from sustained trauma to hepatocytes, including acute damage. Thus, attenuation of hepatocellular lesion may help improve liver functions. The purpose of this study was to explore the potential advantages of vitamin C (VC) intake on acutely intralesional liver in carbon tetrachloride (CCl4)-exposed mice. Here our data showed that VC supplementation contributed to ameliorated vital signs of CCl4-lesioned mice, resulting in dose-dependent reduction of hepatomegaly. VC lowered the levels of liver functional enzymes including alanine aminotransferase (ALT) and glutamic-oxaloacetic transaminase (AST) in serum, while concentration of lactic acid concentration in blood plasma was decreased. VC-administered CCl4-lesioned mice manifested increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), while the malondialdehyde (MDA) content was reduced in liver tissue. Moreover, VC consumption attenuated hepatotoxic injuries of CCl4-lesioned mice, in which the number of TNF-α positive cells was dose-dependently reduced. Furthermore, intrahepatic expression of TRL-4 mRNA, a vital inflammation-regulator, was down-regulated in VC-administered mice. Overall, we conclude that VC has the potentiality of anti-hepatotoxicity that is capable of ameliorating liver functions, speculating that therapeutic mechanism relates to normalizing metabolism and blocking inflammatory stress in the liver. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Monoclonal antibodies passively protect BALB/c mice against Burkholderia mallei aerosol challenge.

    PubMed

    Treviño, Sylvia R; Permenter, Amy R; England, Marilyn J; Parthasarathy, Narayanan; Gibbs, Paul H; Waag, David M; Chanh, Tran C

    2006-03-01

    Glanders is a debilitating disease with no vaccine available. Murine monoclonal antibodies were produced against Burkholderia mallei, the etiologic agent of glanders, and were shown to be effective in passively protecting mice against a lethal aerosol challenge. The antibodies appeared to target lipopolysaccharide. Humoral antibodies may be important for immune protection against B. mallei infection.

  10. The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice.

    PubMed

    Liu, X; Jiao, Y; Cui, B; Gao, X; Xu, J; Zhao, Y

    2016-10-01

    The objective of this study was to investigate whether hepatitis B virus (HBV) infection plays a role in the regulation of autoimmunity for systemic lupus erythematosus (SLE). A total of 21 female BALB/c mice and 21 female HBV transgenic BALB/c mice aged two months were randomly divided into four groups: BALB/c mice, HBV(Tg) mice, pristane-injected BALB/c mice, and pristane-injected HBV(Tg) mice. BALB/c mice and HBV(Tg) mice were given an intraperitoneal injection of 0.5 ml normal saline, and the mice in the other two groups were given an intraperitoneal injection of 0.5 ml pristane. ANA and anti-dsDNA levels in serum were detected by indirect immunofluorescence. Interleukin 2 (IL-2), IL-4, IL-6, IL-17, and TNF-α were measured by Luminex technology. The serum BAFF level was measured using an Elisa kit. Twenty-four weeks after pristane administration, kidneys were removed, dissected, and stained with hematoxylin and eosin and periodic-acid Schiff. At six months after injecting, the ANA titers in pristane-injected HBV(Tg) mice were significantly lower than pristane-injected BALB/c mice. IL-17, TNF-α, and BAFF levels were significantly higher in pristane-injected BALB/c mice than BALB/c mice and pristane-injected HBV(Tg) mice. IL-2, IL-4, and IL-6 levels were much higher in pristane-injected HBV(Tg) mice than pristane-injected BALB/c mice. In pristane-injected HBV(Tg) mice and HBV(Tg) mice, fewer glomerulonephritis changes were found in the kidneys. Our results showed that the incidence of SLE was much lower in HBV(Tg) mice, and that HBV infection helped the SLE mice survive high levels of inflammatory cytokines and severe renal damage. All these findings demonstrated the protective role of HBV in SLE patients via the immunoregulatory networks of the cytokines. © The Author(s) 2016.

  11. CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function

    PubMed Central

    Chawla, Amanpreet Singh; Agrawal, Tanvi; Biswas, Moanaro; Vrati, Sudhanshu; Rath, Satyajit; George, Anna; Medigeshi, Guruprasad R.

    2017-01-01

    Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β–T cells (TCRβ–null) are highly susceptible and die over 10–18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage. PMID:28151989

  12. CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function.

    PubMed

    Jain, Nidhi; Oswal, Neelam; Chawla, Amanpreet Singh; Agrawal, Tanvi; Biswas, Moanaro; Vrati, Sudhanshu; Rath, Satyajit; George, Anna; Bal, Vineeta; Medigeshi, Guruprasad R

    2017-02-01

    Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β-T cells (TCRβ-null) are highly susceptible and die over 10-18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage.

  13. Perilipin overexpression in mice protects against diet-induced obesity

    USDA-ARS?s Scientific Manuscript database

    Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand t...

  14. Minocycline protects against lipopolysaccharide-induced cognitive impairment in mice.

    PubMed

    Hou, Yue; Xie, Guanbo; Liu, Xia; Li, Guoxun; Jia, Congcong; Xu, Jinghua; Wang, Bing

    2016-03-01

    The role of glial cells, especially microglia and astrocytes, in neuroinflammation and cognition has been studied intensively. Lipopolysaccharide (LPS), a commonly used inducer of neuroinflammation, can cause cognitive impairment. Minocycline is known to possess potent neuroprotective activity, but its effect on LPS-induced cognitive impairment is unknown. This study aims to investigate the effects of minocycline on LPS-induced cognitive impairment and glial cell activation in mice. Behavioral tests were conducted for cognitive function, immunohistochemistry for microglial and astrocyte response, and quantitative PCR for mRNA expression of proinflammatory cytokines. Minocycline significantly reversed the decreased spontaneous alternation induced by intrahippocampal administration of LPS in the Y-maze task. In the Morris water maze place navigation test, minocycline decreased the escape latency and distance traveled compared to LPS-treated mice. In the probe test, minocycline-treated mice spent more time in the target quadrant and crossed the platform area more frequently than animals in the LPS-treated group. Minocycline produced a significant decrease in the number of Iba-1- and GFAP-positive hippocampal cells compared to the LPS-treated group. Minocycline-treated mice had significantly reduced hippocampal TNF-α and IL-1β mRNA levels compared with LPS-treated animals. Minocycline caused a significant increase in hippocampal BDNF expression compared to the LPS-treated group. Minocycline can attenuate LPS-induced cognitive impairments in mice. This effect may be associated with its action to suppress the activation of microglia and astrocytes and to normalize BDNF expression. Since neuroinflammatory processes and cognitive impairments are implicated in neurodegenerative disorders, minocycline may be a promising candidate for treating such diseases.

  15. Immunization with Streptococcal Heme Binding Protein (Shp) Protects Mice Against Group A Streptococcus Infection.

    PubMed

    Zhang, Xiaolan; Song, Yingli; Li, Yuanmeng; Cai, Minghui; Meng, Yuan; Zhu, Hui

    2017-01-01

    Streptococcal heme binding protein (Shp) is a surface protein of the heme acquisition system that is an essential iron nutrient in Group A Streptococcus (GAS). Here, we tested whether Shp immunization protects mice from subcutaneous infection. Mice were immunized subcutaneously with recombinant Shp and then challenged with GAS. The protective effects against GAS challenge were evaluated two weeks after the last immunization. Immunization with Shp elicited a robust IgG response, resulting in high anti-Shp IgG titers in the serum. Immunized mice had a higher survival rate and smaller skin lesions than adjuvant control mice. Furthermore, immunized mice had lower GAS numbers at the skin lesions and in the liver, spleen and lung. Histological analysis with Gram staining showed that GAS invaded the surrounding area of the inoculation sites in the skin in control mice, but not in immunized mice. Thus, Shp immunization enhances GAS clearance and reduces GAS skin invasion and systemic dissemination. These findings indicate that Shp is a protective antigen.

  16. Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis

    PubMed Central

    Fensterl, Volker; Wetzel, Jaime L.; Ramachandran, Srividya; Ogino, Tomoaki; Stohlman, Stephen A.; Bergmann, Cornelia C.; Diamond, Michael S.; Virgin, Herbert W.; Sen, Ganes C.

    2012-01-01

    Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2 −/−) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1 −/− mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2−/− mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2 −/− mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2 −/− mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2 −/− mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2−/− mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2 −/− mice. Our study provides a clear demonstration of

  17. Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents.

    PubMed

    Albers, D S; Sonsalla, P K

    1995-12-01

    Neurotoxic doses of methamphetamine (METH) can cause hyperthermia in experimental animals. Damage sustained to dopaminergic nerve terminals by this stimulant can be reduced by environmental cooling or by pharmacological manipulation which attenuates the hyperthermia. Many pharmacological agents with very diverse actions protect against METH-induced neuropathology. Several of these compounds, as well as drugs which do not protect, were investigated to determine if there was a relationship between protection and METH-induced hyperthermia. Mice received METH with or without concurrent administration of other drugs and core (i.e., colonic) temperature was monitored during treatment. The animals were sacrificed > or = 5 days later and neostriatal tyrosine hydroxylase activity and dopamine were measured. Core temperature was significantly elevated (> or = 2 degrees C) in mice treated with doses of METH which produced > or = 90% losses in striatal dopamine but not in mice less severally affected (only 50% loss of dopamine). Concurrent treatment of mice with METH and pharmacological agents which protected partially or completely from METH-induced toxicity also prevented the hyperthermic response (i.e., dopamine receptor antagonists, fenfluramine, dizocilpine, alpha-methyl-p-tyrosine, phenytoin, aminooxyacetic acid and propranol). These findings are consistent with the hypothesis that the hyperthermia produced by METH contributes to its neuropathology. However, studies with reserpine, a compound which dramatically lowers core temperature, demonstrated that hyperthermia per se is not a requirement for METH-induced neurotoxicity. Although core temperature was elevated in reserpinized mice treated with METH as compared with reserpinized control mice, their temperatures remained significantly lower than in nonreserpinized control mice. However, the hypothermic state produced in the reserpinized mice did not provide protection from METH-induced toxicity. These data demonstrate

  18. Abusive head trauma and accidental head injury: a 20-year comparative study of referrals to a hospital child protection team

    PubMed Central

    John, Simon; Vincent, Andrea L; Reed, Peter

    2015-01-01

    Aim To describe children referred for suspected abusive head trauma (AHT) to a hospital child protection team in Auckland, New Zealand. Methods Comparative review of demographics, histories, injuries, investigations and diagnostic outcomes for referrals under 15 years old from 1991 to 2010. Results Records were available for 345 children. Referrals increased markedly (88 in the first decade, 257 in the second), but the diagnostic ratio was stable: AHT 60%, accidental or natural 29% and uncertain cause 11%. The probability of AHT was similar regardless of socio-economic status or ethnicity. In children under 2 years old with accidental head injuries (75/255, 29%) or AHT (180/255, 71%), characteristics of particular interest for AHT included no history of trauma (88/98, 90%), no evidence of impact to the head (84/93, 90%), complex skull fractures with intracranial injury (22/28, 79%), subdural haemorrhage (160/179, 89%) and hypoxic ischaemic injury (38/39, 97%). In children over 2 years old, these characteristics did not differ significantly between children with accidental head injuries (21/47, 45%) and AHT (26/47, 55%). The mortality of AHT was higher in children over 2 years old (10/26, 38%) than under 2 years (19/180, 11%). Conclusions The striking increase in referrals for AHT probably represents increasing incidence. The decision to refer a hospitalised child with a head injury for assessment for possible AHT should not be influenced by socio-economic status or ethnicity. Children over 2 years old hospitalised for AHT are usually injured by mechanisms involving impact and should be considered at high risk of death. PMID:26130384

  19. Protection against vascular leak in neprilysin transgenic mice with complex overexpression pattern.

    PubMed

    Wick, Marilee J; Loomis, Zoe L; Harral, Julie W; Le, Mysan; Wehling, Carol A; Miller, York E; Dempsey, Edward C

    2016-12-01

    Neprilysin (NEP) is a cell surface metallopeptidase found in many tissues. Based mostly on pharmacological manipulations, NEP has been thought to protect blood vessels from plasma extravasation. We have suggested that NEP may protect against pulmonary vascular injury. However, these prior studies did not utilize mice which overexpress NEP. The aims of the present investigation were to develop and characterize doubly transgenic (DT) mice that overexpress NEP universally and conditionally, and to investigate the protective effect that overexpressed NEP may have against plasma extravasation in the vasculature. The duodenum, which is often used to assess vascular permeability, and in which the NEP protein was overexpressed in our DT mice two-fold, was selected as our experimental preparation. We found that substance P-induced plasma extravasation was decreased substantially (3.5-fold) in the duodenums of our doxycycline-treated DT mice, giving independent evidence of NEP's protective effects against plasma extravasation. Transgenic lung NEP protein was not stably expressed in the DT mice, so we were not able to test the effect of NEP overexpression in the lung. Although initially overexpressed nearly nine-fold at that site, pulmonary NEP protein overexpression eventually dissipated. Surprisingly, at a time when there was no lung transgenic NEP protein overexpression, lung NEP mRNA expression was still increased 23-fold, indicating that the expression defect probably is not transcriptional. These studies help to characterize our complex transgenic model of NEP overexpression and further demonstrate NEP's protective effects against plasma extravasation.

  20. Protection of mice deficient in mature B cells from West Nile virus infection by passive and active immunization

    PubMed Central

    Draves, Kevin E.; Young, Lucy B.; Bryan, Marianne A.; Dresch, Christiane; Diamond, Michael S.; Gale, Michael

    2017-01-01

    B cell activating factor receptor (BAFFR)-/- mice have a profound reduction in mature B cells, but unlike μMT mice, they have normal numbers of newly formed, immature B cells. Using a West Nile virus (WNV) challenge model that requires antibodies (Abs) for protection, we found that unlike wild-type (WT) mice, BAFFR-/- mice were highly susceptible to WNV and succumbed to infection within 8 to 12 days after subcutaneous virus challenge. Although mature B cells were required to protect against lethal infection, infected BAFFR-/- mice had reduced WNV E-specific IgG responses and neutralizing Abs. Passive transfer of immune sera from previously infected WT mice rescued BAFFR-/- and fully B cell-deficient μMT mice, but unlike μMT mice that died around 30 days post-infection, BAFFR-/- mice survived, developed WNV-specific IgG Abs and overcame a second WNV challenge. Remarkably, protective immunity could be induced in mature B cell-deficient mice. Administration of a WNV E-anti-CD180 conjugate vaccine 30 days prior to WNV infection induced Ab responses that protected against lethal infection in BAFFR-/- mice but not in μMT mice. Thus, the immature B cells present in BAFFR-/- and not μMT mice contribute to protective antiviral immunity. A CD180-based vaccine may promote immunity in immunocompromised individuals. PMID:29176765

  1. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity

    PubMed Central

    Cappel, David A.; Lantier, Louise; Palmisano, Brian T.; Wasserman, David H.; Stafford, John M.

    2015-01-01

    Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity. PMID:26313355

  2. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.

    PubMed

    Cappel, David A; Lantier, Louise; Palmisano, Brian T; Wasserman, David H; Stafford, John M

    2015-01-01

    Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  3. Cathelicidin Signaling via the Toll-Like Receptor Protects Against Colitis in Mice

    PubMed Central

    Koon, Hon Wai; Shih, David Quan; Chen, Jeremy; Bakirtzi, Kyriaki; Hing, Tressia C; Law, Ivy; Ho, Samantha; Ichikawa, Ryan; Zhao, Dezheng; Xu, Hua; Gallo, Richard; Dempsey, Paul; Cheng, Genhong; Targan, Stephan R; Pothoulakis, Charalabos

    2011-01-01

    Background & Aims Cathelicidin (encoded by Camp) is an anti-microbial peptide in the innate immune system. We examined whether macrophages express cathelicidin in colons of mice with experimental colitis and patients with inflammatory bowel disease; we investigated its signaling mechanisms. Methods Quantitative, real-time, reverse transcription PCR, bacterial 16S PCR, immunofluorescence, and small interfering (si)RNA analyses were performed. Colitis was induced in mice using sodium dextran sulfate (DSS); levels of cathelicidin were measured in human primary monocytes. Results Expression of cathelicidin increased in the inflamed colonic mucosa of mice with DSS-induced colitis, compared with controls. Cathelicidin expression localized to mucosal macrophages in inflamed colon tissues of patients and mice. Exposure of human primary monocytes to E coli DNA induced expression of Camp mRNA, which required signaling by ERK; expression was reduced by siRNAs against toll-like receptor (TLR)9 and MyD88. Intracolonic administration of bacterial DNA to wild-type mice induced expression of cathelicidin in colons of control mice and mice with DSS-induced colitis. Colon expression of cathelicidin was significantly reduced in TLR9 −/− mice with DSS-induced colitis. Compared with wild-type mice, Camp −/− mice developed a more severe form of DSS-induced colitis, particularly after intracolonic administration of E coli DNA. Expression of cathelicidin from bone marrow-derived immune cells regulated DSS induction of colitis in transplantation studies in mice. Conclusions Cathelicidin protects against colitis induction in mice. Increased expression of cathelicidin in monocytes and experimental models of colitis involves activation of TLR9–ERK signaling by bacterial DNA. This pathway might be involved in pathogenesis of ulcerative colitis. PMID:21762664

  4. Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury.

    PubMed

    Luo, Chuanming; Ren, Huixia; Wan, Jian-Bo; Yao, Xiaoli; Zhang, Xiaojing; He, Chengwei; So, Kwok-Fai; Kang, Jing X; Pei, Zhong; Su, Huanxing

    2014-07-01

    Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

  5. Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection.

    PubMed

    Qiu, Xiangguo; Fernando, Lisa; Melito, P Leno; Audet, Jonathan; Feldmann, Heinz; Kobinger, Gary; Alimonti, Judie B; Jones, Steven M

    2012-01-01

    Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 µg) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.

  6. Ischemic preconditioning provides both acute and delayed protection against renal ischemia and reperfusion injury in mice.

    PubMed

    Joo, Jin Deok; Kim, Mihwa; D'Agati, Vivette D; Lee, H Thomas

    2006-11-01

    Acute as well as delayed ischemic preconditioning (IPC) provides protection against cardiac and neuronal ischemia reperfusion (IR) injury. This study determined whether delayed preconditioning occurs in the kidney and further elucidated the mechanisms of renal IPC in mice. Mice were subjected to IPC (four cycles of 5 min of ischemia and reperfusion) and then to 30 min of renal ischemia either 15 min (acute IPC) or 24 h (delayed IPC) later. Both acute and delayed renal IPC provided powerful protection against renal IR injury. Inhibition of Akt but not extracellular signal-regulated kinase phosphorylation prevented the protection that was afforded by acute IPC. Neither extracellular signal-regulated kinase nor Akt inhibition prevented protection that was afforded by delayed renal IPC. Pretreatment with an antioxidant, N-(2-mercaptopropionyl)-glycine, to scavenge free radicals prevented the protection that was provided by acute but not delayed renal IPC. Inhibition of protein kinase C or pertussis toxin-sensitive G-proteins attenuated protection from both acute and delayed renal IPC. Delayed renal IPC increased inducible nitric oxide synthase (iNOS) as well as heat-shock protein 27 synthesis, and the renal protective effects of delayed preconditioning were attenuated by a selective inhibitor of iNOS (l-N(6)[1-iminoethyl]lysine). Moreover, delayed IPC was not observed in iNOS knockout mice. Both acute and delayed IPC were independent of A(1) adenosine receptors (AR) as a selective A(1)AR antagonist failed to block preconditioning and acute and delayed preconditioning occurred in mice that lacked A(1)AR. Therefore, this study demonstrated that acute or delayed IPC provides renal protection against IR injury in mice but involves distinct signaling pathways.

  7. Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia.

    PubMed

    Castellani, Laura N; Peppler, Willem T; Sutton, Charles D; Whitfield, Jamie; Charron, Maureen J; Wright, David C

    2017-08-01

    To determine if glucagon is involved in mediating the increase in blood glucose levels caused by the second-generation antipsychotic drug olanzapine. Whole body glucagon receptor deficient mice (Gcgr -/- ) or WT littermate controls were injected with olanzapine (5mg/kg BW IP) and changes in blood glucose measured over the following 120min. Separate cohorts of mice were treated with olanzapine and changes in pyruvate tolerance, insulin tolerance and whole body substrate oxidation were determined. Olanzapine treatment increased serum glucagon and lead to rapid increases in blood glucose concentrations in WT mice. Gcgr -/- mice were protected against olanzapine-induced increases in blood glucose but this was not explained by differences in terminal serum insulin concentrations, enhanced AKT phosphorylation in skeletal muscle, adipose tissue or liver or differences in RER. In both genotypes olanzapine induced an equivalent degree of insulin resistance as measured using an insulin tolerance test. Olanzapine treatment led to an exaggerated glucose response to a pyruvate challenge in WT but not Gcgr -/- mice and this was paralleled by reductions in the protein content of PEPCK and G6Pase in livers from Gcgr -/- mice. Gcgr -/- mice are protected against olanzapine-induced increases in blood glucose. This is likely a result of reductions in liver glucose output, perhaps secondary to decreases in PEPCK and G6Pase protein content. Our findings highlight the central role of the liver in mediating olanzapine-induced disturbances in glucose homeostasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. [Protective effects of polysaccharides from Dendrobium huoshanense on CCl4-induced acute liver injury in mice].

    PubMed

    Huang, Jing; Li, Sheng-Li; Zhao, Hong-Wei; Pan, Li-Hua; Sun, Hao-Qiao; Luo, Jian-Ping

    2013-02-01

    To study the protective effects of polysaccharides from Dendrobium huoshanense (DHP) against CCl4-induced liver injury in mice. Eighty male Kunming mice were randomly divided into normal control group, model control group, dextran control group, starch control group, hydrolyzate control group, three different dose of DPH groups consisting of high-dosage group, middle-dosage group and low-dosage group (200, 100, 50 mg x kg(-1)). Each group contained ten mice. The mice were treated with DHP via intragastric administration for 15 days before treatment of 50% CCl4 in olive oil for consecutive two days. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum and superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents in liver tissues were determined in all groups. Immunohistochemistry was used to detect the expression of TNF-alpha in hepatic tissue. Hepatic histopathological examination was observed. DHP effectively decreased the activities of ALT and AST in serum and the contents of hepatic MDA, and restored hepatic SOD activities in acute liver injury mice. Liver tissue damage induced by CCl4 was ameliorated in mice with DHP administration through histopathology examination. Furthermore, the expression of TNF-alpha was greatly decreased in groups treated with polysaccharides. DHP has a significantly hepatoprotective effect on CCl4-induced acute liver injury in mice. Protective effect of DHP on the liver may be related to its function of scavenging free radicals and inhibiting lipid peroxidation and TNF-alpha expression.

  9. Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids

    PubMed Central

    Wang, Lirui; Hartmann, Phillipp; Haimerl, Michael; Bathena, Sai P.; Sjöwall, Christopher; Almer, Sven; Alnouti, Yazen; Hofmann, Alan F.; Schnabl, Bernd

    2014-01-01

    Background & aims Chronic liver disease is characterized by fibrosis that may progress to cirrhosis. Nucleotide oligomerization domain 2 (Nod2), a member of the Nod-like receptor (NLR) family of intracellular immune receptors, plays an important role in the defense against bacterial infection through binding to the ligand muramyl dipeptide (MDP). Here, we investigated the role of Nod2 in the development of liver fibrosis. Methods We studied experimental cholestatic liver disease induced by bile duct ligation or toxic liver disease induced by carbon tetrachloride in wild type and Nod2−/− mice. Results Nod2 deficiency protected mice from cholestatic but not toxin-induced liver injury and fibrosis. Most notably, the hepatic bile acid concentration was lower in Nod2−/− mice than wild type mice following bile duct ligation for 3 weeks. In contrast to wild type mice, Nod2−/− mice had increased urinary excretion of bile acids, including sulfated bile acids, and an upregulation of the bile acid efflux transporters MRP2 and MRP4 in tubular epithelial cells of the kidney. MRP2 and MRP4 were downregulated by IL-1β in a Nod2 dependent fashion. Conclusions Our findings indicate that Nod2 deficiency protects mice from cholestatic liver injury and fibrosis through enhancing renal excretion of bile acids that in turn contributes to decreased concentration of bile acids in the hepatocyte. PMID:24560660

  10. Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice.

    PubMed

    Rocha, Viviane Costa Junqueira; França, Luciana Souza de Aragão; de Araújo, Cintia Figueiredo; Ng, Ayling Martins; de Andrade, Candace Machado; Andrade, André Cronemberger; Santos, Emanuelle de Souza; Borges-Silva, Mariana da Cruz; Macambira, Simone Garcia; Noronha-Dutra, Alberto Augusto; Pontes-de-Carvalho, Lain Carlos

    2016-03-01

    Doxorubicin (DOX) is a chemotherapeutic that is widely used for the treatment of many human tumors. However, the development of cardiotoxicity has limited its use. The aim of the present study was to evaluate the possible efficacy of mito-TEMPO (mito-T) as a protective agent against DOX-induced cardiotoxicity in mice. C57BL/6 mice were treated twice with mito-T at low (5 mg/kg body weight) or high (20 mg/kg body weight) dose and once with DOX (24 mg/kg body weight) or saline (0.1 mL/20 g body weight) by means of intraperitoneal injections. The levels of malondialdehyde (MLDA), a marker of lipid peroxidation, and serum levels of creatine kinase were evaluated 48 h after the injection of DOX. DOX induced lipid peroxidation in heart mitochondria (p < 0.001), and DOX-treated mice receiving mito-T at low dose had levels of MLDA significantly lower than the mice that received only DOX (p < 0.01). Furthermore, administration of mito-T alone did not cause any significant changes from control values. Additionally, DOX-treated mice treated with mito-T at high dose showed decrease in serum levels of total CK compared to mice treated with DOX alone (p < 0.05). Our results indicate that mito-T protects mice against DOX-induced cardiotoxicity.

  11. Roles of CD4+ T Cells and Gamma Interferon in Protective Immunity against Babesia microti Infection in Mice

    PubMed Central

    Igarashi, Ikuo; Suzuki, Reiko; Waki, Seiji; Tagawa, Yoh-Ichi; Seng, Seyha; Tum, Sothyra; Omata, Yoshitaka; Saito, Atsushi; Nagasawa, Hideyuki; Iwakura, Yohichiro; Suzuki, Naoyoshi; Mikami, Takeshi; Toyoda, Yutaka

    1999-01-01

    Babesia microti produces a self-limiting infection in mice, and recovered mice are resistant to reinfection. In the present study, the role of T cells in protective immunity against challenge infection was examined. BALB/c mice which recovered from primary infection showed strong protective immunity against challenge infection. In contrast, nude mice which failed to control the primary infection and were cured with an antibabesial drug did not show protection against challenge infection. Treatment of immune mice with anti-CD4 monoclonal antibody (MAb) diminished the protective immunity against challenge infection, but treatment with anti-CD8 MAb had no effect on the protection. Transfer of CD4+ T-cell-depleted spleen cells resulted in higher parasitemia than transfer of CD8+ T-cell-depleted spleen cells. A high level of gamma interferon (IFN-γ), which was produced by CD4+ T cells, was observed for the culture supernatant of spleen cells from immune mice, and treatment of immune mice with anti-IFN-γ MAb partially reduced the protection. Moreover, no protection against challenge infection was found in IFN-γ-deficient mice. On the other hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or tumor necrosis factor alpha did not affect protective immunity. These results suggest essential requirements for CD4+ T cells and IFN-γ in protective immunity against challenge infection with B. microti. PMID:10417185

  12. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice

    SciTech Connect

    Wang, Xingqi; Ouyang, Zijun; You, Qian

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23 days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactonemore » inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. - Highlights: • Obaculactone ameliorates bleomycin-induced pulmonary fibrosis in mice. • Obaculactone mitigates bleomycin-induced inflammatory response in lungs. • Obaculactone exerts inhibitory effects on TGF-β1 signaling and TGF-β1-induced EMT progress.« less

  13. Dietary Phenethyl Isothiocyanate Protects Mice from Colitis Associated Colon Cancer.

    PubMed

    Liu, Yi; Dey, Moul

    2017-09-06

    We have previously reported alleviation of dextran sodium sulfate (DSS)-induced ulcerative colitis signs in phenethyl isothiocyanate (PEITC)-treated mice. Here we investigated chemoprotective activities of PEITC in mice with Azoxymethane-DSS induced colitis associated colon carcinogenesis. We also examined the molecular mediators associated with the PEITC effects using relevant cell lines. A 0.12% PEITC-enriched mouse-diet reduced mucosal and submucosal inflammation as well as glandular atypia by 12% and the frequency of adenocarcinoma by 17% with a concomitant improvement in overall disease activity indices compared to the diseased control group. Lipopolysaccharide-induced in vitro up-regulation of key mediators of inflammation, immune response, apoptosis, and cell proliferation were attenuated by 10 μM PEITC. Three of these mediators showed concentration-dependent reduction in respective mRNAs. Furthermore, PEITC inhibited Nuclear factor kappa B1 (NFκB1) proteins in a concentration-dependent manner. The NFκB1 mRNA expression inversely correlated ( r = −0.940, p = 0.013) with tri-methylation of lysine 27 on histone 3 near its promoter region in a time-dependent manner. These results indicate that PEITC may slow down the development of colon carcinogenesis in an inflammatory intestinal setting which is potentially associated with epigenetic modulation of NFκB1 signaling.

  14. Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury

    PubMed Central

    Wancket, Lyn M.; Meng, Xiaomei; Rogers, Lynette K.; Liu, Yusen

    2012-01-01

    c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1+/+ and Mkp-1−/− mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechanistic studies) or 400 mg/kg (for survival studies). Tissues were collected 1–6 hr post 300 mg/kg dosing to assess glutathione levels, organ damage, and MAPK activation. Mkp-1−/− mice exhibited more rapid plasma clearance of acetaminophen than did Mkp-1+/+ mice, indicated by a quicker decline of plasma acetaminophen level. Moreover, Mkp-1−/− mice suffered more severe liver injury, indicated by higher plasma alanine transaminase activity and more extensive centrilobular apoptosis and necrosis. Hepatic JNK activity in Mkp-1−/− mice was higher than in Mkp-1+/+ mice. Finally, Mkp-1−/− mice displayed a lower overall survival rate and shorter median survival time after dosing with 400 mg/kg acetaminophen. The more severe phenotype exhibited by Mkp-1−/− mice indicates that Mkp-1 plays a protective role during acute acetaminophen overdose, potentially through regulation of JNK. PMID:22623522

  15. Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice*

    PubMed Central

    Guo, Ling; Zheng, Zhong; Ai, Junting; Huang, Bin; Li, Xiang-An

    2014-01-01

    Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1I179N mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1I179N mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1I179N mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis. PMID:24719333

  16. Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Singh, Avneesh K.; Wilson, Michael T.; Hong, Seokmann; Olivares-Villagómez, Danyvid; Du, Caigan; Stanic, Aleksandar K.; Joyce, Sebastian; Sriram, Subramaniam; Koezuka, Yasuhiko; Van Kaer, Luc

    2001-01-01

    Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic model for T cell–mediated autoimmunity. Vα14 natural killer T (NKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I–like protein CD1d. Here, we show that activation of Vα14 NKT cells by the glycosphingolipid α-galactosylceramide (α-GalCer) protects susceptible mice against EAE. β-GalCer, which binds CD1d but is not recognized by NKT cells, failed to protect mice against EAE. Furthermore, α-GalCer was unable to protect CD1d knockout (KO) mice against EAE, indicating the requirement for an intact CD1d antigen presentation pathway. Protection of disease conferred by α-GalCer correlated with its ability to suppress myelin antigen-specific Th1 responses and/or to promote myelin antigen-specific Th2 cell responses. α-GalCer was unable to protect IL-4 KO and IL-10 KO mice against EAE, indicating a critical role for both of these cytokines. Because recognition of α-GalCer by NKT cells is phylogenetically conserved, our findings have identified NKT cells as novel target cells for treatment of inflammatory diseases of the central nervous system. PMID:11748281

  17. DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice.

    PubMed

    Oršolić, Nada; Gajski, Goran; Garaj-Vrhovac, Vera; Dikić, Domagoj; Prskalo, Zvjezdana Špacir; Sirovina, Damir

    2011-04-10

    Diabetes mellitus is associated with a high production of reactive oxygen species, which may cause oxidative DNA damage. High levels of genomic damage have been associated with liver and renal failure as well as immune-system decline. Flavonoids are effective antioxidants and may protect against several chronic diseases including diabetes. This study used the comet assay to assess the levels of DNA damage in the blood, liver and kidney cells in untreated and quercetin (QU) or naringenin treated diabetic mice. In addition, the study was designed to establish whether QU or naringenin might have a biological effect in protecting diabetic mice against oxidative stress by using survival studies to observe total body injury at the level of the organism. QU or naringenin were injected to mice intraperitoneally (i.p.) at a dose of 50mg/kg for 7days starting 2days after a single dose (75mg/kg, i.v.) alloxan injection. These findings suggest that QU or naringenin treatment resulted in a significant increase in the body weight, the haematological and immunological parameters of blood, as well as leading to 100% survival of diabetic mice. The tested flavonoids have protective effects against alloxan-induced DNA-damage in peripheral lymphocytes but not in the liver and kidney cells of diabetic mice. It might be hypothesised that diabetic mice with a high intake of flavonoid-rich foods, and specifically foods rich in quercetin or naringenin, might be relatively protected against long-term complications of diabetes due to decreased oxidative stress. Various co-operative and synergistic action mechanisms of the tested flavonoids may lead to the protection of the whole organism against diabetes. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Inactivated coxsackievirus A10 experimental vaccines protect mice against lethal viral challenge.

    PubMed

    Shen, Chaoyun; Liu, Qingwei; Zhou, Yu; Ku, Zhiqiang; Wang, Lili; Lan, Ke; Ye, Xiaohua; Huang, Zhong

    2016-09-22

    Coxsackievirus A10 (CVA10) has become one of the major causative agents of hand, foot and mouth disease (HFMD). It is now recognized that CVA10 should be targeted for vaccine development. We report here that β-propiolactone inactivated whole-virus based CVA10 vaccines can elicit protective immunity in mice. We prepared two inactivated CVA10 experimental vaccines derived from the prototype strain CVA10/Kowalik and from a clinical isolate CVA10/S0148b, respectively. Immunization with the experimental vaccines elicited CVA10-specific serum antibodies in mice. The antisera from vaccinated mice could potently neutralize in vitro infection with either homologous or heterologous CVA10 strains. Importantly, passive transfer of the anti-CVA10 sera protected recipient mice against CVA10/Kowalik or CVA10/S0148b infections. Moreover, active immunization with the inactivated vaccines also conferred protection against homologous and heterologous infections in mice. Collectively, our results demonstrate the proof-of-concept for inactivated whole-virus based CVA10 vaccines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice.

    PubMed

    Tsutsumi, Yasuo M; Patel, Hemal H; Lai, N Chin; Takahashi, Toshiyuki; Head, Brian P; Roth, David M

    2006-03-01

    Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after

  20. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

    PubMed Central

    Pieper, Andrew A.; Brat, Daniel J.; Krug, David K.; Watkins, Crystal C.; Gupta, Alok; Blackshaw, Seth; Verma, Ajay; Wang, Zhao-Qi; Snyder, Solomon H.

    1999-01-01

    Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD+ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP −/−), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP +/− animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit. PMID:10077636

  1. Exogenous estrogen protects mice from the consequences of obesity and alcohol.

    PubMed

    Holcomb, Valerie B; Hong, Jina; Núñez, Nomelí P

    2012-06-01

    Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. Ovariectomized female mice were fed diets to induce different body weights (calorie restricted, low fat, high fat), provided water or 20% alcohol, implanted with placebo or estrogen pellets and injected with Wnt-1 mouse mammary cancer cells. Our results show that obesity promoted the growth of Wnt-1 tumors and induced fatty liver. Tumors tended to be larger in alcohol-consuming mice and alcohol exacerbated fatty liver in obese mice. Estrogen treatment promoted weight loss in obese mice, which was associated with the suppression of tumor growth and fatty liver. In summary, we show that estrogen protects against obesity, which is associated with the inhibition of fatty liver and tumor growth.

  2. Protective effect of humus extract against Trypanosoma brucei infection in mice.

    PubMed

    Kodama, Hiroshi; Denso; Okazaki, Fumi; Ishida, Saeko

    2008-11-01

    Humic substances are formed during the decomposition of organic matter in humus, and are found in many natural environments in which organic materials and microorganisms are present. Oral administration of humus extract to mice successfully induced effective protection against experimental challenge by the two subspecies, Trypanosoma brucei brucei and T. brucei gambiense. Mortality was most reduced among mice who received a 3% humus extract for 21 days in drinking water ad libitum. Spleen cells from humus-administered mice exhibited significant non-specific cytotoxic activity against L1210 mouse leukemia target cells. Also, spleen cells produced significantly higher amounts of Interferon-gamma when stimulated in vitro with Concanavalin A than cells from normal controls. These results clearly show that administration to mice of humus extract induced effective resistance against Trypanosoma infection. Enhancement of the innate immune system may be involved in host defense against trypanosomiasis.

  3. Maternal vaccination with a fimbrial tip adhesin and passive protection of neonatal mice against lethal human enterotoxigenic Escherichia coli challenge.

    PubMed

    Luiz, Wilson B; Rodrigues, Juliana F; Crabb, Joseph H; Savarino, Stephen J; Ferreira, Luis C S

    2015-12-01

    Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 10(7) bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  4. Maternal Vaccination with a Fimbrial Tip Adhesin and Passive Protection of Neonatal Mice against Lethal Human Enterotoxigenic Escherichia coli Challenge

    PubMed Central

    Luiz, Wilson B.; Rodrigues, Juliana F.; Crabb, Joseph H.

    2015-01-01

    Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 107 bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. PMID:26371126

  5. Monoclonal Antibodies Passively Protect BALB/c Mice Against Burkholderia mallei Aerosol Challenge

    DTIC Science & Technology

    2006-03-01

    November 2005 Glanders is a debilitating disease with no vaccine available. Murine monoclonal antibodies were produced against Burkholderia mallei , the... Glanders is a debilitating disease with no vaccine available. Murine monoclonal antibodies were produced against Burkholderia mallei , the etiologic... Burkholderia mallei auxotroph protects against aerosol-initiated glanders in mice. Vaccine 23:1986–1992. 17. Vyshelesskii, S. N. 1974. Glanders (Equinia). Tr

  6. Adjuvanted multi-epitope vaccines protect HLA-A*1101 transgenic mice against Toxoplasma gondii

    USDA-ARS?s Scientific Manuscript database

    We created and tested multi-epitope DNA or protein vaccines with TLR4 ligand emulsion adjuvant (gluco glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)) for their ability to protect against Toxoplasma gondii in HLA transgenic mice. Our constructs each included five of our best down selecte...

  7. Protective effect of esculin against prooxidant aflatoxin B1-induced nephrotoxicity in mice.

    PubMed

    Naaz, Farah; Abdin, M Z; Javed, Saleem

    2014-02-01

    The study was designed to investigate the protective effect of esculin against pro-oxidant aflatoxin B1 (AFB1)-induced nephrotoxicity in mice. In this study toxicity was developed by oral administration of AFB1 at a dose of 66.60 μg/kg bw/day for 90 days in male Swiss albino mice. Esculin (150 mg/kg bw/0.2 ml/day) and standard compound ascorbic acid (300 mg/kg bw/0.2 ml/day) was given after 30 min of AFB1 administration for 90 days. Protective efficacy was assessed by measuring the levels of lipid peroxidation (LPO) and non-enzymatic antioxidants such as reduced glutathione (GSH) and also by measuring activities of enzymatic antioxidants such as glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) in kidney. Results were analysed at the 30(th), 60(th) and 90(th) day of the daily treatments, which showed a decrease in the level of LPO and an increase in the levels of enzymatic and non-enzymatic antioxidants. The protective effect of esculin was further proved by histopathological findings as it exhibited regenerative activities in mice renal tubules against AFB1-induced nephrotoxicity. The results obtained clearly demonstrate that the protective efficacy of esculin against pro-oxidant AFB1-induced nephrotoxicity in mice might be due to its antioxidants and free radical scavenging properties.

  8. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis.

    PubMed

    Lin, Wensheng; Lin, Yifeng; Li, Jin; Fenstermaker, Ali G; Way, Sharon W; Clayton, Benjamin; Jamison, Stephanie; Harding, Heather P; Ron, David; Popko, Brian

    2013-04-03

    There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.

  9. Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation.

    PubMed

    Manitsopoulos, Nikolaos; Orfanos, Stylianos E; Kotanidou, Anastasia; Nikitopoulou, Ioanna; Siempos, Ilias; Magkou, Christina; Dimopoulou, Ioanna; Zakynthinos, Spyros G; Armaganidis, Apostolos; Maniatis, Nikolaos A

    2015-02-14

    Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury. Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days -2, -1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey's post hoc tests. Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were

  10. Immunization with a Borrelia burgdorferi BB0172-Derived Peptide Protects Mice against Lyme Disease

    PubMed Central

    Small, Christina M.; Ajithdoss, Dharani K.; Rodrigues Hoffmann, Aline; Mwangi, Waithaka; Esteve-Gassent, Maria D.

    2014-01-01

    Lyme disease is the most prevalent arthropod borne disease in the US and it is caused by the bacterial spirochete Borrelia burgdorferi (Bb), which is acquired through the bite of an infected Ixodes tick. Vaccine development efforts focused on the von Willebrand factor A domain of the borrelial protein BB0172 from which four peptides (A, B, C and D) were synthesized and conjugated to Keyhole Limpet Hemocyanin, formulated in Titer Max® adjuvant and used to immunize C3H/HeN mice subcutaneously at days 0, 14 and 21. Sera were collected to evaluate antibody responses and some mice were sacrificed for histopathology to evaluate vaccine safety. Twenty-eight days post-priming, protection was evaluated by needle inoculation of half the mice in each group with 103 Bb/mouse, whereas the rest were challenged with 105Bb/mouse. Eight weeks post-priming, another four groups of similarly immunized mice were challenged using infected ticks. In both experiments, twenty-one days post-challenge, the mice were sacrificed to determine antibody responses, bacterial burdens and conduct histopathology. Results showed that only mice immunized with peptide B were protected against challenge with Bb. In addition, compared to the other the treatment groups, peptide B-immunized mice showed very limited inflammation in the heart and joint tissues. Peptide B-specific antibody titers peaked at 8 weeks post-priming and surprisingly, the anti-peptide B antibodies did not cross-react with Bb lysates. These findings strongly suggest that peptide B is a promising candidate for the development of a new DIVA vaccine (Differentiate between Infected and Vaccinated Animals) for protection against Lyme disease. PMID:24505447

  11. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    SciTech Connect

    Wang, Jun; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan; Cao, Hui

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effectivemore » than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.« less

  12. Protective Effect of Lycium ruthenicum Murr. Against Radiation Injury in Mice

    PubMed Central

    Duan, Yabin; Chen, Fan; Yao, Xingchen; Zhu, Junbo; Wang, Cai; Zhang, Juanling; Li, Xiangyang

    2015-01-01

    The protective effect of Lycium ruthenicum Murr. against radiation injury was examined in mice. Kunming mice were randomly divided into a control group, model group, positive drug group and L. ruthenicum high dose (8 g/kg), L. ruthenicum middle dose (4 g/kg), L. ruthenicum low dose (2 g/kg) treatment groups, for which doses were administered the third day, seventh day and 14th day after irradiation. L. ruthenicum extract was administered orally to the mice in the three treatment groups and normal saline was administered orally to the mice in the control group and model group for 14 days. The positive group was treated with amifostine (WR-2721) at 30 min before irradiation. Except for the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body at one time. Body weight, hemogram, thymus and spleen index, DNA, caspase-3, caspase-6, and P53 contents were observed at the third day, seventh day, and 14th day after irradiation. L. ruthenicum could significantly increase the total red blood cell count, hemoglobin count and DNA contents (p < 0.05). The spleen index recovered significantly by the third day and 14th day after irradiation (p < 0.05). L. ruthenicum low dose group showed a significant reduction in caspase-3 and caspase-6 of serum in mice at the third day, seventh day, and 14th day after irradiation and L. ruthenicum middle dose group experienced a reduction in caspase-6 of serum in mice by the seventh day after irradiation. L. ruthenicum could decrease the expression of P53. The results showed that L. ruthenicum had protective effects against radiation injury in mice. PMID:26193298

  13. Probiotic dahi containing Lactobacillus casei protects against Salmonella enteritidis infection and modulates immune response in mice.

    PubMed

    Jain, Shalini; Yadav, Hariom; Sinha, P R

    2009-06-01

    In the present study, effect of dahi containing probiotic Lactobacillus casei (probiotic dahi) was evaluated to modulate immune response against Salmonella enteritidis infection in mice. Animals were fed with milk products along with standard diet for 2 and 7 days prior to the S. enteritidis challenge and continued on the respective dairy food-supplemented diets during the postchallenge period. Translocation of S. enteritidis in spleen and liver, beta-galactosidase and beta-glucuronidase enzymatic activities and secretory IgA (sIgA) in intestinal fluid, lymphocyte proliferation, and cytokine (interleukin [IL]-2, IL-4, IL-6, and interferon-gamma [IFN-gamma]) production in cultured splenocytes were assessed on day 2, 5, and 8 of the postchallenge period. Colonization of S. enteritidis in liver and spleen was remarkably low in probiotic dahi-fed mice than mice fed milk and control dahi. The beta-galactosidase and beta-glucuronidase activities in intestinal fluid collected from mice prefed for 7 days with probiotic dahi were significantly lower at day 5 and 8 postchallenge than in mice fed milk and control dahi. Levels of sIgA and lymphocyte proliferation rate were also significantly increased in probiotic dahi-fed mice compared with the other groups. Production of IL-2, IL-6, and IFN-gamma increased, whereas IL-4 decreased in splenic lymphocytes collected from probiotic dahi-fed mice. Data showed that dahi prefed for 7 days before S. enteritidis challenge was more effective than when mice were prefed for 2 days with dahi. Moreover, probiotic dahi was more efficacious in protecting against S. enteritidis infection by enhancing innate and adaptive immunity than fermented milk and normal dahi. Results of the present study suggest that prefeeding of probiotic dahi may strengthen the consumer's immune system and may protect infectious agents like S. enteritidis.

  14. Aldose reductase deficiency protects from autoimmune- and endotoxin-induced uveitis in mice.

    PubMed

    Yadav, Umesh C S; Shoeb, Mohammed; Srivastava, Satish K; Ramana, Kota V

    2011-10-17

    To investigate the effect of aldose reductase (AR) deficiency in protecting the chronic experimental autoimmune (EAU) and acute endotoxin-induced uveitis (EIU) in c57BL/6 mice. The WT and AR-null (ARKO) mice were immunized with human interphotoreceptor retinoid-binding peptide (hIRPB-1-20), to induce EAU, or were injected subcutaneously with lipopolysaccharide (LPS; 100 μg) to induce EIU. The mice were killed on day 21 for EAU and at 24 hours for EIU, when the disease was at its peak, and the eyes were immediately enucleated for histologic and biochemical studies. Spleen-derived T-lymphocytes were used to study the antigen-specific immune response in vitro and in vivo. In WT-EAU mice, severe damage to the retinal wall, especially to the photoreceptor layer was observed, corresponding to a pathologic score of ∼2, which was significantly prevented in the ARKO or AR inhibitor-treated mice. The levels of cytokines and chemokines increased markedly in the whole-eye homogenates of WT-EAU mice, but not in ARKO-EAU mice. Further, expression of inflammatory marker proteins such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and vascular cell adhesion molecule (VCAM)-1 was increased in the WT-EIU mouse eyes but not in the ARKO-EIU eyes. The T cells proliferated vigorously when exposed to the hIRPB antigen in vitro and secreted various cytokines and chemokines, which were significantly inhibited in the T cells isolated from the ARKO mice. These findings suggest that AR-deficiency/inhibition protects against acute as well as chronic forms of ocular inflammatory complications such as uveitis.

  15. Protective effects of caffeoylxanthiazonoside isolated from fruits of Xanthium strumarium on sepsis mice.

    PubMed

    Wang, Yan-Hong; Li, Tie-Hua; Wu, Ben-Quan; Liu, Hui; Shi, Yun-Feng; Feng, Ding-Yun

    2015-01-01

    The fruit of Xanthium strumarium L. (Asteraceae) has been used for the treatment of various inflammatory diseases. This study investigates the protective effect of caffeoylxanthiazonoside (CYXD) isolated from fruits of X. strumarium on sepsis mice in vitro and in vivo. Cecal ligation and puncture (CLP) operation was used to establish the sepsis mice model, and sham mice were also performed. CYXD was administered by intraperitoneal injection (10, 20, and 40 mg/kg/d), then the survival rate was measured in 96 h. Additionally, sepsis mice were induced by injection LPS (2 mg/kg); CYXD was administered by intraperitoneal injection (10, 20, and 40 mg/kg/d), then mice were sacrificed, and serum levels of TNF-α and IL-6 were determined by ELISA assay. Furthermore, the ability of CYXD to neutralize LPS was measured by using the LAL test, and expressions of TNF-α, IL-6 were determined by using real-time fluorogenic PCR. Results indicated that CYXD significantly elevated survival rates of sepsis mice induced by CLP (p < 0.05) with survival rates of 35%, 45%, and 65%. Furthermore, the LPS level was decreased obviously by CYXD (1, 2, and 4 mg/L) (p < 0.05). Additionally, CYXD (10, 20, and 40 mg/kg) can not only significantly decrease TNF-α and IL-6 levels induced by LPS in mice's serum (p < 0.05), but also inhibit mRNA expressions of TNF-α and IL-6 induced by LPS in RAW 264.7 cells at doses of 20, 40, and 80 μg/mL (p < 0.05). Our study demonstrated that CYXD has significant protective effects on sepsis mice.

  16. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice

    SciTech Connect

    Li, Guodong; Kong, Bo; Zhu, Yan

    2013-10-15

    Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR{sup −/−} and SHP{sup −/−} mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR{sup −/−} mice and therefore, increased SHP expression in FXR{sup −/−} mice reduces liver tumorigenesis. To test this hypothesis, wemore » generated FXR{sup −/−} mice with overexpression of SHP in hepatocytes (FXR{sup −/−}/SHP{sup Tg}) and determined the contribution of SHP in HCC development in FXR{sup −/−} mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR{sup −/−} mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR{sup −/−} mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. - Highlights: • SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy. • Increased SHP promotes apoptosis. • Bile acids and inflammation maybe critical for HCC formation with FXR deficiency.« less

  17. Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice.

    PubMed

    Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K; Scott, Bethany L; Willcocks, Lisa C; Molina-Cruz, Alvaro; Pierce, Matthew A; Huang, Chiung-yu; Torres-Velez, Fernando J; Smith, Kenneth G C; Barillas-Mury, Carolina; Miller, Louis H; Pierce, Susan K; Bolland, Silvia

    2011-01-18

    Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.

  18. Oral immunization of mice with live Pneumocystis murina protects against Pneumocystis pneumonia

    PubMed Central

    Samuelson, Derrick R.; de la Rua, Nicholas M.; Charles, Tysheena P.; Ruan, Sanbao; Taylor, Christopher M.; Blanchard, Eugene E.; Luo, Meng; Ramsay, Alistair J.; Shellito, Judd E.; Welsh, David A.

    2016-01-01

    Pneumocystis pneumonia is a major cause of morbidity and mortality in immunocompromised patients; particularly those infected with human immunodeficiency virus. In this study, we evaluated the potential of oral immunization with live Pneumocystis to elicit protection against respiratory infection with Pneumocystis murina. C57BL/6 mice vaccinated with live P. murina using a prime-boost vaccination strategy were protected from a subsequent lung challenge with P. murina at 2, 7, 14, and 28 days post infection even after CD4+ T cell depletion. Specifically, vaccinated immunocompetent mice had significantly faster clearance than unvaccinated immunocompetent mice and unvaccinated CD4-depleted mice remained persistently infected with P. murina. Vaccination also increased numbers of CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD11b+ macrophages in the lungs following respiratory infection. In addition, levels of lung, serum, and fecal P. murina-specific IgG and IgA were increased in vaccinated animals. Further, administration of serum from vaccinated mice significantly reduced Pneumocystis lung burden in infected animals compared to control serum. We also found that the diversity of the intestinal microbial community was altered by oral immunization with P. murina. Our data demonstrate for the first time that an oral vaccination strategy prevents Pneumocystis infection. PMID:26864029

  19. Thrombomodulin Contributes to Gamma Tocotrienol-Mediated Lethality Protection and Hematopoietic Cell Recovery in Irradiated Mice

    PubMed Central

    Pathak, Rupak; Shao, Lijian; Ghosh, Sanchita P.; Zhou, Daohong; Boerma, Marjan; Weiler, Hartmut; Hauer-Jensen, Martin

    2015-01-01

    Systemic administration of recombinant thrombomodulin (TM) confers radiation protection partly by accelerating hematopoietic recovery. The uniquely potent radioprotector gamma tocotrienol (GT3), in addition to being a strong antioxidant, inhibits the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) and thereby likely modulates the expression of TM. We hypothesized that the mechanism underlying the exceptional radioprotective properties of GT3 partly depends on the presence of endothelial TM. In vitro studies confirmed that ionizing radiation suppresses endothelial TM (about 40% at 4 hr after 5 Gy γ-irradiation) and that GT3 induces TM expression (about 2 fold at the mRNA level after 5 μM GT3 treatment for 4 hr). In vivo survival studies showed that GT3 was significantly more effective as a radioprotector in TM wild type (TM+/+) mice than in mice with low TM function (TMPro/-). After exposure to 9 Gy TBI, GT3 pre-treatment conferred 85% survival in TM+/+ mice compared to only 50% in TMPro/-. Thus, GT3-mediated radiation lethality protection is partly dependent on endothelial TM. Significant post-TBI recovery of hematopoietic cells, particularly leukocytes, was observed in TM+/+ mice (p = 0.003), but not in TMPro/- mice, despite the fact that GT3 induced higher levels of granulocyte colony stimulating factor (G-CSF) in TMPro/- mice (p = 0.0001). These data demonstrate a critical, G-CSF-independent, role for endothelial TM in GT3-mediated lethality protection and hematopoietic recovery after exposure to TBI and may point to new strategies to enhance the efficacy of current medical countermeasures in radiological/nuclear emergencies. PMID:25860286

  20. Protective effect of magnolol on lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Ni, Yun Feng; Jiang, Tao; Cheng, Qing Shu; Gu, Zhong Ping; Zhu, Yi Fang; Zhang, Zhi Pei; Wang, Jian; Yan, Xiao Long; Wang, Wu Ping; Ke, Chang Kang; Han, Yong; Li, Xiao Fei

    2012-12-01

    Magnolol, a tradition Chinese herb, displays an array of activities including antifungal, antibacterial, and antioxidant effects. To investigate the protective effect of magnolol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intratracheal instillation of magnolol (5 μg/kg) 30 min before LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 in lung tissues was determined by Western blot analysis. Magnolol pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by magnolol pretreatment. The expression of COX-2 was significantly suppressed by magnolol pretreatment. Magnolol potently protected against LPS-induced ALI and the protective effects of magnolol may attribute partly to the suppression of COX-2 expression.

  1. Protective effects of epigallocatechin gallate (EGCG) on streptozotocin-induced diabetic nephropathy in mice.

    PubMed

    Yoon, Sang Pil; Maeng, Young Hee; Hong, Ran; Lee, Byung Rai; Kim, Chong Gue; Kim, Hyun Lee; Chung, Jong Hoon; Shin, Byung Chul

    2014-10-01

    There is increasing evidence suggesting that antioxidants in green tea extracts may protect kidneys on the progression of end-stage renal disease. We investigated the protective impacts of (-)-epigallocatechin 3-O-gallate (EGCG) against streptozotocin (STZ)-induced diabetic nephropathy in mice. The mice were divided into 5 groups (n=10 per group): control (saline, i.p.), STZ (200mg/kg, i.p.), EGCG50 (50mg/kg, S.Q.), EGCG100 (100mg/kg, S.Q.), and EGCG200 (200mg/kg, S.Q.). Animals were sacrificed at scheduled times after EGCG administration and then quantitative and qualitative analysis were performed. Compared with the control group, the STZ group showed an increase in levels of blood glucose, blood urea nitrogen, creatinine and urine protein amounts with a decrease in body weight. All the above parameters were significantly reversed with EGCG treatment, especially in the EGCG100 group. After STZ injection, there was a mesangial proliferation with increased renal osteopontin accumulation and its protein expression in the glomeruli and the proximal tubules. Mice kidneys after EGCG-treatment showed a reduced expression of above parameters and relatively improved histopathological findings. These results indicated that EGCG 100mg/kg might provide an effective protection against STZ-induced diabetic nephropathy in mice by osteopontin suppression. Copyright © 2014 Elsevier GmbH. All rights reserved.

  2. Effects and mechanisms of cavidine protecting mice against LPS-induced endotoxic shock

    SciTech Connect

    Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Zhang,

    LPS sensitized mice are usually considered as an experimental model of endotoxin shock. The present study aims to evaluate effects of cavidine on LPS-induced endotoxin shock. Mice were intraperitoneally administrated with cavidine (1, 3 and 10 mg/kg) or DEX (5 mg/kg) at 1 and 12 h before injecting LPS (30 mg/kg) intraperitoneally. Blood samples, liver, lung and kidney tissues were harvested after LPS injection. The study demonstrated that pretreatment with cavidine reduced the mortality of mice during 72 h after endotoxin injection. In addition, cavidine administration significantly attenuated histological pathophysiology features of LPS-induced injury in lung, liver and kidney. Furthermore,more » cavidine administration inhibited endotoxin-induced production of pro-inflammatory cytokines including TNF-α, IL-6 and HMGB1. Moreover, cavidine pretreatment attenuated the phosphorylation of mitogen-activated protein kinase primed by LPS. In summary, cavidine protects mice against LPS-induced endotoxic shock via inhibiting early pro-inflammatory cytokine TNF-α, IL-6 and late-phase cytokine HMGB1, and the modulation of HMGB1 may be related with MAPK signal pathway. - Highlights: • Cavidine significantly reduced mortality in mice during 72 h after LPS injection. • Cavidine attenuated histopathological changes in lung, liver and kidney. • Cavidine decreased the level of early inflammatory cytokine TNF-α, IL-6 in LPS- stimulated mice. • Cavidine inhibited late inflammatory cytokine HMGB1 through MAPK pathway.« less

  3. Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.

    PubMed

    Sina, Christian; Lipinski, Simone; Gavrilova, Olga; Aden, Konrad; Rehman, Ateequr; Till, Andreas; Rittger, Andrea; Podschun, Rainer; Meyer-Hoffert, Ulf; Haesler, Robert; Midtling, Emilie; Pütsep, Katrin; McGuckin, Michael A; Schreiber, Stefan; Saftig, Paul; Rosenstiel, Philip

    2013-04-01

    Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.

  4. Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin

    PubMed Central

    Albert, Nathaniel D.; Swamydas, Muthulekha; Lee, Chyi-Chia R.; Loetscher, Pius

    2016-01-01

    ABSTRACT Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury. PMID:27993850

  5. Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice.

    PubMed

    Lu, Junyan; Xiang, Guangda; Liu, Min; Mei, Wen; Xiang, Lin; Dong, Jing

    2015-12-01

    The circulating irisin increases energy expenditure and improves insulin resistance in mice and humans. The improvement of insulin resistance ameliorates atherosclerosis. Therefore, we hypothesized that irisin alleviates atherosclerosis in diabetes. Endothelial function was measured by acetylcholine-induced endothelium-dependent vasodilation using aortic rings in apolipoprotein E-Null (apoE(-/-)) streptozotocin-induced diabetic mice. Atherosclerotic lesion was evaluated by plaque area and inflammatory response in aortas. In addition, the endothelium-protective effects of irisin were also further investigated in primary human umbilical vein endothelial cells (HUVECs) in vitro. The in vivo experiments showed that irisin treatment significantly improved endothelial dysfunction, decreased endothelial apoptosis, and predominantly decreased atherosclerotic plaque area of both en face and cross sections when compared with normal saline-treated diabetic mice. Moreover, the infiltrating macrophages and T lymphocytes within plaque and the mRNA expression levels of inflammatory cytokines in aortas were also significantly reduced by irisin treatment in mice. The in vitro experiments revealed that irisin inhibited high glucose-induced apoptosis, oxidative stress and increased antioxidant enzymes expression in HUVECs, and pretreatment with LY294002, l-NAME, AMPK-siRNA or eNOS-siRNA, attenuated the protection of irisin on HUVECs apoptosis induced by high glucose. In addition, the in vivo and in vitro experiments showed that irisin increased the phosphorylation of AMPK, Akt and eNOS in aortas and cultured HUVECs. The present study indicates that systemic administration of irisin may be protected against endothelial injury and ameliorated atherosclerosis in apoE(-/-) diabetic mice. The endothelium-protective action of irisin was through activation of AMPK-PI3K-Akt-eNOS signaling pathway. Irisin could be therapeutic for atherosclerotic vascular diseases in diabetes. Copyright

  6. Toll-like receptor 4-positive macrophages protect mice from Pasteurella pneumotropica-induced pneumonia

    NASA Technical Reports Server (NTRS)

    Hart, Marcia L.; Mosier, Derek A.; Chapes, Stephen K.

    2003-01-01

    This study investigates Toll-like receptor 4 (TLR4)-positive macrophages in early recognition and clearance of pulmonary bacteria. TLR4 is a trans-membrane receptor that is the primary recognition molecule for lipopolysaccharide of gram-negative bacteria. The TLR4(Lps-del) mouse strains C57BL10/ScN (B10) and STOCK Abb(tm1) TLR4(Lps-del) Slc11a1(s)(B10 x C2D) are susceptible to pulmonary infections and develop pneumonia when naturally or experimentally infected by the opportunistic bacterium Pasteurella pneumotropica. Since these mice have the TLR4(Lps-del) genotype, we hypothesized that reconstitution of mice with TLR4-positive macrophages would provide resistance to this bacterium. A cultured macrophage cell line (C2D macrophages) and bone marrow cells from C2D mice were adoptively transferred to B10 and B10 x C2D mice by intraperitoneal injection. C2D macrophages increased B10 and B10 x C2D mouse resistance to P. pneumotropica. In C2D-recipient mice there was earlier transcription of tumor necrosis factor alpha and chemokines JE and macrophage inflammatory protein 2 (MIP-2) in the lungs of B10 and B10 x C2D mice, and there was earlier transcription of KC and MIP-1alpha in B10 x C2D mice. In addition, the course of inflammation following experimental Pasteurella challenge was altered in C2D recipients. C2D macrophages also protected B10 x C2D mice, which lack CD4(+) T cells. These data indicate that macrophages are critical for pulmonary immunity and can provide host resistance to P. pneumotropica. This study indicates that TLR4-positive macrophages are important for early recognition and clearance of pulmonary bacterial infections.

  7. In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin

    PubMed Central

    Radwan, Rasha

    2014-01-01

    The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin. PMID:25317421

  8. Hybrid phage displaying SLAQVKYTSASSI induces protection against Candida albicans challenge in BALB/c mice.

    PubMed

    Wang, Yicun; Su, Quanping; Dong, Shuai; Shi, Hongxi; Gao, Xiang; Wang, Li

    2014-01-01

    The polymorphic fungus Candida albicans (C. albicans) can live as an aggressive pathogen and cause many diseases in hosts, for which no effective vaccine exists. The secreted aspartyl proteinase 2 (Sap2) plays a protective role in systemically infected BALB/c mice. Protective cellular immune responses can be preferentially induced when antigens are displayed on small particles. Therefore, the emphasis is placed on developing new phage vaccine to inhibit C. albicans infection. In this study, the ability of the hybrid phage displaying the epitope SLAQVKYTSASSI and recombinant protein of Sap2 (rSap2) for inducing immune protective responses against C. albicans infection was evaluated by lymphoproliferative assay, to gather cytokine and antibody measurements in BALB/c mice. Our results showed that, strong cellular and humoral immune responses were induced in a mouse model immunized with hybrid phage or rSap2. Furthermore, the protection against lethal challenge with C. albicans was observed in mice vaccinated hybrid phage without adjuvant. These findings demonstrate that the hybrid phage displaying the epitope SLAQVKYTSASSI might be a potential vaccine against C. albicans infections.

  9. Protection against Chlamydia psittaci in mice conferred by Lyt-2+ T cells.

    PubMed Central

    Buzoni-Gatel, D; Guilloteau, L; Bernard, F; Bernard, S; Chardès, T; Rocca, A

    1992-01-01

    A murine model was used to study the respective roles of L3T4+ and Lyt-2+ T cells in protection against Chlamydia psittaci. Donor mice were intravenously (i.v.) infected with 1 x 10(5) plaque-forming units (PFU) per mice of live C. psittaci. One month after inoculation, splenic cells from donors were transferred into syngenic recipients (5 x 10(7) cells/mouse). As measured by splenic colonization on Day 6 after i.v. challenge (1 x 10(5) PFU/mouse), transfer with primed (untreated) cells conferred a 3 log protection in this model. In vitro treatment, before transfer, of splenic cells with anti-Lyt-2 monoclonal antibody (mAb) and complement, markedly impaired the protection in comparison with control mice transferred with primed untreated cells, whereas treatment with anti-L3T4 mAb did not reduce the transferred protection. Resistance to a reinfection with C. psittaci was also studied after selective in vivo depletion of L3T4+ and Lyt-2+ T cells. One month after primary infection, mice were treated with anti-L3T4 or anti-Lyt-2 mAb and challenged thereafter (i.v., 1 x 10(5) PFU). The splenic colonization on Day 6 after challenge demonstrated that treatment with anti-Lyt-2 mAb impaired resistance against a subsequent infection with C. psittaci. Treatment with anti-L3T4 mAb in vivo had no effect on protection, as previously described in vitro. The mechanisms by which Lyt-2+ T cells could participate in the elimination of bacteria were discussed. PMID:1427980

  10. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival.

    PubMed

    Tinkum, Kelsey L; Stemler, Kristina M; White, Lynn S; Loza, Andrew J; Jeter-Jones, Sabrina; Michalski, Basia M; Kuzmicki, Catherine; Pless, Robert; Stappenbeck, Thaddeus S; Piwnica-Worms, David; Piwnica-Worms, Helen

    2015-12-22

    Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.

  11. Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury.

    PubMed

    Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng; Choi, Justin; Moskophidis, Demetrius; Yanasak, Nathan; Dhandapani, Krishnan M; Mivechi, Nahid F

    2014-09-01

    Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat-related activities. The heat-shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of reactive oxygen species-induced p53 target genes Pig1, Pig8, and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP-15. In contrast to Hsp110- or Hsp70i-deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild-type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement in contextual and cued fear conditioning tests and beam balance in wild-type mice that were treated with Celastrol or BGP-15 following TBI compared to TBI-treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI. Our data indicate that loss of Hsp110 or Hsp70 in mice increases brain injury following TBI. (a) One of the mechanisms underlying the increased cell death observed in the absence of these Hsps following TBI is the increased expression of ROS-induced p53 target genes known as Pigs. In addition, (b) using drugs (Celastrol or BGP-15) to increase Hsp70/Hsp110 levels protect cells against TBI, suggesting the beneficial effects of Hsp70/Hsp110 inducers to reduce the pathological consequences of TBI. © 2014 International Society

  12. Brucella lipopolysaccharide reinforced Salmonella delivering Brucella immunogens protects mice against virulent challenge.

    PubMed

    Lalsiamthara, Jonathan; Lee, John Hwa

    2017-06-01

    Intracellular pathogen Salmonella exhibits natural infection broadly analogous to Brucella, this phenomenon makes Salmonella a pragmatic choice for an anti-Brucella vaccine delivery platform. In this study we developed and formulated a combination of four attenuated Salmonella Typhimurium live vector strains delivering heterologous Brucella antigens (rBs), namely lumazine synthase, proline racemase subunit A, lipoprotein outer membrane protein-19, and Cu-Zn superoxide dismutase. With an aim to develop a cross-protecting vaccine, Brucella pan-species conserved rBs were selected. The present study compared the efficacy of smooth and rough variants of Salmonella delivery vector and also evaluated the inclusion of purified Brucella lipopolysaccharide (LPS) in the formulation. Immunization of SPF-BALB/c mice with the vaccine combinations significantly (P≤0.05) reduced splenic wild-type Brucella abortus 544 colonization as compared to non-immunized mice as well as Salmonella only immunized mice. Increased induction of Brucella specific-IgG, sIgA production, and antigen-specific splenocyte proliferative responses were observed in the mice immunized with the formulations as compared to naïve or vector only immunized mice. Modulatory effects of rB and LPS on production of interleukin (IL)-4, IL-12, and interferon-γ were detected in splenocytes of mice immunized with the formulation. Rough Salmonella variant in combination with LPS could further enhance the efficacy of the delivery when applied intraperitoneally. Taken together, it is compelling that Brucella LPS-augmented Salmonella vector delivering immunogenic Brucella proteins may be more suitable than the current non-ideal live Brucella abortus vaccine. The vaccine system also provides a basis for the development of cross-protecting vaccine capable of preventing multispecies brucellosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

    PubMed

    Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

    2017-12-01

    Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Inhibition of the plasma SCUBE1, a novel platelet adhesive protein, protects mice against thrombosis.

    PubMed

    Wu, Meng-Ying; Lin, Yuh-Charn; Liao, Wei-Ju; Tu, Cheng-Fen; Chen, Ming-Huei; Roffler, Steve R; Yang, Ruey-Bing

    2014-07-01

    Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), a secreted and surface-exposed glycoprotein on activated platelets, promotes platelet-platelet interaction and supports platelet-matrix adhesion. Its plasma level is a biomarker of platelet activation in acute thrombotic diseases. However, the exact roles of plasma SCUBE1 in vivo remain undefined. We generated new mutant (Δ) mice lacking the soluble but retaining the membrane-bound form of SCUBE1. Plasma SCUBE1-depleted Δ/Δ mice showed normal hematologic and coagulant features and expression of major platelet receptors, but Δ/Δ platelet-rich plasma showed impaired platelet aggregation in response to ADP and collagen treatment. The addition of purified recombinant SCUBE1 protein restored the aggregation of platelets in Δ/Δ platelet-rich plasma and further enhanced platelet aggregation in +/+ platelet-rich plasma. Plasma deficiency of SCUBE1 diminished arterial thrombosis in mice and protected against lethal thromboembolism induced by collagen-epinephrine treatment. Last, antibodies directed against the epidermal growth factor-like repeats of SCUBE1, which are involved in trans-homophilic protein-protein interactions, protected mice against fatal thromboembolism without causing bleeding in vivo. We conclude that plasma SCUBE1 participates in platelet aggregation by bridging adjacent activated platelets in thrombosis. Blockade of soluble SCUBE1 might represent a novel antithrombotic strategy. © 2014 American Heart Association, Inc.

  15. Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53.

    PubMed

    Page, Angustias; Navarro, Manuel; Suarez-Cabrera, Cristian; Alameda, Josefa P; Casanova, M Llanos; Paramio, Jesús M; Bravo, Ana; Ramirez, Angel

    2016-04-12

    p53 is a protein that causes cell cycle arrest, apoptosis or senescence, being crucial in the process of tumor suppression in several cell types. Different in vitro and animal models have been designed for the study of p53 role in skin cancer. These models have revealed opposing results, as in some experimental settings it appears that p53 protects against skin cancer, but in others, the opposite conclusion emerges. We have generated cohorts of mice with efficient p53 deletion restricted to stratified epithelia and control littermates expressing wild type p53 and studied their sensitivity to both chemically-induced and spontaneous tumoral transformation, as well as the tumor types originated in each experimental group. Our results indicate that the absence of p53 in stratified epithelia leads to the appearance, in two-stage skin carcinogenesis experiments, of a higher number of tumors that grow faster and become malignant more frequently than tumors arisen in mice with wild type p53 genotype. In addition, the histological diversity of the tumor type is greater in mice with epidermal p53 loss, indicating the tumor suppressive role of p53 in different epidermal cell types. Aging mice with p53 inactivation in stratified epithelia developed spontaneous carcinomas in skin and other epithelia. Overall, these results highlight the truly protective nature of p53 functions in the development of cancer in skin and in other stratified epithelia.

  16. Protective effect of Cassia fistula fruit extract on bromobenzene-induced nephrotoxicity in mice.

    PubMed

    Kalantari, Heibatullah; Jalali, Mohammadtaha; Jalali, Amir; Salimi, Abobakr; Alhalvachi, Foad; Varga, Balazs; Juhasz, Bela; Jakab, Anita; Kemeny-Beke, Adam; Gesztelyi, Rudolf; Tosaki, Arpad; Zsuga, Judit

    2011-10-01

    The efficacy of a crude hydro-alcoholic extract of Cassia fistula (golden shower tree) fruit to protect the kidney against bromobenzene-induced toxicity was studied. Negative control mice received normal saline; positive control mice were given 460 mg/kg of bromobenzene; Cassia fistula treated mice received 200, 400, 600 and 800 mg/kg of Cassia fistula fruit extract followed by 460 mg/kg bromobenzene (daily by oral gavage for 10 days). On the 11th day, the mice were sacrificed, blood samples were obtained to assess blood urea nitrogen (BUN) and creatinine levels, and kidneys were removed for histological examination. We found that bromobenzene induced significant nephrotoxicity reflected by an increase in levels of BUN and creatinine that was dose dependently prevented by the Cassia fistula fruit extract. The nephroprotective effect of the Cassia fistula fruit extract was confirmed by the histological examination of the kidneys. To the best of our knowledge, this is the first study to demonstrate the protective effect of Cassia fistula in nephrotoxicity.

  17. Saccharomyces cerevisiae expressing Gp43 protects mice against Paracoccidioides brasiliensis infection.

    PubMed

    Assis-Marques, Mariana Aprigio; Oliveira, Aline Ferreira; Ruas, Luciana Pereira; dos Reis, Thaila Fernanda; Roque-Barreira, Maria Cristina; Coelho, Paulo Sergio Rodrigues

    2015-01-01

    The dimorphic fungus Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis (PCM). It is believed that approximately 10 million people are infected with the fungus and approximately 2% will eventually develop the disease. Unlike viral and bacterial diseases, fungal diseases are the ones against which there is no commercially available vaccine. Saccharomyces cerevisiae may be a suitable vehicle for immunization against fungal infections, as they require the stimulation of different arms of the immune response. Here we evaluated the efficacy of immunizing mice against PCM by using S. cerevisiae yeast expressing gp43. When challenged by inoculation of P. brasiliensis yeasts, immunized animals showed a protective profile in three different assays. Their lung parenchyma was significantly preserved, exhibiting fewer granulomas with fewer fungal cells than found in non-immunized mice. Fungal burden was reduced in the lung and spleen of immunized mice, and both organs contained higher levels of IL-12 and IFN-γ compared to those of non-vaccinated mice, a finding that suggests the occurrence of Th1 immunity. Taken together, our results indicate that the recombinant yeast vaccine represents a new strategy to confer protection against PCM.

  18. Induction of protective immunity against toxoplasmosis in mice by immunization with Toxoplasma gondii RNA.

    PubMed

    Dimier-Poisson, Isabelle; Aline, Fleur; Bout, Daniel; Mévélec, Marie-Noëlle

    2006-03-06

    Toxoplasma gondii enters the mucosal surfaces of the host, and so immunity at these sites is of major interest. Due to the compartmentalization of the immune response, systemic immunization does not induce high levels of immunity at mucosal surfaces. Intranasal immunization has been shown to be very effective in inducing both systemic and mucosal immune responses. Immunization with mRNA can induce both humoral and cell-mediated immune responses, both of which are important in conferring immunity to T. gondii. The efficacy of RNA vaccination by the nasal route with T. gondii RNA was evaluated. We assessed the percentage of cumulative survival after an oral challenge with a lethal dose of T. gondii cysts (40 cysts), and the number of brain cysts following a challenge with a sublethal dose of T. gondii 76 K cysts (15 cysts). Vaccinated mice were found to be significantly better protected than non-immunized mice after a challenge with a lethal dose of cysts; and a challenge with a sublethal dose also resulted in fewer brain cysts than in non-immunized mice. Sera and intestinal secretions of immunized mice recognized T. gondii antigens, suggesting that a specific humoral immune response may occur. Moreover, a specific lymphoproliferative response observed in cervical lymph nodes may confer protection. These preliminary findings suggest that RNA vaccination by a mucosal route could be feasible.

  19. Zika virus infection confers protection against West Nile virus challenge in mice

    PubMed Central

    Vázquez-Calvo, Ángela; Blázquez, Ana-Belén; Escribano-Romero, Estela; Merino-Ramos, Teresa; Saiz, Juan-Carlos; Martín-Acebes, Miguel A; Jiménez de Oya, Nereida

    2017-01-01

    Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. Zika virus (ZIKV), which was initially reported to cause a mild disease, recently spread in the Americas, infecting millions of people. During this recent epidemic, ZIKV infection has been linked to serious neurological diseases and birth defects, specifically Guillain-Barrè syndrome (GBS) and microcephaly. Because information about ZIKV immunity remains scarce, we assessed the humoral response of immunocompetent mice to infection with three viral strains of diverse geographical origin (Africa, Asia and America). No infected animals showed any sign of disease or died after infection. However, specific neutralizing antibodies were elicited in all infected mice. Considering the rapid expansion of ZIKV throughout the American continent and its co-circulation with other medically relevant flaviviruses, such as West Nile virus (WNV), the induction of protective immunity between ZIKV and WNV was analyzed. Remarkably, protection after challenge with WNV was observed in mice previously infected with ZIKV, as survival rates were significantly higher than in control mice. Moreover, previous ZIKV infection enhanced the humoral immune response against WNV. These findings may be relevant in geographical areas where both ZIKV and WNV co-circulate, as well as for the future development of broad-spectrum flavivirus vaccines. PMID:28928416

  20. Oral immunization with recombinant enterovirus 71 VP1 formulated with chitosan protects mice against lethal challenge

    PubMed Central

    2014-01-01

    Background Enterovirus 71 (EV71) is the etiologic agent of hand-foot-and-mouth disease (HFMD) in the Asia-Pacific region, Many strategies have been applied to develop EV71 vaccines but no vaccines are currently available. Mucosal immunization of the VP1, a major immunogenic capsid protein of EV71, may be an alternative way to prevent EV71 infection. Results In this study, mucosal immunogenicity and protect function of recombinant VP1 protein (rVP1) in formulation with chitosan were tested and assessed in female ICR mouse model. The results showed that the oral immunization with rVP1 induced VP1-specific IgA antibodies in intestine, feces, vagina, and the respiratory tract and serum-specific IgG and neutralization antibodies in vaccinated mice. Splenocytes from rVP1-immunized mice induced high levels of Th1 (cytokine IFN-γ), Th2 (cytokine IL-4) and Th3 (cytokine TGF-β) type immune responses after stimulation. Moreover, rVP1-immunized mother mice conferred protection (survival rate up to 30%) on neonatal mice against a lethal challenge of 103 plaque-forming units (PFU) EV71. Conclusions These data indicated that oral immunization with rVP1 in formulation with chitosan was effective in inducing broad-spectrum immune responses and might be a promising subunit vaccine candidate for preventing EV71 infection. PMID:24885121

  1. Virus-like particle-based vaccine against coxsackievirus A6 protects mice against lethal infections.

    PubMed

    Shen, Chaoyun; Ku, Zhiqiang; Zhou, Yu; Li, Dapeng; Wang, Lili; Lan, Ke; Liu, Qingwei; Huang, Zhong

    2016-07-25

    Coxsackievirus A6 (CA6) is emerging as one of the major causative agents of hand, foot, and mouth disease (HFMD) worldwide. However, no vaccine is currently available for preventing CA6 infection. Here, we report the development of a virus-like particle (VLP)-based recombinant vaccine for CA6. We produced CA6 VLPs in insect cells by infecting the cells with a baculovirus coexpressing the genes encoding CA6 P1 and 3CD. Biochemical analyses showed that the produced VLPs consisted of VP0, VP1, and VP3 capsid subunit proteins generated by the cleavage of P1 by 3CD. Mice immunized with these VLPs produced CA6-specific serum antibodies. Passive transfer of antisera from CA6 VLP-immunized mice protected recipient mice from lethal infections caused by homologous and heterologous CA6 strains. Moreover, active immunization of mice with CA6 VLPs efficiently conferred protection against both homologous and heterologous CA6 infections. These results suggested that CA6 VLP-based recombinant vaccine is a promising candidate vaccine for preventing CA6 infection and can be incorporated into a multivalent HFMD vaccine formulation to achieve broad-spectrum and effective prevention of this disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Zika virus infection confers protection against West Nile virus challenge in mice.

    PubMed

    Vázquez-Calvo, Ángela; Blázquez, Ana-Belén; Escribano-Romero, Estela; Merino-Ramos, Teresa; Saiz, Juan-Carlos; Martín-Acebes, Miguel A; Jiménez de Oya, Nereida

    2017-09-20

    Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. Zika virus (ZIKV), which was initially reported to cause a mild disease, recently spread in the Americas, infecting millions of people. During this recent epidemic, ZIKV infection has been linked to serious neurological diseases and birth defects, specifically Guillain-Barrè syndrome (GBS) and microcephaly. Because information about ZIKV immunity remains scarce, we assessed the humoral response of immunocompetent mice to infection with three viral strains of diverse geographical origin (Africa, Asia and America). No infected animals showed any sign of disease or died after infection. However, specific neutralizing antibodies were elicited in all infected mice. Considering the rapid expansion of ZIKV throughout the American continent and its co-circulation with other medically relevant flaviviruses, such as West Nile virus (WNV), the induction of protective immunity between ZIKV and WNV was analyzed. Remarkably, protection after challenge with WNV was observed in mice previously infected with ZIKV, as survival rates were significantly higher than in control mice. Moreover, previous ZIKV infection enhanced the humoral immune response against WNV. These findings may be relevant in geographical areas where both ZIKV and WNV co-circulate, as well as for the future development of broad-spectrum flavivirus vaccines.

  3. DNA vaccination protects mice against Zika virus-induced damage to the testes

    PubMed Central

    Griffin, Bryan D.; Muthumani, Kar; Warner, Bryce M.; Majer, Anna; Hagan, Mable; Audet, Jonathan; Stein, Derek R.; Ranadheera, Charlene; Racine, Trina; De La Vega, Marc-Antoine; Piret, Jocelyne; Kucas, Stephanie; Tran, Kaylie N.; Frost, Kathy L.; De Graff, Christine; Soule, Geoff; Scharikow, Leanne; Scott, Jennifer; McTavish, Gordon; Smid, Valerie; Park, Young K.; Maslow, Joel N.; Sardesai, Niranjan Y.; Kim, J. Joseph; Yao, Xiao-jian; Bello, Alexander; Lindsay, Robbin; Boivin, Guy; Booth, Stephanie A.; Kobasa, Darwyn; Embury-Hyatt, Carissa; Safronetz, David; Weiner, David B.; Kobinger, Gary P.

    2017-01-01

    Zika virus (ZIKV) is an emerging pathogen causally associated with serious sequelae in fetuses, inducing fetal microcephaly and other neurodevelopment defects. ZIKV is primarily transmitted by mosquitoes, but can persist in human semen and sperm, and sexual transmission has been documented. Moreover, exposure of type-I interferon knockout mice to ZIKV results in severe damage to the testes, epididymis and sperm. Candidate ZIKV vaccines have shown protective efficacy in preclinical studies carried out in animal models, and several vaccines have entered clinical trials. Here, we report that administration of a synthetic DNA vaccine encoding ZIKV pre-membrane and envelope (prME) completely protects mice against ZIKV-associated damage to the testes and sperm and prevents viral persistence in the testes following challenge with a contemporary strain of ZIKV. These data suggest that DNA vaccination merits further investigation as a potential means to reduce ZIKV persistence in the male reproductive tract. PMID:28589934

  4. Recombinant Zika virus envelope protein elicited protective immunity against Zika virus in immunocompetent mice

    PubMed Central

    Liu, Zhihua; Li, Min; Liu, Haitao

    2018-01-01

    Zika virus (ZIKV) has caused great public concerns due to its recent large outbreaks and a close association with microcephaly in fetus and Guillain-Barre syndrome in adults. Rapid development of vaccines against ZIKV is a public health priority. To this end, we have constructed and purified recombinant ZIKV envelope protein using both prokaryotic and eukaryotic expression systems, and then tested their immunogenicity and protective efficacy in immune competent mice. Both protein immunogens elicited humoral and cellular immune responses, and protected immune competent mice from ZIKV challenge in vivo. These products could be further evaluated either as stand-alone vaccine candidate, or used in a prime-and-boost regimen with other forms of ZIKV vaccine. PMID:29590178

  5. Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

    SciTech Connect

    Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.

    2006-10-01

    Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethalmore » dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the

  6. Podocyte-Specific GLUT4-Deficient Mice Have Fewer and Larger Podocytes and Are Protected From Diabetic Nephropathy

    PubMed Central

    Guzman, Johanna; Jauregui, Alexandra N.; Merscher-Gomez, Sandra; Maiguel, Dony; Muresan, Cristina; Mitrofanova, Alla; Diez-Sampedro, Ana; Szust, Joel; Yoo, Tae-Hyun; Villarreal, Rodrigo; Pedigo, Christopher; Molano, R. Damaris; Johnson, Kevin; Kahn, Barbara; Hartleben, Bjoern; Huber, Tobias B.; Saha, Jharna; Burke, George W.; Abel, E. Dale; Brosius, Frank C.; Fornoni, Alessia

    2014-01-01

    Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria. PMID:24101677

  7. Protective Effect of Anthocyanins Extract from Blueberry on TNBS-Induced IBD Model of Mice

    PubMed Central

    Wu, Lin-Hua; Xu, Zeng-Lai; Dong, Di; He, Shan-An; Yu, Hong

    2011-01-01

    This study was carried out to evaluate the protective effect of anthocyanins extract of blueberry on trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) model of mice. The study employed female C57BL/6 mice (n = 50), and colitis was induced by intracolonic injection of 0.5 mg of TNBS dissolved in 50% ethanol–phosphate buffered solution. The mice were divided into five groups (n = 10): vehicle, TNBS control and anthocyanins groups that received different doses of anthocyanins extract (10, 20 and 40 mg kg−1) daily for 6 days. Both increase in body weight and diarrhea symptoms were monitored each day. After 6 days, the animals were killed, and the following parameters were assessed: colon length, morphological score, histological score and biochemical assay (NO, myeloperoxidase (MPO), interleukin (IL)-12, IL-10, tumor necrosis factor (TNF)-α and interferon (IFN)-γ). The results showed that the anthocyanins extract of blueberry rendered strong protection against TNBS-induced colonic damage at a dosage of 40 mg kg−1. When compared with the control, anthocyanins extract significantly prevented loss of body weight and ameliorated the scores of diarrhea, morphology and histology. Treatment with anthocyanins extract restored IL-10 excretion, as well as caused reduction in the levels of NO, MPO, IL-12, TNF-α and IFN-γ. Our research revealed the protective effect of anthocyanins extract from blueberry on TNBS-induced experimental colitis in mice, as well as examined whether high levels of dietary blueberries would lower the risk or have protective effects on human IBD, which may require further investigation. PMID:21785630

  8. Aerogenic Vaccination With a Burkholderia mallei Auxotroph Protects Against Aerosol-Initiated Glanders in Mice

    DTIC Science & Technology

    2005-03-14

    Vaccine 23 (2005) 1986–1992 Aerogenic vaccination with a Burkholderia mallei auxotroph protects against aerosol-initiated glanders in mice Ricky L...October 2004 Available online 11 November 2004 Abstract Burkholderia mallei is an obligate mammalian pathogen that causes the zoonotic disease glanders ... Burkholderia mallei , the causative agent of glanders , is gram-negative bacillus. It is a highly adapted parasite of quines and cannot persist in nature

  9. The combination of osthole with baicalin protects mice from Staphylococcus aureus pneumonia.

    PubMed

    Liu, Shui; Liu, Bowen; Luo, Zhao-Qing; Qiu, Jiaming; Zhou, Xuan; Li, Gen; Zhang, Bing; Deng, Xuming; Yang, Zhenguo; Wang, Jianfeng

    2017-01-01

    We reported the inhibition of α-Hemolysin (Hla) production in methicillin-resistant Staphylococcus aureus USA300 by osthole and further investigated the combination of osthole and baicalin in the treatment of staphylococcal pneumonia. Using cytotoxicity assays and a mouse model of intranasal lung infection, we evaluated the effect of combined therapy. Our results suggest that the combination of osthole and baicalin alleviated S. aureus-mediated A549 cell injury and protected mice from S. aureus pneumonia.

  10. Vaccination evokes gender-dependent protection against tularemia infection in C57BL/6Tac mice.

    PubMed

    Sunagar, Raju; Kumar, Sudeep; Franz, Brian J; Gosselin, Edmund J

    2016-06-17

    Francisella tularensis (Ft) is a Category A biothreat agent for which there currently is no FDA-approved vaccine. Thus, there is a substantial effort underway to develop an effective tularemia vaccine. While it is well established that gender can significantly impact susceptibility to primary infection, the impact of gender on vaccine efficacy is not well established. Thus, development of a successful vaccine against tularemia will require an understanding of the impact gender has on vaccine-induced protection against this organism. In this study, a role for gender in vaccine-induced protection following Ft challenge is identified for the first time. In the present study, mucosal vaccination with inactivated Ft (iFt) LVS elicited gender-based protection in C57BL/6Tac mice against respiratory challenge with Ft LVS. Specifically, vaccinated male mice were more susceptible to subsequent Ft LVS challenge. This increased susceptibility in male mice correlated with increased bacterial burden, increased tissue inflammation, and increased proinflammatory cytokine production late in post-challenge infection. In contrast, improved survival of iFt-vaccinated female mice correlated with reduced bacterial burden and enhanced levels of Ft-specific Abs in serum and broncho-alveolar lavage (BAL) fluid post-challenge. Furthermore, vaccination with a live attenuated vaccine consisting of an Ft LVS superoxide dismutase (SodB) mutant, which has proven efficacious against the highly virulent Ft SchuS4 strain, demonstrated similar gender bias in protection post-Ft SchuS4 challenge. Of particular significance is the fact that these are the first studies to demonstrate that gender differences impact disease outcome in the case of lethal respiratory tularemia following mucosal vaccination. In addition, these studies further emphasize the fact that gender differences must be a serious consideration in any future tularemia vaccine development studies. Copyright © 2016 Elsevier Ltd. All

  11. Complement Depletion Protects Lupus-prone Mice from Ischemia-reperfusion-initiated Organ Injury

    DTIC Science & Technology

    2012-10-25

    injury, we sought to evaluate whether complement inhibition mitigates organ damage. We found that complement deple- tion with cobra venom factor... venom factor and C5a receptor antagonist were able to protect mice from local tissue damage, treatment with C5a receptor antagonist was not able to...Complement depletion or blockage of the complement pathway using molecules such as cobra venom factor (CVF) (24, 33) and C5a receptor antagonists (C5aRA

  12. Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity.

    PubMed

    Pu, Shiyun; Ren, Lin; Liu, Qinhui; Kuang, Jiangying; Shen, Jing; Cheng, Shihai; Zhang, Yuwei; Jiang, Wei; Zhang, Zhiyong; Jiang, Changtao; He, Jinhan

    2016-01-01

    Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice. The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. © 2015 The British Pharmacological Society.

  13. Caspase 6 has a protective role in SOD1(G93A) transgenic mice.

    PubMed

    Hogg, Marion C; Mitchem, Mollie R; König, Hans-Georg; Prehn, Jochen H M

    2016-06-01

    In amyotrophic lateral sclerosis (ALS), it has been suggested that the process of neurodegeneration starts at the neuromuscular junction and is propagated back along axons towards motor neurons. Caspase-dependent pathways are well established as a cause of motor neuron death, and recent work in other disease models indicated a role for caspase 6 in axonal degeneration. Therefore we hypothesised that caspase 6 may be involved in motor neuron death in ALS. To investigate the role of caspase 6 in ALS we profiled protein levels of caspase-6 throughout disease progression in the ALS mouse model SOD1(G93A); this did not reveal differences in caspase 6 levels during disease. To investigate the role of caspase 6 further we generated a colony with SOD1(G93A) transgenic mice lacking caspase 6. Analysis of the transgenic SOD1(G93A); Casp6(-/-) revealed an exacerbated phenotype with motor dysfunction occurring earlier and a significantly shortened lifespan when compared to transgenic SOD1(G93A); Casp6(+/+) mice. Immunofluorescence analysis of the neuromuscular junction revealed no obvious difference between caspase 6(+/+) and caspase 6(-/-) in non-transgenic mice, while the SOD1(G93A) transgenic mice showed severe degeneration compared to non-transgenic mice in both genotypes. Our data indicate that caspase-6 does not exacerbate ALS pathogenesis, but may have a protective role. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Protective Effects of Lactobacillus plantarum CCFM8246 against Copper Toxicity in Mice

    PubMed Central

    Li, Xiaoxiao; Zhai, Qixiao; Wang, Gang; Zhang, Qiuxiang; Zhang, Hao; Chen, Wei

    2015-01-01

    Lactobacillus plantarum CCFM8246, which has a relatively strong copper binding capacity and tolerance to copper ions, was obtained by screening from 16 lactic acid bacteria in vitro. The selected strain was then applied to a mouse model to evaluate its protective function against copper intoxication in vivo. The experimental mice were divided into an intervention group and a therapy group; mice in the intervention group received co-administration of CCFM8246 and a copper ion solution by gavage, while mice in the therapy group were treated with CCFM8246 after 4 weeks of copper exposure. In both two groups, mice treated with copper alone and that treated with neither CCFM8246 nor copper served as positive and negative controls, respectively. At the end of the experimental period, the copper content in feces and tissues, the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and oxidation stress indices in liver and kidney tissue were determined. Learning and memory ability was evaluated by Morris water maze experiments. The results indicated that treatment with CCFM8246 significantly increased the copper content in feces to promote copper excretion, reduce the accumulation of copper in tissues, reverse oxidative stress induced by copper exposure, recover the ALT and AST in serum and improve the spatial memory of mice. PMID:26605944

  15. Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice.

    PubMed

    Ince, Sinan; Keles, Hikmet; Erdogan, Metin; Hazman, Omer; Kucukkurt, Ismail

    2012-07-01

    The protective effect of boric acid against liver damage was evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male albino mice were treated intraperitoneally (i.p.) with boric acid (50, 100, and 200 mg/kg) or silymarin daily for 7 days and received 0.2% CCl(4) in olive oil (10 mL/kg, i.p.) on day 7. Results showed that administration of boric acid significantly reduced the elevation in serum levels of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and the level of malondialdehyde in the liver that were induced by CCl(4) in mice. Boric acid treatment significantly increased glutathione content, as well as the activities of superoxide dismutase and catalase in the liver. Boric acid treatment improved the catalytic activity of cytochrome P450 2E1 and maintained activation of nuclear factor kappa light-chain enhancer of activated B cell gene expression, with no effect on inducible nitric oxide synthase gene expression in the livers of mice. Histopathologically, clear decreases in the severity of CCl(4)-induced lesions were observed, particularly at high boric acid concentrations. Results suggest that boric acid exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely the result of both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  16. Alpha-syntrophin deficient mice are protected from adipocyte hypertrophy and ectopic triglyceride deposition in obesity.

    PubMed

    Eisinger, Kristina; Rein-Fischboeck, Lisa; Neumeier, Markus; Schmidhofer, Sandra; Pohl, Rebekka; Haberl, Elisabeth M; Liebisch, Gerhard; Kopp, Andrea; Schmid, Andreas; Krautbauer, Sabrina; Buechler, Christa

    2018-06-01

    Alpha-syntrophin (SNTA) is a molecular adapter protein which is expressed in adipocytes. Knock-down of SNTA in 3T3-L1 preadipocytes increases cell proliferation, and differentiated adipocytes display small lipid droplets. These effects are both characteristics of healthy adipose tissue growth which is associated with metabolic improvements in obesity. To evaluate a role of SNTA in adipose tissue morphology and obesity associated metabolic dysfunction, SNTA deficient mice were fed a standard chow or a high fat diet. Mice deficient of SNTA had less fat mass and smaller adipocytes in obesity when compared to control animals. Accordingly, these animals did not develop liver steatosis and did not store excess triglycerides in skeletal muscle upon high fat diet feeding. SNTA-/- animals were protected from hyperinsulinemia and hepatic insulin resistance. Of note, body-weight, food uptake, and serum lipids were normal in the SNTA null mice. SNTA was induced in adipose tissues but not in the liver of diet induced obese and ob/ob mice. In human subcutaneous and visceral fat of seven patients SNTA was similarly expressed and was not associated with body mass index. Current data demonstrate beneficial effects of SNTA deficiency in obesity which is partly attributed to smaller adipocytes and reduced white adipose tissue mass. Higher SNTA protein in fat depots of obese mice may contribute to adipose tissue hypertrophy and ectopic lipid deposition which has to be confirmed in humans. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Hordenine protects against hyperglycemia-associated renal complications in streptozotocin-induced diabetic mice.

    PubMed

    Su, Shuhao; Cao, Meng; Wu, Guangyuan; Long, Zi; Cheng, Xiaodong; Fan, Junshu; Xu, Zhongrui; Su, Hongfei; Hao, Yiming; Li, Ge; Peng, Jie; Li, Shuang; Wang, Xin

    2018-05-15

    The worldwide prevalence of diabetes and associated metabolic diseases has dramatically increased. Pharmacological treatment of diabetes is still limited. Hordenine (HOR), a phenethylamine alkaloid, is a natural constituent in many plants. The present study was designed to explore the possible anti-diabetic effect of HOR in streptozotocin (STZ)-induced diabetic mice. Combined treatment of HOR and insulin significantly reduced fasting and postprandial blood glucose level in diabetic mice. HOR and insulin did not show evident protective effect against structural and functional injuries of pancreas. Renal histological and functional injuries were significantly improved by HOR or insulin treatment. Moreover, combined treatment of HOR and insulin resulted in a more significant amelioration of renal histological and functional injuries in diabetic mice. HOR induced a decrease of renal IL-1α/β and IL-6 expression, and a reduction of Col1α1 and MMP9 expression and PAS-stained mesangial expansion in glomeruli of diabetic mice. In diabetic mice, HOR significantly decreased Nrf2 expression and increased hnRNPF and hnRNPK expression in kidney. Moreover, HOR showed a synergistic effect with insulin on the expression of these regulators. Renal ROS level and TBARS content in diabetic mice were decreased by HOR. The reduction of renal expression of antioxidant enzymes in diabetic mice was inhibited by HOR and insulin. Furthermore, HOR and insulin function synergistically to play an antioxidant role against oxidative injury in diabetic nephropathy. In conclusion, to the best of our knowledge, we, for the first time, found the anti-diabetic, anti-inflammatory, and anti-fibrotic role of HOR in combination with insulin. HOR functions synergistically with insulin and prevents diabetic nephropathy. However, the molecular mechanism of the synergistic effect of HOR and insulin needs to be elucidated. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Antioxidant Diet Protects Against Emphysema, but Increases Mortality in Cigarette Smoke-Exposed Mice

    PubMed Central

    Nyunoya, Toru; March, Thomas H.; Tesfaigzi, Yohannes; Seagrave, JeanClare

    2012-01-01

    Oxidative stress plays an important role in cigarette smoke-induced lung inflammation and emphysema. We produced an enriched diet by adding freeze-dried fruits and vegetables and additional supplements to the 8604 Teklad Rodent Diet, a standard rodent diet. In this study, we examined the effects of the antioxidant-enriched diet on cigarette smoke-induced lung inflammation and emphysema. CH3/HeN mice were fed either a regular diet or an antioxidant diet. These mice were exposed to filtered air, a low concentration of cigarette smoke (total particulate matter: 100 mg/m3) or a high concentration of cigarette smoke (total particulate matter: 250mg/m3) for 6 hours/day, 5 days/week for total 16 weeks. Surprisingly, increased mortality (53%) was observed in the high concentration of cigarette smoke-exposed mice fed the antioxidant diet compared to the high concentration of cigarette smoke-exposed mice that were fed a regular diet (13%). The necropsy analysis revealed nasal passage obstruction due to mucous plugging in cigarette smoke-exposed mice on the antioxidant diet. However, the antioxidant diet significantly reduced neutrophilic inflammation and emphysema in the high concentration of cigarette smoke-exposed mice as compared to the regular diet /high concentration of cigarette smoke controls. The antioxidant capacity in the bronchoalveolar fluid or oxidative damage to the lung tissue was not affected by the antioxidant diet. Pro-MMP-2, MMP-2, and MMP-9 activity did not correlate with the protective effects of AOD on cigarette smoke-induced emphysema. These data suggest that the antioxidant diet reduced cigarette smoke -induced inflammation and emphysema, but increased mortality in the obligate nose-breathing mice. PMID:21834692

  19. Vaccinia Virus Recombinants: Expression of VSV Genes and Protective Immunization of Mice and Cattle

    NASA Astrophysics Data System (ADS)

    Mackett, M.; Yilma, T.; Rose, J. K.; Moss, B.

    1985-01-01

    Vesicular stomatitis virus (VSV) causes a contagious disease of horses, cattle, and pigs. When DNA copies of messenger RNA's for the G or N proteins of VSV were linked to a vaccinia virus promoter and inserted into the vaccinia genome, the recombinants retained infectivity and synthesized VSV polypeptides. After intradermal vaccination with live recombinant virus expressing the G protein, mice produced VSV-neutralizing antibodies and were protected against lethal encephalitis upon intravenous challenge with VSV. In cattle, the degree of protection against intradermalingually injected VSV was correlated with the level of neutralizing antibody produced following vaccination.

  20. Induction of Protective CTL Responses in Newborn Mice by a Murine Retrovirus

    NASA Astrophysics Data System (ADS)

    Sarzotti, Marcella; Robbins, Deanna S.; Hoffman, Paul M.

    1996-03-01

    The susceptibility of neonates to virus-induced disease is thought to reflect, in part, the immaturity of their immune systems. However, inoculation of newborn mice with low doses of Cas-Br-M murine leukemia virus induced a protective cytotoxic T lymphocyte (CTL) response. The inability of neonates to develop a CTL response to high doses of virus was not the result of immunological immaturity but correlated with the induction of a nonprotective type 2 cytokine response. Thus, the initial viral dose is critical in the development of protective immunity in newborns.

  1. Protection against anthrax and plague by a combined vaccine in mice and rabbits.

    PubMed

    Ren, Jun; Dong, Dayong; Zhang, Jinlong; Zhang, Jun; Liu, Shuling; Li, Bing; Fu, Ling; Xu, Junjie; Yu, Changming; Hou, Lihua; Li, Jianmin; Chen, Wei

    2009-12-09

    The protective antigen (PA) of Bacillus anthracis and the Fraction 1 Capsular Antigen (F1 antigen), V antigen of Yersinia pestis have been demonstrated to be potential immunogens and candidate vaccine sub-units against anthrax and plague respectively. In this study, the authors have investigated the antibody responses and the protective efficacy when the antigens were administered separately or in combination intramuscularly formulation adsorbed to an aluminum hydroxide adjuvant. Results show that immunized rF1 + rV and rPA antigen together was as effective as separately for induction of serological antibody response, and these titers were maintained for over 1 year in mice. An isotype analysis of the serum indicates that the co-administration of these antigens did not influence the antigen-specific IgG1/IgG2a ratio which was consistent with a Th2 bias. Furthermore, the combined vaccine comprising the protein antigens rF1 + rV + rPA has been demonstrated to protect mice from subcutaneous challenge with 10(7) colony-forming units (CFU) virulent Y. pestis strain, and to fully protect rabbit against subcutaneous challenge with 1.2x10(5) colony-forming units (CFU) virulent B. anthracis spores. These data show that the protective efficacy was unaffected when the antigens were administered in combination.

  2. Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer.

    PubMed

    Saxena, Arpit; Fayad, Raja; Kaur, Kamaljeet; Truman, Samantha; Greer, Julian; Carson, James A; Chanda, Anindya

    2017-04-03

    Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Se's protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.

  3. Protective Effect of Selenium on Aflatoxin B1-Induced Testicular Toxicity in Mice.

    PubMed

    Cao, Zheng; Shao, Bing; Xu, Feibo; Liu, Yunfeng; Li, Yanfei; Zhu, Yanzhu

    2017-12-01

    Aflatoxins have been considered as one of the major risk factors of male infertility, and aflatoxin B1 (AFB1) is the most highly toxic and prevalent member of the aflatoxins family. Selenium (Se), an essential nutritional trace mineral for normal testicular development and male fertility, has received extensive intensive on protective effects of male reproductive system due to its potential antioxidant and activating testosterone synthesis. To investigate the protective effect of Se on AFB1-induced testicular toxicity, the mice were orally administered with AFB1 (0.75 mg/kg) and Se (0.2 mg/kg or 0.4 mg/kg) for 45 days. We found that that Se elevated testes index, sperm functional parameters (concentration, malformation, and motility), and the level of serum testosterone in AFB1-exposed mice. Moreover, our results showed that Se attenuated the AFB1-induced oxidative stress and the reduction of testicular testosterone synthesis enzyme protein expression such as steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), and 17β-hydroxysteroid dehydrogenase (17β-HSD) in AFB1-exposed mice. These results demonstrated that Se conferred protection against AFB1-induced testicular toxicity and can be attributed to its antioxidant and increased testosterone level by stimulating protein expression of StAR and testosterone synthetic enzymes.

  4. Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice

    PubMed Central

    Konduru, Krishnamurthy; Bradfute, Steven B.; Jacques, Jerome; Manangeeswaran, Mohanraj; Nakamura, Siham; Morshed, Sufi; Wood, Steven C.; Bavari, Sina

    2011-01-01

    Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGP-Fc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use. PMID:21329775

  5. Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice.

    PubMed

    Scott, Jason M; Lebratti, Tania J; Richner, Justin M; Jiang, Xiaoping; Fernandez, Estefania; Zhao, Haiyan; Fremont, Daved H; Diamond, Michael S; Shin, Haina

    2018-01-17

    Zika virus (ZIKV), which can cause devastating disease in fetuses of infected pregnant women, can be transmitted by mosquito inoculation and sexual routes. Little is known about immune protection against sexually transmitted ZIKV. In this study, we show that previous infection through intravaginal or subcutaneous routes with a contemporary Brazilian strain of ZIKV can protect against subsequent intravaginal challenge with a homologous strain. Both routes of inoculation induced high titers of ZIKV-specific and neutralizing antibody in serum and the vaginal lumen. Virus-specific T cells were recruited to and retained in the female reproductive tract after intravaginal and subcutaneous ZIKV infection. Studies in mice with genetic or acquired deficiencies in B and/or T cells demonstrated that both lymphocyte populations redundantly protect against intravaginal challenge in ZIKV-immune animals. Passive transfer of ZIKV immune IgG or T cells significantly limited intravaginal infection of naïve mice, although antibody more effectively prevented dissemination throughout the reproductive tract. Collectively, our experiments begin to establish the immune correlates of protection against intravaginal ZIKV infection, which should inform vaccination strategies in non-pregnant and pregnant women. IMPORTANCE The recent ZIKV epidemic resulted in devastating outcomes in fetuses and may affect reproductive health. Unlike other flaviviruses, ZIKV can be spread by sexual contact as well as a mosquito vector. While previous studies have identified correlates of protection for mosquito-mediated infection, few have focused on immunity against sexual transmission. As exposure to ZIKV via mosquito bite has likely occurred to many living in endemic areas, our study addresses whether this route of infection can protect against subsequent sexual exposure. We demonstrate that subcutaneous ZIKV infection can protect against subsequent vaginal infection by generating both local antiviral T

  6. Androstenediol and dehydroepiandrosterone protect mice against lethal bacterial infections and lipopolysaccharide toxicity.

    PubMed

    Ben-Nathan, D; Padgett, D A; Loria, R M

    1999-05-01

    The protective effects of the hormones androstenediol (androstene-3beta, 17beta,-diol; AED) and dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA) on the pathophysiology of two lethal bacterial infections and endotoxin shock were examined. The infections included a gram-positive organism (Enterococcus faecalis) and a gram-negative organism (Pseudomonas aeruginosa). Both hormones protected mice from the lethal bacterial infections and from lipopolysaccharide (LPS) challenge. Treatment of animals lethally infected with P. aeruginosa with DHEA resulted in a 43% protection whereas treatment with AED gave a 67% protection. Both hormones also protected completely animals infected with an LD50 dose of E. faecalis. Similarly, the 88% mortality rate seen in LPS challenge was reduced to 17% and 8.5%, by treatment with DHEA and AED, respectively. The protective influences of both steroids were shown not to be directly antibacterial, but primarily an indirect antitoxin reaction. DHEA appears to mediate its protective effect by a mechanism that blocks the toxin-induced production of pathophysiological levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1. AED usually had greater protective effects than DHEA; however, the AED effect was independent of TNF-alpha suppression, both in vivo and in vitro. The data suggest that both DHEA and AED may have a role in the neuro-endocrine regulation of antibacterial immune resistance.

  7. Refined Live Attenuated Salmonella enterica Serovar Typhimurium and Enteritidis Vaccines Mediate Homologous and Heterologous Serogroup Protection in Mice

    PubMed Central

    Schmidlein, Patrick; Simon, Raphael; Pasetti, Marcela F.; Galen, James E.; Levine, Myron M.

    2015-01-01

    Invasive nontyphoidal Salmonella (NTS) infections constitute a major health problem among infants and toddlers in sub-Saharan Africa; these infections also occur in infants and the elderly in developed countries. We genetically engineered a Salmonella enterica serovar Typhimurium strain of multilocus sequence type 313, the predominant genotype circulating in sub-Saharan Africa. We evaluated the capacities of S. Typhimurium and Salmonella enterica serovar Enteritidis ΔguaBA ΔclpX live oral vaccines to protect mice against a highly lethal challenge dose of the homologous serovar and determined protection against other group B and D serovars circulating in sub-Saharan Africa. The vaccines S. Typhimurium CVD 1931 and S. Enteritidis CVD 1944 were immunogenic and protected BALB/c mice against 10,000 50% lethal doses (LD50) of S. Typhimurium or S. Enteritidis, respectively. S. Typhimurium CVD 1931 protected mice against the group B serovar Salmonella enterica serovar Stanleyville (91% vaccine efficacy), and S. Enteritidis CVD 1944 protected mice against the group D serovar Salmonella enterica serovar Dublin (85% vaccine efficacy). High rates of survival were observed when mice were infected 12 weeks postimmunization, indicating that the vaccines elicited long-lived protective immunity. Whereas CVD 1931 did not protect against S. Enteritidis R11, CVD 1944 did mediate protection against S. Typhimurium D65 (81% efficacy). These findings suggest that a bivalent (S. Typhimurium and S. Enteritidis) vaccine would provide broad protection against the majority of invasive NTS infections in sub-Saharan Africa. PMID:26351285

  8. A plant based protective antigen [PA(dIV)] vaccine expressed in chloroplasts demonstrates protective immunity in mice against anthrax.

    PubMed

    Gorantala, Jyotsna; Grover, Sonam; Goel, Divya; Rahi, Amit; Jayadev Magani, Sri Krishna; Chandra, Subhash; Bhatnagar, Rakesh

    2011-06-15

    The currently available anthrax vaccines are limited by being incompletely characterized, potentially reactogenic and have an expanded dosage schedule. Plant based vaccines offer safe alternative for vaccine production. In the present study, we expressed domain IV of Bacillus anthracis protective antigen gene [PA(dIV)] in planta (by nuclear agrobacterium and chloroplast transformation) and E. coli [rPA(dIV)]. The presence of transgene and the expression of PA(dIV) in planta was confirmed by molecular analysis. Expression levels up to 5.3% of total soluble protein (TSP) were obtained with AT rich (71.8% AT content) PA(dIV) gene in transplastomic plants while 0.8% of TSP was obtained in nuclear transformants. Further, we investigated the protective response of plant and E. coli derived PA(dIV) in mice by intraperitoneal (i.p.) and oral immunizations with or without adjuvant. Antibody titers of >10(4) were induced upon i.p. and oral immunizations with plant derived PA(dIV) and oral immunization with E. coli derived PA(dIV). Intraperitoneal injections with adjuvanted E. coli derived PA(dIV), generated highest antibody titers of >10(5). All the immunized groups demonstrated predominant IgG1 titers over IgG2a indicating a polarized Th2 type response. We also evaluated the mucosal antibody response in orally immunized groups. When fecal extracts were analyzed, low sIgA titer was demonstrated in adjuvanted plant and E. coli derived PA(dIV) groups. Further, PA(dIV) antisera enhanced B. anthracis spore uptake by macrophages in vitro and also demonstrated an anti-germinating effect suggesting a potent role at mucosal surfaces. The antibodies from various groups were efficient in neutralizing the lethal toxin in vitro. When mice were challenged with B. anthracis, mice immunized with adjuvanted plant PA(dIV) imparted 60% and 40% protection while E. coli derived PA(dIV) conferred 100% and 80% protection upon i.p. and oral immunizations. Thus, our study is the first attempt in

  9. Native flagellin does not protect mice against an experimental Proteus mirabilis ascending urinary tract infection and neutralizes the protective effect of MrpA fimbrial protein.

    PubMed

    Scavone, Paola; Umpiérrez, Ana; Rial, Analía; Chabalgoity, José A; Zunino, Pablo

    2014-06-01

    Proteus mirabilis expresses several virulence factors including MR/P fimbriae and flagella. Bacterial flagellin has frequently shown interesting adjuvant and protective properties in vaccine formulations. However, native P. mirabilis flagellin has not been analyzed so far. Native P. mirabilis flagellin was evaluated as a protective antigen and as an adjuvant in co-immunizations with MrpA (structural subunit of MR/P fimbriae) using an ascending UTI model in the mouse. Four groups of mice were intranasally treated with either MrpA, native flagellin, both proteins and PBS. Urine and blood samples were collected before and after immunization for specific antibodies determination. Cytokine production was assessed in immunized mice splenocytes cultures. Mice were challenged with P. mirabilis, and bacteria quantified in kidneys and bladders. MrpA immunization induced serum and urine specific anti-MrpA antibodies while MrpA coadministered with native flagellin did not. None of the animals developed significant anti-flagellin antibodies. Only MrpA-immunized mice showed a significant decrease of P. mirabilis in bladders and kidneys. Instead, infection levels in MrpA-flagellin or flagellin-treated mice showed no significant differences with the control group. IL-10 was significantly induced in splenocytes of mice that received native flagellin or MrpA-flagellin. Native P. mirabilis flagellin did not protect mice against an ascending UTI. Moreover, it showed an immunomodulatory effect, neutralizing the protective role of MrpA. P. mirabilis flagellin exhibits particular immunological properties compared to other bacterial flagellins.

  10. Characterisation of the protective immune response following subcutaneous vaccination of susceptible mice against Trichuris muris

    PubMed Central

    Dixon, Helen; Little, Matthew C.; Else, Kathryn J.

    2010-01-01

    Trichuris muris is a laboratory model for the human whipworm Trichuris trichiura which infects approximately 1 billion people in tropical and sub-tropical countries. The development of a vaccine would control trichuriasis by promoting the acquisition of immunity during childhood, thereby reducing faecal egg output by the community into their environment. Resistance to T. muris, defined as expulsion of the parasite prior to patency, requires the development of a T helper 2 (Th2) response during a primary infection. To our knowledge this is the first study to describe the protective immune response in the peripheral lymph nodes (PLN), mesenteric lymph nodes (MLN) and colonic mucosa following s.c. vaccination against T. muris. Susceptible AKR mice were either vaccinated with T. muris excretory–secretory product (ES) in incomplete Freund’s adjuvant (IFA) (ES/IFA) or injected with PBS in IFA (PBS/IFA) and for protection experiments were infected with embryonated infective T. muris eggs 10 days later. The ES/IFA vaccine induced the proliferation of PLN cells and their production of Th2 cytokines and the Th1-associated cytokine IFN-γ. Following a challenge infection, the ES/IFA vaccination offered susceptible mice complete protection. While MLN-derived IFN-γ was produced by infected mice following either ES/IFA vaccination or PBS/IFA, the protection of susceptible mice by ES/IFA was characterised by the production of MLN-derived Th2 cytokines. Goblet cell hyperplasia and the influx and alternative activation of macrophages were observed locally in the gut post-challenge infection. The rate of epithelial turnover did not appear to be increased by vaccination, suggesting that there are differences in the mechanisms of expulsion between ‘natural resistance’ and ‘vaccinated resistance’. High levels of serum IgG1 and cell-bound IgG1 in the colon of mice protected by the ES/IFA vaccine suggest that antibody may be involved in vaccination-induced worm expulsion

  11. Characterisation of the protective immune response following subcutaneous vaccination of susceptible mice against Trichuris muris.

    PubMed

    Dixon, Helen; Little, Matthew C; Else, Kathryn J

    2010-05-01

    Trichuris muris is a laboratory model for the human whipworm Trichuris trichiura which infects approximately 1 billion people in tropical and sub-tropical countries. The development of a vaccine would control trichuriasis by promoting the acquisition of immunity during childhood, thereby reducing faecal egg output by the community into their environment. Resistance to T. muris, defined as expulsion of the parasite prior to patency, requires the development of a T helper 2 (Th2) response during a primary infection. To our knowledge this is the first study to describe the protective immune response in the peripheral lymph nodes (PLN), mesenteric lymph nodes (MLN) and colonic mucosa following s.c. vaccination against T. muris. Susceptible AKR mice were either vaccinated with T. muris excretory-secretory product (ES) in incomplete Freund's adjuvant (IFA) (ES/IFA) or injected with PBS in IFA (PBS/IFA) and for protection experiments were infected with embryonated infective T. muris eggs 10 days later. The ES/IFA vaccine induced the proliferation of PLN cells and their production of Th2 cytokines and the Th1-associated cytokine IFN-gamma. Following a challenge infection, the ES/IFA vaccination offered susceptible mice complete protection. While MLN-derived IFN-gamma was produced by infected mice following either ES/IFA vaccination or PBS/IFA, the protection of susceptible mice by ES/IFA was characterised by the production of MLN-derived Th2 cytokines. Goblet cell hyperplasia and the influx and alternative activation of macrophages were observed locally in the gut post-challenge infection. The rate of epithelial turnover did not appear to be increased by vaccination, suggesting that there are differences in the mechanisms of expulsion between 'natural resistance' and 'vaccinated resistance'. High levels of serum IgG1 and cell-bound IgG1 in the colon of mice protected by the ES/IFA vaccine suggest that antibody may be involved in vaccination-induced worm expulsion. (c) 2009

  12. Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice.

    PubMed

    Bächinger, David; Horvath, Lukas; Eckhard, Andreas; Goosmann, Madeline M; Honegger, Tim; Gassmann, Max; Vogel, Johannes; Naldi, Arianne Monge

    2018-07-01

    Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss. Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycoside-induced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. α-Lipoic Acid Protects Diabetic Apolipoprotien E-deficient Mice from Nephropathy

    PubMed Central

    Yi, Xianwen; Nickeleit, Volker; James, Leighton R; Maeda, Nobuyo

    2010-01-01

    Aim Both hyperglycemia and hyperlipidemia increase oxidative stress, and contribute to the development of diabetic nephropathy (DN). We investigated effects of α-lipoic acid, a natural antioxidant and a cofactor in the multienzyme complexes, on the development of DN in diabetic apolipoprotein E-deficient mice. Methods Twelve-weeks-old male apoE−/− mice on C57BL/6J genetic background were made diabetic with injections of streptozotocin (STZ). STZ-treated diabetic apoE−/− mice and non-diabetic control were fed with a synthetic high fat (HF) diet with or without LA supplementation. Multiple parameters including plasma glucose, cholesterol, oxidative stress markers, cytokines, and kidney cortex gene expression, and glomerular morphology were evaluated. Results LA supplementation markedly protected the beta cells and reduced cholesterol levels, attenuated albuminuria and glomerular mesangial expansion in the diabetic mice. Reno-protection by LA was equally effective regardless of whether the dietary supplementation was started 4 weeks before, simultaneously with, or 4 weeks after the induction of diabetes by STZ. LA supplementation significantly improved DN and oxidative stress in the diabetic mice. Severity of albuminuria was positively correlated with level of thiobarbituric acid reactive substances (TBARs) in the kidney (r2=0.62, P<0.05). Diabetes significantly changed the kidney expression of Rage, Sod2, Tgfb1 and Ctgf, Pdp2, nephrin and Lias. LA supplementation corrected these changes except that it further suppressed the expression of the Lias gene coding for lipoic acid synthase. Conclusions Our data indicate that LA supplementation effectively attenuates the development and progression of DN through its antioxidant effect as well as enhancing glucose oxidation. PMID:20801062

  14. Protective effect of hexane extracts of Uncaria sinensis against photothrombotic ischemic injury in mice.

    PubMed

    Park, Sun Haeng; Kim, Ji Hyun; Park, Se Jin; Bae, Sun Sik; Choi, Young Whan; Hong, Jin Woo; Choi, Byung Tae; Shin, Hwa Kyoung

    2011-12-08

    Uncaria sinensis (US) has been used in traditional Korean medicine to treat vascular disease and to relieve various neurological symptoms. Scientific evidence related to the effectiveness or action mechanism of US on cerebrovascular disease has not been examined experimentally. Here, we investigated the cerebrovascular protective effect of US extracts on photothrombotic ischemic injury in mice. US hexane extracts (HEUS), ethyl acetate extracts (EAEUS) and methanol extracts (MEUS) were administered intraperitoneally 30 min before ischemic insults. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, neurological score and the activation of Akt and eNOS in ischemic brain. HEUS more significantly reduced infarct volume and edema than did EAEUS and MEUS following photothrombotic cortical occlusion. HEUS produced decreased infarct volume and edema size, and improved neurological function in a concentration-dependent manner (10, 50, and 100 mg/kg). However, HEUS did not reduce brain infarction in eNOS KO mice, suggesting that the protective effect of HEUS is primarily endothelium-dependent. Furthermore, HEUS (10-300 μg/ml) produced a concentration-dependent relaxation in mouse aorta and rat basilar artery, which was not seen in eNOS KO mouse aorta, suggesting that HEUS cause vasodilation via an eNOS-dependent mechanism. This correlated with increased phosphorylation of Akt and eNOS in the brains of HEUS-treated mice. HEUS prevent cerebral ischemic damage by regulating Akt/eNOS signaling. US, herbal medicine, may be the basis of a novel strategy for the therapy of stroke. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  15. Prophage Lysin Ply30 Protects Mice from Streptococcus suis and Streptococcus equi subsp. zooepidemicus Infections

    PubMed Central

    Tang, Fang; Li, Dezhi; Wang, Haojin; Ma, Zhe; Lu, Chengping

    2015-01-01

    Streptococcus suis and Streptococcus equi subsp. zooepidemicus are capable of infecting humans and various animals, causing significant problems for the worldwide swine industry. As antibiotic resistance has increased, lysosomal enzymes encoded by phages have shown potential for use against pathogenic bacteria. In this study, a novel bacteriophage lysin, Ply30, encoded by the S. suis prophage phi30c, was recombinantly expressed and purified. Ply30 showed high bacteriolysis activity on S. suis and S. equi subsp. zooepidemicus in vitro. The ratio of the optical density at 600 nm (OD600) with treatment versus the OD600 with no treatment for most tested S. suis and S. equi subsp. zooepidemicus strains decreased from 1 to <0.3 and <0.5, respectively, within 1 h. The results of plate viability assays showed that treated bacteria suffered a 1- to 2-log decrease in CFU within 1 h. The optimal concentration of Ply30 was 50 μg/ml, and the optimal pH was 7. Moreover, Ply30 maintained high activity over a wide pH range (pH 6 to 10). The MICs of Ply30 against Streptococcus strains ranged from 16 to 512 μg/ml. In vivo, a 2-mg dose of Ply30 protected 90% (9/10 mice) of mice from infection with S. equi subsp. zooepidemicus and 80% (8/10 mice) of mice from infection with S. suis. Seven days after lysin Ply30 treatment, bacterial loads were significantly decreased in all tested organs and blood compared with those at 1 h postinfection without Ply30 treatment. Ply30 showed in vitro and in vivo antimicrobial efficiency and protected mice against two kinds of bacterial infections, indicating that Ply30 may be an effective therapeutic against streptococci. PMID:26253669

  16. Prophage lysin Ply30 protects mice from Streptococcus suis and Streptococcus equi subsp. zooepidemicus infections.

    PubMed

    Tang, Fang; Li, Dezhi; Wang, Haojin; Ma, Zhe; Lu, Chengping; Dai, Jianjun

    2015-11-01

    Streptococcus suis and Streptococcus equi subsp. zooepidemicus are capable of infecting humans and various animals, causing significant problems for the worldwide swine industry. As antibiotic resistance has increased, lysosomal enzymes encoded by phages have shown potential for use against pathogenic bacteria. In this study, a novel bacteriophage lysin, Ply30, encoded by the S. suis prophage phi30c, was recombinantly expressed and purified. Ply30 showed high bacteriolysis activity on S. suis and S. equi subsp. zooepidemicus in vitro. The ratio of the optical density at 600 nm (OD600) with treatment versus the OD600 with no treatment for most tested S. suis and S. equi subsp. zooepidemicus strains decreased from 1 to <0.3 and <0.5, respectively, within 1 h. The results of plate viability assays showed that treated bacteria suffered a 1- to 2-log decrease in CFU within 1 h. The optimal concentration of Ply30 was 50 μg/ml, and the optimal pH was 7. Moreover, Ply30 maintained high activity over a wide pH range (pH 6 to 10). The MICs of Ply30 against Streptococcus strains ranged from 16 to 512 μg/ml. In vivo, a 2-mg dose of Ply30 protected 90% (9/10 mice) of mice from infection with S. equi subsp. zooepidemicus and 80% (8/10 mice) of mice from infection with S. suis. Seven days after lysin Ply30 treatment, bacterial loads were significantly decreased in all tested organs and blood compared with those at 1 h postinfection without Ply30 treatment. Ply30 showed in vitro and in vivo antimicrobial efficiency and protected mice against two kinds of bacterial infections, indicating that Ply30 may be an effective therapeutic against streptococci. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  17. Lactobacillus rhamnosus GG Protects against Non-Alcoholic Fatty Liver Disease in Mice

    PubMed Central

    Ritze, Yvonne; Bárdos, Gyöngyi; Claus, Anke; Ehrmann, Veronika; Bergheim, Ina; Schwiertz, Andreas; Bischoff, Stephan C.

    2014-01-01

    Objective Experimental evidence revealed that obesity-associated non-alcoholic fatty liver disease (NAFLD) is linked to changes in intestinal permeability and translocation of bacterial products to the liver. Hitherto, no reliable therapy is available except for weight reduction. Within this study, we examined the possible effect of the probiotic bacterial strain Lactobacillus rhamnosus GG (LGG) as protective agent against experimental NAFLD in a mouse model. Methods Experimental NAFLD was induced by a high-fructose diet over eight weeks in C57BL/J6 mice. Fructose was administered via the drinking water containing 30% fructose with or without LGG at a concentration resulting in approximately 5×107 colony forming units/g body weight. Mice were examined for changes in small intestinal microbiota, gut barrier function, lipopolysaccharide (LPS) concentrations in the portal vein, liver inflammation and fat accumulation in the liver. Results LGG increased beneficial bacteria in the distal small intestine. Moreover, LGG reduced duodenal IκB protein levels and restored the duodenal tight junction protein concentration. Portal LPS (P≤0.05) was reduced and tended to attenuate TNF-α, IL-8R and IL-1β mRNA expression in the liver feeding a high-fructose diet supplemented with LGG. Furthermore liver fat accumulation and portal alanine-aminotransferase concentrations (P≤0.05) were attenuated in mice fed the high-fructose diet and LGG. Conclusions We show for the first time that LGG protects mice from NAFLD induced by a high-fructose diet. The underlying mechanisms of protection likely involve an increase of beneficial bacteria, restoration of gut barrier function and subsequent attenuation of liver inflammation and steatosis. PMID:24475018

  18. Immunoregulatory activity by daucosterol, a beta-sitosterol glycoside, induces protective Th1 immune response against disseminated Candidiasis in mice.

    PubMed

    Lee, Jue-Hee; Lee, Ju Young; Park, Ji Hye; Jung, Hye Sil; Kim, Ju Sun; Kang, Sam Sik; Kim, Yeong Shik; Han, Yongmoon

    2007-05-10

    In the present study, we investigated immunomodulatory effect of daucosterol, a beta-sitosterol glycoside, against disseminated candidiasis caused by Candida albicans. Results showed that direct interaction of daucosterol with C. albicans yeast cells resulted in no growth-inhibition by in vitro susceptibility analysis. In contrast, mice given daucosterol (DS) intraperitoneally before intravenous challenge with live C. albicans yeast cells survived longer than DS-untreated control mice against disseminated candidiasis (P<0.05). By assessment of the fungal CFU in kidneys, DS-treated mice before the challenge developed about 81% fewer kidney CFU than untreated controls. This protection was removable by pretreatment of mice with anti-CD4+ antibody before the DS-treatment and challenge with the yeast. However, the protection was transferable by the CD4+ T cells from DS-treated mice not infected with the yeast. ELISA analysis revealed there were predominant production of IFNgamma and IL-2 cytokines as compared to IL-4, and IL-10 productions in DS-treated mice. By treatment of DS-given mice with anti-mouse IFNgamma, the protection was also abolished. Our studies show that DS protects mice against disseminated candidiasis by the CD4+ Th1 immune response.

  19. Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice.

    PubMed

    Singh, Anant; Kumar, Anil

    2008-04-01

    Sleep deprivation is considered as a risk factor for various diseases. Sleep deprivation leads to behavioral, hormonal, neurochemical and biochemical alterations in the animals. The present study was designed to explore the possible involvement of GABAergic mechanism in protective effect of alprazolam against 72h sleep deprivation-induced behavior alterations and oxidative damage in mice. In the present study, sleep deprivation caused anxiety-like behavior, weight loss, impaired ambulatory movements and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep-deprived mice brain. Treatment with alprazolam (0.25 and 0.5 mg/kg, ip) significantly improved behavioral alterations. Biochemically, alprazolam treatment significantly restored depleted reduced glutathione, catalase activity, reversed raised lipid peroxidation and nitrite level. Combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of alprazolam (0.25mg/kg) significantly antagonized protective effect of alprazolam. However, combination of muscimol (0.05 mg/kg) with alprazolam (0.25 mg/kg, ip) potentiated protective effect of alprazolam. On the basis of these results, it might be suggested that alprazolam might produce protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.

  20. Intranasal administration of live Lactobacillus species facilitates protection against influenza virus infection in mice.

    PubMed

    Youn, Ha-Na; Lee, Dong-Hun; Lee, Yu-Na; Park, Jae-Keun; Yuk, Seong-Su; Yang, Si-Yong; Lee, Hyun-Jeong; Woo, Seo-Hyung; Kim, Hyoung-Moon; Lee, Joong-Bok; Park, Seung-Yong; Choi, In-Soo; Song, Chang-Seon

    2012-01-01

    Influenza virus infections continue to be a significant public health problem. For improved therapies and preventive measures against influenza, there has been an increased tendency in modern medicine involving the use of probiotics. In this study, we compared the protective efficacy of various live and dead Lactobacillus species against challenge with influenza virus in mice according to the administration route and dose. In addition, to understand the underlying mechanism behind this clinical protective effect, we performed immunologic assays including examination of IgA levels and cytokine profiles in the lung. The survival rate of mice receiving intranasal administration of Lactobacillus was higher than after oral administration, and administration of live bacteria was more protective than of dead bacteria. The lung levels of interleukin (IL)-12 and IgA were significantly increased (P<0.05). Conversely, the levels of the pro-inflammatory cytokines tumor necrosis factor-alpha and IL-6 were decreased. Interestingly, there were huge differences in protective effects of various Lactobacillus strains on influenza virus infection. Therefore, for clinical applications, selection of effective strains could be critical and individually optimized application regimens of the selected strains are required. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Targeting of rotavirus VP6 to DEC-205 induces protection against the infection in mice.

    PubMed

    Badillo-Godinez, O; Gutierrez-Xicotencatl, L; Plett-Torres, T; Pedroza-Saavedra, A; Gonzalez-Jaimes, A; Chihu-Amparan, L; Maldonado-Gama, M; Espino-Solis, G; Bonifaz, L C; Esquivel-Guadarrama, F

    2015-08-20

    Rotavirus (RV) is the primary etiologic agent of severe gastroenteritis in human infants. Although two attenuated RV-based vaccines have been licensed to be applied worldwide, they are not so effective in low-income countries, and the induced protection mechanisms have not been clearly established. Thus, it is important to develop new generation vaccines that induce long lasting heterotypic immunity. VP6 constitutes the middle layer protein of the RV virion. It is the most conserved protein and it is the target of protective T-cells; therefore, it is a potential candidate antigen for a new generation vaccine against the RV infection. We determined whether targeting the DEC-205 present in dendritic cells (DCs) with RV VP6 could induce protection at the intestinal level. VP6 was cross-linked to a monoclonal antibody (mAb) against murine DEC-205 (αDEC-205:VP6), and BALB/c mice were inoculated subcutaneously (s.c.) twice with the conjugated containing 1.5 μg of VP6 in the presence of polyinosinic-polycytidylic acid (Poly I:C) as adjuvant. As controls and following the same protocol, mice were immunized with ovalbumin (OVA) cross-linked to the mAb anti-DEC-205 (αDEC-205:OVA), VP6 cross-linked to a control isotype mAb (Isotype:VP6), 3 μg of VP6 alone, Poly I:C or PBS. Two weeks after the last inoculation, mice were orally challenged with a murine RV. Mice immunized with α-DEC-205:VP6 and VP6 alone presented similar levels of serum Abs to VP6 previous to the virus challenge. However, after the virus challenge, only α-DEC-205:VP6 induced up to a 45% IgA-independent protection. Memory T-helper (Th) cells from the spleen and the mesenteric lymph node (MLN) showed a Th1-type response upon antigen stimulation in vitro. These results show that when VP6 is administered parenterally targeting DEC-205, it can induce protection at the intestinal level at a very low dose, and this protection may be Th1-type cell dependent. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. A CpG Oligonucleotide Can Protect Mice From a Low Aerosol Challenge Dose of Burkholderia mallei

    DTIC Science & Technology

    2006-03-01

    may protect victims of a biological attack from glanders . Burkholderia mallei , the causative agent of glanders , natu- rally infects equines, but it can...attack from glanders . 15. SUBJECT TERMS Burkholderia mallei , glanders , oligonucleotides, CpG motif, efficacy, laboratory animals, mice 16...Society for Microbiology. All Rights Reserved. A CpG Oligonucleotide Can Protect Mice from a Low Aerosol Challenge Dose of Burkholderia mallei David M

  3. Protection of Mice against Plasmodium yoelii Sporozoite Challenge with P. yoelii Merozoite Surface Protein 1 DNA Vaccines

    PubMed Central

    Becker, Sylvia I.; Wang, Ruobing; Hedstrom, Richard C.; Aguiar, Joao C.; Jones, Trevor R.; Hoffman, Stephen L.; Gardner, Malcolm J.

    1998-01-01

    Immunization of mice with DNA vaccines encoding the full-length form and C and N termini of Plasmodium yoelii merozoite surface protein 1 provided partial protection against sporozoite challenge and resulted in boosting of antibody titers after challenge. In C57BL/6 mice, two DNA vaccines provided protection comparable to that of recombinant protein consisting of the C terminus in Freund’s adjuvant. PMID:9632624

  4. [Protective Effect of S-isopentenyl-L-cysteine against DNA Damage in Irradiated Mice].

    PubMed

    Zheng, Qi-sheng; Yu, Guang-yun; He, Xin; Jiang, Ming; Chu, Xiao-fei; Zhao, Shu-yi; Fan, Sai-jun; Liu, Pei-xun

    2015-10-01

    To evaluate the protective effect of S-isopentenyl-L-cysteine,a new cysteine derivative,on DNA damage induced by radiation by using acute radiation injury animal models. Forty ICR mice were randomly divided into five groups:the control group,1.0Gy gamma irradiation group,1.0Gy gamma irradiation combined with S-isopentenyl-L-cysteine group,7.2Gy gamma irradiation group,and 7.2Gy gamma irradiation combined with S-isopentenyl-L-cysteine group,with 8 mice in each group.The comet assay and bone marrow polychromatic micronucleus experiments were performed to evaluate the double-strand DNA breaks in ICR mice exposed to 1.0 and 7.2Gy gamma-ray, respectively. The tail DNA percentage,tail length,tail moment,and olive tail moment of peripheral blood lymphocytes in 7.2Gy gamma irradiation group were significantly higher than that of the control group (P<0.01).And it was also observed that above experimental indexes of 7.2Gy gamma irradiation combined with S-isopentenyl-L-cysteine group was significantly less than that of 7.2Gy gamma irradiation group (P<0.05). In addition,the micronucleus rate of 1.0Gy gamma irradiation group and 7.2Gy gamma irradiation group were both significantly higher than in the control group (P<0.01). In addition,in mice given S-isopentenyl-L-cysteine before irradiation,the micronucleus rate of ICR mice exposed to 1.0 and 7.2Gy gamma-ray decreased from (39.5000 ± 3.3141)‰ to (28.1667±4.1345)‰ (P=0.033) and from (76.5000 ± 4.6242)‰ to (22.8333 ± 3.6553)‰(P=0.000),respectively. The bone marrow polychromatic micronucleus experiment indicated that the value of polychromatic erythrocyte (PCE)/normochromatic erythrocyte(NCE) of ICR mice exposed to 1.0 and 7.2Gy gamma-ray was less than the control group(P<0.05). Meanwhile,after irradiating by certain dose,the value of PCE/NCE in mice given S-isopentenyl-L-cysteine before irradiation was significantly higher than the corresponding groups (P<0.05). S-isopentenyl-L-cysteine has a good protective

  5. Topical resiquimod protects against visceral infection with Leishmania infantum chagasi in mice.

    PubMed

    Craft, Noah; Birnbaum, Ron; Quanquin, Natalie; Erfe, Marie Crisel B; Quant, Cara; Haskell, Jacquelyn; Bruhn, Kevin W

    2014-09-01

    New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4(+) and CD8(+) T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  6. Topical Resiquimod Protects against Visceral Infection with Leishmania infantum chagasi in Mice

    PubMed Central

    Craft, Noah; Birnbaum, Ron; Quanquin, Natalie; Erfe, Marie Crisel B.; Quant, Cara; Haskell, Jacquelyn

    2014-01-01

    New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4+ and CD8+ T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections. PMID:25030052

  7. Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin.

    PubMed

    Müller-Redetzky, Holger C; Will, Daniel; Hellwig, Katharina; Kummer, Wolfgang; Tschernig, Thomas; Pfeil, Uwe; Paddenberg, Renate; Menger, Michael D; Kershaw, Olivia; Gruber, Achim D; Weissmann, Norbert; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

    2014-04-14

    Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia. We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation. In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1-3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p < 0.01; prevention of pulmonary restriction) and against VILI-induced liver and gut injury in pneumonia (91% reduction of AST levels p < 0.05, 96% reduction of alanine aminotransaminase (ALT) levels p < 0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut). MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically

  8. Vaccination with Recombinant Microneme Proteins Confers Protection against Experimental Toxoplasmosis in Mice.

    PubMed

    Pinzan, Camila Figueiredo; Sardinha-Silva, Aline; Almeida, Fausto; Lai, Livia; Lopes, Carla Duque; Lourenço, Elaine Vicente; Panunto-Castelo, Ademilson; Matthews, Stephen; Roque-Barreira, Maria Cristina

    2015-01-01

    Toxoplasmosis, a zoonotic disease caused by Toxoplasma gondii, is an important public health problem and veterinary concern. Although there is no vaccine for human toxoplasmosis, many attempts have been made to develop one. Promising vaccine candidates utilize proteins, or their genes, from microneme organelle of T. gondii that are involved in the initial stages of host cell invasion by the parasite. In the present study, we used different recombinant microneme proteins (TgMIC1, TgMIC4, or TgMIC6) or combinations of these proteins (TgMIC1-4 and TgMIC1-4-6) to evaluate the immune response and protection against experimental toxoplasmosis in C57BL/6 mice. Vaccination with recombinant TgMIC1, TgMIC4, or TgMIC6 alone conferred partial protection, as demonstrated by reduced brain cyst burden and mortality rates after challenge. Immunization with TgMIC1-4 or TgMIC1-4-6 vaccines provided the most effective protection, since 70% and 80% of mice, respectively, survived to the acute phase of infection. In addition, these vaccinated mice, in comparison to non-vaccinated ones, showed reduced parasite burden by 59% and 68%, respectively. The protective effect was related to the cellular and humoral immune responses induced by vaccination and included the release of Th1 cytokines IFN-γ and IL-12, antigen-stimulated spleen cell proliferation, and production of antigen-specific serum antibodies. Our results demonstrate that microneme proteins are potential vaccines against T. gondii, since their inoculation prevents or decreases the deleterious effects of the infection.

  9. Protective effects of Moringa oleifera Lam. leaves against arsenic-induced toxicity in mice

    PubMed Central

    Sheikh, Afzal; Yeasmin, Fouzia; Agarwal, Smita; Rahman, Mashiur; Islam, Khairul; Hossain, Ekhtear; Hossain, Shakhawoat; Karim, Md Rezaul; Nikkon, Farjana; Saud, Zahangir Alam; Hossain, Khaled

    2014-01-01

    Objective To evaluate the protective role of leaves of Moringa oleifera (M. oleifera) Lam. against arsenic-induced toxicity in mice. Methods Swiss albino male mice were divided into four groups. The first group was used as non-treated control group while, the second, third, and fourth groups were treated with M. oleifera leaves (50 mg/kg body weight per day), sodium arsenite (10 mg/kg body weight per day) and sodium arsenite plus M. oleifera leaves, respectively. Serum indices related to cardiac, liver and renal functions were analyzed to evaluate the protective effect of Moringa leaves on arsenic-induced effects in mice. Results It revealed that food supplementation of M. oleifera leaves abrogated the arsenic-induced elevation of triglyceride, glucose, urea and the activities of alkaline phospatase, aspartate aminotransferase and alanine aminotransferase in serum. M. oleifera leaves also prevented the arsenic-induced perturbation of serum butyryl cholinesterase activity, total cholesterol and high density lipoprotein cholesterol. Conclusions The results indicate that the leaves of M. oleifera may be useful in reducing the effects of arsenic-induced toxicity. PMID:25183111

  10. Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice.

    PubMed

    Bektur, Nuriye Ezgi; Sahin, Erhan; Baycu, Cengiz; Unver, Gonul

    2016-04-01

    This study was designed to estimate protective effects of silymarin on acetaminophen (N-acetyl-p-aminophenol, paracetamol; APAP)-induced hepatotoxicity and nephrotoxicity in mice. Treatment of mice with overdose of APAP resulted in the elevation of aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) levels in serum, liver, and kidney nitric oxide (NO) levels and significant histological changes including decreased body weight, swelling of hepatocytes, cell infiltration, dilatation and congestion, necrosis and apoptosis in liver, and dilatation of Bowman's capsular space and glomerular capillaries, pale-stained tubules epithelium, cell infiltration, and apoptosis in kidney. Posttreatment with silymarin 1 h after APAP injection for 7 days, however, significantly normalized the body weight, histological damage, serum ALT, AST, BUN, SCr, and tissue NO levels. Our observation suggested that silymarin ameliorated the toxic effects of APAP-induced hepatotoxicity and nephrotoxicity in mice. The protective role of silymarin against APAP-induced damages might result from its antioxidative and anti-inflammatory effects. © The Author(s) 2013.

  11. Conditioned medium from Bifidobacteria infantis protects against Cronobacter sakazakii-induced intestinal inflammation in newborn mice

    PubMed Central

    Weng, Meiqian; Ganguli, Kriston; Zhu, Weishu; Shi, Hai Ning

    2014-01-01

    Necrotizing enterocolitis (NEC) is associated with a high morbidity and mortality in very low birth weight infants. Several hypotheses regarding the pathogenesis of NEC have been proposed but to date no effective treatment is available. Previous studies suggest that probiotic supplementation is protective. We recently reported that probiotic (Bifidobacterium infantis) conditioned medium (PCM) has an anti-inflammatory effect in cultured fetal human intestinal cells (H4) and fetal intestine explants. In this study, we tested in vivo whether PCM protects neonatal mice from developing intestinal inflammation induced by exposure to Cronobacter sakazakii (C. sakazakii), an opportunistic pathogen associated with NEC. We found that infected neonatal mice had a significantly lower body weight than control groups. Infection led to ileal tissue damage including villous rupture, disruption of epithelial cell alignment, intestinal inflammation, apoptotic cell loss, and decreased mucus production. Pretreatment with PCM prevented infection caused decrease in body weight, attenuated enterocyte apoptotic cell death, mitigated reduced mucin production, and maintained ileal structure. Infected ileum expressed reduced levels of IκBα, which could be restored upon pretreatment with PCM. We also observed a nuclear translocation of NF-κB p65 in H4 cells exposed to C. sakazakii, which was prevented in PCM-pretreated cells. Finally, treatment of neonatal mice with PCM prior to infection sustained the capacity of ileal epithelial proliferation. This study suggests that an active component(s) released into the culture medium by B. infantis may prevent ileal damage by a pathogen linked to NEC. PMID:24627567

  12. Protective Effects of Apigenin Against Paraquat-Induced Acute Lung Injury in Mice.

    PubMed

    Luan, Rui-Ling; Meng, Xiang-Xi; Jiang, Wei

    2016-04-01

    This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress.

  13. Protective effect of kombucha mushroom (KM) tea on phenol-induced cytotoxicity in albino mice.

    PubMed

    Yapar, Kursad; Cavusoglu, Kultigin; Oruc, Ertan; Yalcin, Emine

    2010-09-01

    The present study was carried out to evaluate the protective role of kombucha mushroom (KM) tea on cytotoxicity induced by phenol (PHE) in mice. We used weight gain and micronucleus (MN) frequency as indicators of cytotoxicity and supported these parameters with pathological findings. The animals were randomly divided into seven groups: (Group I) only tap water (Group II) 1000 microl kg(-1) b. wt KM-tea, (Group III) 35 mg kg(-1) body wt. PHE (Group IV) 35 mg kg(-1) body wt. PHE + 250 microl kg(-1) b. wt KM-tea (Group V) 35 mg kg(-1) b. wt PHE + 500 microl kg(-1) b. wt KM-tea (Group VI) 35 mg kg(-1) b. wt PHE + 750 microl kg(-1) b. wt KM-tea, (Group VII) 35 mg kg(-1) b. wt PHE + 1000 microl kg(-1) b. wt KM-tea, for 20 consecutive days by oral gavage. The results indicated that all KM-tea supplemented mice showed a lower MN frequency than erythrocytes in only PHE-treated group. There was an observable regression on account of lesions in tissues of mice supplemented with different doses of KM-tea in histopathological observations. In conclusion, the KM-tea supplementation decreases cytotoxicity induced by PHE and its protective role is dose-dependent.

  14. Protease-deficient herpes simplex virus protects mice from lethal herpesvirus infection.

    PubMed Central

    Hippenmeyer, P J; Rankin, A M; Luckow, V A; Neises, G R

    1997-01-01

    Null mutants and attenuated mutants of herpes simplex virus (HSV) have been shown to induce immunity against challenge from wild-type virus. Null viruses with a defect in late gene products would be expected to express more viral genes than viruses with defects in essential early gene products and thus induce a better immune response. Herpesviruses encode a late gene product (serine protease) that is autocatalytic and cleaves the capsid assembly protein during viral replication. To determine whether a virus with a mutation in this gene could induce immunity, we constructed a recombinant virus containing the gusA reporter gene in the protease domain of the HSV type 1 UL26 open reading frame (ORF). Consistent with previous results (M. Gao, L. Matusick-Kumar, W. Hurlburt, S. F. DiTusa, W. W. Newcomb, J. C. Brown, P. J. McCann, I. Deckman, and R. J. Colonno, J. Virol. 68:3702-3712, 1994), recombinant virus could be isolated only from helper cell lines expressing the product of the UL26 ORF. Mice inoculated with the recombinant virus were unaffected by doses of virus that were lethal to mice infected with wild-type virus. Mice which were previously inoculated with the recombinant virus were also protected by a subsequent challenge with wild-type virus in a dose-dependent manner. These results indicate that recombinant viruses lacking the protease gene are avirulent but render protection from subsequent challenge. PMID:8995617

  15. Protective effects of magnesium supplementation on metabolic energy derangements in lipopolysaccharide-induced cardiotoxicity in mice.

    PubMed

    Ahmed, Lamiaa A

    2012-11-05

    Metabolic derangements and bioenergetic failure are major contributors to sepsis-induced multiple organ dysfunctions. Due to the well known role of magnesium (Mg) as a cofactor in many enzymatic reactions that involve energy creation and utilization, the present investigation was directed to estimate the cardioprotective effect of Mg supplementation in lipopolysaccharide (LPS)-induced metabolic energy changes in mice. Oral doses of Mg aspartate (20 or 40 mg/kg) were administered once daily for 7 day. Mice were then subjected to a single intraperitoneal injection of LPS (2 mg/kg). Plasma was separated 3 h after LPS injection for determination of creatine kinase-MB activity. Animals were then sacrificed and the hearts were separated for estimation of tissue thiobarbituric acid reactive substances, reduced glutathione, lactate, pyruvate, adenine nucleotides, creatine phosphate and cardiac Na(+),K(+)-ATPase activity. Finally, electron microscopic examination was performed to visualize the protective effects of Mg pretreatment on mitochondrial ultrastructure. In general, the higher dose of Mg was more effective than the lower dose in ameliorating creatine kinase-MB elevation and the state of oxidative stress, lactate accumulation, pyruvate reduction as well as preserving creatine phosphate, adenine nucleotides and Na(+),K(+)-ATPase activity. Moreover, the higher dose of Mg provided a significant cardioprotection against the mitochondrial ultrastructural changes. Mg therapy can afford a significant protection against metabolic energy derangements and mitochondrial ultrastructural changes induced by LPS cardiotoxicity in mice. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice

    PubMed Central

    Zhang, Yu-Jie; Xu, Dong-Ping; Wang, Fang; Zhou, Yue; Zheng, Jie; Li, Ya; Zhang, Jiao-Jiao

    2017-01-01

    Chronic excessive alcohol consumption (more than 40–80 g/day for males and more than 20–40 g/day for females) could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG) contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT), aspartate transaminase (AST), hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity. PMID:28567423

  17. Chlorogenic acid protects mice against lipopolysaccharide-induced acute lung injury.

    PubMed

    Zhang, Xu; Huang, Huang; Yang, Tingting; Ye, Yin; Shan, Jianhua; Yin, Zhimin; Luo, Lan

    2010-07-01

    Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in human diet. Our previous in vitro study demonstrates that CGA presents anti-inflammatory activities in RAW 264.7 cells. Here we show that CGA protects mice against lipopolysaccharide (LPS)-induced acute lung injury (ALI). We treated mice with CGA (5, 20 and 50 mg/kg body weight) 30 min or 3 h after intratracheal administration of LPS. The histological results showed that CGA, at dose of 50 mg/kg, protected mice from LPS-induced ALI which displayed by edema, haemorrhage, blood vessel and alveolar structural damage. CGA inhibited LPS-increased pulmonary MPO activity and migration of polymorphonuclear neutrophils (PMNs) into bronchoalveolar lavage fluid (BALF). Furthermore, CGA markedly decreased the activity of inducible nitric oxide synthase (iNOS) in lung tissues and thus prevented nitric oxide (NO) release in response to LPS challenge. In conclusion, these results indicated that CGA was greatly effective in inhibiting ALI and might act as a potential therapeutic reagent for treating ALI in the future. 2010 Elsevier Ltd. All rights reserved.

  18. Protective effects of escin against indomethacin-induced gastric ulcer in mice.

    PubMed

    Wang, Tian; Zhao, Shanshan; Wang, Yucun; Yang, Yujiao; Yao, Le; Chu, Liuxiang; Du, Hanhan; Fu, Fenghua

    2014-12-01

    Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18 mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8 mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6 h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.

  19. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice.

    PubMed

    Zhou, Tong; Zhang, Yu-Jie; Xu, Dong-Ping; Wang, Fang; Zhou, Yue; Zheng, Jie; Li, Ya; Zhang, Jiao-Jiao; Li, Hua-Bin

    2017-01-01

    Chronic excessive alcohol consumption (more than 40-80 g/day for males and more than 20-40 g/day for females) could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG) contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT), aspartate transaminase (AST), hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

  20. The possible protective effect of L-carnitine on tilmicosin-induced cardiotoxicity in mice.

    PubMed

    Kart, A; Yapar, K; Karapehlivan, M; Citil, M

    2007-04-01

    The protective effect of L-carnitine was investigated against tilmicosin-induced cardiotoxic effects including blood creatine kinase (CK), CK-MB, total sialic acid as well as the alterations in glutathione and malondialdehyde concentrations in mice. Thirty-two Balb/C mice were divided into four groups including group 1 (control), group 2 (L-carnitine, s.c., 500 mg/kg for 5 days), group 3 (tilmicosin, s.c., single dose of 75 mg/kg) and group 4 (L-carnitine plus tilmicosin). Serum CK, CK-MB and malondialdehyde (MDA) levels were significantly (P < 0.05) higher in group 3 compared with those of other groups. Total sialic acid level in group 3 was found to be significantly (P < 0.05) higher than that in groups 1 and 2, as well. Contrary to these results, glutathione level in group 3 was found to be significantly (P < 0.05) lower than that in groups 1 and 2. In group 4, serum CK, CK-MB, MDA and total sialic acid levels were found to be significantly (P < 0.05) lower than those in group 3. These results suggest that tilmicosin is cardiotoxic in mice as evidenced by higher total sialic acid, CK and CK-MB. In addition, tilmicosin caused the decrease in glutathione and increase in MDA levels. However, administration of L-carnitine could ameliorate these adverse toxic effects of tilmicosin in mice.

  1. Protective effects of osthole on intestinal ischemia-reperfusion injury in mice.

    PubMed

    Zhang, Zhen; Pan, Chen; Wang, Hong-zhi; Li, Yong-xiang

    2014-06-01

    The purpose of this study was to evaluate the effect of intravenous injection of osthole on intestinal ischemia-reperfusion injury and parameters of oxidative stress. In 45 Kunming male mice, treatment included sham surgery (15 mice); intestinal ischemia-reperfusion injury (clamping of the superior mesenteric artery, 2 h; clamp release, 1 h; 15 mice); or osthole treatment before and after ischemia-reperfusion injury (15 mice). Evaluation included histopathology, determination of intestinal wet/dry weight ratio, and measurement of levels of diamine oxidase, superoxide dismutase, malondialdehyde, interleukin 1β, tumor necrosis factor α, and interleukin 2. Intestinal barrier permeability was evaluated with Evans blue test. The mean wet-to-dry weight ratio, Evans blue content, and Chiu score were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than the ischemia-reperfusion group. The mean serum diamine oxidase, malondialdehyde, interleukin 1β, and tumor necrosis factor α levels were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than in the ischemia-reperfusion group. The mean superoxide dismutase activity and interleukin 2 levels were lower in the ischemia-reperfusion than in the sham group and greater in the osthole-treated than in the ischemia-reperfusion group. Treatment with osthole may protect against oxidative stress and tissue damage from intestinal ischemia-reperfusion injury.

  2. Protective effect of mango (Mangifera indica L.) against UVB-induced skin aging in hairless mice.

    PubMed

    Song, Jae Hyoung; Bae, Eun Young; Choi, Goya; Hyun, Jin Won; Lee, Mi Young; Lee, Hye Won; Chae, Sungwook

    2013-04-01

    Mangifera indica L. (Anacardiaceae) is a medicinal plant whose extracts have been described as an antioxidant with anti-inflammatory and immunomodulatory activities. Skin aging is a consequence of chronic sun exposure to the sun and therefore ultraviolet (UV) radiation. Naturally occurring antioxidants are known to reduce skin aging. Therefore, the aim of the present study was to evaluate the protective role of mango extract against UVB-induced skin aging in hairless mice. HR-1 hairless male mice (6 weeks old) were divided into three groups: control (n = 5), UVB-treated vehicle (n = 5), and UVB-treated mango extract (n = 5) groups. UVB-irradiated mice from the mango extract group were orally administered 0.1 ml of water containing 100 mg of mango extract/kg body weight per day. The inhibitory activity of mango extract on wrinkle formation was determined by the analysis of the skin replica, epidermal thickness based on histological examination, and damage to collagen fiber. The mean length of wrinkles in UVB-treated vehicle group significantly improved after the oral administration of mango extract, which significantly inhibited the increase in epidermal thickness and epidermal hypertrophy (P < 0.05). Furthermore, a marked increase in collagen bundles was observed in the UVB-treated group after the administration of mango extract by Masson's trichrome staining. These results indicate that mango extract showed anti-photoaging activity in UVB-irradiated hairless mice. © 2013 John Wiley & Sons A/S.

  3. Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice.

    PubMed

    Martinez, Elisa C; Garg, Ravendra; Shrivastava, Pratima; Gomis, Susantha; van Drunen Littel-van den Hurk, Sylvia

    2016-11-01

    Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and young children. There are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Immunomodulation mediated by a novel formulation consisting of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene (P-I-P) was evaluated in the context of lethal infection with pneumonia virus of mice (PVM). Intranasal delivery of a single dose of P-I-P protected adult mice against PVM when given 24 h prior to challenge. These animals experienced minimal weight loss, no clinical disease, 100% survival, and reduced lung pathology. Similar clinical outcomes were observed in mice treated up to 3 days prior to infection. P-I-P pre-treatment induced early mRNA and protein expression of key chemokine and cytokine genes, reduced the recruitment of neutrophils and eosinophils, decreased virus titers in the lungs, and modulated the delayed exacerbated nature of PVM disease without any short-term side effects. On day 14 post-infection, P-I-P-treated mice were confirmed to be PVM-free. These results demonstrate the capacity of this formulation to prevent PVM and possibly other viral respiratory infections. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. [Protective effect of purple sweet potato flavonoids on CCL4-induced acute liver injury in mice].

    PubMed

    Ye, Shuya; Li, Xiangrong; Shao, Yingying

    2013-11-01

    To investigate the protective effect of purple sweet potato flavonoids (PSPF) on CCl4-induced acute liver injury in mice. Sixty mice were randomly divided into six groups (n=10 in each): blank group, model group, PSPF groups (400 mg*kg(-1), 200 mg*kg-1 and 100 mg*kg(-1)) and positive control group (DDB 150 mg*kg(-1)). Acute liver injury was induced by administration of peanut oil with 0.1% CCl4 (10 mg*kg(-1)) in mice. The viscera index, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured, and the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA) in hepatic tissues were also measured. The pathological changes of liver were observed with microscopy. PSPF significantly decreased serum ALT, AST and LDH levels (P<0.05 or P<0.01) and MDA content in hepatic tissues (P<0.01), increased the activities of SOD (P<0.01). Purple sweet potato total flavonoids can prevent CCl4-induced acute liver injury in mice, which may be related to inhibition of lipid peroxidation and reduction of oxygen free radicals.

  5. Mitochondrial anti-oxidant protects IEX-1 deficient mice from organ damage during endotoxemia

    PubMed Central

    Ramsey, Haley; Wu, Mei X.

    2015-01-01

    Sepsis, a leading cause of mortality in intensive care units worldwide, is often a result of overactive and systemic inflammation following serious infections. We found that mice lacking immediate early responsive gene X-1 (IEX-1) were prone to lipopolysaccharide (LPS) -induced endotoxemia. A nonlethal dose of LPS provoked numerous aberrations in IEX-1 knockout (KO) mice including pancytopenia, increased serum aspartate aminotransferase (AST), and lung neutrophilia, concurrent with liver and kidney damage, followed by death. Given these results, in conjunction with a proven role for IEX-1 in the regulation of reactive oxygen species (ROS) homeostasis during stress, we pre-treated IEX-1 KO mice with Mitoquinone (MitoQ), a mitochondrion-based antioxidant prior to LPS injection. The treatment significantly reduced ROS formation in circulatory cells and protected against pancytopenia and multiple organ failure, drastically increasing the survival rate of IEX-1 KO mice challenged by this low dose of LPS. This study confirms significant contribution of mitochondrial ROS to the etiology of sepsis. PMID:25466275

  6. Administration of kefir-fermented milk protects mice against Giardia intestinalis infection.

    PubMed

    Franco, Mariana Correa; Golowczyc, Marina A; De Antoni, Graciela L; Pérez, Pablo F; Humen, Martín; Serradell, María de los Angeles

    2013-12-01

    Giardiasis, caused by the protozoan Giardia intestinalis, is one of the most common intestinal diseases worldwide and constitutes an important problem for the public health systems of various countries. Kefir is a probiotic drink obtained by fermenting milk with 'kefir grains', which consist mainly of bacteria and yeasts that coexist in a complex symbiotic association. In this work, we studied the ability of kefir to protect mice from G. intestinalis infection, and characterized the host immune response to this probiotic in the context of the intestinal infection. Six- to 8-week-old C75BL/6 mice were separated into four groups: controls, kefir mice (receiving 1 : 100 dilution of kefir in drinking water for 14 days), Giardia mice (infected orally with 4×10(7) trophozoites of G. intestinalis at day 7) and Giardia-kefir mice (kefir-treated G. intestinalis-infected mice), and killed at 2 or 7 days post-infection. Kefir administration was able to significantly reduce the intensity of Giardia infection at 7 days post-infection. An increase in the percentage of CD4(+) T cells at 2 days post-infection was observed in the Peyer's patches (PP) of mice belonging to the Giardia group compared with the control and kefir groups, while the percentage of CD4(+) T cells in PP in the Giardia-kefir group was similar to that of controls. At 2 days post-infection, a reduction in the percentage of B220-positive major histocompatibility complex class II medium cells in PP was observed in infected mice compared with the other groups. At 7 days post-infection, Giardia-infected mice showed a reduction in RcFcε-positive cells compared with the control group, suggesting a downregulation of the inflammatory response. However, the percentages of RcFcε-positive cells did not differ from controls in the kefir and Giardia-kefir groups. An increase in IgA-positive cells was observed in the lamina propria of the kefir group compared with controls at 2 days post-infection. Interestingly, the

  7. Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis.

    PubMed

    Xin, Hong

    2016-01-04

    We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Active Immunizations with Peptide-DC Vaccines and Passive Transfer with Antibodies Protect Neutropenic Mice against Disseminated Candidiasis

    PubMed Central

    Xin, Hong

    2015-01-01

    We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. PMID:26620842

  9. Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice.

    PubMed

    Rahimian, Reza; Zirak, Mohammad Reza; Seyedabadi, Mohammad; Keshavarz, Mojtaba; Rashidian, Amir; Kazmi, Sareh; Jafarian, Amir Hossein; Karimi, Gholamreza; Mousavizadeh, Kazem

    2017-09-01

    Acute pancreatitis (AP) causes morbidity and mortality. The aim of the present study was to investigate the protective effect of tropisetron against AP induced by cerulein. Cerulein (50μg/kg, 5 doses) was used to induce AP in mice. Six hours after final cerulein injection, animals were decapitated. Hepatic/pancreatic enzymes in the serum, pancreatic content of malondialdehyde (MDA), pro-inflammatory cytokines and myeloperoxidase (MPO) activity were measured. Tropisetron significantly attenuated pancreatic injury markers and decreased the amount of elevated serum amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MPO activities and pro-inflammatory cytokines levels caused by AP in mice. Tropisetron didn't affect the pancreatic levels of MDA. Our results suggest that tropisetron could attenuate cerulein-induced AP by combating inflammatory signaling. Further clinical studies are needed to confirm its efficacy in patients with AP. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Cross-protection against Salmonella enteritidis infection in mice. III. Delayed hypersensitivity reaction and clearance of the challenge organism.

    PubMed

    Padmanaban, V D; Mittal, K R

    1979-01-01

    Mice were immunized with live vaccines and with live vaccines with complete adjuvant incorporating Salmonella enteritidis, Salmonella typhi-murium, Salmonella gallinarum or Salmonella pullorum. On the 21st day after vacination, the hypersensitivity reactions elicited by the mice to extracts of the challenge organism (S. enteritidis 5694 SMR) were assessed. The degree of delayed hypersensitivity reaction was compared with the level of protection induced by the vaccine. The role in protection of delayed hypersensitivity is discussed. Clearance of the challenge organism from the liver of previously vaccinated and unvaccinated mice was assessed quantitatively.

  11. Loss of 5‐lipoxygenase activity protects mice against paracetamol‐induced liver toxicity

    PubMed Central

    Pu, Shiyun; Ren, Lin; Liu, Qinhui; Kuang, Jiangying; Shen, Jing; Cheng, Shihai; Zhang, Yuwei; Jiang, Wei; Zhang, Zhiyong; Jiang, Changtao

    2015-01-01

    Background and Purpose Paracetamol (acetaminophen) is the most widely used over‐the‐counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5‐Lipoxygenase (5‐LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5‐LO could protect mice against paracetamol‐induced hepatic toxicity. Experimental Approach Both genetic deletion and pharmacological inhibition of 5‐LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real‐time PCR were used to assess liver toxicity. Key Results Deletion or pharmacological inhibition of 5‐LO in mice markedly ameliorated paracetamol‐induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5‐LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro‐toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5‐LO−/− mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5‐LO−/− mice. Conclusions and Implications The activity of 5‐LO may play a critical role in paracetamol‐induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. PMID:26398229

  12. Physical exercise protects against Alzheimer's disease in 3xTg-AD mice.

    PubMed

    García-Mesa, Yoelvis; López-Ramos, Juan Carlos; Giménez-Llort, Lydia; Revilla, Susana; Guerra, Rafael; Gruart, Agnès; Laferla, Frank M; Cristòfol, Rosa; Delgado-García, José M; Sanfeliu, Coral

    2011-01-01

    Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.

  13. Immunogenicity and protective efficacy of recombinant iron superoxide dismutase protein from Bordetella pertussis in mice models.

    PubMed

    Yılmaz, Çiğdem; Apak, Aycan; Özcengiz, Erkan; Özcengiz, Gülay

    2016-11-01

    Whooping cough (pertussis) is a highly contagious respiratory infection caused by Bordetella pertussis. Although availability of effective pertussis vaccines reportedly decreases the incidence of the disease, B. pertussis circulation in populations has not been eliminated. Thus, it is necessary to find new protein candidates with greater immune protective capacities than the currently available acellular pertussis vaccines. In this study, iron superoxide dismutase (FeSOD) gene (sodB) was cloned, expressed in Escherichia coli and recombinant FeSOD protein thence purified. The recombinant protein (rFeSOD) was formulated with aluminum hydroxide (Alum) or monophosphoryl lipid A (MPLA) and injected intraperitoneally to immunize mice, after which IgG1, IgG2a and IFN-γ titers were measured to assess humoral and cellular responses, respectively, to these immunizations. The extent of bacterial colonization in lungs of intranasally challenged mice was determined 5, 8 and 14 days post-challenge. IgG1 and IgG2a responses were significantly stronger in mice that had been immunized with rFeSOD-MPLA than in those that had received rFeSOD-Alum (P < 0.05). Additionally, IgG2a titers were higher in mice vaccinated with recombinant protein FeSOD (rFeSOD) formulated with MPLA, especially after the second immunization. Immunization with rFeSOD-MPLA also provided a modest, but significant decrease in bacterial counts in lungs of mice (P < 0.05). Antigen specific-IFN-γ responses were significantly stronger in the group vaccinated with rFeSOD-MPLA, which could account for the lower bacterial counts. These findings suggest that rFeSOD protein formulated with MPLA has potential as an acellular pertussis vaccine candidate component. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

  14. Protective immunity conferred by porcine circovirus 2 ORF2-based DNA vaccine in mice.

    PubMed

    Sylla, Seydou; Cong, Yan-Long; Sun, Yi-Xue; Yang, Gui-Lian; Ding, Xue-Mei; Yang, Zhan-Qing; Zhou, Yu-Long; Yang, Minnan; Wang, Chun-Feng; Ding, Zhuang

    2014-07-01

    Post-weaning multisystemic wasting syndrome (PMWS) associated with porcine circovirus type 2 (PCV2) has caused the swine industry significant health challenges and economic damage. Although inactivated and subunit vaccines against PMWS have been used widely, so far no DNA vaccine is available. In this study, with the aim of exploring a new route for developing a vaccine against PCV2, the immunogenicity of a DNA vaccine was evaluated in mice. The pEGFP-N1 vector was used to construct a PCV2 Cap gene recombinant vaccine. To assess the immunogenicity of pEGFP-Cap, 80 BALB/c mice were immunized three times at 2 weekly intervals with pEGFP-Cap, LG-strain vaccine, pEGFP-N1 vector or PBS and then challenged with PCV2. IgG and cytokines were assessed by indirect ELISA and ELISA, respectively. Specimens stained with hematoxylin and eosin (HE) and immunohistochemistry (IHC) techniques were examined histopathologically. It was found that vaccination of the mice with the pEGFP-Cap induced solid protection against PCV2 infection through induction of highly specific serum IgG antibodies and cytokines (IFN-γ and IL-10), and a small PCV2 viral load. The mice treated with the pEGFP-Cap and LG-strain developed no histopathologically detectable lesions (HE stain) and IHC techniques revealed only a few positive cells. Thus, this study demonstrated that recombinant pEGFP-Cap substantially alleviates PCV2 infection in mice and provides evidence that a DNA vaccine could be an alternative to PCV2 vaccines against PMWS. © 2014 The Societies and Wiley Publishing Asia Pty Ltd.

  15. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

    PubMed

    Grossi, Cristina; Rigacci, Stefania; Ambrosini, Stefano; Ed Dami, Teresa; Luccarini, Ilaria; Traini, Chiara; Failli, Paola; Berti, Andrea; Casamenti, Fiorella; Stefani, Massimo

    2013-01-01

    The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

  16. HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice.

    PubMed

    Lieu, Hanh-Tu; Batteux, Frédéric; Simon, Marie-Thérèse; Cortes, Alexandre; Nicco, Carole; Zavala, Flora; Pauloin, Alain; Tralhao, José Guilherme; Soubrane, Olivier; Weill, Bernard; Bréchot, Christian; Christa, Laurence

    2005-09-01

    Human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein HIP/PAP is a secreted C-type lectin belonging to group VII, according to Drickamer's classification. HIP/PAP is overexpressed in liver carcinoma; however, its functional role remains unclear. In this study, we demonstrate that HIP/PAP is a paracrine hepatic growth factor promoting both proliferation and viability of liver cells in vivo. First, a low number of implanted hepatocytes deriving from HIP/PAP-transgenic mice (<1:1,000) was sufficient to stimulate overall recipient severe combined immunodeficiency liver regeneration after partial hepatectomy. After a single injection of HIP/PAP protein, the percentages of bromodeoxyuridine-positive nuclei and mitosis were statistically higher than after saline injection, indicating that HIP/PAP acts as a paracrine mitogenic growth factor for the liver. Comparison of the early events posthepatectomy in control and transgenic mice indicated that HIP/PAP accelerates the accumulation/degradation of nuclear phospho-signal transducer activator transcription factor 3 and tumor necrosis factor alpha level, thus reflecting that HIP/PAP accelerates liver regeneration. Second, we showed that 80% of the HIP/PAP-transgenic mice versus 25% of the control mice were protected against lethal acetaminophen-induced fulminate hepatitis. A single injection of recombinant HIP/PAP induced a similar cytoprotective effect, demonstrating the antiapoptotic effect of HIP/PAP. Comparison of Cu/Zn superoxide dismutase activity and glutathione reductase-like effects in control and transgenic liver mice indicated that HIP/PAP exerts an antioxidant activity and prevents reactive oxygen species-induced mitochondrial damage by acetaminophen overdose. In conclusion, the present data offer new insights into the biological functions of C-type lectins. In addition, HIP/PAP is a promising candidate for the prevention and treatment of liver failure.

  17. Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development.

    PubMed

    Mori, Yoshiko; Kodaka, Tetsuro; Kato, Takako; Kanagawa, Edith M; Kanagawa, Osami

    2009-11-01

    IFN-gamma signaling-deficient non-obese diabetic (NOD) mice develop diabetes with similar kinetics to those of wild-type NOD mice. However, the immunization of IFN-gamma signaling-deficient NOD mice with CFA failed to induce long-term protection, whereas wild-type NOD mice receiving CFA remained diabetes-free. CFA also failed to protect IFN-gamma receptor-deficient (IFN-gammaR(-/-)) NOD mice from the autoimmune rejection of transplanted islets, as it does in diabetic NOD mice, and from disease transfer by spleen cells from diabetic NOD mice. These data clearly show that the pro-inflammatory cytokine IFN-gamma is necessary for the CFA-mediated protection of NOD mice from diabetes. There is no difference in the T(h)1/T(h)17 balance between IFN-gammaR(-/-) NOD and wild-type NOD mice. There is also no difference in the total numbers and percentages of regulatory T (Treg) cells in the lymph node CD4(+) T-cell populations between IFN-gammaR(-/-) NOD and wild-type NOD mice. However, pathogenic T cells lacking IFN-gammaR are resistant to the suppressive effect of Treg cells, both in vivo and in vitro. Therefore, it is likely that CFA-mediated protection against diabetes development depends on a change in the balance between Treg cells and pathogenic T cells, and IFN-gamma signaling seems to control the susceptibility of pathogenic T cells to the inhibitory activity of Treg cells.

  18. Temporal and genetic influences on protection against noise-induced hearing loss by hypoxic preconditioning in mice.

    PubMed

    Gagnon, Patricia M; Simmons, Dwayne D; Bao, Jianxin; Lei, Debin; Ortmann, Amanda J; Ohlemiller, Kevin K

    2007-04-01

    The protective benefits of hypoxic preconditioning (HPC) against permanent noise-induced hearing loss (NIHL) were investigated in mice. Hypoxia induced by exposure to 8% O2 for 4 h conferred significant protection against damaging broadband noise delivered 24-48 h later in male and female CBA/J (CBA) and CBA/CaJ mice. No protection was found in C57BL/6 (B6) mice, their B6.CAST-Cdh23(CAST) (B6.CAST) congenics, or in CBAxB6 F1 hybrid mice over the same interval, suggesting that the potential for HPC depends on one or a few autosomal recessive alleles carried by CBA-related strains, and is not influenced by the Cdh23 locus. Protection against NIHL in CBA mice was associated with significant up-regulation of hypoxia-inducible factor-1alpha (HIF-1alpha) within the organ of Corti, not found in B6.CAST. In both CBA and B6.CAST mice, some hypoxia-noise intervals shorter than 24 h were associated with exacerbation of NIHL. Cellular cascades underlying the early exacerbation of NIHL by hypoxia are therefore common to both strains, and not mechanistically linked to later protection. Elucidation of the events that underlie HPC, and how these are impacted by genetics, may lead to pharmacologic approaches to mimic HPC, and may help identify individuals with elevated risk of NIHL.

  19. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

    SciTech Connect

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.

    1978-12-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplantedmore » Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.« less

  20. Inactivated H7 Influenza Virus Vaccines Protect Mice despite Inducing Only Low Levels of Neutralizing Antibodies.

    PubMed

    Kamal, Ram P; Blanchfield, Kristy; Belser, Jessica A; Music, Nedzad; Tzeng, Wen-Pin; Holiday, Crystal; Burroughs, Ashley; Sun, Xiangjie; Maines, Taronna R; Levine, Min Z; York, Ian A

    2017-10-15

    Avian influenza viruses of the H7 hemagglutinin (HA) subtype present a significant public health threat, as evidenced by the ongoing outbreak of human A(H7N9) infections in China. When evaluated by hemagglutination inhibition (HI) and microneutralization (MN) assays, H7 viruses and vaccines are found to induce lower level of neutralizing antibodies (nAb) than do their seasonal counterparts, making it difficult to develop and evaluate prepandemic vaccines. We have previously shown that purified recombinant H7 HA appear to be poorly immunogenic in that they induce low levels of HI and MN antibodies. In this study, we immunized mice with whole inactivated reverse genetics reassortant (RG) viruses expressing HA and neuraminidase (NA) from 3 different H7 viruses [A/Shanghai/2/2013(H7N9), A/Netherlands/219/2003(H7N7), and A/New York/107/2003(H7N2)] or with human A(H1N1)pdm09 (A/California/07/2009-like) or A(H3N2) (A/Perth16/2009) viruses. Mice produced equivalent titers of antibodies to all viruses as measured by enzyme-linked immunosorbent assay (ELISA). However, the antibody titers induced by H7 viruses were significantly lower when measured by HI and MN assays. Despite inducing very low levels of nAb, H7 vaccines conferred complete protection against homologous virus challenge in mice, and the serum antibodies directed against the HA head region were capable of mediating protection. The apparently low immunogenicity associated with H7 viruses and vaccines may be at least partly related to measuring antibody titers with the traditional HI and MN assays, which may not provide a true measure of protective immunity associated with H7 immunization. This study underscores the need for development of additional correlates of protection for prepandemic vaccines. IMPORTANCE H7 avian influenza viruses present a serious risk to human health. Preparedness efforts include development of prepandemic vaccines. For seasonal influenza viruses, protection is correlated with antibody

  1. Inactivated H7 Influenza Virus Vaccines Protect Mice despite Inducing Only Low Levels of Neutralizing Antibodies

    PubMed Central

    Blanchfield, Kristy; Belser, Jessica A.; Music, Nedzad; Tzeng, Wen-Pin; Holiday, Crystal; Burroughs, Ashley; Sun, Xiangjie; Maines, Taronna R.; Levine, Min Z.; York, Ian A.

    2017-01-01

    ABSTRACT Avian influenza viruses of the H7 hemagglutinin (HA) subtype present a significant public health threat, as evidenced by the ongoing outbreak of human A(H7N9) infections in China. When evaluated by hemagglutination inhibition (HI) and microneutralization (MN) assays, H7 viruses and vaccines are found to induce lower level of neutralizing antibodies (nAb) than do their seasonal counterparts, making it difficult to develop and evaluate prepandemic vaccines. We have previously shown that purified recombinant H7 HA appear to be poorly immunogenic in that they induce low levels of HI and MN antibodies. In this study, we immunized mice with whole inactivated reverse genetics reassortant (RG) viruses expressing HA and neuraminidase (NA) from 3 different H7 viruses [A/Shanghai/2/2013(H7N9), A/Netherlands/219/2003(H7N7), and A/New York/107/2003(H7N2)] or with human A(H1N1)pdm09 (A/California/07/2009-like) or A(H3N2) (A/Perth16/2009) viruses. Mice produced equivalent titers of antibodies to all viruses as measured by enzyme-linked immunosorbent assay (ELISA). However, the antibody titers induced by H7 viruses were significantly lower when measured by HI and MN assays. Despite inducing very low levels of nAb, H7 vaccines conferred complete protection against homologous virus challenge in mice, and the serum antibodies directed against the HA head region were capable of mediating protection. The apparently low immunogenicity associated with H7 viruses and vaccines may be at least partly related to measuring antibody titers with the traditional HI and MN assays, which may not provide a true measure of protective immunity associated with H7 immunization. This study underscores the need for development of additional correlates of protection for prepandemic vaccines. IMPORTANCE H7 avian influenza viruses present a serious risk to human health. Preparedness efforts include development of prepandemic vaccines. For seasonal influenza viruses, protection is correlated with

  2. l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice

    PubMed Central

    Romero, Maritza J.; Yao, Lin; Sridhar, Supriya; Bhatta, Anil; Dou, Huijuan; Ramesh, Ganesan; Brands, Michael W.; Pollock, David M.; Caldwell, Ruth B.; Cederbaum, Stephen D.; Head, C. Alvin; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Robert W.

    2013-01-01

    Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of l-arginine (l-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. l-Citrulline (l-cit) supplementation not only increases l-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of l-arg, in the vasculature. Aims: To investigate whether l-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received l-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and l-cit-treated STZ-rats were evaluated. Results: l-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, l-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. l-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the

  3. Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice.

    PubMed

    Shattuck, Wendy M C; Dyer, Megan C; Desrosiers, Joe; Fast, Loren D; Terry, Frances E; Martin, William D; Moise, Leonard; De Groot, Anne S; Mather, Thomas N

    2014-01-01

    Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) "humanized" mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg "humanized" mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary

  4. PKCδ knockout mice are protected from para-methoxymethamphetamine-induced mitochondrial stress and associated neurotoxicity in the striatum of mice.

    PubMed

    Shin, Eun-Joo; Dang, Duy-Khanh; Tran, Hai-Quyen; Nam, Yunsung; Jeong, Ji Hoon; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Jang, Choon-Gon; Hong, Jau-Shyong; Nabeshima, Toshitaka; Kim, Hyoung-Chun

    2016-11-01

    Para-methoxymethamphetamine (PMMA) is a para-ring-substituted amphetamine derivative sold worldwide as an illegal psychotropic drug. Although PMMA use has been reported to lead to severe intoxication and even death, little is known about the mechanism(s) by which PMMA exerts its neurotoxic effects. Here we found that PMMA treatment resulted in phosphorylation of protein kinase Cδ (PKCδ) and subsequent mitochondrial translocation of cleaved PKCδ. PMMA-induced oxidative stress was more pronounced in mitochondria than in the cytosol. Moreover, treatment with PMMA consistently resulted in significant reductions in mitochondrial membrane potential, mitochondrial complex I activity, and mitochondrial Mn superoxide dismutase-immunoreactivity. In contrast, PMMA treatment led to a significant increase in intramitochondrial Ca 2+ level. Treatment with PMMA also significantly increased ionized calcium binding adaptor molecule 1 (Iba-1)-labeled microglial activation and upregulated tumor necrosis factor alpha (TNF-α) gene expression. PKCδ knockout attenuated these mitochondrial effects and dampened the neurotoxic effects of PMMA. Importantly, TNF-α knockout mice were significantly protected from PMMA-induced increases in phospho-PKCδ expression, mitochondrial translocation of cleaved PKCδ, and Iba-1-labeled microgliosis. Both rottlerin, a pharmacological inhibitor of PKCδ, and etanercept, a pharmacological inhibitor of TNF-α, significantly protected against PMMA-mediated induction of apoptosis, as assessed by terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL) assays. In addition, PKCδ knockout and TNF-α knockout both resulted in decreased PMMA-mediated induction of dopaminergic loss. Therefore, our results suggest that PKCδ mediates PMMA-induced neurotoxicity by facilitating oxidative stress (mitochondria > cytosol), mitochondrial dysfunction, microglial activation, and pro-apoptotic signaling. Our results also indicate that PMMA-induced PKC

  5. Targeting Antigens to Dec-205 on Dendritic Cells Induces Immune Protection in Experimental Colitis in Mice

    PubMed Central

    Wadwa, Munisch; Klopfleisch, Robert; Buer, Jan; Westendorf, Astrid M.

    2016-01-01

    The endocytotic c-type lectin receptor DEC-205 is highly expressed on immature dendritic cells. In previous studies, it was shown that antigen-targeting to DEC-205 is a useful tool for the induction of antigen-specific Foxp3+ regulatory T cells and thereby can prevent inflammatory processes. However, whether this approach is sufficient to mediate tolerance in mucosal tissues like the gut is unknown. In this study, we established a new mouse model in which the adoptive transfer of naive hemagglutinin (HA)-specific CD4+Foxp3– T cells into VILLIN-HA transgenic mice leads to severe colitis. To analyze if antigen-targeting to DEC-205 could protect against inflammation of the gut, VILLIN-HA transgenic mice were injected with an antibody–antigen complex consisting of the immunogenic HA110–120 peptide coupled to an α-DEC-205 antibody (DEC-HA) before adoptive T cell transfer. DEC-HA-treated mice showed significantly less signs of intestinal inflammation as was demonstrated by reduced loss of body weight and histopathology in the gut. Strikingly, abrogated intestinal inflammation was mediated via the conversion of naive HA-specific CD4+Foxp3– T cells into HA-specific CD4+Foxp3+ regulatory T cells. In this study, we provide evidence that antigen-targeting to DEC-205 can be utilized for the induction of tolerance in mucosal organs that are confronted with large numbers of exogenous antigens. PMID:27141310

  6. Radon inhalation protects mice from carbon-tetrachloride-induced hepatic and renal damage.

    PubMed

    Kataoka, Takahiro; Nishiyama, Yuichi; Toyota, Teruaki; Yoshimoto, Masaaki; Sakoda, Akihiro; Ishimori, Yuu; Aoyama, Yutaka; Taguchi, Takehito; Yamaoka, Kiyonori

    2011-12-01

    We assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl(4)-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice.

  7. Naja naja atra Venom Protects against Manifestations of Systemic Lupus Erythematosus in MRL/lpr Mice.

    PubMed

    Zhu, Jiali; Cui, Kui; Kou, Jianqun; Wang, Shuzhi; Xu, Yinli; Ding, Zhihui; Han, Rong; Qin, Zhenghong

    2014-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease and effective therapy for this pathology is currently unavailable. We previously reported that oral administration of Naja naja atra venom (NNAV) had anti-inflammatory and immune regulatory actions. We speculated that NNAV may have therapeutic effects in MRL/lpr SLE mice. Twelve-week-old MRL/lpr mice received oral administration of NNAV (20, 40, and 80 μg/kg) or Tripterygium wilfordii polyglycosidium (10 mg/kg) daily for 16 weeks. The effects of NNAV on SLE manifestations, including skin erythema, proteinuria, and anxiety-like behaviors, were assessed with visual inspection and Multistix 8 SG strips and open field test, respectively. The pathology of spleen and kidney was examined with H&E staining. The changes in autoimmune antibodies and cytokines were determined with ELISA kits. The results showed that NNAV protected against the manifestation of SLE, including skin erythema and proteinuria. In addition, although no apparent histological change was found in liver and heart in MRL/lpr SLE mice, NNAV reduced the levels of glutamate pyruvate transaminase and creatine kinase. Furthermore, NNAV increased serum C3 and reduced concentrations of circulating globulin, anti-dsDNA antibody, and inflammatory cytokines IL-6 and TNF-α. NNAV also reduced lymphadenopathy and renal injury. These results suggest that NNAV may have therapeutic values in the treatment of SLE by inhibiting autoimmune responses.

  8. Protective Cellular Immunity Against Influenza Virus Induced by Plasmid Inoculation of Newborn Mice

    PubMed Central

    Bot, Adrian; Bot, Simona; García-Sastre, Adolfo

    1998-01-01

    Neonate organisms display an intrinsic disability to mount effective immune responses to infectious agents or conventional vaccines. Whereas low. doses of antigens trigger a suboptimal response, higher doses are frequently associated with tolerance induction. We investigated the ability of a plasmid-expressing nucleoprotein of influenza virus to prime a specific cellular immune response when administered to newborn mice. We found that persistent exposure to antigen following plasmid inoculation of neonates leads to a vigorous priming of specific CTLs rather than tolerance induction. The CTLs were cross-reactive against multiple strains of type A influenza viruses and produced IFNγ but no IL-4. The immunity triggered by plasmid inoculation of neonates was protective in terms of pulmonary virus clearance as well as survival rate following lethal challenge with influenza virus. Whereas the persistence of the plasmid at the site of injection was readily demonstrable in adult mice at 3 months after inoculation, mice immunized as newborns displayed no plasmid at 3 months and very little at 1 month after injection. Thus, DNA-based immunization of neonates may prove an effective and safe vaccination strategy for induction of cellular immunity against microbes that cause serious infectious diseases in the early period of life. PMID:9851359

  9. Black Soybean Extract Protects Against TMT-Induced Cognitive Defects in Mice

    PubMed Central

    Jeong, Ji Hee; Jo, Yu Na; Kim, Hyeon Ju; Jin, Dong Eun; Kim, Dae-Ok

    2014-01-01

    Abstract To find a neuroactive compound with a potent inhibitory effect on acetylcholinesterase (AChE) and in vivo anti-amnesic activity from natural resources, we evaluated anthocyanins and nonanthocyanins from black soybean extract. Nonanthocyanins from black soybean extract were the most potent and dose-dependent AChE inhibitors. Intracellular reactive oxygen species accumulation resulting from H2O2 treatment was significantly decreased compared with cells treated with H2O2 only. Nonanthocyanins were also neuroprotective against H2O2 treated neurotoxicity by 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Finally, nonanthocyanins from black soybean in the preadministration group attenuated trimethyltin (TMT)-induced memory injury in both in vivo tests. AChE, prepared from mice brain tissues, was inhibited by nonanthocyanins from black soybean in a dose-dependent manner. Malondialdehyde generation in the brain homogenates of mice treated with nonanthocyanins from black soybean was decreased. We concluded that nonanthocyanins from black soybean had an efficacious in vitro AChE inhibitory activity, and protected against H2O2-induced neurotoxicity. In addition, our findings suggest that nonanthocyanins from black soybean may improve the TMT-induced learning and memory deficit because of AChE inhibition of mice brain tissue. Consequently, these results demonstrate that the nonanthocyanins from black soybean could possess a wide range of beneficial activities for neurodegenerative disorders. PMID:24456358

  10. Inactivated and live, attenuated influenza vaccines protect mice against influenza:Streptococcus pyogenes super-infections

    PubMed Central

    Chaussee, Michael S.; Sandbulte, Heather R.; Schuneman, Margaret J.; DePaula, Frank P.; Addengast, Leslie A.; Schlenker, Evelyn H.; Huber, Victor C.

    2011-01-01

    Mortality associated with influenza virus super-infections is frequently due to secondary bacterial complications. To date, super-infections with Streptococcus pyogenes have been studied less extensively than those associated with S. pneumoniae. This is significant because a vaccine for S. pyogenes is not clinically available, leaving vaccination against influenza virus as our only means for preventing these super-infections. In this study, we directly compared immunity induced by two types of influenza vaccine, either inactivated influenza virus (IIV) or live, attenuated influenza virus (LAIV), for the ability to prevent super-infections. Our data demonstrate that both IIV and LAIV vaccines induce similar levels of serum antibodies, and that LAIV alone induces IgA expression at mucosal surfaces. Upon super-infection, both vaccines have the ability to limit the induction of pro-inflammatory cytokines within the lung, including IFN-γ which has been shown to contribute to mortality in previous models of super-infection. Limiting expression of these pro-inflammatory cytokines within the lungs subsequently limits recruitment of macrophages and neutrophils to pulmonary surfaces, and ultimately protects both IIV- and LAIV-vaccinated mice from mortality. Despite their overall survival, both IIV- and LAIV-vaccinated mice demonstrated levels of bacteria within the lung tissue to levels that are similar to those seen in unvaccinated mice. Thus, influenza virus:bacteria super-infections can be limited by vaccine-induced immunity against influenza virus, but the ability to prevent morbidity is not complete. PMID:21440037

  11. Protective effects of Ziyang tea polysaccharides on CCl4-induced oxidative liver damage in mice.

    PubMed

    Wang, Dongying; Zhao, Yan; Sun, Yanfei; Yang, Xingbin

    2014-01-15

    This study was designed to investigate the hepatoprotective effects of the tea polysaccharides (ZTPs) extracted from a selenium-enriched Ziyang green tea (Camellia sinensis). ZTPs were identified as the heteropolysaccharides with glucose (31.4%), arabinose (23.5%) and galactose (21.8%) being the main constitutive monosaccharides. ZTPs displayed noteworthy scavenging effects against DPPH, OH and O2(-), and high antioxidant effects in vitro, and the effects were further verified by suppressing CCl4-induced oxidative liver damage in mice at 100, 200 and 400mg/kg BW. Administration of ZTPs in mice prior to CCl4 significantly prevented the CCl4-induced increases in serum alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase, as well as hepatic malondialdehyde level. Mice treated with ZTPs showed normal glutathione peroxidase and superoxide dismutase activities, relative to CCl4-treated group. ZTPs also prevented the CCl4-caused liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that ZTPs have protective effects against acute CCl4-induced oxidative liver damage. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Myristica fragrans seed extract protects against dextran sulfate sodium-induced colitis in mice.

    PubMed

    Kim, Hyojung; Bu, Youngmin; Lee, Beom-Joon; Bae, Jinhyun; Park, Sujin; Kim, Jinsung; Lee, Kyungjin; Cha, Jae-Myung; Ryu, Bongha; Ko, Seok-Jae; Han, Gajin; Min, Byungil; Park, Jae-Woo

    2013-10-01

    Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed.

  13. Protective effects of Curcuma longa against neurobehavioral and neurochemical damage caused by cerium chloride in mice.

    PubMed

    Kadri, Yamina; Nciri, Riadh; Brahmi, Noura; Saidi, Saber; Harrath, Abdel Halim; Alwasel, Saleh; Aldahmash, Waleed; El Feki, Abdelfatteh; Allagui, Mohamed Salah

    2018-05-07

    Cerium chloride (CeCl 3 ) is considered an environmental pollutant and a potent neurotoxic agent. Medicinal plants have many bioactive compounds that provide protection against damage caused by such pollutants. Curcuma longa is a bioactive compound-rich plant with very important antioxidant properties. To study the preventive and healing effects of Curcuma longa on cerium-damaged mouse brains, we intraperitoneally injected cerium chloride (CeCl 3 , 20 mg/kg BW) along with Curcuma longa extract, administrated by gavage (100 mg/kg BW), into mice for 60 days. We then examined mouse behavior, brain tissue damage, and brain oxidative stress parameters. Our results revealed a significant modification in the behavior of the CeCl 3 -treated mice. In addition, CeCl 3 induced a significant increment in lipid peroxidation, carbonyl protein (PCO), and advanced oxidation protein product levels, as well as a significant reduction in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Acetylcholinesterase (AChE) activity remarkably increased in the brain of CeCl 3 -treated mice. Histopathological observations confirmed these results. Curcuma longa attenuated CeCl 3 -induced oxidative stress and increased the activities of antioxidant enzymes. It also decreased AChE activity in the CeCl 3 -damaged mouse brain that was confirmed by histopathology. In conclusion, this study suggests that Curcuma longa has a neuroprotective effect against CeCl 3 -induced damage in the brain.

  14. O-Linked β-N-Acetylglucosamine Modification of A20 Enhances the Inhibition of NF-κB (Nuclear Factor-κB) Activation and Elicits Vascular Protection After Acute Endoluminal Arterial Injury.

    PubMed

    Yao, Dan; Xu, Lijuan; Xu, Oufan; Li, Rujun; Chen, Mingxing; Shen, Hui; Zhu, Huajiang; Zhang, Fengyi; Yao, Deshang; Chen, Yiu-Fai; Oparil, Suzanne; Zhang, Zhengang; Gong, Kaizheng

    2018-06-01

    Recently, we have demonstrated that acute glucosamine-induced augmentation of protein O-linked β-N-acetylglucosamine (O-GlcNAc) levels inhibits inflammation in isolated vascular smooth muscle cells and neointimal formation in a rat model of carotid injury by interfering with NF-κB (nuclear factor-κB) signaling. However, the specific molecular target for O-GlcNAcylation that is responsible for glucosamine-induced vascular protection remains unclear. In this study, we test the hypothesis that increased A20 (also known as TNFAIP3 [tumor necrosis factor α-induced protein 3]) O-GlcNAcylation is required for glucosamine-mediated inhibition of inflammation and vascular protection. In cultured rat vascular smooth muscle cells, both glucosamine and the selective O-linked N-acetylglucosaminidase inhibitor thiamet G significantly increased A20 O-GlcNAcylation. Thiamet G treatment did not increase A20 protein expression but did significantly enhance binding to TAX1BP1 (Tax1-binding protein 1), a key regulatory protein for A20 activity. Adenovirus-mediated A20 overexpression further enhanced the effects of thiamet G on prevention of TNF-α (tumor necrosis factor-α)-induced IκB (inhibitor of κB) degradation, p65 phosphorylation, and increases in DNA-binding activity. A20 overexpression enhanced the inhibitory effects of thiamet G on TNF-α-induced proinflammatory cytokine expression and vascular smooth muscle cell migration and proliferation, whereas silencing endogenous A20 by transfection of specific A20 shRNA significantly attenuated these inhibitory effects. In balloon-injured rat carotid arteries, glucosamine treatment markedly inhibited neointimal formation and p65 activation compared with vehicle treatment. Adenoviral delivery of A20 shRNA to the injured arteries dramatically reduced balloon injury-induced A20 expression and inflammatory response compared with scramble shRNA and completely abolished the vascular protection of glucosamine. These results suggest that

  15. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

    PubMed Central

    Lygate, Craig A.; Bohl, Steffen; ten Hove, Michiel; Faller, Kiterie M.E.; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijevic, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen E.; Neubauer, Stefan

    2012-01-01

    Aims Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. Methods and results CrT-OE mice were selected for left ventricular (LV) creatine 20–100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Conclusion Elevation of myocardial creatine by 20–100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia. PMID:22915766

  16. Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition.

    PubMed

    Wang, Shuai; Shi, Xiao-Lei; Feng, Min; Wang, Xun; Zhang, Zhi-Heng; Zhao, Xin; Han, Bing; Ma, Hu-Cheng; Dai, Bo; Ding, Yi-Tao

    2016-09-01

    Liver fibrosis, which is the pathophysiologic process of the liver due to sustained wound healing in response to chronic liver injury, will eventually progress to cirrhosis. Puerarin, a bioactive isoflavone glucoside derived from the traditional Chinese medicine pueraria, has been reported to have many anti-inflammatory and anti-fibrosis properties. However, the detailed mechanisms are not well studied yet. This study aimed to investigate the effects of puerarin on liver function and fibrosis process in mice induced by CCl4. C57BL/6J mice were intraperitoneally injected with 10% CCl4 in olive oil(2mL/kg) with or without puerarin co-administration (100 and 200mg/kg intraperitoneally once daily) for four consecutive weeks. As indicated by the ameliorative serum hepatic enzymes and the reduced histopathologic abnormalities, the data collected showed that puerarin can protect against CCl4-induced chronic liver injury. Moreover, CCl4-induced development of fibrosis, as evidenced by increasing expression of alpha smooth muscle actin(α-SMA), collagen-1, transforming growth factor (TGF)-β and connective tissue growth factor(CTGF) in liver, were suppressed by puerarin. Possible mechanisms related to these suppressive effects were realized by inhibition on NF-κB signaling pathway, reactive oxygen species(ROS) production and mitochondrial dysfunction in vivo. In addition, these protective inhibition mentioned above were driven by down-regulation of PARP-1 due to puerarin because puerarin can attenuate the PARP-1 expression in CCl4-damaged liver and PJ34, a kind of PARP-1 inhibitor, mimicked puerarin's protection. In conclusion, puerarin played a protective role in CCl4-induced liver fibrosis probably through inhibition of PARP-1 and subsequent attenuation of NF-κB, ROS production and mitochondrial dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice.

    PubMed

    Peng, Yuan; Chen, Qian; Yang, Tao; Tao, Yanyan; Lu, Xiong; Liu, Chenghai

    2014-03-01

    Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model

  18. Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice.

    PubMed

    Cavuşoğlu, Kültiğin; Yapar, Kürşad; Oruç, Ertan; Yalçın, Emine

    2011-10-01

    The aim of the present study was to investigate the protective role of Ginkgo biloba L. leaf extract against the active agent of Roundup® herbicide (Monsanto, Creve Coeur, MO, USA). The Swiss Albino mice were randomly divided into six groups, with each group consisting of six animals: Group I (control) received an intraperitoneal injection of dimethyl sulfoxide (0.2 mL, once only), Group II received glyphosate at a dose of 50 mg/kg of body weight, Group III received G. biloba at a dose of 50 mg/kg of body weight, Group IV received G. biloba at a dose of 150 mg/kg of body weight, Group V received G. biloba (50 mg/kg of body weight) and glyphosate (50 mg/kg of body weight), and Group VI received G. biloba (150 mg/kg of body weight) and glyphosate (50 mg/kg of body weight). The single dose of glyphosate was given intraperitoneally. Animals from all the groups were sacrificed at the end of 72 hours, and their blood, bone marrow, and liver and kidney tissues were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and glutathione (GSH) levels and the presence of micronucleus (MN), chromosomal aberrations (CAs), and pathological damages. The results indicated that serum AST, ALT, BUN, and creatinine levels significantly increased in mice treated with glyphosate alone compared with the other groups (P<.05). Besides, glyphosate-induced oxidative damage caused a significant decrease in GSH levels and a significant increase in MDA levels of the liver and kidney tissues. Moreover, glyphosate alone-treated mice presented higher frequencies of CAs, MNs, and abnormal metaphases compared with the controls (P<.05). These mice also displayed a lower mean mitotic index than the controls (P<.05). Treatment with G. biloba produced amelioration in indices of hepatotoxicity, nephrotoxicity, lipid peroxidation, and genotoxicity relative to Group II. Each dose of G. biloba provided significant

  19. G protein-coupled receptor kinase-2-deficient mice are protected from dextran sodium sulfate-induced acute colitis.

    PubMed

    Steury, Michael D; Kang, Ho Jun; Lee, Taehyung; Lucas, Peter C; McCabe, Laura R; Parameswaran, Narayanan

    2018-06-01

    G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase and plays a key role in different disease processes. Previously, we showed that GRK2 knockdown enhances wound healing in colonic epithelial cells. Therefore, we hypothesized that ablation of GRK2 would protect mice from dextran sodium sulfate (DSS)-induced acute colitis. To test this, we administered DSS to wild-type (GRK2 +/+ ) and GRK2 heterozygous (GRK +/- ) mice in their drinking water for 7 days. As predicted, GRK2 +/- mice were protected from colitis as demonstrated by decreased weight loss (20% loss in GRK2 +/+ vs. 11% loss in GRK2 +/- ). lower disease activity index (GRK2 +/+ 9.1 vs GRK2 +/- 4.1), and increased colon lengths (GRK2 +/+ 4.7 cm vs GRK2 +/- 5.3 cm). To examine the mechanisms by which GRK2 +/- mice are protected from colitis, we investigated expression of inflammatory genes in the colon as well as immune cell profiles in colonic lamina propria, mesenteric lymph node, and in bone marrow. Our results did not reveal differences in immune cell profiles between the two genotypes. However, expression of inflammatory genes was significantly decreased in DSS-treated GRK2 +/- mice compared with GRK2 +/+ . To understand the mechanisms, we generated myeloid-specific GRK2 knockout mice and subjected them to DSS-induced colitis. Similar to whole body GRK2 heterozygous knockout mice, myeloid-specific knockout of GRK2 was sufficient for the protection from DSS-induced colitis. Together our results indicate that deficiency of GRK2 protects mice from DSS-induced colitis and further suggests that the mechanism of this effect is likely via GRK2 regulation of inflammatory genes in the myeloid cells.

  20. Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms.

    PubMed

    Lutshumba, Jenny; Liu, Shu; Zhong, Yu; Hou, Tianfei; Daugherty, Alan; Lu, Hong; Guo, Zhenheng; Gong, Ming C

    2018-05-01

    Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development. SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the Timp4 promoter and suppressed Timp4 transcription. These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion. © 2018 American Heart Association, Inc.

  1. Cathelicidin protects against Helicobacter pylori colonization and the associated gastritis in mice.

    PubMed

    Zhang, L; Yu, J; Wong, C C M; Ling, T K W; Li, Z J; Chan, K M; Ren, S X; Shen, J; Chan, R L Y; Lee, C C; Li, M S M; Cheng, A S L; To, K F; Gallo, R L; Sung, J J Y; Wu, W K K; Cho, C H

    2013-07-01

    Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.

  2. Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO.

    PubMed

    Li, Qinchen; Hu, Xinxin; Xuan, Yanhan; Ying, Jianghua; Fei, Yujia; Rong, Jielu; Zhang, Yong; Zhang, Jian; Liu, Chunyan; Liu, Zheng

    2018-03-01

    Gastric ulcers (GUs) are common pathologies that affect many people around the world. Excessive alcohol consumption is one of the main causes of GUs; however, there are still lack of effective drugs for the prevention or therapy of GUs. In this study, we evaluated the protective effects and possible mechanisms of kaempferol (KAE) against acute ethanol-induced lesions to the gastric mucosa in mice. Fasted mice were orally given vehicle (0.9% saline), omeprazole (20 mg/kg), or KAE (40, 80, or 160 mg/kg) for 1 h in different experimental sets prior to the establishment of the GU model by challenge with absolute ethanol (10 ml/kg). Animals were euthanized 1 h after ethanol intake, and their plasma and stomach tissues were subject to further examination. Macroscopic and microscopic lesions, and immunological and biochemical parameters were observed. The effects of inflammation were investigated using the following indicators: tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, myeloperoxidase (MPO), and nitric oxide (NO). Results showed that KAE significantly decreased the ulcer index, increased the preventive index, completely protected the mucosa from lesions, and preserved gastric mucosal glycoprotein. KAE decreased MPO activity and pro-inflammatory cytokine (TNF-α, and IL-1β) levels, and improved NO levels. The gastroprotective activity of KAE might be attributed to the preservation of gastric mucous glycoproteins levels, thus by inhibiting neutrophil accumulation and MPO activity, adjusting the levels of pro-inflammatory cytokines, and improving NO production.

  3. 17 β-estradiol Protects Male Mice from Cuprizone-induced Demyelination and Oligodendrocyte Loss

    PubMed Central

    Taylor, Lorelei C; Puranam, Kasturi; Gilmore, Wendy; Ting, Jenny P-Y.; Matsushima, G.K.

    2010-01-01

    In addition to regulating reproductive functions in the brain and periphery, estrogen has trophic and neuroprotective functions in the central nervous system (CNS). Estrogen administration has been demonstrated to provide protection in several animal models of CNS disorders, including stroke, brain injury, epilepsy, Parkinson’s disease, Alzheimer’s disease, age-related cognitive decline and multiple sclerosis. Here, we use a model of toxin-induced oligodendrocyte death which results in demyelination, reactive gliosis, recruitment of oligodendrocyte precursor cells and subsequent remyelination to study the potential benefit of 17β-estradiol (E2) administration in male mice. The results indicate that E2 partially ameliorates loss of oligodendrocytes and demyelination in the corpus callosum. This protection is accompanied by a delay in microglia accumulation as well as reduced mRNA expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), and insulin-like growth factor-1 (IGF-1). E2 did not significantly alter the accumulation of astrocytes or oligodendrocyte precursor cells, or remyelination. These data obtained from a toxin-induced, T cell-independent model using male mice provide an expanded view of the beneficial effects of estrogen on oligodendrocyte and myelin preservation. PMID:20347981

  4. Proteomic analysis of protective effects of polysaccharides from Salvia miltiorrhiza against immunological liver injury in mice.

    PubMed

    Sun, Xue-Gang; Fu, Xiu-Qiong; Cai, Hong-Bing; Liu, Qiang; Li, Chun-Hua; Liu, Ya-Wei; Li, Ying-Jia; Liu, Zhi-Feng; Song, Yu-Hong; Lv, Zhi-Ping

    2011-07-01

    This study was designed to investigate mechanisms of the protective effects of Salvia miltiorrhiza polysaccharide (SMPS) against lipopolysaccharide (LPS)-induced immunological liver injury (ILI) in Bacille Calmette-Guérin (BCG)-primed mice. Two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis showed that three proteins are down-regulated and six proteins are up-regulated by SMPS. SMPS reduces the degree of liver injury by up-regulating the enzymes of the citric acid cycle, namely malate dehydrogenase (MDH) and 2-oxoglutarate dehydrogenase complex. LPS significantly increases nuclear factor kappa B (NF-κB) activation, inducible nitric oxide synthase (iNOS) expression and MDA level in BCG primed mice liver, whereas SMPS treatment protects against the immunological liver injury through inhibition of the NF-κB activation by up-regulation of PRDX6 and the subsequent attenuation of lipid peroxidation, iNOS expression and inflammation. Copyright © 2011 John Wiley & Sons, Ltd.

  5. Protective Effect of Amphipterygium adstringens Extract on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice

    PubMed Central

    Rodriguez-Canales, Mario; Jimenez-Rivas, Ruben; Canales-Martinez, Maria Margarita; Garcia-Lopez, Ana Judith; Rivera-Yañez, Nelly; Nieto-Yañez, Oscar; Ledesma-Soto, Yadira; Sanchez-Torres, Luvia Enid; Rodriguez-Sosa, Miriam; Terrazas, Luis Ignacio

    2016-01-01

    Amphipterygium adstringens is an endemic species in Mexico commonly known as “cuachalalate.” Healers to treat gastritis, gastric ulcers, and gastrointestinal cancer have traditionally used the bark. We investigated the effects of alcoholic extract of A. adstringens (AaEE) in DSS-induced colitis in mice. The protective effect of AaEE was determined at 200 mg/kg by oral gavage for 10 days. We determine the effect of AaEE on clinical features (disease activity index), antioxidants, anti-inflammatory, and immunomodulatory activities in relation to the activity of SOD, CAT, and GPx, levels of proinflammatory cytokines, and changes both macroscopic and microscopic of the colonic mucosa. AaEE significantly reduced the inflammation of colon and significantly increased SOD and GPx activities. AaEE also significantly decreased TNF-α, IFN-γ, and IL-1β cytokine levels compared to DSS-treated mice and reduced both infiltration of inflammatory cells and the mucosal damage in colon. The results suggested the protective potential of AaEE in DSS-induced colitis and this might be attributed to its phytochemicals compounds that have been found to induce a wide spectrum of activities such as reduction in oxidative stress, suppression of inflammation, modulating numerous signal transduction pathways, and induction of apoptosis. The findings of this study suggest that AaEE has substantial potential for the treatment of inflammatory colitis. PMID:27635116

  6. Protective effects of Aloe sterols against UVB-induced photoaging in hairless mice.

    PubMed

    Misawa, Eriko; Tanaka, Miyuki; Saito, Marie; Nabeshima, Kazumi; Yao, Ruiqing; Yamauchi, Kouji; Abe, Fumiaki; Yamamoto, Yuki; Furukawa, Fukumi

    2017-03-01

    Aloe vera is a traditional medical plant whose gel has been widely used in skin care. Previously, we have identified Aloe sterols from Aloe vera as active ingredients. This study investigated the protective effects of Aloe sterols without polysaccharides, against ultraviolet B (UVB)-induced skin photoaging in mice using Aloe vera gel extract (AVGE) obtained by supercritical fluid extraction. Aloe vera gel extract was supplemented in the diet (12 or 120 ppm), and HR-1 hairless mice were exposed to UVB irradiation for 7 weeks. Skin measurements and histological and analytical studies were performed. Repeated UVB irradiation induced rough wrinkling of skin with water content reduction and hyperkeratosis. AVGE administration resulted in the significant improvement of UVB-induced skin dryness, epidermal thickness, and wrinkle formation. The AVGE group also suppressed the degenerations of dermal collagen fibers and the appearance of cutaneous apoptosis cells induced by UVB. Furthermore, AVGE administration reduced the excess elevation of pro-inflammatory cytokines (IL-1β and TNF-α) and matrix metalloproteinases (MMP-2, MMP-9, MMP-12, and MMP-13) in UVB-exposed skin. The dietary ingestion of Aloe sterols protected against chronic UVB damage in mouse skin, and our results suggest that Aloe sterols may prevent skin photoaging through the anti-inflammation and MMP regulation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice.

    PubMed

    Wu, Chun Fu; Liu, Yan Li; Song, Ming; Liu, Wen; Wang, Jin Hui; Li, Xian; Yang, Jing Yu

    2003-08-01

    In the present study, pseudoginsenoside-F(11) (PF(11)), a saponin that existed in American ginseng, was studied on its protective effect on methamphetamine (MA)-induced behavioral and neurochemical toxicities in mice. MA was intraperitoneally administered at the dose of 10 mg/kg four times at 2-h intervals, and PF(11) was orally administered at the doses of 4 and 8 mg/kg two times at 4-h intervals, 60 min prior to MA administration. The results showed that PF(11) did not significantly influence, but greatly ameliorated, the anxiety-like behavior induced by MA in the light-dark box task. In the forced swimming task, PF(11) significantly shortened the prolonged immobility time induced by MA. In the appetitively motivated T-maze task, PF(11) greatly shortened MA-induced prolonged latency and decreased the error counts. Similar results were also observed in the Morris water maze task. PF(11) significantly shortened the escape latency prolonged by MA. There were significant decreases in the contents of dopamine (DA), 3,4-dihydroxyphenacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoacetic acid (5-HIAA) in the brain of MA-treated mice. PF(11) could partially, but significantly, antagonize MA-induced decreases of DA. The above results demonstrate that PF(11) is effective in protection of MA-induced neurotoxicity and also suggest that natural products, such as ginseng, might be potential candidates for the prevention and treatment of the neurological disorders induced by MA abuse.

  8. IL-33 induces protective effects in adipose tissue inflammation during obesity in mice

    PubMed Central

    Miller, Ashley M.; Asquith, Darren L.; Hueber, Axel J.; Anderson, Lesley A.; Holmes, William M.; McKenzie, Andrew N.; Xu, Damo; Sattar, Naveed; McInnes, Iain B.; Liew, Foo Y.

    2014-01-01

    Rationale Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine IL-33 and its receptor ST2 are expressed in adipose tissue but their role in adipose tissue inflammation during obesity is unclear. Objective To examine the functional role of IL-33 in adipose tissues, and investigate the effects on adipose tissue inflammation and obesity in vivo. Methods and Results We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10), and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages towards an M2 alternatively activated phenotype (CD206+), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed HFD had increased body weight and fat mass, impaired insulin secretion and glucose regulation compared to WT controls fed HFD. Conclusions In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity. PMID:20634488

  9. Recombinant Flagellin-Porcine Circovirus Type 2 Cap Fusion Protein Promotes Protective Immune Responses in Mice

    PubMed Central

    Zhang, Chunyan; Zhu, Shanshan; Wei, Li; Yan, Xu; Wang, Jing; Quan, Rong; She, Ruiping; Hu, Fengjiao; Liu, Jue

    2015-01-01

    The Cap protein of porcine circovirus type 2 (PCV2) that serves as a major host-protective immunogen was used to develop recombinant vaccines for control of PCV2-associated diseases. Growing research data have demonstrated the high effectiveness of flagellin as an adjuvant for humoral and cellular immune responses. Here, a recombinant protein was designed by fusing a modified version of bacterial flagellin to PCV2 Cap protein and expressed in a baculovirus system. When administered without adjuvant to BALB/c mice, the flagellin-Cap fusion protein elicited stronger PCV2-specific IgG antibody response, higher neutralizing antibody levels, milder histopathological changes and lower viremia, as well as higher secretion of cytokines such as TNF-α and IFN-γ that conferred better protection against virus challenge than those in the recombinant Cap alone-inoculated mice. These results suggest that the recombinant Cap protein when fused to flagellin could elicit better humoral and cellular immune responses against PCV2 infection in a mouse model, thereby acting as an attractive candidate vaccine for control of the PCV2-associated diseases. PMID:26070075

  10. 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.

  11. Cerebrosides from Sea Cucumber Protect Against Oxidative Stress in SAMP8 Mice and PC12 Cells.

    PubMed

    Che, Hongxia; Du, Lei; Cong, Peixu; Tao, Suyuan; Ding, Ning; Wu, Fengjuan; Xue, Changhu; Xu, Jie; Wang, Yuming

    2017-04-01

    Alzheimer's disease (AD) is a neurodegenerative disorder. Emerging evidence implicates β-amyloid (Aβ) plays a critical role in the progression of AD. In this study, we investigated the protective effect of cerebrosides obtained from sea cucumber against senescence-accelerated mouse prone 8 (SAMP8) mice in vivo. We also studied the effect of cerebrosides on Aβ-induced cytotoxicity on the rat pheochromocytoma cell (PC12) and the underlying molecular mechanisms. Cerebrosides ameliorated learning and memory deficits and the Aβ accumulation in demented mice, decreased the content of malondialdehyde (MDA), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG), 8-hydroxy-2'-deoxyguanosine (8-oxo-G), and nitric oxide (NO), and enhanced the superoxide dismutase (SOD) activity significantly. The neuroprotective effect of sea cucumber cerebrosides (SCC) was also verified in vitro: the cerebrosides increased the survival rate of PC12 cells, recovered the cellular morphology, downregulated the protein levels of Caspase-9, cleaved Caspase-3, total Caspase-3, and Bax, and upregulated the protein level of Bcl-2, revealing that cerebrosides could inhibit Aβ-induced cell apoptosis. The results showed the protective effect of SCC was regulated by the mitochondria-dependent apoptotic pathway. Our results provide a new approach to developing the marine organisms as functional foods for neuroprotection.

  12. Protection against Fasciola gigantica infection in mice by vaccination with recombinant juvenile-specific cathepsin L.

    PubMed

    Sansri, Veerawat; Meemon, Krai; Changklungmoa, Narin; Kueakhai, Pornanan; Chantree, Pathanin; Chaichanasak, Pannigan; Lorsuwannarat, Natcha; Itagaki, Tadashi; Sobhon, Prasert

    2015-03-24

    Fasciola gigantica cathepsin L1H (FgCatL1H) is one of the major cathepsin L released by juveniles of F. gigantica to aid in the invasion of host's tissues. Due to its high sequence similarity with other cathepsin L (CatL) isoforms of late stage F. gigantica, it was considered to be a good vaccine candidate that can block all CatL-mediated protease activities and affect juveniles as well as adult parasites. In this study, recombinant proFgCatL1H protein expressed in yeast, Pichia pastoris, system was mixed with Freund's adjuvants and used to subcutaneously immunize mice that were later challenged with metacercariae of F. gigantica. The percentage of worm protection in the rproFgCatL1H-vaccinated mice compared to the non-immunized and adjuvant control mice were approximately 62.7% and 66.1%, respectively. Anti-rproFgCatL1H antisera collected from vaccinated mice reacted specifically with rproFgCatL1H and other cathepsin L isoforms of F. gigantica, but the antibodies did not cross react with antigens from other trematode and nematode parasites, including Eurytrema pancreaticum, Opisthorchis viverrini, Fischoederius cobboldi, Cotylophoron cotylophorum, Gigantocotyle explanatum, Paramphistomum cervi, and Setaria labiato-papillosa. The levels of IgG1 and IgG2a in mouse sera increased significantly at two weeks after immunization and were highest during the sixth to eighth weeks after immunization. The IgG1 level was higher than IgG2a at all periods of immunization, implicating the dominance of the Th2 response. The levels of IgG1 and IgG2a in the immune sera were shown to be strongly correlated with the numbers of worm recovery, and the correlation coefficient was higher for IgG1. The levels of serum aspartate aminotransferase and alanine transaminase were significantly lower in the sera of rproFgCatL1H-vaccinated mice than in the infected control mice indicating a lower degree of liver damage. This study demonstrated a high potential of FgCatL1H vaccine, and its

  13. Protective effects of aerobic exercise on acute lung injury induced by LPS in mice

    PubMed Central

    2012-01-01

    Introduction The regular practice of physical exercise has been associated with beneficial effects on various pulmonary conditions. We investigated the mechanisms involved in the protective effect of exercise in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods Mice were divided into four groups: Control (CTR), Exercise (Exe), LPS, and Exercise + LPS (Exe + LPS). Exercised mice were trained using low intensity daily exercise for five weeks. LPS and Exe + LPS mice received 200 µg of LPS intratracheally 48 hours after the last physical test. We measured exhaled nitric oxide (eNO); respiratory mechanics; neutrophil density in lung tissue; protein leakage; bronchoalveolar lavage fluid (BALF) cell counts; cytokine levels in BALF, plasma and lung tissue; antioxidant activity in lung tissue; and tissue expression of glucocorticoid receptors (Gre). Results LPS instillation resulted in increased eNO, neutrophils in BALF and tissue, pulmonary resistance and elastance, protein leakage, TNF-alpha in lung tissue, plasma levels of IL-6 and IL-10, and IL-1beta, IL-6 and KC levels in BALF compared to CTR (P ≤0.02). Aerobic exercise resulted in decreases in eNO levels, neutrophil density and TNF-alpha expression in lung tissue, pulmonary resistance and elastance, and increased the levels of IL-6, IL-10, superoxide dismutase (SOD-2) and Gre in lung tissue and IL-1beta in BALF compared to the LPS group (P ≤0.04). Conclusions Aerobic exercise plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of exercise are mainly mediated by the expression of anti-inflammatory cytokines and antioxidants, suggesting that exercise can modulate the inflammatory-anti-inflammatory and the oxidative-antioxidative balance in the early phase of ALI. PMID:23078757

  14. Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

    PubMed Central

    2013-01-01

    Background Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. Methods Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. Results Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. Conclusion Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients. PMID:23672582

  15. A genetically engineered live attenuated vaccine of Coccidioides posadasii protects BALB/c mice against coccidioidomycosis.

    PubMed

    Xue, Jianmin; Chen, Xia; Selby, Dale; Hung, Chiung-Yu; Yu, Jieh-Juen; Cole, Garry T

    2009-08-01

    Coccidioidomycosis (also known as San Joaquin Valley fever) is an occupational disease. Workers exposed to outdoor dust which contains spores of the soil-inhabiting fungus have a significantly increased risk of respiratory infection. In addition, people with compromised T-cell immunity, the elderly, and certain racial groups, particularly African-Americans and Filipinos, who live in regions of endemicity in the southwestern United States have an elevated incidence of symptomatic infection caused by inhalation of spores of Coccidioides posadasii or Coccidioides immitis. Recurring epidemics and escalation of medical costs have helped to motivate production of a vaccine against valley fever. The major focus has been the development of a defined, T-cell-reactive, recombinant protein vaccine. However, none of the products described to date have provided full protection to coccidioidal disease-susceptible BALB/c mice. Here we describe the first genetically engineered, live, attenuated vaccine that protects both BALB/c and C57BL/6 mice against coccidioidomycosis. Two chitinase genes (CTS2 and CTS3) were disrupted to yield the attenuated strain, which was unable to endosporulate and was no longer infectious. Vaccinated survivors mounted an immune response characterized by production of both T-helper-1- and T-helper-2-type cytokines. Histology revealed well-formed granulomas and markedly diminished inflammation. Significantly fewer organisms were observed in the lungs of survivors than in those of nonvaccinated mice. Additional investigations are required to further define the nature of the live, attenuated vaccine-induced immunity against Coccidioides infection.

  16. Protective effect of δ-amyrone against ethanol-induced gastric ulcer in mice.

    PubMed

    Li, Weifeng; Yao, Huan; Niu, Xiaofeng; Wang, Yu; Zhang, Hailin; Li, Huani; Mu, Qingli

    2015-06-01

    The purpose of this study is to examine the protective effect of δ-amyrone on ethanol-induced gastric ulcer in mice. The mice intragastric administration 75% (0.5 mL/100g) ethanol was pretreated with δ-amyrone (4 and 8 mg/kg) and cimetidine (100 mg/kg) or vehicles in different experimental groups for a continuous three-day, and animals were euthanized 3h after ethanol ingestion. The gastric lesions were significantly attenuated by δ-amyrone (4 and 8 mg/kg) as compared to the ulcer control group. Pre-treatment with δ-amyrone prevented the myeloperoxidase (MPO) activity, production of nitric oxide (NO) in serum, expression of inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB) p65 protein expression. Analysis of cytokines in gastric tissue and serum of ethanol-induced mice showed the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were decreased by δ-amyrone in response to NF-κB p65. These results suggested that δ-amyrone exerts its protective effect on experimental gastric ulcer by inhibiting NF-κB signaling pathways, which subsequently reduces overproduction of the inducible enzymes iNOS and suppresses the release of the inflammatory factors TNF-α, IL-6 and NO. Thus, δ-amyrone shows promise as a therapeutic agent in experimental gastric ulcer. Copyright © 2014 Elsevier GmbH. All rights reserved.

  17. Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system.

    PubMed

    Zhou, Ying; Niu, Chao; Ma, Bo; Xue, Xiaoyan; Li, Zhi; Chen, Zhou; Li, Fen; Zhou, Shan; Luo, Xiaoxing; Hou, Zheng

    2018-03-02

    Given its high resistance, enhanced virulence, and high transmissibility, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia is highly associated with high morbidity and mortality. Anti-virulence therapy is a promising strategy that bypasses the evolutionary pressure on the bacterium to develop resistance. RNAIII-inhibiting peptide (RIP), as an accessory gene regulator (agr)-specific inhibitor, significantly restricts the virulence of S. aureus and protects infected mice from death by blocking the agr quorum sensing system. The protective effects of RIP on the neutropenic mice completely disappeared in a neutrophil-deleted mouse infection model, but not in the macrophage-deleted mice. This result confirmed that the in vivo antibacterial activity of RIP is highly associated with neutrophil function. Phenol-soluble modulins (PSMs), as major leukocyte lysis toxins of CA-MRSA, are directly regulated by the agr system. In this experiment, PSMα1, 2, and 3 significantly induced neutrophil necroptosis by activating mixed lineage kinase-like protein (MLKL) phosphorylation and increasing lactate dehydrogenase release. The S. aureus supernatants harvested from the agr or psmα mutant strains both decreased the phosphorylation level of MLKL and cell lysis. PSMα1-mediated neutrophil lysis was significantly inhibited by necrosulfonamide, necrostatin-1, TNFα antibody, and WRW4. These results showed PSMα1 induced necroptosis depends on formylpeptide receptor 2 (FPR2)-mediated autocrine TNFα. Moreover, the neutrophil necroptosis induced by S. aureus was significantly suppressed and pneumonia was effectively prevented by the blockage of agrA and psmα expression levels. These findings indicate that PSMα-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest that interfering with the agr quorum sensing signaling pathway is a potential therapeutic strategy.

  18. A CpG Oligonucleotide Can Protect Mice from a Low Aerosol Challenge Dose of Burkholderia mallei

    PubMed Central

    Waag, David M.; McCluskie, Michael J.; Zhang, Ningli; Krieg, Arthur M.

    2006-01-01

    Treatment with an oligodeoxynucleotide (ODN) containing CPG motifs (CpG ODN 7909) was found to protect BALB/c mice from lung infection or death after aerosol challenge with Burkholderia mallei. Protection was associated with enhanced levels of gamma interferon (IFN-γ)-inducible protein 10, interleukin-12 (IL-12), IFN-γ, and IL-6. Preexposure therapy with CpG ODNs may protect victims of a biological attack from glanders. PMID:16495571

  19. A CpG oligonucleotide can protect mice from a low aerosol challenge dose of Burkholderia mallei.

    PubMed

    Waag, David M; McCluskie, Michael J; Zhang, Ningli; Krieg, Arthur M

    2006-03-01

    Treatment with an oligodeoxynucleotide (ODN) containing CPG motifs (CpG ODN 7909) was found to protect BALB/c mice from lung infection or death after aerosol challenge with Burkholderia mallei. Protection was associated with enhanced levels of gamma interferon (IFN-gamma)-inducible protein 10, interleukin-12 (IL-12), IFN-gamma, and IL-6. Preexposure therapy with CpG ODNs may protect victims of a biological attack from glanders.

  20. Vitamin D supplementation protects against bone loss associated with chronic alcohol administration in female mice.

    PubMed

    Mercer, Kelly E; Wynne, Rebecca A; Lazarenko, Oxana P; Lumpkin, Charles K; Hogue, William R; Suva, Larry J; Chen, Jin-Ran; Mason, Andrew Z; Badger, Thomas M; Ronis, Martin J J

    2012-11-01

    Chronic alcohol abuse results in decreased bone mineral density (BMD), which can lead to increased fracture risk. In contrast, low levels of alcohol have been associated with increased BMD in epidemiological studies. Alcohol's toxic skeletal effects have been suggested to involve impaired vitamin D/calcium homeostasis. Therefore, dietary vitamin D supplementation may be beneficial in reducing bone loss associated with chronic alcohol consumption. Six-week-old female C57BL/6J mice were pair-fed ethanol (EtOH)-containing liquid diets (10 or 36% total calories) for 78 days. EtOH exposure at 10% calories had no effects on any measured bone or serum parameter. EtOH consumption at 36% of calories reduced BMD and bone strength (P<0.05), decreased osteoblastogenesis, increased osteoclastogenesis, suppressed 1,25-hydroxyvitamin D3 [1,25(OH)2D3] serum concentrations (P<0.05), and increased apoptosis in bone cells compared with pair-fed controls. In a second study, female mice were pair-fed 30% EtOH diets with or without dietary supplementation with vitamin D3 (cholecalciferol; VitD) for 40 days. VitD supplementation in the EtOH diet protected against cortical bone loss, normalized alcohol-induced hypocalcaemia, and suppressed EtOH-induced expression of receptor of nuclear factor-κB ligand mRNA in bone. In vitro, pretreatment of 1,25(OH)2D3 in osteoblastic cells inhibited EtOH-induced apoptosis. In EtOH/VitD mice circulating 1,25(OH)2D3 was lower compared with mice receiving EtOH alone (P<0.05), suggesting increased sensitivity to feedback control of VitD metabolism in the kidney. These findings suggest dietary VitD supplementation may prevent skeletal toxicity in chronic drinkers by normalizing calcium homeostasis, preventing apoptosis, and suppressing EtOH-induced increases in bone resorption.

  1. Protective efficacy of a Toxoplasma gondii rhoptry protein 13 plasmid DNA vaccine in mice.

    PubMed

    Wang, Pei-Yuan; Yuan, Zi-Guo; Petersen, Eskild; Li, Jie; Zhang, Xiu-Xiang; Li, Xiu-Zhen; Li, Hao-Xin; Lv, Zhi-Cheng; Cheng, Tian; Ren, Di; Yang, Gui-Lian; Lin, Rui-Qing; Zhu, Xing-Quan

    2012-12-01

    Toxoplasma gondii is an obligate intracellular parasite infecting humans and other warm-blooded animals, resulting in serious public health problems and economic losses worldwide. Rhoptries are involved in T. gondii invasion and host cell interaction and have been implicated as important virulence factors. In the present study, a DNA vaccine expressing rhoptry protein 13 (ROP13) of T. gondii inserted into eukaryotic expression vector pVAX I was constructed, and the immune protection it induced in Kunming mice was evaluated. Kunming mice were immunized intramuscularly with pVAX-ROP13 and/or with interleukin-18 (IL-18). Then, we evaluated the immune response using a lymphoproliferative assay, cytokine and antibody measurements, and the survival times of mice challenged with the virulent T. gondii RH strain (type I) and the cyst-forming PRU strain (type II). The results showed that pVAX-ROP13 alone or with pVAX/IL-18 induced a high level of specific anti-T. gondii antibodies and specific lymphocyte proliferative responses. Coinjection of pVAX/IL-18 significantly increased the production of gamma interferon (IFN-γ), IL-2, IL-4, and IL-10. Further, challenge experiments showed that coimmunization of pVAX-ROP13 with pVAX/IL-18 significantly (P < 0.05) increased survival time (32.3 ± 2.7 days) compared with pVAX-ROP13 alone (24.9 ± 2.3 days). Immunized mice challenged with T. gondii cysts (strain PRU) had a significant reduction in the number of brain cysts, suggesting that ROP13 could trigger a strong humoral and cellular response against T. gondii cyst infection and that it is a potential vaccine candidate against toxoplasmosis, which provided the foundation for further development of effective vaccines against T. gondii.

  2. Soluble Dietary Fiber Can Protect the Gastrointestinal Mucosa Against Nonsteroidal Anti-Inflammatory Drugs in Mice.

    PubMed

    Satoh, Hiroshi; Urushidani, Tetsuro

    2016-07-01

    Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious problem in patients, but effective therapy is not available at present. The effects of feeding conditions and dietary fiber (DF) on NSAID-induced gastrointestinal lesions were examined in mice. NSAIDs (indomethacin, diclofenac, loxoprofen, aspirin) were administered to male mice in various feeding conditions. Gastrointestinal lesions were examined 24 h after NSAID dosing. Regular diets, dietary-fiber-free diet (FFD), and diets supplemented with various types of DF were given to mice. NSAIDs produced marked ulcers and perforations selectively in the gastric antrum when they were administered after feeding of regular diet for 2 h after a 22-h fast. When NSAIDs, except for aspirin, were administered in unfasted conditions, they caused marked lesions in the small intestine. When mice were given FFD, antral ulcers and intestinal lesions induced by indomethacin (30 mg/kg, s.c.) markedly decreased, but when cellulose, an insoluble DF, was added to FFD, the lesions appeared again. The addition of pectin, a soluble DF, to regular diet containing 4.1 % crude fiber significantly inhibited the formation of antral ulcers as well as intestinal lesions caused by indomethacin or diclofenac (100 mg/kg, s.c.). The results indicated that NSAIDs given after feeding of diet produced ulcers selectively in the gastric antrum. The severity of the gastrointestinal lesions depended on the concentration of soluble or insoluble DF in food. Our results suggest that soluble DF such as pectin may be a safe means for protecting the gastrointestinal mucosa against NSAIDs.

  3. Administration of melatonin protects against acetylsalicylic acid-induced impairment of male reproductive function in mice

    PubMed Central

    Emami, Niloufar Hedayati; Lafout, Farzaneh Mahmoudi; Mohammadghasemi, Fahimeh

    2018-01-01

    Objective(s): Melatonin, an important hormone secreted by the epiphysis, is a powerful anti-oxidant with a high potential to neutralize medical toxins. The goal of this study was to demonstrate the beneficial effect of melatonin on epididymal sperm and reproductive parameters in mice treated with acetylsalicylic acid (ASA). Materials and Methods: Male adult mice were divided into four treatment groups: control, ASA, melatonin, and ASA+melatonin. Mice were administered ASA (50 mg/kg, orally) and/or melatonin (10 mg/kg, intraperitoneally), or vehicle control, for 14 days. Sperm count, sperm motility, and sperm morphology were evaluated to assess fertility. A colorimetric assay was used to measure serum total antioxidant capacity (TAC). A sperm chromatin dispersion (SCD) test was used to assess sperm chromatin integrity. Sex hormone levels were measured by ELISA. Results: Compared to the control group, ASA treatment resulted in a significant decrease in sperm parameters (P<0.05), as well as a decrease in the integrity of sperm chromatin (P<0.01). ASA treatment also reduced serum testosterone and TAC levels (P<0.05). Co-administration of melatonin with ASA significantly improved epididymal sperm parameters and increased serum testosterone and TAC levels compared to the ASA-treated group. LH level was not different in the combined treatment group compared to control or ASA treatment. Conclusion: Short-term administration of ASA (50 mg/kg) has adverse effects on male reproductive function in mice. Co-administration of melatonin protects against ASA-induced impairment of male reproductive function by preventing the reduction in serum TAC and testosterone levels seen with ASA treatment alone. PMID:29456808

  4. Hepcidin protects against lethal E. coli sepsis in mice inoculated with isolates from septic patients.

    PubMed

    Stefanova, Deborah; Raychev, Antoan; Deville, Jaime; Humphries, Romney; Campeau, Shelley; Ruchala, Piotr; Nemeth, Elizabeta; Ganz, Tomas; Bulut, Yonca

    2018-05-07

    Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for protection from infection-associated mortality with the siderophilic pathogens Yersinia enterocolitica and Vibrio vulnificus However, the evolutionary conservation of the hypoferremic response to infection suggests that not only rare siderophilic bacteria but also common pathogens may be targeted by this mechanism. We tested 10 clinical isolates of E. coli from children with sepsis and found that both genetic (hepcidin knockout, HKO) and iatrogenic iron overload (IV iron) potentiated infection with 8 out of 10 studied isolates: after peritoneal injection of E. coli , iron-loaded mice developed sepsis with 60% to 100% mortality within 24h while control wild type mice suffered 0% mortality. Using one strain for more detailed study, we show that iron overload allowed rapid bacterial multiplication and dissemination. We further found that the presence of non-transferrin bound iron (NTBI) in circulation is more important than total plasma or tissue iron in rendering mice susceptible to infection and mortality. Post infection treatment of HKO mice with just two doses of the hepcidin agonist PR73 abolished NTBI and completely prevented sepsis-associated mortality. We demonstrate that siderophilic phenotype extends to clinically common pathogens. The use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism. Copyright © 2018 American Society for Microbiology.

  5. Potential protective effects of Clostridium butyricum on experimental gastric ulcers in mice

    PubMed Central

    Wang, Fang-Yan; Liu, Jia-Ming; Luo, Hai-Hua; Liu, Ai-Hua; Jiang, Yong

    2015-01-01

    AIM: To investigate the effects of Clostridium butyricum (C. butyricum) on experimental gastric ulcers (GUs) induced by alcohol, restraint cold stress, or pyloric ligation in mice, respectively. METHODS: One hundred and twenty mice were randomly allocated into three types of gastric ulcer models (n = 40 each), induced by alcohol, restraint cold stress, or pyloric ligation. In each GU model, 40 mice were allocated into four groups (n = 10 each): the sham control group; model group (GU induction without pretreatment); C. butyricum group (GU induction with C. butyricum pretreatment); and Omeprazole group (GU induction with Omeprazole pretreatment). The effects of C. butyricum were evaluated by examining the histological changes in the gastric mucosal erosion area, the activities of superoxide dismutase (SOD) and catalase (CAT), the level of malondialdehyde (MDA), and the contents of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, leukotriene B4 (LTB4) and 6-keto-PGF-1α (degradation product of PGI2) in the gastric tissue. RESULTS: Our data showed that C. butyricum significantly reduced the gastric mucosal injury area and ameliorated the pathological conditions of the gastric mucosa. C. butyricum not only minimized the decreases in activity of SOD and CAT, but also reduced the level of MDA in all three GU models used in this study. The accumulation of IL1-β, TNF-α and LBT4 decreased, while 6-keto-PGF-1α increased with pretreatment by C. butyricum in all three GU models. CONCLUSION: Our data demonstrated the protective effects of pretreatment with C. butyricum on anti-oxidation and anti-inflammation in different types of GU models in mice. Further studies are needed to explore its potential clinical benefits. PMID:26217085

  6. Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice.

    PubMed

    Li, Wei-Feng; Hao, Ding-Jun; Fan, Ting; Huang, Hui-Min; Yao, Huan; Niu, Xiao-Feng

    2014-02-05

    The quaternary benzo[c]phenanthridine alkaloid, chelerythrine (CHE), is of great practical and research interest because of its pronounced, widespread physiological effects, primarily antimicrobial and anti-inflammatory, arising from its ability to interact with proteins and DNA. Although CHE was originally shown to possess anti-inflammatory properties, its effects on acute gastric ulcer have not been previously explored. The aim of the present study is to evaluate the protective effect of CHE on ethanol induced gastric ulcer in mice. Administration of CHE at doses of 1, 5 and 10mg/kg bodyweight prior to ethanol ingestion dose-dependently inhibited gastric ulcer. The gastric mucosal lesion was assessed by ulcer area, gastric juice acidity, myeloperoxidase (MPO) activities, macroscopic and histopathological examinations. CHE significantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and histological score in a dose-dependent manner. In addition, CHE also significantly inhibited nitric oxide (NO) concentration, pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level in serum and gastric mucosal in the mice exposed to ethanol induced ulceration in a dose-dependent manner. In addition, immunohistochemical analysis revealed that CHE markedly attenuated the overexpression of nuclear factor-κB in gastric mucosa of mice. It was concluded that CHE represents a potential therapeutic option to reduce the risk of gastric ulceration. In addition, acute toxicity study revealed no abnormal sign to the mice treated with CHE (15mg/kg). These findings suggest that the gastroprotective activity of CHE might contribute in adjusting the inflammatory cytokine by regulating the NF-κB signalling pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge.

    PubMed

    Devera, T Scott; Prusator, Dawn K; Joshi, Sunil K; Ballard, Jimmy D; Lang, Mark L

    2015-06-25

    Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.

  8. Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

    PubMed Central

    Clement, Cecilia G.; Evans, Scott E.; Evans, Christopher M.; Hawke, David; Kobayashi, Ryuji; Reynolds, Paul R.; Moghaddam, Seyed J.; Scott, Brenton L.; Melicoff, Ernestina; Adachi, Roberto; Dickey, Burton F.; Tuvim, Michael J.

    2008-01-01

    Rationale: The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity. Objectives: To test the inducibility of lung defenses against bacterial challenge. Methods: Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol. Measurements and Main Results: Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48–72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid. Conclusions: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value. PMID:18388354

  9. Refined live attenuated Salmonella enterica serovar Typhimurium and Enteritidis vaccines mediate homologous and heterologous serogroup protection in mice.

    PubMed

    Tennant, Sharon M; Schmidlein, Patrick; Simon, Raphael; Pasetti, Marcela F; Galen, James E; Levine, Myron M

    2015-12-01

    Invasive nontyphoidal Salmonella (NTS) infections constitute a major health problem among infants and toddlers in sub-Saharan Africa; these infections also occur in infants and the elderly in developed countries. We genetically engineered a Salmonella enterica serovar Typhimurium strain of multilocus sequence type 313, the predominant genotype circulating in sub-Saharan Africa. We evaluated the capacities of S. Typhimurium and Salmonella enterica serovar Enteritidis ΔguaBA ΔclpX live oral vaccines to protect mice against a highly lethal challenge dose of the homologous serovar and determined protection against other group B and D serovars circulating in sub-Saharan Africa. The vaccines S. Typhimurium CVD 1931 and S. Enteritidis CVD 1944 were immunogenic and protected BALB/c mice against 10,000 50% lethal doses (LD50) of S. Typhimurium or S. Enteritidis, respectively. S. Typhimurium CVD 1931 protected mice against the group B serovar Salmonella enterica serovar Stanleyville (91% vaccine efficacy), and S. Enteritidis CVD 1944 protected mice against the group D serovar Salmonella enterica serovar Dublin (85% vaccine efficacy). High rates of survival were observed when mice were infected 12 weeks postimmunization, indicating that the vaccines elicited long-lived protective immunity. Whereas CVD 1931 did not protect against S. Enteritidis R11, CVD 1944 did mediate protection against S. Typhimurium D65 (81% efficacy). These findings suggest that a bivalent (S. Typhimurium and S. Enteritidis) vaccine would provide broad protection against the majority of invasive NTS infections in sub-Saharan Africa. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  10. Infusion of mesenchymal stem cells protects lung transplants from cold ischemia-reperfusion injury in mice.

    PubMed

    Tian, Weijun; Liu, Yi; Zhang, Bai; Dai, Xiangchen; Li, Guang; Li, Xiaochun; Zhang, Zhixiang; Du, Caigan; Wang, Hao

    2015-02-01

    Cold ischemia-reperfusion injury (IRI) is a major cause of graft failure in lung transplantation. Despite therapeutic benefits of mesenchymal stem cells (MSCs) in attenuating acute lung injury, their protection of lung transplants from cold IRI remains elusive. The present study was to test the efficacy of MSCs in the prevention of cold IRI using a novel murine model of orthotopic lung transplantation. Donor lungs from C57BL/6 mice were exposed to 6 h of cold ischemia before transplanted to syngeneic recipients. MSCs were isolated from the bone marrows of C57BL/6 mice for recipient treatment. Gas exchange was determined by the measurement of blood oxygenation, and lung injury and inflammation were assessed by histological analyses. Intravenously delivered MSC migration/trafficking to the lung grafts occurred within 4-hours post-transplantation. As compared to untreated controls, the graft arterial blood oxygenation (PaO2/FiO2) capacity was significantly improved in MSC-treated recipients as early as 4 h post-reperfusion and such improvement continued over time. By 72 h, oxygenation reached normal level that was not seen in controls. MSCs treatment conferred significant protection of the grafts from cold IRI and cell apoptosis, which is correlated with less cellular infiltration, a decrease in proinflammatory cytokines (TNF-α, IL-6) and toll-like receptor 4, and an increase in anti-inflammatory TSG-6 generation. MSCs provide significant protection against cold IRI in lung transplants, and thus may be a promising strategy to improve outcomes after lung transplantation.

  11. Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice.

    PubMed

    Amemiya, Kei; Meyers, Jennifer L; Trevino, Sylvia R; Chanh, Tran C; Norris, Sarah L; Waag, David M

    2006-02-27

    We evaluated the effect of interleukin (IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12. There was a seven- to nine-fold increase in IgG2a levels, and a significant increase in the proliferative response and interferon (IFN)-gamma production by splenocytes from mice that received B. mallei and IL-12. We saw an increase in survivors in the groups of mice that received B. mallei and IL-12 when challenged, compared to mice that received only B. mallei or IL-12. The results suggest that IL-12 can enhance the Th1-like immune response to B. mallei and mediate limited protection from a lethal challenge.

  12. PROTECTION OF MICE AGAINST IRRADIATION AND TETANUS BY HOMOLOGOUS BONE MARROW CELLS FROM HYPERIMMUNIZED DONORS

    SciTech Connect

    Stoloff, I.L.; Weiss, A.J.

    1963-07-01

    Female mice of inbred strains (101 x C3H, BDF, C57B1, Balb/C, C3H, CBA, and LAF) were immunized with 0.2 ml of alum-precipitated tetanus toxoid subcutaneously, followed in 3 weeks by 0.2 ml of fluid toxoid intravenously. Four days after the last injection the marrow was mechanically dispersed and 10- 20 million marrow cells were inoculated intravenously into mice that had received on the previous day a lethal dose of whole-body x irradiation. The LD/sub 96/ for 30 days of each host strain was: BDF, 950 r; LAF, 950 r; 101 x C3H, 900 r; Balb/C, 800 r; C3H, 800 r;more » C57B1, 800 r; and CBA, 700 r. Mice in which isologous bone marrow cells from hyperimmunized donors were transferred to irradiated hosts showed a high degree of protection against irradiation in all strains studied. The percentage of 30-day irradiation survivors follows: C3H, 100%; 101 x C3H, 100%; CBA, 90%; BDF, 90%; Balb/C, 60%; and C57B1, 70%. There were no survivors among groups irradiated but not protected with bone marrow. The percentage of 7- day survivors after toxin challenge for each of 4 different strains receiving isologous cells from hyperimmunized donors ranged between 87 and 100%. Normal mice, similar in weight to the experimental groups (called toxin controls) all died of tetanus within 48 hr of challenge with toxin. Other results showed that homologous disease does not interfere significantly with the in vivo neutralization of tetanus toxin by antitoxin. It was concluded that homologous disease is a clinical entity which, in some donor-host combinations, is associated with a host-vs-graft reaction and, in one strain combination so far tested, is associated with a graft-vshost reaction. The experiments showed that the genetic relation between donor and host is a factor in determining which type of immunologic reaction may occur. (TCO)« less

  13. The protective effect of huperzine A against hepatic ischemia reperfusion injury in mice.

    PubMed

    Yang, Y; Yang, J; Jiang, Q

    2014-06-01

    Nowadays, hepatic ischemia reperfusion (HI/R) injury is regarded as a serious concern in clinical practices. Huperzine A (HupA) is an alkaloid isolated from the Chinese folk medicine huperzia serrate, which has possessed diverse pharmacological actions. A mouse model of HI/R was caused by clamping the hepatic artery, the hepatoportal vein, and the bile duct with a vascular clamp for 30 minutes followed by reperfusion for 6 hours under anesthesia. The sham group experienced the identical procedure without hepatic ischemia. The HupA group received an injection into the tail vein 5 minutes prior to HI/R at the doses of 167 and 500 μg/kg. The vehicle group was injected with physiological saline instead of HupA. The liver function was assessed by determinations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA), and glutathione (GSH) were also measured spectrophotometrically. In addition, the activities of hepatic inflammatory mediators such as nuclear factor kappa B (NF-κB) p65, tumor necrosis factors-α (TNF-α, interleukin-1β (IL-1β) and IL-6 were also measured. Furthermore, the apoptotic damage was evaluated by measuring caspase-3 activity in hepatic tissues. Treatment with HupA in mice at the doses of 167 and 500 μg/kg remarkably reduced serum ALT and AST activities in HupA-treated ischemic mice. Furthermore, HupA treatment could enhance the activities of hepatic tissue SOD, CAT, and GSH but decrease MDA tissue content. The activities of inflammatory cytokines including NF-κB p65, TNF-α, IL-1β and IL-6 were all decreased in ischemic mice treated with HupA. Colorimetric test results illustrated that a marked reduction of caspase-3 activity was found in the HupA-treated group compared with the vehicle group. Our present data suggest that HupA has a protective role against HI/R injury of mice and antioxidative, anti-inflammatory, and antiapoptotic

  14. Immunogenicity and Protective Efficacy of a Plasmodium yoelii Hsp60 DNA Vaccine in BALB/c Mice

    PubMed Central

    Sanchez, Gloria I.; Sedegah, Martha; Rogers, William O.; Jones, Trevor R.; Sacci, John; Witney, Adam; Carucci, Daniel J.; Kumar, Nirbhay; Hoffman, Stephen L.

    2001-01-01

    The gene encoding the 60-kDa heat shock protein of Plasmodium yoelii (PyHsp60) was cloned into the VR1012 and VR1020 mammalian expression vectors. Groups of 10 BALB/c mice were immunized intramuscularly at 0, 3, and 9 weeks with 100 μg of PyHsp60 DNA vaccine alone or in combination with 30 μg of pmurGMCSF. Sera from immunized mice but not from vector control groups recognized P. yoelii sporozoites, liver stages, and infected erythrocytes in an indirect fluorescent antibody test. Two weeks after the last immunization, mice were challenged with 50 P. yoelii sporozoites. In one experiment the vaccine pPyHsp60-VR1012 used in combination with pmurGMCSF gave 40% protection (Fisher's exact test; P = 0.03, vaccinated versus control groups). In a second experiment this vaccine did not protect any of the immunized mice but induced a delay in the onset of parasitemia. In neither experiment was there any evidence of a protective effect against the asexual erythrocytic stage of the life cycle. In a third experiment mice were primed with PyHsp60 DNA, were boosted 2 weeks later with 2 × 103 irradiated P. yoelii sporozoites, and were challenged several weeks later. The presence of PyHsp60 in the immunization regimen did not lead to reduced blood-stage infection or development of parasites in hepatocytes. PyHsp60 DNA vaccines were immunogenic in BALB/c mice but did not consistently, completely protect against sporozoite challenge. The observation that in some of the PyHsp60 DNA vaccine-immunized mice there was protection against infection or a delay in the onset of parasitemia after sporozoite challenge deserves further evaluation. PMID:11349057

  15. CpG oligodeoxyribonucleotides protect mice from Burkholderia pseudomallei but not Francisella tularensis Schu S4 aerosols

    PubMed Central

    2010-01-01

    Studies have shown that CpG oligodeoxyribonucleotides (ODN) protect mice from various bacterial pathogens, including Burkholderia pseudomallei and Francisella tularensis live vaccine strain (LVS), when administered before parenteral challenge. Given the potential to develop CpG ODN as a pre-treatment for multiple bacterial biological warfare agents, we examined survival, histopathology, and cytokine data from CpG ODN-treated C57BL/6 mice to determine whether previously-reported protection extended to aerosolized B. pseudomallei 1026b and highly virulent F. tularensis Schu S4 infections. We found that, although CpG ODN protected mice from aerosolized B. pseudomallei challenges, the immunostimulant failed to benefit the animals exposed to F. tularensis Schu S4 aerosols. Our results, which contrast with earlier F. tularensis LVS studies, highlight potential differences in Francisella species pathogenesis and underscore the need to evaluate immunotherapies against human pathogenic species. PMID:20181102

  16. CpG oligodeoxyribonucleotides protect mice from Burkholderia pseudomallei but not Francisella tularensis Schu S4 aerosols.

    PubMed

    Rozak, David A; Gelhaus, Herbert C; Smith, Mark; Zadeh, Mojgan; Huzella, Louis; Waag, David; Adamovicz, Jeffrey J

    2010-02-05

    Studies have shown that CpG oligodeoxyribonucleotides (ODN) protect mice from various bacterial pathogens, including Burkholderia pseudomallei and Francisella tularensis live vaccine strain (LVS), when administered before parenteral challenge. Given the potential to develop CpG ODN as a pre-treatment for multiple bacterial biological warfare agents, we examined survival, histopathology, and cytokine data from CpG ODN-treated C57BL/6 mice to determine whether previously-reported protection extended to aerosolized B. pseudomallei 1026b and highly virulent F. tularensis Schu S4 infections. We found that, although CpG ODN protected mice from aerosolized B. pseudomallei challenges, the immunostimulant failed to benefit the animals exposed to F. tularensis Schu S4 aerosols. Our results, which contrast with earlier F. tularensis LVS studies, highlight potential differences in Francisella species pathogenesis and underscore the need to evaluate immunotherapies against human pathogenic species.

  17. Interleukin-12 Induces a Th1-Like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

    DTIC Science & Technology

    2006-01-01

    sublethal and lethal intraperitoneal glanders ( Burkholderia mallei ). Vet Pathol 2000;37:626–36. [34] Jankovic D, Caspar P, Zweig M, Garcia-Moll M...Vaccine 24 (2006) 1413–1420 Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice Kei Amemiya...IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12

  18. The Protective Effect of Selenium on Oxidative Stress Induced by Waterpipe (Narghile) Smoke in Lungs and Liver of Mice.

    PubMed

    Charab, Mohamad A; Abouzeinab, Noura S; Moustafa, Mohamed E

    2016-12-01

    Waterpipe smoking is common in the Middle East populations and results in health problems. In this study, we investigated the effects of exposure of mice to waterpipe smoke on oxidative stress in lungs and liver and the effects of selenium administration before smoke exposure on the oxidative stress. Twenty-four mice were divided equally into four groups: (i) the control mice received no exposure or treatment; (ii) mice exposed to waterpipe smoke; (iii) mice received intraperitoneal injection of 0.59 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke; and (iv) mice received intraperitoneal injection of 1.78 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke. Mice were exposed to waterpipe smoke every other day for four times within 8 successive days. Malondialdehyde and nitric oxide levels were significantly higher in the lungs and liver, while the activities of superoxide dismutase, glutathione peroxidase-1, and catalase were significantly lower in the waterpipe smoke group when compared to control mice. Treating mice with 1.78 μg selenium/kg body weight significantly restored the normal levels of these parameters. Histological examinations of lungs and liver confirmed the protective actions of selenium against the effects of exposure to waterpipe smoke. In conclusion, exposure of mice to waterpipe smoke-induced oxidative stress in lungs and liver. Administration of low level of selenium, 1.78 μg selenium/kg body weight as sodium selenite, exerted protective effects against oxidative stress induced by exposure to waterpipe smoke.

  19. Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice

    SciTech Connect

    Wang, Jian-Qing; Second Affiliated Hospital, Anhui Medical University, Hefei 230601; Chen, Xi

    2013-01-15

    A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl{sub 4})-induced hepatic fibrosis. Phenylbutyric acid (PBA) is a well-known chemical chaperone that inhibits endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling. In the present study, we investigated the effects of PBA on CCl{sub 4}-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl{sub 4} (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl{sub 4} + PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl{submore » 4} injection to the end. As expected, PBA significantly attenuated CCl{sub 4}-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl{sub 4}-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl{sub 4}-induced hepatic nuclear factor kappa B (NF-κB) p65 translocation and extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) phosphorylation. Interestingly, CCl{sub 4}-induced α-smooth muscle actin (α-SMA), a marker for the initiation phase of HSC activation, was significantly attenuated in mice pretreated with PBA. Correspondingly, CCl{sub 4}-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl{sub 4}-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl{sub 4}-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation. Highlights: ► CCl{sub 4} induces hepatic ER stress, inflammation, HSC activation and hepatic fibrosis. ► PBA alleviates CCl{sub 4}-induced hepatic ER stress and UPR signaling activation. ► PBA inhibits CCl{sub 4

  20. Human Anti-Plague Monoclonal Antibodies Protect Mice from Yersinia pestis in a Bubonic Plague Model

    PubMed Central

    Xiao, Xiaodong; Zhu, Zhongyu; Dankmeyer, Jennifer L.; Wormald, Michael M.; Fast, Randy L.; Worsham, Patricia L.; Cote, Christopher K.; Amemiya, Kei; Dimitrov, Dimiter S.

    2010-01-01

    Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a naïve phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans. PMID:20976274

  1. Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice

    PubMed Central

    Wong, Jennifer C.; Dutton, Stacey B. B.; Collins, Stephen D.; Schachter, Steven; Escayg, Andrew

    2016-01-01

    De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15–20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy. PMID:27799911

  2. Human anti-plague monoclonal antibodies protect mice from Yersinia pestis in a bubonic plague model.

    PubMed

    Xiao, Xiaodong; Zhu, Zhongyu; Dankmeyer, Jennifer L; Wormald, Michael M; Fast, Randy L; Worsham, Patricia L; Cote, Christopher K; Amemiya, Kei; Dimitrov, Dimiter S

    2010-10-13

    Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a naïve phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans.

  3. [Protective effects of five different types of Dendrobium on CCl4-induced liver injury in mice].

    PubMed

    Wang, Kai; Sui, Dan-Juan; Wang, Chang-Suo; Yang, Li; Ouyang, Zhen; Chen, Nai-Fu; Han, Bang-Xing; Wei, Yuan

    2017-05-01

    This study aims to investigate the protective effect of Dendrobium huoshanense, D.officinale(Huoshan), D.officinale(Yunnan), D.moniliforme and D. henanense on CCl4-induced hepatic damage in mice. C57BL/6 mice were randomly divided into control group, model group, high-dose(7.5 g•kg⁻¹) and low-dose (1.25 g•kg⁻¹) groups of the five Dendrobium. Each group was intragastrically administered with drugs for 2 weeks. The control group was intraperitoneally injected with Olive oil solution, while the other groups were intraperitoneally given 0.5%CCl4combined with Olive oil solution 2 h later after the last administration. Subsequently, ALT and AST activities in serum, SOD activities and MDA contents in liver tissues were determined in all groups 16 h later after administration. The liver index was calculated, and hepatic histopathological examination was performed. The mRNA expressions of IL-1β, IL-6 and TNF-α were analyzed by Real-time PCR. Compared with the CCl4 model group, the activities of ALT and AST in serum decreased significantly in the five different Dendrobium groups. Meanwhile, in liver tissues, the levels of MDA reduced obviously, while the SOD activities markedly increased. Furthermore, liver tissue damage induced by CCl4 was ameliorated according to the histopathological examination. IL-1β, IL-6 and TNF-α mRNA expressions in D.huoshanense-treated liver tissues were significantly decreased. In conclusion, the five different Dendrobium groups showed hepatoprotective effects on CCl4-induced acute liver injury in mice. However, there were differences among Dendrobium of different types and origins. The protect effect of D.huoshanense is the most obvious, and the order of the protective effect of the other Dendrobium from high to low is D.officinale(Yunnan), D. officinale(Huoshan), D.henanense and D.moniliforme. The differences between the different types of Dendrobium might be related to their chemical components. Copyright© by the Chinese

  4. Intranasal Immunization with Nontypeable Haemophilus influenzae Outer Membrane Vesicles Induces Cross-Protective Immunity in Mice

    PubMed Central

    Roier, Sandro; Leitner, Deborah R.; Iwashkiw, Jeremy; Schild-Prüfert, Kristina; Feldman, Mario F.; Krohne, Georg; Reidl, Joachim; Schild, Stefan

    2012-01-01

    Abstract Haemophilus influenzae is a Gram-negative human-restricted bacterium that can act as a commensal and a pathogen of the respiratory tract. Especially nontypeable H. influenzae (NTHi) is a major threat to public health and is responsible for several infectious diseases in humans, such as pneumonia, sinusitis, and otitis media. Additionally, NTHi strains are highly associated with exacerbations in patients suffering from chronic obstructive pulmonary disease. Currently, there is no licensed vaccine against NTHi commercially available. Thus, this study investigated the utilization of outer membrane vesicles (OMVs) as a potential vaccine candidate against NTHi infections. We analyzed the immunogenic and protective properties of OMVs derived from various NTHi strains by means of nasopharyngeal immunization and colonization studies with BALB/c mice. The results presented herein demonstrate that an intranasal immunization with NTHi OMVs results in a robust and complex humoral and mucosal immune response. Immunoprecipitation revealed the most important immunogenic proteins, such as the heme utilization protein, protective surface antigen D15, heme binding protein A, and the outer membrane proteins P1, P2, P5 and P6. The induced immune response conferred not only protection against colonization with a homologous NTHi strain, which served as an OMV donor for the immunization mixtures, but also against a heterologous NTHi strain, whose OMVs were not part of the immunization mixtures. These findings indicate that OMVs derived from NTHi strains have a high potential to act as a vaccine against NTHi infections. PMID:22880074

  5. Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice.

    PubMed

    Sun, Xue; Duan, Xingping; Wang, Changyuan; Liu, Zhihao; Sun, Pengyuan; Huo, Xiaokui; Ma, Xiaodong; Sun, Huijun; Liu, Kexin; Meng, Qiang

    2017-07-05

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside, on NAFLD induced by a high-fat diet (HFD) in mice, and further to elucidate the mechanisms underlying GA protection. GA treatment significantly reduced the relative liver weight, serum ALT, AST activities, levels of serum lipid, blood glucose and insulin. GA suppressed lipid accumulation in liver. Further mechanism investigation indicated that GA reduced hepatic lipogenesis via downregulating SREBP-1c, FAS and SCD1 expression, increased fatty acids β-oxidation via an increase in PPARα, CPT1α and ACADS, and promoted triglyceride metabolism through inducing LPL activity. Furthermore, GA reduced gluconeogenesis through repressing PEPCK and G6Pase, and increased glycogen synthesis through an induction in gene expression of PDase and GSK3β. In addition, GA increased insulin sensitivity through upregulating phosphorylation of IRS-1 and IRS-2. In conclusion, GA produces protective effect against NAFLD, due to regulation of genes involved in lipid, glucose homeostasis and insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Clostridium perfringens beta toxin DNA prime-protein boost elicits enhanced protective immune response in mice.

    PubMed

    Solanki, Amit Kumar; Bhatia, Bharati; Kaushik, Himani; Deshmukh, Sachin K; Dixit, Aparna; Garg, Lalit C

    2017-07-01

    Clostridium perfringens beta toxin (CPB) is the primary pathogenic factor responsible for necrotic enteritis in sheep, cattle and humans. Owing to rapid progression of the disease, vaccination is the only possible recourse to avoid high mortality in animal farms and huge economic losses. The present study reports evaluation of a cpb gene-based DNA vaccine encoding the beta toxin of C. perfringens with homologous as well as heterologous booster strategy. Immunization strategy employing heterologous booster with heat-inactivated rCPB mounted stronger immune response when compared to that generated by homologous booster. Antibody isotyping and cytokine ELISA demonstrated the immune response to be Th1-biased mixed immune response. While moderate protection of immunized BALB/c and C57BL/6 mice against rCPB challenge was observed with homologous booster strategy, heterologous booster strategy led to complete protection. Thus, beta toxin-based DNA vaccine using the heterologous prime-boosting strategy was able to generate better immune response and conferred greater degree of protection against high of dose rCPB challenge than homologous booster regimen, making it an effective vaccination approach against C. perfringens beta toxin.

  7. Licorice Pretreatment Protects Against Brain Damage Induced by Middle Cerebral Artery Occlusion in Mice.

    PubMed

    Lim, Chiyeon; Lim, Sehyun; Lee, Byoungho; Kim, Buyeo; Cho, Suin

    2018-05-01

    Licorice is extracted from the roots of plants in the Glycyrrhiza genus, especially Glycyrrhiza uralensis in China and Korea. It has several pharmacological activities, including neuro-protective, anti-fungal, and anti-cariogenic effects. Ischemia/reperfusion-induced brain injury is a leading cause of adult disability and death; thus, the identification of anti-apoptotic, neuro-protective therapeutic agents is viewed as an attractive drug development strategy. Infarct volumes and the expression of several apoptosis-related proteins, including Bcl-xL, Bcl-2, caspase-8, and caspase-9, were evaluated by western blotting in the brains of mice subjected to middle cerebral artery occlusion (MCAO). Three consecutive days of oral pretreatment with the methanol extract of licorice (GRex) significantly reduced infarct volumes 24 h after MCAO. In addition, GRex effectively inhibited the activation of caspase-9 by upregulating protein expression of Bcl-xL and Bcl-2. The neuro-protective effect of licorice was due to its regulation of apoptosis-related proteins. These data suggest that licorice could be a potential candidate for the treatment of ischemia-induced brain damage.

  8. Protective effects of granulocyte colony-stimulating factor on endotoxin shock in mice with retrovirus-induced immunodeficiency syndrome.

    PubMed

    Toki, S; Hiromatsu, K; Aoki, Y; Makino, M; Yoshikai, Y

    1997-10-01

    Mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) were hypersensitive to lipopolysaccharide (LPS)-induced lethal shock accompanied by marked elevations of systematic interleukin 1beta (IL-beta) and interferon gamma (IFN-gamma) after LPS challenge. Pretreatment with 10 microg of recombinant human granulocyte colony-stimulating factor (rhG-CSF) protected MAIDS mice from hypersensitivity to LPS-induced lethal shock and this protection was concomitant with suppression of IFN-gamma production. Copyright 1997 Academic Press Limited.

  9. Protective effect of ethyl pyruvate on mice sperm parameters in phenylhydrazine induced hemolytic anemia.

    PubMed

    Mozafari, Ali Akbar; Shahrooz, Rasoul; Ahmadi, Abbas; Malekinjad, Hassan; Mardani, Karim

    2016-01-01

    The aim of the present study was to assess the protective effect of ethyl pyruvate (EP) on sperm quality parameters, testosterone level and malondialdehyde (MDA) in phenylhydrazine (PHZ) treated mice. For this purpose, 32 NMRI mice with the age range of 8 to 10 weeks, weight average 26.0 ± 2.0 g, were randomly divided into four equal groups. The control group (1) received normal saline (0. 1 mL per day) by intraperitoneal injection (IP). Group 2 (PHZ group) was treated with initial dose of PHZ (8 mg 100 g(-1), IP) followed by 6 mg 100 g(-1) , IP every 48 hr. Group 3, (Group PHZ+EP) received PHZ (according to the previous prescription) with EP (40 mg kg(-1), daily, IP). Ethyl pyruvate group (4) received only EP (40 mg kg(-1), daily, IP). Treatment period was 35 days. After euthanasia, sperms from caudal region of epididymis were collected and the total mean sperm count, sperm viability, motility and morphology were determined. Testis tissue MDA and serum testosterone levels of all experimental groups were also evaluated. A considerable reduction in mean percentage of number, natural morphology of sperm, sperm motility and viability and serum testosterone concentration besides DNA injury increment among mice treating with PHZ in comparison with control group were observed. However, in PHZ+EP group the above mentioned parameters were improved. This study showed that PHZ caused induction of toxicity on sperm parameters and reduction of testosterone as well as the increment of MDA level and EP as an antioxidant could reduce destructive effects of PHZ on sperm parameters, testosterone level and lipid peroxidation.

  10. Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans.

    PubMed

    Knatko, Elena V; Ibbotson, Sally H; Zhang, Ying; Higgins, Maureen; Fahey, Jed W; Talalay, Paul; Dawe, Robert S; Ferguson, James; Huang, Jeffrey T-J; Clarke, Rosemary; Zheng, Suqing; Saito, Akira; Kalra, Sukirti; Benedict, Andrea L; Honda, Tadashi; Proby, Charlotte M; Dinkova-Kostova, Albena T

    2015-06-01

    The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro-inflammatory factors IL6 and IL1β, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. ©2015 American Association for Cancer Research.

  11. Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation.

    PubMed

    Long, Huibao; Xu, Bincan; Luo, Yanling; Luo, Keqin

    2016-05-01

    NLRP3 inflammasome activation is recently reported to be linked to the pathogenesis of sepsis. Artemisinin is shown to play beneficial effects in sepsis. However, the impacts of artemisinin on burn sepsis have not been investigated. This study is designed to investigate the role of artemisinin in burn sepsis and the involvement of NLRP3 inflammasome activation. Male BALB/c mice were randomly divided into sham burn, burn, burn sepsis, and artemisinin treated groups. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Adhesion molecules and neutrophil infiltration in lung and heart were detected by real-time polymerase chain reaction. Mortality rates were monitored. Artemisinin was added to Raw 264.7 cells that were stimulated with burn sepsis serum in the presence/absence of an inhibitor of NLRP3 inflammasome, 3, 4-methylenedioxy-β-nitrostyrene. Interleukin (IL) 1β and IL-18 messenger RNA expression as well as NLRP3 and caspase 1 protein were measured. Production of inflammatory cytokines in serum, levels of adhesion molecules and neutrophil infiltration in lung and heart, and mortality rate of burn septic mice were significantly higher than those of control. These effects were attenuated by artemisinin. Artemisinin down-regulated protein levels of NLRP3 and caspase 1 and inhibited the increases of IL-1β and IL-18 messenger RNA expression from Raw 264.7 cells that were stimulated with burn sepsis serum. These effects of artemisinin were not further strengthened in the presence of 4-methylenedioxy-β-nitrostyrene. Artemisinin protects mice from burn sepsis by attenuating the inflammatory response and alleviating inflammatory infiltration in vital organs, likely through inhibiting the activation of NLRP3 inflammasome. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans

    PubMed Central

    Knatko, Elena V.; Ibbotson, Sally H.; Zhang, Ying; Higgins, Maureen; Fahey, Jed W.; Talalay, Paul; Dawe, Robert S.; Ferguson, James; Huang, Jeffrey T.-J.; Clarke, Rosemary; Zheng, Suqing; Saito, Akira; Kalra, Sukirti; Benedict, Andrea L.; Honda, Tadashi; Proby, Charlotte M.; Dinkova-Kostova, Albena T.

    2015-01-01

    The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated, are lower than those that arise in their wild-type counterparts. Pharmacological Nrf2 activation by topical bi-weekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacological Nrf2 activation lowers the expression of the pro-inflammatory factors interleukin (IL)-6 and IL-1β, and cyclooxygenase (COX)-2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane, reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate end-point for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen, and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. PMID:25804610

  13. Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.

    PubMed

    Kanaan, Georges N; Ichim, Bianca; Gharibeh, Lara; Maharsy, Wael; Patten, David A; Xuan, Jian Ying; Reunov, Arkadiy; Marshall, Philip; Veinot, John; Menzies, Keir; Nemer, Mona; Harper, Mary-Ellen

    2018-04-01

    Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Edaravone Protect against Retinal Damage in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Liu, Xiaoyi; Chen, Xi; Xie, Ping; Yuan, Songtao; Zhang, Weiwei; Lin, Xiaojun; Liu, Qinghuai

    2014-01-01

    Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes. PMID:24897298

  15. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

    SciTech Connect

    Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Huang, Huimin; Niu, Xiaofeng, E-mail: niuxf@mail.xjtu.edu.cn

    Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increasedmore » pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. - Highlights: • THC decreased ethanol-induced pro-inflammatory cytokine release. • THC inhibited the production of NO in serum and gastric tissue. • THC reduced NF-κB expression and MPO accumulation in ethanol-induced gastric tissue.« less

  16. Heat-stable oral alga-based vaccine protects mice from Staphylococcus aureus infection.

    PubMed

    Dreesen, Imke A J; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

    2010-02-01

    While 15 million deaths per year are caused by communicable pathogens worldwide, health care authorities emphasize the considerable impact of poverty on the incidence of infectious diseases. The emergence of antigen-expressing plant tissues (e.g. rice, tomato, potato) has indicated the potential of land plants for low-cost vaccines in oral immunization programs. In this study, we engineered the chloroplasts of the unicellular green alga Chlamydomonas reinhardtii for the stable expression of the D2 fibronectin-binding domain of Staphylococcus aureus fused with the cholera toxin B subunit (CTB), under the control of rbcL UTRs. Analysis of sera and faeces of mice, fed for 5 weeks with transgenic algae grown in confined Wave Bioreactor, revealed the induction of specific mucosal and systemic immune responses. Algae-based vaccination significantly reduced the pathogen load in the spleen and the intestine of treated mice and protected 80% of them against lethal doses of S. aureus. Importantly, the alga vaccine was stable for more than 1.5 years at room temperature. These results indicate that C. reinhardtii may play an important role in molecular pharming, as it combines the beneficial features of land plant vaccines, while offering unmatched ease of growth compared to other members of the plant kingdom. Copyright 2010 Elsevier B.V. All rights reserved.

  17. Protective effect of Tribulus terrestris fruit extract on cerulein-induced acute pancreatitis in mice.

    PubMed

    Borran, Mina; Minaiyan, Mohsen; Zolfaghari, Behzad; Mahzouni, Parvin

    2017-01-01

    Antioxidant, anti-inflammatory, analgesic and antimicrobial activities of Tribulus terrestris ( T. terrestris ) could be helpful in the treatment of acute pancreatitis; thus, this study was designed to investigate the effects of T. terrestris on cerulein-induced acute pancreatitis in mice. Three doses (100, 200 and 400 mg/kg) of T. terrestris hydro-alcoholic extract were administered both orally (60 minutes before pancreatitis induction, p.o.) and intra-peritoneally (30 minutes before pancreatitis induction, i.p.) to different groups of mice (n=6). Pancreatitis was induced by five injections (i.p.) of cerulein 50μg/kg body weight with 1 hr intervals. Animals were euthanized 5 hr after the last injection of cerulein and tissue injures were assessed biochemically and pathologically. T. terrestris extract 200 and 400mg/kg (p.o.) and T. terrestris extract 400 mg/kg (i.p.) reduced pancreatic tissue myeloperoxidase (MPO) activity and serum amylase and lipase levels and alleviated histological parameters. These data suggest that T. terrestris hydro-alcoholic extract was effective in protecting against experimental acute pancreatitis and possibly the efficacy depends on dose and route of administration.

  18. Protective effect of Tribulus terrestris fruit extract on cerulein-induced acute pancreatitis in mice

    PubMed Central

    Borran, Mina; Minaiyan, Mohsen; Zolfaghari, Behzad; Mahzouni, Parvin

    2017-01-01

    Objective: Antioxidant, anti-inflammatory, analgesic and antimicrobial activities of Tribulus terrestris (T. terrestris) could be helpful in the treatment of acute pancreatitis; thus, this study was designed to investigate the effects of T. terrestris on cerulein-induced acute pancreatitis in mice. Materials and Methods: Three doses (100, 200 and 400 mg/kg) of T. terrestris hydro-alcoholic extract were administered both orally (60 minutes before pancreatitis induction, p.o.) and intra-peritoneally (30 minutes before pancreatitis induction, i.p.) to different groups of mice (n=6). Pancreatitis was induced by five injections (i.p.) of cerulein 50μg/kg body weight with 1 hr intervals. Animals were euthanized 5 hr after the last injection of cerulein and tissue injures were assessed biochemically and pathologically. Results: T. terrestris extract 200 and 400mg/kg (p.o.) and T. terrestris extract 400 mg/kg (i.p.) reduced pancreatic tissue myeloperoxidase (MPO) activity and serum amylase and lipase levels and alleviated histological parameters. Conclusion: These data suggest that T. terrestris hydro-alcoholic extract was effective in protecting against experimental acute pancreatitis and possibly the efficacy depends on dose and route of administration. PMID:28748172

  19. Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice

    PubMed Central

    Li, Lihua; Weng, Zhiyong; Yao, Chenjuan; Song, Yuanlin; Ma, Tonghui

    2015-01-01

    Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1−/− mice were used to create the MI model. Under physiological conditions, AQP1−/− mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays, and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1α in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1α levels in endothelial cells and decreased cellular apoptosis following MI. PMID:26348407

  20. Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

    PubMed

    Kawano, Ken-Ichi; Umemura, Kazuo

    2013-05-01

    The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd.

  1. A genetically adjuvanted influenza B virus vector increases immunogenicity and protective efficacy in mice.

    PubMed

    Kittel, Christian; Wressnigg, Nina; Shurygina, Anna Polina; Wolschek, Markus; Stukova, Marina; Romanovskaya-Romanko, Ekatherina; Romanova, Julia; Kiselev, Oleg; Muster, Thomas; Egorov, Andrej

    2015-10-01

    The existence of multiple antigenically distinct types and subtypes of influenza viruses allows the construction of a multivalent vector system for the mucosal delivery of foreign sequences. Influenza A viruses have been exploited successfully for the expression of extraneous antigens as well as immunostimulatory molecules. In this study, we describe the development of an influenza B virus vector whose functional part of the interferon antagonist NS1 was replaced by human interleukin 2 (IL2) as a genetic adjuvant. We demonstrate that IL2 expressed by this viral vector displays immune adjuvant activity in immunized mice. Animals vaccinated with the IL2 viral vector showed an increased hemagglutination inhibition antibody response and higher protective efficacy after challenge with a wild-type influenza B virus when compared to mice vaccinated with a control virus. Our results demonstrate that it is feasible to construct influenza B vaccine strains expressing immune-potentiating foreign sequences from the NS genomic segment. Based on these data, it is now hypothetically possible to create a trivalent (or quadrivalent) live attenuated influenza vaccine in which each component expresses a selected genetic adjuvant with tailored expression levels.

  2. The protective effect of 18β-Glycyrrhetinic acid against UV irradiation induced photoaging in mice.

    PubMed

    Kong, Song-Zhi; Chen, Hai-Ming; Yu, Xiu-Ting; Zhang, Xie; Feng, Xue-Xuan; Kang, Xin-Huang; Li, Wen-Jie; Huang, Na; Luo, Hui; Su, Zi-Ren

    2015-01-01

    It has been confirmed that repeated exposure of skin to ultraviolet (UV) radiation results in cutaneous oxidative stress and inflammation, which act in concert to cause premature skin aging, well known as photoaging. 18β-Glycyrrhetinic acid (GA), widely used to treat various tissue inflammations, is the main active component of licorice root, and has also been shown to possess favorable anti-oxidative property and modulating immunity function. In the present study, we investigated the potential protective effect of GA on UV-induced skin photoaging in a mouse model. During the experimental period of ten consecutive weeks, the dorsal depilated skin of mice was treated with topical GA for 2 hours prior to UV irradiation. The results showed that GA pretreatment significantly alleviated the macroscopic and histopathological damages in mice skin caused by UV. Meanwhile, the data also indicated that GA markedly up-regulated the activities of the antioxidant enzymes (SOD, GSH-Px), and increased the content of skin collagen, while obviously decreased malonaldehyde level and inhibited high expressions of matrix metalloproteinase-1 (MMP-1) and -3 (MMP-3), as well as down-regulated the expression of inflammatory cytokines such as IL-6, TNF-α and IL-10. Taken together, these findings amply demonstrate that GA observably attenuates UV-induced skin photoaging mainly by virtue of its antioxidative and anti-inflammatory properties, as well as regulating the abnormal expression of MMP-1 and MMP-3. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Anti-Staphylococcus aureus single-chain variable region fragments provide protection against mastitis in mice.

    PubMed

    Wang, Man; Zhang, Yan; Zhu, Jianguo

    2016-03-01

    Staphylococcus aureus is a leading causative agent of bovine mastitis, which can result in significant economic losses to the dairy industry. However, available vaccines against bovine mastitis do not confer adequate protection, although passive immunization with antibodies may be useful to prevent disease. Hence, we constructed a bovine single-chain variable region fragment (scFv) phage display library using cDNAs from peripheral blood lymphocytes of cows with S. aureus-induced mastitis. After four rounds of selection, eight scFvs that bound S. aureus antigens with high affinity were obtained. The framework regions of the variable domains (VH and VL) of the eight scFvs were highly conserved, and the complementarity-determining regions (CDRs) displayed significant diversity, especially CDR3 of the VH domain. All eight scFvs inhibited S. aureus growth in culture medium. Lactating mice were challenged by injecting S. aureus into the fourth mammary gland. Histopathological analysis showed that treatment with these scFvs prior to bacterial challenge maintained the structure of the mammary acini, decreased infiltration of polymorphonuclear neutrophils, increased levels of interferon-gamma and interleukin-4, and reduced tumor necrosis factor-alpha levels in mammary tissues, as compared with mice treatment with physiological saline (P < 0.05). These novel bovine scFvs may be suitable candidates for therapeutic agents for the prevention of S. aureus-induced bovine mastitis.

  4. Protective effect of Heliotropium eichwaldi against cisplatin-induced nephrotoxicity in mice.

    PubMed

    Sharma, Surendra Kr; Goyal, Naveen

    2012-05-01

    The aim of the present study was to evaluate the nephroprotective effect of methanolic extract of Heliotropium eichwaldii (MHE) in mice with cisplatin-induced acute renal damage. Nephrotoxicity was induced by a single intraperitoneal injection of cisplatin (16mg/kg). Swiss albino mice were injected with vehicle, cisplatin, cisplatin plus MHE 200 mg/kg and cisplatin plus MHE 400mg/kg, respectively. MHE was administered for 7 d at a dose of 200 and 400 mg/kg per day orally starting 4 d before cisplatin injection. Animals were sacrificed 3d after treatment and blood as well as kidney tissue was isolated and analyzed. The various parameters such as blood urea nitrogen (BUN), serum creatinine (CRE), malondialdehyde (MDA), and catalase (CAT) and superoxide dismutase (SOD) activities were analyzed. MHE treatment significantly reduced BUN and serum CRE levels elevated by cisplatin administration (P<0.05). Also, it significantly attenuated cisplatin-induced increase in MDA level and improved the decreased CAT and SOD activities in renal cortical homogenates (P<0.05). Additionally, histopathological examination and scoring showed that MHE markedly ameliorated cisplatin-induced renal tubular necrosis. MHE can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  5. Mangiferin antagonizes TNF-α-mediated inflammatory reaction and protects against dermatitis in a mice model.

    PubMed

    Zhao, Yunpeng; Wang, Wenhan; Wu, Xihai; Ma, Xiaoqian; Qu, Ruize; Chen, Xiaomin; Liu, Chenghao; Liu, Yaoge; Wang, Xiaokai; Yan, Pengcheng; Zhang, Hao; Pan, Jingrui; Li, Weiwei

    2017-04-01

    This study aimed to investigate whether mangiferin played a protective role in a well-established dermatitis mouse model and tumor necrosis factor alpha (TNF-α)-induced RAW264.7 macrophages. Contact dermatitis is an inflammatory skin disease in the clinic, while its underlying mechanism still remains to be elucidated. Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-d-glucoside (C-glucosyl xanthone), a natural antioxidant that was reported to inhibit inflammatory reactions, has been recently proved to be a potential therapy for inflammation. As a result, the oxazolone-induced dermatitis mice models were established to explore whether mangiferin has an anti-inflammatory role in vivo. The phosphate-buffered saline treatment groups showed emblematic skin inflammation, whereas the administration of mangiferin obviously inhibited dermatitis in the mice models. Furthermore, exogenous mangiferin alleviated the inflammatory reaction in TNF-α-induced macrophages by suppressing the production of inflammation- and oxidative stress-associated molecules. Also, mangiferin treatment repressed the activation of nuclear factor-kappaB signaling pathway. To sum up, mangiferin could provide a new target for the therapy and prevention of skin inflammation. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Metabolomic analysis for the protective effects of mangiferin on sepsis-induced lung injury in mice.

    PubMed

    Wang, Yilin; Liu, Yang; Cao, Qiqi; Shi, Xuan; Lu, Hongtao; Gao, Songyan; Yang, Rui

    2018-06-01

    This study aimed to investigate the efficacy of mangiferin, including its known antioxidant and anti-inflammatory effects on sepsis-induced lung injury induced by a classical cecal ligation and puncture (CLP) models in mouse using a metabolomics approach. A total of 24 mice were randomly divided into four groups: the sham group was given saline before sham operation. The CLP group received the CLP operation only. HMF and LMF groups were given mangiferin treatment of high dose and low dose of mangiferin, respectively, before the CLP operation. One week after treatment, the mice were sacrificed and their lungs were collected for metabolomics analysis. We developed ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry to perform lung metabolic profiling analysis. With the methods of principal component analysis and partial least squares discriminant analysis, 58 potential metabolites associated with amino acid metabolism, purine metabolism, lipid metabolism and energy regulation were observed to be increased or reduced in HMF and LMF groups compared with the CLP group. Conclusively, our results suggest that mangiferin plays a protective role in the moderation of sepsis-induced lung injury through reducing oxidative stress, regulating lipid metabolism and energy biosynthesis. Copyright © 2018 John Wiley & Sons, Ltd.

  7. Edaravone protect against retinal damage in streptozotocin-induced diabetic mice.

    PubMed

    Yuan, Dongqing; Xu, Yidan; Hang, Hui; Liu, Xiaoyi; Chen, Xi; Xie, Ping; Yuan, Songtao; Zhang, Weiwei; Lin, Xiaojun; Liu, Qinghuai

    2014-01-01

    Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.

  8. Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance.

    PubMed

    Gutierrez, Dario A; Muralidhar, Sathya; Feyerabend, Thorsten B; Herzig, Stephan; Rodewald, Hans-Reimer

    2015-05-05

    Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent Kit(W/Wv) and Kit-independent Cpa3(Cre/+) mast-cell-deficient mouse strains, employing diet-induced or genetic (Lep(Ob/Ob) background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Transplantation of human dental pulp-derived stem cells protects against heatstroke in mice.

    PubMed

    Tseng, Ling-Shu; Chen, Sheng-Hsien; Lin, Mao-Tsun; Lin, Ying-Chu

    2015-01-01

    Stem cells from human exfoliated deciduous tooth pulp (SHED) is a promising approach for the treatment of stroke and spinal cord injury. In this study, we investigated the therapeutic effects of SHED for the treatment of multiple organ (including brain, particularly hypothalamus) injury in heatstroke mice. ICR male mice were exposed to whole body heating (WBH; 41.2°C, relative humidity 50-55%, for 1 h) and then returned to normal room temperature (26°C). We observed that intravenous administration of SHED immediately post-WBH exhibited the following therapeutic benefits for recovery after heatstroke: (a) inhibition of WBH-induced neurologic and thermoregulatory deficits; (b) reduction of WBH-induced ischemia, hypoxia, and oxidative damage to the brain (particularly the hypothalamus); (c) attenuation of WBH-induced increased plasma levels of systemic inflammatory response molecules, such as tumor necrosis factor-α and intercellular adhesion molecule-1; (d) improvement of WBH-induced hypothalamo-pituitary-adrenocortical (HPA) axis activity (as reflected by enhanced plasma levels of both adrenocorticotrophic hormone and corticosterone); and (e) attenuation of WBH-induced multiple organ apoptosis as well as lethality. In conclusion, post-WBH treatment with SHED reduced induction of proinflammatory cytokines and oxidative radicals, enhanced plasma induction of both adrenocorticotrophic hormone and corticosterone, and improved lethality in mouse heatstroke. The protective effect of SHED may be related to a decreased inflammatory response, decreased oxidative stress, and an increased HPA axis activity following the WBH injury.

  10. Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

    PubMed

    Hetzel, Miriam; Mucci, Adele; Blank, Patrick; Nguyen, Ariane Hai Ha; Schiller, Jan; Halle, Olga; Kühnel, Mark-Philipp; Billig, Sandra; Meineke, Robert; Brand, Daniel; Herder, Vanessa; Baumgärtner, Wolfgang; Bange, Franz-Christoph; Goethe, Ralph; Jonigk, Danny; Förster, Reinhold; Gentner, Bernhard; Casanova, Jean-Laurent; Bustamante, Jacinta; Schambach, Axel; Kalinke, Ulrich; Lachmann, Nico

    2018-02-01

    Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 ( IFNGR1 or IFNGR2 ) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that express Ifnγr1 either constitutively or myeloid specifically. Transduction of mouse Ifnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifnγr1 -/- mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. © 2018 by The American Society of Hematology.

  11. Protective Role of Grape Seed Proanthocyanidins Against Ccl4 Induced Acute Liver Injury in Mice.

    PubMed

    Zou, Jinfa; Qi, Fengjie; Ye, Liping; Yao, Suyan

    2016-03-17

    We investigated the effect of grape seed proanthocyanidins (GSPs) on carbon tetrachloride (CCl4)-induced acute liver injury. Sixty SPF KM mice were randomly divided into 6 groups: the control group, CCl4-model group, bifendate group (DDB group), and low-, moderate-, and high-dose GSP groups. The following parameters were measured: serum levels of alanine aminotransferase (ALT); aspartate aminotransferase (AST); tumor necrosis factor (TNF)-α; interleukin-6 (IL-6); high-mobility group box (HMGB)-1; body weight; liver, spleen, and thymus indexes; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity; HMGB1 mRNA; malondialdehyde (MDA) content; hepatocyte proliferation; and changes in liver histology. Compared to the CCl4-model group, decreases in liver index and increases in thymus index significantly increased SOD and GSH-Px activities and reduced MDA content, and higher hepatocyte proliferative activity was found in all GSP dose groups and the DDB group (all P<0.001). Compared with the CCl4-model group, serum TNF-α and IL-6 levels and HMGB 1 mRNA and protein expressions decreased significantly in the high GSP dose group (all P<0.05). Our results provide strong evidence that administration of GSPs might confer significant protection against CCl4-induced acute liver injury in mice.

  12. Protective effect of wedelolactone against CCl4-induced acute liver injury in mice.

    PubMed

    Lu, Yang; Hu, DongMei; Ma, ShanBo; Zhao, Xian; Wang, Shan; Wei, Guo; Wang, XiFang; Wen, AiDong; Wang, JingWen

    2016-05-01

    Eclipta, a traditional Chinese medicine, has been used to treat liver disease for centuries. However, the chemical basis and biological mechanisms of Eclipta remain elusive. The current study aims to investigate the hepatoprotective effect of wedelolactone (WEL), a major coumarin in Eclipta, using C57BL/6 mice with carbon tetrachloride CCl4-induced acute liver injury (ALI). Our data showed that WEL markedly decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatic histopathology changes. WEL also significantly decreased the content of MDA in liver tissues, meanwhile increased the activities of antioxidant enzymes SOD and GSH-Px. In addition, WEL reduced the protein expression of TNF-α, IL-1β and IL-6, as well as mRNA expression. Western blot results revealed that WEL repressed phosphorylation of extracellular signal-regulated kinase (ERK) and translocation of NF-κB p65 from cytoplasm to nucleus and enhanced the phosphorylation of c-Jun. N-terminal kinase (JNK). Moreover, results showed that WEL significantly inhibited CCl4-induced hepatocytes apoptosis, markedly suppressed the down-regulation of Bax and active Caspase-3 expression and accelerated the expression of Bcl-2. Overall, the findings indicate that WEL exhibits a protective effect against CCl4-induced ALI in mice by enhancing the antioxidative defense system, suppressing the inflammatory response and cell apoptosis of liver. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Indomethacin inhabits the NLRP3 inflammasome pathway and protects severe acute pancreatitis in mice.

    PubMed

    Lu, Guotao; Pan, Yiyuan; Kayoumu, Abudurexiti; Zhang, Ling; Yin, Tao; Tong, Zhihui; Li, Baiqiang; Xiao, Weiming; Ding, Yanbing; Li, Weiqin

    2017-11-04

    Clinical studies have confirmed that indomethacin (Indo) can reduce the incidence and severity of post-endoscopicretrogradecholangio-pancreatography pancreatitis (PEP) effectively. However, the role of Indo on severe acute pancreatitis (SAP) is not clear. In the present study, we aimed to explore the effects of Indo treatment on SAP model induced by caerulein combined with lipopolysaccharide. After intraperitoneal injection of Indo in mice, both the severity of SAP and the serum levels of amylase, lipase, and proinflammatory cytokines were decreased. Furthermore, the mRNA and protein levels of NLRP3 inflammasome pathway (NLRP3,ASC and IL-1β) in pancreatic tissues were down-regulated. In vitro experiments, by isolating the pancreatic acinar cells (PACs) from mice, we found that Indo significantly reduced lactate dehydrogenase(LDH) excretion, increased the cell activity, and inhibited the NLRP3 inflammasome pathway of PACs. Taken together, our data showed that Indo could protect pancreatic acinar cell from injury by inhabiting NLRP3 pathway and decreased the severity of SAP accordingly. Copyright © 2017. Published by Elsevier Inc.

  14. Protective effect of saponins from Panax notoginseng against doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Liu, Li; Shi, Run; Shi, Qiang; Cheng, Yiyu; Huo, Yang

    2008-02-01

    The dried rhizome of Panax notoginseng is a traditional Chinese herb extensively used for treatment of cardiovascular diseases and other ailments. Panax notoginseng saponins (PNS) are known as the major pharmacologically active constituents. The purpose of this study was to investigate the cardioprotective effects of PNS against doxorubicin-induced cardiotoxicity and its possible influence on the anti-tumor activity of doxorubicin. Five groups of ICR mice were treated with saline (control group), doxorubicin alone (20 mg/kg I. P.), PNS alone, doxorubicin pretreated with PNS (100 mg/kg I. G. for 5 consecutive days) or amifostine (single dose of 200 mg/kg I. V., used as positive control). After 72 h of doxorubicin treatment, cardiac function, serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) and activities of antioxidant enzymes in heart tissue were measured. Pretreatment with PNS significantly protected the mice from DOX-induced cardiotoxicity as evidenced from improved ventricular contractile function, lower levels of serum LDH, CK and CK-MB, minimal morphological changes in hearts, and normalization of myocardial superoxide dismutase, glutathione peroxidase and catalase activities. Additionally, IN VITRO cytotoxic studies demonstrated that PNS did not compromise the inhibitory effect of doxorubicin on the proliferation of cancer cells. These results imply the potentially clinical application of PNS to overcome the negative side effects of doxorubicin.

  15. Protective effects of Houttuynia cordata aqueous extract in mice consuming a high saturated fat diet.

    PubMed

    Lin, Ming-cheng; Hsu, Pei-chun; Yin, Mei-chin

    2013-02-01

    The protective effects of Houttuynia cordata aqueous extract (HCAE) in mice consuming a high saturated fat diet (HFD) were examined. HCAE, at 0.5, 1, or 2%, was supplied in drinking water for 8 weeks. HCAE was rich in phenolic acids and flavonoids. HCAE intake at 1 and 2% decreased body weight, epididymal fat, insulin resistance, triglyceride and total cholesterol contents in plasma and liver from HFD-treated mice (p < 0.05). HFD enhanced hepatic activity of malic enzyme, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase; and augmented the hepatic level of saturated fatty acids (p < 0.05). HCAE intake at 2% reduced malic enzyme and FAS activities, and lowered saturated fatty acids content in liver (p < 0.05). HCAE suppressed HFD induced oxidative and inflammatory stress in the heart and liver via reducing the malondialdehyde level, retaining glutathione content and glutathione peroxidase activity, decreasing tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 production (p < 0.05). These results support that Houttuynia cordata is a potent food against HFD induced obesity, and oxidative and inflammatory injury.

  16. Protection against endotoxin-induced foetal resorption in mice by desferrioxamine and ebselen.

    PubMed Central

    Gower, J. D.; Baldock, R. J.; O'Sullivan, A. M.; Doré, C. J.; Coid, C. R.; Green, C. J.

    1990-01-01

    Endotoxin was administered to mice on their 13th day of pregnancy at doses which caused the resorption of approximately 50% of the implanted foetuses. The iron chelator desferrioxamine was found to significantly inhibit the percentage of resorptions induced by endotoxin in a dose-dependent manner. The highest dose of desferrioxamine (5 mg) given intravenously 30 min prior to, immediately after, and 4 and 24 h after endotoxin inoculation, reduced the percentage of resorptions from 56.9 to 17.9%. Administration of the novel selenium-containing compound ebselen, which is both an antioxidant and an inhibitor of leukotriene synthesis, was also found to significantly protect against endotoxin-induced foetal resorptions, reducing the percentage of resorbed foetuses from 52.9 to 26.0% when given at a dose of 50 mg/kg (s.c.) at the time of endotoxin inoculation and 24 and 48 h following. Both these compounds also significantly reduced the increase in spleen weights observed when the mice were given endotoxin. These results provide evidence that the iron-catalysed production of hydroxyl radicals from other oxygen-derived species and the formation of leukotrienes play an important role in the mechanism by which endotoxin causes foetal resorptions in the mouse. PMID:2205283

  17. Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism.

    PubMed

    Wang, Yimin; Luo, Xiao; Pan, Hao; Huang, Wei; Wang, Xueping; Wen, Huali; Shen, Kezhen; Jin, Baiye

    2015-09-01

    Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1β followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice. Copyright © 2015. Published by Elsevier Ltd.

  18. Equine Immunoglobulin and Equine Neutralizing F(ab')₂ Protect Mice from West Nile Virus Infection.

    PubMed

    Cui, Jiannan; Zhao, Yongkun; Wang, Hualei; Qiu, Boning; Cao, Zengguo; Li, Qian; Zhang, Yanbo; Yan, Feihu; Jin, Hongli; Wang, Tiecheng; Sun, Weiyang; Feng, Na; Gao, Yuwei; Sun, Jing; Wang, Yanqun; Perlman, Stanley; Zhao, Jincun; Yang, Songtao; Xia, Xianzhu

    2016-12-18

    West Nile virus (WNV) is prevalent in Africa, Europe, the Middle East, West Asia, and North America, and causes epidemic encephalitis. To date, no effective therapy for WNV infection has been developed; therefore, there is urgent need to find an efficient method to prevent WNV disease. In this study, we prepared and evaluated the protective efficacy of immune serum IgG and pepsin-digested F(ab')₂ fragments from horses immunized with the WNV virus-like particles (VLP) expressing the WNV M and E proteins. Immune equine F(ab')₂ fragments and immune horse sera efficiently neutralized WNV infection in tissue culture. The passive transfer of equine immune antibodies significantly accelerated the virus clearance in the spleens and brains of WNV infected mice, and reduced mortality. Thus, equine immunoglobulin or equine neutralizing F(ab')₂ passive immunotherapy is a potential strategy for the prophylactic or therapeutic treatment of patients infected with WNV.

  19. Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

    PubMed

    Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

    2018-06-01

    As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  20. A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates.

    PubMed

    Baker, Sarah M; Davitt, Christopher J H; Motyka, Natalya; Kikendall, Nicole L; Russell-Lodrigue, Kasi; Roy, Chad J; Morici, Lisa A

    2017-12-09

    Burkholderia mallei is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. B. mallei is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against B. mallei of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from B. pseudomallei provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the B. pseudomallei OMV vaccine could cross-protect against B. mallei . We immunized C57Bl/6 mice and rhesus macaques with B. pseudomallei OMVs and subsequently challenged animals with aerosolized B. mallei . Immunization with B. pseudomallei OMVs significantly protected mice against B. mallei and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of B.mallei- specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with B. pseudomallei OMVs provided protection against glanders and induced B.mallei -specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens.

  1. A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates

    PubMed Central

    Davitt, Christopher J. H.; Motyka, Natalya; Kikendall, Nicole L.; Roy, Chad J.

    2017-01-01

    Burkholderia mallei is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. B. mallei is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against B. mallei of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from B. pseudomallei provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the B. pseudomallei OMV vaccine could cross-protect against B. mallei. We immunized C57Bl/6 mice and rhesus macaques with B. pseudomallei OMVs and subsequently challenged animals with aerosolized B. mallei. Immunization with B. pseudomallei OMVs significantly protected mice against B. mallei and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of B.mallei-specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with B. pseudomallei OMVs provided protection against glanders and induced B.mallei-specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens. PMID:29232837

  2. Protective effects of α-mangostin against acetaminophen-induced acute liver injury in mice.

    PubMed

    Fu, Tianhua; Wang, Shijie; Liu, Jinping; Cai, Enbo; Li, Haijun; Li, Pingya; Zhao, Yan

    2018-05-15

    The purpose of this study was to evaluate the protective effects of α-mangostin against acetaminophen (APAP)-induced acute liver injury and discover its potential mechanisms in mice. Mice were continuously treated with α-mangostin (12.5 and 25 mg/kg) by intragastric administration once daily for 6 days, and injected intraperitoneally with APAP (300 mg/kg) after 1 h of α-mangostin administration on the last day. After APAP exposure for 24 h, the liver and serum were gathered to evaluate the hepatotoxicity. The results showed that α-mangostin effectively decreased the serum levels of alanine aminotransferase, aspartate transaminase, tumor necrosis factor (TNF-α), interleukin-1β and 6 (IL-1β, IL-6), and hepatic malondialdehyde level; and recovered hepatic glutathione (GSH), superoxide dismutase and catalase activities. Liver histopathological observation provided further evidence that α-mangostin pretreatment significantly inhibited APAP-induced hepatocellular necrosis, infiltration of inflammatory cell and hyperemia. According to the analysis of western-blot and RT-PCR detection, α-mangostin pretreatment validly inhibited the phosphorylation of ERK, JNK and p38 MAPK induced by APAP, which was consistent with the changes of TNF-α, IL-6 and IL-1β levels; the phosphorylation of IκBα and the translocation of NF-κBp65 were also attenuated by α-mangostin. These results provided a new mechanism for the protective effects of α-mangostin against APAP-induced acute liver injury. α-Mangostin significantly restrainted the oxidative stress induced by APAP. Moreover, the anti-inflammatory property of α-mangostin, which is mediated by the NF-κB and MAPK signaling pathways, also contributed to its hepatoprotective effect. Taken together, we believed that α-mangostin might be a potential material for drug development against drug-related hepatotoxicity. Copyright © 2018. Published by Elsevier B.V.

  3. MKEY, a Peptide Inhibitor of CXCL4-CCL5 Heterodimer Formation, Protects Against Stroke in Mice.

    PubMed

    Fan, Yifang; Xiong, Xiaoxing; Zhang, Yongming; Yan, Dongmei; Jian, Zhihong; Xu, Baohui; Zhao, Heng

    2016-09-15

    MKEY, a synthetic cyclic peptide inhibitor of CXCL4-CCL5 heterodimer formation, has been shown to protect against atherosclerosis and aortic aneurysm formation by mediating inflammation, but whether it modulates neuroinflammation and brain injury has not been studied. We therefore studied the role of MKEY in stroke-induced brain injury in mice. MKEY was injected into mice after stroke with 60 minutes of middle cerebral artery occlusion. Infarct volume and neurological deficit scores were measured. Protein levels of CCL5 and its receptor CCR5 were detected by Western blot and fluorescence-activated cell sorting (FACS), respectively. Numbers of microglia-derived macrophages (MiMΦs) and monocyte-derived MΦs (MoMΦs) in the brain, and their subsets, based on the surface markers CD45, CD11b, CCR2, CX3CR1, and Ly6C, were analyzed by FACS. MΦs and neutrophil infiltration in the ischemic brain were stained with CD68 and myeloperoxidase (MPO), respectively, and assessed by immunofluorescent confocal microscopy. The results showed that expressions of CCL5 and its receptor CCR5, were increased in the ischemic brain after stroke. MKEY injection significantly reduced infarct sizes and improved neurological deficit scores measured 72 hours after stroke. In addition, MKEY injection inhibited the number of MoMΦs, but not MiMΦs, in the ischemic brain. Furthermore, MKEY inhibited protein expression levels of Ly6C,CCR2, and CX3CR1 on MoMΦs. Lastly, the confocal study also suggests that the number of CD68-positive MΦs and MPO-positive neutrophils was inhibited by MKEY injection. MKEY injection protects against stroke-induced brain injury, probably by inhibiting MoMΦ-mediated neuroinflammation. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  4. A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

    PubMed Central

    Phoolcharoen, Waranyoo; Dye, John M.; Kilbourne, Jacquelyn; Piensook, Khanrat; Pratt, William D.; Arntzen, Charles J.; Chen, Qiang; Mason, Hugh S.; Herbst-Kralovetz, Melissa M.

    2011-01-01

    Ebola hemorrhagic fever is an acute and often deadly disease caused by Ebola virus (EBOV). The possible intentional use of this virus against human populations has led to design of vaccines that could be incorporated into a national stockpile for biological threat reduction. We have evaluated the immunogenicity and efficacy of an EBOV vaccine candidate in which the viral surface glycoprotein is biomanufactured as a fusion to a monoclonal antibody that recognizes an epitope in glycoprotein, resulting in the production of Ebola immune complexes (EICs). Although antigen–antibody immune complexes are known to be efficiently processed and presented to immune effector cells, we found that codelivery of the EIC with Toll-like receptor agonists elicited a more robust antibody response in mice than did EIC alone. Among the compounds tested, polyinosinic:polycytidylic acid (PIC, a Toll-like receptor 3 agonist) was highly effective as an adjuvant agent. After vaccinating mice with EIC plus PIC, 80% of the animals were protected against a lethal challenge with live EBOV (30,000 LD50 of mouse adapted virus). Surviving animals showed a mixed Th1/Th2 response to the antigen, suggesting this may be important for protection. Survival after vaccination with EIC plus PIC was statistically equivalent to that achieved with an alternative viral vector vaccine candidate reported in the literature. Because nonreplicating subunit vaccines offer the possibility of formulation for cost-effective, long-term storage in biothreat reduction repositories, EIC is an attractive option for public health defense measures. PMID:22143779

  5. Toll-like receptor 4 protects against stress-induced ulcers via regulation of glucocorticoid production in mice.

    PubMed

    Wang, Liang; Luo, Pengfei; Zhang, Fang; Zhang, Yuelu; Wang, Xingtong; Chang, Fei; Zhang, Yuechan; Tang, Hongtai; Xia, Zhaofan

    2017-01-01

    Stress-induced gastric ulcer is an important life-threatening condition, while the molecular basis of its development is incompletely understood. Toll-like receptor 4 (TLR4), an innate immune pattern recognition receptor, can induce pro-inflammatory transcription, aggravating a stress ulcer. The present study found that TLR4 played a protective role in a mouse model of water immersion (23 °C) restraint stress. Wild-type (WT) and TLR4 -/- male mice were respectively divided into five groups (5 per group), and exposed to the stressor for 0, 0.5, 1, 2, or 4 hours. Gastric ulcer index, determined post mortem, increased with time in both types of mice but was greater in TLR4 -/- mice. Furthermore, increased serum cortisol and corticosterone concentrations were observed in WT mice only, and such increases were detected only in WT mice 4 h after lipopolysaccharide (LPS) treatment (2 mg/kg, intraperitoneal injection). Moreover, the administration of cortisol alleviated the gastric injury in TLR4 -/- mice. Western blotting showed expression in the adrenal of P450scc (CYP11A1), the first rate-limiting enzyme in the synthesis of steroids, was increased 4 h after water immersion restraint stress or LPS treatment in WT mice, but was conversely decreased in TLR4 -/- mice after either stressor. Furthermore, in adrenal glands of TLR4 -/- mice, structural distortion of mitochondria (which contain CYP11A1) was found with electron microscopy, and lack of lipid-storing droplets was found using light microscopy on adrenal cryosections stained with Oil red O. These data indicate that TLR4 plays a protective role in stress-induced gastric ulcer that is exerted via impacting synthesis of glucocorticoid in the adrenal gland.

  6. Muscle-protective effects of Schisandrae Fructus extracts in old mice after chronic forced exercise.

    PubMed

    Kim, Ki-Young; Ku, Sae-Kwang; Lee, Ki-Won; Song, Chang-Hyun; An, Won G

    2018-02-15

    Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill., is a well-known traditional herb used in Asia for enhancing physical work capacity as well as providing anti-stress and anti-inflammatory effects. Extracts of SF (SFe) have also been reported to increase skeletal muscle mass and inhibit muscle atrophy. We examined whether SFe had muscle-protective effects in old mice after chronic forced exercises, and, if so, relevant mechanisms. Ten-month-old aged male mice were divided into six groups. One group received no forced swimming after oral administration of distilled water (Intact); the other groups received forced swimming after administration of distilled water (SW), oxymetholone (OXY), or SFe at 500, 250 and 125mg/kg (SFe500, SFe250, and SFe125, respectively). Forced swimming was conducted for 2min at 30min after oral administration; the treatment was repeated for 28 days. Muscle thickness, weight, lean proportion, and strength were examined. The sampled muscles were subjected to histopathological and biochemical analyses. Plasma was examined by biochemical analyses. The thicknesses of the calf muscle and the sampled gastrocnemius and soleus, protein proportion and muscle strength increased significantly in the SW group versus Intact, and they were further increased in the SFe and OXY groups versus SW. The forced swimming in the SW group upregulated mRNA expression related to protein synthesis (Akt1, PI3K) and muscle growth (A1R, TRPV4), while it downregulated mRNAs related to protein degradation (atrogin-1, MuRF1) and muscle growth inhibitor (myostatin, SIRT1). The detected upregulation and downregulation were enhanced in the SFe groups. In addition, the SFe administration inhibited lipid peroxidation and reactive oxygen species, and accelerated activities of endogenous anti-oxidants and anti-oxidant enzymes. Plasma biochemistry showed decreases in creatine, creatine kinase and LDH in the SFe groups versus SW, suggesting muscle-protective

  7. Protective effects of selenium on fluoride induced alterations in certain enzymes in brain of mice.

    PubMed

    Reddy, K Pratap; Sailaja, G; Krishnaiah, Chirumari

    2009-09-01

    This study reports the protective effects of selenium on fluoride induced alterations in the activities of pro-oxidative (xanthine oxidase (XOD), lipid peroxidation (LPO) free radical scavenging, [catalase, superoxide dismutase (SOD), glutathione-s-transferase (GST), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione) and metabolic (glucose-6-phosphate dehydrogenase, alanine amino transferase (ALAT), aspartate aminotransferase (AAT), creatine phosphokinase (CPK), acid phosphatase (AP), alkaline phosphatase (ALP)] enzymes along with fluoride and selenium levels in brain of mice. Animals were divided into control, NaF treated group (20 mg kg(-1) body wt.(-1) intraperitonial) and Selenium+NaF treated group (sodium selenite, 5 microg of selenium/0.2 ml distilled water kg(-1) body wt.(-1) day) and were maintained for 14 days on respective treatments. The decreased bodyweight (-11.35%) as well as organosomatic index (-15.1%) of brain in NaF group were recovered in treatment of selenium along with NaF. The increased accumulation of fluoride (32.1%) in brain observed in NaF treated group compared to control was diminished in selenium+NaF treated group. Selenium levels (3.03%) increased in selenium+NaF treated group in compared to decrement in NaF treatment. The SOD (-16.6%), Catalase (-21.5%), GST(-13.72%), GPX (-19.16%), GR (-44.97%) activities and Glutathione (-23%) content in NaF treated group were decreased significantly compared to controls, which were significantly (p < 0.01) recovered in selenium+NaF group. Increased XOD (10.85%) and LPO (8.61%) levels observed in brain of NaF treated mice were reversed with selenium treatment. Glucose-6-phosphate dehydrogenase (-46.98%), ALAT (-10.44%), AAT (-10.21%), CPK (-27.98%) were decreased and alkaline phosphatase (10.6%), acid phosphatase (24.09%) increased in brain of mice after administration of NaF. All metabolic enzymes were significantly (p < 0.01) reversed after administration of selenium to the Na

  8. Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene.

    PubMed

    Mason, H S; Haq, T A; Clements, J D; Arntzen, C J

    1998-08-01

    The authors have designed and constructed a plant-optimize synthetic gene encoding the Escherichia coli heat-labile enterotoxin B subunit (LT-B), for use in transgenic plants as an edible vaccine against enterotoxigenic E. coli. Expression of the synthetic LT-B gene in potato plants under the control of a constitutive promoter yielded increased accumulation of LT-B in leaves and tubers, as compared to the bacterial LT-B gene. The plant-derived LT-B assembled into native pentameric structures as evidenced by its ability to bind ganglioside. The authors demonstrated immunogenicity by feeding mice the raw tubers and comparing the anti-LT-B serum IgG and faecal IgA to that produced in mice gavaged with bacterial LT-B. Mice were fed three weekly doses of 5 g tuber tissue containing either 20 or 50 micrograms LT-B, or gavaged weekly with 5 micrograms of LT-B from recombinant E. coli. One week after the third dose, mice immunized with potato LT-B had higher levels of serum and mucosal anti-LT-B than those gavaged with bacterial LT-B. Mice were challenged by oral administration of 25 micrograms LT, and protection assessed by comparing the gut/carcass mass ratios. Although none of the mice were completely protected, the higher dose potato vaccine compared favourably with the bacterial vaccine. These findings show that an edible vaccine against E. coli LT-B is feasible.

  9. Mice chronically infected with chimeric HIV resist peripheral and brain superinfection: a model of protective immunity to HIV.

    PubMed

    Kelschenbach, Jennifer L; Saini, Manisha; Hadas, Eran; Gu, Chao-Jiang; Chao, Wei; Bentsman, Galina; Hong, Jessie P; Hanke, Tomas; Sharer, Leroy R; Potash, Mary Jane; Volsky, David J

    2012-06-01

    Infection by some viruses induces immunity to reinfection, providing a means to identify protective epitopes. To investigate resistance to reinfection in an animal model of HIV disease and its control, we employed infection of mice with chimeric HIV, EcoHIV. When immunocompetent mice were infected by intraperitoneal (IP) injection of EcoHIV, they resisted subsequent secondary infection by IP injection, consistent with a systemic antiviral immune response. To investigate the potential role of these responses in restricting neurotropic HIV infection, we established a protocol for efficient EcoHIV expression in the brain following intracranial (IC) inoculation of virus. When mice were inoculated by IP injection and secondarily by IC injection, they also controlled EcoHIV replication in the brain. To investigate their role in EcoHIV antiviral responses, CD8+ T lymphocytes were isolated from spleens of EcoHIV infected and uninfected mice and adoptively transferred to isogenic recipients. Recipients of EcoHIV primed CD8+ cells resisted subsequent EcoHIV infection compared to recipients of cells from uninfected donors. CD8+ spleen cells from EcoHIV-infected mice also mounted modest but significant interferon-γ responses to two HIV Gag peptide pools. These findings suggest EcoHIV-infected mice may serve as a useful system to investigate the induction of anti-HIV protective immunity for eventual translation to human beings.

  10. Immunization of C57BL/6 Mice with GRA2 Combined with MPL Conferred Partial Immune Protection against Toxoplasma gondii

    PubMed

    Babaie, Jalal; Amiri, Samira; Homayoun, Robab; Azimi, Ebrahim; Mohabati, Reyhaneh; Berizi, Mahboobe; Sadaie, M. Reza; Golkar, Majid

    2018-01-01

    We have previously reported that immunization with GRA2 antigen of Toxoplasma gondii induces protective immunity in CBA/J (H2k) and BALB/c mice (H2d). We aimed to examine whether immunization of a distinct strain of rodent with recombinant dense granule antigens (GRA2) combined with monophosphorryl lipid A (MPL) adjuvant elicits protective immune response against T. gondii. C57BL/6 (H2b haplotype) mice were immunized with GRA2, formulated in MPL adjuvant. Strong humoral response, predominantly of IgG1 subclass and cellular response, IFN-γ, was detected at three weeks post immunization. Mice immunized with GRA2 had significantly (p < 0.01) fewer brain cysts than those in the adjuvant group, upon challenge infection. Despite the production of a strong antibody response, IFN-γ production and brain cyst reduction were not significant when the immunized mice were infected four months after the immunization. We can conclude that GRA2 immunization partially protects against T. gondii infection in C57BL/6 mice, though the potency and longevity of this antigen as a standalone vaccine may vary in distinct genetic backgrounds. This observation further emphasizes the utility of GRA2 for incorporation into a multi-antigenic vaccine against T. gondii.

  11. Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice.

    PubMed

    Mendias, Christopher L; Bakhurin, Konstantin I; Gumucio, Jonathan P; Shallal-Ayzin, Mark V; Davis, Carol S; Faulkner, John A

    2015-08-01

    The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN(+/-) and MSTN(-/-) mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN(+/+) and MSTN(-/-) mice, MSTN(+/-) mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  12. Interleukin-12 Induces a Th1-like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

    DTIC Science & Technology

    2005-09-02

    protection from a lethal challenge. 15. SUBJECT TERMS Burkholderia mallei , glanders , cytokines, immune response, humoral, cellular, laboratory animals...model of sublethal and lethal intraperitoneal glanders ( Burkholderia mallei ). Vet Pathol 2000;37:626–36. [34] Jankovic D, Caspar P, Zweig M, Garcia...Vaccine 24 (2006) 1413–1420 Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice Kei Amemiya

  13. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

    SciTech Connect

    Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.

    2008-08-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. {sup 14}C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAPmore » hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by {sup 3}H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.« less

  14. Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice.

    PubMed

    Moayeri, Mahtab; Tremblay, Jacqueline M; Debatis, Michelle; Dmitriev, Igor P; Kashentseva, Elena A; Yeh, Anthony J; Cheung, Gordon Y C; Curiel, David T; Leppla, Stephen; Shoemaker, Charles B

    2016-01-06

    Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  15. Immunological response and protection of mice immunized with plasmid encoding Toxoplasma gondii glycolytic enzyme malate dehydrogenase.

    PubMed

    Hassan, I A; Wang, S; Xu, L; Yan, R; Song, X; XiangRui, L

    2014-12-01

    Toxoplasma gondii Malate dehydrogenase (TgMDH) plays an important role as part of the energy production cycle. In this investigation, immunological changes and protection efficiency of this protein delivered as a DNA vaccine have been evaluated. Mice were intramuscularly immunized with pTgMDH, followed by challenge with virulent T. gondii RH strain, 2 weeks after the booster immunization. Compared to the control groups, the results showed that pTgMDH has stimulated specific humoral response as demonstrated by significant high titers of total IgG and subclasses IgG1 and IgG2a , beside IgA and IgM, but not IgE. Analysis of cytokine profiles revealed significant increases of IFN-γ, IL-4 and IL-17, while no significant changes were detected in TGF-β1. In cell-mediated response, both T lymphocytes subpopulations CD4(+) and CD8(+) were positively recruited as significant percentages were recorded in response to immunization with TgMDH. Significant long survival rate, 17 days, has been observed in the TgMDH vaccinated group, in contrast with control groups which died within 8-9 days after challenge. These results demonstrated that TgMDH could induce significant immunological responses leading to a considerable level of protection against acute toxoplasmosis infection. © 2014 John Wiley & Sons Ltd.

  16. Protective effects of tenuigenin on Staphylococcus aureus-induced pneumonia in mice.

    PubMed

    Yu, Bin; Qiao, Jiutao; Shen, Yongbin; Li, Lianyong

    2017-09-01

    Pneumonia is the leading cause of death in infants and young children. Staphylococcus aureus (S.aureus) is one of the most important bacteria that leads to pneumonia. Tenuigenin (TGN), a major active component isolated from the root of the Chinese herb Polygala tenuifolia, has been known to have anti-inflammatory effect. In this study, we aimed to investigate the protective effects of TGN on S.aureus-induced pneumonia in mice. The results showed that TGN significantly attenuated S.aureus-induced lung histopathological changes. TGN also inhibited lung wet/dry (W/D) ratio, and inflammatory cytokines TNF-α and IL-1β production. Furthermore, S.aureus-induced NF-κB activation was significantly inhibited by the treatment of TGN. In conclusion, the results of this study showed that TGN protected against S.aureus-induced pneumonia by inhibiting NF-κB activation. TGN might be a potential agent in the treatment of pneumonia induced by S.aureus. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

    PubMed

    Fu, Zhongjie; Wang, Zhongxiao; Liu, Chi-Hsiu; Gong, Yan; Cakir, Bertan; Liegl, Raffael; Sun, Ye; Meng, Steven S; Burnim, Samuel B; Arellano, Ivana; Moran, Elizabeth; Duran, Rubi; Poblete, Alexander; Cho, Steve S; Talukdar, Saswata; Akula, James D; Hellström, Ann; Smith, Lois E H

    2018-05-01

    Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes. © 2018 by the American Diabetes Association.

  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. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.

    PubMed Central

    Waring, P M; Waring, L J; Billington, T; Metcalf, D

    1995-01-01

    Leukemia inhibitory factor (LIF) has recently been associated with septic shock in humans. In this study we sought to determine, in mice, the role of LIF in septic shock. During sublethal endotoxemia, serum LIF levels, as determined by radio-receptor competition assay, peaked at 2 h and were low (3 ng/ml), whereas in lethal Escherichia coli septic shock serum LIF levels rose progressively (> 30 ng/ml) in the premorbid phase coincident with the development of tissue injury. Single i.v. injections of high doses (up to 50 micrograms per mouse) of recombinant murine LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 micrograms per mouse per day) for 3-4 days induced a fatal catabolic state without evidence of preceding hemodynamic collapse or shock. Simultaneous or subsequent administration of high doses of LIF had no effect on mortality from sublethal and lethal E. coli septic shock, whereas prior administration conferred significant protection against lethality (P << 0.001 by log-rank test), an effect that was dose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced serum tumor necrosis factor concentration (P < 0.05), reduction in the number of viable bacteria (P < 0.05), and prevention of sepsis-induced tissue injury. These observations suggest that systemic LIF production is part of the host response to both endotoxin and sepsis-induced tissue injury. Images Fig. 2 Fig. 5 PMID:7877978

  20. The protective effect of astaxanthin on fetal alcohol spectrum disorder in mice.

    PubMed

    Zheng, Dong; Li, Yi; He, Lei; Tang, Yamei; Li, Xiangpen; Shen, Qingyu; Yin, Deling; Peng, Ying

    2014-09-01

    Astaxanthin is a strong antioxidant with the ability of reducing the markers of inflammation. To explore the protective effect of astaxanthin on maternal ethanol induced embryonic deficiency, and to investigate the underlying mechanisms, we detected the morphology, expression of neural marker genes, oxidative stress indexes, and inflammatory factors in mice model of fetal alcohol spectrum disorder with or without astaxanthin pretreatment. Our results showed that astaxanthin blocked maternal ethanol induced retardation of embryonic growth, and the down-regulation of neural marker genes, Otx1 and Sox2. Moreover, astaxanthin also reversed the increases of malondialdehyde (MDA), hydrogen peroxide (H2O2), and the decrease of glutathione peroxidase (GPx) in fetal alcohol spectrum disorder. In addition, maternal ethanol induced up-regulation of toll-like receptor 4 (TLR4), and the down-streaming myeloid differentiation factor 88 (MyD88), NF-κB, TNF-α, and IL-1β in embryos, and this was inhibited by astaxanthin pretreatment. These results demonstrated a protective effect of astaxanthin on fetal alcohol spectrum disorder, and suggested that oxidative stress and TLR4 signaling associated inflammatory reaction are involved in this process. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. β-glucans from Coriolus versicolor protect mice against S. typhimurium challenge by activation of macrophages.

    PubMed

    Shi, Shao-Hua; Yang, Wen-Tao; Huang, Ke-Yan; Jiang, Yan-Long; Yang, Gui-Lian; Wang, Chun-Feng; Li, Yu

    2016-05-01

    The effects of β-glucans from Coriolus versicolor (CVP), which are extracted from a well-known immune stimulator C. versicolor, have been demonstrated extensively in vitro and in vivo. However, until now, the phagocytic activity has not been elucidated. Hence, the objective of the present study was to identify the antibacterial activity of CVP or CVP-treated macrophages by an analysis of cell cytotoxicity, phagocytic activity, intracellular bacterial survival, macrophage activation, production of nitric oxide (NO) and expression of inducible nitric oxide synthase (iNOS) in CVP-treated macrophages using flow cytometry, RT-PCR, a gentamicin protection assay, a Nitric oxide assay and an iNOS enzymatic activity assay. The results indicate that CVP-treated macrophages can phagocytize and kill bacteria, probably due to the production of NO and iNOS. More importantly, CVP-treated macrophages are effective at protecting mice against the challenge of Salmonella typhimurium. The results of this study suggest that the antibacterial effects of CVP are probably caused by the activation of innate immune cells, especially macrophages, because the activated macrophage produces NO, which kills bacteria. These phenomena indicate the possibility of CVP as a potential alternative for antibiotics against resistant bacteria. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. γ-Oryzanol protects against acute cadmium-induced oxidative damage in mice testes.

    PubMed

    Spiazzi, Cristiano C; Manfredini, Vanusa; Barcellos da Silva, Fabiana E; Flores, Erico M M; Izaguirry, Aryele P; Vargas, Laura M; Soares, Melina B; Santos, Francielli W

    2013-05-01

    Cadmium is a non-essential heavy metal that is present at low levels mainly in food and water and also in cigar smoke. The present study evaluated the testicular damage caused by acute cadmium exposure and verified the protective role of γ-oryzanol (ORY). Mice were administrated with a single dose of 2.5mg/kg of CdCl2, and then treated with ORY (50mM in canola oil, 5mL/kg). Testes were removed after 24h and tested for lipid peroxidation (TBARS), protein carbonylation, DNA breakage, ascorbic acid, cadmium and non-proteic thiols contents, and for the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and δ-aminolevulic acid dehydratase (δ-ALA-D). Cadmium presented a significant alteration in all parameters, except GPx and CAT activities. Therapy reduced in a slight degree cadmium concentration in testes (around 23%). ORY restored SOD and GST activities as well as TBARS production to the control levels. Furthermore, ORY partially recovered δ-ALA-D activity inhibited by cadmium. This study provides the first evidence on the therapeutic properties of ORY in protecting against cadmium-induced testicular toxicity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice.

    PubMed

    Diao, Lei; Mei, Qiao; Xu, Jian-Ming; Liu, Xiao-Chang; Hu, Jing; Jin, Juan; Yao, Qiang; Chen, Mo-Li

    2012-03-14

    To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice. Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling. Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function.

  4. Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice

    PubMed Central

    Diao, Lei; Mei, Qiao; Xu, Jian-Ming; Liu, Xiao-Chang; Hu, Jing; Jin, Juan; Yao, Qiang; Chen, Mo-Li

    2012-01-01

    AIM: To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice. METHODS: Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. RESULTS: Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling. CONCLUSION: Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function. PMID:22416180

  5. Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection.

    PubMed

    Spry, Malinda L; Vanover, Jillian C; Scott, Timothy; Abona-Ama, Osama; Wakamatsu, Kazumasa; Ito, Shosuke; D'Orazio, John A

    2009-04-01

    We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.

  6. Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice.

    PubMed

    Liu, Baohai; Piao, Xuehua; Guo, Lianyi; Liu, Shanshan; Chai, Fang; Gao, Leming

    2016-06-01

    Ursolic acid (UA) has been reported to have a protective effect in colitis. However, the underlying mechanisms remain to be elucidated. In the present study, experimental ulcerative colitis was induced in male BALB/c mice by the administration of 5% dextran sulfate sodium (DSS) for 7 days, followed by treatment with UA for another 7 days. Hematoxylin & eosin staining was performed to evaluate colon tissue damage, and enzyme assays were used to measure malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon homogenate. In addition, serum levels of interleukin (IL)‑1β and tumor necrosis factor (TNF)‑α were measured using an ELISA, and the level of nuclear factor (NF)‑κB p65 in the colonic tissues was assessed by western blotting. The 7‑day DSS administration induced marked colon damage, increased the serum levels of IL‑1β and TNF‑α, increased MDA content and decreased SOD activity in the colon homogenate. These changes were significantly improved by treatment with UA. UA also reduced the DSS‑stimulated high nuclear level of NF‑κB p65 in the colon tissues. These results demonstrate a protective role of UA in ulcerative colitis, and suggest that anti-inflammatory and antioxidant activities are involved in the underlying mechanisms.

  7. A multiagent filovirus DNA vaccine delivered by intramuscular electroporation completely protects mice from ebola and Marburg virus challenge.

    PubMed

    Grant-Klein, Rebecca J; Van Deusen, Nicole M; Badger, Catherine V; Hannaman, Drew; Dupuy, Lesley C; Schmaljohn, Connie S

    2012-11-01

    We evaluated the immunogenicity and protective efficacy of DNA vaccines expressing the codon-optimized envelope glycoprotein genes of Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus (Musoke and Ravn). Intramuscular or intradermal delivery of the vaccines in BALB/c mice was performed using the TriGrid™ electroporation device. Mice that received DNA vaccines against the individual viruses developed robust glycoprotein-specific antibody titers as determined by ELISA and survived lethal viral challenge with no display of clinical signs of infection. Survival curve analysis revealed there was a statistically significant increase in survival compared to the control groups for both the Ebola and Ravn virus challenges. These data suggest that further analysis of the immune responses generated in the mice and additional protection studies in nonhuman primates are warranted.

  8. Synergistic protection of mice against plague with monoclonal antibodies specific for the F1 and V antigens of Yersinia pestis.

    PubMed

    Hill, Jim; Copse, Catherine; Leary, Sophie; Stagg, Anthony J; Williamson, E Diane; Titball, Richard W

    2003-04-01

    Monoclonal antibodies specific for Yersinia pestis V antigen and F1 antigen, administered singly or in combination, protected mice in models of bubonic and pneumonic plague. Antibodies showed synergy when administered prophylactically and as a therapy 48 h postinfection. Monoclonal antibodies therefore have potential as a treatment for plague.

  9. The protein DIIIC-2, aggregated with a specific oligodeoxynucleotide and adjuvanted in alum, protects mice and monkeys against DENV-2.

    PubMed

    Gil, Lázaro; Marcos, Ernesto; Izquierdo, Alienys; Lazo, Laura; Valdés, Iris; Ambala, Peris; Ochola, Lucy; Hitler, Rikoi; Suzarte, Edith; Álvarez, Mayling; Kimiti, Prisilla; Ndung'u, James; Kariuki, Thomas; Guzmán, María Guadalupe; Guillén, Gerardo; Hermida, Lisset

    2015-01-01

    Previously, we reported the ability of the chimeric protein DIIIC-2 (domain III of the dengue envelope protein fused to the capsid protein of dengue-2 virus), to induce immunity and protection in mice, when it is highly aggregated with a non-defined oligodeoxynucleotide (ODN) and adjuvanted in alum. In this work, three different defined ODNs were studied as aggregating agents. Our results suggest that the nature of the ODN influences the capacity of protein DIIIC-2 to activate cell-mediated immunity in mice. Consequently, the ODN 39M was selected to perform further experiments in mice and nonhuman primates. Mice receiving the preparation 39M-DIIIC-2 were solidly protected against dengue virus (DENV) challenge. Moreover, monkeys immunized with the same preparation developed neutralizing antibodies, as measured by four different neutralization tests varying the virus strains and the cell lines used. Two of the immunized monkeys were completely protected against challenge, whereas the third animal had a single day of low-titer viremia. This is the first work describing the induction of short-term protection in monkeys by a formulation that is suitable for human use combining a recombinant protein from DENV with alum.

  10. Protective effect of N-acetylcysteine against ethanol-induced gastric ulcer: A pharmacological assessment in mice

    PubMed Central

    Jaccob, Ausama Ayoob

    2015-01-01

    Aim: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-acetylcysteine (NAC) against ethanol-induced gastric ulcer models in mice. Materials and Methods: A total of 41 mice were allocated into six groups consisted of 7 mice each. Groups 1 (normal control) and 2 (ulcer control) received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6th group received ranitidine (50 mg/kg). All drugs administered orally once daily for 7 days, on the 8th day absolute ethanol (7 ml/kg) was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination. Results: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group. Conclusion: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by anti-secretory, cytoprotective, histological and biochemical data, but the molecular mechanisms behind such protection are complex. PMID:26401392

  11. MAPK phosphotase 5 deficiency contributes to protection against blood-stage Plasmodium yoelii 17XL infection in mice.

    PubMed

    Cheng, Qianqian; Zhang, Qingfeng; Xu, Xindong; Yin, Lan; Sun, Lin; Lin, Xin; Dong, Chen; Pan, Weiqing

    2014-04-15

    Cell-mediated immunity plays a crucial role in the development of host resistance to asexual blood-stage malaria infection. However, little is known of the regulatory factors involved in this process. In this study, we investigated the impact of MAPK phosphotase 5 (MKP5) on protective immunity against a lethal Plasmodium yoelii 17XL blood-stage infection using MKP5 knockout C57BL/6 mice. Compared with wild-type control mice, MKP5 knockout mice developed significantly lower parasite burdens with prolonged survival times. We found that this phenomenon correlated with a rapid and strong IFN-γ-dependent cellular immune response during the acute phase of infection. Inactivation of IFN-γ by the administration of a neutralizing Ab significantly reduced the protective effects in MKP5 knockout mice. By analyzing IFN-γ production in innate and adaptive lymphocyte subsets, we observed that MKP5 deficiency specifically enhanced the IFN-γ response mediated by CD4+ T cells, which was attributable to the increased stimulatory capacity of splenic CD11c+ dendritic cells. Furthermore, following vaccination with whole blood-stage soluble plasmodial Ag, MKP5 knockout mice acquired strongly enhanced Ag-specific immune responses and a higher level of protection against subsequent P. yoelii 17XL challenge. Finally, we found the enhanced response mediated by MKP5 deficiency resulted in a lethal consequence in mice when infected with nonlethal P. yoelii 17XNL. Thus, our data indicate that MKP5 is a potential regulator of immune resistance against Plasmodium infection in mice, and that an understanding of the role of MKP5 in manipulating anti-malaria immunity may provide valuable information on the development of better control strategies for human malaria.

  12. AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice.

    PubMed

    Carneiro, Lionel; Asrih, Mohamed; Repond, Cendrine; Sempoux, Christine; Stehle, Jean-Christophe; Leloup, Corinne; Jornayvaz, François R; Pellerin, Luc

    2017-12-01

    Hepatic steatosis is the first step leading to non-alcoholic fatty liver disease, which represents a major complication of obesity. Here, we show that MCT1 haploinsufficient mice resist to hepatic steatosis development when fed a high fat diet. They exhibit a reduced hepatic capacity to metabolize monocarboxylates such as lactate compared to wildtype mice. To understand how this resistance to steatosis develops, we used HFD fed wildtype mice with hepatic steatosis and MCT1 haploinsufficient mice to study hepatic metabolism. AMPK is constitutively activated in the liver of MCT1 haploinsufficient mice, leading to an inactivation of SREBP1. Therefore, expression of key transcription factors for lipid metabolism, such as PPARα and γ, CHREB, or SREBP1 itself, as well as several enzymes including FAS and CPT1, was not upregulated in these mice when fed a high fat diet. It is proposed that reduced hepatic lactate metabolism is responsible for the protection against hepatic steatosis in MCT1 haploinsufficient mice via a constitutive activation of AMPK and repression of several major elements involved in hepatic lipid metabolism. Our results support a role of increased lactate uptake in hepatocytes during HFD that, in turn, induce a metabolic shift stimulating SREBP1 activity and lipid accumulation. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  13. Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: protective effect of alpha-lipoic acid.

    PubMed

    Manda, Kailash; Ueno, Megumi; Moritake, Takashi; Anzai, Kazunori

    2007-02-12

    Reactive oxygen species are implicated in neurodegeneration and cognitive disorders due to higher vulnerability of neuronal tissues. The cerebellum is recently reported to be involved in cognitive function. Therefore, present study aimed at investigating the role alpha-lipoic acid against radiation-induced oxidative stress and antioxidant status in cerebellum and its correlation with cognitive dysfunction. We observed spontaneous motor activities and spatial memory task of mice using pyroelectric infrared sensor and programmed video tracking system, respectively. Whole body X-irradiation (6 Gy) of mice substantially impaired the reference memory and motor activities of mice. However, acute intraperitoneal treatment of mice with alpha-lipoic acid prior to irradiation significantly attenuated such cognitive dysfunction. Alpha-lipoic acid pretreatment exerted a very high magnitude of protection against radiation-induced augmentation of protein carbonyls and thiobarbituric acid reactive substance (TBARS) in mice cerebellum. Further, radiation-induced deficit of total, nonprotein and protein-bound sulfhydryl (T-SH, NP-SH, PB-SH) contents of cerebellum and plasma ferric reducing power (FRAP) was also inhibited by alpha-lipoic acid pre-treatment. Moreover, alpha-lipoic acid treated mice showed an intact cytoarchitecture of cerebellum, higher counts of intact Purkinje cells and granular cells in comparison to untreated irradiated mice. Results clearly indicate that alpha-lipoic acid is potent neuroprotective antioxidant.

  14. Liposome-antigen-nucleic acid complexes protect mice from lethal challenge with western and eastern equine encephalitis viruses.

    PubMed

    Phillips, Aaron T; Schountz, Tony; Toth, Ann M; Rico, Amber B; Jarvis, Donald L; Powers, Ann M; Olson, Ken E

    2014-02-01

    Alphaviruses are mosquito-borne viruses that cause significant disease in animals and humans. Western equine encephalitis virus (WEEV) and eastern equine encephalitis virus (EEEV), two New World alphaviruses, can cause fatal encephalitis, and EEEV is a select agent of concern in biodefense. However, we have no antiviral therapies against alphaviral disease, and current vaccine strategies target only a single alphavirus species. In an effort to develop new tools for a broader response to outbreaks, we designed and tested a novel alphavirus vaccine comprised of cationic lipid nucleic acid complexes (CLNCs) and the ectodomain of WEEV E1 protein (E1ecto). Interestingly, we found that the CLNC component, alone, had therapeutic efficacy, as it increased survival of CD-1 mice following lethal WEEV infection. Immunization with the CLNC-WEEV E1ecto mixture (lipid-antigen-nucleic acid complexes [LANACs]) using a prime-boost regimen provided 100% protection in mice challenged with WEEV subcutaneously, intranasally, or via mosquito. Mice immunized with LANACs mounted a strong humoral immune response but did not produce neutralizing antibodies. Passive transfer of serum from LANAC E1ecto-immunized mice to nonimmune CD-1 mice conferred protection against WEEV challenge, indicating that antibody is sufficient for protection. In addition, the LANAC E1ecto immunization protocol significantly increased survival of mice following intranasal or subcutaneous challenge with EEEV. In summary, our LANAC formulation has therapeutic potential and is an effective vaccine strategy that offers protection against two distinct species of alphavirus irrespective of the route of infection. We discuss plausible mechanisms as well the potential utility of our LANAC formulation as a pan-alphavirus vaccine.

  15. Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity

    SciTech Connect

    Kong, Bo; Csanaky, Iván L.; Aleksunes, Lauren M.

    Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity ofmore » the Mrp2 substrate, α-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4 weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury. -- Highlights: ► High-fat diet decreases hepatic Mrp2 expression only in female but not in male mice. ► HFD significantly reduces early-phase biliary ANIT excretion in female mice. ► HFD protects female mice against ANIT-induced liver injury.« less

  16. Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure.

    PubMed

    Leonis, Mike A; Toney-Earley, Kenya; Degen, Sandra J F; Waltz, Susan E

    2002-11-01

    The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK(-/-) mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK(-/-) mice. Paradoxically, treatment of Ron TK(-/-) mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.

  17. Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax.

    PubMed

    Chen, Zhaochun; Schneerson, Rachel; Lovchik, Julie A; Dai, Zhongdong; Kubler-Kielb, Joanna; Agulto, Liane; Leppla, Stephen H; Purcell, Robert H

    2015-08-01

    The immunogenicity of Bacillus anthracis capsule (poly-γ-D-glutamic acid [PGA]) conjugated to recombinant B. anthracis protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10(3) were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 10(3). An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were ≤300, with the antibodies peaking above 10(4) following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of B. anthracis. Most important, the PGA-TT-induced antibodies protected mice from a lethal challenge with virulent B. anthracis spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  18. Protective effects of cassia seed ethanol extract against carbon tetrachloride-induced liver injury in mice.

    PubMed

    Xie, Qing; Guo, Fang-Fang; Zhou, Wen

    2012-01-01

    Oxidative stress has been recognized as a critical pathogenetic mechanism for the initiation and the progression of hepatic injury in a variety of liver disorders. Antioxidants, including many natural compounds or extracts, have been used to cope with liver disorders. The present study was designed to investigate the hepatoprotective effects of cassia seed ethanol extract (CSE) in carbon tetrachloride (CCl(4))-induced liver injury in mice. The animals were pre-treated with different doses of CSE (0.5, 1.0, 2.0 g/kg body weight) or distilled water for 5 days, then were injected intraperitoneally with CCl(4) (0.1% in corn oil, v/v, 20 ml/kg body weight), and sacrificed at 16 hours after CCl(4) exposure. The serum aminotransferase activities, histopathological changes, hepatic and mitochondrial antioxidant indexes, and cytochrome P450 2E1 (CYP2E1) activities were examined. Consistent with previous studies, acute CCl(4) administration caused great lesion to the liver, shown by the elevation of the serum aminotransferase activities, mitochondria membrane permeability transition (MPT), and the ballooning degeneration of hepatocytes. However, these adverse effects were all significantly inhibited by CSE pretreatment. CCl(4)-induced decrease of the CYP2E1 activity was dose-dependently inhibited by CSE pretreatment. Furthermore, CSE dramatically decreased the hepatic and mitochondrial malondialdehyde (MDA) levels, increased the hepatic and mitochondrial glutathione (GSH) levels, and restored the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione S-transferase (GST). These results suggested that CSE could protect mice against CCl(4)-induced liver injury via enhancement of the antioxidant capacity.

  19. Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice.

    PubMed

    Hassan, Samar M; Khalaf, Marwa M; Sadek, Sawsan A; Abo-Youssef, Amira M

    2017-12-01

    Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity. This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. Adult female Wistar Albino mice were divided into eight groups (n = 8). Group I served as normal control. Groups II, III and IV received apigenin (3 mg/kg, i.p.), myricetin (3 mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5 mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated. Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues. Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects.

  20. 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity.

    PubMed

    Pajarillo, Edward; Johnson, James; Kim, Judong; Karki, Pratap; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2018-03-01

    Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. N-acetylcysteine Protects Mice from High Fat Diet-induced Metabolic Disorders.

    PubMed

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-08-01

    To study the effects of N-acetylcysteine (NAC, C5H9NO3S) on diet-induced obesity and obesity-related metabolic disorders. Six-week-old male C57BL/6 mice fed a chow or high-fat diet (HFD) were treated with NAC (2 g/L) in drinking water for 11 weeks. Its influences on body weight and food intake were manually measured, and influence on body composition were analyzed by magnetic residence imaging. Glucose meter and ELISA were used to determine serum glucose and insulin levels, as well as lipid content in the liver. The effects of NAC treatment on mRNA levels of genes involved in inflammation, thermogenesis, and lipid metabolism in various tissues were determined by real time PCR. NAC supplementation inhibited the increase of fat mass and the development of obesity when mice were fed an HFD. NAC treatment significantly lowered HFD-induced macrophage infiltration, and enhanced adiponectin gene expression, resulting in reduced hyperglycemia and hyperinsulinemia, and improvement of insulin resistance. NAC oral administration suppressed hepatic lipid accumulation, as evidenced by lower levels of triglyceride and cholesterol in the liver. The beneficial effects are associated with a decrease of hepatic Pparγ and its target gene expression, and an increase in the expression of genes responsible for lipid oxidation and activation of farnesoid X receptor. Furthermore, NAC treatment also stimulates expression of thermogenic genes. These results provide direct proof of the protective potential of NAC against HFD-induced obesity and obesity-associated metabolic disorders.

  2. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Chen, Tong; Mou, Yi; Tan, Jiani; Wei, Linlin; Qiao, Yixue; Wei, Tingting; Xiang, Pengjun; Peng, Sixun; Zhang, Yihua; Huang, Zhangjian; Ji, Hui

    2015-03-01

    CDDO-Me, initiated in a phase II clinical trial, is a potential useful therapeutic agent for cancer and inflammatory dysfunctions, whereas the therapeutic efficacy of CDDO-Me on LPS-induced acute lung injury (ALI) has not been reported as yet. The purpose of the present study was to explore the protective effect of CDDO-Me on LPS-induced ALI in mice and to investigate its possible mechanism. BalB/c mice received CDDO-Me (0.5mg/kg, 2mg/kg) or dexamethasone (5mg/kg) intraperitoneally 1h before LPS stimulation and were sacrificed 6h later. W/D ratio, lung MPO activity, number of total cells and neutrophils, pulmonary histopathology, IL-6, IL-1β, and TNF-α in the BALF were assessed. Furthermore, we estimated iNOS, IL-6, IL-1β, and TNF-α mRNA expression and NO production as well as the activation of the three main MAPKs, AkT, IκB-α and p65. Pretreatment with CDDO-Me significantly ameliorated W/D ratio, lung MPO activity, inflammatory cell infiltration, and inflammatory cytokine production in BALF from the in vivo study. Additionally, CDDO-Me had beneficial effects on the intervention for pathogenesis process at molecular, protein and transcriptional levels in vitro. These analytical results provided evidence that CDDO-Me could be a potential therapeutic candidate for treating LPS-induced ALI. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation.

    PubMed

    Ma, Jilei; Teng, Xindong; Wang, Xiaochun; Fan, Xionglin; Wu, Yaqi; Tian, Maopeng; Zhou, Zijie; Li, Longmeng

    2017-08-01

    Adult tuberculosis (TB) is the main cause of TB epidemic and death. The infection results mainly by endogenous reactivation of latent TB infection and secondarily transmitted by exogenous infection. There is no vaccine for adult TB. To this end, we first chose antigens from a potential antigenic reservoir. The antigens strongly recognized T cells from latent and active TB infections that responded to antigens expressed by Mycobacterium tuberculosis cultured under different metabolic states. Fusions of single-stage polyprotein CTT3H, two-stage polyprotein A1D4, and multistage CMFO were constructed. C57BL/6 mice vaccinated with DMT adjuvant ed CMFO (CMFO-DMT) were protected more significantly than by CTT3H-DMT, and efficacy was similar to that of the only licensed vaccine, Bacillus Calmette-Guérin (BCG) and A1D4-DMT in the M. tuberculosis primary infection model. In the setting of BCG priming and latent TB infection, M. tuberculosis in the lung and spleen was eliminated more effectively in mice boosted with CMFO-DMT rather than with BCG, A1D4-DMT, or CTT3H-DMT. In particular, sterile immunity was only conferred by CMFO-DMT, which was associated with expedited homing of interferon-gamma + CD4 + T EM and interleukin-2 + T CM cells from the spleen to the infected lung. CMFO-DMT represents a promising candidate to prevent the occurrence of adult TB through both prophylactic and therapeutic methods, and warrants assessment in preclinical and clinical trials. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Protective effects of Scrophularia striata in Ovalbumin-induced mice asthma model

    PubMed Central

    2013-01-01

    Background Scrophularia striata Boiss. (Scrophulariaceae) is a plant growing in the northeastern part of Iran and being used as a traditional herb for various inflammatory disorders. This study was designed to investigate the protective effects of the Scrophularia striata extract in Ovalbumin (OVA) induced-asthma mice model. Methods OVA-sensitized mice were intrapritonealy treated with two doses (100 and 200 mg/kg) of the extract on days 8 to 14 separately. Broncoalveolar lavage fluids (BALF) was collected 48 h after the final OVA challenge and then the number of eosinophils and other inflammatory cells were assessed by direct microscopic counting. In addition, total immunoglubolin (Ig) E and OVA-specific IgE levels in serum, IL-4 and IL-5 cytokines in BALF were determined by Enzyme-Linked Immunosorbent Assay. Moreover, phytochemical assay by thin layer chromatography (TLC) and the 2, 2 diphenyl-1-picrylhydrazyl (DPPH) were used to evaluate the main compounds and the antioxidant capacity of the plant extract, respectively. Results The results showed that the main components; including flavonoids, phenolic compounds and phenyl propanoids were presented in the S. striata extract. In addition, the treatment with extract significantly reduced the number of inflammatory cells and suppressed T-helper 2 (Th2) cytokines including IL-4 and IL-5 in BALF. Also, total IgE and OVA-specific IgE levels in the serum decreased. Conclusion Collectively, it is concluded that the extract has the potential to modulate the Th2 cytokines and could be used as immunomodulatory agent in the treatment of allergic asthma. PMID:23837463

  5. [The protective effects of agmatine in zymosan induced acute lung injury in mice].

    PubMed

    Gu, Ying; Fan, Xia; Zhang, Chun; Yang, Xue; Bao, Yi-xi; Liang, Hua-ping

    2011-11-01

    To examine the protective effects of agmatine (AGM) administration on zymosan (ZYM)-induced inflammatory response and acute lung injury (ALI) in mice. 32 adult male C57BL/6 mice were randomly divided into four groups (n=8 each) to receive i. p. administration of:() phosphate buffer saline (PBS, 0. 5 ml); © AGM (200 mg/kg); © ZYM (500 mg/kg)+PBS (0.5 ml),and ® AGM (200 mg/kg)-ZYM (500 mg/kg). Blood samples and peritoneal exudates were collected from the animals 12 hours after drug administration for concentration of tumor necrosis factor-a (TNF-a),interleukin-6 (IL-6) and nitric oxide (NO) by enzyme linked immunosorbent assay (ELISA). Lung tissue samples were also collected at the same time for histological examination, and determination of tissue content of TNF-a, IL-6, myeloperoxidase (MPO) activity and nuclear factor-KB p65 (NF-cB p65) DNA-binding activity. 12 hours after ZYM injection, the treated mice became lethargic, their activity and water consumption were both reduced, AGM greatly improved the general status, activity, and water consumption in treated mice, while attenuated the increase of TNF-a (ng/L: 252. 6+ 32. 1 vs. 421. 7- 76. 7, 295. 7 ± 78. 6vs. 592. 0 ± 84. 3, both P<0. 05) , IL-6 (ng/L: 2 198. 8 281.8 vs. 4 725. 3 615.4, 19 829. 3 ± 3 647. Ovs. 47 751. 3 ± 5 264.8, both P<0. 05) and NO (pmol/L: 33. 2 ± 4. 3 vs. 50. 2 ± 5. 2, 14.0 ± 3. 6 vs. 45.4 ± 5. 2, both P<0. 05) in serum and peritoneal exudates caused by ZYM. AGM also attenuated the increase of TNF-a (ng/L: 245. 7 ± 39. 1 vs. 378. 3 ± 67. 6, P<0. 05), IL-6 (ng/L: 810. 3 ± 175. 6 vs. 1 172. 4 ± 203.3,P <0. 05), MPO activity (ng/mg: 24. 9 4. 4 vs. 37. 3 5.8, P< 0. 05) and NF-iB p65 optical density(absorbance value: 0. 272 + 0. 029 vs. 0. 347 ± 0. 037, P 0.05) in the lung tissue seen in ZYM treated animals. There was no significant difference between normal PBS and AGM treated group in all the indexes examined. Histological examination demonstrated that ZYM treated animals had

  6. β-Catenin is Essential for Ethanol Metabolism and Protection Against Alcohol-mediated Liver Steatosis in Mice

    PubMed Central

    Liu, Shiguang; Yeh, Tzu-Hsuan; Singh, Vijay P.; Shiva, Sruti; Krauland, Lindsay; Li, Huanan; Zhang, Pili; Kharbanda, Kusum; Ritov, Vladimir; Monga, Satdarshan P. S.; Scott, Donald K.; Eagon, Patricia K.; Behari, Jaideep

    2011-01-01

    The liver plays a central role in ethanol metabolism and oxidative stress is implicated in alcohol-mediated liver injury. β-Catenin regulates hepatic metabolic zonation and adaptive response to oxidative stress. We hypothesized that β-catenin regulates the hepatic response to ethanol ingestion. Female liver-specific β-catenin knockout (KO) mice and wild type (WT) littermates were fed the Lieber-Decarli liquid diet (5% ethanol) in a pair-wise fashion. Liver histology, biochemistry, and gene expression studies were performed. Plasma alcohol and ammonia levels were measured using standard assays. Ethanol-fed KO mice exhibited systemic toxicity and early mortality. KO mice exhibited severe macrovesicular steatosis and five to six-fold higher serum ALT and AST levels. KO mice had modest increase in hepatic oxidative stress, lower expression of mitochondrial superoxide dismutase (SOD-2), and lower citrate synthase activity, the first step in the tricarboxylic acid cycle. N-Acetyl cysteine (NAC) did not prevent ethanol-induced mortality in KO mice. In WT livers, β-catenin was found to co-precipitate with FoxO3, the upstream regulator of SOD-2. Hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and expression were lower in KO mice. Hepatic cytochrome P450 2E1 protein levels were upregulated in ethanol-fed WT mice but were nearly undetectable in KO mice. These changes in ethanol-metabolizing enzymes were associated with 30-fold higher blood alcohol levels in KO mice. Conclusion β-catenin is essential for hepatic ethanol metabolism and plays a protective role in alcohol-mediated liver steatosis. Our results strongly suggest that integration of these functions by β-catenin is critical for adaptation to ethanol ingestion in vivo. PMID:22031168

  7. Protective effects of seed melon extract on CCl4-induced hepatic fibrosis in mice.

    PubMed

    Zhan, Yuan-Yuan; Wang, Jin-Hui; Tian, Xing; Feng, Shi-Xiu; Xue, Lin; Tian, Li-Ping

    2016-12-04

    Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao, was also known as watermelon belongs to family Cucurbitaceae, variously used as healthy food and in the treatment of liver and lungs problems. Currently, Citrullus lanatus has become a major economic crop of medicinal and edible effects with regional characteristics. This study was designed to evaluate the hepatoprotective and antioxidant activity of the seed melon (Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao) extract (SME) against carbon tetrachloride (CCl 4 ) induced hepatic fibrosis in mice. In this study, mice were randomly divided into 7 groups, including normal control, model, silymarin tablets as the positive control, SME 100, 200, 400, and 800mg/kg. After 8 weeks, activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), hyaluronic acid (HA) and laminin (LN) were checked. The levels of antioxidant enzymes such as superoxide dismutase (SOD), glutataion (GSH) and glutathione peroxidase (GSH-Px) were determined after SME administration. The hydroxyproline (HYP) levels, malondialdehyde (MDA) levels and histopathologic examinations of hepatocyte fibrosis were also determined. Additionally, effects of SME on alpha-smooth muscle actin (α-SMA) and transforming growth factor beta-1(TGF-β1) protein expressions were determined. We found that SME could significantly lower the serum levels of hepatic enzyme markers AST, ALT, HA and LN (P<0.01). Compared with the CCl 4 -only treatment group, levels of hepatic SOD and GSH-Px were significantly increased, and the MDA levels were remarkably decreased in mice treated by SME at medium dose (400mg/kg) and high dose (800mg/kg) (P<0.01). A histological examination of the liver showed that lesions, including necrosis, lymphocyte infiltration and fatty degeneration, were partially healed by treatment with SME. The results of protein expressions studies displayed that SME could inhibit α-SMA and TGF

  8. PTGS-2–PTGER2/4 Signaling Pathway Partially Protects From Diabetogenic Toxicity of Streptozotocin in Mice

    PubMed Central

    Vennemann, Antje; Gerstner, Anemone; Kern, Niklas; Ferreiros Bouzas, Nerea; Narumiya, Shuh; Maruyama, Takayuki; Nüsing, Rolf M.

    2012-01-01

    Prostanoids are suggested to participate in diabetes pathology, but their roles are controversially discussed. The purpose of the current study was to examine the role of cyclooxygenase (prostaglandin synthase [PTGS]) enzymes and prostaglandin (PG) E2 signaling pathways in streptozotocin (STZ)-induced type 1 diabetes. Blood glucose, insulin, and survival rate were studied in mice with targeted disruption of the genes for PTGS and PGE receptors (PTGERs). PGE2 was found as the main prostanoid formed by the pancreas. Contrarily to PTGS-1, deficiency of PTGS-2 activity significantly amplified STZ effect, causing dramatic loss of insulin production and rise in blood glucose and death rate. STZ metabolism was unaffected by PTGS deficiency. Diabetogenicity of STZ in PTGER1−/−, PTGER2−/−, PTGER3−/−, and PTGER4−/− mice was comparable to control mice. In striking contrast, combined knockout of PTGER2 and PTGER4 by blocking PTGER4 in PTGER2−/− mice strongly enhanced STZ pathology. Treatment of PTGS-2−/− and wild-type mice with PTGER2/PTGER4 agonists partially protected against STZ-induced diabetes and restored β-cell function. Our data uncover a previously unrecognized protective role of PTGS-2–derived PGE2 in STZ-induced diabetes mediated by the receptor types PTGER2 and PTGER4. These findings offer the possibility to intervene in early progression of type 1 diabetes by using PTGER-selective agonists. PMID:22522619

  9. PTGS-2-PTGER2/4 signaling pathway partially protects from diabetogenic toxicity of streptozotocin in mice.

    PubMed

    Vennemann, Antje; Gerstner, Anemone; Kern, Niklas; Ferreiros Bouzas, Nerea; Narumiya, Shuh; Maruyama, Takayuki; Nüsing, Rolf M

    2012-07-01

    Prostanoids are suggested to participate in diabetes pathology, but their roles are controversially discussed. The purpose of the current study was to examine the role of cyclooxygenase (prostaglandin synthase [PTGS]) enzymes and prostaglandin (PG) E(2) signaling pathways in streptozotocin (STZ)-induced type 1 diabetes. Blood glucose, insulin, and survival rate were studied in mice with targeted disruption of the genes for PTGS and PGE receptors (PTGERs). PGE(2) was found as the main prostanoid formed by the pancreas. Contrarily to PTGS-1, deficiency of PTGS-2 activity significantly amplified STZ effect, causing dramatic loss of insulin production and rise in blood glucose and death rate. STZ metabolism was unaffected by PTGS deficiency. Diabetogenicity of STZ in PTGER1(-/-), PTGER2(-/-), PTGER3(-/-), and PTGER4(-/-) mice was comparable to control mice. In striking contrast, combined knockout of PTGER2 and PTGER4 by blocking PTGER4 in PTGER2(-/-) mice strongly enhanced STZ pathology. Treatment of PTGS-2(-/-) and wild-type mice with PTGER2/PTGER4 agonists partially protected against STZ-induced diabetes and restored β-cell function. Our data uncover a previously unrecognized protective role of PTGS-2-derived PGE(2) in STZ-induced diabetes mediated by the receptor types PTGER2 and PTGER4. These findings offer the possibility to intervene in early progression of type 1 diabetes by using PTGER-selective agonists.

  10. Protective effect of artemisinin on chronic alcohol induced-liver damage in mice.

    PubMed

    Zhao, Xiaoyan; Wang, Liqing; Zhang, Hao; Zhang, Duoduo; Zhang, Zhihao; Zhang, Jie

    2017-06-01

    The liver disease related to chronic alcohol consumption is one of the leading causes of death for alcoholics. The efficient drug to ameliorate the alcoholic liver injury was needed urgently. The present study was performed to investigate whether artemisinin possessed the protective effect against chronic alcohol consumption. 50 male Kunming mice were divided into 5 groups: control group (C): 10ml/kg saline+10ml/kg saline, alcohol group (A): 10ml/kg 56%(v/v) alcohol+10ml/kg saline, low dose group of artemisinin (L): 10ml/kg 56%(v/v) alcohol+30mg/kg/day artemisinin, medium dose group of artemisinin (M): 10ml/kg 56%(v/v) alcohol+60mg/kg/day artemisinin, high dose group of artemisinin (H): 10ml/kg 56%(v/v) alcohol+120mg/kg/day artemisinin. Drugs were given orally every day. The general state of mice was observed and the levels of serum activities of AST and ALT were detected after treatment with drugs for 30days. Besides, the liver weight index was calculated and histopathological analysis was performed. We successfully demonstrated that treatment with high dose of artemisinin significantly decreased the elevated levels of AST (p<0.05) and ALT (p<0.01) in plasma, as well as the liver weight index (p<0.01). The loss of body weight, tissue injury, oedema and inflammatory cell infiltration in the hepatocytes were found in the A group. These symptoms were remarkably alleviated in animals treated with artemisinin. Artemisinin can inhibit the activation of NF-кB and the expression of inflammatory cytokines inducible nitric oxide synthase. Besides, it can also enhance the stability of liver cell membrane, and reduce the damage of liver cell membrane and liver cell. Artemisinin showed a protective effect against chronic alcohol poisoning and it has a great potential for the clinical application to treat the liver injury induced by alcohol. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection.

    PubMed

    Ribes, Sandra; Meister, Tanja; Ott, Martina; Redlich, Sandra; Janova, Hana; Hanisch, Uwe-Karsten; Nessler, Stefan; Nau, Roland

    2014-01-23

    Prophylaxis with unmethylated cytosine phosphate guanidine (CpG) oligodeoxynucleotides (ODN) protects against several systemic experimental infections. Escherichia coli is a major cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients. Wild-type (wt) and Toll-like receptor 9 (TLR9)-deficient mice were rendered neutropenic by intraperitoneal administration of the anti-Ly-6G monoclonal antibody. Immunocompetent and neutropenic mice received intraperitoneal CpG ODN or vehicle 72 h prior to induction of E. coli K1 meningoencephalitis. Pre-treatment with CpG ODN significantly increased survival of neutropenic wt mice from 33% to 75% (P = 0.0003) but did not protect neutropenic TLR9-/- mice. The protective effect of CpG ODN was associated with an enhanced production of interleukin (IL)-12/IL-23p40 with sustained increased levels in serum and spleen at least for 17 days after conditioning compared to buffer-treated animals. CpG-treated neutropenic wt mice showed reduced bacterial concentrations and increased recruitment of Ly6ChighCCR2+ monocytes in brain and spleen 42 h after infection. The levels of macrophage inflammatory protein 1α (MIP-1α) and interferon gamma (IFN-γ) in spleen were higher 42 h after infection in CpG-treated compared to buffer-treated neutropenic animals. In immunocompetent mice, prophylaxis with CpG ODN did not significantly increase survival compared to the buffer group (60% vs. 45%, P = 0.2). These findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.

  12. Immunization with the recombinant antigen Ss-IR induces protective immunity to infection with Strongyloides stercoralis in mice.

    PubMed

    Abraham, David; Hess, Jessica A; Mejia, Rojelio; Nolan, Thomas J; Lok, James B; Lustigman, Sara; Nutman, Thomas B

    2011-10-19

    Human intestinal infections with the nematode Strongyloides stercoralis remain a significant problem worldwide and a vaccine would be a useful addition to the tools available to prevent and control this infection. The goal of this study was to test single antigens for their efficacy in a vaccine against S. stercoralis larvae in mice. Alum was used as the adjuvant in these studies and antigens selected for analysis were either recognized by protective human IgG (Ss-TMY-1, Ss-EAT-6, and Ss-LEC-5) or were known to be highly immunogenic in humans (Ss-NIE-1 and Ss-IR). Only mice immunized with the Ss-IR antigen demonstrated a significant decrease of approximately 80% in the survival of larval parasites in the challenge infection. Antibodies, recovered from mice with protective immunity to S. stercoralis after immunization with Ss-IR, were used to locate the antigen in the larvae. Confocal microscopy revealed that IgG from mice immunized with Ss-IR bound to the surface of the parasites and observations by electron microscopy indicated that IgG bound to granules in the glandular esophagus. Serum collected from mice immunized with Ss-IR passively transferred immunity to naïve mice. These studies demonstrate that Ss-IR, in combination with alum, induces high levels of protective immunity through an antibody dependent mechanism and may therefore be suitable for further development as a vaccine against human strongyloidiasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. A recombinant bivalent fusion protein rVE confers active and passive protection against Yersinia enterocolitica infection in mice.

    PubMed

    Singh, Amit Kumar; Kingston, Joseph Jeyabalaji; Murali, Harishchandra Sripathy; Batra, Harsh Vardhan

    2014-03-05

    In the present study, a bivalent chimeric protein rVE comprising immunologically active domains of Yersinia pestis LcrV and YopE was assessed for its prophylactic abilities against Yersinia enterocolitica O:8 infection in murine model. Mice immunized with rVE elicited significantly higher antibody titers with substantial contribution from the rV component (3:1 ratio). Robust and significant resistance to Y. enterocolitica infection with 100% survival (P<0.001) was seen in rVE vaccinated mice when intra peritoneal (I.P.) challenged with 10(8)CFU of Y. enterocolitica O:8 against the 75%, 60% and 75% survival seen in mice immunized with rV, rE, rV+rE, respectively. Macrophage monolayer supplemented with anti-rVE polysera illustrated efficient protection (89.41% survival) against challenge of Y. enterocolitica O:8. In contrast to sera from sham-immunized mice, immunization with anti-rVE polysera provided complete protection to BALB/c mice against I.P. challenge with 10(8)CFU of Y. enterocolitica O:8 and developed no conspicuous signs of infection in necropsy. The histopathological analysis of microtome sections confirmed significantly reduced lesion size or no lesion in liver and intestine upon infection in anti-rVE immunized mice. The findings from this study demonstrated the fusion protein rVE as a potential candidate subunit vaccine and showed the functional role of antibodies in protection against Y. enterocolitica infections. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Dietary broccoli protects against fatty liver development but not against progression of liver cancer in mice pretreated with diethylnitrosamine

    PubMed Central

    Chen, Yung-Ju; Myracle, Angela D.; Wallig, Matthew A.; Jeffery, Elizabeth H.

    2016-01-01

    Western-style high fat, high sugar diets are associated with non-alcoholic fatty liver disease (NAFLD) and increased liver cancer risk. Sulforaphane from broccoli may protect against these. Previously we initiated broccoli feeding to mice prior to exposure to the hepatocarcinogen diethylnitrosamine (DEN), and saw protection against NAFLD and liver cancer. Here we administered DEN to unweaned mice, initiating broccoli feeding two weeks later, to determine if broccoli protects against cancer progression. Specifically, male 15-day-old C57BL/6J mice were given DEN and placed on a Western or Western+10%Broccoli diet from the age of 4 weeks through 7 months. Dietary broccoli decreased hepatic triacylglycerols, NAFLD, liver damage and tumour necrosis factor by month 5 without changing body weight or relative liver weight, but did not slow carcinogenesis, seen in 100% of mice. We conclude that broccoli, a good source of sulforaphane, slows progression of hepatic lipidosis, but not tumourigenesis in this robust model. PMID:27672403

  15. Orally administered live attenuated Salmonella Typhimurium protects mice against lethal infection with H1N1 influenza virus.

    PubMed

    Kamble, Nitin Machindra; Hajam, Irshad Ahmed; Lee, John Hwa

    2017-03-01

    Pre-stimulation of toll-like receptors (TLRs) by agonists has been shown to increase protection against influenza virus infection. In this study, we evaluated the protective response generated against influenza A/Puerto Rico/8/1934 (PR8; H1N1) virus by oral and nasal administration of live attenuated Salmonella enterica serovar Typhimurium, JOL911 strain, in mice. Oral and nasal inoculation of JOL911 significantly increased the mRNA copy number of TLR-2, TLR4 and TLR5, and downstream type I interferon (IFN) molecules, IFN-α and IFN-β, both in peripheral blood mononuclear cells (PBMCs) and in lung tissue. Similarly, the mRNA copy number of interferon-inducible genes (ISGs), Mx and ISG15, were significantly increased in both the orally and the nasally inoculated mice. Post PR8 virus lethal challenge, the nasal JOL911 and the PBS control group mice showed significant loss of body weight with 70% and 100% mortality, respectively, compared to only 30% mortality in the oral JOL911 group mice. Post sub-lethal challenge, the significant reduction in PR8 virus copy number in lung tissue was observed in oral [on day 4 and 6 post-challenge (dpc)] and nasal (on 4dpc) than the PBS control group mice. The lethal and sub-lethal challenge showed that the generated stimulated innate resistance (StIR) in JOL911 inoculated mice conferred resistance to acute and initial influenza infection but might not be sufficient to prevent the PR8 virus invasion and replication in the lung. Overall, the present study indicates that oral administration of attenuated S. Typhimurium can pre-stimulate multiple TLR pathways in mice to provide immediate early StIR against a lethal H1N1 virus challenge. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung.

    PubMed

    Seyedmousavi, Seyedmojtaba; Davis, Michael J; Sugui, Janyce A; Pinkhasov, Tzvia; Moyer, Shannon; Salazar, Andres M; Chang, Yun C; Kwon-Chung, Kyung J

    2018-03-27

    Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus , A. nidulans , and A. tanneri , in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA. IMPORTANCE Patients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). While Aspergillus fumigatus is the most-studied Aspergillus species, CGD patients

  17. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice*

    PubMed Central

    Su, Hong-ming; Feng, Li-na; Zheng, Xiao-dong; Chen, Wei

    2016-01-01

    Background: Myricetin is a naturally occurring antioxidant commonly found in various plants. However, little information is available with respect to its direct anti-obesity effects. Objective: This study was undertaken to investigate the effect of myricetin on high-fat diet (HFD)-induced obesity in C57BL/6 mice. Results: Administration of myricetin dramatically reduced the body weight of diet-induced obese mice compared with solely HFD-induced mice. Several parameters related to obesity including serum glucose, triglyceride, and cholesterol were significantly decreased in myricetin-treated mice. Moreover, obesity-associated oxidative stress (glutathione peroxidase (GPX) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA)) and inflammation (tumor necrosis factor-α (TNF-α)) were ameliorated in myricetin-treated mice. Further investigation revealed that the protective effect of myricetin against HFD-induced obesity in mice appeared to be partially mediated through the down-regulation of mRNA expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP-1c). Conclusions: Consumption of myricetin may help to prevent obesity and obesity-related metabolic complications. PMID:27256677

  18. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice.

    PubMed

    Su, Hong-Ming; Feng, Li-Na; Zheng, Xiao-Dong; Chen, Wei

    2016-06-01

    Myricetin is a naturally occurring antioxidant commonly found in various plants. However, little information is available with respect to its direct anti-obesity effects. This study was undertaken to investigate the effect of myricetin on high-fat diet (HFD)-induced obesity in C57BL/6 mice. Administration of myricetin dramatically reduced the body weight of diet-induced obese mice compared with solely HFD-induced mice. Several parameters related to obesity including serum glucose, triglyceride, and cholesterol were significantly decreased in myricetin-treated mice. Moreover, obesity-associated oxidative stress (glutathione peroxidase (GPX) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA)) and inflammation (tumor necrosis factor-α (TNF-α)) were ameliorated in myricetin-treated mice. Further investigation revealed that the protective effect of myricetin against HFD-induced obesity in mice appeared to be partially mediated through the down-regulation of mRNA expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP-1c). Consumption of myricetin may help to prevent obesity and obesity-related metabolic complications.

  19. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice

    PubMed Central

    Williams, Jessica A.; Ni, Hong-Min; Ding, Yifeng

    2015-01-01

    Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. PMID:26159696

  20. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice.

    PubMed

    Williams, Jessica A; Ni, Hong-Min; Ding, Yifeng; Ding, Wen-Xing

    2015-09-01

    Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. Copyright © 2015 the American Physiological Society.

  1. Protective Effect of Procyanidin B2 against CCl4-Induced Acute Liver Injury in Mice.

    PubMed

    Yang, Bing-Ya; Zhang, Xiang-Yu; Guan, Sheng-Wen; Hua, Zi-Chun

    2015-07-03

    Procyanidin B2 has demonstrated several health benefits and medical properties. However, its protective effects against CCl4-induced hepatotoxicity have not been clarified. The present study aimed to investigate the hepatoprotective effects of procyanidin B2 in CCl4-treated mice. Our data showed that procyanidin B2 significantly decreased the CCl4-induced elevation of serum alanine aminotransferase activities, as well as improved hepatic histopathological abnormalities. Procyanidin B2 also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD, CAT and GSH-Px. Further research demonstrated that procyanidin B2 decreased the expression of TNF-α, IL-1β, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibited the translocation of nuclear factor-kappa B (NF-κB) p65 from the cytosol to the nuclear fraction in mouse liver. Moreover, CCl4-induced apoptosis in mouse liver was measured by (terminal-deoxynucleotidyl transferase mediated nick end labeling) TUNEL assay and the cleaved caspase-3. Meanwhile, the expression of apoptosis-related proteins Bax and Bcl-xL was analyzed by Western blot. Results showed that procyanidin B2 significantly inhibited CCl4-induced hepatocyte apoptosis, markedly suppressed the upregulation of Bax expression and restored the downregulation of Bcl-xL expression. Overall, the findings indicated that procyanidin B2 exhibited a protective effect on CCl4-induced hepatic injury by elevating the antioxidative defense potential and consequently suppressing the inflammatory response and apoptosis of liver tissues.

  2. Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Ghosh, Prosenjit; Biswas, Jaydip; Bhattacharya, Sudin

    2014-08-01

    Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  3. Two Novel Salmonella Bivalent Vaccines Confer Dual Protection against Two Salmonella Serovars in Mice

    PubMed Central

    Zhao, Xinxin; Dai, Qinlong; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Wang, Mingshu; Chen, Shun; Sun, Kunfeng; Yang, Qiao; Wu, Ying; Cheng, Anchun

    2017-01-01

    Newport lethal challenge. All of the mice in the three vaccine-immunized groups survived the lethal Salmonella Typhimurium challenge. In contrast, SLT26 (pCZ11) and SLT27 (pCZ11) conferred full protection against lethal Salmonella Newport challenge, but SLT25 (pCZ11) provided only 50% heterologous protection. Thus, we developed two novel Salmonella bivalent vaccines, SLT26 (pCZ11) and SLT27 (pCZ11), suggesting that the delivery of a heterologous O-antigen in attenuated Salmonella strains is a prospective approach for developing Salmonella vaccines with broad serovar coverage. PMID:28929089

  4. Hydrogen Treatment Protects Mice Against Chronic Pancreatitis by Restoring Regulatory T Cells Loss.

    PubMed

    Chen, Luguang; Ma, Chao; Bian, Yun; Li, Jing; Wang, Tiegong; Su, Li; Lu, Jianping

    2017-01-01

    Chronic pancreatitis is an inflammatory disease of the pancreas characterized by progressive tissue destruction and fibrogenesis. The development of chronic pancreatitis is associated with immune cell dysregulation. Currently, the specific and effective treatment of chronic pancreatitis remains absent. By using an L-arginine induced chronic pancreatitis mouse model, we tested the therapeutic potential of hydrogen, a strong hydroxyl radicals scavenger, in the chronic pancreatitis model. Tissue inflammation, damage and fibrosis were analyzed on HE, TUNEL, MPO, and sirius staining. Pancreas levels of MDA content, SOD activity, TNF-α , IL-10 cytokine expression and serum amylase and lipase activity were determined by ELISA and absorbance assay. Apoptosis, T cells subtype proportion and intracellular level of reactive oxygen species (ROS) were analyzed by flow cytometry. Tregs adoptive transfer and CD25 neutralization were used to validate the role of Tregs in chronic pancreatitis. We found that hydrogen treatment significantly improved multiple symptoms of chronic pancreatitis. The number of Tregs was reduced in chronic pancreatitis mice, while hydrogen treatment restored the Treg loss by L-arginine administrations. Depletion of Tregs abolished the protective effect of hydrogen treatment in chronic pancreatitis. In vitro study showed that hydrogen blocked ROS generation in Tregs and promoted Tregs survival. Hydrogen treatment showed reliable benefits in controlling the severity of chronic pancreatitis. Our study supported that hydrogen could be used as a novel treatment in chronic pancreatitis patient in the future. © 2017 The Author(s). Published by S. Karger AG, Basel.

  5. Stepwise Engineering of Heterodimeric Single Domain Camelid VHH Antibodies That Passively Protect Mice from Ricin Toxin*

    PubMed Central

    Vance, David J.; Tremblay, Jacqueline M.; Mantis, Nicholas J.; Shoemaker, Charles B.

    2013-01-01

    In an effort to engineer countermeasures for the category B toxin ricin, we produced and characterized a collection of epitopic tagged, heavy chain-only antibody VH domains (VHHs) specific for the ricin enzymatic (RTA) and binding (RTB) subunits. Among the 20 unique ricin-specific VHHs we identified, six had toxin-neutralizing activity: five specific for RTA and one specific for RTB. Three neutralizing RTA-specific VHHs were each linked via a short peptide spacer to the sole neutralizing anti-RTB VHH to create VHH “heterodimers.” As compared with equimolar concentrations of their respective monovalent monomers, all three VHH heterodimers had higher affinities for ricin and, in the case of heterodimer D10/B7, a 6-fold increase in in vitro toxin-neutralizing activity. When passively administered to mice at a 4:1 heterodimer:toxin ratio, D10/B7 conferred 100% survival in response to a 10 × LD50 ricin challenge, whereas a 2:1 heterodimer:toxin ratio conferred 20% survival. However, complete survival was achievable when the low dose of D10/B7 was combined with an IgG1 anti-epitopic tag monoclonal antibody, possibly because decorating the toxin with up to four IgGs promoted serum clearance. The two additional ricin-specific heterodimers, when tested in vivo, provided equal or greater passive protection than D10/B7, thereby warranting further investigation of all three heterodimers as possible therapeutics. PMID:24202178

  6. Stepwise engineering of heterodimeric single domain camelid VHH antibodies that passively protect mice from ricin toxin.

    PubMed

    Vance, David J; Tremblay, Jacqueline M; Mantis, Nicholas J; Shoemaker, Charles B

    2013-12-20

    In an effort to engineer countermeasures for the category B toxin ricin, we produced and characterized a collection of epitopic tagged, heavy chain-only antibody VH domains (VHHs) specific for the ricin enzymatic (RTA) and binding (RTB) subunits. Among the 20 unique ricin-specific VHHs we identified, six had toxin-neutralizing activity: five specific for RTA and one specific for RTB. Three neutralizing RTA-specific VHHs were each linked via a short peptide spacer to the sole neutralizing anti-RTB VHH to create VHH "heterodimers." As compared with equimolar concentrations of their respective monovalent monomers, all three VHH heterodimers had higher affinities for ricin and, in the case of heterodimer D10/B7, a 6-fold increase in in vitro toxin-neutralizing activity. When passively administered to mice at a 4:1 heterodimer:toxin ratio, D10/B7 conferred 100% survival in response to a 10 × LD50 ricin challenge, whereas a 2:1 heterodimer:toxin ratio conferred 20% survival. However, complete survival was achievable when the low dose of D10/B7 was combined with an IgG1 anti-epitopic tag monoclonal antibody, possibly because decorating the toxin with up to four IgGs promoted serum clearance. The two additional ricin-specific heterodimers, when tested in vivo, provided equal or greater passive protection than D10/B7, thereby warranting further investigation of all three heterodimers as possible therapeutics.

  7. Humanized theta-defensins (retrocyclins) enhance macrophage performance and protect mice from experimental anthrax infections.

    PubMed

    Welkos, S; Cote, C K; Hahn, U; Shastak, O; Jedermann, J; Bozue, J; Jung, G; Ruchala, P; Pratikhya, P; Tang, T; Lehrer, R I; Beyer, W

    2011-09-01

    Retrocyclins are humanized versions of the -defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal factor. We now report that retrocyclins are extensively bound by components of native mouse, human, and fetal calf sera, that heat-inactivated sera show greatly enhanced retrocyclin binding, and that native and (especially) heat-inactivated sera greatly reduce the direct activities of retrocyclins against spores and vegetative cells of B. anthracis. Nevertheless, we also found that retrocyclins protected mice challenged in vivo by subcutaneous, intraperitoneal, or intranasal instillation of B. anthracis spores. Retrocyclin 1 bound extensively to B. anthracis spores and enhanced their phagocytosis and killing by murine RAW264.7 cells. Based on the assumption that spore-bound RC1 enters phagosomes by "piggyback phagocytosis," model calculations showed that the intraphagosomal concentration of RC1 would greatly exceed its extracellular concentration. Murine alveolar macrophages took up fluorescently labeled retrocyclin, suggesting that macrophages may also acquire extracellular RC1 directly. Overall, these data demonstrate that retrocyclins are effective in vivo against experimental murine anthrax infections and suggest that enhanced macrophage function contributes to this property.

  8. Apigenin protects mice from pneumococcal pneumonia by inhibiting the cytolytic activity of pneumolysin.

    PubMed

    Song, Meng; Li, Li; Li, Meng; Cha, Yonghong; Deng, Xuming; Wang, Jianfeng

    2016-12-01

    Streptococcus pneumoniae is an important human pathogenic bacterium that can cause various life-threatening infections. Pneumolysin (PLY), the pore-forming toxin that forms large pores in the cell membrane, is a key virulence factor secreted by S. pneumoniae that penetrates the physical defenses of the host and plays an important role in the pathogenesis of pneumococcal diseases, such as pneumonia, meningitis, bacteremia and otitis media. This study showed that apigenin, one of the bioflavonoids widely found in herbs, inhibits PLY-induced hemolysis by inhibiting the oligomerization of PLY and has no anti-S. pneumoniae activity. In addition, when PLY was incubated with human alveolar epithelial (A549) cells, apigenin could effectively alleviate PLY-mediated cell injury. In vivo studies further demonstrated that apigenin could protect mice against S. pneumoniae pneumonia. These results imply that apigenin could directly interact with PLY to decrease the pathogenicity of S. pneumoniae and that novel therapeutics against S. pneumoniae PLY might provide greater effectiveness in combatting S. pneumoniae pneumonia. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

    PubMed Central

    Zhang, Bin; Shen, Qiang; Chen, Yaping; Pan, Ruile; Kuang, Shihuan; Liu, Guiyan; Sun, Guibo; Sun, Xiaobo

    2017-01-01

    Diabetic cardiomyopathy (DCM) has been increasingly considered as a main cause of heart failure and death in diabetic patients. At present, no effective treatment exists to prevent its development. In the present study, we describe the potential protective effects and mechanisms of myricitrin (Myr) on the cardiac function of streptozotosin-induced diabetic mice and on advanced glycation end products (AGEs)-induced H9c2 cardiomyocytes. In vitro experiments revealed that pretreatment with Myr significantly decreased AGEs-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells. These effects are correlated with Nrf2 activation and NF-κB inhibition. In vivo investigation demonstrated that oral administration of Myr at 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins. Finally, Myr improved diastolic dysfunction and attenuated histological abnormalities. Mechanistically, Myr attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and ERK phosphorylation in the diabetic heart. Collectively, these results strongly indicate that Myr exerts cardioprotective effects against DCM through the blockage of inflammation, oxidative stress, and apoptosis. This suggests that Myr might be a potential therapeutic agent for the treatment of DCM. PMID:28287141

  10. Vaccination with lentiviral vector expressing the nfa1 gene confers a protective immune response to mice infected with Naegleria fowleri.

    PubMed

    Kim, Jong-Hyun; Sohn, Hae-Jin; Lee, Jinyoung; Yang, Hee-Jong; Chwae, Yong-Joon; Kim, Kyongmin; Park, Sun; Shin, Ho-Joon

    2013-07-01

    Naegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. The nfa1 gene (360 bp), cloned from a cDNA library of N. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. The nfa1 gene plays an important role in the pathogenesis of N. fowleri infection. To examine the effect of nfa1 DNA vaccination against N. fowleri infection, we constructed a lentiviral vector (pCDH) expressing the nfa1 gene. For the in vivo mouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing the nfa1 gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing the nfa1 gene also exhibited significantly higher survival rates (90%) after challenge with N. fowleri trophozoites. Finally, the nfa1 vaccination effectively induced protective immunity by humoral and cellular immune responses in N. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool against N. fowleri infection.

  11. Vaccination with Lentiviral Vector Expressing the nfa1 Gene Confers a Protective Immune Response to Mice Infected with Naegleria fowleri

    PubMed Central

    Kim, Jong-Hyun; Sohn, Hae-Jin; Lee, Jinyoung; Yang, Hee-Jong; Chwae, Yong-Joon; Kim, Kyongmin; Park, Sun

    2013-01-01

    Naegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. The nfa1 gene (360 bp), cloned from a cDNA library of N. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. The nfa1 gene plays an important role in the pathogenesis of N. fowleri infection. To examine the effect of nfa1 DNA vaccination against N. fowleri infection, we constructed a lentiviral vector (pCDH) expressing the nfa1 gene. For the in vivo mouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing the nfa1 gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing the nfa1 gene also exhibited significantly higher survival rates (90%) after challenge with N. fowleri trophozoites. Finally, the nfa1 vaccination effectively induced protective immunity by humoral and cellular immune responses in N. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool against N. fowleri infection. PMID:23677321

  12. Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics

    PubMed Central

    Saitta, Kyle S.; Zhang, Carmen; Lee, Kang Kwang; Fujimoto, Kazunori; Redinbo, Matthew R.; Boelsterli, Urs A.

    2014-01-01

    We have previously demonstrated that a small molecule inhibitor of bacterial β-glucuronidase (Inh-1; [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]) protected mice against diclofenac (DCF)-induced enteropathy. Here we report that Inh-1 was equally protective against small intestinal injury induced by other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin (10 mg/kg, ip) and ketoprofen (100 mg/kg, ip).Inh-1 provided complete protection if given prior to DCF (60 mg/kg, ip), and partial protection if administered 3-h post-DCF, suggesting that the temporal window of mucosal protection can be extended for drugs undergoing extensive enterohepatic circulation.Pharmacokinetic analysis of Inh-1 revealed an absolute bioavailability (F) of 21% and a short t1/2 of <1 h. This low F was shown to be due to hepatic first-pass metabolism, as confirmed with the pan-CYP inhibitor, 1-aminobenzotriazole.Using the fluorescent probe 5 (and 6)-carboxy-2′,7′-dichlorofluorescein, we demonstrated that Inh-1 did not interfere with hepatobiliary export of glucuronides in gall bladder-cannulated mice.These data are compatible with the hypothesis that pharmacological inhibition of bacterial β-glucuronidase-mediated cleavage of NSAID glucuronides in the small intestinal lumen can protect against NSAID-induced enteropathy caused by locally high concentrations of NSAID aglycones. PMID:23829165

  13. BALB/c mice display more enhanced BCG vaccine induced Th1 and Th17 response than C57BL/6 mice but have equivalent protection.

    PubMed

    Garcia-Pelayo, M Carmen; Bachy, Véronique S; Kaveh, Daryan A; Hogarth, Philip J

    2015-01-01

    It is generally assumed that the inbred mouse strains BALB/c (H-2(d)) and C57BL/6 (H-2(b)) respond to mycobacterial infection with distinct polarisation of T helper responses, with C57BL/6 predisposed to Th1 and BALB/c to Th2. We investigated this in a BCG-immunisation, Mycobacterium bovis challenge model. Following immunisation, lung and spleen cell cytokine responses to in vitro re-stimulation with a cocktail of seven secreted, immunogenic, recombinant mycobacterial proteins were determined. In both lung and spleen, BALB/c cells produced at least 2-fold more IFN-γ, and up to 7-fold more IL-2 and IL-17 than C57BL/6 cells, whereas IL-10 production was reciprocally increased in C57BL/6 mice. These data suggest that, contrary to reports in the literature, specific mycobacterial antigens are able to induce strong Th1 and Th17 responses in BALB/c mice following BCG vaccination, whilst in C57BL/6 mice, the Th1 response is partly counterbalanced by IL-10. After subsequent M. bovis low dose challenge, protection, as measured in the lungs and dissemination to the spleen, was equivalent in BALB/c and C57BL/6 mice, indicating that BCG-induced immunity was equivalent in both strains. Thus, the differential immune responses do not appear to have a role in protection, but further, as yet unidentified, specific immune responses play a significant role. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  14. Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy

    PubMed Central

    Dotson, Abby L.; Zhu, Wenbin; Libal, Nicole; Alkayed, Nabil J.; Offner, Halina

    2014-01-01

    Stroke is a leading cause of death and disability in the United States. The lack of clinical success in stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from experimental stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to stroke that allow unique targeting of stroke immunotherapies. PMID:25309326

  15. Recombinant canine adenovirus type-2 expressing TgROP16 provides partial protection against acute Toxoplasma gondii infection in mice.

    PubMed

    Li, Xiu-Zhen; Lv, Lin; Zhang, Xu; Anchang, Kenneth Yongabi; Abdullahi, Auwalu Yusuf; Tu, Liqing; Wang, Xiaohu; Xia, Lijun; Zhang, Xiu-Xiang; Feng, Weili; Lu, Chunxia; Li, Shoujun; Yuan, Zi-Guo

    2016-11-01

    We previously demonstrated that the survival time of BALB/c mice challenged with Toxoplasma gondii RH strain was prolonged by immunising the mice with a eukaryotic vector expressing the protein ROP16 of T. gondii. Building upon previous findings, we are exploring improved vaccination strategies to enhance protection. In this work, a novel recombinant canine adenovirus type 2 expressing ROP16 (CAV-2-ROP16) of T. gondii was constructed and identified to express ROP16 in Madin-Darby canine kidney cells (MDCK) cells by western blot (WB) and indirect immunofluorescence (IFA) assays. Intramuscular immunisation of BALB/c mice with CAV-2-ROP16 was performed to evaluate the humoral and cellular immune responses. This vaccination triggered significant humoral and cellular responses, including ROP16-stimulated lymphoproliferation (P<0.05). Compared to control groups, the CAV-2-ROP16 immunised mice had high production of IFN-γ, IL-2 and IL-12 (P<0.05), with a predominance of IgG2a production, but not IL-10 (P>0.05), revealing that a predominant Th1-type response had developed. The cell-mediated cytotoxic activity with high levels of IFN-γ and TNF-α was significantly increased in both CD4 + and CD8 + T-cell compartments in the mice immunised with CAV-2-ROP16 (P<0.05), compared to three control groups. In addition, when immunised mice were challenged with the RH strain of T. gondii, they showed a significantly increased survival rate (25%) 80days post infection compared with control mice that all died within seven days (P<0.05). The 25% protection rate elicited by the recombinant virus CAV-2-ROP16 has not been achieved in the field of anti-T. gondii vaccination until now. Our work presents the successful use of recombinant virus CAV-2-ROP16 in vaccination protocols to protect against intraperitoneal challenge with the virulent RH strain of T. gondii. This system was shown to be extremely efficient in eliciting humoral and cellular immune responses that led to a significant

  16. Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice.

    PubMed

    He, Wenqian; Chen, Chi-Jene; Mullarkey, Caitlin E; Hamilton, Jennifer R; Wong, Christine K; Leon, Paul E; Uccellini, Melissa B; Chromikova, Veronika; Henry, Carole; Hoffman, Kevin W; Lim, Jean K; Wilson, Patrick C; Miller, Matthew S; Krammer, Florian; Palese, Peter; Tan, Gene S

    2017-10-10

    The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.

  17. Protective immunity against Naegleria fowleri infection on mice immunized with the rNfa1 protein using mucosal adjuvants.

    PubMed

    Lee, Jinyoung; Yoo, Jong-Kyun; Sohn, Hae-Jin; Kang, Hee-kyoung; Kim, Daesik; Shin, Ho-Joon; Kim, Jong-Hyun

    2015-04-01

    The free-living amoeba, Naegleria fowleri, causes a fatal disease called primary amoebic meningoencephalitis (PAM) in humans and experimental animals. Of the pathogenic mechanism of N. fowleri concerning host tissue invasion, the adherence of amoeba to hose cells is the most important. We previously cloned the nfa1 gene from N. fowleri. The protein displayed immunolocalization in the pseudopodia, especially the food-cups structure, and was related to the contact-dependent mechanism of the amoebic pathogenicity in N. fowleri infection. The cholera toxin B subunit (CTB) and Escherichia coli heat-labile enterotoxin B subunit (LTB) have been used as potent mucosal adjuvants via the parenteral route of immunization in most cases. In this study, to examine the effect of protective immunity of the Nfa1 protein for N. fowleri infection with enhancement by CTB or LTB adjuvants, intranasally immunized BALB/c mice were infected with N. fowleri trophozoites for the development of PAM. The mean time to death of mice immunized with the Nfa1 protein using LTB or CTB adjuvant was prolonged by 5 or 8 days in comparison with that of the control mice. In particular, the survival rate of mice immunized with Nfa1 plus CTB was 100% during the experimental period. The serum IgG levels were significantly increased in mice immunized with Nfa1 protein plus CTB or LTB adjuvants. These results suggest that the Nfa1 protein, with CTB or LTB adjuvants, induces strong protective immunity in mice with PAM due to N. fowleri infection.

  18. Shikonin derivatives protect immune organs from damage and promote immune responses in vivo in tumour-bearing mice.

    PubMed

    Long, Su; GuangZhi, Yan; BaoJie, Guan; Wei, Xu; YanYong, Hao; YingLi, Wang; Yang, Zhang; LiHua, Liu

    2012-01-01

    Shikonin, a major component of Lithospermum erythrorhizon and Arnebia euchroma, exhibits antiinflammatory, immunomodulatory and antitumour activities. Although many recent studies have focused on the antitumour effects of shikonin, the exact mechanisms underlying its antitumour and immunomodulatory effects in tumour-bearing mice remain unclear. The aim of the present study was to investigate the antitumour and immunomodulatory effects of shikonin derivatives (ShD) in tumour-bearing mice. Swiss mice inoculated with hepatoma HepA(22) or sarcoma 180 (S(180)) cells were treated with ShD or 5-fluorouracil (5Fu). Survival time, immune organs, natural killer cell activity, lymphocytes, lymphocyte transformation and interleukin (IL)-2 production were analysed. ShD significantly prolonged the survival (median survival time prolonged by >7 days) of tumour-bearing mice in a dose-dependent manner, inhibited the growth of transplantable neoplasms (inhibitory rate, > 33%), and recovered (at [ShD] = 2.5 mg/kg/day) or increased (at [ShD] > 5 mg/kg/day) the number of CD3- and CD19-positive cells. ShD also played a role in protecting the immune organs from damage and reversed or enhanced immune responses, as noted by the nearly normal thymic structure; enlarged splenic corpuscles; and improved natural killer cell activity, lymphocyte transformation and IL-2 production in ShD-treated mice. ShD reduced the tumour load of tumour-bearing mice and protected the immune organs against tumour-induced damage and immune function impairment. Copyright © 2011 John Wiley & Sons, Ltd.

  19. Failure of antioxidants to protect against angiotensin II-induced aortic rupture in aged apolipoprotein(E)-deficient mice.

    PubMed

    Jiang, F; Jones, G T; Dusting, G J

    2007-11-01

    Oxidative stress may be involved in the development of abdominal aortic aneurysms (AAAs). Previous studies indicate that antioxidants protect against AAA formation during chronic angiotensin (Ang) II infusion in apolipoprotein E-deficient (ApoE(0)) mice. We here examine if these protective effects also occurred in aged ApoE(0) mice. Male ApoE(0) mice (50-60 weeks) were randomly divided into 4 groups: saline, Ang II (1000 ng kg(-1) min(-1) for 4 weeks), Ang II plus antioxidants (0.1% vitamin E in food plus 0.1% vitamin C in drinking water), and Ang II plus losartan (30 mg kg(-1) day(-1)). Exogenous Ang II increased systolic blood pressure by 40 mmHg and resulted in the formation of pseudoaneurysms (rupture and extramural haematoma) in the abdominal aorta in 50% of animals. True aneurysmal dilatation was rarely observed. Antioxidants decreased systemic oxidative stress (plasma malondialdehyde), but had only minor effects on aortic rupture, relative to the complete prevention by losartan. Immunohistochemistry revealed strong matrix metalloproteinase-9 (MMP-9) expression in atherosclerotic plaques and at the sites of rupture. Antioxidants did not affect tumour necrosis factor-alpha-stimulated MMP-9 release from U937 cells. In addition, antioxidants had little effects on Ang II-induced renal dysfunction. In contrast to previous findings in younger mice, antioxidants had only minor effects on Ang II-induced aortic rupture in aged mice. Our results demonstrate that the pathological features of the aneurysmal remodelling induced by Ang II in old ApoE(0) mice are distinct from those of human AAA.

  20. Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

    PubMed

    Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

    2016-10-01

    Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. [Changes of nitric oxide after trichloroethylene irritation in hairless mice skin and protection of ginkgo biloba extract and vitamin E].

    PubMed

    Wang, Liang; Shen, Tong; Zhou, Cheng-fan; Yu, Jun-feng; Zhu, Qi-xing

    2009-04-01

    To study the changes of nitric oxide (NO) in the BALB/c hairless mice skin after trichloroethylene (TCE) irritation and the protection of ginkgo biloba extract (GbE) and vitamin E (VE). 132 BALB/c hairless mice were randomly divided into blank control group, solvent group (olive oil), TCE groups (20%TCE, 40%TCE, 80%TCE and 100%TCE), GbE groups (0.1%GbE, 1%GbE and 10%GbE) and VE groups (5%VE, 10% VE and 20% VE), with 11 animals in each group, 5 for acute irritation test and 6 for the cumulative irritation test. The skin irritation was observed, and the levels of NO in the dorsal skin of BALB/C hairless mice were detected. The kit of NO was used to detect the levels of NO in the dorsal skin of BALB/c hairless mice. (1) The skin presented erythema and edema after TCE irritation both in acute irritation and cumulative irritation test and the skin inflammation showed time-dose effect relationship; the mice skin was protected in GbE or VE groups. (2) In the acute stimulation test, the levels of NO in 80%TCE group (69.895 +/- 9.605 micromol/mg pro) and 100%TCE group (77.273 +/- 9.290 micromol/mg pro) were significantly different compared with blank control group and solvent control group (P < 0.05 or P < 0.01). In the protection group, the NO level were reduced, with the statistically significant differences. (3) In acute irritation test, the levels of NO in 80%TCE group (60.362 +/- 9.817 micromol/mg pro) and 100%TCE group (68.027 +/- 9.354 micromol/mg pro) were significantly different compared with blank control group and solvent control group, (P < 0.05 or P < 0.01); In the protection group, 1% GbE, 10% GbE, 10% VE and 20%VE could reduce the levels of NO, with statistically significant differences. TCE can produce the irritation on the dorsal skin of BALB/c hairless mice and induce the significant increase of the NO levels. GbE and VE can protect the skin from TCE irritation damage.

  2. Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice.

    PubMed

    Sharma, Veena; Sharma, Sadhana; Pracheta

    2012-12-01

    The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice.

  3. Turmeric Bioprocessed with Mycelia from the Shiitake Culinary-Medicinal Mushroom Lentinus edodes (Agaricomycetes) Protects Mice Against Salmonellosis.

    PubMed

    Kim, Sung Phil; Lee, Sang Jong; Nam, Seok Hyun; Friedman, Mendel

    2017-01-01

    This study investigated the suppressive mechanisms of an extract from bioprocessed Lentinus edodes mycelial liquid culture supplemented with turmeric (bioprocessed Curcuma longa extract [BPCLE]) against murine salmonellosis. The BPLCE extract from the bioprocessed mycelia of the Salmonella Typhimurium into murine RAW 264.7 macrophage cells, elimination of intracellular bacteria, and elevation of inducible nitric oxide synthase expression. Dietary administration of BPCLE activated leukocytes from the mice infected with Salmonella through the intraperitoneal route. The enzyme-linked immunosorbent assay of the cytokines produced by splenocytes from infected mice showed significant increases in the levels of Th1 cytokines, including interleukin (IL)-1β, IL-2, IL-6, and IL-12. Histology showed that dietary administration of BPCLE protected against necrosis of the liver resulting from a sublethal dose of Salmonella. In addition, the treatment (1) extended the lifespan of lethally infected mice, (2) suppressed the invasion of Salmonella into human Caco-2 colorectal adenocarcinoma cells, (3) increased excretion of the bacterium in the feces, (4) suppressed the translocation of the Salmonella to internal organs, and (5) increased total immunoglobulin A in both serum and intestinal fluids. BPCLE protected the mice against salmonellosis via cooperative effects that include the upregulation of the Th1 immune reaction, prevention of translocation of bacteria across the intestinal epithelial cells, and increased immunoglobulin A production in serum and intestinal fluids.

  4. Increased production of omega-3 fatty acids protects retinal ganglion cells after optic nerve injury in mice.

    PubMed

    Peng, Shanshan; Shi, Zhe; Su, Huanxing; So, Kwok-Fai; Cui, Qi

    2016-07-01

    Injury to the central nervous system causes progressive degeneration of injured axons, leading to loss of the neuronal bodies. Neuronal survival after injury is a prerequisite for successful regeneration of injured axons. In this study, we investigated the effects of increased production of omega-3 fatty acids and elevation of cAMP on retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) crush injury in adult mice. We found that increased production of omega-3 fatty acids in mice enhanced RGC survival, but not axonal regeneration, over a period of 3 weeks after ON injury. cAMP elevation promoted RGC survival in wild type mice, but no significant difference in cell survival was seen in mice over-producing omega-3 fatty acids and receiving intravitreal injections of CPT-cAMP, suggesting that cAMP elevation protects RGCs after injury but does not potentiate the actions of the omega-3 fatty acids. The observed omega-3 fatty acid-mediated neuroprotection is likely achieved partially through ERK1/2 signaling as inhibition of this pathway by PD98059 hindered, but did not completely block, RGC protection. Our study thus enhances our current understanding of neural repair after CNS injury, including the visual system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Targeted deletion of Kif18a protects from colitis-associated colorectal (CAC) tumors in mice through impairing Akt phosphorylation

    SciTech Connect

    Zhu, Houbao; Xu, Wangyang; Zhang, Hongxin

    2013-08-16

    Highlights: •Kif18A is up-regulated in CAC of mouse model. •Kif18a{sup −/−} mice are protected from CAC. •Tumor cells from Kif18a{sup −/−} mice undergo more apoptosis. •Kif18A deficiency induces poor Atk phosphorylation. -- Abstract: Kinesins are a superfamily of molecular motors involved in cell division or intracellular transport. They are becoming important targets for chemotherapeutic intervention of cancer due to their crucial role in mitosis. Here, we demonstrate that the kinesin-8 Kif18a is overexpressed in murine CAC and is a crucial promoter during early CAC carcinogenesis. Kif18a-deficient mice are evidently protected from AOM–DSS-induced colon carcinogenesis. Kif18A is responsible for proliferation ofmore » colonic tumor cells, while Kif18a ablation in mice promotes cell apoptosis. Mechanistically, Kif18a is responsible for induction of Akt phosphorylation, which is known to be associated with cell survival regulation. In conclusion, Kif18a is critical for colorectal carcinogenesis in the setting of inflammation by mechanisms of increased PI3K-AKT signaling. Inhibition of Kif18A activity may be useful in the prevention or chemotherapeutic intervention of CAC.« less

  6. Protective effects of hot spring water drinking and radon inhalation on ethanol-induced gastric mucosal injury in mice

    PubMed Central

    Etani, Reo; Kataoka, Takahiro; Kanzaki, Norie; Sakoda, Akihiro; Tanaka, Hiroshi; Ishimori, Yuu; Mitsunobu, Fumihiro; Taguchi, Takehito

    2017-01-01

    ABSTRACT Radon therapy using radon (222Rn) gas is classified into two types of treatment: inhalation of radon gas and drinking water containing radon. Although short- or long-term intake of spa water is effective in increasing gastric mucosal blood flow, and spa water therapy is useful for treating chronic gastritis and gastric ulcer, the underlying mechanisms for and precise effects of radon protection against mucosal injury are unclear. In the present study, we examined the protective effects of hot spring water drinking and radon inhalation on ethanol-induced gastric mucosal injury in mice. Mice inhaled radon at a concentration of 2000 Bq/m3 for 24 h or were provided with hot spring water for 2 weeks. The activity density of 222Rn ranged from 663 Bq/l (start point of supplying) to 100 Bq/l (end point of supplying). Mice were then orally administered ethanol at three concentrations. The ulcer index (UI), an indicator of mucosal injury, increased in response to the administration of ethanol; however, treatment with either radon inhalation or hot spring water inhibited the elevation in the UI due to ethanol. Although no significant differences in antioxidative enzymes were observed between the radon-treated groups and the non-treated control groups, lipid peroxide levels were significantly lower in the stomachs of mice pre-treated with radon or hot spring water. These results suggest that hot spring water drinking and radon inhalation inhibit ethanol-induced gastric mucosal injury. PMID:28498931

  7. Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses.

    PubMed

    Frei, Julia C; Nyakatura, Elisabeth K; Zak, Samantha E; Bakken, Russell R; Chandran, Kartik; Dye, John M; Lai, Jonathan R

    2016-01-13

    Filoviruses (Ebola and Marburg) cause severe hemorrhagic fever. There are five species of ebolavirus; among these, the Ebola (Zaire) and Sudan viruses (EBOV and SUDV, respectively) are highly pathogenic and have both caused recurring, large outbreaks. However, the EBOV and SUDV glycoprotein (GP) sequences are 45% divergent and thus antigenically distinct. Few antibodies with cross-neutralizing properties have been described to date. We used antibody engineering to develop novel bispecific antibodies (Bis-mAbs) that are cross-reactive toward base epitopes on GP from EBOV and SUDV. These Bis-mAbs exhibit potent neutralization against EBOV and SUDV GP pseudotyped viruses as well as authentic pathogens, and confer a high degree (in one case 100%) post-exposure protection of mice from both viruses. Our studies show that a single agent that targets the GP base epitopes is sufficient for protection in mice; such agents could be included in panfilovirus therapeutic antibody cocktails.

  8. Short- and long-term immunogenicity and protection induced by non-replicating smallpox vaccine candidates in mice and comparison with the traditional 1st generation vaccine.

    PubMed

    Ferrier-Rembert, Audrey; Drillien, Robert; Tournier, Jean-Nicolas; Garin, Daniel; Crance, Jean-Marc

    2008-03-25

    This study assessed three non-replicating smallpox vaccine candidates (modified vaccinia Ankara (MVA), NYVAC and HR) for their immunogenicity and ability to protect mice against an intranasal cowpox virus challenge and compared them with the traditional replicating vaccine. A single immunisation with the non-replicating vaccines induced a complete protection from death at short-term, but was not fully protective when mice were challenged 150 days post-vaccination with protection correlated with the specific neutralizing antibodies and CD4(+) T-cells responses. Prime-boost vaccination enabled effective long-term protection from death for mice vaccinated with MVA, but protection from disease and CD4(+) T-cell level were lower than the ones induced by the traditional vaccine over the long-term period. Further investigations are necessary with MVA to determine the optimal conditions of immunisation to induce at long-term immunogenicity and protection observed with the 1st generation smallpox vaccine.

  9. Protection of mice against fission neutron irradiation by WR-2721 or WR-151327

    SciTech Connect

    Steel, L.K.; Jacobs, A.J.; Giambarresi, L.I.

    1987-03-01

    Two phosphorothioate compounds, WR-2721 and WR-151327, were examined for their radioprotective efficacies against the effects of fission neutron irradiation in male and female mice. Within sex groups no significant difference in lethality at 30 or 100 days postirradiation was found between WR-2721 or WR-151327 pretreatment. The dose modification factors (DMFs) for male mice treated with either compound were 1.29 (LD50/30) and 1.24 (LD50/100), and those for drug-treated female mice were 1.21 (LD50/30) and 1.19 (LD50/100). Both WR-2721 and WR-151327 were found to be equally radioprotective when compared using DMFs as the end point. WR-151327 (500 mg/kg, ip) was found tomore » be significantly more toxic to both male and female B6D2F1 mice than equimolar amounts of WR-2721. Small but significant sex differences in radioprotection were found: the DMFs for female mice pretreated with either compound were lower than those for similarly treated male mice; the incidence of mortality 31-100 days postexposure in male mice pretreated with WR-151327 was greater than for female mice. In addition, sex differences were noted in drug toxicity. Toxic death in female mice given WR-151327 (500 mg/kg, ip) is 2.6 times more probable than in males.« less

  10. Adaptive and maladaptive responses in skin: mild heat exposure protects against UVB-induced photoaging in mice.

    PubMed

    Haarmann-Stemmann, Thomas; Boege, Fritz; Krutmann, Jean

    2013-04-01

    In this issue, Matsuda et al. demonstrate the protective effect of mild heat preconditioning on UVB-induced photoaging in SKH-1 hairless mice. Mild heat exposure stimulates the upregulation of HSP70 chaperones, which inhibit the activities of matrix-degenerating enzymes, thereby avoiding wrinkle formation. This newly identified heat-mediated process of adaptation to UVB radiation exposure opens new opportunities to slow extrinsic skin aging.

  11. Protective effects of grape stem extract against UVB-induced damage in C57BL mice skin.

    PubMed

    Che, Denis Nchang; Xie, Guang Hua; Cho, Byoung Ok; Shin, Jae Young; Kang, Hyun Ju; Jang, Seon Il

    2017-08-01

    Humans have become exposed to another form of a trait which is ultraviolet B (UVB) radiation reaching the earth's surface. This has become a major source of oxidative stress that ultimately leads to inflammation, DNA damage, photoaging and pigmentation disorders etc. Although several studies have shown the photo-protective role of different grape parts like the fruits and seeds, little or no data demonstrating the in vivo photo-protective role of grape stem, which is the most discarded part of the grape are available. We evaluated the protective influence of grape stem extract against UVB-induced oxidative damage in C57BL mice characterized by epidermal hyperplasia, pigmentation, collagen degradation and inflammation. Grape stem extract was administered topically 1week before UVB irradiation (120mJ/cm 2 ) and continued until the termination of the experiment. A group of non-irradiated mice and a group of irradiated mice topically administered with propylene were used as a negative and positive control. Epidermal thickness, pigmentation, erythema, mast cell and neutrophil infiltration, collagen degradation and COX-2, Nrf2, and HO-1 expressions were evaluated. Grape stem extract markedly recovered skin damage induced by the UVB radiation through the prevention of epidermal hyperplasia, pigmentation, erythema, mast cell and neutrophil infiltrations, collagen degradation and COX-2, Nrf2, and HO-1 expressions. Our study demonstrated for the first time in C57BL mice that grape stem extract reduces UVB-induced oxidative damage and hence can play a protective role in skin photo-damage. Copyright © 2017. Published by Elsevier B.V.

  12. Protective Effect of Pinus koraiensis Needle Water Extract Against Oxidative Stress in HepG2 Cells and Obese Mice

    PubMed Central

    Won, Sae Bom; Jung, Ga-young; Kim, Juhae; Chung, Young Shin; Hong, Eun Kyung

    2013-01-01

    Abstract Needles of pine species are rich in polyphenols, which may exert beneficial effects on human health. The present study was conducted to evaluate the in vitro and in vivo antioxidant effects of Pinus koraiensis needle water extracts (PKW). HepG2 cells were pretreated with various concentrations of PKW (from 10−3 to 1 mg/mL) and oxidative stress was induced by tert-butyl hydroperoxide (t-BOOH). In the animal model, male ICR mice were fed a high-fat diet for 6 weeks to induce obesity, and then mice were continually fed a high-fat diet with or without orally administered PKW (400 mg/kg body weight) for 5 weeks. Pretreatment with PKW prevented significant increases in cytotoxicity and catalase activity induced by t-BOOH in HepG2 cells. Similarly, the catalase protein expression levels elevated by t-BOOH were abrogated in cells pretreated with PKW. In mice fed a high-fat diet, PKW significantly increased hepatic activities of catalase and glutathione reductase and lower lipid peroxidation levels were observed in the liver and kidney of mice with PKW supplementation. The present study demonstrates that PKW protects against oxidative stress in HepG2 cells treated with t-BOOH and in mice fed a high-fat diet. PMID:23822143

  13. Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice.

    PubMed

    Conforti, Laura; Wilbrey, Anna; Morreale, Giacomo; Janeckova, Lucie; Beirowski, Bogdan; Adalbert, Robert; Mazzola, Francesca; Di Stefano, Michele; Hartley, Robert; Babetto, Elisabetta; Smith, Trevor; Gilley, Jonathan; Billington, Richard A; Genazzani, Armando A; Ribchester, Richard R; Magni, Giulio; Coleman, Michael

    2009-02-23

    The slow Wallerian degeneration (Wld(S)) protein protects injured axons from degeneration. This unusual chimeric protein fuses a 70-amino acid N-terminal sequence from the Ube4b multiubiquitination factor with the nicotinamide adenine dinucleotide-synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1. The requirement for these components and the mechanism of Wld(S)-mediated neuroprotection remain highly controversial. The Ube4b domain is necessary for the protective phenotype in mice, but precisely which sequence is essential and why are unclear. Binding to the AAA adenosine triphosphatase valosin-containing protein (VCP)/p97 is the only known biochemical property of the Ube4b domain. Using an in vivo approach, we show that removing the VCP-binding sequence abolishes axon protection. Replacing the Wld(S) VCP-binding domain with an alternative ataxin-3-derived VCP-binding sequence restores its protective function. Enzyme-dead Wld(S) is unable to delay Wallerian degeneration in mice. Thus, neither domain is effective without the function of the other. Wld(S) requires both of its components to protect axons from degeneration.

  14. Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice.

    PubMed

    Figeac, Florence; Andersen, Ditte C; Nipper Nielsen, Casper A; Ditzel, Nicholas; Sheikh, Søren P; Skjødt, Karsten; Kassem, Moustapha; Jensen, Charlotte H; Abdallah, Basem M

    2018-05-01

    Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Protective effects of osthole, a natural derivative of coumarin, against intestinal ischemia-reperfusion injury in mice.

    PubMed

    Dong, Wenpeng; Zhang, Zhen; Liu, Zhengjun; Liu, Hao; Wang, Xianyue; Bi, Shenghui; Wang, Xiaowu; Ma, Tao; Zhang, Weida

    2013-06-01

    Intestinal ischemia/reperfusion (I/R) injury is considered to be associated with high morbidity and mortality rates. Osthole, a natural derivative of coumarin, has been shown to exert a variety of pharmacological and therapeutic effects under physiological and pathological conditions. In the present study, to investigate the protective effects of osthole against intestinal I/R injury, various doses of osthole (5, 10, 25 and 50 mg/kg) were pre-administered to mice subjected to intestinal I/R injury. A dose-dependent increase in the survival rate was observed in the osthole-treated mice. Pre-treatment with osthole (50 mg/kg) attenuated the destruction of epithelial cells within the villi induced by intestinal I/R injury, and suppressed oxidative stress, neutrophil infiltration and modulated nitric oxide (NO) levels. Moreover, the increased IκBα phosphorylation and nuclear factor (NF)-κB nuclear translocation induced by I/R injury were significantly decreased following pre-treatment with osthole. Taken together, our data demonstrate that osthole exerts protective effects against intestinal I/R injury in mice by suppressing oxidative stress, neutrophil infiltration and NO levels, partly through the inhibition of NF-κB nuclear translocation. Hence, the findings of the present study provide insight into the mechanisms through which osthole exerts its protective effects against intestinal I/R injury.

  16. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis

    PubMed Central

    Manoury, Boris; Nenan, Soazig; Leclerc, Olivier; Guenon, Isabelle; Boichot, Elisabeth; Planquois, Jean-Michel; Bertrand, Claude P; Lagente, Vincent

    2005-01-01

    Background Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47phox -/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. Methods Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. Results BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47phox -/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. Conclusions These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis. PMID:15663794

  17. Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

    PubMed

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-10-01

    Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. Copyright © 2016 by the Research Society on Alcoholism.

  18. Dietary fisetin supplementation protects against alcohol-induced liver injury in mice

    PubMed Central

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-01-01

    Background Overproduction of reactive oxygen species (ROS) is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary inverventions for multiple diseases including ALD. The objective of the present study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. Methods C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol diet for four weeks with or without fisetin supplementation at 10 mg/kg/d. Results Alcohol feeding induced lipid accumulation in the liver and increased plasma ALT and AST activities, which were attenuated by fisetin suplementation. The ethanol concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin suplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin suplementation remarkably reduced hepatic NADPH oxidase 4 (NOX4) levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal (4HNE) levels after alcohol exposure. Alcohol-induced apoptosis and upregulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin suplementation attenuated alcohol-induced hepatic streatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. Conclusion The present study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating ethanol clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. PMID:27575873

  19. Dolichos lablab Protects Against Nonalcoholic Fatty Liver Disease in Mice Fed High-Fat Diets.

    PubMed

    Im, A-Rang; Kim, Yun Hee; Kim, Young Hwa; Yang, Won-Kyung; Kim, Seung Hyung; Song, Kwang Hoon

    2017-12-01

    Hyacinth bean, Dolichos lablab or Lablab purpureus, has been used for centuries in India and China as an edible pod and animal forage, as well as to treat diarrhea and other gastrointestinal disease in traditional Korean medicine. Recently, we have demonstrated that D. lablab extract (DLL-Ex) prevented free fatty acid-induced lipid accumulation in an in vitro cellular nonalcoholic fatty liver disease (NAFLD) model. In this study, we, thus, aimed at clarifying the hepatoprotective effects of DLL-Ex in a high-fat diet-induced in vivo animal NAFLD model, as well as at elucidating underlying mechanisms of identified effects. Sixty, 6-week-old, male C57BL/6J mice were randomly divided into six groups: a control group fed a low-fat diet, four high-fat diet (HFD) groups, three receiving daily oral supplementation of DLL-Ex (25, 50, and 100 mg/kg/day), and one HFD group receiving daily oral supplementation of MILK (100 mg/kg/day). Effects of DLL-Ex supplementation were evaluated by histopathological and histochemical assessments. DLL-Ex supplementation inhibited HFD-induced increases in body weight and body fat mass and ameliorated increases in body weight, manifested as decreased liver function tests, lower serum triglycerides and cholesterol levels, and increased serum adiponectin levels. The expression of hepatic genes involved in lipid droplet accumulation and in fatty acid uptake was also decreased. We provide evidence of a protective effect of DLL-Ex against HFD-induced fatty liver disease in an animal model.

  20. Protection mediated by chemokine CXCL10 in BALB/c mice infected by Leishmania infantum

    PubMed Central

    Figueiredo, Webertty Mayk Eufrásio; Viana, Sayonara de Melo; Alves, Dorotheia Teixeira; Guerra, Priscila Valera; Coêlho, Zirlane Castelo Branco; Barbosa, Helene Santos; Teixeira, Maria Jania

    2017-01-01

    BACKGROUND Visceral leishmaniasis (VL) caused by Leishmania infantum is characterised by the loss of the ability of the host to generate an effective immune response. Chemokines have a direct involvement in the pathogenesis of leishmaniasis, causing a rapid change in the expression of these molecules during infection by Leishmania. OBJECTIVES Herein, it was investigated the role of CXCL10 in controlling infection by L. infantum. METHODS RAW 264.7 macrophages were infected with L. infantum in vitro and treated or not with CXCL10 (25, 50 and 100 ng/mL). Parasite load, as well as nitric oxide (NO), IL-4 and IL-10 production were assessed at 24 and 48 h after infection. In vivo, BALB/c mice were infected and treated or not with CXCL10 (5 μg/kg) at one, three and seven days of infection. Parasite load, IFN-g, IL-4, TGF-β and IL-10 were evaluated one, seven and 23 days post treatment. FINDINGS In vitro, CXCL10 reduced parasitic load, not dependent on NO, and inhibited IL-10 and IL-4 secretion. In vivo, CXCL10 was able to reduce the parasite load in both liver and spleen, four weeks after infection, representing a higher decrease in the number of parasites in these organs, also induced IFN-γ at day 23 after treatment, correlating with the decrease in parasite load, and reduced IL-10 and TGF-β. MAIN CONCLUSIONS This study suggests a partial protective role of CXCL10 against L. infantum, mediated by IFN-g, not dependent on NO, and with suppression of IL-10 and TGF-β. These data may provide information for the development of new approaches for future therapeutic interventions for VL. PMID:28767981

  1. Protective effect of dammarane sapogenins against chemotherapy-induced myelosuppression in mice.

    PubMed

    Yang, Yanyan; Xu, Shuping; Xu, Qiuxia; Liu, Xinmin; Gao, Yue; Steinmetz, Andre; Wang, Ning; Wang, Tianshan; Qiu, Guosong

    2011-06-01

    Chemotherapy is the most common way to treat malignancies, but myelosuppression, one of its common side-effects, is a formidable problem. The present study described the protective role of dammarane sapogenins (DS), an active fraction from oriental ginseng, on myelosuppression induced by cyclophosphamide (CP) in mice. DS was orally administered at different dosages (37.5, 75, and 150 mg/kg) for 10 d after CP administration (200 mg/kg intraperitoneally). The results showed that DS increased the number of white blood cells (WBC) on day 3 and day 7 (P < 0.05), such that WBC levels were increased by 105.7 ± 29.5% at 75 mg/kg of DS on day 3 (P < 0.05, compared with the CP group). Similar results were observed in red blood cells and platelets in DS-treated groups. The colony-forming assay demonstrated that the depressed numbers of CFU-GM (colony-forming unit-granulocyte and macrophage), CFU-E (colony-forming unit-erythroid), BFU-E (burst-forming unit-erythroid), CFU-Meg (colony-forming unit-megakaryocyte) and CFU-GEMM (colony-forming unit-granulocyte, -erythrocyte, -monocyte and -megakaryocyte) induced by CP were significantly reversed after DS treatment. Moreover, the ameliorative effect of DS on myelosuppression was also observed in the femur by hematoxylin/eosin staining. In DS-treated groups, ConA-induced splenocyte proliferation was enhanced significantly at all the doses (37.5, 75, 150 mg/kg) on day 3 at the rate of 50.3 ± 8.0%, 77.6 ± 8.5% and 44.5 ± 8.4%, respectively, while lipopolysaccharide-induced proliferation was increased mainly on day 7 (P < 0.01), with an increased rate of 39.8 ± 5.6%, 34.9 ± 6.6% and 38.3 ± 7.3%, respectively. The thymus index was also markedly increased by 70.4% and 36.6% at 75 mg/kg on days 3 and 7, respectively, as compared with the CP group. In summary, DS has a protective function against CP-induced myelosuppression. Its mechanism might be related to stimulating hematopoiesis recovery, as well as enhancing the immunological

  2. Protective effect of esculin on streptozotocin-induced diabetic renal damage in mice.

    PubMed

    Kang, Ki Sung; Lee, Woojung; Jung, Yujung; Lee, Ji Hwan; Lee, Seungyong; Eom, Dae-Woon; Jeon, Youngsic; Yoo, Hye Hyun; Jin, Ming Ji; Song, Kyung Il; Kim, Won Jun; Ham, Jungyeob; Kim, Hyoung Ja; Kim, Su-Nam

    2014-03-05

    The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 ± 29.8 and 9.7 ± 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3β in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney.

  3. Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice.

    PubMed

    Kim, Ahreum; Hur, Yun-Gyoung; Gu, Sunwha; Cho, Sang-Nae

    2017-11-01

    The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis -infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses ( P < 0.05) and recalled gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-6, and IL-17 responses ( P < 0.05 or P < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log 10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4 + T cells producing protective cytokines, such as IFN-γ and IL-17, in lungs and spleens ( P < 0.01) and CD4 + multifunctional T cells producing IFN-γ, tumor necrosis factor alpha (TNF-α), and/or IL-17 ( P < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-γ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo , may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients. Copyright © 2017 American Society for Microbiology.

  4. GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice.

    PubMed

    Schwenk, Robert W; Baumeier, Christian; Finan, Brian; Kluth, Oliver; Brauer, Christine; Joost, Hans-Georg; DiMarchi, Richard D; Tschöp, Matthias H; Schürmann, Annette

    2015-03-01

    Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions. Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1-oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1-oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. In contrast to GLP-1, GLP-1-oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1-oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1-oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. GLP-1-oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone.

  5. Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice.

    PubMed

    Surolia, Ranu; Karki, Suman; Kim, Hyunki; Yu, Zhihong; Kulkarni, Tejaswini; Mirov, Sergey B; Carter, A Brent; Rowe, Steven M; Matalon, Sadis; Thannickal, Victor J; Agarwal, Anupam; Antony, Veena B

    2015-08-01

    Pulmonary exposure to cadmium, a major component of cigarette smoke, has a dramatic impact on lung function and the development of emphysema. Cigarette smoke exposure induces heme oxygenase-1 (HO-1), a cytoprotective enzyme. In this study, we employed a truncated mouse model of emphysema by intratracheal instillation of cadmium (CdCl2) solution (0.025% per 1 mg/kg body wt) in HO-1(+/+), HO-1(-/-), and overexpressing humanized HO-1 bacterial artificial chromosome (hHO-1BAC) mice. We evaluated the role of HO-1 in cadmium-induced emphysema in mice by analyzing histopathology, micro-computed tomography scans, and lung function tests. CdCl2-exposed HO-1(-/-) mice exhibited more severe emphysema compared with HO-1(+/+) or hHO-1BAC mice. Loss of pulmonary endothelial cells (PECs) from the alveolar capillary membrane is recognized to be a target in emphysema. PECs from HO-1(+/+), HO-1(-/-), and hHO-1BAC were employed to define the underlying molecular mechanism for the protection from emphysema by HO-1. Electron microscopy, expression of autophagic markers (microtubule-associated protein 1B-light chain 3 II, autophagy protein 5, and Beclin1) and apoptotic marker (cleaved caspase 3) suggested induction of autophagy and apoptosis in PECs after CdCl2 treatment. CdCl2-treated HO-1(-/-) PECs exhibited downregulation of autophagic markers and significantly increased cleaved caspase 3 expression and activity (∼4-fold higher). Moreover, hHO-1BAC PECs demonstrated upregulated autophagy and absence of cleaved caspase 3 expression or activity. Pretreatment of HO-1(+/+) PECs with rapamycin induced autophagy and resulted in reduced cell death upon cadmium treatment. Induction of autophagy following CdCl2 treatment was found to be protective from apoptotic cell death. HO-1 induced protective autophagy in PECs and mitigated cadmium-induced emphysema. Copyright © 2015 the American Physiological Society.

  6. Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice

    PubMed Central

    Surolia, Ranu; Karki, Suman; Kim, Hyunki; Yu, Zhihong; Kulkarni, Tejaswini; Mirov, Sergey B.; Carter, A. Brent; Rowe, Steven M.; Matalon, Sadis; Thannickal, Victor J.; Agarwal, Anupam

    2015-01-01

    Pulmonary exposure to cadmium, a major component of cigarette smoke, has a dramatic impact on lung function and the development of emphysema. Cigarette smoke exposure induces heme oxygenase-1 (HO-1), a cytoprotective enzyme. In this study, we employed a truncated mouse model of emphysema by intratracheal instillation of cadmium (CdCl2) solution (0.025% per 1 mg/kg body wt) in HO-1+/+, HO-1−/−, and overexpressing humanized HO-1 bacterial artificial chromosome (hHO-1BAC) mice. We evaluated the role of HO-1 in cadmium-induced emphysema in mice by analyzing histopathology, micro-computed tomography scans, and lung function tests. CdCl2-exposed HO-1−/− mice exhibited more severe emphysema compared with HO-1+/+ or hHO-1BAC mice. Loss of pulmonary endothelial cells (PECs) from the alveolar capillary membrane is recognized to be a target in emphysema. PECs from HO-1+/+, HO-1−/−, and hHO-1BAC were employed to define the underlying molecular mechanism for the protection from emphysema by HO-1. Electron microscopy, expression of autophagic markers (microtubule-associated protein 1B-light chain 3 II, autophagy protein 5, and Beclin1) and apoptotic marker (cleaved caspase 3) suggested induction of autophagy and apoptosis in PECs after CdCl2 treatment. CdCl2-treated HO-1−/− PECs exhibited downregulation of autophagic markers and significantly increased cleaved caspase 3 expression and activity (∼4-fold higher). Moreover, hHO-1BAC PECs demonstrated upregulated autophagy and absence of cleaved caspase 3 expression or activity. Pretreatment of HO-1+/+ PECs with rapamycin induced autophagy and resulted in reduced cell death upon cadmium treatment. Induction of autophagy following CdCl2 treatment was found to be protective from apoptotic cell death. HO-1 induced protective autophagy in PECs and mitigated cadmium-induced emphysema. PMID:26071551

  7. Monoassociation with probiotic Lactobacillus delbrueckii UFV-H2b20 stimulates the immune system and protects germfree mice against Listeria monocytogenes infection.

    PubMed

    dos Santos, Liliane Martins; Santos, Mônica Morais; de Souza Silva, Humberto Pereira; Arantes, Rosa Maria Esteves; Nicoli, Jacques Robert; Vieira, Leda Quercia

    2011-02-01

    In the present study, we investigated the protective effects of Lactobacillus delbrueckii UFV-H2b20 on the resistance to Listeria monocytogenes infection in gnotobiotic mice. Germfree mice or monoassociated mice were infected with L. monocytogenes, and the microbiological and immunological responses were evaluated after 1, 3, and 5 days of infection. Monoassociation with L. delbrueckii was capable of protecting mice against death caused by L. monocytogenes and induced a faster clearance of the bacteria in the liver, spleen, and peritoneal cavity at days 1, 3, and 5 post-infection. Also, monoassociated mice displayed less liver injury than germfree mice. The production of TNF-α in the serum, peritoneal cavity, and gut was augmented in monoassociated mice. Likewise, the levels of IFN-γ found on supernatants of spleen cells cultures were higher after the monoassociation. In addition, increased production of nitric oxide in peritoneal cell cultures supernatants and in serum was observed in mice that received L. delbrueckii. The monoassociation with L. delbrueckii induced higher production of IL-10 in the mucosal immune system. We conclude that monoassociation with L. delbrueckii UFV-H2b20 protects mice from death caused by L. monocytogenes infection by favoring effector responses while preventing their immunopathological consequences.

  8. Protective effects of vitamin E and Cornus mas fruit extract on methotrexate-induced cytotoxicity in sperms of adult mice.

    PubMed

    Zarei, Leila; Sadrkhanlou, Rajabali; Shahrooz, Rasoul; Malekinejad, Hassan; Eilkhanizadeh, Behroz; Ahmadi, Abbas

    2014-01-01

    This study was aimed to assess the protective effects of Cornus mas fruit extract (CMFE) and vitamin E (Vit E) on sperm quality parameters in the methotrexate (MTX)-treated mice. Forty-eight young adult male mice (8-12 weeks) were randomly divided into six groups including control and test groups. The control group received normal saline orally , and the test groups were treated MTX (20 mg kg(-1), ip, once weekly), MTX + CMFE (250 mg kg(-1)), MTX + CMFE (500 mg kg(-1)), MTX + CMFE (1000 mg kg(-1)), and MTX + Vit E (100 IU kg(-1), po) for 35 consecutive days. On day 35, after euthanasia the epididymal sperms were isolated. Then the total mean sperm count, sperm viability and motility were determined. The total antioxidant capacity (TAOC) of all experimental groups were also evaluated. The MTX-treated animals showed a significant changes in all parameters of sperm quality assessment compared to the control group. Both Vit E and CMFE were able to protect from MTX-induced effects on sperm maturity and DNA damage. Co-administration of MTX and CMFE and/or Vit E resulted in protection from MTX-reduced TAOC. In conclusion, these data suggested that MTX administration could adversely affect the sperm quality. Moreover, the protective effect of Vit E and CMFE on MTX-induced sperm toxicity was also documented.

  9. Nfib hemizygous mice are protected from hyperoxic lung injury and death.

    PubMed

    Kumar, Vasantha H S; Chaker El Khoury, Joseph; Gronostajski, Richard; Wang, Huamei; Nielsen, Lori; Ryan, Rita M

    2017-08-01

    Nuclear Factor I ( Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild-type (Wt) littermates were exposed to 100% O 2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real-time PCR Unexpectedly, Nfib hemizygous mice (0/14-0%) had significantly lower mortality compared to Wt mice (10/22-45%) at 80 h of hyperoxia ( P  < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP-2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild-type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild-type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  10. Protection of mice against fission-neutron irradiation by WR-2721 or WR-151327

    SciTech Connect

    Steel, L.K.; Jacobs, A.J.; Giambarresi, L.I.

    1987-01-01

    Two phosphorothioate compounds, WR-2721 and WR-151327, were examined for their radioprotective efficacies against the effects of fission-neutron irradiation in male and female mice. Within sex groups no significant difference in lethality at 30 or 100 days postirradiation was found between WR-2721 or WR-151327 pretreatment. The dose-modification factors (DMFs) for male mice treated with either compound were 1.29 (LD50/30) and 1.24 (LD50/100), and those for drug-treated female mice were 1.21 (LD50/30) and 1.19 (LD50/100). Both WR-2721 and WR-151327 were found to be equally radioprotective when compared using DMFs as the end point. WR-151327 were found to be equally radioprotective when comparedmore » using DMFs as the end point. WR-151327 (500 mg/kg, ip) was found to be significantly more toxic to both male and female B6D2F1 mice than equimolar amounts of WR-2721. Small but significant sex differences in radioprotection were found: the DMFs for female mice pretreated with either compound were lower than those for similarly treated male mice; the incidence of mortality 31-100 days postexposure in male mice pretreated with WR-151327 was greater than for female mice. In addition, sex differences were noted in drug toxicity. Toxic death in female mice given WR-151327 (500 mg/kg, ip) is 2.6 times more probable than in males.« less

  11. Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3-A20 in Ischemic Stroke.

    PubMed

    Wang, Shu-Na; Xu, Tian-Ying; Wang, Xia; Guan, Yun-Feng; Zhang, Sai-Long; Wang, Pei; Miao, Chao-Yu

    2016-09-01

    NAMPT is a novel therapeutic target of ischemic stroke. The aim of this study was to investigate the effect of a potential NAMPT activator, P7C3-A20, an aminopropyl carbazole derivative, on ischemic stroke. In vitro study, neuron protection effect of P7C3-A20 was investigated by co-incubation with primary neurons subjected to oxygen-glucose deprivation (OGD) or oxygen-glucose deprivation/reperfusion (OGD/R) injury. In vivo experiment, P7C3-A20 was administrated in middle cerebral artery occlusion (MCAO) rats and infarct volume was examined. Lastly, the brain tissue nicotinamide adenine dinucleotide (NAD) levels were detected in P7C3-A20 treated normal or MCAO mice. Cell viability, morphology, and Tuj-1 staining confirmed the neuroprotective effect of P7C3-A20 in OGD or OGD/R model. P7C3-A20 administration significantly reduced cerebral infarction in MCAO rats. Moreover, brain NAD levels were elevated both in normal and MCAO mice after P7C3-A20 treatment. P7C3-A20 has neuroprotective effect in cerebral ischemia. The study contributes to the development of NAMPT activators against ischemic stroke and expands the horizon of the neuroprotective effect of aminopropyl carbazole chemicals. © 2016 John Wiley & Sons Ltd.

  12. Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting autophagy in mice

    PubMed Central

    Shi, Hongbo; Han, Weijia; Shi, Honglin; Ren, Feng; Chen, Dexi; Chen, Yu; Duan, Zhongping

    2017-01-01

    Background Augmenter of liver regeneration (ALR) exerts strong hepatoprotective properties in various animal models of liver injury, but its protective mechanisms have not yet been explored. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of this study was to test the hypothesis that ALR may protect against acute liver injury through the autophagic pathway. Methods The level and role of ALR in liver injury were studied in a mouse model of acute liver injury induced by carbon tetrachloride (CCl4). The effect of ALR on autophagy was analyzed in vitro and in vivo. After autophagy was inhibited by 3-methyladenine (3-MA), apoptosis and proliferation were detected in the mouse model with acute liver injury. The ALR and autophagic levels were measured in patients with liver cirrhosis (LC) and acute liver failure (ALF), respectively. Results During the progression of acute liver injury, the ALR levels increased slightly in early stage and significantly decreased in late stage in mice Treatment with an ALR plasmid via tail vein injection protected mice against acute liver injury. The protective effect of ALR relied on the induction of autophagy, which was supported by the following evidence: (1) ALR overexpression directly induced autophagy flux in vitro and in vivo; and (2) ALR treatment suppressed apoptosis and promoted proliferation in mice exposed to CCl4, but the inhibition of autophagy reversed these effects. More importantly, the ALR levels decreased in patients with LC and ALF compared with normal controls. Conclusion We demonstrated that ALR ameliorated liver injury via an autophagic mechanism, which indicates a potential therapeutic application for liver injury. PMID:28061452

  13. Fermented herbal formula KIOM-MA-128 protects against acute colitis induced by dextran sodium sulfate in mice.

    PubMed

    Kim, Dong-Gun; Lee, Mi-Ra; Yoo, Jae-Myung; Park, Kwang-Il; Ma, Jin-Yeul

    2017-07-05

    Colitis is a well-known subtype of inflammatory bowel disease and is caused by diverse factors. Previous research has shown that KIOM-MA elicits anti-inflammatory and anti-allergic effects on various diseases. KIOM-MA-128, our novel herbal formula, was generated from KIOM-MA using probiotics to improve the therapeutic efficacy. We investigated whether KIOM-MA-128 has protective activity in a mouse model of acute colitis induced by dextran sodium sulfate (DSS). Colitis was induced by DSS administered to ICR mice in drinking water. KIOM-MA-128 (125 or 250 mg/kg) was orally administered once per day. The body weights of the mice were measured daily, and colonic endoscopies were performed at 5 and 8 days. Colon length as well as histological and cytokine changes were observed at the end of drug administration. KIOM-MA-128 has pharmacological activity in an acute colitis model. KIOM-MA-128 reduced the loss of body weight and disease activity index (DAI) and inhibited the abnormally short colon lengths and the colonic damage in this mouse model of acute colitis. Moreover, KIOM-MA-128 suppressed pro-inflammatory cytokine expression and maintained the integrity of the tight junctions during DSS-induced colitis. The results indicated that KIOM-MA-128 protects against DSS-induced colitis in mice and suggested that this formula might be a candidate treatment for inflammatory bowel disease (IBD).

  14. Protective Effect of Boiled and Freeze-dried Mature Silkworm Larval Powder Against Diethylnitrosamine-induced Hepatotoxicity in Mice.

    PubMed

    Cho, Jae-Min; Kim, Kee-Young; Ji, Sang-Deok; Kim, Eun-Hee

    2016-09-01

    Hepatocellular carcinoma (HCC) is a representative inflammation-associated cancer and known to be the most frequent tumors. HCC may also induce important pro- and anti-tumor immune reactions. However, the underlying mechanisms are unsatisfactorily identified. We investigated the protective effect of boiled and freeze-dried mature silkworm larval powder (BMSP) on diethylnitrosamine (DEN)-induced hepatotoxicity in mice. Mice were fed with diet containing BMSP (0.1, 1, and 10 g/kg) for two weeks and DEN (100 mg/kg, intraperitoneally) was injected 18 hours before the end of this experiment. Liver toxicity was determined in serum and histopathological examination was assessed in the liver tissues. Infiltration of immune cells and expressions of inflammatory cytokines and chemokines were also examined. Pretreatment with BMSP reduced necrotic and histopathological changes induced by DEN in the liver. Measurement of serum biochemical indicators, the levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase, showed that pretreatment with BMSP also decreased DEN-induced hepatotoxicity. In addition, BMSP inhibited the macrophage and CD31 infiltration in a dose-dependent manner. The expressions of interleukin-1β, IFN-γ and chemokines for T cell activation were decreased in BMSP pretreatment groups. BMSP may have a protective effect against acute liver injury by inhibiting necrosis and inflammatory response in DEN-treated mice.

  15. PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice

    PubMed Central

    Huang, Wen; Chen, Lei; Zhang, Bei; Park, Minseon; Toborek, Michal

    2014-01-01

    The strategies to protect against the disrupted blood–brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPARα agonist) or rosiglitazone (PPARγ agonist). In contrast, exposure to GW9662 (PPARγ antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1. PMID:24424383

  16. Anti-oxidative protection against iron overload-induced liver damage in mice by Cajanus cajan (L.) Millsp. leaf extract.

    PubMed

    Sarkar, Rhitajit; Hazra, Bibhabasu; Mandal, Nripendranath

    2013-02-01

    In view of the contribution of iron deposition in the oxidative pathologic process of liver disease, the potential of 70% methanolic extract of C. cajan leaf (CLME) towards antioxidative protection against iron-overload-induced liver damage in mice has been investigated. DPPH radical scavenging and protection of Fenton reaction induced DNA damage was conducted in vitro. Post oral administration of CLME to iron overloaded mice, the levels of antioxidant and serum enzymes, hepatic iron, serum ferritin, lipid peroxidation, and protein carbonyl and hydroxyproline contents were measured, in comparison to deferasirox treated mice. Oral treatment of the plant extract effectively lowered the elevated levels of liver iron, lipid peroxidation, protein carbonyl and hydroxyproline. There was notable increment in the dropped levels of hepatic antioxidants. The dosage of the plant extract not only made the levels of serum enzymes approach normal value, but also counteracted the overwhelmed serum ferritin level. The in vitro studies indicated potential antioxidant activity of CLME. The histopathological observations also substantiated the ameliorative function of the plant extract. Accordingly, it is suggested that Cajanus cajan leaf can be a useful herbal remedy to suppress oxidative damage caused by iron overload.

  17. Acid sphingomyelinase deficiency in Western diet-fed mice protects against adipocyte hypertrophy and diet-induced liver steatosis.

    PubMed

    Sydor, Svenja; Sowa, Jan-Peter; Megger, Dominik A; Schlattjan, Martin; Jafoui, Sami; Wingerter, Lena; Carpinteiro, Alexander; Baba, Hideo A; Bechmann, Lars P; Sitek, Barbara; Gerken, Guido; Gulbins, Erich; Canbay, Ali

    2017-05-01

    Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1 -/- ) genotype affects diet-induced NAFLD. Smpd1 -/- mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks. Liver and adipose tissue morphology and mRNA expression were assessed. Quantitative proteome analysis of liver tissue was performed. Expression of selected genes was quantified in adipose and liver tissue of obese NAFLD patients. Although Smpd1 -/- mice exhibited basal steatosis with normal chow, no aggravation of NAFLD-type injury was observed with a Western diet. This protective effect was associated with the absence of adipocyte hypertrophy and the increased expression of genes associated with brown adipocyte differentiation. In white adipose tissue from obese patients with NAFLD, no expression of these genes was detectable. To further elucidate which pathways in liver tissue may be affected by Smpd1 -/- , we performed an unbiased proteome analysis. Protein expression in WD-fed Smpd1 -/- mice indicated a reduction in Rictor (mTORC2) activity; this reduction was confirmed by diminished Akt phosphorylation and altered mRNA expression of Rictor target genes. These findings indicate that the protective effect of Asm deficiency on diet-induced steatosis is conferred by alterations in adipocyte morphology and lipid metabolism and by reductions in Rictor activation.

  18. Protective effect of Lagerstroemia speciosa against dextran sulfate sodium induced ulcerative colitis in C57BL/6 mice.

    PubMed

    Chaudhary, Ghanshyam; Mahajan, Umesh B; Goyal, Sameer N; Ojha, Shreesh; Patil, Chandragouda R; Subramanya, Sandeep B

    2017-01-01

    The protective effect of methanolic extract of Lagerstroemia speciosaleaves (LS) was evaluated against dextran sulfate sodium (DSS) induced ulcerative colitis in C57BL/6 mice. The administration of DSS (2.5% in drinking water ad libitum) in C57BL/6 mice induced ulcerative colitis in 7 days. The LS was orally administered for 7 days at daily doses of 100 and 200 mg/kg. At the end of 7 days of treatment the animals were sacrificed, colonic tissues were removed and processed for further analysis of oxidative stress, and histopathology. In DSS treated mice the oxidative stress markers were elevated compared to controls. There was also significant reduction in the anti-oxidant defense levels marked by reduced cellular glutathione, catalase, and superoxide dismutase. The DSS-induced damage to the colon epithelium was evident from a significant increase in the lipid peroxidation. The histology of colon sections revealed inflammatory changes and marked impairment in the integrity of the mucosal lining with inflammatory changes. Both the doses of LS significantly prevented DSS-induced inflammatory and ulcerative damages of the colon, reduced lipid peroxidation and also restored the levels of innate antioxidants in the colon tissue. These findings indicate the protective effects of LS against the DSS-induced inflammatory and oxidative damage in the mouse colon. Further investigation involving bioactivity guided fractionation of the LS can yield potent constituent which may have a significant role in the treatment of inflammatory bowel disease and ulcerative colitis.

  19. Intradermal Vaccination With Adjuvanted Ebola Virus Soluble Glycoprotein Subunit Vaccine by Microneedle Patches Protects Mice Against Lethal Ebola Virus Challenge.

    PubMed

    Liu, Ying; Ye, Ling; Lin, Fang; Gomaa, Yasmine; Flyer, David; Carrion, Ricardo; Patterson, Jean L; Prausnitz, Mark R; Smith, Gale; Glenn, Gregory; Wu, Hua; Compans, Richard W; Yang, Chinglai

    2018-06-08

    In this study, we investigated immune responses induced by purified Ebola virus (EBOV) soluble glycoprotein (sGP) subunit vaccines via intradermal immunization with microneedle (MN) patches in comparison with intramuscular (IM) injection in mice. Our results showed that MN delivery of EBOV sGP was superior to IM injection in eliciting higher levels and longer lasting antibody responses against EBOV sGP and GP antigens. Moreover, sGP-specific immune responses induced by MN or IM immunizations were effectively augmented by formulating sGP with a saponin-based adjuvant, and they were shown to confer complete protection of mice against lethal mouse-adapted EBOV (MA-EBOV) challenge. In comparison, mice that received sGP without adjuvant by MN or IM immunizations succumbed to lethal MA-EBOV challenge. These results show that immunization with EBOV sGP subunit vaccines with adjuvant by MN patches, which have been shown to provide improved safety and thermal stability, is a promising approach to protect against EBOV infection.

  20. Protective effects of the dietary supplementation of turmeric (Curcuma longa L.) on sodium arsenite-induced biochemical perturbation in mice.

    PubMed

    Karim, Md Rezaul; Haque, Abedul; Islam, Khairul; Ali, Nurshad; Salam, Kazi Abdus; Saud, Zahangir Alam; Hossain, Ekhtear; Fajol, Abul; Akhand, Anwarul Azim; Himeno, Seiichiro; Hossain, Khaled

    2010-12-01

    The present study was undertaken to evaluate the protective effect of turmeric powder on arsenic toxicity through mice model. Swiss albino male mice were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were treated with turmeric powder (T, 50 mg/kg body weight/day), sodium arsenite (Sa, 10 mg/kg body weight/day) and turmeric plus Sa (T+Sa), respectively. Results showed that oral administration of Sa reduced the weight gain of the mice compared to the control group and food supplementation of turmeric prevented the reduction of weight gain. Turmeric abrogated the Sa-induced elevation of serum urea, glucose, triglyceride (TG) level and alanine aminotransferase (ALT) activity except the activity of alkaline phosphatase (ALP). Turmeric also prevented the Sa-induced perturbation of serum butyryl cholinesterase activity (BChE). Therefore, ameliorating effect of turmeric on Sa-treated mice suggested the future application of turmeric to reduce or to prevent arsenic toxicity in human.

  1. [Protective effect of polysaccharides extracts from corn silk against cyclophosphamide induced host damages in mice bearing H22 tumors].

    PubMed

    Wu, Xian-chuang; Du, Gang-jun; Song, Xiao-yong; Zhang, Yong-zhou; Liu, Yu-xin

    2014-10-01

    To study the protective effect of polysaccharides from corn silk (PCS) against cyclophosphamide (CTX) induced host damages in mice bearing H22 tumors. The ascitic and solid tumor bearing mice model were established to investigate the anti-tumor effects of different dose of PCS (100, 200 and 300 mg/kg). The effects of PCS alone and with combination of CTX on tumor weight, survival time, thymus and spleen index, white blood cell, nucleated cell of marrow, serum ALT and AST level were tested. The high-dose PCS (300 mg/kg) had significant inhibitory effects on tumor. After combination with CTX, the tumor inhibitory ratio was enhanced to 68.71%, the survival time of tumor-burdened ascites tumor mice was significantly prolonged to 72.07% compared with CTX group. The Q value of combination group was 0.997. Thymus and spleen index, white blood cell, nucleated cell of marrow decreased by CTX were ameliorated significantly. The level of ALT and AST increased by CTX were reduced by combination with PCS. PCS has a potent inhibitory effect on the growth of implanted H22 tumors in mice and has a synergetic effect and an attenuated toxic effect in combination with CTX.

  2. Emodin protects mice against radiation-induced mortality and intestinal injury via inhibition of apoptosis and modulation of p53.

    PubMed

    Wang, Jing; Zhang, Yue; Zhu, Qiuzhen; Liu, Yulan; Cheng, Hao; Zhang, Yuefan; Li, Tiejun

    2016-09-01

    The aim of this study was to explore the protective effect of emodin, a plant-derived anthraquinone, against gamma radiation-induced mortality and intestinal injury in mice, and to investigate the radioprotective molecular mechanism. C57BL/6 male mice were pre-treated with emodin for 7days via oral gavage before gamma radiation. We found that pretreatment with emodin prolonged mice survival time after 9Gy total body irradiation (TBI). Mice were sacrificed at 1 week after 7Gy TBI, we found that emodin attenuated intestinal morphological changes and increased villus height, crypt numbers, and reduced villus and crypt apoptosis as well as inhibited the expression of p53. MTT assay, flow cytometry, Hoechst 33258 staining, real-time PCR, and Western blotting indicated that emodin pretreatment can effectively increase human umbilical venous endothelial cells (HUVECs) viability and attenuate cell apoptosis; it also inhibited the expression of p53, Bax, and Caspase3 in HUVECs after irradiation. In summary, these results suggest the potential of emodin as an effective radioprotectant against radiation-induced intestinal injury. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. The protective effect of 20(S)-protopanaxadiol (PPD) against chronic sleep deprivation (CSD)-induced memory impairments in mice.

    PubMed

    Lu, Cong; Lv, Jingwei; Dong, Liming; Jiang, Ning; Wang, Yan; Fan, Bei; Wang, Fengzhong; Liu, Xinmin

    2018-03-01

    Sleep deprivation (SD) is associated with oxidative stress that causes learning and memory impairment. 20(S)-Protopanaxadiol (PPD), one of the protopanaxadiol-type saponins, has antioxidant and neuroprotective effect. This study was designed to research the protective effect of PPD against cognitive deficits induced by chronic sleep deprivation (CSD) in mice. The CSD model was induced by subjecting the mice to our self-made Sleep Interruption Apparatus (SIA) continuously for 14 days. The memory enhancing effects of PPD were evaluated by behavioral tests and the related mechanism was further explored by observing the oxidative stress changes in the cortex and hippocampus of mice. The results revealed that PPD (20 and 40 μmol/kg, i.p.) administration significantly improved the cognitive performance of CSD model mice in object location recognition experiment, novel object recognition task and Morris water maze test. Furthermore, PPD effectively restored the levels/activities of antioxidant defense biomarkers in the cortex and hippocampus, including the superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, glutathione (GSH), and lipid peroxidation (LPO). In conclusion, PPD could attenuate cognitive deficits induced by CSD, and the neuroprotective effect of PPD might be mediated by alleviation of oxidative stress. It was assumed that PPD has the potential to be a neuroprotective substance for cognition dysfunction. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. A combination of thalidomide and augmentin protects BALB/c mice suffering from Klebsiella pneumoniae B5055-induced sepsis.

    PubMed

    Kumar, V; Harjai, K; Chhibber, S

    2009-04-01

    Despite extensive research, the mortality associated with sepsis in hospitals remains very high. We have evaluated the protective immunomodulatory effect of thalidomide alone or with Augmentin in Klebsiella pneumoniae B5055-induced sepsis in BALB/c mice. The mouse model of sepsis was developed by placing K. pneumoniae B5055 entrapped in fibrin and thrombin clots in the peritoneal cavity of mice. The septic mice were treated with thalidomide alone (30 mg/kg/day/po), Augmentin alone (20 microg/ml/ip) and with their combination. the thalidomide-alone treated mice showed 75% survival whereas 60% of the Augmentin-alone treated group survived. Combination treatment provided 100% survival. Treatment with thalidomide alone significantly (p<0.05) decreased interleukin-1 alpha (IL-1alpha), nitric oxide (NO) and malondialdehyde (MDA) levels in the serum without significantly (p<0.05) decreasing the bacterial count in blood. Augmentin alone only decreased the bacterial load in blood significantly (p<0.05). However, a combination of thalidomide with Augmentin significantly (p<0.05) decreased both the bacterial count and inflammatory mediators.

  5. Evaluation of protective efficacy of Spirulina platensis in Balb/C mice with candidiasis.

    PubMed

    Soltani, M; Khosravi, A-R; Asadi, F; Shokri, H

    2012-12-01

    This study was aimed at evaluating the immunostimulatory effect of Spirulina platensis in prophylaxis of Balb/C mice with systemic candidiasis. In first experiment, 40 mice were divided into four groups, ten mice per each group, for cytokines assay. Animals received a dose of 800mg/kg of S. platensis for 4days and then were intravenously inoculated with 1×10(6) Candida albicans. Control groups received 0.2mL and 0.1mL normal saline for prophylaxis and inoculation, respectively. Five mice from each group were euthanized after 24hours and 72hours and the serum levels of IFN-γ and TNF-α were measured by Enzyme-linked immunosorbent assay (ELISA) method. In second experiment, two mice groups with systemic candidiasis, 11 mice per each group, were included to evaluate the survival rate. Animals were monitored for 30days and the kidneys, liver, lungs and spleen were analyzed for fungal invasion. The results indicated that the Spirulina-treated mice produced more IFN-g and TNF-α level than their control groups. This infected group showed that the mean survival time (28.86±2.7) was significantly (P<0.05) higher than control group (13.9±3.34). They also exhibited that fungal clearance in selected organs at death time represents significant differences between spleen and liver (P<0.05). Prophylaxis with S. platensis had synergistic effect through producing cytokines such as TNF-α and IFN-γ. Our results provide important information for the potential application of S. platensis in the treatment and resistance of Balb/C mice with systemic candidiasis. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  6. Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia.

    PubMed

    Iwaniec, Urszula T; Turner, Russell T

    2013-03-01

    A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kit(W/W-v)) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to the development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kit(W/W-v) mice. Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kit(W/W-v) mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kit(W/W-v) mice. However, ovx in WT and kit(W/W-v) mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Protective Effect of 940 nm Laser on Gamma-Irradiated Mice

    PubMed Central

    Efremova, Yulia; Navratil, Leos

    2015-01-01

    Abstract Objective: The purpose of this study was to investigate the radioprotective features of 940 nm laser on the life span of mice, and absolute counts of blood cells and their proportions in gamma-irradiated mice. Background data: An important feature of laser light is activation of mitotic division and differentiation of cells, which may be useful in activation of hematopoiesis in gamma-irradiated organisms. Materials and methods: Mice were randomly assigned to 11 groups according to the type(s) of influence. Generally, mice were irradiated in three different ways: with laser at different fluences, with gamma irradiation, or by combination of laser at different fluences and gamma irradiation in a different order. Mice were treated with 940 nm laser at 3, 12, or 18 J/cm2 and/or a lethal dose of gamma irradiation (8.7 Gy). Each group was randomly subdivided into two subgroups, in which the life span of the mice and blood cell counts (on 12th and 45th day after gamma irradiation) were analyzed. Results: Laser (940 nm) at a fluence of 3 J/cm2 significantly prolonged the life span of gamma-irradiated mice (p<0.05). In the same group, counts of white blood cells, lymphocytes, and neutrophils were higher on day 12 than in the gamma group. On day 45 after gamma irradiation, some signs of hematopoiesis repair were found in blood. There were no significant differences in counts of erythrocytes, monocytes, neutrophils, or the proportion of neutrophils between this group and the control group. Conclusions: In summary, 940 nm laser at a fluence of 3 J/cm2 demonstrates radioprotective features in an experiment with lethally irradiated mice. Mechanisms responsible for this effect will be investigated in further studies. PMID:25654740

  8. A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease.

    PubMed

    Zhou, Jingran; Wu, Ruiqiong; High, Anthony A; Slaughter, Clive A; Finkelstein, David; Rehg, Jerold E; Redecke, Vanessa; Häcker, Hans

    2011-11-01

    Toll-like receptors (TLRs) are expressed on innate immune cells and trigger inflammation upon detection of pathogens and host tissue injury. TLR-mediated proinflammatory-signaling pathways are counteracted by partially characterized anti-inflammatory mechanisms that prevent exaggerated inflammation and host tissue damage as manifested in inflammatory diseases. We biochemically identified a component of TLR-signaling pathways, A20-binding inhibitor of NF-κB (ABIN1), which recently has been linked by genome-wide association studies to the inflammatory diseases systemic lupus erythematosus and psoriasis. We generated ABIN1-deficient mice to study the function of ABIN1 in vivo and during TLR activation. Here we show that ABIN1-deficient mice develop a progressive, lupus-like inflammatory disease characterized by expansion of myeloid cells, leukocyte infiltrations in different parenchymatous organs, activated T and B lymphocytes, elevated serum Ig levels, and the appearance of autoreactive antibodies. Kidneys develop glomerulonephritis and proteinuria, reflecting tissue injury. Surprisingly, ABIN1-deficient macrophages exhibit normal regulation of major proinflammatory signaling pathways and mediators but show selective deregulation of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) and its target genes, such as colony-stimulating factor 3 (Csf3), nitric oxide synthase, inducible (Nos2), and S100 calcium-binding protein A8 (S100a8). Their gene products, which are intimately linked to innate immune cell expansion (granulocyte colony-stimulating factor), cytotoxicity (inducible nitric oxide synthase), and host factor-derived inflammation (S100A8), may explain, at least in part, the inflammatory phenotype observed. Together, our data reveal ABIN1 as an essential anti-inflammatory component of TLR-signaling pathways that controls C/EBPβ activity.

  9. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

    PubMed

    Palanivel, R; Fullerton, M D; Galic, S; Honeyman, J; Hewitt, K A; Jorgensen, S B; Steinberg, G R

    2012-11-01

    Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

  10. Protective effects of radon inhalation on carrageenan-induced inflammatory paw edema in mice.

    PubMed

    Kataoka, Takahiro; Teraoka, Junichi; Sakoda, Akihiro; Nishiyama, Yuichi; Yamato, Keiko; Monden, Mayuko; Ishimori, Yuu; Nomura, Takaharu; Taguchi, Takehito; Yamaoka, Kiyonori

    2012-04-01

    We assessed whether radon inhalation inhibited carrageenan-induced inflammation in mice. Carrageenan (1% v/v) was injected subcutaneously into paws of mice that had or had not inhaled approximately 2,000 Bq/m(3) of radon for 24 h. Radon inhalation significantly increased superoxide dismutase (SOD) and catalase activities and significantly decreased lipid peroxide levels in mouse paws, indicating that radon inhalation activates antioxidative functions. Carrageenan administration induced paw edema and significantly increased tumor necrosis factor-alpha (TNF-α) and nitric oxide in serum. However, radon inhalation significantly reduced carrageenan-induced paw edema. Serum TNF-α levels were lower in the radon-treated mice than in sham-treated mice. In addition, SOD and catalase activities in paws were significantly higher in the radon-treated mice than in the sham-treated mice. These findings indicated that radon inhalation had anti-inflammatory effects and inhibited carrageenan-induced inflammatory paw edema.

  11. Severe hypertriglyceridemia does not protect from ischemic brain injury in gene-modified hypertriglyceridemic mice.

    PubMed

    Chen, Yong; Liu, Ping; Qi, Rong; Wang, Yu-Hui; Liu, George; Wang, Chun

    2016-05-15

    Hypertriglyceridemia (HTG) is a weak risk factor in primary ischemic stroke prevention. However, clinical studies have found a counterintuitive association between a good prognosis after ischemic stroke and HTG. This "HTG paradox" requires confirmation and further explanation. The aim of this study was to experimentally assess this paradox relationship using the gene-modified mice model of extreme HTG. We first used the human Apolipoprotein CIII transgenic (Tg-ApoCIII) mice and non-transgenic (Non-Tg) littermates to examine the effect of HTG on stroke. To our surprise, infarct size, neurological deficits, brain edema, BBB permeability, neuron density and lipid peroxidation were the same in Tg-ApoCIII mice and Non-Tg mice after temporary middle cerebral artery occlusion (tMCAO). In the late phase (21 days after surgery), no differences were found in brain atrophy, neurological dysfunctions, weight and mortality between the two groups. To confirm the results in Tg-ApoCIII mice, Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1(GPIHBP1) knockout mice, another severe HTG mouse model, were used and yielded similar results. Our study demonstrates for the first time that extreme HTG does not affect ischemic brain injuries in the tMCAO mouse model, indicating that the association between HTG and good outcomes after ischemic stroke probably represents residual unmeasured confounding. Further clinical and prospective population-based studies are needed to explore variables that contribute to the paradox. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Protection of mice from fatal bubonic and pneumonic plague by passive immunization with monoclonal antibodies against the F1 protein of Yersinia pestis.

    PubMed

    Anderson, G W; Worsham, P L; Bolt, C R; Andrews, G P; Welkos, S L; Friedlander, A M; Burans, J P

    1997-04-01

    Monoclonal antibodies (MAbs) to the fraction 1 (F1) protein of Yersinia pestis protected mice against fatal pneumonic as well as bubonic plague from wild-type F1+ organisms. The rare isolation of a virulent F1- isolate from surviving animals supports earlier studies suggesting that improved vaccines should consist of immunogens to protect against F1- variants. The high degree of protection with IgG MAb suggests that secretory IgA is not required for protection from pneumonic plague.

  13. Isoflurane preconditioning protects neurons from male and female mice against oxygen and glucose deprivation and is modulated by estradiol only in neurons from female mice.

    PubMed

    Johnsen, D; Murphy, S J

    2011-12-29

    The volatile anesthetic, isoflurane, can protect the brain if administered before an insult such as an ischemic stroke. However, this protective "preconditioning" response to isoflurane is specific to males, with females showing an increase in brain damage following isoflurane preconditioning and subsequent focal cerebral ischemia. Innate cell sex is emerging as an important player in neuronal cell death, but its role in the sexually dimorphic response to isoflurane preconditioning has not been investigated. We used an in vitro model of isoflurane preconditioning and ischemia (oxygen and glucose deprivation, OGD) to test the hypotheses that innate cell sex dictates the response to isoflurane preconditioning and that 17β-estradiol attenuates any protective effect from isoflurane preconditioning in neurons via nuclear estrogen receptors. Sex-segregated neuron cultures derived from postnatal day 0-1 mice were exposed to either 0% or 3% isoflurane preconditioning for 1 h. In separate experiments, 17β-estradiol and the non-selective estrogen receptor antagonist ICI 182,780 were added 24 h before preconditioning and then removed at the end of the preconditioning period. Twenty-three hours after preconditioning, all cultures underwent 2 h of OGD. Twenty-four hours following OGD, cell viability was quantified using calcein-AM fluorescence. We observed that isoflurane preconditioning increased cell survival following subsequent OGD regardless of innate cell sex, but that the presence of 17β-estradiol before and during isoflurane preconditioning attenuated this protection only in female neurons independent of nuclear estrogen receptors. We also found that independent of preconditioning treatment, female neurons were less sensitive to OGD compared with male neurons and that transient treatment with 17β-estradiol protected both male and female neurons from subsequent OGD. More studies are needed to determine how cell type, cell sex, and sex steroids like 17β-estradiol may

  14. Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Protective, Noninfectious Vaccine against Ebola Virus Challenge in Mice

    PubMed Central

    Lennemann, Nicholas J.; Herbert, Andrew S.; Brouillette, Rachel; Rhein, Bethany; Bakken, Russell A.; Perschbacher, Katherine J.; Cooney, Ashley L.; Miller-Hunt, Catherine L.; Ten Eyck, Patrick; Biggins, Julia; Olinger, Gene; Dye, John M.

    2017-01-01

    ABSTRACT The recent Ebola virus (EBOV) epidemic in West Africa demonstrates the potential for a significant public health burden caused by filoviral infections. No vaccine or antiviral is currently FDA approved. To expand the vaccine options potentially available, we assessed protection conferred by an EBOV vaccine composed of vesicular stomatitis virus pseudovirions that lack native G glycoprotein (VSVΔG) and bear EBOV glycoprotein (GP). These pseudovirions mediate a single round of infection. Both single-dose and prime/boost vaccination regimens protected mice against lethal challenge with mouse-adapted Ebola virus (ma-EBOV) in a dose-dependent manner. The prime/boost regimen provided significantly better protection than a single dose. As N-linked glycans are thought to shield conserved regions of the EBOV GP receptor-binding domain (RBD), thereby blocking epitopes within the RBD, we also tested whether VSVΔG bearing EBOV GPs that lack GP1 N-linked glycans provided effective immunity against challenge with ma-EBOV or a more distantly related virus, Sudan virus. Using a prime/boost strategy, high doses of GP/VSVΔG partially or fully denuded of N-linked glycans on GP1 protected mice against ma-EBOV challenge, but these mutants were no more effective than wild-type (WT) GP/VSVΔG and did not provide cross protection against Sudan virus. As reported for other EBOV vaccine platforms, the protection conferred correlated with the quantity of EBOV GP-specific Ig produced but not with the production of neutralizing antibodies. Our results show that EBOV GP/VSVΔG pseudovirions serve as a successful vaccination platform in a rodent model of Ebola virus disease and that GP1 N-glycan loss does not influence immunogenicity or vaccination success. IMPORTANCE The West African Ebola virus epidemic was the largest to date, with more than 28,000 people infected. No FDA-approved vaccines are yet available, but in a trial vaccination strategy in West Africa, recombinant

  15. Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.

    PubMed

    Jones, Gareth W; McLeod, Louise; Kennedy, Catherine L; Bozinovski, Steven; Najdovska, Meri; Jenkins, Brendan J

    2015-02-01

    Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed. Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells. Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques. Copyright © 2014 Elsevier Ireland Ltd

  16. Embryonic catalase protects against ethanol embryopathies in acatalasemic mice and transgenic human catalase-expressing mice in embryo culture

    SciTech Connect

    Miller-Pinsler, Lutfiya; Wells, Peter G., E-mail: pg.wells@utoronto.ca; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario

    Reactive oxygen species (ROS) have been implicated in the mechanism of ethanol (EtOH) teratogenicity, but the protective role of the embryonic antioxidative enzyme catalase is unclear, as embryonic activity is only about 5% of maternal levels. We addressed this question in a whole embryo culture model. C57BL/6 mouse embryos expressing human catalase (hCat) or their wild-type (C57BL/6 WT) controls, and C3Ga.Cg-Cat{sup b}/J catalase-deficient, acatalasemic (aCat) mouse embryos or their wild-type C3HeB/FeJ (C3H WT) controls, were explanted on gestational day (GD) 9 (plug = GD 1), exposed for 24 h to 2 or 4 mg/mL EtOH or vehicle, and evaluated formore » functional and morphological changes. hCat and C57BL/6 WT vehicle-exposed embryos developed normally, while EtOH was embryopathic in C57BL/6 WT embryos, evidenced by decreases in anterior neuropore closure, somites developed, turning and head length, whereas hCat embryos were protected (p < 0.001). Maternal pretreatment of C57BL/6 WT dams with 50 kU/kg PEG-catalase (PEG-cat) 8 h prior to embryo culture, which increases embryonic catalase activity, blocked all EtOH embryopathies (p < 0.001). Vehicle-exposed aCat mouse embryos had lower yolk sac diameters compared to WT controls, suggesting that endogenous ROS are embryopathic. EtOH was more embryopathic in aCat embryos than WT controls, evidenced by reduced head length and somite development (p < 0.01), and trends for reduced anterior neuropore closure, turning and crown–rump length. Maternal pretreatment of aCat dams with PEG-Cat blocked all EtOH embryopathies (p < 0.05). These data suggest that embryonic catalase is a determinant of risk for EtOH embryopathies. - Highlights: • Ethanol (EtOH) exposure causes structural embryopathies in embryo culture. • Genetically enhanced catalase (hCat) protects against EtOH embryopathies. • Genetically deficient catalase (aCat) exacerbates EtOH embryopathies. • Embryonic catalase is developmentally important. • Et

  17. Activation of the innate immune system provides broad-spectrum protection against in