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Sample records for substantially protects mice

  1. Bordetella pertussis Infection or Vaccination Substantially Protects Mice against B. bronchiseptica Infection

    PubMed Central

    Goebel, Elizabeth M.; Zhang, Xuqing; Harvill, Eric T.

    2009-01-01

    Although B. bronchiseptica efficiently infects a wide range of mammalian hosts and efficiently spreads among them, it is rarely observed in humans. In contrast to the many other hosts of B. bronchiseptica, humans are host to the apparently specialized pathogen B. pertussis, the great majority having immunity due to vaccination, infection or both. Here we explore whether immunity to B. pertussis protects against B. bronchiseptica infection. In a murine model, either infection or vaccination with B. pertussis induced antibodies that recognized antigens of B. bronchiseptica and protected the lower respiratory tract of mice against three phylogenetically disparate strains of B. bronchiseptica that efficiently infect naïve animals. Furthermore, vaccination with purified B. pertussis-derived pertactin, filamentous hemagglutinin or the human acellular vaccine, Adacel, conferred similar protection against B. bronchiseptica challenge. These data indicate that individual immunity to B. pertussis affects B. bronchiseptica infection, and suggest that the high levels of herd immunity against B. pertussis in humans could explain the lack of observed B. bronchiseptica transmission. This could also explain the apparent association of B. bronchiseptica infections with an immunocompromised state. PMID:19707559

  2. Child protection decisions to substantiate hospital child protection teams' reports of suspected maltreatment.

    PubMed

    Jedwab, Merav; Benbenishty, Rami; Chen, Wendy; Glasser, Saralee; Siegal, Gil; Lerner-Geva, Liat

    2015-02-01

    The present study focuses on the way child protection officers (CPOs) in Israel assess suspected abuse and neglect (SCAN) reports made by hospital child protection teams (CPTs), to determine whether the alleged maltreatment is substantiated. The study was conducted in six medical centers and included 358 reports investigated by CPOs for SCAN. A structured questionnaire was completed by hospital CPTs to capture all relevant information on each child referred to the CPTs. Structured phone interviews were conducted with each of the CPOs who received a CPT report. Bivariate associations and multivariate logistic regressions were conducted to estimate the substantiation rate of cases reported by CPTs and the types of maltreatment substantiated, as well as to identify case characteristics of the child and the family that were associated with the CPOs' substantiation decision. CPO follow-up investigations revealed a substantiation rate of 53.5%. The maltreatment type most commonly substantiated was neglect. The case characteristics associated with substantiation included socio-demographic background, parents' health and functioning, previous contact with social services, characteristics of the hospital referral, medical findings and an assessment of the parents' behaviors. The findings of the study highlighted the importance of cooperation between the health and welfare services and the policy makers. This cooperation is essential for identifying early signs of maltreatment. Enhanced cooperation and effective information transfer between various professionals would help prevent or at least reduce the recurrence of maltreatment and would ensure that the children and their families are treated appropriately.

  3. How Child Protective Services Investigators Decide to Substantiate Mothers for Failure-to-Protect in Sexual Abuse Cases

    ERIC Educational Resources Information Center

    Coohey, Carol

    2006-01-01

    The purpose of this study was to determine how Child Protective Services (CPS) investigators decide to substantiate mothers for failure-to-protect from sexual abuse. A case-comparison study was used to compare 31 mothers who were and 62 mothers who were not substantiated for failure-to-protect by CPS. The multivariate analysis showed that mothers…

  4. What Criteria Do Child Protective Services Investigators Use to Substantiate Exposure to Domestic Violence?

    ERIC Educational Resources Information Center

    Coohey, Carol

    2007-01-01

    The primary purpose of this study is to determine whether child protective services investigators apply a recognizable set of criteria to substantiate batterers and victims of battering for exposing their children to domestic violence. Although domestic violence occurred in 35% of the 1,248 substantiated incidents of child maltreatment, only 31…

  5. What Criteria Do Child Protective Services Investigators Use to Substantiate Exposure to Domestic Violence?

    ERIC Educational Resources Information Center

    Coohey, Carol

    2007-01-01

    The primary purpose of this study is to determine whether child protective services investigators apply a recognizable set of criteria to substantiate batterers and victims of battering for exposing their children to domestic violence. Although domestic violence occurred in 35% of the 1,248 substantiated incidents of child maltreatment, only 31…

  6. What criteria do child protective services investigators use to substantiate exposure to domestic violence?

    PubMed

    Coohey, Carol

    2007-01-01

    The primary purpose of this study is to determine whether child protective services investigators apply a recognizable set of criteria to substantiate batterers and victims of battering for exposing their children to domestic violence. Although domestic violence occurred in 35% of the 1,248 substantiated incidents of child maltreatment, only 31 (7.1%) couples were investigated for exposing a child to domestic violence or failing to protect a child from domestic violence. All of the batterers investigated and in the caregiver role when their children were exposed to domestic violence were substantiated. The unsubstantiated victims of battering tended to use more protective behaviors (M=3.82) than the substantiated victims (M=2.00); yet, at the case level, using more than one protective behavior did not seem to be a criterion used to substantiate the victims. Instead, it appears that investigators were discriminating between those protective behaviors by the victims that ended contact between the batterers and the children--for a substantial amount of time--and those that did not in both the substantiation and removal decision. Key issues related to applying criteria in incidents involving domestic violence are discussed along with recommendations to further refine and document them.

  7. Comments on "How Child Protective Services Investigators Decide to Substantiate Mothers for Failure-to-Protect in Sexual Abuse Cases"

    ERIC Educational Resources Information Center

    Shadoin, Amy L.; Carnes, Connie N.

    2006-01-01

    This commentary discusses the decisions of child protective service (CPS) investigators to substantiate mothers for failure-to-protect (FTP) in child sexual abuse cases. Four areas are identified in which the scientific literature remains inadequate to fully inform child maltreatment researchers, CPS practitioners and child welfare policymakers on…

  8. Multidisciplinary Child Protection Decision Making About Physical Abuse: Determining Substantiation Thresholds and Biases

    PubMed Central

    Jent, Jason F.; Eaton, Cyd K.; Knickerbocker, Lauren; Lambert, Walter F.; Merrick, Melissa T.; Dandes, Susan K.

    2011-01-01

    The current study examined the threshold at which multidisciplinary child protection team (CPT) professionals substantiate physical abuse allegations and the extent that they utilize potentially biased constructs in their decision making when presented with the same case evidence. State legal definitions of child maltreatment are broad. Therefore, the burden of interpretation is largely on CPT professionals who must determine at what threshold physical acts by parents surpass corporal discipline and constitute child physical abuse. Biased or subjective decisions may be made if certain case-specific characteristics or CPT professionals’ personal characteristics are used in making physical abuse determinations. Case vignettes with visual depictions of inflicted injuries were sent to CPT professionals in Florida and their substantiation decisions, personal beliefs about corporal discipline, and coercive discipline were collected. Results of the study demonstrated relatively high agreement among professionals across vignettes about what constitutes physical abuse. Further, CPT professionals strongly considered their perceptions of the severity of inflicted injuries in substantiation decisions. Although case specific characteristics did not bias decisions in a systematic way, some CPT professional characteristics influenced the substantiation of physical abuse. Practice implications and future directions of research are discussed. PMID:21804681

  9. Chemokine-adjuvanted electroporated DNA vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge.

    PubMed

    Kutzler, M A; Wise, M C; Hutnick, N A; Moldoveanu, Z; Hunter, M; Reuter, M A; Yuan, S; Yan, J; Ginsberg, A A; Sylvester, A; Pahar, B; Carnathan, D G; Kathuria, N; Khan, A S; Montefiori, D; Sardesai, N Y; Betts, M R; Mestecky, J; Marx, P A; Weiner, D B

    2016-01-01

    There have been encouraging results for the development of an effective HIV vaccine. However, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. We addressed some of these issues by using a simian immunodeficiency virus (SIV) DNA vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal SIV challenge in rhesus macaque (RhM) model. We previously reported on the ability of CCR9 and CCR10 ligand (L) adjuvants to enhance mucosal and systemic IgA and IgG responses in small animals. In this study, RhMs were intramuscularly immunized five times with either DNA or DNA plus chemokine adjuvant delivered by electroporation followed by challenge with SIVsmE660. Sixty-eight percent of all vaccinated animals (P<0.01) remained either uninfected or had aborted infection compared with only 14% in the vaccine naïve group. The highest protection was observed in the CCR10L chemokines group, where six of nine animals had aborted infection and two remained uninfected, leading to 89% protection (P<0.001). The induction of mucosal SIV-specific antibodies and neutralization titers correlated with trends in protection. These results indicate the need to further investigate the contribution of chemokine adjuvants to modulate immune responses and the role of mucosal antibodies in SIV/HIV protection.

  10. Chemokine Adjuvanted Electroporated-DNA Vaccine Induces Substantial Protection from Simian Immunodeficiency Virus Vaginal Challenge

    PubMed Central

    Hutnick, N A; Moldoveanu, Z; Hunter, M; Reuter, M; Yuan, S; Yan, J; Ginsberg, A; Sylvester, A; Pahar, B; Carnathan, D; Kathuria, N; Khan, A S; Montefiori, D; Sardesai, N Y; Betts, M R; Mestecky, J; Marx, P; Weiner, D B

    2015-01-01

    There have been encouraging results for the development of an effective HIV vaccine. However, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. We addressed some of these issues by using a simian immunodeficiency virus (SIV) DNA vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal SIV challenge in rhesus macaque (RhM) model. We previously reported on the ability of CCR9 and CCR10 ligand (L) adjuvants to enhance mucosal and systemic IgA and IgG in small animals. In this study, RhMs were intramuscularly immunized five times with either DNA or DNA plus chemokine adjuvant delivered by electroporation followed by challenge with SIVsmE660. Sixty-eight percent of all vaccinated animals (P=0.0016) remained either uninfected or had aborted infection compared to only 14% in the vaccine naïve group. The highest protection was observed in the CCR10L chemokines group, where 6 of 9 animals had aborted infection and two remained uninfected, leading to 89% protection (P=0.0003). The induction of mucosal SIV-specific antibodies and neutralization titers correlated with trends in protection. These results indicate the need to further investigate the contribution of chemokine adjuvants to modulate immune responses and the role of mucosal antibodies in SIV/HIV protection. PMID:25943275

  11. Commentary on "How Child Protective Service Investigators Decide to Substantiate Mothers for Failure-to-Protect in Sexual Abuse Cases"

    ERIC Educational Resources Information Center

    Vieth, Victor I.

    2006-01-01

    As this author traveled around the country, many university professors and domestic violence advocates told him that prosecuting or even intervening with social services is morally "wrong" in cases in which parents fail to protect their children. There are two problems with these arguments. First, these arguments assume that mothers should "never"…

  12. γ-Tocotrienol does not substantially protect DS neurons from hydrogen peroxide-induced oxidative injury.

    PubMed

    Then, Sue-Mian; Sanfeliu, Coral; Top, Gapor M; Wan Ngah, Wan Zurinah; Mazlan, Musalmah

    2012-01-05

    Down syndrome (DS) neurons are more susceptible to oxidative stress and previous studies have shown that vitamin E was able to reduce oxidative stress and improve DS neurons' viability. Therefore, this study was done to investigate the protective role of γ-tocotrienol (γT3) in DS neurons from hydrogen peroxide (H2O2) -induced oxidative stress. The pro-apoptosis tendency of γT3 was compared to α-tocopherol (αT) in non-stress condition as well. Primary culture of DS and euploid neurons were divided into six groups of treatment: control, H2O2, γT3 pre-treatment with H2O2, γT3 only, αT pre-treatment with H2O2 and αT only. The treatments were assessed by MTS assay and apoptosis assay by single-stranded DNA (ssDNA) apoptosis ELISA assay, Hoechst and Neu-N immunofluorescence staining. The cellular uptake of γT3 and αT was determined by HPLC while protein expressions were determined by Western blot. Comparison between groups was made by the Student's t test, one-way ANOVA and Bonferroni adjustment as well as two-way ANOVA for multiple comparisons. One day incubation of γT3 was able to reduced apoptosis of DS neurons by 10%, however γT3 was cytotoxic at longer incubation period (14 days) and at concentrations ≥ 100 μM. Pre-treatment of αT and γT3 only attenuate apoptosis and increase cell viability in H2O2-treated DS and euploid neurons by 10% in which the effects were minimal to maintain most of the DS cells' morphology. γT3 act as a free radical scavenger by reducing ROS generated by H2O2. In untreated controls, DS neurons showed lower Bcl-2/Bax ratio and p53 expression compared to normal neurons, while cPKC and PKC-δ expressions were higher in DS neurons. On the other hand, pre-treatment of γT3 in H2O2-treated DS neurons have reduced Bcl-2/Bax ratio, which was not shown in euploid neurons. This suggests that pre-treatment of γT3 did not promote DS cell survival. Meanwhile γT3 and αT treatments without H2O2 as well as pre-treatment of γT3 and

  13. Antisense Reduction of Tau in Adult Mice Protects against Seizures

    PubMed Central

    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.

    2013-01-01

    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. PMID:23904623

  14. Methylprednisolone Protection Against Endotoxin in Lead-Sensitized Mice

    PubMed Central

    Marecki, Nelda M.

    1974-01-01

    Lead-sensitized BALB/c male mice are protected against Escherichia coli endotoxin by the intraperitoneal administration of 6α-methylprednisolone. This protection is dependent on time of administration of the methylprednisolone. PMID:4596282

  15. 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

  16. 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.

  17. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours

    PubMed Central

    Reiman, A; Srinivasan, V; Barone, G; Last, J I; Wootton, L L; Davies, E G; Verhagen, M M; Willemsen, M A; Weemaes, C M; Byrd, P J; Izatt, L; Easton, D F; Thompson, D J; Taylor, A M

    2011-01-01

    Background: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. Methods: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. Results: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. Conclusion: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age. PMID:21792198

  18. Hydrogen Protects Mice from Radiation Induced Thymic Lymphoma in BALB/c Mice

    PubMed Central

    Zhao, Luqian; Zhou, Chuanfeng; Zhang, Jian; Gao, Fu; Li, Bailong; Chuai, Yunhai; Liu, Cong; Cai, Jianming

    2011-01-01

    Ionizing radiation (IR) is a well-known carcinogen, however the mechanism of radiation induced thymic lymphoma is not well known. Moreover, an easy and effective method to protect mice from radiation induced thymic lymphoma is still unknown. Hydrogen, or H2, is seldom regarded as an important agent in medical usage, especially as a therapeutic gas. Here in this study, we found that H2 protects mice from radiation induced thymic lymphoma in BALB/c mice. PMID:21448340

  19. Leishmania pifanoi amastigote antigens protect mice against cutaneous leishmaniasis.

    PubMed Central

    Soong, L; Duboise, S M; Kima, P; McMahon-Pratt, D

    1995-01-01

    In the search for a leishmaniasis vaccine, extensive studies have been carried out with promastigote (insect stage) molecules. Information in this regard on amastigote (mammalian host stage) molecules is limited. To investigate host immune responses to Leishmania amastigote antigens, we purified three stage-specific antigens (A2, P4, and P8) from in vitro-cultivated amastigotes of Leishmania pifanoi by using immunoaffinity chromatography. We found that with Corynebacterium parvum as an adjuvant, three intraperitoneal injections of 5 micrograms of P4 or P8 antigen provided partial to complete protection of BALB/c mice challenged with 10(5) to 10(7) L. pifanoi promastigotes. These immunized mice developed significantly smaller or no lesions and exhibited a 39- to 1.6 x 10(5)-fold reduction of lesion parasite burden after 15 to 20 weeks of infection. In addition, P8 immunization resulted in complete protection against L. amazonensis infection of CBA/J mice and partial protection of BALB/c mice, suggesting that this antigen provided cross-species protection of mice with different H-2 haplotypes. At different stages during infection, vaccinated mice exhibited profound proliferative responses to parasite antigens and increased levels of gamma interferon production, suggesting that a Th1 cell-mediated immune response is associated with the resistance in these mice. Taken together, the data in this report indicate the vaccine potential of amastigote-derived antigens. PMID:7642292

  20. Context-specific protection of TGFα null mice from osteoarthritis.

    PubMed

    Usmani, Shirine E; Ulici, Veronica; Pest, Michael A; Hill, Tracy L; Welch, Ian D; Beier, Frank

    2016-07-26

    Transforming growth factor alpha (TGFα) is a growth factor involved in osteoarthritis (OA). TGFα induces an OA-like phenotype in articular chondrocytes, by inhibiting matrix synthesis and promoting catabolic factor expression. To better understand TGFα's potential as a therapeutic target, we employed two in vivo OA models: (1) post-traumatic and (2) aging related OA. Ten-week old and six-month old male Tgfa null mice and their heterozygous (control) littermates underwent destabilization of the medial meniscus (DMM) surgery. Disease progression was assessed histologically using the Osteoarthritis Research Society International (OARSI) scoring system. As well, spontaneous disease progression was analyzed in eighteen-month-old Tgfa null and heterozygous mice. Ten-week old Tgfa null mice were protected from OA progression at both seven and fourteen weeks post-surgery. No protection was seen however in six-month old null mice after DMM surgery, and no differences were observed between genotypes in the aging model. Thus, young Tgfa null mice are protected from OA progression in the DMM model, while older mice are not. In addition, Tgfa null mice are equally susceptible to spontaneous OA development during aging. Thus, TGFα might be a valuable therapeutic target in some post-traumatic forms of OA, however its role in idiopathic disease is less clear.

  1. Context-specific protection of TGFα null mice from osteoarthritis

    PubMed Central

    Usmani, Shirine E.; Ulici, Veronica; Pest, Michael A.; Hill, Tracy L.; Welch, Ian D.; Beier, Frank

    2016-01-01

    Transforming growth factor alpha (TGFα) is a growth factor involved in osteoarthritis (OA). TGFα induces an OA-like phenotype in articular chondrocytes, by inhibiting matrix synthesis and promoting catabolic factor expression. To better understand TGFα’s potential as a therapeutic target, we employed two in vivo OA models: (1) post-traumatic and (2) aging related OA. Ten-week old and six-month old male Tgfa null mice and their heterozygous (control) littermates underwent destabilization of the medial meniscus (DMM) surgery. Disease progression was assessed histologically using the Osteoarthritis Research Society International (OARSI) scoring system. As well, spontaneous disease progression was analyzed in eighteen-month-old Tgfa null and heterozygous mice. Ten-week old Tgfa null mice were protected from OA progression at both seven and fourteen weeks post-surgery. No protection was seen however in six-month old null mice after DMM surgery, and no differences were observed between genotypes in the aging model. Thus, young Tgfa null mice are protected from OA progression in the DMM model, while older mice are not. In addition, Tgfa null mice are equally susceptible to spontaneous OA development during aging. Thus, TGFα might be a valuable therapeutic target in some post-traumatic forms of OA, however its role in idiopathic disease is less clear. PMID:27457421

  2. Protective Effect of Proanthocyanidins in Cadmium Induced Neurotoxicity in Mice.

    PubMed

    Dong, C

    2015-10-01

    Cadmium (Cd) is a potent neurotoxic heavy metal, known to induce oxidative stress and membrane disturbances in brain. Proanthocyanidins (PACs), the most abundant polyphenol class in the human diet, have protective effects on oxidative stress and other metabolic disorders. Based on the cellular protective effect of PACs, we aimed to investigate whether PACs could protect the neuronal cells from Cd-induced excitotoxicity. The experiment was carried out on mice model and also in primary culture of hippocampal neurons isolated from neonatal mice. The Cd-induced changes in acetylcholinesterase (AChE) activity, oxidative stress markers (lipid peroxidation/lipid hydroperoxidation), antioxidant status and Akt phosphorylation were measured in the mice brain with or without PACs treatment. Mice intoxicated with cadmium (5 mg/kg/day) for 4 weeks had significantly (p<0.05) reduced the AChE levels, elevated the levels of oxidative stress markers along with the significant (p<0.05) decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants in mice brain tissue. In contrast, administration of PACs (100 mg/kg/day) for 4 weeks in cadmium-intoxicated mice had significantly (p<0.05) protected the cadmium-mediated changes. In addition, PACs treatment in cultured mice hippocampal neurons had protected Cd-induced excitotoxicity by activating Akt phosphorylation, decreasing the caspase-3 level and improving the neuronal cell survival rate up to 24 h. Altogether, our data suggest that PACs plays a crucial role on neuroprotection in combating the cadmium induced oxidative neurotoxicity in mice brain by influencing the activation of AChE/Akt phosphorylation, antioxidant status, controlling the membrane damage (lipid peroxidation) and apoptotic protein caspase-3. © Georg Thieme Verlag KG Stuttgart · New York.

  3. CD5 (Ly-1)-negative, conventional splenic B cells make a substantial contribution to the bromelain plaque-forming cell response in CBA and BW mice.

    PubMed Central

    Andrew, E M; Annis, W; Kahan, M; Maini, R N

    1990-01-01

    CD5 (Ly-1) B cells are a minor subpopulation in mouse spleen and are thought to be responsible for the production of natural autoantibodies to bromelain-treated autologous erythrocytes (Br-RBC). Here it is shown that substantial numbers of conventional, CD5-negative, splenic B cells also secrete these antibodies in CBA and (NZB x NZW)F1 mice, whereas in NZB and BALB/c mice they are all produced by the CD5 B-cell population. However, stimulation with bacterial lipopolysaccharide in vivo preferentially activates the CD5 B-cell group to anti-Br-RBC antibody secretion. PMID:1692301

  4. Dendritic Cell Targeting of Bacillus anthracis Protective Antigen Expressed by Lactobacillus acidophilus Protects Mice from Lethal Challenge

    DTIC Science & Technology

    2008-10-28

    Dendritic cell targeting of Bacillus anthracis protective antigen expressed by Lactobacillus acidophilus protects mice from lethal challenge M...lethal chal- lenge. A vaccine strategy was established by using Lactobacillus acidophilus to deliver Bacillus anthracis protective antigen (PA) via...4. TITLE AND SUBTITLE Dendritic cell targeting of Bacillus anthracis protective antigen expressed by Lactobacillus acidophilus protects mice

  5. Chimeric plantibody passively protects mice against aerosolized ricin challenge.

    PubMed

    Sully, Erin K; Whaley, Kevin J; Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H; Pauly, Michael H; Velasco, Jesus; Hiatt, Ernie; Morton, Josh; Swope, Kelsi; Roy, Chad J; Zeitlin, Larry; Mantis, Nicholas J

    2014-05-01

    Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation.

  6. Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis

    PubMed Central

    Luo, Guanpingsheng; Gebremariam, Teclegiorgis; Lee, Hongkyu; Edwards, John E.; Kovanda, Laura

    2014-01-01

    We studied the in vitro and in vivo efficacies of the investigational drug isavuconazole against mucormycosis due to Rhizopus delemar. Isavuconazole was effective, with MIC and minimal fungicidal concentration (MFC) values ranging between 0.125 and 1.00 μg/ml. A high dose of isavuconazole prolonged the survival time and lowered the tissue fungal burden of cyclophosphamide/cortisone acetate-treated mice infected with R. delemar and was as effective as a high-dose liposomal amphotericin B treatment. These results support the further development of this azole against mucormycosis. PMID:24492363

  7. Macrophages in protective immunity to Hymenolepis nana in mice.

    PubMed

    Asano, K; Muramatsu, K; Ito, A; Okamoto, K

    1992-12-01

    When mice were treated with carrageenan just before infection with eggs of Hymenolepis nana, they failed to exhibit sterile immunity to the egg challenge, with evidence of a decrease in the number of peripheral macrophages (Mø) and the rate of carbon clearance. Although there were high levels of interleukin-1 (IL-1) released into the intestinal tracts of the parasitized mice at challenge infection, there was almost no release of IL-1 in those treated with carrageenan just before challenge. These results strongly suggest that Mø have an important role in protective immunity to H. nana in mice.

  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. 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

  10. Quench Protection for the MICE Cooling Channel Coupling Magnet

    SciTech Connect

    Guo, Xing Long; Xu, Feng Yu; Wang, Li; Green, Michael A.; Pan, Heng; Wu, Hong; Liu, X.K.; Jia, Lin Xiang; Amm, Kathleen

    2008-08-02

    This paper describes the passive quench protection system selected for the muon ionization cooling experiment (MICE) cooling channel coupling magnet. The MICE coupling magnet will employ two methods of quench protection simultaneously. The most important method of quench protection in the coupling magnet is the subdivision of the coil. Cold diodes and resistors are put across the subdivisions to reduce both the voltage to ground and the hot-spot temperature. The second method of quench protection is quench-back from the mandrel, which speeds up the spread of the normal region within the coils. Combining quench back with coil subdivision will reduce the hot spot temperature further. This paper explores the effect on the quench process of the number of coil sub-divisions, the quench propagation velocity within the magnet, and the shunt resistance.

  11. Skeletal maturation substantially affects elastic tissue properties in the endosteal and periosteal regions of loaded mice tibiae.

    PubMed

    Checa, Sara; Hesse, Bernhard; Roschger, Paul; Aido, Marta; Duda, Georg N; Raum, Kay; Willie, Bettina M

    2015-07-01

    Although it is well known that the bone adapts to changes in the mechanical environment by forming and resorbing the bone matrix, little is known about the influence of mechanical loading on tissue material properties of the pre-existing and newly formed bone. In this study, we analyzed the newly formed and pre-existing tissue after two weeks of controlled in vivo axial compressive loading in tibia of young (10 week-old) and adult (26 week-old) female mice and compared to the control contralateral limb, by means of scanning acoustic microscopy. Additionally, we used quantitative backscattered electron imaging to determine the bone mineral density distribution within the newly formed and pre-existing bone of young mice. No significant differences were found in tissue stiffness or mineral density in the pre-existing bone tissue as a result of external loading. In the endosteal region, 10 and 26 week loaded animals showed a 9% reduction in bone tissue stiffness compared to control animals. An increase of 200% in the mineral apposition rate in this region was observed in both age groups. In the periosteal region, the reduction in bone tissue stiffness and the increase in bone mineral apposition rate as a result of loading were two times higher in the 10 compared to the 26 week old animals. These data suggest that, during growth and skeletal maturation, the response of bone to mechanical loading is a deposition of new bone matrix, where the tissue amount but not its mineral or elastic properties are influenced by animal age.

  12. Interleukin-18 protects mice from Enterovirus 71 infection.

    PubMed

    Li, Zheng; Wang, Hongbin; Chen, Yihui; Niu, Junling; Guo, Qiuhong; Leng, Qibin; Huang, Zhong; Deng, Zhirui; Meng, Guangxun

    2017-08-01

    Previous study has demonstrated that the NLRP3 inflammasome is essential for protecting murine host against Enterovirus 71 (EV71) infection. However, the underlying mechanism remained unknown. Here we discovered that the pleiotropic cytokine interleukin-18 (IL-18), an NLRP3 inflammasome-dependent effector protein, exhibits a protective capability against EV71 challenge. Deficiency of IL-18 in mice exacerbated EV71 infection, which was reflected by increased viral replication, elevated production of interferons (IFN-β, IFN-γ), proinflammatory cytokines (TNF-α, IL-6) and chemokine CCL2,as well as decreased survival of experimental animals. Conversely, administration of recombinant IL-18 considerably restrained EV71 infection in IL-18 deficient mice. Thus, our results revealed a protective role for IL-18 against EV71 challenge, and indicated a novel therapeutic application for IL-18 in EV71 associated hand, foot, and mouth disease (HFMD). Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Frostbite Protection in Mice Expressing an Antifreeze Glycoprotein

    PubMed Central

    Heisig, Martin; Mattessich, Sarah; Rembisz, Alison; Acar, Ali; Shapiro, Martin; Booth, Carmen J.; Neelakanta, Girish; Fikrig, Erol

    2015-01-01

    Ectotherms in northern latitudes are seasonally exposed to cold temperatures. To improve survival under cold stress, they use diverse mechanisms to increase temperature resistance and prevent tissue damage. The accumulation of anti-freeze proteins that improve cold hardiness occurs in diverse species including plants, arthropods, fish, and amphibians. We previously identified an Ixodes scapularis anti-freeze glycoprotein, named IAFGP, and demonstrated its cold protective function in the natural tick host and in a transgenic Drosophila model. Here we show, in a transgenic mouse model expressing an anti-freeze glycoprotein, that IAFGP protects mammalian cells and mice from cold shock and frostbite respectively. Transgenic skin samples showed reduced cell death upon cold storage ex vivo and transgenic mice demonstrated increased resistance to frostbite injury in vivo. IAFGP actively protects mammalian tissue from freezing, suggesting its application for the prevention of frostbite, and other diseases associated with cold exposure. PMID:25714402

  14. Nasal immunization with Lactococcus lactis expressing the pneumococcal protective protein A induces protective immunity in mice.

    PubMed

    Medina, Marcela; Villena, Julio; Vintiñi, Elisa; Hebert, Elvira María; Raya, Raúl; Alvarez, Susana

    2008-06-01

    Nisin-controlled gene expression was used to develop a recombinant strain of Lactococcus lactis that is able to express the pneumococcal protective protein A (PppA) on its surface. Immunodetection assays confirmed that after the induction with nisin, the PppA antigen was predictably and efficiently displayed on the cell surface of the recombinant strain, which was termed L. lactis PppA. The production of mucosal and systemically specific antibodies in adult and young mice was evaluated after mice were nasally immunized with L. lactis PppA. Immunoglobulin M (IgM), IgG, and IgA anti-PppA antibodies were detected in the serum and bronchoalveolar lavage fluid of adult and young mice, which showed that PppA expressed in L. lactis was able to induce a strong mucosal and systemic immune response. Challenge survival experiments demonstrated that immunization with L. lactis PppA was able to increase resistance to systemic and respiratory infection with different pneumococcal serotypes, and passive immunization assays of naïve young mice demonstrated a direct correlation between anti-PppA antibodies and protection. The results presented in this study demonstrate three major characteristics of the effectiveness of nasal immunization with PppA expressed as a protein anchored to the cell wall of L. lactis: it elicited cross-protective immunity against different pneumococcal serotypes, it afforded protection against both systemic and respiratory challenges, and it induced protective immunity in mice of different ages.

  15. 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??104LD50). 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. ?? 2002 Elsevier Science Ltd. All rights reserved.

  16. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease.

    PubMed

    Flamant, Martin; Placier, Sandrine; Rodenas, Anita; Curat, Cyrile Anne; Vogel, Wolfgang F; Chatziantoniou, Christos; Dussaule, Jean-Claude

    2006-12-01

    A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.

  17. Picroside II protects against sepsis via suppressing inflammation in mice

    PubMed Central

    Huang, Ying; Zhou, Miao; Li, Chengbao; Chen, Yuanli; Fang, Wei; Xu, Guo; Shi, Xueyin

    2016-01-01

    Picroside II, an iridoid compound extracted from Picrorhiza, exhibits anti-inflammatory and anti-apoptotic activities. We explored the protective effects and mechanisms of picroside II in a mouse model of sepsis induced by cecal ligation and puncture (CLP), using three groups of mice: Group A (sham), Group B (CLP+NS) and Group C (CLP+20 mg/kg picroside II). The mortality in mice with sepsis was decreased by the administration of picroside II, and lung injury was alleviated simultaneously. Picroside II treatment enhanced bacterial clearance in septic mice. Further, picroside II treatment alleviated the inflammatory response in sepsis and enhanced immune function by inhibiting the activation of NLRP3 inflammasome and NF-κB pathways. Picroside II may represent an anti-inflammatory drug candidate, providing novel insight into the treatment of sepsis. PMID:28078023

  18. Protective immunity to Brucella ovis in BALB/c mice following recovery from primary infection or immunization with subcellular vaccines.

    PubMed Central

    Jiménez de Bagüés, M P; Elzer, P H; Blasco, J M; Marín, C M; Gamazo, C; Winter, A J

    1994-01-01

    Experiments were performed with BALB/c mice to elucidate the roles of humoral and cell-mediated immune responses in the acquisition of protective immunity to Brucella ovis and to compare infection immunity with immunity developed through vaccination with a hot saline extract (HS) of B. ovis. Mice convalescing from a primary infection with B. ovis displayed a high level of resistance to reinfection, as evidenced by splenic bacterial counts decreased over 10,000-fold from control groups at 2 weeks after challenge. Passive transfer assays revealed that protection was mediated by both T lymphocytes and antibodies but that antibodies had a substantially greater role on the basis of log units of protection that were transferred. Antibodies specific for HS proteins in sera from convalescent mice were predominantly of the immunoglobulin G 2a and 3 isotypes. Vaccination with HS conferred good protection against B. ovis, but protection was greatly enhanced by the incorporation of QS-21 or other adjuvants. Protection provided by the HS vaccine resulted largely from immune responses to its protein moieties. A critical evaluation of the protective efficacy of the rough lipopolysaccharide component of HS was precluded by its poor immunogenicity in BALB/c mice. HS-QS-21 afforded protection against challenge infection with B. ovis as good as that which developed after a primary infection and as good as or better than that provided by attenuated Brucella melitensis vaccine strain Rev 1. Passive transfer experiments confirmed that the magnitudes of both humoral and cell-mediated forms of protective immunity were equivalent in mice vaccinated with HS-QS-21 and those recovering from a primary infection. Protective immunity to B. ovis in mice therefore resembled that to Brucella abortus, except that the relative roles of humoral and cell-mediated immunity, rather than being equivalent, were shifted toward a greater role for antibodies. PMID:8300219

  19. Protective effect of carnosine on febrile seizures in immature mice.

    PubMed

    Dai, Yun-Jian; Wu, Deng-Chang; Feng, Bo; Hou, Wei-wei; Xu, Ceng-Lin; Ohtsu, Hiroshi; Chen, Zhong; Hu, Wei-Wei

    2015-02-19

    Febrile seizures (FSs) are the most common type of convulsions in childhood and complex FSs represent an increased risk for development of temporal lobe epilepsy. The aim of this study was to analyze the anticonvulsant effects of carnosine, an endogenous dipeptide composed of alanine and histidine, on hyperthermia induced seizure in immature mice. Injection of carnosine significantly increased the latency and decreased the duration of FSs in a dose-dependent manner. In addition, histidine had similar effects on FSs as carnosine. The protective effect of carnosine or histidine was completely abolished by α-fluoromethylhistidine (α-FMH), a selective and irreversible histidine decarboxylase inhibitor, or in histidine decarboxylase deficient (HDC-KO) mice. Peripheral carnosine administration increased the level of carnosine, histidine and histamine in the cortex and hippocampus of mice pups, but decreased glutamate contents in the cortex and hippocampus. These results indicate that carnosine can protect against FSs in mice pups through its conversion to histamine, suggesting that it may serve as an efficient anti-FSs drug in the future. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Vaccine protection of leukopenic mice against Staphylococcus aureus bloodstream infection.

    PubMed

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

    2014-11-01

    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.

  1. 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

  2. Partial purification of protective antigens from Nippostrongylus brasiliensis in mice.

    PubMed

    Rhalem, A; Bourdieu, C; Luffau, G; Pery, P

    1988-01-01

    The purification of antigens from Nippostrongylus brasiliensis, through their ability to provoke cellular proliferation of immune cells and through their recognition by antibodies, led to an antigenic preparation which was extracted from adult worms and which contained only two proteins (MW 14 and 43 Kd). Mice which were vaccinated by the oral route after the entrapment of these two proteins in liposomes were strongly protected.

  3. Tumor suppressor p53 protects mice against Listeria monocytogenes infection

    PubMed Central

    Wang, Shaohui; Liu, Pingping; Wei, Jianchao; Zhu, Zixiang; Shi, Zixue; Shao, Donghua; Ma, Zhiyong

    2016-01-01

    Tumor suppressor p53 is involved in regulating immune responses, which contribute to antitumor and antiviral activity. However, whether p53 has anti-bacterial functions remains unclear. Listeria monocytogenes (LM) causes listeriosis in humans and animals, and it is a powerful model for studying innate and adaptive immunity. In the present study, we illustrate an important regulatory role of p53 during LM infection. p53 knockout (p53KO) mice were more susceptible to LM infection, which was manifested by a shorter survival time and lower survival rate. p53KO mice showed significant impairments in LM eradication. Knockdown of p53 in RAW264.7 and HeLa cells resulted in increased invasion and intracellular survival of LM. Furthermore, the invasion and intracellular survival of LM was inhibited in p53-overexpressing RAW264.7 and HeLa cells. LM-infected p53KO mice exhibited severe clinical symptoms and organ injury, presumably because of the abnormal production of the pro-inflammatory cytokines TNF-α, IL-6, IL-12, and IL-18. Decreased IFN-γ and GBP1 productions were observed in LM-infected p53-deficient mice or cells. The combination of these defects likely resulted in the overwhelming LM infection in the p53KO mice. These observations indicate that p53 serves as an important regulator of the host innate immune that protects against LM infection. PMID:27644341

  4. Inducible epithelial resistance protects mice against leukemia-associated pneumonia.

    PubMed

    Leiva-Juárez, Miguel M; Ware, Hayden H; Kulkarni, Vikram V; Zweidler-McKay, Patrick A; Tuvim, Michael J; Evans, Scott E

    2016-08-18

    Despite widespread infection prevention efforts, pneumonia remains the leading cause of death among patients with acute leukemia, due to complex disease- and treatment-dependent immune defects. We have reported that a single inhaled treatment with a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) induces protective mucosal defenses in mice against a broad range of pathogens. As Pam2-ODN-induced protection persists despite depletion of several leukocyte populations, we tested whether it could prevent pneumonia in a mouse model of acute myeloid leukemia (AML) remission induction therapy. Pam2-ODN prevented death due to pneumonia caused by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Aspergillus fumigatus when mice were heavily engrafted with leukemia cells, had severe chemotherapy-induced neutropenia or both. Pam2-ODN also extended survival of pneumonia in NSG mice engrafted with primary human AML cells. Protection was associated with rapid pathogen killing in the lungs at the time of infection and with reduced pathogen burdens at distant sites at the end of observation. Pathogen killing was inducible directly from isolated lung epithelial cells and was not abrogated by the presence of leukemia cells or cytotoxic agents. Pam2-ODN had no discernible effect on replication rate, total tumor population, or killing by chemotherapy of mouse or human leukemia cells, either in vitro or in vivo. Taken together, we report that therapeutic stimulation of lung epithelial defenses robustly protects against otherwise lethal pneumonias despite the profound immune dysfunction associated with acute leukemia and its treatment. These findings may suggest an opportunity to protect this population during periods of peak vulnerability. © 2016 by The American Society of Hematology.

  5. Protective effects of two Lactobacillus plantarum strains in hyperlipidemic mice

    PubMed Central

    Wang, Li-Xin; Liu, Kai; Gao, Da-Wei; Hao, Ji-Kui

    2013-01-01

    AIM: To investigate the effects of Lactobacillus plantarum (L. plantarum) CAI6 and L. plantarum SC4 on hyperlipidemic mice. METHODS: Male Kunming mice were fed a high-cholesterol diet for 28 d to construct hyperlipidemic models. Hyperlipidemic mice and normal mice were assigned to 3 groups which were separately treated with L. plantarum CAI6, L. plantarum SC4, and physiological saline through oral gavage for 28 d. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured by commercially available enzyme kits. FACS Calibur flow cytometry was used to examine hepatic and renal nuclear factor-erythroid 2-related factor 2 (Nrf2) expression. The morphology of livers was checked by hematoxylin and eosin staining and optical microscope observation. RESULTS: Compared with normal mice, hyperlipidemic mice possessed significantly higher TC (3.50 ± 0.43 vs 2.89 ± 0.36, P < 0.01), TG (1.76 ± 0.07 vs 1.10 ± 0.16, P < 0.01), and LDL-C (1.72 ± 0.20 vs 0.82 ± 0.10, P< 0.01) levels, resulting in an increase of atherogenic index (AI) (2.34 ± 1.60 vs 0.93 ± 0.55, P < 0.05) and LDL-C/HDL-C ratio (1.43 ± 0.12 vs 0.51 ± 0.16, P < 0.05). After treatment with L. plantarum CAI6/L. plantarum SC4, TG (1.43 ± 0.27/1.54 ± 0.10 vs 1.76 ± 0.07, P < 0.01/P < 0.05) and LDL-C (1.42 ± 0.07/1.47 ± 0.12 vs 1.72 ± 0.20, P < 0.01/P < 0.01) in hyperlipidemic mice significantly decreased. In addition, TC, HDL-C, AI, and LDL-C/HDL-C ratio were all positively changed. Meanwhile, the treatment markedly alleviated hepatic steatosis and significantly stimulated Nrf2 expression (73.79 ± 0.80/72.96 ± 1.22 vs 54.94 ± 1.84, P < 0.01/P < 0.01) in hepatocytes of hyperlipidemic mice. CONCLUSION: L. plantarum CAI6 and L. plantarum SC4 may protect against cardiovascular disease by lipid metabolism regulation and Nrf2-induced antioxidative defense in hyperlipidemic mice. PMID:23716997

  6. Decision making in child protection: An international comparative study on maltreatment substantiation, risk assessment and interventions recommendations, and the role of professionals' child welfare attitudes.

    PubMed

    Benbenishty, Rami; Davidson-Arad, Bilha; López, Mónica; Devaney, John; Spratt, Trevor; Koopmans, Carien; Knorth, Erik J; Witteman, Cilia L M; Del Valle, Jorge F; Hayes, David

    2015-11-01

    Child welfare professionals regularly make crucial decisions that have a significant impact on children and their families. The present study presents the Judgments and Decision Processes in Context model (JUDPIC) and uses it to examine the relationships between three independent domains: case characteristic (mother's wish with regard to removal), practitioner characteristic (child welfare attitudes), and protective system context (four countries: Israel, the Netherlands, Northern Ireland and Spain); and three dependent factors: substantiation of maltreatment, risk assessment, and intervention recommendation. The sample consisted of 828 practitioners from four countries. Participants were presented with a vignette of a case of alleged child maltreatment and were asked to determine whether maltreatment was substantiated, assess risk and recommend an intervention using structured instruments. Participants' child welfare attitudes were assessed. The case characteristic of mother's wish with regard to removal had no impact on judgments and decisions. In contrast, practitioners' child welfare attitudes were associated with substantiation, risk assessments and recommendations. There were significant country differences on most measures. The findings support most of the predictions derived from the JUDPIC model. The significant differences between practitioners from different countries underscore the importance of context in child protection decision making. Training should enhance practitioners' awareness of the impact that their attitudes and the context in which they are embedded have on their judgments and decisions.

  7. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

    PubMed Central

    Xu, Suowen; Yin, Meimei; Koroleva, Marina; Mastrangelo, Michael A.; Zhang, Wenbo; Bai, Peter; Little, Peter J.; Jin, Zheng Gen

    2016-01-01

    SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease. PMID:27249230

  8. Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

    PubMed Central

    Li, Ruidong; Wang, Yaxin; Ma, Zhijun; Ma, Muyuan; Wang, Di; Xie, Gengchen; Yin, Yuping

    2016-01-01

    Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS). Maresin 1 (Mar1) is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP) with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS) and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb) pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation. PMID:28042205

  9. Protective Effects of Platycodon grandiflorum Aqueous Extract on Thioacetamide-induced Fulminant Hepatic Failure in Mice

    PubMed Central

    Lim, Jong-Hwan; Kim, Tae-Won; Park, Sang-Jin; Song, In-Bae; Kim, Myoung-Seok; Kwon, Hyo-Jung; Cho, Eun-Sang; Son, Hwa-Young; Lee, Sang-Wook; Suh, Joo-Won; Kim, Jong-Woo; Yun, Hyo-In

    2011-01-01

    The aim of the present study was to evaluate the protective activity of aqueous extract from Platycodon grandiflorum (BC703) on thioacetamide (TA)-induced hepatotoxicity in mice. We found that BC703 significantly decreased mortality and the change in serum transaminase following TA administration. The group treated with BC703 at doses of 1, 5, and 10 mg/kg produced significant hepatoprotective effects against TA-induced liver damage by decreasing the activities of serum enzymes, nitric oxide and lipid peroxidation in dose-dependent manners. Histopathological studies further substantiated the protective effect of BC703. These results show the hepatoprotective activity of aqueous extract from Platycodon grandiflorum on thioacetamide-induced fulminant hepatic failure. PMID:22319234

  10. Inhibition of retrograde transport protects mice from lethal ricin challenge.

    PubMed

    Stechmann, Bahne; Bai, Siau-Kun; Gobbo, Emilie; Lopez, Roman; Merer, Goulven; Pinchard, Suzy; Panigai, Laetitia; Tenza, Danièle; Raposo, Graça; Beaumelle, Bruno; Sauvaire, Didier; Gillet, Daniel; Johannes, Ludger; Barbier, Julien

    2010-04-16

    Bacterial Shiga-like toxins are virulence factors that constitute a significant public health threat worldwide, and the plant toxin ricin is a potential bioterror weapon. To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus. Here, we used high-throughput screening to identify small molecule inhibitors that protect cells from ricin and Shiga-like toxins. We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity. In mice, one compound clearly protects from lethal nasal exposure to ricin. Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target.

  11. The treatment of mice with Lactobacillus casei induces protection against Babesia microti infection.

    PubMed

    Bautista-Garfias, C R; Gómez, M B; Aguilar, B R; Ixta, O; Martínez, F; Mosqueda, J

    2005-12-01

    In this study, we report that administration of Lactobacillus casei confers protection to mice against the intracellular protozoan Babesia microti. Mice treated with L. casei orally or intraperitoneally were inoculated 7 days later with an infectious dose of B. microti. Mice treated with lactobacilli showed significant reduction in the percentage of parasitized erythrocytes (PPE) compared to untreated mice. When mice were inoculated intraperitoneally with L. casei 3 or 0 days before challenge with B. microti, the PPE was significantly lower compared to untreated mice and there were no differences between treated mice and mice immune to B. microti infection. When mice treated with live or dead L. casei were compared to mice inoculated with Freund Complete Adjuvant before a B. microti infection, a significant reduction of PPE was observed. These results show the protective effect of L. casei administered to mice against a B. microti infection and suggest that it might act by stimulating the innate immune system.

  12. Absence of apolipoprotein E protects mice from cerebral malaria

    PubMed Central

    Kassa, Fikregabrail Aberra; Van Den Ham, Kristin; Rainone, Anthony; Fournier, Sylvie; Boilard, Eric; Olivier, Martin

    2016-01-01

    Cerebral malaria claims the life of millions of people each year, particularly those of children, and is a major global public health problem. Thus, the identification of novel malaria biomarkers that could be utilized as diagnostic or therapeutic targets is becoming increasingly important. Using a proteomic approach, we previously identified unique biomarkers in the sera of malaria-infected individuals, including apolipoprotein E (ApoE). ApoE is the dominant apolipoprotein in the brain and has been implicated in several neurological disorders; therefore, we were interested in the potential role of ApoE in cerebral malaria. Here we report the first demonstration that cerebral malaria is markedly attenuated in ApoE−/− mice. The protection provided by the absence of ApoE was associated with decreased sequestration of parasites and T cells within the brain, and was determined to be independent from the involvement of ApoE receptors and from the altered lipid metabolism associated with the knock-out mice. Importantly, we demonstrated that treatment of mice with the ApoE antagonist heparin octasaccharide significantly decreased the incidence of cerebral malaria. Overall, our study indicates that the reduction of ApoE could be utilized in the development of therapeutic treatments aimed at mitigating the neuropathology of cerebral malaria. PMID:27647324

  13. ALK7 protects against pathological cardiac hypertrophy in mice.

    PubMed

    Huang, He; Tang, Yanhong; Wu, Gang; Mei, Yang; Liu, Wanli; Liu, Xiaoxiong; Wan, Nian; Liu, Yu; Huang, Congxin

    2015-10-01

    Activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors, is expressed in various tissues, including the heart. However, the participation of ALK7 in the regulation of cardiac hypertrophy has not yet been studied. Here, we sought to determine the regulatory role and underlying mechanisms of ALK7 in cardiac hypertrophy. We performed aortic banding (AB) in ALK7-knockout mice, cardiac-specific ALK7-transgenic mice, and the wild-type littermates of these mice. Cardiac hypertrophy was evaluated using pathological analysis, echocardiographic measurement, haemodynamic measurement, and molecular analysis. Our results revealed that ALK7 disruption led to an aggravated cardiac hypertrophic response that was accompanied by increased cardiac fibrosis and reduced contractile function, whereas cardiac-specific ALK7 overexpression exhibited the opposite phenotype in response to pressure overload. Similarly, ALK7 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we demonstrated that ALK7-dependent cardioprotection was mediated largely through inhibition of the MEK-ERK1/2 signalling pathway. Our data suggest that ALK7 acts as a novel regulator of pathological cardiac hypertrophy via the negative regulation of MEK-ERK1/2 signalling and may serve as a potential therapeutic target for pathological cardiac hypertrophy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  14. Absence of apolipoprotein E protects mice from cerebral malaria.

    PubMed

    Kassa, Fikregabrail Aberra; Van Den Ham, Kristin; Rainone, Anthony; Fournier, Sylvie; Boilard, Eric; Olivier, Martin

    2016-09-20

    Cerebral malaria claims the life of millions of people each year, particularly those of children, and is a major global public health problem. Thus, the identification of novel malaria biomarkers that could be utilized as diagnostic or therapeutic targets is becoming increasingly important. Using a proteomic approach, we previously identified unique biomarkers in the sera of malaria-infected individuals, including apolipoprotein E (ApoE). ApoE is the dominant apolipoprotein in the brain and has been implicated in several neurological disorders; therefore, we were interested in the potential role of ApoE in cerebral malaria. Here we report the first demonstration that cerebral malaria is markedly attenuated in ApoE(-/-) mice. The protection provided by the absence of ApoE was associated with decreased sequestration of parasites and T cells within the brain, and was determined to be independent from the involvement of ApoE receptors and from the altered lipid metabolism associated with the knock-out mice. Importantly, we demonstrated that treatment of mice with the ApoE antagonist heparin octasaccharide significantly decreased the incidence of cerebral malaria. Overall, our study indicates that the reduction of ApoE could be utilized in the development of therapeutic treatments aimed at mitigating the neuropathology of cerebral malaria.

  15. 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

  16. Cannabinoid receptor 2 protects against acute experimental sepsis in mice.

    PubMed

    Gui, Huan; Sun, Yang; Luo, Zhu-Min; Su, Ding-Feng; Dai, Sheng-Ming; Liu, Xia

    2013-01-01

    The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R(-/-)). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R(-/-) splenocytes but completely abolished in CB2R(-/-) peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I κ B α degradation and NF- κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.

  17. Protective effect of corticosteroids on radiation pneumonitis in mice

    SciTech Connect

    Gross, N.J.; Narine, K.R.; Wade, R.

    1988-01-01

    We explored the protective effect of corticosteroids on the mortality of mice that received thoracic irradiation. Methylprednisolone, 100 mg/kg/week, given from 11 weeks after gamma irradiation of the thorax resulted in an increase in the LD50 (11-26 weeks) from 14.3 +/- 0.3 (mean +/- SE) Gy to 17.6 +/- 0.4 Gy, P less than 0.001, a protection factor of 1.2. Withdrawal of steroids at various times during the period of radiation pneumonitis resulted in accelerated mortality in the next 2-4 weeks, so that the cumulative mortality caught up with that of control animals by 4 weeks after steroid withdrawal. However, after the end of the usual period of pneumonitis withdrawal of steroids did not result in accelerated mortality, suggesting that the time when steroids are protective corresponds to the duration of pneumonitis. A smaller dose of steroids, 25 mg/kg/week, was found to be as protective as the larger dose used in the above experiments. The possibility that corticosteroids reduce mortality, even when given many weeks after radiation, may have important practical and theoretical implications.

  18. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission.

    PubMed

    Balazs, Alejandro B; Ouyang, Yong; Hong, Christin M; Chen, Joyce; Nguyen, Steven M; Rao, Dinesh S; An, Dong Sung; Baltimore, David

    2014-03-01

    The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.

  19. Heat stress and protection from permanent acoustic injury in mice.

    PubMed

    Yoshida, N; Kristiansen, A; Liberman, M C

    1999-11-15

    The inner ear can be permanently damaged by overexposure to high-level noise; however, damage can be decreased by previous exposure to moderate level, nontraumatic noise (). The mechanism of this "protective" effect is unclear, but a role for heat shock proteins has been suggested. The aim of the present study was to directly test protective effects of heat stress in the ear. For physiological experiments, CBA/CaJ mice were exposed to an intense octave band of noise (8-16 kHz) at 100 dB SPL for 2 hr, either with or without previous whole-body heat stress (rectal temperature to 41. 5 degrees C for 15 min). The interval between heat stress and sound exposure varied in different groups from 6 to 96 hr. One week later, inner ear function was assessed in each animal via comparison of compound action potential thresholds to mean values from unexposed controls. Permanent threshold shifts (PTSs) were approximately 40 dB in the group sound-exposed without previous heat stress. Heat-stressed animals were protected from acoustic injury: mean PTS in the group with 6 hr heat-stress-trauma interval was reduced to approximately 10 dB. This heat stress protection disappeared when the treatment-trauma interval surpassed 24 hr. A parallel set of quantitative PCR experiments measured heat-shock protein mRNA in the cochlea and showed 100- to 200-fold increase over control 30 min after heat treatment, with levels returning to baseline at 6 hr after treatment. Results are consistent with the idea that upregulation of heat shock proteins protects the ear from acoustic injury.

  20. Thiolated Recombinant Human Tumor Necrosis Factor-Alpha Protects against Plasmodium berghei K173-Induced Experimental Cerebral Malaria in Mice

    PubMed Central

    Postma, Nancy S.; Hermsen, Rob C.; Crommelin, Daan J. A.; Eling, Wijnand M. C.; Zuidema, Jan

    1999-01-01

    The introduction of reactive thiol groups in recombinant human tumor necrosis factor (TNF) alpha (rhTNF-α) by the reagent succinimidyl-S-acetylthioacetate resulted in the formation of a chemically stabilized rhTNF-α trimer (rhTNFα-AT; as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis). rhTNFα-AT showed a substantially enhanced protective efficacy against the development of experimental murine cerebral malaria (ECM) after intravenous injection compared to the protective efficacy of nonmodified rhTNF-α. Administration of thiolated rhTNF-α with protected thiol groups (rhTNFα-ATA; no stabilized trimers in vitro) exhibited the same protective efficacy against ECM, while in vitro bioactivity was reduced. Parasitemia was significantly suppressed in rhTNF-treated mice that were protected against ECM but not in treated mice that developed ECM. Protection against ECM was not related to increased concentrations in plasma of soluble TNF receptor 1 and 2 directly after injection or at the moment of development of ECM in nontreated mice. The results indicate that thiolation of rhTNF-α leads to the formation of stable trimers with increased potential in vivo. PMID:10223910

  1. Silymarin Protects Against Acute Ethanol-Induced Hepatotoxicity in Mice

    PubMed Central

    Song, Zhenyuan; Deaciuc, Ion; Song, Ming; Lee, David Y.-W.; Liu, Yanze; Ji, Xiaosheng; McClain, Craig

    2014-01-01

    Background Accumulated evidence has demonstrated that both oxidative stress and abnormal cytokine production, especially tumor necrosis factor-α (TNF), play important etiological roles in the pathogenesis of alcoholic liver disease (ALD). Agents that have both antioxidant and anti-inflammation properties, particularly anti-TNF production, represent promising therapeutic interventions for ALD. We investigated the effects and the possible mechanism(s) of silymarin on liver injury induced by acute ethanol (EtOH) administration. Methods Nine-week-old mice were divided into 4 groups, control, silymarin treatment, EtOH treatment, and silymarin/EtOH treatment, with 6 mice in each group. Because control and silymarin values were virtually identical, only control treatment is shown for ease of viewing. Ethanol-treated mice received EtOH [5 g/kg body weight (BW)] by gavage every 12 hours for a total of 3 doses. Control mice received an isocalorical maltose solution. In the silymarin/EtOH group, silymarin was dissolved in the EtOH and gavaged simultaneously with EtOH at a dose of 200 mg/kg BW. At 4 hours after the last dosing, the mice were anesthetized and subsequent serum alanine aminotransferase (ALT) level, hepatic lipid peroxidation, enzymatic activity of hepatic cytochrome P450 2E1, hepatic TNF-α, and glutathione (GSH) levels were measured. Histopathological change was assessed by hematoxylin and eosin staining. Results Acute EtOH administration caused prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. Supplementation with a standardized silymarin attenuated these adverse changes induced by acute EtOH administration. Conclusions Silymarin protects against the liver injury caused by acute EtOH administration. In view of its nontoxic nature, it may be developed as an effective therapeutic

  2. 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.

  3. Gentamicin-induced nephrotoxicity in mice: protection by loop diuretics.

    PubMed Central

    Whiting, P. H.; Petersen, J.; Simpson, J. G.

    1981-01-01

    Gentamicin, at doses of 50 or 100 mg/kg body wt administered daily to healthy male MF1 mice by i.p. injection for either 7 or 10 days caused proximal tubular cell damage shown both by the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and by electron microscopy. The tubular damage was maximal at 7 days. Concomitant administration of any of 3 diuretics-frusemide, bumetanide or piretanide at 5,0.5 and 1 mg/kg body wt/day respectively-resulted in less tubular damage than that caused by gentamicin alone. This finding of protection by diuretics contrasts with those of previous studies of combination gentamicin-diuretic therapy. Images Fig. 3 Fig. 4 PMID:7236500

  4. Melanocortins protect against multiple organ dysfunction syndrome in mice

    PubMed Central

    Bitto, Alessandra; Polito, Francesca; Altavilla, Domenica; Irrera, Natasha; Giuliani, Daniela; Ottani, Alessandra; Minutoli, Letteria; Spaccapelo, Luca; Galantucci, Maria; Lodi, Renzo; Guzzo, Giuseppe; Guarini, Salvatore; Squadrito, Francesco

    2011-01-01

    BACKGROUND AND PURPOSE Melanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analogue [Nle4, D-Phe7]α-MSH (NDP-α-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS). EXPERIMENTAL APPROACH MODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-α-MSH (340 µg·kg−1 day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC4 receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-α-MSH. KEY RESULTS At day 7, in the liver and lung NDP-α-MSH, significantly reduced mRNA expression of tumour necrosis factor-α (TNF-α), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-α plasma levels; furthermore, NDP-α-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-α-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS These data indicate that NDP-α-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting. PMID:21039420

  5. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice

    PubMed Central

    Barman, P K; Mukherjee, R; Prusty, B K; Suklabaidya, S; Senapati, S; Ravindran, B

    2016-01-01

    Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1β as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1β and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1β in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose. PMID:27171266

  6. Melatonin protects uterus and oviduct exposed to nicotine in mice

    PubMed Central

    Saadat, Seyedeh Nazanin Seyed; Jahromi, Sina Khajeh; Homafar, Mohammad Amin; Haghiri, Mostafa

    2014-01-01

    Smoking is associated with higher infertility risk. The aim of this study was to evaluate protective effects of melatonin on the uterus and oviduct in mice exposed to nicotine. Adult female mice (n=32) were divided into four groups. Group A: control animals received normal saline, Group B: injected with nicotine 40µg/kg, Group C: injected with melatonin 10 µg, Group D: injected with nicotine 40µg/kg and melatonin 10 µg. All animals were treated over 15 days intraperitoneally. On the 16th day, animals in the estrus phase were dissected and their uterus and oviducts were removed. Immunohistochemistry was recruited for studying apoptosis and for detection of estrogen receptor (ER) alpha in luminal epithelium of the uterus and oviduct. Enzyme-linked immunosorbent assay was used for serum estradiol level determination. Nicotine in group B decreased estradiol level and ERalpha numbers both in the uterus and oviduct (p<0.05). Co-administration of melatonin-nicotine in Group D ameliorated the histology of the uterus and oviduct, increased ERalpha numbers and reduced apoptosis in the uterus and oviduct compared with the nicotine Group B (p<0.05). This study indicates that nicotine impairs the histology of the uterus and oviduct and co-administration of melatonin-nicotine ameliorates these findings, partly through alteration in ERalpha numbers and reduction of apoptosis. PMID:26038675

  7. 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

  8. 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.

  9. Baicalin Protects Mice from Lethal Infection by Enterohemorrhagic Escherichia coli

    PubMed Central

    Zhang, Yong; Qi, Zhimin; Liu, Yan; He, Wenqi; Yang, Cheng; Wang, Quan; Dong, Jing; Deng, Xuming

    2017-01-01

    Shiga-like toxin-producing Escherichia coli (STEC) O157:H7 poses grave challenges to public health by its ability to cause severe colonic diseases and renal failure in both human and animals. Shiga-like toxins are the major pathogenic factor for some highly virulent E. coli expecially Shiga-like toxin 2. Conventional treatments such as antibiotics can facilitate the release of the toxin thus potentially exacerbate the diseases. Small molecule inhibitors and antibodies capable of neutralizing the toxins are the two major venues for the development of therapeutics against enterohemorrhagic serotype E. coli infection. While promising and potentially effective at clinical settings, these approaches need to overcome obstacles such as the limited routes of administration, responses from the host immune system, which are known to differ greatly among individuals. Our previous studies demonstrate that Baicalin (BAI), a flavonoid compound isolated from Scutellaria baicalensis protects against rStx2-induced cell cytotoxicity and also protects mice from lethal rStx2 challenges by inducing Stx2 to form inactive oligomers. In this manuscript, we present some exciting work showing that baicalin is an effective agent for therapeutic treatment of STEC O157:H7 infection. PMID:28337193

  10. Baicalin Protects Mice from Lethal Infection by Enterohemorrhagic Escherichia coli.

    PubMed

    Zhang, Yong; Qi, Zhimin; Liu, Yan; He, Wenqi; Yang, Cheng; Wang, Quan; Dong, Jing; Deng, Xuming

    2017-01-01

    Shiga-like toxin-producing Escherichia coli (STEC) O157:H7 poses grave challenges to public health by its ability to cause severe colonic diseases and renal failure in both human and animals. Shiga-like toxins are the major pathogenic factor for some highly virulent E. coli expecially Shiga-like toxin 2. Conventional treatments such as antibiotics can facilitate the release of the toxin thus potentially exacerbate the diseases. Small molecule inhibitors and antibodies capable of neutralizing the toxins are the two major venues for the development of therapeutics against enterohemorrhagic serotype E. coli infection. While promising and potentially effective at clinical settings, these approaches need to overcome obstacles such as the limited routes of administration, responses from the host immune system, which are known to differ greatly among individuals. Our previous studies demonstrate that Baicalin (BAI), a flavonoid compound isolated from Scutellaria baicalensis protects against rStx2-induced cell cytotoxicity and also protects mice from lethal rStx2 challenges by inducing Stx2 to form inactive oligomers. In this manuscript, we present some exciting work showing that baicalin is an effective agent for therapeutic treatment of STEC O157:H7 infection.

  11. Effect of antiflagellar serum in the protection of mice against Clostridium chauvoei.

    PubMed

    Tamura, Y; Tanaka, S

    1984-02-01

    Specific antiflagellar serum of Clostridium chauvoei showed a powerful protective effect which prevented bacterial growth in the liver, but not in infected muscle, against intramuscular challenge with calcium chloride-activated spores in normal mice. No protective effect was observed in mice with polymorphonuclear leucocytes depleted by cyclophosphamide treatment. The antiflagellar serum had approximately the same protective effect in mice with macrophages blocked selectively by carrageenan as it did in normal mice. We suggest that the antiflagellar serum exerted its effect by opsonic function and that opsonized C. chauvoei was eliminated mainly by polymorphonuclear leucocytes rather than by macrophages.

  12. Power Supply and Quench Protection for the MICE ChannelMagnets

    SciTech Connect

    Green, Michael A.; Witte, Holger

    2005-09-07

    This report discusses the power supply and quench protection system selected for the MICE superconducting coupling and focusing magnets. First, the MICE focusing and coupling magnet parameters are presented. Second, the report describes passive quench protection systems for these focusing and coupling magnets. Thermal quench-back from the magnet mandrel, which is a key to the MICE magnet quench protection system, is also discussed. A system of diodes and resistors is used to control the voltage to ground as the magnet quenches. Third, the report presents the magnet power supply parameters for MICE magnets.

  13. Active protection of mice against Salmonella typhi by immunization with strain-specific porins.

    PubMed

    Isibasi, A; Ortiz-Navarrete, V; Paniagua, J; Pelayo, R; González, C R; García, J A; Kumate, J

    1992-01-01

    NIH mice were immunized with between 2.5 and 30 micrograms of two highly purified porins, 34 kDa and 36 kDa, isolated from the virulent strain Salmonella typhi 9,12, Vi:d. Of mice immunized with 10 micrograms of porins, 90% were protected against a challenge with up to 500 LD50 (50% lethal doses) of S. typhi 9,12,Vi:d and only 30% protection was observed in mice immunized with the same dose of porins but challenged with the heterologous strain Salmonella typhimurium. These results demonstrate the utility of porins for the induction of a protective status against S. typhi in mice.

  14. Participation of platelets in protection against larval Taenia taeniaeformis infection in mice.

    PubMed

    Kakuda, T; Ooi, H K; Oku, Y; Kamiya, M

    1996-03-01

    The participation of platelets in the protection against larval Taenia taeniaeformis was studied. CB-17 SCID mice, susceptible to T. taeniaeformis, were protected against a challenge infection with T. taeniaeformis by the passive transfer of platelets from T. taeniaeformis-infected normal CB-17 mice, resistant to T. taeniaeformis.

  15. Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza.

    PubMed

    Limberis, Maria P; Adam, Virginie S; Wong, Gary; Gren, Jason; Kobasa, Darwyn; Ross, Ted M; Kobinger, Gary P; Tretiakova, Anna; Wilson, James M

    2013-05-29

    The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD₅₀ (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.

  16. Lupeol Protects Against Cerulein-Induced Acute Pancreatitis in Mice.

    PubMed

    Kim, Min-Jun; Bae, Gi-Sang; Choi, Sun Bok; Jo, Il-Joo; Kim, Dong-Goo; Shin, Joon-Yeon; Lee, Sung-Kon; Kim, Myoung-Jin; Song, Ho-Joon; Park, Sung-Joo

    2015-10-01

    Lupeol is a triterpenoid commonly found in fruits and vegetables and is known to exhibit a wide range of biological activities, including antiinflammatory and anti-cancer effects. However, the effects of lupeol on acute pancreatitis specifically have not been well characterized. Here, we investigated the effects of lupeol on cerulein-induced acute pancreatitis in mice. Acute pancreatitis was induced via an intraperitoneal injection of cerulein (50 µg/kg). In the lupeol treatment group, lupeol was administered intraperitoneally (10, 25, or 50 mg/kg) 1 h before the first cerulein injection. Blood samples were taken to determine serum cytokine and amylase levels. The pancreas was rapidly removed for morphological examination and used in the myeloperoxidase assay, trypsin activity assay, and real-time reverse transcription polymerase chain reaction. In addition, we isolated pancreatic acinar cells using a collagenase method to examine the acinar cell viability. Lupeol administration significantly attenuated the severity of pancreatitis, as was shown by reduced pancreatic edema, and neutrophil infiltration. In addition, lupeol inhibited elevation of digestive enzymes and cytokine levels, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and interleukin (IL)-6. Furthermore, lupeol inhibited the cerulein-induced acinar cell death. In conclusion, these results suggest that lupeol exhibits protective effects on cerulein-induced acute pancreatitis.

  17. Equine hyperimmune serum protects mice against Clostridium difficile spore challenge.

    PubMed

    Yan, Weiwei; Shin, Kang-Soon; Wang, Shih-Jon; Xiang, Hua; Divers, Thomas; McDonough, Sean; Bowman, James; Rowlands, Anne; Akey, Bruce; Mohamed, Hussni; Chang, Yung-Fu

    2014-01-01

    Clostridium (C.) difficile is a common cause of nosocomial diarrhea in horses. Vancomycin and metronidazole have been used as standard treatments but are only moderately effective, which highlights the need for a novel alternative therapy. In the current study, we prepared antiserum of equine origin against both C. difficile toxins A and B as well as whole-cell bacteria. The toxin-neutralizing activities of the antibodies were evaluated in vitro and the prophylactic effects of in vivo passive immunotherapy were demonstrated using a conventional mouse model. The data demonstrated that immunized horses generated antibodies against both toxins A and B that possessed toxin-neutralizing activity. Additionally, mice treated with the antiserum lost less weight without any sign of illness and regained weight back to a normal range more rapidly compared to the control group when challenged orally with 10(7) C. difficile spores 1 day after serum injection. These results indicate that intravenous delivery of hyperimmune serum can protect animals from C. difficile challenge in a dose-dependent manner. Hence, immunotherapy may be a promising prophylactic strategy for preventing C. difficile infection in horses.

  18. Equine hyperimmune serum protects mice against Clostridium difficile spore challenge

    PubMed Central

    Yan, Weiwei; Shin, Kang-Soon; Wang, Shih-Jon; Xiang, Hua; Divers, Thomas; McDonough, Sean; Bowman, James; Rowlands, Anne; Akey, Bruce; Mohamed, Hussni

    2014-01-01

    Clostridium (C.) difficile is a common cause of nosocomial diarrhea in horses. Vancomycin and metronidazole have been used as standard treatments but are only moderately effective, which highlights the need for a novel alternative therapy. In the current study, we prepared antiserum of equine origin against both C. difficile toxins A and B as well as whole-cell bacteria. The toxin-neutralizing activities of the antibodies were evaluated in vitro and the prophylactic effects of in vivo passive immunotherapy were demonstrated using a conventional mouse model. The data demonstrated that immunized horses generated antibodies against both toxins A and B that possessed toxin-neutralizing activity. Additionally, mice treated with the antiserum lost less weight without any sign of illness and regained weight back to a normal range more rapidly compared to the control group when challenged orally with 107 C. difficile spores 1 day after serum injection. These results indicate that intravenous delivery of hyperimmune serum can protect animals from C. difficile challenge in a dose-dependent manner. Hence, immunotherapy may be a promising prophylactic strategy for preventing C. difficile infection in horses. PMID:24136208

  19. Sappanone A protects mice against cisplatin-induced kidney injury.

    PubMed

    Kang, Lin; Zhao, Huanfen; Chen, Chen; Zhang, Xiuzhi; Xu, Mingtang; Duan, Huijun

    2016-09-01

    Cisplatin (CP) is an anti-cancer drug that often causes nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan, has been known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the protective effects and mechanism of SA on CP-induced kidney injury in mice. The results showed that treatment of SA improved CP-induced histopathalogical injury and renal dysfunction. SA also inhibited CP-induced MPO, MDA, TNF-α and IL-1β production and up-regulated the activities of SOD and GSH-PX decreased by CP. SA significantly inhibited the apoptosis rate of kidney tissues induced by CP. Furthermore, SA was found to inhibit CP-induced NF-κB activation. Treatment of SA up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. In vitro, SA dose-dependently inhibited CP-induced TNF-α and IL-1β production and NF-κB activation in HK-2 cells. In conclusion, these results suggested that SA inhibited CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation. SA was a potential therapeutic drug for treating CP-induced kidney injury.

  20. 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.

  1. Caveolin-1 Protects B6129 Mice against Helicobacter pylori Gastritis

    PubMed Central

    Hitkova, Ivana; Yuan, Gang; Anderl, Florian; Gerhard, Markus; Kirchner, Thomas; Reu, Simone; Röcken, Christoph; Schäfer, Claus; Schmid, Roland M.; Vogelmann, Roger; Ebert, Matthias P. A.; Burgermeister, Elke

    2013-01-01

    Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies (“humming bird”) compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells. PMID:23592983

  2. Mucosal and systemic immunization with a novel attenuated pneumococcal vaccine candidate confer serotype independent protection against Streptococcus pneumoniae in mice.

    PubMed

    Wu, Kaifeng; Yao, Run; Wang, Hong; Pang, Dan; Liu, Yusi; Xu, Hongmei; Zhang, Shuai; Zhang, Xuemei; Yin, Yibing

    2014-07-16

    Despite the availability of effective vaccines, Streptococcus pneumoniae is still one of the major infectious diseases causing substantial morbidity and mortality in children under 5 years old. In this study, we demonstrate the protective efficacy of S. pneumoniae SPY1, a novel live attenuated vaccine strain against pneumococcal infection in murine models. This strain was characterized by defects in three important pneumococcal virulence factors including capsule, teichoic acids and pneumolysin. The lactate dehydrogenase assays and in vivo animal experiments demonstrated a significantly attenuated virulence and a reduced nasopharyngeal colonization for the SPY1 strain. We also show that mucosal and systemic immunization with the live SPY1 strain induced protective immune responses against pneumococci. Mucosal immunization with SPY1 offered better protection against colonization challenge with strains TIGR4 and serotype 19F than systemic SPY1 immunization. In invasive infection models, mucosal vaccination with the SPY1 strain conferred complete protection against D39 and clinical serotype 6B and 3 strains. Notably, intranasal vaccination with the SPY1 strain conferred superior protection against pneumococcal invasive disease compared with the commercial available vaccines. SPY1 strain was shown to elicit high levels of serotype-independent antibodies and a mixed cellular immune response. Besides, the SPY1 serum was able to passively protect mice against invasive challenge with D39 strain, indicating the protective effect of the antibody-mediated responses. Together, the SPY1 strain may be a promising live vaccine strain to protect pneumococcal infection.

  3. Mechanism of T-cell mediated protection in newborn mice against a Chlamydia infection.

    PubMed

    Pal, Sukumar; de la Maza, Luis M

    2013-01-01

    To determine the immune components needed for protection of newborn mice against Chlamydia muridarum, animals born to Chlamydia-immunized and to sham-immunized dams were infected intranasally with C. muridarum at 2 post-natal days. T-cells isolated from immunized or sham-immunized adult mice were adoptively transferred to newborn mice at the time of infection. Also, to establish what cytokines are involved in protection, IFN-γ, TNF-α, IL-10, and IL-12 were passively transferred to newborn mice. To assess the Chlamydia burden in the lungs mice were euthanized at 12 post-natal days. When T-cells from immunized adult mice were transferred, mice born to and fed by immunized dams were significantly protected as evidenced by the reduced number of Chlamydia isolated from the lungs compared to mice born to and fed by sham-immunized dams. Transfer of IFN-γ and TNF-α also significantly reduced the number of Chlamydia in the lungs of mice born to immunized dams. Transfer of IL-10 or IL-12 did not result in a significant reduction of Chlamydia. In vitro T-cell proliferation data suggest that neonatal antigen presenting cells can present Chlamydia antigens to adult T-cells. In conclusion, maternal antibodies and Chlamydia specific T-cells or Th1 cytokines are required for protection of neonates against this pathogen.

  4. Mucosal vaccine made from live, recombinant Lactococcus lactis protects mice against pharyngeal infection with Streptococcus pyogenes.

    PubMed

    Mannam, Praveen; Jones, Kevin F; Geller, Bruce L

    2004-06-01

    A novel vaccine (LL-CRR) made from live, nonpathogenic Lactococcus lactis that expresses the conserved C-repeat region (CRR) of M protein from Streptococcus pyogenes serotype 6 was tested in mice. Nasally vaccinated mice produced CRR-specific salivary immunoglobulin A (IgA) and serum IgG. Subcutaneously vaccinated mice produced CRR-specific serum IgG but not salivary IgA. A combined regimen produced responses similar to the salivary IgA of nasally vaccinated mice and serum IgG of subcutaneously vaccinated mice. Mice vaccinated nasally or with the combined regimen were significantly protected against pharyngeal infection following a nasal challenge with S. pyogenes M serotype 14. Mice vaccinated subcutaneously were not protected against pharyngeal infection. Mice in all three LL-CRR vaccination groups were significantly protected against the lethal effects of S. pyogenes. Only 1 of 77 challenged mice that were vaccinated with LL-CRR died, whereas 60 of 118 challenged mice that were vaccinated with a control strain or phosphate-buffered saline died. In conclusion, mucosal vaccination with LL-CRR produced CRR-specific salivary IgA and serum IgG, prevented pharyngeal infection with S. pyogenes, and promoted survival.

  5. Protection of mice against vaginal colonisation by Mycoplasma pulmonis.

    PubMed

    Taylor-Robinson, D; Furr, P M

    1994-03-01

    Resistance against vaginal colonisation by Mycoplasma pulmonis in strain TO mice after exposure to the mycoplasma was investigated. Eighteen mice from which M. pulmonis had been eliminated from the vagina, either naturally or by antibiotic therapy, were resistant to vaginal recolonisation. Specific antibody was measured by an indirect microimmunofluorescence technique and the geometric mean titre (GMT) for each group of mice is presented. Almost all of 31 mice that had developed circulating antibody (GMT 83) or local antibody (GMT 40), or both, after vaginal exposure were resistant to re-colonisation, as were those in which antibodies could not be detected. Seven other mice which had been colonised only in the oropharynx previously and which possessed antibody--circulating (GMT 64) or local (GMT 30), or both--were resistant to vaginal colonisation, but 13 mice with little or no antibody after lack of colonisation at either anatomical site were susceptible. All of 15 mice given killed M. pulmonis organisms intravenously, despite developing circulating antibody in high titre (GMT 122), were susceptible to vaginal colonisation, as were 14 of 15 mice that developed circulating (GMT 15) and local antibodies after being given killed organisms intravaginally. However, 25 mice with high titres of circulating (GMT 154-170) or local (GMT 20) antibody, or both, after receiving live organisms intravenously, were less susceptible to vaginal colonisation (17 becoming colonised) than were 21 non-immunised mice (all becoming colonised) and the organisms were eradicated more rapidly from the former. Despite this, the mice that were colonised following intravenous inoculation of live organisms had pre-challenge antibody titres that were as great as those that were not colonised.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Protection of mice from infection with Streptococcus pneumoniae by anti-phosphocholine antibody.

    PubMed Central

    Yother, J; Forman, C; Gray, B M; Briles, D E

    1982-01-01

    Anti-phosphocholine (PC) antibody mediated protection against many strains of Streptococcus pneumoniae, and hybridoma anti-PC antibodies protected mice from fatal infections with types 1 and 3 S. pneumoniae. Live types 1, 3, 5, 6A, and 19F S. pneumoniae had similar amounts of surface PC accessible to antibody. Furthermore, mice expressing the X-linked immunodeficiency (xid) of the CBA/N strain were found to be more susceptible to infection with S. pneumoniae of types 3, 6A, and 19F than were immunologically normal mice. The only exception to these results was with the type 5 strain, which was highly virulent for both xid and normal mice. In addition, we were unable to protect mice against infection with the type 5 strain by using anti-PC antibody. PMID:7076292

  7. Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation.

    PubMed

    Xu, Guilian; Fromholt, Susan; Ayers, Jacob I; Brown, Hilda; Siemienski, Zoe; Crosby, Keith W; Mayer, Christopher A; Janus, Christopher; Borchelt, David R

    2015-05-01

    There has been great interest in enhancing endogenous protein maintenance pathways such as the heat-shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in amyotrophic lateral sclerosis and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co-expression of αB-crystallin (αB-crys) has been shown to inhibit the formation of detergent-insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express αB-crys at > 6-fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing αB-crys alone contained 20% more motor neurons per section than littermate controls. Raising αB-crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent-insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of αB-crys in spinal motor neurons by 6-fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation. Enhancing the protein chaperone function may present a therapeutic approach to amyotrophic lateral sclerosis caused by mutations in SOD1, and other neurodegenerative disorders characterized by cytosolic protein aggregation. Previous studies in cell models suggested that the chaperone known as αB-crystallin (αB-crys) can prevent mutant SOD1 aggregation. We report that transgenic expression of αB-crys at > 6-fold the normal level in spinal

  8. Schistosome Syntenin Partially Protects Vaccinated Mice against Schistosoma mansoni Infection

    PubMed Central

    Figueiredo, Barbara C.; Assis, Natan R. G.; Morais, Suellen B.; Ricci, Natasha D.; Pinheiro, Carina S.; Martins, Vicente P.; Bicalho, Rodrigo M.; Da'dara, Akram A.; Skelly, Patrick J.; Oliveira, Sergio C.

    2014-01-01

    Background Schistosomiasis is a neglected tropical disease caused by several species of trematode of the genus Schistosoma. The disease affects more than 200 million people in the world and causes up to 280,000 deaths per year, besides having high morbidity due to chronic illness that damages internal organs. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Among the most promising molecules as vaccine candidates are the proteins present in the tegument and digestive tract of the parasite. Methodology/Principal Findings In this study, we describe for the first time Schistosoma mansoni syntenin (SmSynt) and we evaluate its potential as a recombinant vaccine. We demonstrate by real-time PCR that syntenin is mainly expressed in intravascular life stages (schistosomula and adult worms) of the parasite life cycle and, by confocal microscopy, we localize it in digestive epithelia in adult worms and schistosomula. Administration of siRNAs targeting SmSynt leads to the knock-down of syntenin gene and protein levels, but this has no demonstrable impact on parasite morphology or viability, suggesting that high SmSynt gene expression is not essential for the parasites in vitro. Mice immunization with rSmSynt, formulated with Freund's adjuvant, induces a Th1-type response, as suggested by the production of IFN-γ and TNF-α by rSmSynt-stimulated cultured splenocytes. The protective effect conferred by vaccination with rSmSynt was demonstrated by 30–37% reduction of worm burden, 38–43% reduction in the number, and 35–37% reduction in the area, of liver granulomas. Conclusions/Significance Our report is the first characterization of syntenin in Schistosoma mansoni and our data suggest that this protein is a potential candidate for the development of a multi-antigen vaccine to

  9. Microbiota protects mice against acute alcohol-induced liver injury

    PubMed Central

    Chen, Peng; Miyamoto, Yukiko; Mazagova, Magdalena; Lee, Kuei-Chuan; Eckmann, Lars; Schnabl, Bernd

    2015-01-01

    Background Chronic alcohol abuse is associated with intestinal bacterial overgrowth, increased intestinal permeability, and translocation of microbial products from the intestine to the portal circulation and liver. Translocated microbial products contribute to experimental alcoholic liver disease. Aim To investigate the physiological relevance of the intestinal microbiota in alcohol-induced liver injury. Methods We subjected germ-free and conventional C57BL/6 mice to a model of acute alcohol exposure that mimics binge drinking. Results Germ-free mice showed significantly greater liver injury and inflammation after oral gavage of ethanol compared with conventional mice. In parallel, germ-free mice exhibited increased hepatic steatosis and upregulated expression of genes involved in fatty acid and triglyceride synthesis compared with conventional mice after acute ethanol administration. The absence of microbiota was also associated with increased hepatic expression of ethanol metabolizing enzymes, which led to faster ethanol elimination from the blood and lower plasma ethanol concentrations. Intestinal levels of ethanol metabolizing genes showed regional expression differences, and were overall higher in germ-free relative to conventional mice. Conclusion Our findings indicate that absence of the intestinal microbiota increases hepatic ethanol metabolism and the susceptibility to binge-like alcohol drinking. PMID:26556636

  10. 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.

  11. Colchicine protects mice from the lethal effect of an agonistic anti-Fas antibody

    PubMed Central

    Feng, Guoping; Kaplowitz, Neil

    2000-01-01

    The aim of this study was to determine whether colchicine, which has been reported to protect against various hepatotoxic insults, influences the susceptibility of mice to the agonistic anti-Fas antibody, Jo2. All mice that were pretreated with colchicine (2 mg/kg) survived the lethal challenge of intraperitoneal administration of 10 μg of Jo2, whereas all control mice pretreated with γ-lumicolchicine succumbed to the challenge. Twelve micrograms of Jo2 killed less than half of colchicine-pretreated mice and its lethal effects were delayed relative to control mice, which all died within 8 hours. Other microtubule-disrupting agents such as Taxol, vinblastine, and nocodazole also improved the survival of mice treated with the lethal dose of Jo2. Histologic examination showed that colchicine protected against Jo2-induced fulminant liver injury, and TUNEL assay demonstrated that colchicine protected against massive apoptosis of hepatocytes. Hepatocytes isolated from colchicine-pretreated mice exhibited decreased susceptibility to Jo2-induced apoptosis. In addition, colchicine pretreatment reduced surface expression of Fas and decreased Jo2- and TNF-α–induced apoptosis of cultured hepatocytes in the presence of actinomycin D, but did not affect the susceptibility of cultured sinusoidal endothelial cells to Jo2-induced apoptosis. Remarkably, Fas and TNF receptor-1 mRNA and intracellular protein levels increased after colchicine treatment, indicating that colchicine protects against death ligand–induced apoptosis in the liver by decreasing death-receptor targeting to the cell surface. PMID:10675359

  12. Immune responses in mice against herpes simplex virus: mechanisms of protection against facial and ganglionic infections.

    PubMed Central

    Zweerink, H J; Martinez, D; Lynch, R J; Stanton, L W

    1981-01-01

    We performed experiments with mice to determine the nature of the immune response(s) that prevents primary infections of the skin and the trigeminal ganglia with herpes simplex virus. Immunization with infectious herpes simplex virus, inactivated virus, or material enriched for viral glycoproteins protected hairless mice against primary facial and ganglionic infections. Live and inactivated viruses induced neutralizing antibodies, whereas glycoprotein material did not. Instead, glycoprotein material induced antibodies that were largely directed against two glycopolypeptides with molecular weights of 120,000 to 130,000. Hairless mice immunized with glycoprotein material responded faster than control mice in the synthesis of neutralizing antibodies after challenge with infectious virus. Congenital athymic BALB/c (nu/nu) mice were protected against primary facial infections after immunization with glycoprotein material, but glycoprotein-specific antibodies were not induced. Images PMID:6260662

  13. TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

    PubMed Central

    Washington, A. Valance; Gibot, Sébastien; Acevedo, Ismael; Gattis, James; Quigley, Laura; Feltz, Robert; De La Mota, Alina; Schubert, Rebecca L.; Gomez-Rodriguez, Julio; Cheng, Jun; Dutra, Amalia; Pak, Evgenia; Chertov, Oleg; Rivera, Linette; Morales, Jessica; Lubkowski, Jacek; Hunter, Robert; Schwartzberg, Pamela L.; McVicar, Daniel W.

    2009-01-01

    Triggering receptor expressed on myeloid cells–like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte α-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1–/– mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1–/– mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1–/– mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1–mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation. PMID:19436112

  14. Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance.

    PubMed

    Stubbins, R E; Najjar, K; Holcomb, V B; Hong, J; Núñez, N P

    2012-01-01

    Obesity is associated with insulin resistance, liver steatosis and low-grade inflammation. The role of oestrogen in sex differences in the above co-morbidities is not fully understood. Our aim was to assess the role oestrogen has in modulating adipocyte size, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. To determine the role oestrogen has in the above co-morbidities related to obesity, we randomized C57BL/6J mice into four groups (15 mice per group): (i) male, (ii) non-ovariectomized female (novx), (iii) ovariectomized female (ovx) and (iv) ovariectomized female mice supplemented with 17β estradiol (ovx-E). Mice received either a low-fat (LF) or a high-fat (HF) diet for 10 weeks. Outcomes measured were bodyweight, body fat, adipocyte diameter, adipose tissue lipolysis markers, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. Male and ovx-female mice consuming the HF diet had a higher propensity of gaining weight, specifically in the form of body fat. Oestrogen protected female mice from adipocyte hypertrophy and from developing adipose tissue oxidative stress and inflammation. Moreover, novx-female and ovx-female+E mice had higher phosphorylated levels of protein kinase A and hormone sensitive lipase, markers associated with lipolysis. Additionally, male and ovx female mice had a higher propensity of developing liver steatosis and insulin resistance. In contrast, oestrogen protected female mice from developing liver steatosis and from becoming insulin resistant. We show that oestrogen protects female mice from adipocyte hypertrophy and adipose tissue oxidative stress and inflammation. Furthermore, oestrogen prevented female mice from developing liver steatosis and from becoming insulin resistant. © 2011 Blackwell Publishing Ltd.

  15. 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

  16. 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...

  17. Type I interferon signaling protects mice from lethal henipavirus infection.

    PubMed

    Dhondt, Kévin P; Mathieu, Cyrille; Chalons, Marie; Reynaud, Joséphine M; Vallve, Audrey; Raoul, Hervé; Horvat, Branka

    2013-01-01

    Hendra virus (HeV) and Nipah virus (NiV) are closely related, recently emerged paramyxoviruses that form Henipavirus genus and are capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. However, in contrast to many other species and despite expression of functional virus entry receptors, mice are resistant to henipavirus infection. We report here the susceptibility of mice deleted for the type I interferon receptor (IFNAR-KO) to both HeV and NiV. Intraperitoneally infected mice developed fatal encephalitis, with pathology and immunohistochemical features similar to what was found in humans. Viral RNA was found in the majority of analyzed organs, and sublethally infected animals developed virus-specific neutralizing antibodies. Altogether, these results reveal IFNAR-KO mice as a new small animal model to study HeV and NiV pathogenesis, prophylaxis, and treatment and suggest the critical role of type I interferon signaling in the control of henipavirus infection.

  18. PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice.

    PubMed

    Maffei, Angelo; Cifelli, Giuseppe; Carnevale, Raimondo; Iacobucci, Roberta; Pallante, Fabio; Fardella, Valentina; Fardella, Stefania; Hirsch, Emilio; Lembo, Giuseppe; Carnevale, Daniela

    2017-01-01

    Cardiovascular diseases, including cardiomyopathy, are the major complications in diabetes. A deeper understanding of the molecular mechanisms leading to cardiomyopathy is critical for developing novel therapies. We proposed phosphoinositide3-kinase gamma (PI3Kγ) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kγ in cardiac remodeling to pressure overload. Given the availability of a pharmacological inhibitor of this molecular target GE21, we tested the validity of our hypothesis by inducing diabetes in mice with genetic ablation of PI3Kγ or knock-in for a catalytically inactive PI3Kγ. Mice were made diabetic by streptozotocin. Cardiac function was assessed by serial echocardiographic analyses, while fibrosis and inflammation were evaluated by histological analysis. Diabetes induced cardiac dysfunction in wild-type mice. Systolic dysfunction was completely prevented, and diastolic dysfunction was partially blocked, in both PI3Kγ knock-out and kinase-dead mice. Cardiac dysfunction was similarly rescued by administration of the PI3Kγ inhibitor GE21 in a dose-dependent manner. These actions of genetic and pharmacological PI3Kγ inhibition were associated with a decrease in inflammation and fibrosis in diabetic hearts. Our study demonstrates a fundamental role of PI3Kγ in diabetic cardiomyopathy in mice and the beneficial effect of pharmacological PI3Kγ inhibition, highlighting its potential as a promising strategy for clinical treatment of cardiac complications of diabetic patients. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  19. Role of interleukin-6 in the induction of protective T cells during mycobacterial infections in mice.

    PubMed Central

    Appelberg, R; Castro, A G; Pedrosa, J; Minóprio, P

    1994-01-01

    Interleukin-6 (IL-6) has been shown to regulate numerous functions of the immune system including the differentiation of T-cell subpopulations. Here we examined the involvement of this cytokine in the in vivo generation of a population of T cells able to protect mice against mycobacterial infections. BALB/c mice were infected intravenously with Mycobacterium avium 2447 and anti-IL-6 monoclonal antibodies were administered intraperitoneally throughout the course of the infection. Control mice were able to control the mycobacterial proliferation 1 month after inoculation, whereas mice whose IL-6 had been blocked showed progressive bacterial growth. To distinguish a role for IL-6 associated to the induction or expression of immunity mediated by T cells, we immunized mice with M. bovis bacillus Calmette-Guérin (BCG) Pasteur and challenged them 2 months later with M. avium. One group of mice received anti-IL-6 during the BCG vaccination and another during the M. avium challenge. When M. avium proliferation was assessed at day 30 of the challenge, it was found that the administration of anti-IL-6 during vaccination reduced the protection afforded by BCG compared to administration of the isotype control antibody. No difference in bacterial proliferation was observed at day 30 of challenge when antibodies were administered during M. avium challenge. Our results show that protective T cells arise during M. avium infections in mice after differentiating in the presence of IL-6. PMID:7959868

  20. 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.

  1. Semen Hoveniae extract protects against acute alcohol-induced liver injury in mice.

    PubMed

    Du, Jian; He, Da; Sun, Lian-Na; Han, Ting; Zhang, Hong; Qin, Lu-Ping; Rahman, Khalid

    2010-08-01

    The protective effects of Semen Hoveniae extract (SHE) from Hovenia dulcis Thunb. (Rhamnaceae) on acute alcohol-induced liver injury were investigated in vivo using mice as test models. In the present study, SHE (150, 300, 600 mg/kg/day) was given to mice by intragastric administration for 4 days. Mice were gavaged with 60% ethanol 10 mL/kg after the last dose of extract. Six hours after alcohol administration, liver injury was evaluated by biochemical examination. Lipid peroxidation and the activity of antioxidants were measured by spectrophotometric methods. In mice, administration of SHE significantly decreased the activities of alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum. Administration of SHE also protected against alcohol-induced alcohol dehydrogenase (ADH) elevation in mice. Concurrently, there was an augmentation in the activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione S-transferase (GST), and glutathione (GSH), and it also facilitated alcohol metabolism. Acute toxicity tests showed that a single dose of oral SHE up to 22 g/kg did not result in any death or toxic side effects in mice during 14 days' observation. These results demonstrate that SHE could protect against acute alcohol-induced liver injury without any toxic side effects. Therefore, Semen Hoveniae has potential for the development of a clinically useful agent which could protect the liver from alcohol-induced injury.

  2. Local delivery of Granulocyte/Macrophage Colony Stimulating Factor protects mice from lethal pneumococcal pneumonia1

    PubMed Central

    Steinwede, Kathrin; Tempelhof, Ole; Bolte, Kristine; Maus, Regina; Bohling, Jennifer; Ueberberg, Bianca; Länger, Florian; Christman, John W.; Paton, James C.; Ask, Kjetil; Maharaj, Shyam; Kolb, Martin; Gauldie, Jack; Welte, Tobias; Maus, Ulrich A.

    2013-01-01

    The growth factor granulocyte/macrophage-colony stimulating factor (GM-CSF) has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia. Our data show that intra-alveolar delivery of Ad-GM-CSF led to sustained increased pSTAT5 expression and PU.1 protein expression in alveolar macrophages during a 28 day observation period. Pulmonary Ad-GM-CSF delivery two or four weeks prior to infection of mice with S. pneumoniae significantly reduced mortality rates relative to control vector treated mice. This increased survival was accompanied by increased iNOS expression, antibacterial activity and a significant reduction in caspase 3 dependent apoptosis and secondary necrosis of lung sentinel cells. Importantly, therapeutic treatment of mice with recombinant GM-CSF improved lung protective immunity and accelerated bacterial clearance after pneumococcal challenge. We conclude that prophylactic delivery of GM-CSF triggers long-lasting immunostimulatory effects in the lung in vivo and rescues mice from lethal pneumococcal pneumonia by improving antibacterial immunity. These data support use of novel antibiotic-independent immunostimulatory therapies to protect patients against bacterial pneumonias. PMID:22003204

  3. Pathogenicity of different rabies virus isolates and protection test in vaccinated mice.

    PubMed

    Cunha, Elenice M S; Nassar, Alessandra F C; Lara, Maria do Carmo C S H; Villalobos, Eliana C M; Sato, Go; Kobayashi, Yuki; Shoji, Youko; Itou, Takuya; Sakai, Takeo; Ito, Fumio H

    2010-01-01

    This study was aimed to evaluate and compare the pathogenicity of rabies virus isolated from bats and dogs, and to verify the efficacy of a commercial rabies vaccine against these isolates. For evaluation of pathogenicity, mice were inoculated by the intramuscular route (IM) with 500MICLD₅₀/0.03 mL of the viruses. The cross-protection test was performed by vaccinating groups of mice by the subcutaneous route and challenged through the intracerebral (IC) route. Isolates were fully pathogenic when inoculated by the IC route. When inoculated intramuscularly, the pathogenicity observed showed different death rates: 60.0% for the Desmodus rotundus isolate; 50.0% for dog and Nyctinomops laticaudatus isolates; 40.0% for Artibeus lituratus isolate; 9.5% Molossus molossus isolate; and 5.2% for the Eptesicus furinalis isolate. Mice receiving two doses of the vaccine and challenged by the IC route with the isolates were fully protected. Mice receiving only one dose of vaccine were partially protected against the dog isolate. The isolates from bats were pathogenic by the IC route in mice. However, when inoculated through the intramuscular route, the same isolates were found with different degrees of pathogenicity. The results of this work suggest that a commercial vaccine protects mice from infection with bat rabies virus isolates, in addition to a canine rabies virus isolate.

  4. Protective effects of sunscreening agents on photocarcinogenesis, photoaging, and DNA damage in XPA gene knockout mice.

    PubMed

    Horiki, S; Miyauchi-Hashimoto, H; Tanaka, K; Nikaido, O; Horio, T

    2000-10-01

    We investigated the protective effects of commercial sunscreening agents against UVB-induced photoresponses in group A xeroderma pigmentosum (XPA) model mice. XPA gene-deficient mice are defective in nucleotide excision repair and show a high incidence of skin tumors and severe acute inflammation in response to UVB irradiation, in a similar manner to XP patients. SPF 10 and SPF 60 sunscreens protected partially and almost completely, respectively, ear swelling responses produced by UVB up to 200 mJ/cm2 in (-/-) mice. XPA (-/-) mice were irradiated three times a week to a cumulative dose of 2.6 J/cm2 UVB for a period of 24 weeks with or without SPF 10 or SPF 60 sunscreen. UV-induced skin tumors had developed in all unprotected (-/-) mice (13.3 tumors per mouse) at the completion of UVB irradiation. The SPF 60 sunscreen afforded stronger protection against photocarcinogenesis (1.0 tumors per mouse) than the SPF 10 sunscreen (4.4 tumors per mouse). Regarding photoaging, SPF 60 sunscreen also protected against mast cell infiltration (79% inhibition), elastic fiber accumulation, and dermal cyst proliferation in XPA (-/-) mice compared with unprotected (-/-) mice. In (-/-) mice, the SPF 60 sunscreen provided stronger protection against cyclobutane pyrimidine dimer formation shown immunohistologically following irradiation with 200 mJ/cm2 UVB than the SPF 10 sunscreen. The XPA model mouse is a useful animal for the evaluation of the photoprotective ability of sunscreens because photoresponses, even chronic changes, can be easily and quickly induced experimentally.

  5. A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes

    PubMed Central

    Radu, Dorel L.; Noben-Trauth, Nancy; Hu-Li, Jane; Paul, William E.; Bona, Constantin A.

    2000-01-01

    Autoimmune insulin-dependent diabetes mellitus (IDDM) occurs spontaneously in mice-bearing transgenes encoding the influenza hemagglutinin under the control of the rat insulin promoter and a T cell receptor specific for an hemagglutinin peptide associated with I-Ed. Such “double transgenic” mice expressing wild-type or targeted IL-4Rα genes were examined for the onset of IDDM. Eight of 11 mice homozygous for wild-type IL-4Rα were hyperglycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the targeted allele were hyperglycemic at this time. Most 1L-4Rα−/− mice remained normoglycemic to 36 weeks of age. Although only 10% of double transgenic mice homozygous for the wild-type IL-4Rα allele survived to 30 weeks, 80% of mice homozygous for the targeted allele did so. Heterozygous mice displayed an intermediate frequency of diabetes. Even as late as 270 days of age, mice homozygous for the targeted allele had no insulitis or only peri-insulitis. Thus, the inability to respond to IL-4 and/or IL-13 protects mice against IDDM in this model of autoimmunity. PMID:11050183

  6. Treatment with Isorhamnetin Protects the Brain Against Ischemic Injury in Mice.

    PubMed

    Zhao, Jin-Jing; Song, Jin-Qing; Pan, Shu-Yi; Wang, Kai

    2016-08-01

    Ischemic stroke is a major cause of morbidity and mortality, yet lacks effective neuroprotective treatments. The aim of this work was to investigate whether treatment with isorhamnetin protected the brain against ischemic injury in mice. Experimental stroke mice underwent the filament model of middle cerebral artery occlusion with reperfusion. Treatment with isorhamnetin or vehicle was initiated immediately at the onset of reperfusion. It was found that treatment of experimental stroke mice with isorhamnetin reduced infarct volume and caspase-3 activity (a biomarker of apoptosis), and improved neurological function recovery. Treatment of experimental stroke mice with isorhamnetin attenuated cerebral edema, improved blood-brain barrier function, and upregulated gene expression of tight junction proteins including occludin, ZO-1, and claudin-5. Treatment of experimental stroke mice with isorhamnetin activated Nrf2/HO-1, suppressed iNOS/NO, and led to reduced formation of MDA and 3-NT in ipsilateral cortex. In addition, treatment of experimental stroke mice with isorhamnetin suppressed activity of MPO (a biomarker of neutrophil infiltration) and reduced protein levels of IL-1β, IL-6, and TNF-α in ipsilateral cortex. Furthermore, it was found that treatment of experimental stroke mice with isorhamnetin reduced mRNA and protein expression of NMDA receptor subunit NR1 in ipsilateral cortex. In conclusion, treatment with isorhamnetin protected the brain against ischemic injury in mice. Isorhamnetin could thus be envisaged as a countermeasure for ischemic stroke but remains to be tested in humans.

  7. Arginine butyrate per os protects mdx mice against cardiomyopathy, kyphosis and changes in axonal excitability.

    PubMed

    Vianello, Sara; Bouyon, Sophie; Benoit, Evelyne; Sebrié, Catherine; Boerio, Delphine; Herbin, Marc; Roulot, Morgane; Fromes, Yves; de la Porte, Sabine

    2014-11-01

    Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by lack of dystrophin, a sub-sarcolemmal protein, which leads to dramatic muscle deterioration. We studied in mdx mice, the effects of oral administration of arginine butyrate (AB), a compound currently used for the treatment of sickle cell anemia in children, on cardiomyopathy, vertebral column deformation and electromyographic abnormalities. Monthly follow-up by echocardiography from the 8th month to the 14th month showed that AB treatment protected the mdx mice against drastic reduction (20-23%) of ejection fraction and fractional shortening, and also against the ≈20% ventricular dilatation and 25% cardiac hypertrophy observed in saline-treated mdx mice. The phenotypic improvement was corroborated by the decrease in serum CK level and by better fatigue resistance. Moreover, AB treatment protected against the progressive spinal deformity observed in mdx mice, another similarity with DMD patients. The value of the kyphosis index in AB-treated mice reached 94% of the value in C57BL/10 mice. Finally, axonal excitability parameters such as the membrane resting potential, the threshold and amplitude of the action potential, the absolute and relative refractory periods and the supernormal and subnormal periods, recorded from caudal and plantar muscles in response to excitability tests, that were modified in saline-treated mdx mice were not significantly changed, compared with wild-type animals, in AB-treated mdx mice. All of these results suggest that AB could be a potential treatment for DMD patients.

  8. Human lactoferrin protects against Streptococcus mutans-induced caries in mice.

    PubMed

    Velusamy, S K; Markowitz, K; Fine, D H; Velliyagounder, K

    2016-03-01

    The objective of this study is to evaluate the importance of human lactoferrin (hLF) in an experimental caries induced by Streptococcus mutans in a lactoferrin-knockout (LFKO(-/-)) mouse model compared with C576J/BL wild-type (WT) mice. The WT and LFKO(-/-) mice were infected with S. mutans (1 × 10(8) cells) and/or sham infection. Furthermore, the effect of hLF administration was evaluated in LFKO(-/-) mice infected with S. mutans. Mice were assessed for colonization, salivary pH, and caries development. The results showed that the lactoferrin-knockout infected (LFKO(-/-) I) mice had significantly higher colonization with S. mutans (P = 0.02), lower salivary pH (P = 0.01), and more carious lesions (P = 0.01) when compared to wild-type infected (WTI) mice. In addition, the administration of hLF did not show any evidence of S. mutans colonization as well as carious lesions (P = 0.001) in LFKO(-/-) I mice when compared to untreated LFKO(-/-) I mice. These results show that endogenous LF protects against S. mutans-induced caries and that exogenous hLF can exert a protective effect against caries development. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. A High Incidence of Meiotic Silencing of Unsynapsed Chromatin Is Not Associated with Substantial Pachytene Loss in Heterozygous Male Mice Carrying Multiple Simple Robertsonian Translocations

    PubMed Central

    Vasco, Chiara; Berríos, Soledad; Parra, María Teresa; Viera, Alberto; Rufas, Julio S.; Zuccotti, Maurizio; Garagna, Silvia; Fernández-Donoso, Raúl

    2009-01-01

    Meiosis is a complex type of cell division that involves homologous chromosome pairing, synapsis, recombination, and segregation. When any of these processes is altered, cellular checkpoints arrest meiosis progression and induce cell elimination. Meiotic impairment is particularly frequent in organisms bearing chromosomal translocations. When chromosomal translocations appear in heterozygosis, the chromosomes involved may not correctly complete synapsis, recombination, and/or segregation, thus promoting the activation of checkpoints that lead to the death of the meiocytes. In mammals and other organisms, the unsynapsed chromosomal regions are subject to a process called meiotic silencing of unsynapsed chromatin (MSUC). Different degrees of asynapsis could contribute to disturb the normal loading of MSUC proteins, interfering with autosome and sex chromosome gene expression and triggering a massive pachytene cell death. We report that in mice that are heterozygous for eight multiple simple Robertsonian translocations, most pachytene spermatocytes bear trivalents with unsynapsed regions that incorporate, in a stage-dependent manner, proteins involved in MSUC (e.g., γH2AX, ATR, ubiquitinated-H2A, SUMO-1, and XMR). These spermatocytes have a correct MSUC response and are not eliminated during pachytene and most of them proceed into diplotene. However, we found a high incidence of apoptotic spermatocytes at the metaphase stage. These results suggest that in Robertsonian heterozygous mice synapsis defects on most pachytene cells do not trigger a prophase-I checkpoint. Instead, meiotic impairment seems to mainly rely on the action of a checkpoint acting at the metaphase stage. We propose that a low stringency of the pachytene checkpoint could help to increase the chances that spermatocytes with synaptic defects will complete meiotic divisions and differentiate into viable gametes. This scenario, despite a reduction of fertility, allows the spreading of Robertsonian

  10. Maternal immunity partially protects newborn mice against a Chlamydia trachomatis intranasal challenge

    PubMed Central

    Pal, Sukumar; Tatarenkova, Olga; de la Maza, Luis M.

    2010-01-01

    To determine the role of maternal immunity in protecting newborn mice against a C. trachomatis infection female BALB/c mice were immunized intranasally (i.n.) with 104 inclusion forming units (IFU) of the C. trachomatis mouse pneumonitis biovar (MoPn). As a control, another group of female mice was sham-immunized i.n. with HeLa cell extracts. Immunized animals mounted strong immune responses as evidenced by high Chlamydia-specific antibody titers in serum and milk. Newborn mice born from immunized and sham-immunized dams were challenged i.n. with 103 IFU of MoPn at 2-post natal days (PND). Following inoculation, newborn mice were euthanized at 7-PND and 18-PND and the lungs, spleen and intestine were cultured for Chlamydia. Overall, no significant differences were observed between the mice born from and fed by immunized dams and mice born from and fed by sham-immunized dams. Of the mice born from immunized dams, 75% and 25% had positive lung cultures at 7-PND and 18-PND, respectively. Of the mice born from sham-immunized dams, 82% and 50% had positive lung cultures for those same days. When the number of IFU recovered from the lungs and spleens were compared between the two groups no significant differences were observed. However, when the number of IFU recovered from the small intestine were compared, significant differences were observed between the two groups of newborn mice (2×105 versus 32×106 at 7-PND and 9.2×106 versus 85×106 at 18-PND). In conclusion, maternal immunity plays a limited role in protecting newborn mice against a Chlamydia infection. PMID:20554327

  11. Over-Expression of CD200 Protects Mice from Dextran Sodium Sulfate Induced Colitis

    PubMed Central

    Chen, Zhiqi; Yu, Kai; Zhu, Fang; Gorczynski, Reginald

    2016-01-01

    Background and aim CD200:CD200 receptor (CD200R) interactions lead to potent immunosuppression and inhibition of autoimmune inflammation. We investigated the effect of "knockout"of CD200 or CD200R, or over-expression of CD200, on susceptibility to dextran sodium sulfate (DSS)—induced colitis, a mouse model of inflammatory bowel disease (IBD). Methods Acute or chronic colitis was induced by administration of dextran sodium sulfate (DSS) in four groups of age-matched C57BL/6 female mice: (1) CD200-transgenic mice (CD200tg); (2) wild-type (WT) mice; (3) CD200 receptor 1-deficient (CD200R1KO) mice; and (4) CD200-deficient (CD200KO) mice. The extent of colitis was determined using a histological scoring system. Colon tissues were collected for quantitative RT-PCR and Immunohistochemical staining. Supernatants from colonic explant cultures and mononuclear cells isolated from colonic tissue were used for ELISA. Results CD200KO and CD200R1KO mice showed greater sensitivity to acute colitis than WT mice, with accelerated loss of body weight, significantly higher histological scores, more severe infiltration of macrophages, neutrophils and CD3+ cells, and greater expression of macrophage-derived inflammatory cytokines, whose production was inhibited in vitro (in WT/CD200KO mouse cells) by CD200. In contrast, CD200tg mice showed less sensitivity to DSS compared with WT mice, with attenuation of all of the features seen in other groups. In a chronic colitis model, greater infiltration of Foxp3+ regulatory T (Treg) cells was seen in the colon of CD200tg mice compared to WT mice, and anti-CD25 mAb given to these mice attenuated protection. Conclusions The CD200:CD200R axis plays an immunoregulatory role in control of DSS induced colitis in mice. PMID:26841120

  12. Protective action of calcium phytate against acute lead toxicity in mice

    SciTech Connect

    Wise, A.

    1981-12-01

    Forty female MF1 mice were fed diets with and without calcium phytate. Addition of lead acetate resulted in toxic effects. After necropsy liver and kidneys were removed and analyzed for lead by flameless atomic absorption spectroscopy. Calcium phytate did not affect the nutritional status of the mice. It was concluded from the study that calcium phytate might be employed as a natural protective factor against lead toxicity. (JMT)

  13. The Inductive Coupling of the Magnets in MICE and its Effect onQuench Protection

    SciTech Connect

    Green, Michael A.; Witte, Holger

    2005-09-08

    The inductive coupling between various MICE magnet circuits is described. The consequences of this coupling on magnet charging and quenching are discussed. Magnet quench protection is achieved through the use of quench-back. Calculations of the quenching of a magnet due to quench-back resulting from circulating currents induced in the magnet mandrel due to quenching of an adjacent magnet are discussed. This report describes how the MICE magnet channel will react when magnets in that channel are quenched.

  14. 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.

  15. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension

    PubMed Central

    Geraci, Mark W.; Gao, Bifeng; Shepherd, David C.; Moore, Mark D.; Westcott, Jay Y.; Fagan, Karen A.; Alger, Lori A.; Tuder, Rubin M.; Voelkel, Norbert F.

    1999-01-01

    Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI2) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels, but the importance of this deficiency for lung vascular remodeling remains unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypothesis, transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA. Transgenic mice (Tg+) and nontransgenic littermates (Tg–) were subjected to a simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg+ mice produced 2-fold more pulmonary 6-keto prostaglandin F1α (PGF1α) levels than did Tg– mice. After exposure to chronic hypobaric hypoxia, Tg+ mice have lower RVSP than do Tg– mice. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg+ mice in comparison with vessel wall hypertrophy in the Tg– mice. These studies demonstrate that Tg+ mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important implications for the pathogenesis and treatment of severe pulmonary hypertension. PMID:10359560

  16. Quench Protection for the MICE Cooling Channel CouplingMagnet

    SciTech Connect

    Green, M.A.; Wang, L.; Guo, X.L.

    2007-11-20

    The MICE coupling coil is fabricated from Nb-Ti, which hashigh quench propagation velocities within the coil in all directionscompared to coils fabricated with other superconductors such as niobiumtin. The time for the MICE coupling coil to become fully normal throughnormal region propagation in the coil is shorter than the time needed fora safe quench (as defined by a hot-spot temperature that is less than 300K). A MICE coupling coil quench was simulated using a code written at theInstitute of Cryogenics and Superconductive Technology (ICST) at theHarbin Institute of Technology (HIT). This code simulates quench backfrom the mandrel as well as normal region propagation within the coil.The simulations included sub-division of the coil. Each sub-division hasa back to back diodes and resistor across the coil. Current flows in theresistor when there is enough voltage across the coil to cause current toflow through the diodes in the forward direction. The effects of thenumber of coil sub-divisions and the value of the resistor across thesub-division on the quench were calculated with and without quench back.Sub-division of the coupling coil reduces the peak voltage to ground, thelayer-to-layer voltage and the magnet hot-spot temperature. Quench backreduces the magnet hot-spot temperature, but the peak voltage to groundand layer-to-layer voltage are increased, because the magnet quenchesfaster. The resistance across the coil sub-division affects both thehot-spot temperature and the peak voltage to ground.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24875538

  18. Therapeutic Inducers of the HSP70/HSP110 Protect Mice Against Traumatic Brain Injury

    PubMed Central

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

    2014-01-01

    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 ROS-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 of 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. PMID:24903326

  19. Protective effects of phyllanthus emblica leaf extract on sodium arsenite-mediated adverse effects in mice.

    PubMed

    Sayed, Sadia; Ahsan, Nazmul; Kato, Masashi; Ohgami, Nobutaka; Rashid, Abdur; Akhand, Anwarul Azim

    2015-02-01

    Groundwater contamination of arsenic is the major cause of a serious health hazard in Bangladesh. No specific treatment is yet available to manage the large number of individuals exposed to arsenic. In this study, we evaluated the protective effects of Phyllanthus emblica (Indian gooseberry or Amla) leaf extract (PLE) on arsenic-mediated toxicity in experimental mice. Male Swiss albino mice were divided into three different groups (n=6/group). 'Control' mice received arsenic free water together with normal feed. Mice in the remaining two groups designated 'SA' and 'SA+PLE' were exposed to sodium arsenite (SA, 10 µg/g body weight/day) through drinking water in addition to receiving normal feed and PLE-supplemented feed, respectively. The weight gain of SA-exposed mice was decreased compared with the controls; however, this decrease in body weight gain was prevented when the feed was supplemented with PLE. A secondary effect of arsenic was enlargement of the liver, kidney and spleen of SA-group mice. Deposition of arsenic in those organs was demonstrated by ICP-MS. When PLE was supplemented in the feed the enlargement of the organs was minimized; however, the deposition of arsenic was not significantly reduced. These results indicated that PLE may not block arsenic deposition in tissue directly but rather may play a protective role to reduce arsenic-induced toxicity. Therefore, co-administration of PLE in arsenic-exposed animals might have a future therapeutic application for protecting against arsenic-mediated toxicity.

  20. Spores from two distinct colony types of the strain Bacillus subtilis PB6 substantiate anti-inflammatory probiotic effects in mice.

    PubMed

    Foligné, Benoît; Peys, Eric; Vandenkerckhove, Jan; Van Hemel, Johan; Dewulf, Joëlle; Breton, Jérôme; Pot, Bruno

    2012-12-01

    Reducing symptoms of inflammatory bowel diseases (IBD) by dietary supplements represents more than ever an attractive clinical approach. Since the use of spore forming bacteria may offer interesting advantages, the aim of the study was to address the anti-inflammatory potential of Bacillus >subtilis strain PB6 (ATCC - PTA 6737) spores, provided as a powder preparation. The immunomodulatory potential of strain PB6 was first characterized in vitro on human immunocompetent cells for both the commercial spore powder (Anaban™) and two phenotypic variants of the vegetative form. Assessment of the in vivo anti-inflammatory capacity of the standard spore powder and a variant spore powder preparation was performed using a mouse model of acute, TNBS-induced colitis. Performance was compared with the drug prednisolone, and was based on blinded macroscopic and histological scores, blood inflammatory markers and measurements of infiltration of mucosal neutrophils. Strain PB6 induced substantial levels of IL-10 but very low levels of IL-12, TNFα and IFNγ on human PBMC. Both spore powders prevented colitis as shown by significant reductions of near all inflammatory read-outs. B. subtilis strain PB6, provided as a preparation of spores, shows pre-clinical anti-inflammatory effects, suggesting further evaluation in a clinical intervention trial, e.g. with IBD type patients. Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  1. Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia1

    PubMed Central

    Lembo, Annalisa; Pelletier, Mark; Iyer, Ravi; Timko, Michele; Dudda, Jan C.; West, T. Eoin; Wilson, Christopher B.; Hajjar, Adeline M.; Skerrett, Shawn J.

    2011-01-01

    Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30–60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-γ. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia. PMID:18490759

  2. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity.

    PubMed

    Hartmann, Phillipp; Seebauer, Caroline T; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M; Brandl, Katharina; Ho, Samuel B; Schnabl, Bernd

    2016-03-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome.

  3. Protective Effects of Royal Jelly on Oxymetholone-Induced Liver Injury in Mice.

    PubMed

    Nejati, Vahid; Zahmatkesh, Ensieh; Babaei, Mohammad

    2016-09-01

    The present study was carried out to investigate the possible protective effects of royal jelly (RJ) on oxymetholone (OXM)-induced oxidative liver injuries in mice. In total, 32 adult male NMRI mice were divided into four groups of eight mice each. Mice in groups 1 and 2 were orally administered 5 mg/kg/day OXM for 30 days. At the same time, mice in group 3 received RJ at a dose of 100 mg/kg/day. Saline control and RJ control groups were also included in this study. Administration of 5 mg/kg OXM resulted in a significant decrease in total antioxidant capacity and catalase activity, as well as a significant increase in malondialdehyde (P<0.05). In addition, OXM-administrated mice showed a slight increase in liver enzymes, including alanine amino transferase, aspartate amino transferase, and alkaline phosphatase. Although OXM caused histopathological changes in the liver, RJ could significantly improve all of the above-mentioned parameters at a dose of 100 mg/kg. The results of the present study indicated that RJ has a partially protective effect on OXM-induced liver toxicity in mice.

  4. Induction and expression of protective T cells during Mycobacterium avium infections in mice.

    PubMed Central

    Appelberg, R; Pedrosa, J

    1992-01-01

    Mycobacterium avium is an opportunistic pathogen that infects individuals suffering from chronic lung disease or immunocompromised patients such as AIDS patients. Here we show that a highly virulent isolate of M. avium proliferated as extensively in T cell deficient as in immunocompetent mice. T cell deficient mice allowed a progressive growth of a less virulent AIDS-derived isolate of M. avium while immunocompetent mice arrested the growth of this isolate. Adoptive transfer of T cell enriched spleen cells between congenic strains of mice differing at the Bcg/Ity/Lsh locus showed that only naturally resistant BALB/c.Bcgr (C.D2) mice infected with the highly virulent strain of M. avium or the naturally susceptible BALB/c mice infected with the lower virulence isolate developed protective T cells and that these cells only mediated protection when transferred to naturally susceptible, but not to naturally resistant, mice. Both strains of M. avium proliferated in bone marrow-derived macrophages cultured in vitro and they were both susceptible to the bacteriostatic effects induced in the macrophages by crude lymphokines produced by concanavalin A-stimulated spleen cells. PMID:1544223

  5. Protective Effects of Royal Jelly on Oxymetholone- Induced Liver Injury in Mice

    PubMed Central

    Nejati, Vahid; Zahmatkesh, Ensieh; Babaei, Mohammad

    2016-01-01

    Background: The present study was carried out to investigate the possible protective effects of royal jelly (RJ) on oxymetholone (OXM)-induced oxidative liver injuries in mice. Methods: In total, 32 adult male NMRI mice were divided into four groups of eight mice each. Mice in groups 1 and 2 were orally administered 5 mg/kg/day OXM for 30 days. At the same time, mice in group 3 received RJ at a dose of 100 mg/kg/day. Saline control and RJ control groups were also included in this study. Results: Administration of 5 mg/kg OXM resulted in a significant decrease in total antioxidant capacity and catalase activity, as well as a significant increase in malondialdehyde (P<0.05). In addition, OXM-administrated mice showed a slight increase in liver enzymes, including alanine amino transferase, aspartate amino transferase, and alkaline phosphatase. Although OXM caused histopathological changes in the liver, RJ could significantly improve all of the above-mentioned parameters at a dose of 100 mg/kg. Conclusion: The results of the present study indicated that RJ has a partially protective effect on OXM-induced liver toxicity in mice. PMID:27178489

  6. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity

    PubMed Central

    Hartmann, Phillipp; Seebauer, Caroline T.; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M.; Brandl, Katharina; Ho, Samuel B.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome. PMID:26702135

  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. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

    PubMed

    Fagman, Johan B; Wilhelmson, Anna S; Motta, Benedetta M; Pirazzi, Carlo; Alexanderson, Camilla; De Gendt, Karel; Verhoeven, Guido; Holmäng, Agneta; Anesten, Fredrik; Jansson, John-Olov; Levin, Malin; Borén, Jan; Ohlsson, Claes; Krettek, Alexandra; Romeo, Stefano; Tivesten, Åsa

    2015-04-01

    Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism. © FASEB.

  9. The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice

    PubMed Central

    Yi, Yun-Min; Cai, Li; Shao, Yi; Xu, Man; Yi, Jing-Lin

    2015-01-01

    AIM To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE+/− mice (AChE knockout mice) of various ages. METHODS Cultured ARPE-19 cells were treated with hydrogen peroxide (H2O2) at concentrations of 0, 250, 500, 1000 and 2000 µmol/L and protein levels were measured using Western blot. Intraperitoneal injections of tacrine and donepezil (0.1 mg/mL, 0.2 mg/mL and 0.4 mg/mL) were respectively given to AChE+/− mice aged 2mo and 4mo and wild-type S129 mice for 7d; phosphate buffered saline (PBS) was administered to the control group. The mice were sacrificed after 30d by in vitro cardiac perfusion and retinal samples were taken. AChE-deficient mice were identified by polymerase chain reaction (PCR) analysis using specific genotyping protocols obtained from the Jackson Laboratory website. H&E staining, immunofluorescence and Western blot were performed to observe AChE protein expression changes in the retinal pigment epithelial (RPE) cell layer. RESULTS Different concentrations of H2O2 induced AChE expression during RPE cell apoptosis. AChE+/− mice retina were thinner than those in wild-type mice (P<0.05); the retinal structure was still intact at 2mo but became thinner with increasing age (P<0.05); furthermore, AChE+/− mice developed more slowly than wild-type mice (P<0.05). Increased concentrations of tacrine and donepezil did not significantly improve the protection of the retina function and morphology (P>0.05). CONCLUSION In vivo, tacrine and donepezil can inhibit the expression of AChE; the decrease of AChE expression in the retina is beneficial for the development of the retina. PMID:26558196

  10. Pancreatic STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction.

    PubMed

    Shigekawa, Minoru; Hikita, Hayato; Kodama, Takahiro; Shimizu, Satoshi; Li, Wei; Uemura, Akio; Miyagi, Takuya; Hosui, Atsushi; Kanto, Tatsuya; Hiramatsu, Naoki; Tatsumi, Tomohide; Takeda, Kiyoshi; Akira, Shizuo; Takehara, Tetsuo

    2012-12-01

    The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that controls expressions of several genes involved in cell survival, proliferation and differentiation, and tissue inflammation. However, the significance of pancreatic STAT3 in acute pancreatitis remains unclear. We generated conditional STAT3 knockout (stat3(Δ/Δ)) mice by crossing stat3(flox/flox) mice with Pdx1-promoter Cre transgenic mice. Caerulein administration activated pancreatic STAT3 and induced acute pancreatitis as early as 3 hours in wild-type mice, and full recovery from the induced pancreatic injury was observed within 7 days. The levels of serum amylase and lipase and histologic scores of pancreatic necrosis and inflammatory cell infiltration were significantly higher at 3 hours in stat3(Δ/Δ) mice than in stat3(flox/flox) mice. Pancreatic recovery after pancreatitis was significantly delayed in stat3(Δ/Δ) mice compared with stat3(flox/flox) mice. Although stat3(flox/flox) mice had marked production in the pancreas of pancreatitis-associated protein 1 (PAP1), a serum acute phase protein, this induction was completely abrogated in stat3(Δ/Δ) mice. Enforced production of PAP1 by a hydrodynamic procedure in the liver significantly suppressed pancreatic necrosis and inflammation and also promoted pancreatic regeneration and recovery in stat3(Δ/Δ) mice to levels similar to those observed in stat3(flox/flox) mice. In conclusion, pancreatic STAT3 is indispensable for PAP1 production, and this STAT3/PAP1 pathway plays a protective role in caerulein-induced pancreatitis.

  11. Protective Effects of Fluoxetine on Decompression Sickness in Mice

    PubMed Central

    Blatteau, Jean-Eric; Barre, Sandrine; Pascual, Aurelie; Castagna, Olivier; Abraini, Jacques H.; Risso, Jean-Jacques; Vallee, Nicolas

    2012-01-01

    Massive bubble formation after diving can lead to decompression sickness (DCS) that can result in central nervous system disorders or even death. Bubbles alter the vascular endothelium and activate blood cells and inflammatory pathways, leading to a systemic pathophysiological process that promotes ischemic damage. Fluoxetine, a well-known antidepressant, is recognized as having anti-inflammatory properties at the systemic level, as well as in the setting of cerebral ischemia. We report a beneficial clinical effect associated with fluoxetine in experimental DCS. 91 mice were subjected to a simulated dive at 90 msw for 45 min before rapid decompression. The experimental group received 50 mg/kg of fluoxetine 18 hours before hyperbaric exposure (n = 46) while controls were not treated (n = 45). Clinical assessment took place over a period of 30 min after surfacing. At the end, blood samples were collected for blood cells counts and cytokine IL-6 detection. There were significantly fewer manifestations of DCS in the fluoxetine group than in the controls (43.5% versus 75.5%, respectively; p = 0.004). Survivors showed a better and significant neurological recovery with fluoxetine. Platelets and red cells were significantly decreased after decompression in controls but not in the treated mice. Fluoxetine reduced circulating IL-6, a relevant marker of systemic inflammation in DCS. We concluded that fluoxetine decreased the incidence of DCS and improved motor recovery, by limiting inflammation processes. PMID:23145072

  12. Utilization of cholera toxin B as a mucosal adjuvant elicits antibody-mediated protection against S. pneumoniae infection in mice

    PubMed Central

    Wiedinger, Kari; Pinho, Daniel; Bitsaktsis, Constantine

    2017-01-01

    Backgound: The introduction of the pneumococcal conjugate and polysaccharide vaccines have been valuable tools for combating invasive pneumococcal infection in children and healthy adults. Despite the available vaccination strategies, pneumococcal pneumonia and associated diseases continue to cause substantial morbidity and mortality, particularly in individuals with chronic disease and ageing populations. Next-generation pneumococcal vaccines will need to be highly immunogenic across patient populations providing both mucosal and systemic protective immunity. Mucosal immunization is an effective strategy for stimulating the immune response at the site of pathogen entry while increasing systemic immunity. In this study we utilized intranasal immunization with pneumococcal surface protein A (PspA), in combination with the mucosal adjuvant cholera toxin B (CTB), to characterize the immune components providing protection against S. pneumoniae challenge. Methods: Mice were immunized intranasally with CTB and PspA individually, and in combination, followed by lethal bacterial challenge with S. pneumoniae, strain A66.1. Animals were monitored for survival and tested for lung bacterial burden, cytokine production as well as S. pneumoniae-specific antibody titer in mouse sera. The primary immunological contributor to the observed protection was confirmed by cytokine neutralization and serum passive transfer. Results: The combination of CTB and PspA provided complete protection against bacterial challenge, which coincided with a significant decrease in lung bacterial burden. Increases in the T-helper (Th) 1 cytokines, interferon (IFN)-γ and interleukin (IL)-2 were observed in the lung 24 h post-challenge while decreases in proinflammatory mediators IL-6 and tumor necrosis factor (TNF)-α were also recorded at the same time point. The adjuvanted PspA immunization induced significant titers of S. pneumoniae-specific antibody in the serum of mice prior to infection. Serum

  13. Hepatic scavenger receptor BI protects against polymicrobial-induced sepsis through promoting LPS clearance in mice.

    PubMed

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

    2014-05-23

    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 Scarb1(I179N) 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 Scarb1(I179N) mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1(I179N) 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.

  14. Lactoferrin Protects Against Acetaminophen-Induced Liver Injury in Mice

    PubMed Central

    Yin, Hao; Cheng, Linling; Holt, Michael; Hail, Numsen; MacLaren, Robert; Ju, Cynthia

    2010-01-01

    Acetaminophen-induced liver injury (AILI) is a significant health problem and represents the most frequent cause of drug-induced liver failure in the United States. The development and implementation of successful therapeutic intervention strategies have been demanding, due to significant limitations associated with the current treatment for AILI. Lactoferrin (Lac), a glycoprotein present in milk, has been demonstrated to possess a multitude of biological functions. Our study demonstrated a profound protective effect of Lac in a murine model of AILI, which was not dependent on its iron binding ability, inhibition of acetaminophen (APAP) metabolism, or a direct cytoprotective effect on hepatocytes. Instead, Lac treatment significantly attenuated APAP-induced liver sinusoidal endothelial cell dysfunction and ameliorated hepatic microcirculation disorder. This protective effect of Lac appeared to be dependent on hepatic resident macrophages (Kupffer cells, KC). Collectively, our data indicated that Lac, through activation of KC, inhibited APAP-induced liver sinusoidal endothelial cell damage and improved hepatic congestion, thereby protecting against AILI. These findings reveal the significant therapeutic potential of Lac during AILI and other types of liver diseases. PMID:20099297

  15. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  16. Preoperative Fasting Protects against Renal Ischemia-Reperfusion Injury in Aged and Overweight Mice

    PubMed Central

    Jongbloed, Franny; de Bruin, Ron W. F.; Pennings, Jeroen L. A.; Payán-Gómez, César; van den Engel, Sandra; van Oostrom, Conny T.; de Bruin, Alain; Hoeijmakers, Jan H. J.; van Steeg, Harry; IJzermans, Jan N. M.; Dollé, Martijn E. T.

    2014-01-01

    Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice. Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice. Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. A mRNA analysis indicated the involvement of metabolic processes including fatty acid oxidation and retinol metabolism, and the NRF2-mediated stress response. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well. PMID:24959849

  17. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice

    PubMed Central

    Fagman, Johan B.; Wilhelmson, Anna S.; Motta, Benedetta M.; Pirazzi, Carlo; Alexanderson, Camilla; De Gendt, Karel; Verhoeven, Guido; Holmäng, Agneta; Anesten, Fredrik; Jansson, John-Olov; Levin, Malin; Borén, Jan; Ohlsson, Claes; Krettek, Alexandra; Romeo, Stefano; Tivesten, Åsa

    2015-01-01

    Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)–dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)–deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (−41%; thoracic aorta), subcutaneous fat mass (−44%), and cholesterol levels (−35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.—Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J.-O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice. PMID:25550469

  18. 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

  19. Protective effect of berberine on serum glucose levels in non-obese diabetic mice.

    PubMed

    Chueh, Wei-Han; Lin, Jin-Yuarn

    2012-03-01

    Among the active components in traditional anti-diabetic herbal plants, berberine which is an isoquinoline alkaloid exhibits promising potential for its potent anti-inflammatory and hypoglycemic effects. However, the berberine effect on serum glucose levels in type 1 diabetes (T1D) subjects still remains unknown. This study investigated berberine's effects on serum glucose levels using non-obese diabetic (NOD) mice that spontaneously develop T1D. The NOD mice were randomly divided into four groups, administered water with 50, 150, and 500 mg berberine/kg bw, respectively, through 14 weeks. ICR mice were also selected as a species control group to compare with the NOD mice. Changes in body weight, oral glucose challenge, and serum glucose levels were determined to identify the protective effect of berberine on T1D. After the 14-week oral supplementation, berberine decreased fasting serum glucose levels in NOD mice close to the levels in normal ICR mice in a dose dependent manner. Serum berberine levels showed a significantly (P<0.05) negative and non-linear correlation with fasting glucose levels in berberine-administered NOD mice. Our results suggested that berberine supplemented at appropriate doses for 14 weeks did not cause toxic side effects, but improved hyperglycemia in NOD mice.

  20. Swim training does not protect mice from skeletal muscle oxidative damage following a maximum exercise test.

    PubMed

    Barreto, Tatiane Oliveira; Cleto, Lorena Sabino; Gioda, Carolina Rosa; Silva, Renata Sabino; Campi-Azevedo, Ana Carolina; de Sousa-Franco, Junia; de Magalhães, José Carlos; Penaforte, Claudia Lopes; Pinto, Kelerson Mauro de Castro; Cruz, Jader dos Santos; Rocha-Vieira, Etel

    2012-07-01

    We investigated whether swim training protects skeletal muscle from oxidative damage in response to a maximum progressive exercise. First, we investigated the effect of swim training on the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the gastrocnemius muscle of C57Bl/6 mice, 48 h after the last training session. Mice swam for 90 min, twice a day, for 5 weeks at 31°C (± 1°C). The activities of SOD and CAT were increased in trained mice (P < 0.05) compared to untrained group. However, no effect of training was observed in the activity of GPx. In a second experiment, trained and untrained mice were submitted to a maximum progressive swim test. Compared to control mice (untrained, not acutely exercised), malondialdehyde (MDA) levels were increased in the skeletal muscle of both trained and untrained mice after maximum swim. The activity of GPx was increased in the skeletal muscle of both trained and untrained mice, while SOD activity was increased only in trained mice after maximum swimming. CAT activity was increased only in the untrained compared to the control group. Although the trained mice showed increased activity of citrate synthase in skeletal muscle, swim performance was not different compared to untrained mice. Our results show an imbalance in the activities of SOD, CAT and GPx in response to swim training, which could account for the oxidative damage observed in the skeletal muscle of trained mice in response to maximum swim, resulting in the absence of improved exercise performance.

  1. Ostα−/− mice are not protected from western diet‐induced weight gain

    PubMed Central

    Hammond, Christine L.; Wheeler, Sadie G.; Ballatori, Nazzareno; Hinkle, Patricia M.

    2015-01-01

    Abstract Organic solute transporterα‐OSTβ is a bile acid transporter important for bile acid recycling in the enterohepatic circulation. In comparison to wild‐type mice, Ostα−/− mice have a lower bile acid pool and increased fecal lipids and they are relatively resistant to age‐related weight gain and insulin resistance. These studies tested whether Ostα−/− mice are also protected from weight gain, lipid changes, and insulin resistance which are normally observed with a western‐style diet high in both fat and cholesterol (WD). Wild‐type and Ostα−/− mice were fed a WD, a control defined low‐fat diet (LF) or standard laboratory chow (CH). Surprisingly, although the Ostα−/− mice remained lighter on LF and CH diets, they weighed the same as wild‐type mice after 12 weeks on the WD even though bile acid pool levels remained low and fecal lipid excretion remained elevated. Mice of both genotypes excreted relatively less lipid when switched from CH to LF or WD. WD caused slightly greater changes in expression of genes involved in lipid transport in the small intestines of Ostα−/− mice than wild‐type, but the largest differences were between CH and defined diets. After WD feeding, Ostα−/− mice had lower serum cholesterol and hepatic lipids, but Ostα−/− and wild‐type mice had equivalent levels of muscle lipids and similar responses in glucose and insulin tolerance tests. Taken together, the results show that Ostα−/− mice are able to adapt to a western‐style diet despite low bile acid levels. PMID:25626867

  2. Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice.

    PubMed

    Li, Jilin; Zhai, Yufeng; Ao, Lihua; Hui, Haipeng; Fullerton, David A; Dinarello, Charles A; Meng, Xianzhong

    2017-07-01

    Myocardial inflammatory responses to endotoxemia are enhanced in old mice, which results in worse cardiac dysfunction. Anti-inflammatory cytokine interleukin (IL)-37 has a broad effect on innate immunoresponses. We hypothesized that IL-37 suppresses myocardial inflammatory responses to protect cardiac function during endotoxemia in old mice. Old (20-24month) wild-type (WT), and IL-37 transgenic (IL-37tg) mice were treated with lipopolysaccharide (LPS, 0.5mg/kg, iv) or normal saline (0.1ml/mouse, iv). Six hours later, left ventricle (LV) function was assessed using a pressure-volume microcatheter. Levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in plasma and myocardial tissue, as well as mononuclear cell density in the myocardium, were examined. Cardiac microvascular endothelial cells isolated from WT and IL-37tg mice were treated with LPS (0.2µg/ml) for 0.5-24h. Nuclear factor-kappa B (NF-κB) p65 phosphorylation was examined by immunoblotting, and MCP-1 levels in cell culture supernatant was determined using enzyme-linked immunosorbent assay. LV dysfunction in old WT endotoxemic mice was accompanied by up-regulated MCP-1, myocardial accumulation of mononuclear cells and production of TNF-α, IL-1β and IL-6. Expression of IL-37 suppressed myocardial inflammatory responses to endotoxemia in old mice, resulting in improved LV function. Treatment of old WT endotoxemic mice with recombinant IL-37 also improved LV function. In vitro experiments revealed that cardiac microvascular endothelial cells from IL-37tg mice had attenuated NF-κB activation and MCP-1 production following LPS stimulation. In conclusion, IL-37 is potent to suppress myocardial inflammation and protects against cardiac dysfunction during endotoxemia in old mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress.

    PubMed

    Williams, C David; McGill, Mitchell R; Farhood, Anwar; Jaeschke, Hartmut

    2013-08-01

    Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Fas Receptor-deficient lpr Mice are protected against Acetaminophen Hepatotoxicity due to Higher Glutathione Synthesis and Enhanced Detoxification of Oxidant Stress

    PubMed Central

    Williams, C. David; McGill, Mitchell R.; Farhood, Anwar; Jaeschke, Hartmut

    2013-01-01

    Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. Conclusion: Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice. PMID:23628456

  5. Immunization of mice with a novel recombinant molecular chaperon confers protection against Brucella melitensis infection.

    PubMed

    Ghasemi, Amir; Jeddi-Tehrani, Mahmood; Mautner, Josef; Salari, Mohammad Hossein; Zarnani, Amir-Hassan

    2014-11-20

    Brucella spp. are zoonotic Gram-negative intracellular pathogens with the ability to survive and replicate in phagocytes. It has been shown that bacterial proteins expressed abundantly in this niche are stress-related proteins capable of triggering effective immune responses. BMEI1549 is a molecular chaperone designated DnaK that is expressed under stress conditions and helps to prevent formation of protein aggregates. In order to study the potential of DnaK as a prospective Brucella subunit vaccine, immunogenicity and protective efficacy of recombinant DnaK from Brucella melitensis was evaluated in BALB/c mice. The dnak gene was cloned, expressed in Escherichia coli, and the resulting recombinant protein used as subunit vaccine. DnaK-immunized mice showed a strong lymphocyte proliferative response to in vitro antigen stimulation. Although comparable levels of antigen-specific IgG2a and IgG1 were observed in immunized mice, high amounts of IFN-γ, IL-12 and IL-6, no detectable level of IL-4 and very low levels of IL-10 and IL-5 were produced by splenocytes of vaccinated mice suggesting induction of a Th1 dominant immune response by DnaK. Compared to control animals, mice vaccinated with DnaK exhibited a significant degree of protection against subsequent Brucella infection (p<0.001), albeit this protection was less than the protection conferred by Rev.1 (p<0.05). A further increase in protection was observed, when DnaK was combined with recombinant Omp31. Notably, this combination, as opposed to each component alone, induced statistically similar level of protection as induced by Rev.1 suggesting that DnaK could be viewed as a promising candidate for the development of a subunit vaccine against brucellosis.

  6. Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

    PubMed Central

    Gerecke, Kim M.; Jiao, Yun; Pagala, Viswajeeth; Smeyne, Richard J.

    2012-01-01

    Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/−) with strain-matched wild-type (WT) mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/− mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/− mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons. PMID:22912838

  7. Protection against adriamycin (doxorubicin)-induced toxicity in mice by several clinically used drugs.

    PubMed

    Shinozawa, S; Gomita, Y; Araki, Y

    1987-02-01

    Protective effects of clinically used drugs against adriamycin (ADM)-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.). The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg), 402.2% for dextran sulfate (MDS, 300 mg/kg), 121.6% for flavin adenine dinucleotide (20 mg/kg), 236.3% for adenosine triphosphate disodium (50 mg/kg), 213.7% for reduced glutathione (100 mg/kg), 121.6% for phytonadione (50 mg/kg), 155.2% for inositol nicotinate (Ino-N, 500 mg/kg), 335.5% for nicomol (1000 mg/kg), 157.5% for nicardipine (10 mg/kg) and 123.3% for dipyridamol (50 mg/kg). Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.

  8. Protective efficacy of a recombinant Newcastle disease virus expressing glycoprotein of vesicular stomatitis virus in mice.

    PubMed

    Zhang, Minmin; Ge, Jinying; Li, Xiaofang; Chen, Weiye; Wang, Xijun; Wen, Zhiyuan; Bu, Zhigao

    2016-02-24

    Vesicular stomatitis virus (VSV) causes severe losses to the animal husbandry industry. In this study, a recombinant Newcastle disease virus (NDV) expressing the glycoprotein (G) of VSV (rL-VSV-G) was constructed and its pathogenicity and immune protective efficacy in mouse were evaluated. In pathogenicity evaluation test, the analysis of the viral distribution in mouse organs and body weight change showed that rL-VSV-G was safe in mice. In immune protection assay, the recombinant rL-VSV-G triggered a high titer of neutralizing antibodies against VSV. After challenge, the wild-type (wt) VSV viral load in mouse organs was lower in rL-VSV-G group than that in rLaSota groups. wt VSV was not detected in the blood, liver, or kidneys of mice, whereas it was found in these tissues in control groups. The mice body weight had no significant change after challenge in the rL-VSV-G group. Additionally, suckling mice produced from female mice immunized with rL-VSV-G were partially protected from wt VSV challenge. These results demonstrated that rL-VSV-G may be a suitable candidate vaccine against vesicular stomatitis (VS).

  9. Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice.

    PubMed

    Jiang, Shu-Hua; Ping, Li-Feng; Sun, Feng-Yan; Wang, Xiao-Lei; Sun, Zhi-Juan

    2016-12-01

    Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice.

  10. Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice

    PubMed Central

    Jiang, Shu-Hua; Ping, Li-Feng; Sun, Feng-Yan; Wang, Xiao-Lei; Sun, Zhi-Juan

    2016-01-01

    Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice. PMID:28101182

  11. Identification of a new immunogenic candidate conferring protection against Brucella melitensis infection in mice.

    PubMed

    Ghasemi, Amir; Zarnani, Amir-Hassan; Ghoodjani, Abolfazl; Rezania, Simin; Salari, Mohammad Hossein; Jeddi-Tehrani, Mahmood

    2014-11-01

    Identification of bacterial proteins that contribute to the replication and survival of the engulfed bacteria within phagolysosome is critical in the pathogenesis of intracellular bacteria. Heat shock proteins (HSPs) are molecular chaperones that prevent unwanted protein aggregation and protect the bacteria against cell stress. In order to study the potential of HspA for development of a Brucella subunit vaccine, immunogenicity and protective efficacy of recombinant HspA (rHspA) from Brucella melitensis was evaluated in BALB/c mice. The hspA gene was cloned in pDEST42 and the resulting recombinant protein was used as subunit vaccine. rHspA elicited mixed TH1/TH2 immune responses with higher titers of specific IgG1 than IgG2a. In lymphocyte transformation assay, splenocytes of immunized mice exhibited a strong recall proliferative response with high amounts of IFN-γ, IL-12, IL-10 and IL-6 and very low levels of IL-5 and IL-4 production. The protective effect of rHspA was evaluated by administering rHspA to mice that resulted in a significant reduction in bacterial load and high degree of protection against B. melitensis challenge compared to control mice (p<0.001). These results suggest that rHspA may be a useful candidate for the development of subunit vaccine against brucellosis.

  12. 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...

  13. 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.

  14. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice.

    PubMed

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Protective effect of polypeptide from Chlamys farreri on hairless mice damaged by ultraviolet A.

    PubMed

    Wang, Chun-Bo; Yao, Ru-Yong; Liu, Zhan-Tao; Zhong, Wei-Zhen; Liu, Xiao-Ping; Wang, Yue-Jun

    2002-09-01

    To study the protective effect of the polypeptide isolated from Chlamys farreri (PCF) on hairless mice skin damaged by ultraviolet A. Enzymes and malondialdehyde (MDA) were determined by biochemical methods; the expressions of Bcl-2 protein and NOS protein were examined by immunohistochemical technique. The ultra-structure of the skin was observed through electronic microscope. PCF could enhance the activities of glutathione peroxidase (GSH-px), superoxide dismutase (SOD), and total anti-oxidative capacity (T-AOC). Also PCF could reduce the amount of MDA, increase the expression of Bcl-2 protein, and inhibit the expression of NOS protein. The ultra-structure of epidermis and fibroblasts remained normal in 20 % PCF groups; there were vacuoles in smooth endoplasm reticulum in epidermis of mice and the number of rough endoplasm reticulum in fibroblasts was decreased in model group. PCF had the protective effects on hairless mice skin damaged by ultraviolet A via its anti-oxidative mechanisms.

  16. The vaccine candidate BLSOmp31 protects mice against Brucella canis infection.

    PubMed

    Clausse, Maria; Díaz, Alejandra G; Ghersi, Giselle; Zylberman, Vanesa; Cassataro, Juliana; Giambartolomei, Guillermo H; Goldbaum, Fernando A; Estein, Silvia M

    2013-12-09

    Canine brucellosis represents a major reproductive problem worldwide and it is considered a zoonotic disease. New approaches are therefore urgently needed to develop an effective and safe immunization strategy against Brucella canis. In the present study, BALB/c mice were subcutaneously immunized with the recombinant chimera rBLSOmp31 formulated in different adjuvants. The different strategies induced a vigorous immunoglobulin G (IgG) response, with high titers of IgG1 as well as IgG2. Besides, spleen cells from rBLSOmp31-immunized mice produced gamma interferon and IL-4, suggesting the induction of a mixed Th1-Th2. Vaccination with rBLSOmp31-IFA formulation provided the best protection levels comparable with that given by control vaccines. None of the immunization strategies induced serological interference in diagnosis. Hitherto, this is the first report that a recombinant vaccine confers protection against B. canis in mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice

    PubMed Central

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Summary Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. PMID:26786657

  18. Humoral Immunity through Immunoglobulin M Protects Mice from an Experimental Actinomycetoma Infection by Nocardia brasiliensis

    PubMed Central

    Salinas-Carmona, Mario C.; Pérez-Rivera, Isabel

    2004-01-01

    An experimental model of infection with Nocardia brasiliensis, used as an example of a facultative intracellular pathogen, was tested. N. brasiliensis was injected into the rear foot pads of BALB/c mice to establish an infection. Within 30 days, infected animals developed a chronic actinomycetoma infection. Batch cultures of N. brasiliensis were used to purify P61, P38, and P24 antigens; P61 is a catalase, and P38 is a protease with strong caseinolytic activity. Active and passive immunizations of BALB/c mice with these three purified soluble antigens were studied. Protection was demonstrated for actively immunized mice. However, immunity lasted only 30 days. Other groups of immunized mice were bled at different times, and their sera were passively transferred to naive recipients that were then infected with N. brasiliensis. Sera collected 5, 6, and 7 days after donor immunization conferred complete, long-lasting protection. The protective effect of passive immunity decreased when sera were collected 2 weeks after donor immunization. However, neither the early sera (1-, 2-, and 3-day sera) nor the later sera (30- or 45-day sera) prevented the infection. Hyperimmune sera with the highest levels of immunoglobulin G (IgG) to N. brasiliensis antigens did not protect at all. The antigens tested induced two IgM peaks. The first peak was present 3 days after immunization but was not antigen specific and did not transfer protection. The second peak was evident 7 days after immunization, was an IgM response, was antigen specific, and conferred protection. This results clearly demonstrate that IgM antibodies protect the host against a facultative intracellular bacterium. PMID:15385456

  19. Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso: A Randomised, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Konaté, Amadou T.; Yaro, Jean Baptiste; Ouédraogo, Amidou Z.; Diarra, Amidou; Gansané, Adama; Soulama, Issiaka; Kangoyé, David T.; Kaboré, Youssouf; Ouédraogo, Espérance; Ouédraogo, Alphonse; Tiono, Alfred B.; Ouédraogo, Issa N.; Chandramohan, Daniel; Cousens, Simon; Milligan, Paul J.; Sirima, Sodiomon B.; Greenwood, Brian; Diallo, Diadier A.

    2011-01-01

    77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65–1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72–0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded. Conclusions IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission. Trial Registration ClinicalTrials.gov NCT00738946 Please see later in the article for the Editors' Summary PMID:21304925

  20. NRF2 plays a protective role in diabetic retinopathy in mice

    PubMed Central

    Xu, Zhenhua; Wei, Yanhong; Gong, Junsong; Cho, Hongkwan; Park, James K.; Sung, Ee-Rah; Huang, Hu; Wu, Lijuan; Eberhart, Charles; Handa, James T.; Du, Yunpeng; Kern, Timothy S.; Thimmulappa, Rajesh; Barber, Alistair J.; Biswal, Shyam; Duh, Elia J.

    2014-01-01

    Aims/hypothesis Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Methods Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. Results NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood–retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. Conclusions/interpretation These results indicate that NRF2 is an important protective mechanism regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy. PMID:24186494

  1. Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection.

    PubMed

    Wozniak, Karen L; Hole, Camaron R; Yano, Junko; Fidel, Paul L; Wormley, Floyd L

    2014-07-01

    Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce IFN-γ, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with WT Cryptococcus. Given that individuals with suppressed CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured levels of antimicrobial peptides lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of lipocalin-2, S100A8, S100A9 and SAA3 as well as TLR4(+) and RAGE(+) macrophages and dendritic cells in mice inoculated with H99γ compared with WT H99. Similar results were observed in the lungs of H99γ-immunized, compared with heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22-deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared with WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.

  2. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production.

    PubMed

    Arendash, G W; Schleif, W; Rezai-Zadeh, K; Jackson, E K; Zacharia, L C; Cracchiolo, J R; Shippy, D; Tan, J

    2006-11-03

    A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.

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

    SciTech Connect

    Wang, Jun; Cao, Hui; Wang, Hongjie; Yin, Guoxiao; Du, Jiao; Xia, Fei; Lu, Jingli; Xiang, Ming

    2015-06-15

    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 effective 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.

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

    PubMed

    Feng, Xiaosheng; Jia, Aiqing

    2014-08-01

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

  5. Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin.

    PubMed

    García-Suárez, María del Mar; Cima-Cabal, María Dolores; Flórez, Noelia; García, Pilar; Cernuda-Cernuda, Rafael; Astudillo, Aurora; Vázquez, Fernando; De los Toyos, Juan R; Méndez, F Javier

    2004-08-01

    Pneumolysin (PLY) is an important virulence factor of Streptococcus pneumoniae. We examined the ability of three murine monoclonal antibodies (MAbs) to PLY (PLY-4, PLY-5, and PLY-7) to affect the course of pneumococcal pneumonia in mice. The intravenous administration of antibodies PLY-4 and PLY-7 protected the mice from the lethal effect of the purified toxin. Mice treated with PLY-4 before intranasal inoculation of S. pneumoniae type 2 survived longer (median survival time, 100 h) than did untreated animals (median survival time, 60 h) (P < 0.0001). The median survival time for mice treated with a combination of PLY-4 and PLY-7 was 130 h, significantly longer than that for mice given isotype-matched indifferent MAbs (P = 0.0288) or nontreated mice (P = 0.0002). The median survival time for mice treated with a combination of three MAbs was significantly longer (>480 h) than that for mice treated with PLY-5 (48 h; P < 0.0001), PLY-7 (78 h; P = 0.0007), or PLY-4 (100 h; P = 0.0443) alone. Similarly, the survival rate for mice treated with three MAbs (10 of 20 mice) was significantly higher than the survival rate obtained with PLY-5 (1 of 20; P = 0.0033), PLY-4 (2 of 20; P = 0.0138), or PLY-7 (3 of 20; P = 0.0407) alone. These results suggest that anti-PLY MAbs act with a synergistic effect. Furthermore, MAb administration was associated with a significant decrease in bacterial lung colonization and lower frequencies of bacteremia and tissue injury with respect to the results for the control groups.

  6. Absence of intestinal microbiota does not protect mice from diet-induced obesity.

    PubMed

    Fleissner, Christine K; Huebel, Nora; Abd El-Bary, Mohamed Mostafa; Loh, Gunnar; Klaus, Susanne; Blaut, Michael

    2010-09-01

    The gut microbiota has been implicated in host nutrient absorption and energy homeostasis. We studied the influence of different diets on body composition in germ-free (GF) and conventional (CV) mice. GF and CV male adult C3H mice were fed ad libitum a semi-synthetic low-fat diet (LFD; carbohydrate-protein-fat ratio: 41:42:17; 19.8 kJ/g), a high-fat diet (HFD; 41:16:43; 21.4 kJ/g) or a commercial Western diet (WD; 41:19:41; 21.5 kJ/g). There was no difference in body weight gain between GF and CV mice on the LFD. On the HFD, GF mice gained more body weight and body fat than CV mice, and had lower energy expenditure. GF mice on the WD gained significantly less body fat than GF mice on the HFD. GF mice on both HFD and WD showed increased intestinal mRNA expression of fasting-induced adipose factor/angiopoietin-like protein 4 (Fiaf/Angptl4), but they showed no major changes in circulating Fiaf/Angptl4 compared with CV mice. The faecal microbiota composition of the CV mice differed between diets: the proportion of Firmicutes increased on both HFD and WD at the expense of the Bacteroidetes. This increase in the Firmicutes was mainly due to the proliferation of one family within this phylum: the Erysipelotrichaceae. We conclude that the absence of gut microbiota does not provide a general protection from diet-induced obesity, that intestinal production of Fiaf/Angptl4 does not play a causal role in gut microbiota-mediated effects on fat storage and that diet composition affects gut microbial composition to larger extent than previously thought.

  7. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

    PubMed

    Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie; Qu, Qiang; Fan, Fang; Klaassen, Curtis D

    2014-01-01

    Oxidative stress and glutathione (GSH) depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO) mice were treated with microcystin (50 μg/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc). Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  8. Stevioside protects LPS-induced acute lung injury in mice.

    PubMed

    Yingkun, Nie; Zhenyu, Wang; Jing, Lin; Xiuyun, Lu; Huimin, Yu

    2013-02-01

    Stevioside, a diterpene glycoside component of Stevia rebaudiana, has been known to exhibit anti-inflammatory properties. To evaluate the effect and the possible mechanism of stevioside in lipopolysaccharide (LPS)-induced acute lung injury, male BALB/c mice were pretreated with stevioside or dexamethasone 1 h before intranasal instillation of LPS. Seven hours later, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid (BALF) were measured by using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were also determined. The right lung was excised for histological examination and analysis of myeloperoxidase activity and nitrate/nitrite content. Cyclooxygenase 2 (COX-2), inducible NO synthase (iNOS), nuclear factor-kappa B (NF-κB), inhibitory kappa B protein were detected by western blot. The results showed that stevioside markedly attenuated the LPS-induced histological alterations in the lung. Stevioside inhibited the production of pro-inflammatory cytokines and the expression of COX-2 and iNOS induced by LPS. In addition, not only was the wet-to-dry weight ratio of lung tissue significantly decreased, the number of total cells, neutrophils, and macrophages in the BALF were also significantly reduced after treatment with stevioside. Moreover, western blotting showed that stevioside inhibited the phosphorylation of IκB-α and NF-κB caused by LPS. Taken together, our results suggest that anti-inflammatory effect of stevioside against the LPS-induced acute lung injury may be due to its ability of inhibition of the NF-κB signaling pathway. Stevioside may be a promising potential therapeutic reagent for acute lung injury treatment.

  9. Aldose Reductase Deficiency Protects from Autoimmune- and Endotoxin-Induced Uveitis in Mice

    PubMed Central

    Yadav, Umesh C. S.; Shoeb, Mohammed; Srivastava, Satish K.

    2011-01-01

    Purpose. 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. Methods. 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. Results. 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. Conclusions. These findings suggest that AR-deficiency/inhibition protects against acute as well as chronic forms of ocular inflammatory complications such as uveitis. PMID:21911582

  10. Recombinant Toxoplasma gondii phosphoglycerate mutase 2 confers protective immunity against toxoplasmosis in BALB/c mice.

    PubMed

    Wang, Hai-Long; Wen, Li-Min; Pei, Yan-Jiang; Wang, Fen; Yin, Li-Tian; Bai, Ji-Zhong; Guo, Rui; Wang, Chun-Fang; Yin, Guo-Rong

    2016-01-01

    Toxoplasmosis is one of the most widespread zoonoses worldwide. It has a high incidence and can result in severe disease in humans and livestock. Effective vaccines are needed to limit and prevent infection with Toxoplasma gondii. In this study, we evaluated the immuno-protective efficacy of a recombinant Toxoplasma gondii phosphoglycerate mutase 2 (rTgPGAM 2) against T. gondii infection in BALB/c mice. We report that the mice nasally immunised with rTgPGAM 2 displayed significantly higher levels of special IgG antibodies against rTgPGAM 2 (including IgG1, IgG2a and IgAs) and cytokines (including IFN-γ, IL-2 and IL-4) in their blood sera and supernatant of cultured spleen cells compared to those of control animals. In addition, an increased number of spleen lymphocytes and enhanced lymphocyte proliferative responses were observed in the rTgPGAM 2-immunised mice. After chronic infection and lethal challenge with the highly virulent T. gondii RH strain by oral gavage, the survival time of the rTgPGAM 2-immunised mice was longer (P < 0.01) and the survival rate (70%) was higher compared with the control mice (P < 0.01). The reduction rate of brain and liver tachyzoites in rTgPGAM 2-vaccinated mice reached approximately 57% and 69% compared with those of the control mice (P < 0.01). These results suggest that rTgPGAM 2 can generate protective immunity against T. gondii infection in BALB/c mice and may be a promising antigen in the further development of an effective vaccine against T. gondii infection. © H.-L. Wang et al., published by EDP Sciences, 2016.

  11. 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

  12. Recombinant Toxoplasma gondii phosphoglycerate mutase 2 confers protective immunity against toxoplasmosis in BALB/c mice

    PubMed Central

    Wang, Hai-Long; Wen, Li-Min; Pei, Yan-Jiang; Wang, Fen; Yin, Li-Tian; Bai, Ji-Zhong; Guo, Rui; Wang, Chun-Fang; Yin, Guo-Rong

    2016-01-01

    Toxoplasmosis is one of the most widespread zoonoses worldwide. It has a high incidence and can result in severe disease in humans and livestock. Effective vaccines are needed to limit and prevent infection with Toxoplasma gondii. In this study, we evaluated the immuno-protective efficacy of a recombinant Toxoplasma gondii phosphoglycerate mutase 2 (rTgPGAM 2) against T. gondii infection in BALB/c mice. We report that the mice nasally immunised with rTgPGAM 2 displayed significantly higher levels of special IgG antibodies against rTgPGAM 2 (including IgG1, IgG2a and IgAs) and cytokines (including IFN-γ, IL-2 and IL-4) in their blood sera and supernatant of cultured spleen cells compared to those of control animals. In addition, an increased number of spleen lymphocytes and enhanced lymphocyte proliferative responses were observed in the rTgPGAM 2-immunised mice. After chronic infection and lethal challenge with the highly virulent T. gondii RH strain by oral gavage, the survival time of the rTgPGAM 2-immunised mice was longer (P < 0.01) and the survival rate (70%) was higher compared with the control mice (P < 0.01). The reduction rate of brain and liver tachyzoites in rTgPGAM 2-vaccinated mice reached approximately 57% and 69% compared with those of the control mice (P < 0.01). These results suggest that rTgPGAM 2 can generate protective immunity against T. gondii infection in BALB/c mice and may be a promising antigen in the further development of an effective vaccine against T. gondii infection. PMID:26984115

  13. Endothelial Expression of Scavenger Receptor Class B, Type I Protects against Development of Atherosclerosis in Mice

    PubMed Central

    2015-01-01

    The role of scavenger receptor class B, type I (SR-BI) in endothelial cells (EC) was examined in several novel transgenic mouse models expressing SR-BI in endothelium of mice with normal C57Bl6/N, apoE-KO, or Scarb1-KO backgrounds. Mice were also created expressing SR-BI exclusively in endothelium and liver. Endothelial expression of the Tie2-Scarb1 transgene had no significant effect on plasma lipoprotein levels in mice on a normal chow diet but on an atherogenic diet, significantly decreased plasma cholesterol levels, increased plasma HDL cholesterol (HDL-C) levels, and protected mice against atherosclerosis. In 8-month-old apoE-KO mice fed a normal chow diet, the Tie2-Scarb1 transgene decreased aortic lesions by 24%. Mice expressing SR-BI only in EC and liver had a 1.5 ± 0.1-fold increase in plasma cholesterol compared to mice synthesizing SR-BI only in liver. This elevation was due mostly to increased HDL-C. In EC culture studies, SR-BI was found to be present in both basolateral and apical membranes but greater cellular uptake of cholesterol from HDL was found in the basolateral compartment. In summary, enhanced expression of SR-BI in EC resulted in a less atherogenic lipoprotein profile and decreased atherosclerosis, suggesting a possible role for endothelial SR-BI in the flux of cholesterol across EC. PMID:26504816

  14. Prion protein participates in the protection of mice from lipopolysaccharide infection by regulating the inflammatory process.

    PubMed

    Liu, Jin; Zhao, Deming; Liu, Chunfa; Ding, Tianjian; Yang, Lifeng; Yin, Xiaomin; Zhou, Xiangmei

    2015-01-01

    Despite the overwhelming evidence of the involvement of prion protein (PrP) in prion disease pathogenesis, the normal functions of this cell surface glycoprotein remain unclear. Previously, we showed that PrP may have a dual regulatory role by regulating the opposite poles of pro-inflammation and anti-inflammation as well as tissue repair in activated microglia. In the present work, we compared the mRNA expression of inflammation-related cytokines (TNF-α, IL-1β, IL-6, NOS2, and IL-10) and IL-4-related alternative activation markers (Arg1 and Mrc1) after lipopolysaccharide (LPS) challenge in the brain and spleen and examined peripheral leukocyte recovery and LPS-induced mortality in PrP knockout mice (PrP(-/-)) and wild-type (WT) mice. During the acute phase, WT mice exhibited higher levels of pro-inflammatory cytokines in the brain and spleen than in PrP(-/-) mice, while PrP(-/-) mice sustained higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines, Arg1, and Mrc1 during the later phase. PrP(-/-) mice also exhibited a slower peripheral leukocyte recovery process and higher mortality in response to LPS-induced septic shock. These results suggest that the PrP may participate in the protection of mice from LPS infection by regulating the process of inflammatory response.

  15. TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

    PubMed Central

    Souza, Ana C P; Tsuji, Takayuki; Baranova, Irina N; Bocharov, Alexander V; Wilkins, Kenneth J; Street, Jonathan M; Alvarez-Prats, Alejandro; Hu, Xuzhen; Eggerman, Thomas; Yuen, Peter S T; Star, Robert A

    2015-01-01

    Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD. PMID:26416975

  16. Protective immunity against Leishmania major induced by Leishmania tropica infection of BALB/c mice.

    PubMed

    Mahmoudzadeh-Niknam, Hamid; Kiaei, Simin Sadat; Iravani, Davood

    2011-02-01

    Leishmania (L.) tropica is a causative agent of human cutaneous and viscerotropic leishmaniasis. Immune response to L. tropica in humans and experimental animals are not well understood. We previously established that L. tropica infection induces partial protective immunity against subsequent challenge infection with Leishmania major in BALB/c mice. Aim of the present study was to study immunologic mechanisms of protective immunity induced by L. tropica infection, as a live parasite vaccine, in BALB/c mouse model. Mice were infected by L. tropica, and after establishment of the infection, they were challenged by L. major. Our findings shows that L. tropica infection resulted in protection against L. major challenge in BALB/c mice and this protective immunity is associated with: (1) a DTH response, (2) higher IFN-γ and lower IL-10 response at one week post-challenge, (3) lower percentage of CD4(+) lymphocyte at one month post-challenge, and (4) the source of IFN-γ and IL-10 were mainly CD4(-) lymphocyte up to one month post-challenge suggesting that CD4(-) lymphocytes may be responsible for protection induced by L. tropica infection in the studied intervals.

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

    PubMed Central

    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

    2011-01-01

    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. PMID:21187399

  18. Protection against Influenza Virus Infection of Mice Fed Bifidobacterium breve YIT4064

    PubMed Central

    Yasui, Hisako; Kiyoshima, Junko; Hori, Tetuji; Shida, Kan

    1999-01-01

    Mice fed Bifidobacterium breve YIT4064 and immunized orally with influenza virus were more strongly protected against influenza virus infection of the lower respiratory tract than ones immunized with influenza virus only. The number of mice with enhanced anti-influenza virus immunoglobulin G (IgG) in serum upon oral administration of B. breve YIT4064 and oral immunization with influenza virus was significantly greater than that upon oral immunization with influenza virus only. These findings demonstrated that the oral administration of B. breve YIT4064 increased anti-influenza virus IgG antibodies in serum and protected against influenza virus infection. The oral administration of B. breve YIT4064 may enhance antigen-specific IgG against various pathogenic antigens taken orally and induce protection against various virus infections. PMID:10066652

  19. Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

    PubMed

    Bao, Lam Q; Nhi, Dang M; Huy, Nguyen T; Kikuchi, Mihoko; Yanagi, Tetsuo; Hamano, Shinjiro; Hirayama, Kenji

    2015-01-28

    Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection. C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia. The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts. CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

  20. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease

    PubMed Central

    Zenewicz, Lauren A.; Yancopoulos, George D.; Valenzuela, David M.; Murphy, Andrew J.; Stevens, Sean; Flavell, Richard A.

    2012-01-01

    Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by dysfunctional innate and/or adaptive immunity. This aberrant immune response leads to the secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract leading to further inflammation. IL-22 is a Th17 T cell associated cytokine that is bi-functional with both pro-inflammatory and protective effects on tissues depending on the inflammatory context. We show herein that IL-22 protects mice from IBD. Interestingly, this protection is not only mediated by CD4 T cells, but IL-22 expressing NK cells also confer protection. In addition, IL-22 expression is differentially regulated between NK cell subsets. Thus, both the innate and adaptive immune responses have developed protective mechanisms to counteract the damaging effects of inflammation on tissues. PMID:19100701

  1. Oral Immunization of Mice with Live Pneumocystis murina Protects against Pneumocystis Pneumonia.

    PubMed

    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

    2016-03-15

    Pneumocystis pneumonia is a major cause of morbidity and mortality in immunocompromised patients, particularly those infected with HIV. 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 d postinfection 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. Furthermore, administration of serum from vaccinated mice significantly reduced Pneumocystis lung burden in infected animals compared with control serum. We also found that the diversity of the intestinal microbial community was altered by oral immunization with P. murina. To our knowledge, our data demonstrate for the first time that an oral vaccination strategy prevents Pneumocystis infection. Copyright © 2016 by The American Association of Immunologists, Inc.

  2. 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

  3. Alpha-methyl-homocysteine thiolactone protects lung of BALB/c mice irradiated with 6 Gy

    NASA Astrophysics Data System (ADS)

    Lubec, G.; Foltinova, J.; Leplawy, T.; Mallinger, R.; Tichatschek, E.; Getoff, N.

    1996-06-01

    The radiation protective activity of intraperitoneally administered alpha-methyl-homocysteine thiolactone (α-MHCTL; 100 mg/kg body weight) in female BALB/c mice and such treated with cysteine treated (100 mg/kg body weight), using unirradiated and placebo treated irradiated mice were tested as controls. 6 Gy whole body irradiated was applied and after a period of three weeks the animals were sacrificed and lungs were taken for morphometry and the determination of o-tyrosine. Septal areas were highest in the irradiated, placebo treated mice (68.67 + 9.82% septal area to total area)and lowest in the α-MHCTL treated irradiated mice (55.67 +11.29%), significant at the p < 0.05 level. Morphometric data were accompanied by highest levels of o-tyrosine, a reliable parameter for OH-attack, in the irradiated, placebo treated group with 1.87 + 0.40 μM/g lung tissue and 0.32 + 0.13 gmM/g lung tissue in the αMHCTL treated group; the statistical difference was significant. Significant radiation protection in the mammalian system at the morphological and biochemical level were found. The potent effect could be explained by the influence of alpha-alkylation in homocysteine thiolactone (HCTL) which renders amino acids unmetabolizeable, nontoxic, increases lipophilicity and therefore improving permeability through membranes. The present report confirms morphological data on the radiation protective activity of this interesting thiol compound.

  4. Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice

    PubMed Central

    Sanchez, Jamila R.; Reddick, Traci L.; Perez, Marissa; Centonze, Victoria E.; Mitra, Sankar; Izumi, Tadahide; McMahan, C. Alex; Walter, Christi A.

    2015-01-01

    Increased paternal age is associated with a greater risk of producing children with genetic disorders originating from de novo germline mutations. Mice mimic the human condition by displaying an age-associated increase in spontaneous mutant frequency in spermatogenic cells. The observed increase in mutant frequency appears to be associated with a decrease in the DNA repair protein, AP endonuclease1 (APEX1) and Apex1 heterozygous mice display an accelerated paternal age effect as young adults. In this study, we directly tested if APEX1 over-expression in cell lines and transgenic mice could prevent increases in mutagenesis. Cell lines with ectopic expression of APEX1 had increased APEX1 activity and lower spontaneous and induced mutations in the lacI reporter gene relative to the control. Spermatogenic cells obtained from mice transgenic for human APEX1 displayed increased APEX1 activity, were protected from the age-dependent increase in spontaneous germline mutagenesis, and exhibited increased apoptosis in the spermatogonial cell population. These results directly indicate that increases in APEX1 level confer protection against the murine paternal age effect, thus highlighting the role of APEX1 in preserving reproductive health with increasing age and in protection against genotoxin-induced mutagenesis in somatic cells. PMID:26201249

  5. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection

    PubMed Central

    Samuelsson, Christofer; Hausmann, Jürgen; Lauterbach, Henning; Schmidt, Michaela; Akira, Shizuo; Wagner, Hermann; Chaplin, Paul; Suter, Mark; O’Keeffe, Meredith; Hochrein, Hubertus

    2008-01-01

    Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of ectromelia virus (ECTV), the causative agent of mousepox, completely depended on TLR9. The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV. In contrast, we found that the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) activated DCs by both TLR9-dependent and -independent pathways. We therefore tested whether we could use the broader induction of immune responses by MVA to protect mice from a lethal infection with ECTV. Indeed, MVA given at the same time as a lethal dose of ECTV protected mice from death. Importantly, MVA also rescued TLR9-deficient mice if administered 2 full days after an otherwise lethal infection with ECTV. Therefore, these data suggest an essential role for TLR9 in the defense against poxviruses. In addition, postexposure application of MVA may protect against lethal poxvirus infection. PMID:18398511

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

    PubMed Central

    2011-01-01

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

  7. Protective Effects of Baicalin on Decidua Cells of LPS-Induced Mice Abortion

    PubMed Central

    Wang, Xiaodan; Zhao, Yantao; Zhong, Xiuhui

    2014-01-01

    The study was carried out to investigate the protective effects of Baicalin on decidual cells of LPS-induced abortion mice. In the in vitro experiment, the decidual cells were cultured by uterus tissue mass cultivation sampled at day 6 of pregnancy, and gradient concentrations of LPS were used to determine the optimal LPS concentration of the injured decidual cells model. The injured decidual cells were treated with Baicalin (4 μg/mL) to determine the protective role of Baicalin. In the in vivo experiment, lipopolysaccharide (LPS) was injected intravenously via the tail vein to induce abortion at day 6 of pregnancy, and the mice were given different concentrations of Baicalin by oral gavage consecutively at days 7 to 8 of pregnancy. On day 9 of gestation, the mice were sacrificed. The TNF and progesterone contents in the serum were assayed by ELISA. The results clearly revealed that Baicalin can prevent the injury to decidual cells from LPS dose dependently, TNF was decreased significantly (P < 0.01) compared to LPS group, and there was no effect on the progesterone. These findings suggest that Baicalin has protective effects on the injured decidual cells in the pregnant mice. PMID:25386564

  8. Complement Regulatory Protein CD46 Protects against Choroidal Neovascularization in Mice

    PubMed Central

    Lyzogubov, Valeriy; Wu, Xiaobo; Jha, Purushottam; Tytarenko, Ruslana; Triebwasser, Michael; Kolar, Grant; Bertram, Paula; Bora, Puran S.; Atkinson, John P.; Bora, Nalini S.

    2015-01-01

    Dysregulation of the complement system is increasingly recognized as a contributing factor in age-related macular degeneration. Although the complement regulator CD46 is expressed ubiquitously in humans, in mouse it was previously thought to be expressed only on spermatozoa. We detected CD46 mRNA and protein in the posterior ocular segment (neuronal retina, retinal pigment epithelium, and choroid) of wild-type (WT) C57BL/6J mice. Cd46−/− knockout mice exhibited increased levels of the membrane attack complex and of vascular endothelial growth factor (VEGF) in the retina and choroid. The Cd46−/− mice were also more susceptible to laser-induced choroidal neovascularization (CNV). In Cd46−/− mice, 19% of laser spots were positive for CNV at day 2 after treatment, but no positive spots were detected in WT mice. At day 3, 42% of laser spots were positive in Cd46−/− mice, but only 11% in WT mice. A fully developed CNV complex was noted in both Cd46−/− and WT mice at day 7; however, lesion size was significantly (P < 0.05) increased in Cd46−/− mice. Our findings provide evidence for expression of CD46 in the mouse eye and a role for CD46 in protection against laser-induced CNV. We propose that the Cd46−/− mouse has a greater susceptibility to experimental CNV because of insufficient complement inhibition, which leads to increased membrane attack complex deposition and VEGF expression. PMID:25019227

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

    SciTech Connect

    Li, Guodong; Kong, Bo; Zhu, Yan; Zhan, Le; Williams, Jessica A.; Tawfik, Ossama; Kassel, Karen M.; Luyendyk, James P.; Wang, Li; Guo, Grace L.

    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, we 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.

  10. [Protective effects of human bone marrow mesenchymal stem cells on hematopoietic organs of irradiated mice].

    PubMed

    Chen, Ling-Zhen; Yin, Song-Mei; Zhang, Xiao-Ling; Chen, Jia-Yu; Wei, Bo-Xiong; Zhan, Yu; Yu, Wei; Wu, Jin-Ming; Qu, Jia; Guo, Zi-Kuan

    2012-12-01

    The objective of this study was to explore the protective effects of human bone marrow mesenchymal stem cells (MSC) on hematopoietic organs of irradiated mice. Human bone marrow MSC were isolated, ex vivo expanded, and identified by cell biological tests. Female BALB/c mice were irradiated with (60)Co γ-ray at a single dose of 6 Gy, and received different doses of human MSC and MSC lysates or saline via tail veins. The survival of mice was record daily, and the femurs and spleens were harvested on day 9 and 16 for pathologic examination. The histological changes were observed and the cellularity was scored. The results showed that the estimated survival time of MSC- and MSC lysate-treated mice was comparable to that of controls. The hematopoiesis in the bone marrow of mice that received high-dose (5×10(6)) of MSC or MSC lysates was partially restored on day 9 and the capacity of hemopoietic tissue and cellularity scorings were significantly elevated as compared with that of controls (P < 0.05). Proliferative nudes were also obviously observed in the spleens of mice that received high-dose of MSC or MSC lysates on d 9 after irradiation. The histological structures of the spleen and bone marrow of the mice that received high-doses (5×10(6)) of MSC or MSC lysates were restored to normal, the cell proliferation displayed extraordinarily active. Further, the cellularity scores of the bone marrow were not significantly different between the high-dose MSC and MSC lysate-treated mice. It is concluded that the bone marrow MSC can promote the hematopoietic recovery of the irradiated mice, which probably is associated with the bioactive materials inherently existed in bone marrow cells.

  11. NADPH oxidase-1 deficiency offers little protection in Salmonella typhimurium-induced typhlitis in mice

    PubMed Central

    Chu, Fong-Fong; Esworthy, R Steven; Doroshow, James H; Shen, Binghui

    2016-01-01

    AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium (S. Tm) in a mouse model. METHODS Eight-week-old male wild-type (WT) and Nox1 knockout (KO) C57BL6/J (B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for mRNA/cDNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU. RESULTS We found Nox1-knockout (Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations: (1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice; (2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose (2 × 106 CFU) for which the Nox1-KO had one-log lower CFU than WT mice; (3) there is no difference in cecal pathology between WT and Nox1-KO groups; and (4) there are no S. Tm infection-induced changes in gene expression levels (IL-1b, TNF-α, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum. CONCLUSION Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection. PMID:28028364

  12. H5N1 influenza virus-like particle vaccine protects mice from heterologous virus challenge better than whole inactivated virus.

    PubMed

    Ren, Zhiguang; Ji, Xianliang; Meng, Lingnan; Wei, Yurong; Wang, Tiecheng; Feng, Na; Zheng, Xuexing; Wang, Hualei; Li, Nan; Gao, Xiaolong; Jin, Hongli; Zhao, Yongkun; Yang, Songtao; Qin, Chuan; Gao, Yuwei; Xia, Xianzhu

    2015-03-16

    The highly pathogenic avian influenza (HPAI) H5N1 virus has become highly enzootic since 2003 and has dynamically evolved to undergo substantial evolution. Clades 2.3.2.1 and 2.3.4 have become the most dominant lineage in recent years, and H5N8 avian influenza outbreaks have been reported Asia. The current approach to generate influenza virus vaccines uses embryonated chicken eggs for large-scale production, although such vaccines have been poorly immunogenic to heterologous virus challenge. In the current study, virus-like particles (VLP) based on A/meerkat/Shanghai/SH-1/2012 (clade 2.3.2.1) and comprising hemagglutinin (HA), neuraminidase (NA), and matrix (M1) were produced using a baculovirus expression system to develop effective protection for different H5 HPAI clade challenges. Mice immunized with VLP demonstrated stronger humoral and cellular immune responses than mice immunized with whole influenza virus (WIV), with 20-fold higher IgG antibody titers against A/meerkat/Shanghai/SH-1/2012 after boost. Notably, the WIV vaccine group showed partial protection (80% survival) to homologous challenge, little protection (40% survival) to heterologous challenge, and 20% survival to H5N8 challenge, whereas all mice in the VLP+CFA group survived. These results provide insight for the development of effective prophylactic vaccines based on VLPs with cross-clade protection for the control of current H5 HPAI outbreaks in humans.

  13. Escherichia coli strains colonising the gastrointestinal tract protect germfree mice against Salmonella typhimurium infection

    PubMed Central

    Hudault, S; Guignot, J; Servin, A

    2001-01-01

    BACKGROUND—Escherichia coli is part of the normal gastrointestinal microflora which exerts a barrier effect against enteropathogens. Several E coli strains develop a protective effect against other Enterobacteriaceae.
AIMS—Two E coli strains, EM0, a human faecal strain, and JM105 K-12 were tested for their ability to prevent in vivo and in vitro infection by Salmonella typhimurium C5.
METHODS—Inhibition of C5 cell invasion by E coli was investigated in vitro using Caco-2/TC7 cells. The protective effect of E coli was examined in vivo in germfree or conventional C3H/He/Oujco mice orally infected by the lethal strain C5.
RESULTS—EMO expresses haemolysin and cytotoxic necrotising factor in vitro. In vitro, the two strains did not prevent the growth of C5 by secreted microcins or modified cell invasion of C5. In vivo, establishment of EM0 or JM105 in the gut of germfree mice resulted in a significant increase in the number of surviving mice: 11/12 and 9/12, respectively, at 58 days after infection (2×106/mouse) versus 0/12 in control germfree group at 13 days after infection. Colonisation level and translocation rate of C5 were significantly reduced during the three days after infection. In contrast, no reduction in faecal C5 excretion was observed in C5 infected conventional mice (1×108/mouse) receiving the EM0 or JM105 cultures daily.
CONCLUSIONS—Establishment of E coli strains, which do not display antimicrobial activity, protects germfree mice against infection and delays the establishment of C5 in the gut. Possible mechanisms of defence are discussed.


Keywords: Escherichia coli; gastrointestinal infection; Salmonella; germfree mice; bacterial antagonism PMID:11413110

  14. PROTECTIVE EFFECTS OF PHYLLANTHUS EMBLICA LEAF EXTRACT ON SODIUM ARSENITE-MEDIATED ADVERSE EFFECTS IN MICE

    PubMed Central

    SAYED, SADIA; AHSAN, NAZMUL; KATO, MASASHI; OHGAMI, NOBUTAKA; RASHID, ABDUR; AKHAND, ANWARUL AZIM

    2015-01-01

    ABSTRACT Groundwater contamination of arsenic is the major cause of a serious health hazard in Bangladesh. No specific treatment is yet available to manage the large number of individuals exposed to arsenic. In this study, we evaluated the protective effects of Phyllanthus emblica (Indian gooseberry or Amla) leaf extract (PLE) on arsenic-mediated toxicity in experimental mice. Male Swiss albino mice were divided into three different groups (n=6/group). ‘Control’ mice received arsenic free water together with normal feed. Mice in the remaining two groups designated ‘SA’ and ‘SA+PLE’ were exposed to sodium arsenite (SA, 10 µg/g body weight/day) through drinking water in addition to receiving normal feed and PLE-supplemented feed, respectively. The weight gain of SA-exposed mice was decreased compared with the controls; however, this decrease in body weight gain was prevented when the feed was supplemented with PLE. A secondary effect of arsenic was enlargement of the liver, kidney and spleen of SA-group mice. Deposition of arsenic in those organs was demonstrated by ICP-MS. When PLE was supplemented in the feed the enlargement of the organs was minimized; however, the deposition of arsenic was not significantly reduced. These results indicated that PLE may not block arsenic deposition in tissue directly but rather may play a protective role to reduce arsenic-induced toxicity. Therefore, co-administration of PLE in arsenic-exposed animals might have a future therapeutic application for protecting against arsenic-mediated toxicity. PMID:25797979

  15. 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

  16. 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

  17. Nrf2 activation protects the liver from ischemia/ reperfusion injury in mice

    PubMed Central

    Kudoh, Kazuhiro; Uchinami, Hiroshi; Yoshioka, Masato; Seki, Ekihiro; Yamamoto, Yuzo

    2014-01-01

    Objective To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Summary Background Data Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Methods Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. Results After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Conclusions Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery. PMID:24368646

  18. Establishing Substantial Equivalence: Transcriptomics

    NASA Astrophysics Data System (ADS)

    Baudo, María Marcela; Powers, Stephen J.; Mitchell, Rowan A. C.; Shewry, Peter R.

    Regulatory authorities in Western Europe require transgenic crops to be substantially equivalent to conventionally bred forms if they are to be approved for commercial production. One way to establish substantial equivalence is to compare the transcript profiles of developing grain and other tissues of transgenic and conventionally bred lines, in order to identify any unintended effects of the transformation process. We present detailed protocols for transcriptomic comparisons of developing wheat grain and leaf material, and illustrate their use by reference to our own studies of lines transformed to express additional gluten protein genes controlled by their own endosperm-specific promoters. The results show that the transgenes present in these lines (which included those encoding marker genes) did not have any significant unpredicted effects on the expression of endogenous genes and that the transgenic plants were therefore substantially equivalent to the corresponding parental lines.

  19. Protective immunity in mice achieved with dry powder formulation and alternative delivery of plague F1-V vaccine.

    PubMed

    Huang, Joanne; D'Souza, Ajit J; Alarcon, Jason B; Mikszta, John A; Ford, Brandi M; Ferriter, Matthew S; Evans, Michelle; Stewart, Todd; Amemiya, Kei; Ulrich, Robert G; Sullivan, Vincent J

    2009-05-01

    The potential use of Yersinia pestis as a bioterror agent is a great concern. Development of a stable powder vaccine against Y. pestis and administration of the vaccine by minimally invasive methods could provide an alternative to the traditional liquid formulation and intramuscular injection. We evaluated a spray-freeze-dried powder vaccine containing a recombinant F1-V fusion protein of Y. pestis for vaccination against plaque in a mouse model. Mice were immunized with reconstituted spray-freeze-dried F1-V powder via intramuscular injection, microneedle-based intradermal delivery, or noninvasive intranasal administration. By intramuscular injection, the reconstituted powder induced serum antibody responses and provided protection against lethal subcutaneous challenge with 1,000 50% lethal doses of Y. pestis at levels equivalent to those elicited by unprocessed liquid formulations (70 to 90% protection). The feasibility of intradermal and intranasal delivery of reconstituted powder F1-V vaccine was also demonstrated. Overall, microneedle-based intradermal delivery was shown to be similar in efficacy to intramuscular injection, while intranasal administration required an extra dose of vaccine to achieve similar protection. In addition, the results suggest that seroconversion against F1 may be a better predictor of protection against Y. pestis challenge than seroconversion against either F1-V or V. In summary, we demonstrate the preclinical feasibility of using a reconstituted powder F1-V formulation and microneedle-based intradermal delivery to provide protective immunity against plague in a mouse model. Intranasal delivery, while feasible, was less effective than injection in this study. The potential use of these alternative delivery methods and a powder vaccine formulation may result in substantial health and economic benefits.

  20. Molecular decoys: ligand-binding recombinant proteins protect mice from curarimimetic neurotoxins.

    PubMed Central

    Gershoni, J M; Aronheim, A

    1988-01-01

    Mimic ligand-binding sites of the nicotinic acetylcholine receptor bind d-tubocurarine and alpha-bungarotoxin in vitro. Injection of such binding sites into mice could act as molecular decoys in vivo, providing protection against toxic ligands. This hypothesis of molecular "decoyance" has been tested in greater than 250 mice. Bacterially produced cholinergic binding sites provided a 2-fold increase in the survival rate of animals challenged with curarimimetic neurotoxins. Possible considerations for decoy designs and their applications are discussed. Images PMID:3375254

  1. Vaccine Protection against Bacillus cereus-Mediated Respiratory Anthrax-Like Disease in Mice

    PubMed Central

    Oh, So-Young; Maier, Hannah; Schroeder, Jay; Richter, G. Stefan; Elli, Derek; Musser, James M.; Quenee, Lauriane E.; Missiakas, Dominique M.

    2013-01-01

    Bacillus cereus strains harboring a pXO1-like virulence plasmid cause respiratory anthrax-like disease in humans, particularly in welders. We developed mouse models for intraperitoneal as well as aerosol challenge with spores of B. cereus G9241, harboring pBCXO1 and pBC218 virulence plasmids. Compared to wild-type B. cereus G9241, spores with a deletion of the pBCXO1-carried protective antigen gene (pagA1) were severely attenuated, whereas spores with a deletion of the pBC218-carried protective antigen homologue (pagA2) were not. Anthrax vaccine adsorbed (AVA) immunization raised antibodies that bound and neutralized the pagA1-encoded protective antigen (PA1) but not the PA2 orthologue encoded by pagA2. AVA immunization protected mice against a lethal challenge with spores from B. cereus G9241 or B. cereus Elc4, a strain that had been isolated from a fatal case of anthrax-like disease. As the pathogenesis of B. cereus anthrax-like disease in mice is dependent on pagA1 and PA-neutralizing antibodies provide protection, AVA immunization may also protect humans from respiratory anthrax-like death. PMID:23319564

  2. Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets.

    PubMed

    Wang, Lulan; Liu, Su-Yang; Chen, Hsiang-Wen; Xu, Juan; Chapon, Maxime; Zhang, Tao; Zhou, Fan; Wang, Yao E; Quanquin, Natalie; Wang, Guiqin; Tian, Xiaoli; He, Zhanlong; Liu, Longding; Yu, Wenhai; Sanchez, David Jesse; Liang, Yuying; Jiang, Taijiao; Modlin, Robert; Bloom, Barry R; Li, Qihan; Deng, Jane C; Zhou, Paul; Qin, F Xiao-Feng; Cheng, Genhong

    2017-03-08

    New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

  3. 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

  4. In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin.

    PubMed

    Maher, Ahmed; Radwan, Rasha; Breitinger, Hans-Georg

    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.

  5. Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice.

    PubMed

    Deal, Cailin; Balazs, Alejandro B; Espinosa, Diego A; Zavala, Fidel; Baltimore, David; Ketner, Gary

    2014-08-26

    Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.

  6. 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.

  7. Protective effect of geranylgeranylacetone on trinitrobenzene sulfonic acid-induced colitis in mice.

    PubMed

    Ohkawara, Tatsuya; Nishihira, Jun; Takeda, Hiroshi; Katsurada, Takehiko; Kato, Kanji; Yoshiki, Takashi; Sugiyama, Toshiro; Asaka, Masahiro

    2006-02-01

    Geranylgeranylacetone (GGA) has recently been reported to have a protective effect against ischemic, injurious and apoptotic stress in several tissues. The aim of this study was to determine the effect of GGA on colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. Colitis was induced by intrarectal instillation of TNBS in 50% ethanol in BALB/c mice. Survival, change in body weight and change in wet colon weight were assessed. Histological score in the colon was evaluated 5 days after TNBS treatment. The level of myeloperoxidase (MPO) activity in the colon was also determined. Immunohistochemistry for CD4 in the colon was performed. In addition, the level of heat shock protein (HSP) 70 in the colon was determined by Western blot analysis. Mice were orally treated with GGA (300 mg/kg) 2 h before and every other day after starting TNBS administration. Treatment with GGA markedly improved the survival rate, and reduced the loss of body weight and loss of wet colon weight in mice with TNBS-induced colitis. GGA also suppressed the increase in MPO activity and the number of CD4-positive cells infiltrating the colons of mice with TNBS-induced colitis. Furthermore, treatment with GGA remarkably up-regulated the expression of HSP70 in the colons of mice with TNBS-induced colitis. Our results provide further evidence that GGA has therapeutic potential for intestinal inflammation.

  8. STAT1 signaling is essential for protection against Cryptococcus neoformans infection in mice.

    PubMed

    Leopold Wager, Chrissy M; Hole, Camaron R; Wozniak, Karen L; Olszewski, Michal A; Wormley, Floyd L

    2014-10-15

    Nonprotective immune responses to highly virulent Cryptococcus neoformans strains, such as H99, are associated with Th2-type cytokine production, alternatively activated macrophages, and inability of the host to clear the fungus. In contrast, experimental studies show that protective immune responses against cryptococcosis are associated with Th1-type cytokine production and classical macrophage activation. The protective response induced during C. neoformans strain H99γ (C. neoformans strain H99 engineered to produce murine IFN-γ) infection correlates with enhanced phosphorylation of the transcription factor STAT1 in macrophages; however, the role of STAT1 in protective immunity to C. neoformans is unknown. The current studies examined the effect of STAT1 deletion in murine models of protective immunity to C. neoformans. Survival and fungal burden were evaluated in wild-type and STAT1 knockout (KO) mice infected with either strain H99γ or C. neoformans strain 52D (unmodified clinical isolate). Both strains H99γ and 52D were rapidly cleared from the lungs, did not disseminate to the CNS, or cause mortality in the wild-type mice. Conversely, STAT1 KO mice infected with H99γ or 52D had significantly increased pulmonary fungal burden, CNS dissemination, and 90-100% mortality. STAT1 deletion resulted in a shift from Th1 to Th2 cytokine bias, pronounced lung inflammation, and defective classical macrophage activation. Pulmonary macrophages from STAT1 KO mice exhibited defects in NO production correlating with inefficient inhibition of fungal proliferation. These studies demonstrate that STAT1 signaling is essential not only for regulation of immune polarization but also for the classical activation of macrophages that occurs during protective anticryptococcal immune responses.

  9. 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.

  10. 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.

  11. γδ T cells are indispensable for interleukin-23-mediated protection against Concanavalin A-induced hepatitis in hepatitis B virus transgenic mice.

    PubMed

    Meng, Ziyu; Wang, Jingya; Yuan, Yifang; Cao, Guangchao; Fan, Shuobing; Gao, Chao; Wang, Li; Li, Zheng; Wu, Xiaoli; Wu, Zhenzhou; Zhao, Liqing; Yin, Zhinan

    2017-05-01

    Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between γδ T cells and liver damage in patients with hepatitis B virus (HBV). However, whether γδ T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation-induced hepatitis is unknown. In this study, using HBV transgenic (HBs-Tg) and HBs-Tg T-cell receptor-δ-deficient (TCR-δ(-/-) ) mice, we found that mice genetically deficient in γδ T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon-γ (IFN-γ) levels and more extensive necrosis. γδ T-cell deficiency resulted in elevated IFN-γ in CD4(+) T cells but not in natural killer or natural killer T cells. The depletion of CD4(+) T cells and neutralization of IFN-γ reduced liver damage in HBs-Tg and HBs-Tg-TCR-δ(-/-) mice to a similar extent. Further investigation revealed that HBs-Tg mice showed an enhanced interleukin-17 (IL-17) signature. The administration of exogenous IL-23 enhanced IL-17A production from Vγ4 γδ T cells and ameliorated liver damage in HBs-Tg mice, but not in HBs-Tg-TCR-δ(-/-) mice. In summary, our results demonstrated that γδ T cells played a protective role in restraining Con A-induced hepatitis by inhibiting IFN-γ production from CD4(+) T cells and are indispensable for IL-23-mediated protection against Con A-induced hepatitis in HBs-Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation-induced liver damage.

  12. Quantitative relationship between anticapsular antibody measured by enzyme-linked immunosorbent assay or radioimmunoassay and protection of mice against challenge with Streptococcus pneumoniae serotype 4.

    PubMed Central

    Musher, D M; Johnson, B; Watson, D A

    1990-01-01

    We have recently shown that a substantial proportion of antibody to pneumococcal polysaccharide as measured by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay is removed by adsorption with pneumococcal cell wall polysaccharide (CWPS). The present study was undertaken to validate the hypothesis that only serotype-specific antibody that remains after adsorption with CWPS provides protection against pneumococcal infection. Serum samples were obtained from human subjects before and after they had been vaccinated with pneumococcal polysaccharide vaccine. Antibody to Streptococcus pneumoniae serotype 4 was measured by ELISA without adsorption or after adsorption of serum with CWPS. Groups of mice were injected with graded doses of serum and then challenged intraperitoneally with 10, 100, or 1,000 50% lethal doses (LD50) of S. pneumoniae serotype 4. Without adsorption, prevaccination sera from five healthy adults appeared to contain up to 33 micrograms of antibody to S. pneumoniae serotype 4 antigen per ml; adsorption with CWPS removed all detectable antibody, and pretreating mice with up to 0.1 ml of these sera (less than or equal to 3.3 micrograms of antibody) failed to protect them against challenge with 100 LD50. In contrast, postvaccination sera contained 2.9 to 30 micrograms of antibody per ml that was not removed by adsorption. Diluting sera to administer desired amounts of serotype-specific immunoglobulin G showed a significant relationship between protection and antibody remaining after adsorption (P less than 0.05 by linear regression analysis); 150 ng was uniformly protective against 1,000 LD50, and 50 ng was protective against 100 LD50. These studies have, for the first time, quantitated the amount of serotype-specific antibody that protects mice against challenge with S. pneumoniae type 4. In light of these observations, it is necessary to reassess current concepts regarding the presence of antipneumococcal antibody in the unvaccinated

  13. Mucosal immunization with Shigella flexneri outer membrane vesicles induced protection in mice.

    PubMed

    Camacho, A I; de Souza, J; Sánchez-Gómez, S; Pardo-Ros, M; Irache, J M; Gamazo, C

    2011-10-26

    Vaccination appears to be the only rational prophylactic approach to control shigellosis. Unfortunately, there is still no safe and efficacious vaccine available. We investigated the protection conferred by a new vaccine containing outer membrane vesicles (OMVs) from Shigella flexneri with an adjuvant based on nanoparticles in an experimental model of shigellosis in mice. OMVs were encapsulated in poly(anhydride) nanoparticles prepared by a solvent displacement method with the copolymer PMV/MA. OMVs loaded into NPs (NP-OMVs) were homogeneous and spherical in shape, with a size of 197nm (PdI=0.06). BALB/c mice (females, 9-week-old, 20±1g) were immunized by intradermal, nasal, ocular (20μg) or oral route (100μg) with free or encapsulated OMV. Thirty-five days after administration, mice were infected intranasally with a lethal dose of S. flexneri (1×10(7)CFU). The new vaccine was able to protect fully against infection when it was administered via mucosa. By intradermal route the NP-OMVs formulation increased the protection from 20%, obtained with free extract, to 100%. Interestingly, both OMVs and OMV-NP induced full protection when administered by the nasal and conjuntival route. A strong association between the ratio of IL-12p40/IL-10 and protection was found. Moreover, low levels of IFN-γ correlate with protection. Under the experimental conditions used, the adjuvant did not induce any adverse effects. These results place OMVs among promising candidates to be used for vaccination against Shigellosis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. 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

  15. 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.

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26644583

  17. Eicosapentaenoic acid decreases TNF-α and protects dystrophic muscles of mdx mice from degeneration.

    PubMed

    Machado, Rafael Ventura; Mauricio, Adriana Fogagnolo; Taniguti, Ana Paula Tiemi; Ferretti, Renato; Neto, Humberto Santo; Marques, Maria Julia

    2011-03-01

    In dystrophin-deficient fibers of mdx mice and in Duchenne muscular dystrophy, inflammation and increased production of tumor necrosis factor alpha (TNF-α) contribute to myonecrosis. We examined the effects of eicosapentaenoic acid (EPA) on dystrophic muscle degeneration. Mdx mice (14 days old) received EPA for 16 days. The sternomastoid, diaphragm and biceps brachii muscles were removed. Control mdx mice received vehicle. EPA decreased creatine kinase and myonecrosis and reduced the levels of TNF-α. These results suggest that EPA plays a protective role in dystrophic muscle degeneration, possibly by reducing TNF-α, and support further investigations of EPA as a potential therapy for dystrophinopathies. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. Immunization with truncated envelope protein of Zika virus induces protective immune response in mice.

    PubMed

    Han, Jian-Feng; Qiu, Yang; Yu, Jiu-Yang; Wang, Hong-Jiang; Deng, Yong-Qiang; Li, Xiao-Feng; Zhao, Hui; Sun, Han-Xiao; Qin, Cheng-Feng

    2017-08-30

    The global spread of Zika virus (ZIKV) as well as its unexpected link to infant microcephaly have resulted in serious public health concerns. No antiviral drugs against ZIKV is currently available, and vaccine development is of high priority to prepare for potential ZIKV pandemic. In the present study, a truncated E protein with the N-terminal 90% region reserved (E90) from a contemporary ZIKV strain was cloned and expressed in Escherichia coli, purified by a Ni-NTA column, and characterized by Western blotting assays. Immunization with recombinant E90 induced robust ZIKV-specific humoral response in adult BALB/c mice. Passive transfer of the antisera from E90-immunized mice conferred full protection against lethal ZIKV challenge in a neonatal mice model. Our results indicate that recombinant ZIKV E90 described here represents as a promising ZIKV subunit vaccine that deserves further clinical development.

  19. Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis.

    PubMed

    Sionov, Edward; Mayer-Barber, Katrin D; Chang, Yun C; Kauffman, Keith D; Eckhaus, Michael A; Salazar, Andres M; Barber, Daniel L; Kwon-Chung, Kyung J

    2015-08-01

    Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6Chigh monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses.

  20. Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice.

    PubMed

    Ban, Kechen; Peng, Zhanglong; Pati, Shibani; Witkov, Richard B; Park, Pyong Woo; Kozar, Rosemary A

    2015-11-01

    We have shown in a rodent model of hemorrhagic shock (HS) that fresh frozen plasma (FFP) reduces lung inflammation and injury that are correlated with restitution of syndecan-1. As the gut is believed to contribute to distant organ injury and inflammation after shock, the current study sought to determine if the protective effects of plasma would extend to the gut and to elucidate the contribution of syndecan-1 to this protective effect. We also examined the potential role of TNFα, and a disintegrin and metalloproteinase (ADAM)-17, both intestinal sheddases of syndecan-1. Wild-type (WT) and syndecan-1 (KO) mice were subjected to HS followed by resuscitation with lactated Ringer's (LR) or FFP and compared with shock alone and shams. Small bowel and blood were obtained after 3  h for analysis of mucosal injury and inflammation and TNFα and ADAM-17 protein expression and activity. After HS, gut injury and inflammation were significantly increased compared with shams. Resuscitation with LR decreased both injury and inflammation that were further lessened by FFP. KO mice displayed worsened gut injury and inflammation after HS compared with WT mice, and LR and FFP equivalently inhibited injury and inflammation. Both systemic and intestinal TNFα and ADAM-17 followed similar trends, with increases after HS, reduction by LR, and a further decrease by FFP in WT but not KO mice. In conclusion, FFP decreased gut injury and inflammation after hemorrhagic shock, an effect that was abrogated in syndecan-1 mice. Plasma also decreased TNFα and ADAM-17, representing a potential mechanistic link to its protection via syndecan-1.

  1. Lacteal immunity to enteric cryptosporidiosis in mice: immune dams do not protect their suckling pups.

    PubMed Central

    Moon, H W; Woodmansee, D B; Harp, J A; Abel, S; Ungar, B L

    1988-01-01

    The susceptibilities of passively immunized principal and nonimmunized control suckling mice to orogastric challenge with Cryptosporidium parvum oocysts were compared. Principals were suckled by dams that had recovered from C. parvum infection. Controls were suckled by dams reared free of C. parvum infection. Principals and controls were equally susceptible to challenge. Principals were susceptible even when their dams were hyperimmunized by oral and parenteral booster inoculations with C. parvum oocysts. Immune dams produced serum antibody against C. parvum, while nonimmune dams did not. Anti-cryptosporidia immunoglobulin G (IgG) and IgA were demonstrated in whey extracted from the stomachs of principals that had suckled immune dams but not in whey extracted from the stomachs of controls. It was concluded that passive lacteal immunity is not an efficient means of protection against cryptosporidiosis in mice. As in other coccidian infections, protective immunity against cryptosporidiosis may depend more on immune cells than on antibody. PMID:3343052

  2. Passive Immunization against Cachectin/Tumor Necrosis Factor Protects Mice from Lethal Effect of Endotoxin

    NASA Astrophysics Data System (ADS)

    Beutler, B.; Milsark, I. W.; Cerami, A. C.

    1985-08-01

    A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin.

  3. MERS-CoV spike nanoparticles protect mice from MERS-CoV infection.

    PubMed

    Coleman, Christopher M; Venkataraman, Thiagarajan; Liu, Ye V; Glenn, Gregory M; Smith, Gale E; Flyer, David C; Frieman, Matthew B

    2017-03-14

    The Middle East respiratory syndrome coronavirus (MERS-CoV) was first discovered in late 2012 and has gone on to cause over 1800 infections and 650 deaths. There are currently no approved therapeutics or vaccinations for MERS-CoV. The MERS-CoV spike (S) protein is responsible for receptor binding and virion entry to cells, is immunodominant and induces neutralizing antibodies in vivo, all of which, make the S protein an ideal target for anti-MERS-CoV vaccines. In this study, we demonstrate protection induced by vaccination with a recombinant MERS-CoV S nanoparticle vaccine and Matrix-M1 adjuvant combination in mice. The MERS-CoV S nanoparticle vaccine produced high titer anti-S neutralizing antibody and protected mice from MERS-CoV infection in vivo.

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

    PubMed

    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

    2017-06-07

    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.

  5. 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

  6. Baicalein protects mice against radiation-induced DNA damages and genotoxicity.

    PubMed

    Gandhi, Nitin Motilal

    2013-07-01

    Baicalein is the major flavonoid extracted from the root of Scutellaria baicaleins. This flavonoid is used extensively in Chinese herbal medicine. In the present study baicalein is evaluated for its radioprotective properties. Human blood cells when exposed to the γ-radiation ex vivo in presence of baicalein underwent the reduced DNA damage compared to the control. Baicalein administration prior to the whole-body γ-radiation (4 Gy) exposure of mice resulted in protecting the damage to the DNA as measured in their blood cells by alkaline comet assay. Mice when exposed to the radiation (whole body; 1.7 Gy) resulted in damage to the bone marrow as measured by micronucleated reticulocyte (MNRET) formation. Baicalein pre-treatment reduces the radiation induced damage to the bone marrow cells, as there was decrease in the percentage MNRET formation. These findings indicate radio-protecting ability of baicalein.

  7. Lacteal immunity to enteric cryptosporidiosis in mice: immune dams do not protect their suckling pups.

    PubMed

    Moon, H W; Woodmansee, D B; Harp, J A; Abel, S; Ungar, B L

    1988-03-01

    The susceptibilities of passively immunized principal and nonimmunized control suckling mice to orogastric challenge with Cryptosporidium parvum oocysts were compared. Principals were suckled by dams that had recovered from C. parvum infection. Controls were suckled by dams reared free of C. parvum infection. Principals and controls were equally susceptible to challenge. Principals were susceptible even when their dams were hyperimmunized by oral and parenteral booster inoculations with C. parvum oocysts. Immune dams produced serum antibody against C. parvum, while nonimmune dams did not. Anti-cryptosporidia immunoglobulin G (IgG) and IgA were demonstrated in whey extracted from the stomachs of principals that had suckled immune dams but not in whey extracted from the stomachs of controls. It was concluded that passive lacteal immunity is not an efficient means of protection against cryptosporidiosis in mice. As in other coccidian infections, protective immunity against cryptosporidiosis may depend more on immune cells than on antibody.

  8. 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.

  9. 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.

  10. Aerosol Vaccination Induces Robust Protective Immunity to Homologous and Heterologous Influenza Infection in Mice

    PubMed Central

    Smith, Jennifer Humberd; Brooks, Paula; Johnson, Scott; Tompkins, S. Mark; Custer, Koren M.; Haas, Debra L.; Mair, Raydel; Papania, Mark; Tripp, Ralph A.

    2011-01-01

    Live-attenuated influenza vaccine (LAIV) delivered by large droplet intranasal spray is efficacious against infection. However, many of the large droplets are trapped in the external nares and do not reach the target nasal airway tissues. Smaller droplets might provide better distribution yielding similar protection with lower doses. We evaluated 20 and 30 micron aerosol delivery of influenza virus in mice. A 15 second aerosol exposure optimally protected against homologous and heterologous influenza infection and induced a robust immune response. These results demonstrate the feasibility of nasal vaccination using aerosolized particles, providing a strategy to improve vaccine efficacy and delivery. PMID:21300100

  11. Establishing Substantial Equivalence: Metabolomics

    NASA Astrophysics Data System (ADS)

    Beale, Michael H.; Ward, Jane L.; Baker, John M.

    Modern ‘metabolomic’ methods allow us to compare levels of many structurally diverse compounds in an automated fashion across a large number of samples. This technology is ideally suited to screening of populations of plants, including trials where the aim is the determination of unintended effects introduced by GM. A number of metabolomic methods have been devised for the determination of substantial equivalence. We have developed a methodology, using [1H]-NMR fingerprinting, for metabolomic screening of plants and have applied it to the study of substantial equivalence of field-grown GM wheat. We describe here the principles and detail of that protocol as applied to the analysis of flour generated from field plots of wheat. Particular emphasis is given to the downstream data processing and comparison of spectra by multivariate analysis, from which conclusions regarding metabolome changes due to the GM can be assessed against the background of natural variation due to environment.

  12. Oral Administration of Fermented Soymilk Products Protects the Skin of Hairless Mice against Ultraviolet Damage

    PubMed Central

    Kano, Mitsuyoshi; Kubota, Norihiro; Masuoka, Norie; Hori, Tetsuji; Miyazaki, Kouji; Ishikawa, Fumiyasu

    2016-01-01

    The protective effect of isoflavones on skin damage from ultraviolet (UV) radiation and their bioavailability were investigated in ovariectomized hairless mice fed diets composed of fermented soymilk containing aglycone forms of isoflavones or control soymilk containing glucose-conjugated forms of isoflavones. The erythema intensity of dorsal skin was significantly higher in ovariectomized mice than in sham-operated mice (p < 0.05). The erythema intensity and epidermal thickness of dorsal skin were significantly lower in the fermented soymilk diet group than in the control diet group (each p < 0.05). Levels of cyclobutane pyrimidine dimers in dorsal skin were significantly lower in the fermented soymilk diet group than in the control group (p < 0.05). Serum and dorsal skin isoflavone concentrations were significantly higher in the fermented soymilk diet group than in the soymilk diet group (p < 0.05). These results indicate that oral administration of a fermented soymilk diet increases isoflavone concentrations in the blood and skin, effectively scavenging the reactive oxygen species generated by UV irradiation and exerting an estrogen-like activity, with a consequent protective effect on skin photodamage in hairless mice. PMID:27556484

  13. Protective effect of naringin against ankylosing spondylitis via ossification, inflammation and oxidative stress in mice.

    PubMed

    Liu, Kang; Wu, Lianguo; Shi, Xiaolin; Wu, Fengqing

    2016-08-01

    Naringin is an abundant flavanone in pomelo, grapefruit as well as lime and its variants, has been shown to exhibit certain antioxidative, anti-inflammatory, anti-cancer and hypoglycemic effects. The aim of the current study was to evaluate the protective effects of naringin against ankylosing spondylitis (AS) and to elucidate the potential underlying mechanism. Firstly, a mouse model of ankylosing spondylitis (AS) was established. Next, osteocalcin (OC), alkaline phosphatase (ALP) and triglyceride (TG) activity values, inflammatory factor and oxidative stress were evaluated in the AS mice. Then, the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) protein expression levels in the AS mice were investigated using western blot analysis. The results showed that naringin increased OC, ALP and TG activity values in the AS mouse model. Furthermore, inflammatory factor and oxidative stress levels in the AS mice were restrained by treatment with naringin. Furthermore, JAK2 and STAT3 protein expression levels were reduced by treatment with naringin. In conclusion, the present results indicated that the protective effects of naringin against AS are exerted via the induction of ossification, suppression of inflammation and oxidative stress and the downregulation of JAK2/STAT3 in mice.

  14. Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production.

    PubMed Central

    Danenberg, H D; Alpert, G; Lustig, S; Ben-Nathan, D

    1992-01-01

    Recent reports have demonstrated an immunomodulating activity of dehydroepiandrosterone (DHEA) different from that described for glucocorticoids. The present study was designed to test DHEA's activity in endotoxic shock and to investigate its effect on endotoxin-induced production of tumor necrosis factor (TNF). Mortality of CD-1 mice exposed to a lethal dose of lipopolysaccharide (LPS; 800 micrograms per mouse) was reduced from 95 to 24% by treatment with a single dose of DHEA, given 5 min before LPS. LPS administration resulted in high levels of TNF, a response that was significantly blocked by DHEA, both in vivo and in vitro. DHEA treatment also reduced LPS-induced increments in serum corticosterone levels, a parameter considered not to be mediated by TNF. In another experimental model, mice sensitized with D-galactosamine, followed by administration of recombinant human TNF, were subjected to 89% mortality rate, which was reduced to 55% in DHEA-treated mice. These data show that DHEA protects mice from endotoxin lethality. The protective effect is probably mediated by reduction of TNF production as well as by effecting both TNF-induced and non-TNF-induced phenomena. PMID:1444309

  15. 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.

  16. 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.

  17. Protective effect of naringin against ankylosing spondylitis via ossification, inflammation and oxidative stress in mice

    PubMed Central

    Liu, Kang; Wu, Lianguo; Shi, Xiaolin; Wu, Fengqing

    2016-01-01

    Naringin is an abundant flavanone in pomelo, grapefruit as well as lime and its variants, has been shown to exhibit certain antioxidative, anti-inflammatory, anti-cancer and hypoglycemic effects. The aim of the current study was to evaluate the protective effects of naringin against ankylosing spondylitis (AS) and to elucidate the potential underlying mechanism. Firstly, a mouse model of ankylosing spondylitis (AS) was established. Next, osteocalcin (OC), alkaline phosphatase (ALP) and triglyceride (TG) activity values, inflammatory factor and oxidative stress were evaluated in the AS mice. Then, the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) protein expression levels in the AS mice were investigated using western blot analysis. The results showed that naringin increased OC, ALP and TG activity values in the AS mouse model. Furthermore, inflammatory factor and oxidative stress levels in the AS mice were restrained by treatment with naringin. Furthermore, JAK2 and STAT3 protein expression levels were reduced by treatment with naringin. In conclusion, the present results indicated that the protective effects of naringin against AS are exerted via the induction of ossification, suppression of inflammation and oxidative stress and the downregulation of JAK2/STAT3 in mice. PMID:27446336

  18. 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

  19. Protective Effects of Lactobacillus plantarum CCFM8610 against Acute Cadmium Toxicity in Mice

    PubMed Central

    Zhai, Qixiao; Wang, Gang; Zhao, Jianxin; Liu, Xiaoming; Zhang, Hao

    2013-01-01

    This study evaluated the protective effects of Lactobacillus plantarum CCFM8610, a selected probiotic with good cadmium binding capacity, against acute cadmium toxicity in mice. Ninety mice were divided into prevention and therapy groups. In the prevention groups, CCFM8610 was administered at 109 CFU once daily for 7 days, followed by a single oral dose of cadmium chloride at 1.8 mg cadmium for each mouse. In the therapy groups, the same dose of CCFM8610 was administered for 2 days after an identical single dose of cadmium exposure. Mice that received neither cadmium nor culture or that received cadmium alone served as negative and positive controls, respectively. The effects of both living and dead CCFM8610 on cadmium ion concentrations in feces, liver, and kidney were determined. Moreover, the alterations in reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and histopathology in the liver and kidney were investigated. The results showed that compared to the mice that received cadmium only, CCFM8610 treatment can effectively decrease intestinal cadmium absorption, reduce tissue cadmium accumulation, alleviate renal and hepatic oxidative stress, and ameliorate hepatic histopathological changes. Living CCFM8610 administered after cadmium exposure offered the most significant protection. Our results suggested that CCFM8610 is more effective against acute cadmium toxicity than a simple antioxidant treatment due to its special physiological functions and that it can be considered a new dietary therapeutic strategy against acute cadmium toxicity. PMID:23263961

  20. Renal Protective Effects of 17β-Estradiol on Mice with Acute Aristolochic Acid Nephropathy.

    PubMed

    Shi, Min; Ma, Liang; Zhou, Li; Fu, Ping

    2016-10-18

    Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by a Chinese herb containing aristolochic acid. Excessive death of renal tubular epithelial cells (RTECs) characterized the acute phase of AAN. Therapies for acute AAN were limited, such as steroids and angiotensin-receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACEIs). It was interesting that, in acute AAN, female patients showed relative slower progression to renal failure than males. In a previous study, female hormone 17β-estradiol (E2) was found to attenuate renal ischemia-reperfusion injury. Thus, the aim of this study was to investigate the potential protective role of E2 in acute AAN. Compared with male C57BL/6 mice of acute AAN, lower serum creatinine (SCr) and less renal injury, together with RTEC apoptosis in females, were found. Treatment with E2 in male AAN mice reduced SCr levels and attenuated renal tubular injury and RTEC apoptosis. In the mice kidney tissue and human renal proximal tubule cells (HK-2 cells), E2 both attenuated AA-induced cell apoptosis and downregulated the expression of phosphor-p53 (Ser15), p53, and cleaved-caspase-3. This study highlights that E2 exhibited protective effects on the renal injury of acute AAN in male mice by reducing RTEC apoptosis, which might be related to inhibiting the p53 signaling pathway.

  1. Long-Term Antithrombotic Protection by in Vivo Depletion of Platelet Glycoprotein VI in Mice

    PubMed Central

    Nieswandt, Bernhard; Schulte, Valerie; Bergmeier, Wolfgang; Mokhtari-Nejad, Rabée; Rackebrandt, Kirsten; Cazenave, Jean-Pierre; Ohlmann, Philippe; Gachet, Christian; Zirngibl, Hubert

    2001-01-01

    Coronary artery thrombosis is often initiated by abrupt disruption of the atherosclerotic plaque and activation of platelets on the subendothelial layers in the disrupted plaque. The extracellular matrix protein collagen is the most thrombogenic constituent of the subendothelial layer; therefore, a selective inhibition of the collagen activation pathway in platelets may provide strong antithrombotic protection while preserving other platelet functions. Here we demonstrate that treatment of mice with a monoclonal antibody against the activating platelet collagen receptor glycoprotein VI (GPVI; JAQ1) results in specific depletion of the receptor from circulating platelets and abolished responses of these cells to collagen and collagen-related peptides (CRPs). JAQ1-treated mice were completely protected for at least 2 wk against lethal thromboembolism induced by infusion of a mixture of collagen (0.8 mg/kg) and epinephrine (60 μg/ml). The tail bleeding times in JAQ1-treated mice were only moderately increased compared with control mice probably because the treatment did not affect platelet activation by other agonists such as adenosine diphosphate or phorbol myristate acetate. These results suggest that GPVI might become a target for long-term prophylaxis of ischemic cardiovascular diseases and provide the first evidence that it is possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo. PMID:11181698

  2. Cellular glutathione peroxidase protects mice against lethal oxidative stress induced by various doses of diquat.

    PubMed

    Fu, Y; Cheng, W H; Ross, D A; Lei, X g

    1999-11-01

    This study was to determine if cellular glutathione peroxidase (GPX1) protects against acute oxidative stress induced by diquat. Lethality and hepatic biochemical indicators in GPX1 knockout mice [GPX1(-/-)] were compared with those of wild-type mice (WT) after an intraperitoneal injection of diquat at 6, 12, 24, or 48 mg/kg of body weight. Although the WT survived all the doses, the GPX1(-/-) survived only 6 mg diquat/kg and were killed by 12, 24, and 48 mg diquat/kg at 52, 4.4 and 3.9 hr, respectively. Compared with those of surviving mice that were sacrificed on Day 7, the dead GPX1(-/-) had diquat dose-dependent increases (P < 0.05) in plasma alanine aminotransferase (ALT) activities. The GPX1(-/-) also had higher (P < 0.05) liver carbonyl contents than those of the WT, but the differences were irrespective of diquat doses. Whereas hepatic total GPX and phospholipid hydroperoxide glutathione peroxidase activities or hepatic GPX1 protein was not significantly affected by the diquat treatment, liver thioredoxin reductase and catalase activities were lower (P < 0.05) in the GPX1(-/-) injected with 12 mg diquat/kg than those of other groups. In conclusion, normal GPX1 expression is necessary to protect mice against the lethality, hepatic protein oxidation, and elevation of plasma ALT activity induced by 12-48 mg diquat/kg.

  3. Protective Effects of Metallothionein on Isoniazid and Rifampicin-Induced Hepatotoxicity in Mice

    PubMed Central

    Xu, Peiyu; Wang, Yimei; Zhao, Jun; Jia, Li; Fu, Ze; Jing, Li; Liu, Gang; Peng, Shuangqing

    2013-01-01

    Isoniazid (INH) and Rifampicin (RFP) are widely used in the world for the treatment of tuberculosis, but the hepatotoxicity is a major concern during clinical therapy. Previous studies showed that these drugs induced oxidative stress in liver, and several antioxidants abated this effect. Metallothionein (MT), a member of cysteine-rich protein, has been proposed as a potent antioxidant. This study attempts to determine whether endogenous expression of MT protects against INH and RFP-induced hepatic oxidative stress in mice. Wild type (MT+/+) and MT-null (MT−/−) mice were treated intragastrically with INH (150 mg/kg), RFP (300 mg/kg), or the combination (150 mg/kg INH +300 mg/kg RFP) for 21 days. The results showed that MT−/− mice were more sensitive than MT+/+ mice to INH and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations, increased serum AST levels and liver index, and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status. Furthermore, INH increased the protein expression of hepatic CYP2E1 and INH/RFP (alone or in combination) decreased the expression of hepatic CYP1A2. These findings clearly demonstrate that basal MT provides protection against INH and RFP-induced toxicity in hepatocytes. The CYP2E1 and CYP1A2 were involved in the pathogenesis of INH and RFP-induced hepatotoxicity. PMID:23967274

  4. Dengue Type-2 Virus Envelope Protein Made Using Recombinant Baculovirus Protects Mice Against Virus Challenge

    DTIC Science & Technology

    1994-01-01

    the envelope (E) glycoprotein of dengue 2 virus was cloned into baculovirus (IAutographa californical nuclear polyhedrosis virus, AcNPV). The...polyclonal, anti- dengue type 2 antibody and a dengue type 2-specific, neutralizing monoclonal antibody. Balb/c mice immunized with the recombinant...antigen produced only non-neutralizing antibody against dengue 2 virus but were partially protected against morbidity and mortality after

  5. Humanized Monoclonal Antibody That Passively Protects Mice against Systemic and Intranasal Ricin Toxin Challenge

    PubMed Central

    Sully, Erin K.; Bohorova, Natasha; Bohorov, Ognian; Kim, Do; Pauly, Michael H.; Whaley, Kevin J.

    2016-01-01

    PB10 is a murine monoclonal antibody against an immunodominant epitope on ricin toxin's enzymatic subunit. Here, we characterize a fully humanized version of PB10 IgG1 (hPB10) and demonstrate that it has potent in vitro and in vivo toxin-neutralizing activities. We also report the minimum serum concentrations of hPB10 required to protect mice against 10 times the 50% lethal dose of ricin when delivered by injection and inhalation. PMID:27466351

  6. 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

  7. 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

    2017-03-27

    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.

  8. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

    PubMed

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne; Brandt, Claus; Zerahn, Bo; Pedersen, Bente Klarlund; Gehl, Julie

    2009-06-12

    Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01) in EPO transfected obese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet,) 21.9+/-1.4 g (EPO, normal diet), 35.3+/-3.3 g (control, high-fat diet) and 28.8+/-2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

  9. Erythropoietin Over-Expression Protects against Diet-Induced Obesity in Mice through Increased Fat Oxidation in Muscles

    PubMed Central

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne; Brandt, Claus; Zerahn, Bo; Pedersen, Bente Klarlund; Gehl, Julie

    2009-01-01

    Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo. At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01) in EPO transfected obese mice; thus the mice weighed 21.9±0.8 g (control, normal diet,) 21.9±1.4 g (EPO, normal diet), 35.3±3.3 g (control, high-fat diet) and 28.8±2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass. The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles. In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles. PMID:19521513

  10. Previous immunization of mice with herpes simplex virus type-1 strain MP protects against secondary corneal infection.

    PubMed

    Sandstrom, I K; Foster, C S; Wells, P A; Knipe, D; Caron, L; Greene, M I

    1986-08-01

    Herpes simplex virus (HSV)-induced ocular disease is occurring in epidemic proportions throughout the world, and is the number one cause of unilateral corneal blindness in all developed countries. We have found, in a mouse model of herpes simplex keratitis (HSK), that products encoded by the Igh-1 locus on chromosome 12 exert a profound influence on the immune/inflammatory response in the cornea after HSV inoculation in the cornea. Thus, mice with Igh-1c or Igh-1d phenotype routinely develop extreme keratopathy and loss of corneal clarity after HSV encounter in the eye, while congenic strains expressing other Igh-1 phenotypes develop substantially less keratopathy. We examined the effect of previous subcutaneous immunization with the mutant, less virulent, MP strain of HSV on the development of keratitis and encephalitis after secondary corneal inoculation with strains MP, mP, F, and KOS. A/J mice (Igh-1c), 5-6 weeks old, were injected sc with live HSV-1 strain MP. Controls were injected with culture media without virus. Three weeks later both immunized and control nonimmunized animals were challenged in the cornea with HSV-1, strains MP, mP, F, and KOS. The animals were clinically scored for keratitis and encephalitis at regular intervals for 21 days following corneal challenge. None of the immunized animals challenged in the cornea with strain MP, 5 X 10(4) plaque-forming units (PFU), developed clinical signs of encephalitis compared to 86% of unimmunized controls. Of the immunized animals challenged in the cornea with strain MP, 5 X 10(4) PFU, only 18% developed a mild keratitis, while 96% of unimmunized controls developed severe keratitis. Mice immunized subcutaneously with MP and subsequently challenged corneally with other HSV-1 strains (mP, F, or KOS) were also protected from development of severe keratopathy.

  11. Protection Against H7 Subtype Influenza Virus Infection in Mice by Passive Transfer of Neutralizing Monoclonal Antibody.

    PubMed

    Zhang, Zhuo; Liu, Ming; Zheng, Shimin

    2015-10-01

    H7 subtype influenza viruses pose serious threats to both the poultry industry and public health. Recent human infections of avian H7N9 influenza viruses with substantial morbidity and mortality have raised concerns about this virus becoming a potential pandemic pathogen. Neutralizing antibodies have been proven to be highly effective in blocking influenza virus infections. In this study, in order to develop an antibody-based immunoprophylaxis against H7 subtype influenza virus, we first generated a neutralizing monoclonal antibody (MAb) by using a pseudotyped lentiviral vector carrying the hemagglutinin protein of H7 subtype influenza virus. In vitro studies demonstrated that this neutralizing MAb completely inhibited the infection of an H7 subtype influenza virus to cells. The protective efficacy of this MAb was then further tested in a mouse model. It was shown that passive immunization of this MAb protected mice from local virus challenge. Results of the current study lay a foundation for the development of neutralizing MAb-mediated prophylactic strategies to combat human H7 influenza virus infections.

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

    SciTech Connect

    Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.; Mumtaz, Moiz M.; Latendresse, John R.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    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 lethal 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 systemic

  13. Protective effect of Flt3L on organ structure during advanced multiorgan dysfunction syndrome in mice

    PubMed Central

    TIAN, GUANG; LU, JIANGYANG; GUO, HUIQIN; LIU, QIAN; WANG, HONGWEI

    2015-01-01

    The present study aimed to examine whether fms-related tyrosine kinase 3 ligand (Flt3L) protects the organs of mice with multiorgan dysfunction syndrome (MODS). Male C57BL/6 mice were randomly assigned to normal control, MODS and Flt3L treatment groups. The mouse models of MODS were established using intraperitoneal zymosan injections, followed by normal saline injections. The treatment group received 5 μg/kg Flt3L for seven days, beginning on day five following zymosan injection. On day 12, the mortality rates of the Flt3L treatment and the MODS groups were 7 and 18%, respectively. Marked pathological changes were observed in the liver, lungs, kidneys and heart of the mice with MODS, including degeneration and focal necrosis of parenchyma cells. Mild pathological changes were observed in different organs of the Flt3L-treated mice. In the MODS group, the number of CD4+ T lymphocytes was significantly reduced, whereas the number of CD8+ T lymphocytes was significantly increased compared with that in the normal control group; thus, the CD4+/CD8+ ratio was reduced. In the Flt3L treatment group, the average number of CD4+ T lymphocytes was not significantly different to the average number of CD4+ T lymphocytes in the normal group. In conclusion, Flt3L administration improved the immune status and alleviated the organ damage in mice with late-phase MODS. PMID:25672780

  14. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis

    PubMed Central

    Cabrera, Sandra; Fernández, Álvaro F.; Mariño, Guillermo; Aguirre, Alina; Suárez, María F.; Español, Yaiza; Vega, José A.; Laurà, Rosaria; Fueyo, Antonio; Fernández-García, M. Soledad; Freije, José M.P.; Kroemer, Guido; López-Otín, Carlos

    2013-01-01

    The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b−/− mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b−/− mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency. PMID:23782979

  15. Protective effect of vitamin A on ARA-C induced intestinal damage in mice.

    PubMed

    Elli, Murat; Aydin, Oguz; Bilge, Sirri; Bozkurt, Ayhan; Dagdemir, Ayhan; Pinarli, Faruk Guclu; Acar, Sabri

    2009-01-01

    Cytarabine (ARA-C) has been used for many years in the treatment of patients with leukemia and lymphoma. Gastrointestinal ulceration and mucositis are two of the well-known side effects of ARA-C. We set out to investigate whether vitamin A (VA) can help prevent ARA-C-induced mucosal lesions in mice. Mice were divided into 5 groups. Group I (control group) received only saline; group II received ARA-C plus saline; group III received ARA-C plus VA; group IV received ARA-C plus a lipid solution, and group V received VA alone. VA (5000 IU/kg) was administered orally to the mice once daily for 7 days. ARA-C (3.6 mg) was administered intraperitoneally for 5 days to groups II, III and IV, starting on the third day of VA treatment. Intestinal segments from the proximal end of the jejunum of treated mice were isolated. There was improved mucosal integrity, less necrosis and increased villus length with advanced mucosal proliferation in crypts in the VA plus ARA-C group when compared to the ARA-C groups without VA. We conclude that VA has a protective effect against ARA-C-induced mucosal damage in mice.

  16. Protective effect of polyclonal and monoclonal antibodies against abortion in mice infected by Chlamydia psittaci.

    PubMed

    Buzoni-Gatel, D; Bernard, F; Andersen, A; Rodolakis, A

    1990-08-01

    The role of antibody in preventing placental and fetal infection by Chlamydia psittaci was studied in mice. Pregnant mice were passively immunized with polyclonal sera or monoclonal antibodies (mAbs) at day 11 of gestation. The mice were intravenously challenged the following day with the virulent AB7 ovine abortion strain of C. psittaci. Mice were either killed on day 16 of gestation to determine placental and fetal chlamydial infection levels or were permitted to have and raise their young until 8 days old for comparison of survival rates. Immune sera produced a decrease in both placental and fetal infection and reduced the number of young dying in utero or shortly after birth. Polyclonal sera to the highly invasive AB7 and AB4 strains or to the invasive 1B strain were more effective than serum to the invasive AB13 strain. The B577/F3 and B577/A11 monoclonal antibodies gave almost complete protection, with only low levels of placental infection and no detectable fetal infection or decrease in survival rate. The study demonstrates that immune sera and type-specific mAbs can passively transfer resistance to placental and fetal colonization and to abortion and fetal loss in mice intravenously challenged with P. psittaci.

  17. 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.

  18. Protective effect of resveratrol against neuronal damage following transient global cerebral ischemia in mice.

    PubMed

    Hong, Jeong-Ho; Lee, Hyung; Lee, Seong-Ryong

    2016-01-01

    Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol which is rich in grape seeds and skin. Several studies have revealed that resveratrol possesses neuroprotective effects. In the case of global brain ischemia, there are few reports regarding the protective effect of resveratrol. Therefore, the influence of resveratrol on neuronal damage after transient global brain ischemia remains to be clarified. In the current study, C57BL/6 black mice were subjected to 20 min of transient global brain ischemia and followed by 72 h of reperfusion. Resveratrol (20 or 40 mg/kg, once daily, dissolved in 0.5% carboxymethylcellulose) was administered orally for 7 days before ischemia and daily until the mice were euthanized. The effect of lower or higher dose of resveratrol on neuronal damage, matrix metalloproteinase (MMP) activity and in situ DNA fragmentation (TUNEL) assay in the hippocampus after global ischemia was examined. Neuronal damages were remarkable in CA1 and CA2 pyramidal cell layers after global ischemia. In resveratrol-treated mice (40 mg/kg), neuronal damage was significantly reduced compared with vehicle-treated mice. Mice treated with resveratrol showed reduced MMP-9 activity. Resveratrol also inhibited TUNEL staining. These data suggest that resveratrol, a natural polyphenol, reduces hippocampal neuronal cell damage following transient global ischemia by reducing MMP-9 activity.

  19. 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.

  20. 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

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

    PubMed

    Tian, Fengwei; Xiao, Yue; 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.

  2. Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice.

    PubMed

    Justicia, Carles; Salas-Perdomo, Angélica; Pérez-de-Puig, Isabel; Deddens, Lisette H; van Tilborg, Geralda A F; Castellví, Clara; Dijkhuizen, Rick M; Chamorro, Ángel; Planas, Anna M

    2017-06-01

    Hyperglycemia at stroke onset is associated with poor long-term clinical outcome in numerous studies. Hyperglycemia induces intracellular acidosis, lipid peroxidation, and peroxynitrite production resulting in the generation of oxidative and nitrosative stress in the ischemic tissue. Here, we studied the effects of acute hyperglycemia on in vivo intercellular adhesion molecule-1 (ICAM-1) expression, neutrophil recruitment, and brain damage after ischemia/reperfusion in mice and tested whether the natural antioxidant uric acid was protective. Hyperglycemia was induced by i.p. administration of dextrose 45 min before transient occlusion of the middle cerebral artery. Magnetic resonance imaging (MRI) was performed at 24 h to measure lesion volume. A group of normoglycemic and hyperglycemic mice received an i.v. injection of micron-sized particles of iron oxide (MPIOs), conjugated with either anti-ICAM-1 antibody or control IgG, followed by T2*w MRI. Neutrophil infiltration was studied by immunofluorescence and flow cytometry. A group of hyperglycemic mice received an i.v. infusion of uric acid (16 mg/kg) or the vehicle starting after 45 min of reperfusion. ICAM-1-targeted MPIOs induced significantly larger MRI contrast-enhancing effects in the ischemic brain of hyperglycemic mice, which also showed more infiltrating neutrophils and larger lesions than normoglycemic mice. Uric acid reduced infarct volume in hyperglycemic mice but it did not prevent vascular ICAM-1 upregulation and did not significantly reduce the number of neutrophils in the ischemic brain tissue. In conclusion, hyperglycemia enhances stroke-induced vascular ICAM-1 and neutrophil infiltration and exacerbates the brain lesion. Uric acid reduces the lesion size after ischemia/reperfusion in hyperglycemic mice.

  3. Protective effect of vitamin C in female Swiss mice dermally-exposed to the tannery effluent.

    PubMed

    Rabelo, Letícia Martins; Estrela, Fernanda Neves; E Silva, Bianca Costa; Mendes, Bruna de Oliveira; Vaz, Boniek Gontijo; Rodrigues, Aline Sueli de Lima; Malafaia, Guilherme

    2017-08-01

    Previous studies involving the oral exposure of mice to tannery effluents have found neurotoxic effects. However, studies about the effects the dermal exposure to pollutant have on the cognitive function of females have not been found in the literature. Thus, the aim of the current study is to investigate whether the dermal exposure of female Swiss mice to tannery effluents (2 h/day for 20 days) can cause cognitive impairment, as it was already evidenced in male Swiss mice. Furthermore, based on the administration of vitamin C (before or after the exposure to the xenobiotic), the current study also aims to assess the protective effect of vitamin C in female Swiss mice dermally-exposed to the tannery effluent. Female Swiss mice exposed to the tannery effluent (without vitamin supplementation) have shown lower novel object recognition index during the test session of the novel object recognition task, and they have descended significantly faster from the inhibitory avoidance platform when they were compared to mice belonging to the other groups, therefore evidencing memory deficit. However, the test performance of females receiving vitamin C was similar to that of control animals. Thus, the current study confirms the initial hypothesis that the dermal exposure to the pollutant, even for a short period, causes cognitive deficit in female Swiss mice. The herein presented findings also provide evidence that the mechanisms of action of the tannery effluent in these animals are related to oxidative damages in specific brain regions directed to the formation of short memory to perform aversive and object recognition tasks. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer

    PubMed Central

    Richter, Cornelia; Herrero San Juan, Martina; Weigmann, Benno; Bergis, Dominik; Dauber, Katrin; Muders, Michael H.; Baretton, Gustavo B.; Pfeilschifter, Josef Martin; Bonig, Halvard; Brenner, Sebastian; Radeke, Heinfried H.

    2017-01-01

    In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies. PMID:28191009

  5. 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.

  6. 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

  7. 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.

  8. Comparative Analysis of the Immunogenicity and Protective Effects of Inactivated EV71 Vaccines in Mice

    PubMed Central

    Mao, Qunying; Dong, Chenghong; Li, Xiuling; Gao, Qiang; Guo, Zengbing; Yao, Xin; Wang, Yiping; Gao, Fan; Li, Fengxiang; Xu, Miao; Yin, Weidong; Li, Qihan; Shen, Xinliang; Liang, Zhenglun; Wang, Junzhi

    2012-01-01

    Background Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China. Methods and Findings This comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD50 of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14–21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90–100% survival), while the ED50 of NAb responses and protective effects varied among three FCP-As. Conclusions These studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment

  9. 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

  10. Antioxidants protect calsequestrin-1 knockout mice from halothane- and heat-induced sudden death.

    PubMed

    Michelucci, Antonio; Paolini, Cecilia; Canato, Marta; Wei-Lapierre, Lan; Pietrangelo, Laura; De Marco, Alessandro; Reggiani, Carlo; Dirksen, Robert T; Protasi, Feliciano

    2015-09-01

    Mice lacking calsequestrin-1 (CASQ1-null), a Ca-binding protein that modulates the activity of Ca release in the skeletal muscle, exhibit lethal hypermetabolic episodes that resemble malignant hyperthermia in humans when exposed to halothane or heat stress. Because oxidative species may play a critical role in malignant hyperthermia crises, we treated CASQ1-null mice with two antioxidants, N-acetylcysteine (NAC, Sigma-Aldrich, Italy; provided ad libitum in drinking water) and (±)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox, Sigma-Aldrich; administered by intraperitoneal injection), before exposure to halothane (2%, 1 h) or heat (41°C, 1 h). NAC and Trolox significantly protected CASQ1-null mice from lethal episodes, with mortality being 79% (n = 14), 25% (n = 16), and 20% (n = 5) during halothane exposure and 86% (n = 21), 29% (n = 21), and 33% (n = 6) during heat stress in untreated, NAC-treated, and Trolox-treated mice, respectively. During heat challenge, an increase in core temperature in CASQ1-null mice (42.3° ± 0.1°C, n=10) was significantly reduced by both NAC and Trolox (40.6° ± 0.3°C, n = 6 and 40.5° ± 0.2°C, n = 6). NAC treatment of CASQ1-null muscles/mice normalized caffeine sensitivity during in vitro contracture tests, Ca transients in single fibers, and significantly reduced the percentage of fibers undergoing rhabdomyolysis (37.6 ± 2.5%, 38/101 fibers in 3 mice; 11.6 ± 1.1%, 21/186 fibers in 5 mice). The protective effect of antioxidant treatment likely resulted from mitigation of oxidative stress, because NAC reduced mitochondrial superoxide production, superoxide dismutase type-1 expression, and 3-nitrotyrosine expression, and increased both reduced glutathione and reduced glutathione/oxidized glutathione ratio. These studies provide a deeper understanding of the mechanisms that underlie hyperthermic crises in CASQ1-deficient muscle and demonstrate that antioxidant pretreatment may prevent them.

  11. 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.

  12. The assembly conformation of rotavirus VP6 determines its protective efficacy against rotavirus challenge in mice.

    PubMed

    Pastor, Ana Ruth; Rodríguez-Limas, William A; Contreras, Martha A; Esquivel, Ernesto; Esquivel-Guadarrama, Fernando; Ramírez, Octavio T; Palomares, Laura A

    2014-05-19

    Viral protein assemblies have shown to be superior immunogens used in commercial vaccines. However, little is known about the effect of protein assembly structure in immunogenicity and the protection conferred by a vaccine. In this work, rotavirus VP6, a polymorphic protein that assembles into nanotubes, icosahedra (dlRLP) or trimers was used to compare the immune response elicited by three different assemblies. VP6 is the most antigenic and abundant rotavirus structural protein. It has been demonstrated that antibodies against VP6 interfere with the replication cycle of rotavirus, making it a vaccine candidate. Groups of mice were immunized with either nanotubes, dlRLP or trimers and the humoral response (IgG and IgA titers) was measured. Immunized mice were challenged with EDIM rotavirus and protection against rotavirus infection, measured as viral shedding, was evaluated. Immunization with nanotubes resulted in the highest IgG titers, followed by immunization with dlRLP. While immunization with one dose of nanotubes was sufficient to reduce viral shedding by 70%, two doses of dlRLP or trimers were required to obtain a similar protection. The results show that the type of assembly of VP6 results in different humoral responses and protection efficacies against challenge with live virus. This information is important for the design of recombinant vaccines in general.

  13. 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.

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

    PubMed

    Peng, Xinyan; Jiang, Yujun

    2014-10-01

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

  15. Simultaneous immunization of mice with Omp31 and TF provides protection against Brucella melitensis infection.

    PubMed

    Ghasemi, Amir; Jeddi-Tehrani, Mahmood; Mautner, Josef; Salari, Mohammad Hossein; Zarnani, Amir-Hassan

    2015-10-13

    Brucella vaccines consisting of live attenuated Brucella strains are currently used in livestock, but safety concerns preclude their application in humans. Subunit vaccines have recently emerged as safe and efficacious alternatives in both humans and animals. In this study, subunit vaccines were developed that consisted of a recombinant outer membrane protein (rOmp31) and the trigger factor chaperone protein (rTF) of Brucella melitensis, either alone or in combination. BALB/c mice that were immunized with rOmp31+rTF showed comparable but slightly higher TF-specific IgG1 and IgG2a antibodies as compared to mice with rTF alone. Indeed, mice given this combination had titers of rOmp31-specific antibodies similar to those immunized with rOmp31 alone. In lymphocyte reactivation experiments, the splenocytes of immunized mice, whether given either of these antigens alone or as a cocktail, exhibited a strong antigen-specific recall proliferative response and expressed high amounts of IFN-γ, IL-12, IL-10 and IL-6. Both rTF and rTF+rOmp31 vaccinated mice exhibited significantly higher CD4 and CD8 levels compared to the PBS group. The combination of rOmp31 and rTF provided protection against B. melitensis infection comparable to that of vaccine strain Rev.1. In comparison to rTF alone, combination of rTF and rOmp31 caused only a slight increase in protection level. Although combination of rTF and rOmp31 caused a non-significant increase in IFN-γ induction, antibody level, proliferation index and CD4 and CD8 frequencies compared to rTF alone, its cumulative effects on aforesaid parameters may be viewed as a better efficacy.

  16. C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis.

    PubMed

    Malhi, Harmeet; Kropp, Erin M; Clavo, Vinna F; Kobrossi, Christina R; Han, JaeSeok; Mauer, Amy S; Yong, Jing; Kaufman, Randal J

    2013-06-28

    Nonalcoholic fatty liver disease is a heterogeneous disorder characterized by liver steatosis; inflammation and fibrosis are features of the progressive form nonalcoholic steatohepatitis. The endoplasmic reticulum stress response is postulated to play a role in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. In particular, C/EBP homologous protein (CHOP) is undetectable under normal conditions but is induced by cellular stress, including endoplasmic reticulum stress. Chop wild type (Chop(+/+)) and knock-out (Chop(-/-)) mice were used in these studies to elucidate the role of CHOP in the pathogenesis of fatty liver disease. Paradoxically, Chop(-/-) mice developed greater liver injury, inflammation, and fibrosis than Chop(+/+) mice, with greater macrophage activation. Primary, bone marrow-derived, and peritoneal macrophages from Chop(+/+) and Chop(-/-) were challenged with palmitic acid, an abundant saturated free fatty acid in plasma and liver lipids. Where palmitic acid treatment activated Chop(+/+) and Chop(-/-) macrophages, Chop(-/-) macrophages were resistant to its lipotoxicity. Chop(-/-) mice were sensitized to liver injury in a second model of dietary steatohepatitis using the methionine-choline-deficient diet. Analysis of bone marrow chimeras between Chop(-/-) and Chop(+/+) mice demonstrated that Chop in macrophages protects from liver injury and inflammation when fed the methionine-choline-deficient diet. We conclude that Chop deletion has a proinflammatory effect in fatty liver injury apparently due to decreased cell death of activated macrophages, resulting in their net accumulation in the liver. Thus, macrophage CHOP plays a key role in protecting the liver from steatohepatitis likely by limiting macrophage survival during lipotoxicity.

  17. C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis*

    PubMed Central

    Malhi, Harmeet; Kropp, Erin M.; Clavo, Vinna F.; Kobrossi, Christina R.; Han, JaeSeok; Mauer, Amy S.; Yong, Jing; Kaufman, Randal J.

    2013-01-01

    Nonalcoholic fatty liver disease is a heterogeneous disorder characterized by liver steatosis; inflammation and fibrosis are features of the progressive form nonalcoholic steatohepatitis. The endoplasmic reticulum stress response is postulated to play a role in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. In particular, C/EBP homologous protein (CHOP) is undetectable under normal conditions but is induced by cellular stress, including endoplasmic reticulum stress. Chop wild type (Chop+/+) and knock-out (Chop−/−) mice were used in these studies to elucidate the role of CHOP in the pathogenesis of fatty liver disease. Paradoxically, Chop−/− mice developed greater liver injury, inflammation, and fibrosis than Chop+/+ mice, with greater macrophage activation. Primary, bone marrow-derived, and peritoneal macrophages from Chop+/+ and Chop−/− were challenged with palmitic acid, an abundant saturated free fatty acid in plasma and liver lipids. Where palmitic acid treatment activated Chop+/+ and Chop−/− macrophages, Chop−/− macrophages were resistant to its lipotoxicity. Chop−/− mice were sensitized to liver injury in a second model of dietary steatohepatitis using the methionine-choline-deficient diet. Analysis of bone marrow chimeras between Chop−/− and Chop+/+ mice demonstrated that Chop in macrophages protects from liver injury and inflammation when fed the methionine-choline-deficient diet. We conclude that Chop deletion has a proinflammatory effect in fatty liver injury apparently due to decreased cell death of activated macrophages, resulting in their net accumulation in the liver. Thus, macrophage CHOP plays a key role in protecting the liver from steatohepatitis likely by limiting macrophage survival during lipotoxicity. PMID:23720735

  18. Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury.

    PubMed

    Bae, Soo Han; Sung, Su Haeng; Lee, Hye Eun; Kang, Ha Tan; Lee, Se Kyoung; Oh, Sue Young; Woo, Hyun Ae; Kil, In Sup; Rhee, Sue Goo

    2012-11-15

    To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up-regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole-induced oxidative damage to the liver was greater in PrxIII(-/-) mice than in wild-type mice. Such damage was also increased in Srx(-/-) mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria.

  19. Peroxiredoxin III and Sulfiredoxin Together Protect Mice from Pyrazole-Induced Oxidative Liver Injury

    PubMed Central

    Sung, Su Haeng; Lee, Hye Eun; Kang, Ha Tan; Lee, Se Kyoung; Oh, Sue Young; Woo, Hyun Ae; Kil, In Sup

    2012-01-01

    Abstract Aims: To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. Results: Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up-regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole-induced oxidative damage to the liver was greater in PrxIII−/− mice than in wild-type mice. Such damage was also increased in Srx−/− mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. Innovation: The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. Conclusion: The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria. Antioxid. Redox Signal. 17, 1351–1361. PMID:22490042

  20. 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

  1. 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.

  2. Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice.

    PubMed

    Rahmatollahi, Mahdieh; Baram, Somayeh Mahmoodi; Rahimian, Reza; Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-07-01

    Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.

  3. Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

    PubMed

    Du, Xiaogang; Wang, Junpeng; Niu, Xinli; Smith, Donald; Wu, Dayong; Meydani, Simin Nikbin

    2014-02-01

    Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function.

  4. Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice.

    PubMed

    Gai, Zhibo; Gui, Ting; Hiller, Christian; Kullak-Ublick, Gerd A

    2016-01-29

    Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (Grp78), and C/EBP-homologous protein, markers of endoplasmic reticulum stress, was more prominent in the proximal tubules of 15 obese patients compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid, renal injury, renal lipid accumulation, apoptosis, and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following obeticholic acid treatment. Culturing renal proximal tubular cells with free fatty acid and FXR agonists showed that FXR activation protected cells from free fatty acid-induced oxidative stress and endoplasmic reticulum stress, as denoted by a reduction in the level of reactive oxygen species staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide/glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury.

  5. Protective effects of Huangqin Decoction against ulcerative colitis and associated cancer in mice

    PubMed Central

    Hu, Chunping; Cheng, Xiaolan; Xu, Yuehua; Cai, Xueting; Wang, Min; Yang, Chung S.; Cao, Peng

    2016-01-01

    Individuals with ulcerative colitis (UC) are at a high risk for developing colorectal cancer (CRC). Huangqin Decoction (HQD), a traditional Chinese medicinal formula chronicled in the Shang Han Lun, is commonly used to treat gastrointestinal symptoms. However, experimental evidence for supporting the clinical practice is lacking. This study used modern biomedical approaches to investigate the protective/preventive effects of HQD in dextran sulfate sodium (DSS)-induced acute/chronic UC and azoxymethane (AOM)/DSS-induced CRC in mice. HQDs were prepared in 4 different ways: HQD-1 and HQD-2 were prepared in boiling water, whereas HQD-3 and HQD-4 were prepared in heated ethanol (70%). For HQD-1 and HQD-3, the 4 constituent herbs were processed together, whereas for HQD-2 and HQD4, these herbs were processed individually and then combined. The mice were administered 9.1 g/kg HQD via oral gavage daily. HQD-1 significantly inhibited DSS-induced acute UC, whereas HQD-3 and HQD-4 exhibited mild ameliorative effects; but HQD-2 had no protective effect and resulted in a higher mortality rate. This higher mortality rate may be due to the greater abundance of baicalein and wogonin in HQD-2 than HQD-1. Furthermore, HQD-1 protected against DSS-induced chronic UC and significantly inhibited AOM/DSS-induced CRC in mice. HQD-1 also inhibited the production of inflammatory cytokines and increased antioxidant capacity both in chronic DSS and AOM/DSS treated mice. Overall, HQD-1 inhibits the development of acute/chronic colitis and prevents colitis-associated CRC, possibly by inhibiting inflammation and preventing oxidative stress induced cellular damage. PMID:27557503

  6. 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.

  7. Immunization with live Neisseria lactamica protects mice against meningococcal challenge and can elicit serum bactericidal antibodies.

    PubMed

    Li, Yanwen; Zhang, Qian; Winterbotham, Megan; Mowe, Eva; Gorringe, Andrew; Tang, Christoph M

    2006-11-01

    Natural immunity against Neisseria meningitidis is thought to develop following nasopharyngeal colonization with this bacterium or other microbes expressing cross-reactive antigens. Neisseria lactamica is a commensal of the upper respiratory tract which is often carried by infants and young children; epidemiological evidence indicates that colonization with this bacterium can elicit serum bactericidal activity (SBA) against Neisseria meningitidis, the most validated correlate of protective immunity. Here we demonstrate experimentally that immunization of mice with live N. lactamica protects animals against lethal meningococcal challenge and that some, but not all, strains of N. lactamica elicit detectable SBA in immunized animals regardless of the serogroup of N. meningitidis. While it is unlikely that immunization with live N. lactamica will be implemented as a vaccine against meningococcal disease, understanding the basis for the induction of cross-protective immunity and SBA should be valuable in the design of subunit vaccines for the prevention of this important human infection.

  8. G6PD protects from oxidative damage and improves healthspan in mice

    PubMed Central

    Nóbrega-Pereira, Sandrina; Fernandez-Marcos, Pablo J.; Brioche, Thomas; Gomez-Cabrera, Mari Carmen; Salvador-Pascual, Andrea; Flores, Juana M.; Viña, Jose; Serrano, Manuel

    2016-01-01

    Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg mice have higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS. PMID:26976705

  9. GroEL provides protection against Bacillus anthracis infection in BALB/c mice.

    PubMed

    Sinha, Kanchan; Bhatnagar, Rakesh

    2010-01-01

    Heat shock proteins (Hsps) of the HSP60 and HSP70 family are highly conserved and essential to all living organisms. Hsps are immunodominant in numerous microbial infections and have been investigated for their vaccine potential. We investigated the immunogenicity and protective efficacy of GroEL and DnaK of B. anthracis in murine model. Both Hsps were found to be highly immunogenic with mixed antibody response (both IgG1 and IgG2a), indicating stimulation of both humoral and cell-mediated immunity. Cytokine profile also confirmed robust T-cell response with increase in lymphocyte proliferation. Immunization with GroEL conferred 100% protection to mice against B. anthracis infection whereas DnaK couldn't provide protection.

  10. Protective effect of topically applied olive oil against photocarcinogenesis following UVB exposure of mice.

    PubMed

    Budiyanto, A; Ahmed, N U; Wu, A; Bito, T; Nikaido, O; Osawa, T; Ueda, M; Ichihashi, M

    2000-11-01

    Reactive oxygen species have been shown to play a role in ultraviolet light (UV)-induced skin carcinogenesis. Vitamin E and green tea polyphenols reduce experimental skin cancers in mice mainly because of their antioxidant properties. Since olive oil has also been reported to be a potent antioxidant, we examined its effect on UVB-induced skin carcinogenesis in hairless mice. Extra-virgin olive oil was applied topically before or after repeated exposure of mice to UVB. The onset of UVB-induced skin tumors was delayed in mice painted with olive oil compared with UVB control mice. However, with increasing numbers of UVB exposures, differences in the mean number of tumors between UVB control mice and mice pretreated with olive oil before UVB exposure (pre-UVB group) were lost. In contrast, mice that received olive oil after UVB exposure (post-UVB group) showed significantly lower numbers of tumors per mouse than those in the UVB control group throughout the experimental period. The mean number of tumors per mouse in the UVB control, pre-UVB and post-UVB groups was 7.33, 6.69 and 2.64, respectively, in the first experiment, and 8.53, 9.53 and 3.36 in the second experiment. Camellia oil was also applied, using the same experimental protocol, but did not have a suppressive effect. Immunohistochemical analysis of DNA damage in the form of cyclobutane pyrimidine dimers (CPD), (6-4) photoproducts and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in samples taken 30 min after a single exposure of UVB showed no significant difference between UVB-irradiated control mice and the pre-UVB group. In the post-UVB group, there were lower levels of 8-OHdG in epidermal nuclei, but the formation of CPD and (6-4) photoproducts did not differ. Exposure of olive oil to UVB before application abrogated the protective effect on 8-OHdG formation. These results indicate that olive oil topically applied after UVB exposure can effectively reduce UVB-induced murine skin tumors, possibly via its

  11. MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation.

    PubMed

    Gupta, Paridhi; Gayen, Manoshi; Smith, Joan T; Gaidamakova, Elena K; Matrosova, Vera Y; Grichenko, Olga; Knollmann-Ritschel, Barbara; Daly, Michael J; Kiang, Juliann G; Maheshwari, Radha K

    2016-01-01

    The radioprotective capacity of a rationally-designed Mn2+-decapeptide complex (MDP), based on Mn antioxidants in the bacterium Deinococcus radiodurans, was investigated in a mouse model of radiation injury. MDP was previously reported to be extraordinarily radioprotective of proteins in the setting of vaccine development. The peptide-component (DEHGTAVMLK) of MDP applied here was selected from a group of synthetic peptides screened in vitro for their ability to protect cultured human cells and purified enzymes from extreme damage caused by ionizing radiation (IR). We show that the peptides accumulated in Jurkat T-cells and protected them from 100 Gy. MDP preserved the activity of T4 DNA ligase exposed to 60,000 Gy. In vivo, MDP was nontoxic and protected B6D2F1/J (female) mice from acute radiation syndrome. All irradiated mice treated with MDP survived exposure to 9.5 Gy (LD70/30) in comparison to the untreated mice, which displayed 63% lethality after 30 days. Our results show that MDP provides early protection of white blood cells, and attenuates IR-induced damage to bone marrow and hematopoietic stem cells via G-CSF and GM-CSF modulation. Moreover, MDP mediated the immunomodulation of several cytokine concentrations in serum including G-CSF, GM-CSF, IL-3 and IL-10 during early recovery. Our results present the necessary prelude for future efforts towards clinical application of MDP as a promising IR countermeasure. Further investigation of MDP as a pre-exposure prophylactic and post-exposure therapeutic in radiotherapy and radiation emergencies is warranted.

  12. 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

  13. MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation

    PubMed Central

    Smith, Joan T.; Gaidamakova, Elena K.; Matrosova, Vera Y.; Grichenko, Olga; Knollmann-Ritschel, Barbara; Daly, Michael J.; Kiang, Juliann G.

    2016-01-01

    The radioprotective capacity of a rationally-designed Mn2+-decapeptide complex (MDP), based on Mn antioxidants in the bacterium Deinococcus radiodurans, was investigated in a mouse model of radiation injury. MDP was previously reported to be extraordinarily radioprotective of proteins in the setting of vaccine development. The peptide-component (DEHGTAVMLK) of MDP applied here was selected from a group of synthetic peptides screened in vitro for their ability to protect cultured human cells and purified enzymes from extreme damage caused by ionizing radiation (IR). We show that the peptides accumulated in Jurkat T-cells and protected them from 100 Gy. MDP preserved the activity of T4 DNA ligase exposed to 60,000 Gy. In vivo, MDP was nontoxic and protected B6D2F1/J (female) mice from acute radiation syndrome. All irradiated mice treated with MDP survived exposure to 9.5 Gy (LD70/30) in comparison to the untreated mice, which displayed 63% lethality after 30 days. Our results show that MDP provides early protection of white blood cells, and attenuates IR-induced damage to bone marrow and hematopoietic stem cells via G-CSF and GM-CSF modulation. Moreover, MDP mediated the immunomodulation of several cytokine concentrations in serum including G-CSF, GM-CSF, IL-3 and IL-10 during early recovery. Our results present the necessary prelude for future efforts towards clinical application of MDP as a promising IR countermeasure. Further investigation of MDP as a pre-exposure prophylactic and post-exposure therapeutic in radiotherapy and radiation emergencies is warranted. PMID:27500529

  14. Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia and reperfusion injury in mice.

    PubMed

    Wang, Jiliang; Deng, Xiuling; Yi, Shengen; Pathil, Anita; Zhang, Wujuan; Setchell, Kenneth; Stremmel, Wolfgang; Chamulitrat, Walee

    2015-04-01

    The ischemia and reperfusion (I/R) injury that occurs during liver transplantation causes severe complications leading to transplantation failure. We have designed a cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which promotes the survival of cultured hepatocellular cell lines and inhibits apoptosis and inflammation in the in vivo models of liver injury. Here, we show that UDCA-LPE increased the viability of mouse hepatocytes by activating the Akt/glycogen synthase kinase 3β survival signaling pathways. We further tested whether UDCA-LPE could protect hepatic I/R injury in mice by clamping liver lobes of C57/BL6 mice for 90 min of ischemia followed by unclamping and reperfusion for 2 h. Two regimens for UDCA-LPE treatment were carried out; with a single dose of 100 mg/kg UDCA-LPE intraperitoneally injected 30 min prior to ischemia and a double dose of 50 mg/kg UDCA-LPE given 30 min prior to ischemia and just prior to reperfusion. Using histology and liver enzyme determination, we observed that hepatic I/R caused significant hepatic necrosis, which was decreased in UDCA-LPE-treated mice undergoing I/R. Ursodeoxycholyl LPE concomitantly protected against I/R-induced apoptosis (cleaved caspase 3, cleaved poly[ADP-ribose] polymerase 1), inflammation (IL-1β, CD11b, chemokine ligands 2 and 3, chemokine receptor 2), and portal fibrogenesis (α-smooth muscle actin, plasminogen activator inhibitor 1), as determined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses. The protection by UDCA-LPE was found to be better in the double-dose than in the single-dose regimen. Thus, UDCA-LPE promoted the survival of mouse hepatocytes and protected against hepatic I/R injury and thus may be of therapeutic use in liver transplantation settings.

  15. 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.

  16. Establishing Substantial Equivalence: Proteomics

    NASA Astrophysics Data System (ADS)

    Lovegrove, Alison; Salt, Louise; Shewry, Peter R.

    Wheat is a major crop in world agriculture and is consumed after processing into a range of food products. It is therefore of great importance to determine the consequences (intended and unintended) of transgenesis in wheat and whether genetically modified lines are substantially equivalent to those produced by conventional plant breeding. Proteomic analysis is one of several approaches which can be used to address these questions. Two-dimensional PAGE (2D PAGE) remains the most widely available method for proteomic analysis, but is notoriously difficult to reproduce between laboratories. We therefore describe methods which have been developed as standard operating procedures in our laboratory to ensure the reproducibility of proteomic analyses of wheat using 2D PAGE analysis of grain proteins.

  17. Protective effects of Zhuyeqing liquor on the immune function of normal and immunosuppressed mice in vivo

    PubMed Central

    2013-01-01

    Background Zhuyeqing Liquor (ZYQL), a well-known Chinese traditional health liquor, has various biological properties, including anti-oxidant, anti-inflammatory, immunoenhancement and cardiovascular protective effects. Methods The protective effects of Zhuyeqing Liquor (ZYQL) on the immune function was investigated in vivo in normal healthy mice and immunosuppressed mice treated with Cyclophosphamide (Cy, 100 mg/kg) by intraperitoneal injection on days 4, 8 and 12. ZYQL (100, 200 and 400 mg/kg) was administered via gavage daily for 14 days. The phagocytotic function of mononuclear phagocytic system was detected with carbon clearance methods, the levels of interleukin-6 (IL-6) and interferon-gamma (IFN-γ) in serum were detected with Enzyme linked immunosorbent assay (ELISA). Immune organs were weighed and organ indexes (organ weight/body weight) of thymus and spleen were calculated. Meanwhile, the activity of lysozyme (LSZ) in serum and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) in spleen tissue were measured. Results ZYQL significantly upgrades the K value for clearance of carbon particles in normal mice treated with ZYQL (400 mg/kg) and immunosuppressed mice treated with ZYQL (100, 200 and 400 mg/kg) together with Cy (100 mg/kg) in vivo. The treatment of ZYQL (100, 200 and 400 mg/kg) effectively increased the activity of serum lysozyme as well as promoted the serum levels of IL-6 and IFN-γ in normal mice and immunosuppressed mice. Furthermore, ZYQL (100, 200 and 400 mg/kg) had an antioxidant effects in immune system by enhancing the antioxidant enzyme activity of SOD, CAT and GSH-Px in vivo. In addition, ZYQL (100, 200 and 400 mg/kg) effectively elevated the Cy-induced decreased organ index (thymus and spleen). Conclusions The present work shows that the dose-dependent administration of ZYQL is capable of influencing immune responses, which implying that its valuable functional health may be attributed

  18. p21 Protects “Super p53” Mice from the Radiation-Induced Gastrointestinal Syndrome

    PubMed Central

    Sullivan, Julie M.; Jeffords, Laura B.; Lee, Chang-Lung; Rodrigues, Rafaela; Ma, Yan; Kirsch, David G.

    2012-01-01

    Exposure of the gastrointestinal (GI) tract to high doses of radiation can lead to lethality from the GI syndrome. Although the molecular mechanism regulating the GI syndrome remains to be fully defined, we have recently demonstrated that p53 within the GI epithelial cells controls the radiation-induced GI syndrome. Mice lacking p53 in the GI epithelium were sensitized to the GI syndrome, while transgenic mice with one additional copy of p53 called “Super p53” mice were protected from the GI syndrome. Here, we cross “Super p53” mice to p21−/− mice that lack the cyclin-dependent kinase inhibitor p21. Super p53; p21−/− mice are sensitized to the GI syndrome compared to Super p53 mice that retain one p21 allele. In addition, mice lacking p21 are not protected from the GI syndrome with one extra copy of p53. These results suggest that p21 protects “Super p53” mice from the GI syndrome. PMID:22165824

  19. The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice

    PubMed Central

    Gomes, Isabele B. S.; Porto, Marcella L.; Santos, Maria C. L. F. S.; Campagnaro, Bianca P.; Gava, Agata L.; Meyrelles, Silvana S.; Pereira, Thiago M. C.; Vasquez, Elisardo C.

    2015-01-01

    Aims: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE−/−). Methods: Streptozotocin was used to induce diabetes (100 mg/kg/day, 3 days) in male apoE−/− mice (8 week-old). After 6 weeks, the mice were randomly separated into DQ: diabetic apoE−/− mice treated with quercetin (10 mg/kg/day, 4 weeks, n = 8), DV: diabetic ApoE−/− mice treated with vehicle (n = 8) and ND: non-treated non-diabetic mice (n = 8). Results: Quercetin treatment diminished polyuria (~30%; p < 0.05), glycemia (~25%, p < 0.05), normalized the hypertriglyceridemia. Moreover, this bioflavonoid diminished creatininemia (~30%, p < 0.01) and reduced proteinuria but not to normal levels. We also observed protective effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight/body weight. Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical changes (decrease in glucose and triglycerides serum levels) and reduction of glomerulosclerosis. Thus, this study highlights the relevance of quercetin as an alternative therapeutic option for DN, including in diabetes associated with dyslipidemia. PMID:26388784

  20. Receptor MAS protects mice against hypothermia and mortality induced by endotoxemia.

    PubMed

    Souza, Laura L; Duchene, Johan; Todiras, Mihail; Azevedo, Luciano C P; Costa-Neto, Claudio M; Alenina, Natalia; Santos, Robson A; Bader, Michael

    2014-04-01

    The renin-angiotensin (Ang) system is involved in maintaining cardiovascular function by regulating blood pressure and electrolyte homeostasis. More recently, alternative pathways within the renin-angiotensin system have been described, such as the ACE-2/Ang-(1-7)/Mas axis, with opposite effects to the ones of the ACE/Ang-II/AT1 axis. Correspondingly, our previous work reported that Ang-(1-7) via its receptor Mas inhibits the mRNA expression of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α increased by lipopolysaccharide (LPS) in mouse peritoneal macrophages. These data led us to investigate the functional role of the Ang-(1-7)/Mas axis in an in vivo LPS model. In this work, we present evidence that Ang-(1-7) via Mas significantly reduced the LPS-increased production of circulating cytokines, such as IL-6, IL-12, and CXCL-1. This inhibitory effect was mediated by Mas because it was not detectable in Mas-deficient (Mas) mice. Accordingly, IL-6, CXCL-1, and CXCL-2 levels were higher after LPS treatment in the absence of Mas. Mas mice were less resistant to LPS-induced endotoxemia, their survival rate being 50% compared with 95% in wild-type mice. Telemetric analyses showed that Mas mice presented more pronounced LPS-induced hypothermia with a 3°C lower body temperature compared with wild-type mice. Altogether, our findings suggest that Ang-(1-7) and Mas inhibit LPS-induced cytokine production and hypothermia and thereby protect mice from the fatal consequences of endotoxemia.

  1. 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.

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

    PubMed

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

    2016-02-01

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

  3. 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

  4. Protective Effect of Thymoquinone Against Morphine Injuries to Kidneys of Mice.

    PubMed

    Jalili, Cyrus; Salahshoor, Mohammad Reza; Hoseini, Mohsen; Roshankhah, Shiva; Sohrabi, Maryam; Shabanizadeh, Ahmad

    2017-03-01

    Thymoquinone is a phytochemical compound found in the plant Nigella sativa. It has various pharmacological effects such as antioxidant and anti-apoptotic. Morphine can increase the generation of free radicals. It is mainly excreted through the kidneys and causes disturbing effects. This study was designed to evaluate protective effects of thymoquinone against morphine-induced damages to the kidneys of mice. Various doses of thymoquinone (4.5 mg/kg, 9 mg/kg, and 18 mg/kg) were intraperitoneally administered along with morphine to 48 male mice for 20 consequent days. These mice were compared with a control group with saline injection, morphine group, and groups with same doses of thymoquinone only (n = 6 in each group). Blood urea nitrogen, serum creatinine, and serum nitric oxide levels, as well kidney weight and histology were assessed after the interventions. Morphine administration significantly decreased kidney weight and the number and mean diameter of the glomeruli. Increased levels of blood urea nitrogen, serum creatinine, and serum nitric oxide were also noted with morphine compared to the control group (P < .05). However, administration of thymoquinone and thymoquinone plus morphine significantly enhanced kidney weight, number and mean diameter of the glomeruli. All of the groups with thymoquinone were also associated with reduced blood urea nitrogen, serum creatinine, and serum nitric oxide levels compared to the morphine group (P < .05). It seems that antioxidant and anti-apoptotic effects of thymoquinone could protect of the kidneys against damage due to morphine toxicity.

  5. Testosterone Depletion by Castration May Protect Mice from Heat-Induced Multiple Organ Damage and Lethality

    PubMed Central

    Lin, Chian-Yuh; Lin, Mao-Tsun; Cheng, Ruei-Tang; Chen, Sheng-Hsien

    2010-01-01

    When the vehicle-treated, sham-operated mice underwent heat stress, the fraction survival and core temperature at +4 h of body heating were found to be 5 of 15 and 34.4°C ± 0.3°C, respectively. Castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero, protected the mice from heat-induced death (fraction survival, 13/15) and reduced the hypothermia (core temperature, 37.3°C). The beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl- transferase- mediatedαUDP-biotin nick end-labeling staining, were significantly prevented by castration. In addition, heat-induced neuronal damage, as indicated by cell shrinkage and pyknosis of nucleus, to the hypothalamus was also castration-prevented. Again, the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke, were significantly reversed by testosterone replacement. The data indicate that testosterone depletion by castration may protect mice from heatstroke-induced multiple organ damage and lethality. PMID:20396666

  6. 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.

  7. 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.

  8. Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice.

    PubMed

    Tian, Xia; Sun, Lingyan; Gou, Lingshan; Ling, Xin; Feng, Yan; Wang, Ling; Yin, Xiaoxing; Liu, Yi

    2013-03-29

    The present work was aimed to study the protective effect of l-theanine on chronic restraint stress (CRS)-induced cognitive impairments in mice. The stress was produced by restraining the animals in well-ventilated polypropylene tubes (3.2 cm in diameter ×10.5 cm in length) for 8h once daily for 21 consecutive days. L-theanine (2 and 4 mg/kg) was administered 30 min before the animals subjected to acute immobilized stress. At week 4, mice were subjected to Morris water maze and step-through tests to measure the cognitive function followed by oxidative parameters and corticosterone as well as catecholamines (norepinephrine and dopamine) subsequently. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters and catecholamine levels in the hippocampus and the cerebral cortex as well as corticosterone and catecholamine levels in the serum. However, not only did l-theanine treatment exhibit a reversal of the cognitive impairments and oxidative damage induced by CRS, but also reversed the abnormal level of corticosterone in the serum as well as the abnormal levels of catecholamines in the brain and the serum. This study indicated the protective effect of l-theanine against CRS-induced cognitive impairments in mice.

  9. 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.

  10. 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

  11. 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.

  12. Lycopene protects against acute zearalenone-induced oxidative, endocrine, inflammatory and reproductive damages in male mice.

    PubMed

    Boeira, Silvana Peterini; Funck, Vinícius Rafael; Borges Filho, Carlos; Del'Fabbro, Lucian; de Gomes, Marcelo Gomes; Donato, Franciele; Royes, Luiz Fernando Freire; Oliveira, Mauro Schneider; Jesse, Cristiano Ricardo; Furian, Ana Flávia

    2015-03-25

    Male mice received lycopene for 10 days before a single oral administration of zearalenone (ZEA). After 48 h testes and blood were collected. Mice treated with lycopene/ZEA exhibited amelioration of the hematological changes. Lycopene prevented the reduction in the number and motility of spermatozoa and testosterone levels, indicating a protective effect in the testicular damage induced by ZEA. Lycopene was also effective in protecting against the decrease in glutathione-S-transferase, glutathione peroxidase, glutathione reductase and δ-aminolevulinic acid dehydratase activities caused by ZEA in the testes. Exposure of animals to ZEA induced modification of antioxidant and inflammatory status with increase of reduced glutathione (GSH) levels and increase of the oxidized glutathione, interleukins 1β, 2, 6, 10, tumor necrosis factor-α and bilirubin levels. Lycopene prevented ZEA-induced changes in GSH levels and inhibited the processes of inflammation, reducing the damage induced by ZEA. Altogether, our results indicate that lycopene was able to prevent ZEA-induced damage in the mice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Protective Effect of Silymarin against Acrolein-Induced Cardiotoxicity in Mice

    PubMed Central

    Taghiabadi, Elahe; Imenshahidi, Mohsen; Abnous, Khalil; Mosafa, Fatemeh; Sankian, Mojtaba; Memar, Bahram; Karimi, Gholamreza

    2012-01-01

    Reactive α,β-unsaturated aldehydes such as acrolein (ACR) are major components of environmental pollutants and have been implicated in the neurodegenerative and cardiac diseases. In this study, the protective effect of silymarin (SN) against cardiotoxicity induced by ACR in mice was evaluated. Studies were performed on seven groups of six animals each, including vehicle-control (normal saline + 0.5% w/v methylcellulose), ACR (7.5 mg/kg/day, gavage) for 3 weeks, SN (25, 50 and 100 mg/kg/day, i.p.) plus ACR, vitamin E (Vit E, 100 IU/kg, i.p.) plus ACR, and SN (100 mg/kg, i.p.) groups. Mice received SN 7 days before ACR and daily thereafter throughout the study. Pretreatment with SN attenuated ACR-induced increased levels of malondialdehyde (MDA), serum cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB), as well as histopathological changes in cardiac tissues. Moreover, SN improved glutathione (GSH) content, superoxide dismutase (SOD), and catalase (CAT) activities in heart of ACR-treated mice. Western blot analysis showed that SN pretreatment inhibited apoptosis provoked by ACR through decreasing Bax/Bcl-2 ratio, cytosolic cytochrome c content, and cleaved caspase-3 level in heart. In conclusion, SN may have protective effects against cardiotoxicity of ACR by reducing lipid peroxidation, renewing the activities of antioxidant enzymes, and preventing apoptosis. PMID:23320028

  14. Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Ishii, Isao; Kamata, Shotaro; Hagiya, Yoshifumi; Abiko, Yumi; Kasahara, Tadashi; Kumagai, Yoshito

    2015-12-01

    The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of N-acetyl-p-benzoquinone imine (NAPQI), a potent electrophilic metabolite that forms protein adducts. The fundamental roles of glutathione in the effective conjugation/clearance of NAPQI have been established, giving a molecular basis for the clinical use of N-acetylcysteine as a sole antidote. Recent evidence from in vitro experiments suggested that sulfide anions (S(2-)) to yield hydrogen sulfide anions (HS(-)) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS(-) against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (Cth(-/-)) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into Cth(-/-) mice resulted in highly elevated levels of serum alanine/aspartate aminotransferases and lactate dehydrogenase associated with marked increases in oncotic hepatocytes; all of which were significantly inhibited by intraperitoneal preadministration of sodium hydrosulfide (NaHS). NaHS preadministration significantly suppressed APAP-induced serum malondialdehyde level increases without abrogating APAP-induced rapid depletion of hepatic glutathione. These results suggest that exogenous HS(-) protects hepatocytes by directly scavenging reactive NAPQI rather than by increasing cystine uptake and thereby elevating intracellular glutathione levels, which provides a novel therapeutic approach against acute APAP poisoning.

  15. 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.

  16. Protective effects of silica hydride against carbon tetrachloride-induced hepatotoxicity in mice.

    PubMed

    Hsu, Yu-Wen; Tsai, Chia-Fang; Chuang, Wen-Chen; Chen, Wen-Kang; Ho, Yung-Chyuan; Lu, Fung-Jou

    2010-06-01

    The protective effects of MegaHydrate silica hydride against liver damage were evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male ICR mice were orally treated with silica hydride (104, 208 and 520 mg/kg) or silymarin (200 mg/kg) daily, with administration of CCl(4) (1 mL/kg, 20% CCl4 in olive oil) twice a week for eight weeks. The results showed that oral administration of silica hydride significantly reduced the elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride (TG), and cholesterol and the level of malondialdehyde (MDA) in the liver that were induced by CCl(4) in mice. Moreover, the silica-hydride treatment was also found to significantly increase the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px), as well as increase the GSH content, in the liver. Liver histopathology also showed that silica hydride reduced the incidence of liver lesions induced by CCl(4). The results suggest that silica hydride exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely due to both the increase of antioxidant-defense system activity and the inhibition of lipid peroxidation. Copyright 2010 Elsevier Ltd. All rights reserved.

  17. Glutathione reductase targeted to type II cells does not protect mice from hyperoxic lung injury.

    PubMed

    Heyob, Kathryn M; Rogers, Lynette K; Welty, Stephen E

    2008-12-01

    Exposure of the lung epithelium to reactive oxygen species without adequate antioxidant defenses leads to airway inflammation, and may contribute to lung injury. Glutathione peroxidase catalyzes the reduction of peroxides by oxidation of glutathione (GSH) to glutathione disulfide (GSSG), which can in turn be reduced by glutathione reductase (GR). Increased levels of GSSG have been shown to correlate negatively with outcome after oxidant exposure, and increased GR activity has been protective against hyperoxia in lung epithelial cells in vitro. We tested the hypothesis that increased GR expression targeted to type II alveolar epithelial cells would improve outcome in hyperoxia-induced lung injury. Human GR with a mitochondrial targeting sequence was targeted to mouse type II cells using the SPC promoter. Two transgenic lines were identified, with Line 2 having higher lung GR activities than Line 1. Both transgenic lines had lower lung GSSG levels and higher GSH/GSSG ratios than wild-type. Six-week-old wild-type and transgenic mice were exposed to greater than 95% O2 or room air (RA) for 84 hours. After exposure, Line 2 mice had higher right lung/body weight ratios and lavage protein concentrations than wild-type mice, and both lines 1 and 2 had lower GSSG levels than wild-type mice. These findings suggest that GSSG accumulation in the lung may not play a significant role in the development of hyperoxic lung injury, or that compensatory responses to unregulated GR expression render animals more susceptible to hyperoxic lung injury.

  18. Fisetin protects against hepatosteatosis in mice by inhibiting miR-378.

    PubMed

    Jeon, Tae-Il; Park, Jin Wook; Ahn, Jiyun; Jung, Chang Hwa; Ha, Tae Youl

    2013-11-01

    Lipid homeostasis in vertebrates is regulated at many levels including synthesis, degradation, and distribution. MicroRNAs (miRNAs) are key regulators of lipid homeostasis. The use of phytochemicals to target miRNA (miR) could provide new therapeutic approaches to human diseases. Thus, we investigated the regulation of lipid metabolism by the flavonoid fisetin during experimental analysis of hepatic miRs in mice. Mice were separated into three groups. One group was maintained on the normal diet and the other two groups were fed either a high-fat (HF) diet or HF supplemented with fisetin. We found that fisetin lowered hepatic fat accumulation in HF mice and reversed abnormal expressions of lipid metabolism genes. The co-expression of miR-378 and its host gene PGC-1β was significantly induced by HF, whereas fisetin prevented the induction of both genes. We also identified nuclear respiratory factor-1 (NRF-1), a critical regulator of the mitochondrial function, as a direct target of miR-378. Dietary fisetin protects against hepatosteatosis in association with modulation of lipid metabolism genes and miR-378 in mice. These observations suggest that the use of fisetin to target miRs could be an effective prevention or intervention against metabolic diseases. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Protective effect of L-theanine on carbon tetrachloride-induced acute liver injury in mice.

    PubMed

    Jiang, Wei; Gao, Min; Sun, Shuai; Bi, Aijing; Xin, Yinqiang; Han, Xiaodong; Wang, Liangbin; Yin, Zhimin; Luo, Lan

    2012-06-01

    We studied effects of L-theanine, a unique amino acid in tea, on carbon tetrachloride (CCl(4))-induced liver injury in mice. The mice were pre-treated orally with L-theanine (50, 100 or 200 mg/kg) once daily for seven days before CCl(4) (10 ml/kg of 0.2% CCl(4) solution in olive oil) injection. L-theanine dose-dependently suppressed the increase of serum activity of ALT and AST and bilirubin level as well as liver histopathological changes induced by CCl(4) in mice. L-theanine significantly prevented CCl(4)-induced production of lipid peroxidation and decrease of hepatic GSH content and antioxidant enzymes activities. Our further studies demonstrated that L-theanine inhibited metabolic activation of CCl(4) through down-regulating cytochrome P450 2E1 (CYP2E1). As a consequence, L-theanine inhibited oxidative stress-mediated inflammatory response which included the increase of TNF-α and IL-1β in sera, and expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in livers. CCl(4)-induced activation of apoptotic related proteins including caspase-3 and PARP in mouse livers was also prevented by L-theanine treatment. In summary, L-theanine protects mice against CCl(4)-induced acute liver injury through inhibiting metabolic activation of CCl(4) and preventing CCl(4)-induced reduction of anti-oxidant capacity in mouse livers to relieve inflammatory response and hepatocyte apoptosis.

  20. Protective effect of alpha-linolenic acid on gentamicin-induced ototoxicity in mice.

    PubMed

    Kaplan, Halil Mahir; Şingirik, Ergin; Erdoğan, Kıvılcım Eren; Doran, Figen

    2017-07-31

    Alpha-linolenic acid is one of the fatty acids known as omega 3. Previous studies have shown the antioxidant and anti-inflammatory effects of alpha-linolenic acid, which prevented cell damage by inhibiting apoptotic pathway. Also, it is known that gentamicin activates apoptotic mediators and causes necrosis in the kidney. Due to this reason, we planned a study to evaluate the protective effects of alpha-linolenic acid on gentamicin induced ototoxicity by evaluating inflammation and apoptotic mediators. For this purpose, 100 mg/kg gentamicin (i.p; intraperitoneally) and 200 mg/kg alpha-linolenic acid (gavage) are administered to mice for 9 days. On 9th and 10th days, rotarod performance was assessed to test the effect of gentamicin and alpha-linolenic acid treatment on the motor coordination of mice. Gentamicin treatment decreased fall latency of mice and gentamicin treatment together with alpha-linolenic acid increased fall latency of mice. Gentamicin treatment also increased expression of phospholipase A2(plA2), cyclooxygenase-2(COX-2) and inducible nitric oxide syntheses (iNOS). Furthermore, it increased Bax and caspase-3, which are proapoptotic proteins and decreased bcl-2 that is an antiapoptotic protein. Gentamicin treatment together alpha-linolenic acid recovered the change of expression of these enzymes. In conclusion, this study showed that alpha-linolenic acid will be useful to prevent gentamicin-induced ototoxicity by inhibiting apoptosis and inflammation.

  1. 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.

  2. Long-term flaxseed oil supplementation diet protects BALB/c mice against Streptococcus pneumoniae infection.

    PubMed

    Saini, Archana; Harjai, Kusum; Mohan, Harsh; Punia, Raj Pal Singh; Chhibber, Sanjay

    2010-02-01

    Intense host immune response to infection contributes significantly to the pathology of pneumococcal pneumonia. Therefore, the regulation of host immune response is critical for the successful outcome of pneumonia in such patients. The aim of the present study was to investigate the effect of n-3 PUFA, i.e. flaxseed oil supplementation for short (4 weeks) as well as long (9 weeks) term, on the course of S. pneumoniae D39 serotype 2 infection in mice. The efficacy of flaxseed oil supplementation was investigated in terms of survival of animals and production of various inflammatory molecules (malondialdehyde, myeloperoxidase, nitric oxide) in the lung homogenate of animals. This was correlated with bacteriological and histopathological parameters. The immunomodulation was studied in terms of cytokines in the lungs following infection with Streptococcus pneumoniae. Results suggest that long-term flaxseed supplementation protected the mice against bacterial colonization of lungs with Streptococcus pneumoniae with reduced histopathological involvement of lung tissue. Moderate pneumonia was observed in supplemented, infected mice compared to severe pneumonia seen in control mice. This was accompanied by decreased inflammatory markers (malondialdehyde, myeloperoxidase, nitric oxide) as the disease progressed. In addition, difference in the levels of pro-inflammatory (TNF-alpha and IL-1beta) and anti-inflammatory (IL-10) cytokines was observed in the flaxseed fed animals. On the contrary, short-term supplementation did not show such an effect on lung colonization.

  3. 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

  4. Sustained Protection in Mice Immunized with Fractional Doses of Salmonella Enteritidis Core and O Polysaccharide-Flagellin Glycoconjugates

    PubMed Central

    Simon, Raphael; Wang, Jin Y.; Boyd, Mary A.; Tulapurkar, Mohan E.; Ramachandran, Girish; Tennant, Sharon M.; Pasetti, Marcela; Galen, James E.; Levine, Myron M.

    2013-01-01

    Non-typhoidal Salmonella (NTS) serovars S. Enteritidis and S. Typhimurium are a major cause of invasive bacterial disease (e.g., bacteremia, meningitis) in infants and young children in sub-Saharan Africa and also occasionally cause invasive disease in highly susceptible hosts (young infants, the elderly, and immunocompromised subjects) in industrialized countries. No licensed vaccines exist against human NTS infections. NTS core and O polysaccharide (COPS) and FliC (Phase 1 flagellin subunits) each constitute protective antigens in murine models. S. Enteritidis COPS conjugated to FliC represents a promising vaccine approach that elicits binding and opsonophagocytic antibodies and protects mice against lethal challenge with virulent S. Enteritidis. We examined the protective efficacy of fractional dosages of S. Enteritidis COPS:FliC conjugate vaccines in mice, and also established that protection can be passively transferred to naïve mice by administering sera from mice immunized with conjugate. Mice were immunized with three doses of either 10 µg, 2.5 µg (full dose), 0.25 µg, or 0.025 µg S. Enteritidis COPS:FliC conjugate at 28 day intervals. Antibody titers to COPS and FliC measured by ELISA fell consonant with progressively smaller vaccine dosage levels; anti-FliC IgG responses remained robust at fractional dosages for which anti-COPS serum IgG titers were decreased. Nevertheless, >90% protection against intraperitoneal challenge was observed in mice immunized with fractional dosages of conjugate that elicited diminished titers to both FliC and COPS. Passive transfer of immune sera from mice immunized with the highest dose of COPS:FliC to naïve mice was also protective, demonstrating the role of antibodies in mediating protection. These results provide important insights regarding the potency of Salmonella glycoconjugate vaccines that use flagellin as a carrier protein. PMID:23741368

  5. Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis.

    PubMed

    Valentine, Catherine H; Hellman, Judith; Beasley-Topliffe, Laura K; Bagchi, Aranya; Warren, H Shaw

    2006-01-01

    Multiple older studies report that immunoglobulin directed to rough mutant bacteria, such as E. coli J5, provides broad protection against challenge with heterologous strains of Gram-negative bacteria. This protection was initially believed to occur through binding of immunoglobulin to bacterial lipopolysaccharide (LPS). However, hundreds of millions of dollars have been invested in attempting to develop clinically-effective anti-LPS monoclonal antibodies without success, and no study has shown that IgG from this antiserum binds LPS. Identification of the protective mechanism would facilitate development of broadly protective human monoclonal antibodies for treating sepsis. IgG from this antiserum binds 2 bacterial outer membrane proteins: murein lipoprotein (MLP) and peptidoglycan-associated lipoprotein (PAL). Both of these outer membrane proteins are highly conserved, have lipid domains that are anchored in the bacterial membrane, are shed from bacteria in blebs together with LPS, and activate cells through Toll-like receptor 2. Our goal in the current work was to determine if passive immunization directed to MLP and PAL protects mice from Gram-negative sepsis. Neither monoclonal nor polyclonal IgG directed to MLP or PAL conferred survival protection in 3 different models of sepsis: cecal ligation and puncture, an infected burn model, and an infected fibrin clot model mimicking peritonitis. Our results are not supportive of the hypothesis that either anti-MLP or anti-PAL IgG are the protective antibodies in the previously described anti-rough mutant bacterial antisera. These studies suggest that a different mechanism of protection is involved.

  6. Purified recombinant organophosphorus acid anhydrase protects mice against soman. (Reannouncement with new availability information)

    SciTech Connect

    Broomfield, C.A.

    1992-12-31

    Since pharmacologic treatments of organophosphorus anticholinesterases (OPs) are nearing their practical limit other types of treatment are being sought. One approach is the prophylactic administration of scavengers that will detoxify OPs before they reach their critical target site. Using mice that were sensitized to OPs by depletion of their serum carboxylesterase with cresylbenzodioxaphosphorin oxide (CBDP), we have shown that animals pretreated intravenously with a purified organophosphorus acid anhydride hydrolase (parathionase) (0.10 mg per g body wt.) are not measurably affected by up to 34.4 microgram soman per kg, a dose more than double that which is lethal to untreated animals. This result indicates that this approach is worthy of exploration and development for protecting military personnel and agricultural workers against OP intoxication. Scavengers, pretreatment, soman, OP intoxication, mice.

  7. Recombinant vaccinia virus/Venezuelan equine encephalitis (VEE) virus protects mice from peripheral VEE virus challenge.

    PubMed

    Kinney, R M; Esposito, J J; Mathews, J H; Johnson, B J; Roehrig, J T; Barrett, A D; Trent, D W

    1988-12-01

    Mice immunized with recombinant vaccinia virus (VACC) expressing Venezuelan equine encephalitis (VEE) virus capsid protein and glycoproteins E1 and E2 or with attenuated VEE TC-83 virus vaccine developed VEE-specific neutralizing antibody and survived intraperitoneal challenge with virulent VEE virus strains including Trinidad donkey (subtype 1AB), P676 (subtype 1C), 3880 (subtype 1D), and Everglades (subtype 2). However, unlike immunization with TC-83 virus, immunization with the recombinant VACC/VEE virus did not protect mice from intranasal challenge with VEE Trinidad donkey virus. These results suggest that recombinant VACC/VEE virus is a vaccine candidate for equines and humans at risk of mosquito-transmitted VEE disease but not for laboratory workers at risk of accidental exposure to aerosol infection with VEE virus.

  8. Aqueous Extract of Clerodendranthus spicatus Exerts Protective Effect on UV-Induced Photoaged Mice Skin

    PubMed Central

    Li, Cai-lan

    2016-01-01

    Clerodendranthus spicatus (Thunb.) C.Y.Wu (CS) is commonly used to treat kidney diseases in traditional Chinese medicine for its prominent anti-inflammatory effect and nourishing function to kidneys. In this study, aqueous extract of CS was assessed for its protective effect on UV-induced skin damage of mice. The chemical compositions of CS aqueous extract were determined by HPLC-ESI-MS/MS, in which 10 components were identified. During the experimental period, CS (0.9, 1.8, and 3.6 g/mL) was externally applied to shaved dorsal skins of mice prior to UV irradiation, daily for ten weeks. The results presented that CS (3.6 g/mL) apparently improved photodamaged skin appearance such as erythema, edema, and coarseness. The abnormal epidermal thickening was significantly reduced, and the dermal structures became more complete. The underlying protective mechanisms were associated with improving antioxidant enzymes activities including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), downregulating inflammatory cytokines (IL-1β, IL-6, TNF-α, COX-2, and PGE2) expressions, recovering collagen density, and reducing matrix metalloproteinases productions. Sun protection factor of CS (3.6 g/mL) was 16.21 ± 0.03. Our findings for the first time demonstrated that CS had therapeutic effect on the photoaged skin. The results indicated that CS is a potential agent for photoprotective cosmetics. PMID:27847530

  9. Chemical Profiles and Protective Effect of Hedyotis diffusa Willd in Lipopolysaccharide-Induced Renal Inflammation Mice

    PubMed Central

    Ye, Jian-Hong; Liu, Meng-Hua; Zhang, Xu-Lin; He, Jing-Yu

    2015-01-01

    Protective effect of Hedyotis diffusa (H. diffusa) Willd against lipopolysaccharide (LPS)-induced renal inflammation was evaluated by the productions of cytokines and chemokine, and the bioactive constituents of H. diffusa were detected by the ultra-fast liquid chromatography -diode array detector-quadrupole-time of flight mass spectrometry (UFLC-DAD-Q-TOF-MS/MS) method. As the results showed, water extract of H. diffusa (equal to 5.0 g/kg body weight) obviously protected renal tissues, significantly suppressed the productions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1, as well as significantly promoted the production of IL-10 in serum and renal tissues. According the chemical profiles of H. diffusa, flavonoids, iridoid glycosides and anthraquinones were greatly detected in serum from H. diffusa extract treatment mice. Two main chemotypes, including eight flavonoids and four iridoid glycosides were found in renal tissues from H. diffusa extract treatment mice. The results demonstrated that water extract of H. diffusa had protective effect on renal inflammation, which possibly resulted from the bioactive constituents consisting of flavonoids, iridoids and anthraquinones. PMID:26580602

  10. Synthetic glycoprotein D-related peptides protect mice against herpes simplex virus challenge.

    PubMed Central

    Eisenberg, R J; Cerini, C P; Heilman, C J; Joseph, A D; Dietzschold, B; Golub, E; Long, D; Ponce de Leon, M; Cohen, G H

    1985-01-01

    Glycoprotein D (gD) of herpes simplex virus (HSV) protects mice from a lethal challenge by either HSV type 1 (HSV-1; oral) or HSV-2 (genital). We evaluated whether synthetic peptides representing residues 1 through 23 of gD (mature protein) can be used as a potential synthetic herpesvirus vaccine. The immunogenicity of the peptides was demonstrated by the biological reactivity of antipeptide sera in immunoprecipitation and neutralization assays. All sera which immunoprecipitated gD had neutralizing against both HSV-1 and HSV-2. The highest titers were found in animals immunized with the longest peptides. The region of residues 1 through 23 was immunogenic regardless of whether the type 1 or type 2 sequence was presented to the animal. Immunization of mice with gD or synthetic peptides conferred solid protection against a footpad challenge with HSV-2. However, the peptides were not as effective as gD in protection against an intraperitoneal challenge. The results suggested that synthetic vaccines based on gD show promise and should be more rigorously tested in a variety of animal models. Images PMID:2999419

  11. A recombinant capsid protein from Dengue-2 induces protection in mice against homologous virus.

    PubMed

    Lazo, Laura; Hermida, Lisset; Zulueta, Aída; Sánchez, Jorge; López, Carlos; Silva, Ricardo; Guillén, Gerardo; Guzmán, María G

    2007-01-22

    In the present work, we study the immunogenicity and protective capacity of a recombinant capsid protein from Dengue-2 virus. The capsid gene was cloned under the T5 phage promoter and expressed in Escherichia coli. The recombinant protein was obtained mainly associated to the soluble fraction upon cellular disruption and exhibited a pattern of high aggregation, determined by gel filtration chromatography. The semipurified preparation was inoculated in mice and after three doses, no antiviral antibodies were induced. On the other hand, mice intracranially challenged with homologous lethal virus, exhibited statistically significant protection with respect to the control group. These results describe, for the first time, the protective capacity of the capsid protein of Dengue virus indicating the existence of a protector mechanism, which is totally independent of the antibodies. This lack of induction of antiviral antibodies makes the capsid protein an attractive vaccine candidate against dengue since eliminates the potential risk of the induction of antibody dependent enhancement associated to the current vaccines under study.

  12. Irsogladine maleate, a gastric mucosal protectant, suppresses intestinal polyp development in Apc-mutant mice

    PubMed Central

    Onuma, Wakana; Tomono, Susumu; Miyamoto, Shinngo; Fujii, Gen; Hamoya, Takahiro; Fujimoto, Kyoko; Miyoshi, Noriyuki; Fukai, Fumio; Wakabayashi, Keiji; Mutoh, Michihiro

    2016-01-01

    This study aimed to identify gastric mucosal protectants that suppress intestinal tumorigenesis in a mouse model. We chose six gastric mucosal protectants (ecabet sodium hydrate, irsogladine maleate, rebamipide, sofalcone, teprenone and troxipide) and examined their effects on the activity of oxidative stress-related transcriptional factors, including AP-1, NF-jB, NRF2, p53 and STAT3, in Caco-2 cells using a luciferase reporter gene assay. Among the six protectants, irsogladine maleate clearly inhibited NF-jB and AP-1 transcriptional activity. Furthermore, the chemopreventive property of irsogladine maleate was examined in a Min mouse model of familial adenomatous polyposis. Treatment with irsogladine maleate at doses of 5 and 50 ppm significantly reduced the number of intestinal polyps to 69% and 66% of the untreated control value, respectively. In these polyps, mRNA levels of the downstream targets of NF-jB, such as IL-1β and IL-6, were decreased by irsogladine maleate treatment. Moreover, the levels of oxidative stress-related markers, reactive carbonyl species, in the livers of Min mice were clearly decreased following the administration of irsogladine maleate. This study demonstrated that irsogladine maleate suppresses intestinal polyp formation in Min mice partly through the NF-jB signaling pathway, thus reducing oxidative stress. PMID:26840084

  13. Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice

    PubMed Central

    Chuai, Yunhai; Shen, Jianliang; Qian, Liren; Wang, Yicun; Huang, Yuecheng; Gao, Fu; Cui, Jianguo; Ni, Jin; Zhao, Luqian; Liu, Shulin; Sun, Xuejun; Li, Bailong; Cai, Jianming

    2012-01-01

    Summary Background Recent studies show that molecular hydrogen (dihydrogen, H2) has potential as an effective and safe radioprotective agent through reducing oxidative stress. The aim of this study was to investigate whether H2 is able to protect spermatogenesis and hematopoiesis from radiation-induced injuries. Material/Methods H2 was dissolved in physiological saline using an apparatus produced by our department. 60Co-gamma rays in the irradiation centre were used for irradiation. Spermatid head counts and histological analysis were used to evaluate spermatogenesis. Endogenous hematopoietic spleen colony formation (endoCFUs), bone marrow nucleated cells (BMNC) and peripheral blood (PB) leukocytes were used to evaluate hemopoiesis. Results This study demonstrates that treating mice with H2 before ionizing radiation (IR) can increase the spermatid head count and protect seminiferous epithelium from IR. This study also demonstrates that H2 could significantly increase the number of endoCFUs, BMNC and PB leukocyte. Conclusions This study suggests that hydrogen-rich saline could partially protect spermatogenesis and hematopoiesis in irradiated mice. PMID:22367121

  14. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia.

    PubMed

    Gomes, Rachel Novaes; Castro-Faria-Neto, Hugo C; Bozza, Patricia T; Soares, Milena B P; Shoemaker, Charles B; David, John R; Bozza, Marcelo T

    2005-12-01

    Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mug of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.

  15. [In vitro protective effect of methionine against cisplatin's damage to the cochlear hair cell of mice].

    PubMed

    Xue, Chan; Zhou, Yong-Qing; Gao, Hai-Tao; Ma, Ying-Yu; Wang, Na; Qu, Yan

    2011-02-01

    To establish an in vitro model of mouse cochlear basilar membrane impairment using cisplatin, and observe the protective effect of methionine on the hair cells. The cochlear basilar membrane samples of thirty two Kunming mice were harvested on the 2nd day after birth and randomly divided into four groups. Each group had 16 samples. Overnight preincubation the cochlear organ followed by appropriate treatment respectively as follows: the serum-free culture medium, the serum-free culture medium with methionine and cisplatin, the cisplatinum-containing serum-free culture medium, and the methionine-containing serum-free culture medium. The protective effect of methionine for injury of cochlea hair cells induced by cisplatin was observed by myosin-VI immunofluorescence, light microscopy, laser confocal scanning microscope and hair cells counting. The outer hair cells (OHC) and inner hair cells (IHC) of control group and methionine group were not damaged. The outer and inner hair cells of cisplatin group were damaged in various degree, and had remarkable difference compared with control group and methionine group (P < 0.05). The outer hair cells and inner hair cells of cisplatin + methionine group were damaged less than the cisplatin group with remarkable difference (t(IHC) = 3.929, t(OHC) = 8.582, P < 0.05). Cisplatinum could damage the cochlear hair cells of the basal membrane in Kunming mice. Methionine might protect against cisplatin's damage on the cochlear hair cells.

  16. Irsogladine maleate, a gastric mucosal protectant, suppresses intestinal polyp development in Apc-mutant mice.

    PubMed

    Onuma, Wakana; Tomono, Susumu; Miyamoto, Shinngo; Fujii, Gen; Hamoya, Takahiro; Fujimoto, Kyoko; Miyoshi, Noriyuki; Fukai, Fumio; Wakabayashi, Keiji; Mutoh, Michihiro

    2016-02-23

    This study aimed to identify gastric mucosal protectants that suppress intestinal tumorigenesis in a mouse model. We chose six gastric mucosal protectants (ecabet sodium hydrate, irsogladine maleate, rebamipide, sofalcone, teprenone and troxipide) and examined their effects on the activity of oxidative stress-related transcriptional factors, including AP-1, NF-jB, NRF2, p53 and STAT3, in Caco-2 cells using a luciferase reporter gene assay. Among the six protectants, irsogladine maleate clearly inhibited NF-jB and AP-1 transcriptional activity. Furthermore, the chemopreventive property of irsogladine maleate was examined in a Min mouse model of familial adenomatous polyposis. Treatment with irsogladine maleate at doses of 5 and 50 ppm significantly reduced the number of intestinal polyps to 69% and 66% of the untreated control value, respectively. In these polyps, mRNA levels of the downstream targets of NF-jB, such as IL-1β and IL-6, were decreased by irsogladine maleate treatment. Moreover, the levels of oxidative stress-related markers, reactive carbonyl species, in the livers of Min mice were clearly decreased following the administration of irsogladine maleate. This study demonstrated that irsogladine maleate suppresses intestinal polyp formation in Min mice partly through the NF-jB signaling pathway, thus reducing oxidative stress.

  17. B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.

    PubMed

    Feldman, Amy G; Tucker, Rebecca M; Fenner, Erika K; Pelanda, Roberta; Mack, Cara L

    2013-01-01

    A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-α(-/-)) mice received RRV shortly after birth. Ig-α(-/-) RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α(-/-) mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-α(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α(-/-) mice were not the sole reason for protection from disease. Conclusion : B cell deficient Ig-α(-/-) mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.

  18. Protective effect of salidroside on cardiac apoptosis in mice with chronic intermittent hypoxia.

    PubMed

    Lai, Mei-Chih; Lin, Jaung-Geng; Pai, Pei-Ying; Lai, Mei-Hsin; Lin, Yueh-Min; Yeh, Yu-Lan; Cheng, Shiu-Min; Liu, Yi-fan; Huang, Chih-Yang; Lee, Shin-Da

    2014-07-01

    The goal of this study is to determine if salidroside has protective effects on hypoxia-induced cardiac widely dispersed apoptosis in mice with severe sleep apnea model. Sixty-four C57BL/6J mice 5-6 months of age were divided into four groups, i.e. Control group (21% O2, 24h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60s, 20% O2 alternating 60s, 8h per day, 8 weeks, n=16); and Hypoxia+S10 and Hypoxia+S 30 groups (Hypoxia for 1st 4 weeks, hypoxia pretreated 10mg/kg and 30 mg/kg salidroside by oral gavage per day for 2nd 4 weeks, n=16 and 16). The excised hearts from four groups were measured by the heart weight index, H&E staining, TUNEL-positive assays and Western blotting. TUNEL-positive apoptotic cells in mice heart were less in Hypoxia+S10 and Hypoxia+S30 than those in the Hypoxia group. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways) were decreased in Hypoxia+S10 and Hypoxia+S30. In the mitochondria pathway, the protein levels of BcLx, Bcl2, and Bid (anti-apoptotic Bcl2 family) in Hypoxia+S10 and Hypoxia+S30 were more than those in Hypoxia. The protein levels of Bax, t-Bid, activated caspase 9, and activated caspase 3 were less in Hypoxia+S10 and Hypoxia+S30 than those in hypoxia. Our findings suggest that salidroside has protective effects on chronic intermittent hypoxia-induced Fas-dependent and mitochondria-dependent apoptotic pathways in mice hearts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Protection of swiss albino mice against whole-body gamma irradiation by Mentha piperita (Linn.).

    PubMed

    Samarth, R M; Goyal, P K; Kumar, Ashok

    2004-07-01

    The radioprotective effects of Mentha oil (Mentha piperita Linn.) against radiation induced haematological alterations in peripheral blood and the survival of Swiss albino mice were studied. Mentha oil 40 micro L/animal/day for 3 consecutive days when fed orally prior to whole-body gamma irradiation (8 Gy) showed protection of the animals in terms of the survival percentage and haematological parameters in mice. Fifty per cent of the animals died within 20 days and 100% mortality was observed up to 30 days post-irradiation in the control irradiated group. Whereas only 17% of the mice died within 30 days in the experimental group (Mentha oil pretreated irradiated). The total RBC count decreased maximally at 24 h (3.45 +/- 0.20 x 10(12)/L, p < 0.001), similar observations were obtained for the WBC count, haemoglobin content and haematocrit percentage in the irradiated control animals. However, in irradiated animals pretreated with Mentha oil, although the initial values of haematological components were lower they later showed a remarkable recovery reaching normal at 30 days post-irradiation compared with the irradiated control animals. In general, the recovery of the blood cell number in irradiated animals depends on the survival of stem cells and their derivatives. The results from the present study suggest that the oil of Mentha piperita (Linn.) has a radioprotective role in stimulating/protecting the haematopoietic system. Hence, enhanced survival and an increase in the haematological constituents of peripheral blood of mice against lethal gamma radiation was observed.

  20. Immunization against Multidrug-Resistant Acinetobacter baumannii Effectively Protects Mice in both Pneumonia and Sepsis Models

    PubMed Central

    Huang, Weiwei; Yao, Yufeng; Long, Qiong; Yang, Xu; Sun, Wenjia; Liu, Cunbao; Jin, Xiaomei; li, Yang; Chu, Xiaojie; Chen, Bin; Ma, Yanbing

    2014-01-01

    Objective Acinetobacter baumannii is considered the prototypical example of a multi- or pan- drug-resistant bacterium. It has been increasingly implicated as a major cause of nosocomial and community-associated infections. This study proposed to evaluate the efficacy of immunological approaches to prevent and treat A. baumannii infections. Methods Mice were immunized with outer membrane vesicles (OMVs) prepared from a clinically isolated multidrug-resistant strain of A. baumannii. Pneumonia and sepsis models were used to evaluate the efficacy of active and passive immunization with OMVs. The probable effective mechanisms and the protective potential of clonally distinct clinical isolates were investigated in vitro using an opsonophagocytic assay. Results Intramuscular immunization with OMVs rapidly produced high levels of OMV-specific IgG antibodies, and subsequent intranasal challenge with A. baumannii elicited mucosal IgA and IgG responses. Both active and passive immunization protected the mice from challenges with homologue bacteria in a sepsis model. Bacterial burden in bronchoalveolar lavage fluids (BALF), lung, and spleen, inflammatory cell infiltration in BALF and lung, and inflammatory cytokine accumulation in BALF was significantly suppressed in the pneumonia model by both active and passive immunization strategies. The antisera from immunized mice presented with significant opsonophagocytic activities in a dose-dependent manner against not only homologous strains but also five of the other six clonally distinct clinical isolates. Conclusions Utilizing immunological characteristics of outer membrane proteins to elevate protective immunity and circumvent complex multidrug-resistance mechanisms might be a viable approach to effectively control A. baumannii infections. PMID:24956279

  1. Mutant Brucella abortus membrane fusogenic protein induces protection against challenge infection in mice.

    PubMed

    de Souza Filho, Job Alves; de Paulo Martins, Vicente; Campos, Priscila Carneiro; Alves-Silva, Juliana; Santos, Nathalia V; de Oliveira, Fernanda Souza; Menezes, Gustavo B; Azevedo, Vasco; Cravero, Silvio Lorenzo; Oliveira, Sergio Costa

    2015-04-01

    Brucella species can cause brucellosis, a zoonotic disease that causes serious livestock economic losses and represents a public health threat. The mechanism of virulence of Brucella spp. is not yet fully understood. Therefore, it is crucial to identify new molecules that serve as virulence factors to better understand this host-pathogen interplay. Here, we evaluated the role of the Brucella membrane fusogenic protein (Mfp) and outer membrane protein 19 (Omp19) in bacterial pathogenesis. In this study, we showed that B. abortus Δmfp::kan and Δomp19::kan deletion mutant strains have reduced persistence in vivo in C57BL/6 and interferon regulatory factor 1 (IRF-1) knockout (KO) mice. Additionally, 24 h after macrophage infection with a Δmfp::kan or Δomp19::kan strain expressing green fluorescent protein (GFP) approximately 80% or 65% of Brucella-containing vacuoles (BCVs) retained the late endosomal/lysosomal marker LAMP-1, respectively, whereas around 60% of BCVs containing wild-type S2308 were found in LAMP-1-negative compartments. B. abortus Δomp19::kan was attenuated in vivo but had a residual virulence in C57BL/6 and IRF-1 KO mice, whereas the Δmfp::kan strain had a lower virulence in these same mouse models. Furthermore, Δmfp::kan and Δomp19::kan strains were used as live vaccines. Challenge experiments revealed that in C57BL/6 and IRF-1 KO mice, the Δmfp::kan strain induced greater protection than the vaccine RB51 and protection similar that of vaccine S19. However, a Δomp19::kan strain induced protection similar to that of RB51. Thus, these results demonstrate that Brucella Mfp and Omp19 are critical for full bacterial virulence and that the Δmfp::kan mutant may serve as a potential vaccine candidate in future studies.

  2. 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

  3. Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice.

    PubMed

    Li, Xiangming; Huang, Jing; Zhang, Min; Funakoshi, Ryota; Sheetij, Dutta; Spaccapelo, Roberta; Crisanti, Andrea; Nussenzweig, Victor; Nussenzweig, Ruth S; Tsuji, Moriya

    2016-08-31

    A number of studies have shown that CD8+ T cells mediate protective anti-malaria immunity in a mouse model. However, whether human CD8+ T cells play a role in protection against malaria remains unknown. We recently established human immune system (HIS) mice harboring functional human CD8+ T cells (HIS-CD8 mice) by transduction with HLA-A∗0201 and certain human cytokines using recombinant adeno-associated virus-based gene transfer technologies. These HIS-CD8 mice mount a potent, antigen-specific HLA-A∗0201-restricted human CD8+ T-cell response upon immunization with a recombinant adenovirus expressing a human malaria antigen, the Plasmodium falciparum circumsporozoite protein (PfCSP), termed AdPfCSP. In the present study, we challenged AdPfCSP-immunized HIS-CD8 mice with transgenic Plasmodium berghei sporozoites expressing full-length PfCSP and found that AdPfCSP-immunized (but not naïve) mice were protected against subsequent malaria challenge. The level of the HLA-A∗0201-restricted, PfCSP-specific human CD8+ T-cell response was closely correlated with the level of malaria protection. Furthermore, depletion of human CD8+ T cells from AdPfCSP-immunized HIS-CD8 mice almost completely abolished the anti-malaria immune response. Taken together, our data show that human CD8+ T cells mediate protective anti-malaria immunity in vivo.

  4. 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.

  5. Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis

    PubMed Central

    Bai, Xiyuan; Shang, Shaobin; Henao-Tamayo, Marcela; Basaraba, Randall J.; Ovrutsky, Alida R.; Matsuda, Jennifer L.; Takeda, Katsuyuki; Chan, Mallory M.; Dakhama, Azzeddine; Kinney, William H.; Trostel, Jessica; Bai, An; Honda, Jennifer R.; Achcar, Rosane; Hartney, John; Joosten, Leo A. B.; Kim, Soo-Hyun; Orme, Ian; Dinarello, Charles A.; Ordway, Diane J.; Chan, Edward D.

    2015-01-01

    Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32γTg mice, including tumor necrosis factor-alpha (TNFα) positive lung macrophages and dendritic cells, and IFN-gamma (IFNγ) and TNFα positive CD4+ and CD8+ T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32β were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to MTB. PMID:25820174

  6. Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions.

    PubMed

    Craige, Siobhan M; Kant, Shashi; Reif, Michaella; Chen, Kai; Pei, Yongmei; Angoff, Rebecca; Sugamura, Koichi; Fitzgibbons, Timothy; Keaney, John F

    2015-12-01

    Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E-/- mice +/- endothelial Nox4 (ApoE-/- + EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE-/- + EC Nox4 mice as compared to the ApoE-/- littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE-/- + EC Nox4 mice compared to ApoE-/- alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE-/- + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance

    PubMed Central

    Kim, Teayoun; He, Lan; Johnson, Maria S.; Li, Yan; Zeng, Ling; Ding, Yishu; Long, Qinqiang; Moore, John F.; Sharer, Jon D.; Nagy, Tim R.; Young, Martin E.; Wood, Philip A.; Yang, Qinglin

    2014-01-01

    Background Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. Methods We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b+/−) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. Results We found that Cpt1b+/− mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b+/− mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b+/− skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b+/− but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. Conclusion The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. PMID:25309812

  8. 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.

  9. 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

  10. Protective effect of sugar cane extract against dextran sulfate sodium-induced colonic inflammation in mice.

    PubMed

    Wang, Bin; Li, Yansen; Mizu, Masami; Furuta, Toma; Li, ChunMei

    2017-02-01

    Sugar cane extract (SCE) exhibits various biological effects and has been reported to enhance animal growth performance. However, the effect of SCE on inflammation in animals is still obscure. To study the effects and underlying mechanism of SCE on dextran sulfate sodium (DSS)-induced colonic inflammation, forty female ICR mice (26.63±0.19g, 6-week-old) were assigned into four groups: a control group (Cont), a DSS-challenged group (DSS), a SCE-supplemented group (SCE), and a DSS+SCE group (DSS+SCE). Mice in Cont group and DSS group were fed basic diet and other mice received 1% SCE supplemented in basic diet from 6-week to 8-week-old. Mice in DSS and DSS+SCE groups were also given a 4% DSS solution from 7-week to 8-week-old via drinking water to induce colonic inflammation. After 2 weeks, mice were sacrificed and samples were collected. The results showed that dietary SCE alleviated DSS induced growth suppression, splenic damage, colonic histological changes, colonic inflammation, oxidative stress, and colonic dysfunction of tight junctions. Meanwhile, the DSS exposure activated nuclear transcription factor kappa B p65 and inhibited nuclear factor E2-related factor 2 (Nrf2), while SCE markedly attenuated the DSS-promoted effect on the p65 nuclear accumulation and the DSS-inhibited effect on the Nrf2 nuclear accumulation. In conclusion, SCE conferred a protective role in the DSS-induced inflammation and the mechanism might be associated with the activated signals of the nuclear factor kappa B p65 and Nrf2.

  11. The Polyphenol Oleuropein Aglycone Protects TgCRND8 Mice against Aß Plaque Pathology

    PubMed Central

    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. PMID:23951225

  12. Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice

    PubMed Central

    2014-01-01

    Background Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms. Methods Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS−/−) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS−/− mice with BLM-induced pulmonary fibrosis. Results The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS−/− mice. Long-term treatment with the supplemental NO donor in n/i/eNOS−/− mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs. Conclusions These results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis. PMID:25092105

  13. Parainfluenza Virus 5 Expressing the G Protein of Rabies Virus Protects Mice after Rabies Virus Infection

    PubMed Central

    Huang, Ying; Chen, Zhenhai; Huang, Junhua

    2014-01-01

    Rabies remains a major public health threat around the world. Once symptoms appear, there is no effective treatment to prevent death. In this work, we tested a recombinant parainfluenza virus 5 (PIV5) strain expressing the glycoprotein (G) of rabies (PIV5-G) as a therapy for rabies virus infection: we have found that PIV5-G protected mice as late as 6 days after rabies virus infection. PIV5-G is a promising vaccine for prevention and treatment of rabies virus infection. PMID:25552723

  14. A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia.

    PubMed

    van den Berg, Sanne; Bonarius, Hendrik P J; van Kessel, Kok P M; Elsinga, Goffe S; Kooi, Neeltje; Westra, Hans; Bosma, Tjibbe; van der Kooi-Pol, Magdalena M; Koedijk, Danny G A M; Groen, Herman; van Dijl, Jan Maarten; Buist, Girbe; Bakker-Woudenberg, Irma A J M

    2015-01-01

    Due to substantial therapy failure and the emergence of antibiotic-resistant Staphylococcus aureus strains, alternatives for antibiotic treatment of S. aureus infections are urgently needed. Passive immunization using S. aureus-specific monoclonal antibodies (mAb) could be such an alternative to prevent and treat severe S. aureus infections. The invariantly expressed immunodominant staphylococcal antigen A (IsaA) is a promising target for passive immunization. Here we report the development of the human anti-IsaA IgG1 mAb 1D9, which was shown to bind to all 26 S. aureus isolates tested. These included both methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA, respectively). Immune complexes consisting of IsaA and 1D9 stimulated human as well as murine neutrophils to generate an oxidative burst. In a murine bacteremia model, the prophylactic treatment with a single dose of 5 mg/kg 1D9 improved the survival of mice challenged with S. aureus isolate P (MSSA) significantly, while therapeutic treatment with the same dose did not influence animal survival. Neither prophylactic nor therapeutic treatment with 5 mg/kg 1D9 resulted in improved survival of mice with S. aureus USA300 (MRSA) bacteremia. Importantly, our studies show that healthy S. aureus carriers elicit an immune response which is sufficient to generate protective mAbs against invariant staphylococcal surface antigens. Human mAb 1D9, possibly conjugated to for example another antibody, antibiotics, cytokines or chemokines, may be valuable to fight S. aureus infections in patients.

  15. Helminth protection against autoimmune diabetes in NOD mice is independent of a type 2 immune shift and requires TGFβ

    PubMed Central

    Hübner, Marc P; Shi, Yinghui; Torrero, Marina N; Mueller, Ellen; Larson, David; Soloviova, Kateryna; Gondorf, Fabian; Hoerauf, Achim; Killoran, Kristin E.; Stocker, J Thomas; Davies, Stephen J; Tarbell, Kristin V; Mitre, Edward

    2011-01-01

    Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient nonobese diabetic (NOD) mice and whether depletion or absence of regulatory T cells, IL-10, or TGFβ alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or antibody production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4-deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4-deficient NOD mice were accompanied by increases in CD4+CD25+FoxP3+ regulatory T cell frequencies and numbers, respectively, and helminth infection increased proliferation of CD4+FoxP3+ cells. However, depletion of CD25+ cells in NOD mice or FoxP3+ T cells from splenocytes transferred into NOD.scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGFβ, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity as helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGFβ. PMID:22174447

  16. 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.

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

    PubMed Central

    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

  18. 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

  19. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters.

    PubMed

    Su, Yan Ru; Ishiguro, Hiroyuki; Major, Amy S; Dove, Dwayne E; Zhang, Wenwu; Hasty, Alyssa H; Babaev, Vladimir R; Linton, MacRae F; Fazio, Sergio

    2003-10-01

    The antiatherogenic effect of high-density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) has been largely attributed to their key roles in reverse cholesterol transport (RCT) and cellular cholesterol efflux. Substantial evidence shows that overexpression of human apoA-I reduces atherosclerosis in animal models. However, it is uncertain whether this protection is due to an increase in plasma HDL level or to a local effect in the artery wall. To test the hypothesis that expression of human apoA-I in macrophages can promote RCT in the artery wall, we used a retroviral construct expressing human apoA-I cDNA (MFG-HAI) to transduce ApoE(-/-) bone marrow cells and then transplanted these cells into ApoE(-/-) mice with preexisting atherosclerosis. ApoE(-/-) mice reconstituted with MFG-HAI marrow had a significant reduction (30%) in atherosclerotic lesions in the proximal aorta compared to control mice that received marrow expressing MFG parental virus. Peritoneal macrophages isolated from MFG-HAI mice showed a four- to fivefold increase in mRNA expression levels of both ATP-binding cassette (ABC) A1 and ABCG1 compared to controls. Our data demonstrate that gene transfer-mediated expression of human apoA-I in macrophages can compensate in part for apoE deficiency and delay the progression of atherosclerotic lesions by stimulating ABC-dependent cholesterol efflux and RCT.

  20. Antibody to the E3 Glycoprotein Protects Mice against Lethal Venezuelan Equine Encephalitis Virus Infection▿

    PubMed Central

    Parker, Michael D.; Buckley, Marilyn J.; Melanson, Vanessa R.; Glass, Pamela J.; Norwood, David; Hart, Mary Kate

    2010-01-01

    Six monoclonal antibodies were isolated that exhibited specificity for a furin cleavage site deletion mutant (V3526) of Venezuelan equine encephalitis virus (VEEV). These antibodies comprise a single competition group and bound the E3 glycoprotein of VEEV subtype I viruses but failed to bind the E3 glycoprotein of other alphaviruses. These antibodies neutralized V3526 virus infectivity but did not neutralize the parental strain of Trinidad donkey (TrD) VEEV. However, the E3-specific antibodies did inhibit the production of virus from VEEV TrD-infected cells. In addition, passive immunization of mice demonstrated that antibody to the E3 glycoprotein provided protection against lethal VEEV TrD challenge. This is the first recognition of a protective epitope in the E3 glycoprotein. Furthermore, these results indicate that E3 plays a critical role late in the morphogenesis of progeny virus after E3 appears on the surfaces of infected cells. PMID:20926570

  1. Protective effects of S-sulfonated human gamma globulin against experimental infections in mice.

    PubMed Central

    Tomioka, H; Iwamura, Y; Suzuki, Y; Ohtomo, S; Hashimoto, Y

    1980-01-01

    S-sulfonated gamma globulin (GGS), newly developed as a safe drug for intravenous use, was studied for its protective effects against some experimental infections in mice. Gamma globulin showed a good protective activity against infections due to Streptococcus pneumoniae and Escherichia coli and was moderately active against infections due to Staphylococcus aureus and Pseudomonas aeruginosa. In most cases, the potency of GGS was almost the same as that of original native gamma globulin. The duration of GGS activity in vivo was found to be comparable to that of native gamma globulin and much higher than that of pepsin-digested gamma globulin. In the control of infection due to E. coli, specific antibody was found to play a central role in the antibacterial action of GGS. When GGS was administered in combination with the antibiotics gentamicin and cefazolin for the control of infections due to S. pneumoniae or E. coli, a clear synergistic effect was observed. PMID:6160106

  2. Inactivated West Nile Virus (WNV) vaccine, Duvaxyn WNV, protects against a highly neuroinvasive lineage 2 WNV strain in mice.

    PubMed

    Venter, Marietjie; van Vuren, Petrus Janse; Mentoor, Juliet; Paweska, Janusz; Williams, June

    2013-08-20

    Lineage 2 West Nile Virus (WNV) is endemic to southern Africa and Madagascar, and has recently been associated with encephalitis outbreaks in humans and horses in South Africa, central Europe, Italy and Greece. Commercial vaccines have mostly been evaluated against WNV lineage 1 strains and their efficacy against lineage 2 strains rarely reported. To evaluate protection of Duvaxyn WNV vaccine against lineage 2 strains associated with encephalitis in South Africa, mice were vaccinated twice intramuscularly three weeks apart, and challenged four weeks later with highly neuroinvasive lineage 1 strain NY385/99 or lineage 2 strain SPU93/01. Neutralising antibody titres were measured at the time of challenge and three weeks later. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were conducted on brains of mice that succumbed during the trial, on controls and on vaccinated mice that survived. Serum neutralising antibodies in vaccinated mice were detected but low three weeks after primovaccination. Three weeks post-challenge, vaccinated mice had significantly higher serum neutralising antibody titres against both lineages than unvaccinated controls. After challenge, all vaccinated mice remained healthy but all unvaccinated mice demonstrated severe neurological signs with 75% mortality rate. WNV was not detected in brains of vaccinated mice whereas virus replicated in most unvaccinated mice challenged with either lineage. Gross and microscopic lesions were found only in unvaccinated mice challenged with both lineages. Duvaxyn WNV vaccine provided complete protection against challenge with lineage 2 WNV and stimulated significant cross protective neutralising antibodies in mice against lineage 2. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Transplantation of bone marrow genetically engineered to express proinsulin II protects against autoimmune insulitis in NOD mice.

    PubMed

    Chan, James; Clements, Warren; Field, Judith; Nasa, Zeyad; Lock, Peter; Yap, Felicia; Toh, Ban-Hock; Alderuccio, Frank

    2006-11-01

    Type 1 diabetes (T1D) is a T-cell-dependent autoimmune disease resulting from destructive inflammation (insulitis) of the insulin-producing pancreatic beta-cells. Transgenic expression of proinsulin II by a MHC class II promoter or transfer of bone marrow from these transgenic mice protects NOD mice from insulitis and diabetes. We assessed the feasibility of gene therapy in the NOD mouse as an approach to treat T1D by ex vivo genetic manipulation of normal hematopoietic stem cells (HSCs) with proinsulin II followed by transfer to recipient mice. HSCs were isolated from 6-8-week-old NOD female mice and transduced in vitro with retrovirus encoding enhanced green fluorescent protein (EGFP) and either proinsulin II or control autoantigen. Additional control groups included mice transferred with non-manipulated bone marrow and mice which did not receive bone marrow transfer. EGFP-sorted or non-sorted HSCs were transferred into pre-conditioned 3-4-week-old female NOD mice and insulitis was assessed 8 weeks post-transfer. Chimerism was established in all major lymphoid tissues, ranging from 5-15% in non-sorted bone marrow transplants to 20-45% in EGFP-sorted bone marrow transplants. The incidence and degree of insulitis was significantly reduced in mice receiving proinsulin II bone marrow compared to controls. However, the incidence of sialitis in mice receiving proinsulin II bone marrow and control mice was not altered, indicating protection from insulitis was antigen specific. We show for the first time that ex vivo genetic manipulation of HSCs to express proinsulin II followed by transplantation to NOD mice can establish molecular chimerism and protect from destructive insulitis in an antigen-specific manner.

  4. 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

  5. Protective effects of Ganoderma lucidum spore on cadmium hepatotoxicity in mice.

    PubMed

    Jin, Hai; Jin, Feng; Jin, Jia-Xing; Xu, Jie; Tao, Ting-Ting; Liu, Jie; Huang, Hou-Jin

    2013-02-01

    The medicinal fungus Ganoderma lucidum has been shown to have hepatoprotective effects. G. lucidum contains triterpenes and polysaccharides, and the Sporoderm-broken G. lucidum powder is particular beneficial. This study utilized G. lucidum spore to examine its effect on [Cd(II)]-induced hepatotoxicity in mice and the mechanism of the protection. Mice were pretreated with G. lucidum spore (0.1, 0.5, and 1.0 g/kg, po, for 7 days), and subsequently challenged with a hepatotoxic dose of Cd(II) (3.7 mg/kg, ip). Liver injury was evaluated 8h later. G. lucidum spore protected against Cd(II)-induced liver injury in a dose-dependent manner, as evidenced by serum alanine aminotransferase, aspartate aminotransferase and histopathology. To examine the mechanism of protection, subcellular distribution of Cd(II) was determined. G. lucidum spore decreased Cd(II) accumulation in hepatic nuclei, mitochondria, and microsomes, but increased Cd(II) distribution to the cytosol, where Cd(II) is sequestered by metallothionein, a protein against Cd(II) toxicity. Indeed, G. lucidum spore induced hepatic metallothionein-1 mRNA 8-fold, and also increased metallothionein protein as determined by the Cd(II)/hemoglobin assay. Cd(II)-induced oxidative stress was also decreased by G. lucidum spore, as evidenced by decreased formation of malondialdehyde. In summary, G. lucidum spore is effective in protection against Cd(II)-induced hepatotoxicity, and this effect is due, at least in part, to the induction of hepatic metallothionein to achieve beneficial effects.

  6. 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.

  7. Characterization of Outer Membrane Vesicles from Brucella melitensis and Protection Induced in Mice

    PubMed Central

    Avila-Calderón, Eric Daniel; Lopez-Merino, Ahidé; Jain, Neeta; Peralta, Humberto; López-Villegas, Edgar Oliver; Sriranganathan, Nammalwar; Boyle, Stephen M.; Witonsky, Sharon; Contreras-Rodríguez, Araceli

    2012-01-01

    The outer membrane vesicles (OMVs) from smooth B. melitensis 16 M and a derived rough mutant, VTRM1 strain, were purified and characterized with respect to protein content and induction of immune responses in mice. Proteomic analysis showed 29 proteins present in OMVs from B. melitensis 16 M; some of them are well-known Brucella immunogens such as SOD, GroES, Omp31, Omp25, Omp19, bp26, and Omp16. OMVs from a rough VTRM1 induced significantly higher expression of IL-12, TNFα, and IFNγ genes in bone marrow dendritic cells than OMVs from smooth strain 16 M. Relative to saline control group, mice immunized intramuscularly with rough and smooth OMVs were protected from challenge with virulent strain B. melitensis 16 M just as well as the group immunized with live strain B. melitensis Rev1 (P < 0.005). Additionally, the levels of serum IgG2a increased in mice vaccinated with OMVs from rough strain VTRM1 consistent with the induction of cell-mediated immunity. PMID:22242036

  8. Polychlorinated biphenyls induce proinflammatory cytokine release and dopaminergic dysfunction: protection in interleukin-6 knockout mice.

    PubMed

    Goodwill, Meleik Hebert; Lawrence, David A; Seegal, Richard F

    2007-02-01

    Proinflammatory cytokines are not only important mediators of brain development, but also pose an increased risk for neurodegeneration following exposure to neurotoxicants or trauma. We have used the ubiquitous environmental and occupational neurotoxicant polychlorinated biphenyls (PCBs) to investigate the putative role of inflammatory agents in mediating processes involved in basal ganglia dysfunctions. PCBs induced inflammatory responses in C57BL/6 adult male mice, significantly elevating serum levels of IL-6 (31%), IL-1beta (71%) and TNF-alpha (22%) and significantly reducing striatal dopamine (DA, 21%), tyrosine hydroxylase (TH, 26%), dopamine transporter (DAT, 39%), and synaptophysin (29%) concentrations. We also exposed mice deficient in the proinflammatory cytokine interleukin-6 (IL-6-/-) to PCBs, to explore the role of this specific cytokine in mediating PCB-induced DA neurodegeneration. Not only did the PCB-treated IL-6-/- mice exhibit a decrease in serum levels of IL-1beta and TNF-alpha, but they were also protected from PCB-induced striatal dopaminergic dysfunction, displaying no signs of toxicant-induced reductions in DA levels, or TH, DAT or synaptophysin expression. Taken together, these results suggest that: (1) PCB exposure results in a peripheral inflammatory response associated with striatal terminal degeneration; and (2) the absence of IL-6 prevents PCB-induced dopaminergic losses in the striatum.

  9. Black tattoos protect against UVR-induced skin cancer in mice.

    PubMed

    Lerche, Catharina M; Sepehri, Mitra; Serup, Jørgen; Poulsen, Thomas; Wulf, Hans Christian

    2015-09-01

    Black tattoos may involve risk of cancer owing to polycyclic aromatic hydrocarbons including benzo(a)pyrene (BaP) in inks. Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and black tattoo may therefore potentially be very problematic, but has not been previously studied. Immunocompetent C3.Cg/TifBomTac mice (n = 99) were tattooed on the back with Starbrite Tribal Black(™) . This ink has a high content of the carcinogen BaP. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. Controls were 'tattooed' without ink. All irradiated mice developed SCCs while no malignant tumours were found in the nonirradiated group. In the tattooed and irradiated group, the development of the first, second and third SCC was significantly delayed in comparison with the irradiated controls without black tattoos (212, 232, 247 days vs. 163, 183, 191 days, P < 0.001). In UVR-irradiated black tattoos, remarkably, the development of UVR-induced skin cancer was delayed by the tattoos. Skin reflectance measurement indicated that the protective effect of black pigment in the dermis might be attributed to UVR absorption by black pigment below the epidermis and thereby reduction of backscattered radiation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    PubMed Central

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

    2016-01-01

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

  11. 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.

  12. Mitochondrial and Metabolic Dysfunction in Renal Convoluted Tubules of Obese Mice: Protective Role of Melatonin

    PubMed Central

    Giugno, Lorena; Lavazza, Antonio; Reiter, Russel J.; Rodella, Luigi Fabrizio; Rezzani, Rita

    2014-01-01

    Obesity is a common and complex health problem, which impacts crucial organs; it is also considered an independent risk factor for chronic kidney disease. Few studies have analyzed the consequence of obesity in the renal proximal convoluted tubules, which are the major tubules involved in reabsorptive processes. For optimal performance of the kidney, energy is primarily provided by mitochondria. Melatonin, an indoleamine and antioxidant, has been identified in mitochondria, and there is considerable evidence regarding its essential role in the prevention of oxidative mitochondrial damage. In this study we evaluated the mechanism(s) of mitochondrial alterations in an animal model of obesity (ob/ob mice) and describe the beneficial effects of melatonin treatment on mitochondrial morphology and dynamics as influenced by mitofusin-2 and the intrinsic apoptotic cascade. Melatonin dissolved in 1% ethanol was added to the drinking water from postnatal week 5–13; the calculated dose of melatonin intake was 100 mg/kg body weight/day. Compared to control mice, obesity-related morphological alterations were apparent in the proximal tubules which contained round mitochondria with irregular, short cristae and cells with elevated apoptotic index. Melatonin supplementation in obese mice changed mitochondria shape and cristae organization of proximal tubules, enhanced mitofusin-2 expression, which in turn modulated the progression of the mitochondria-driven intrinsic apoptotic pathway. These changes possibly aid in reducing renal failure. The melatonin-mediated changes indicate its potential protective use against renal morphological damage and dysfunction associated with obesity and metabolic disease. PMID:25347680

  13. 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

  14. 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

  15. Protective Effect of Royal Jelly on In Vitro Fertilization (IVF) in Male Mice Treated with Oxymetholone

    PubMed Central

    Zahmatkesh, Ensieh; Najafi, Gholamreza; Nejati, Vahid

    2015-01-01

    Objective This study aimed to investigate the effects of royal jelly (RJ) on catalase, total antioxidant capacity and embryo development in adult mice treated with oxymetholone (OXM). Materials and Methods In this exprimental study, 32 male and 96 female adult Naval Medical Research Institute (NMRI) mice (7-9 weeks of age) with a ratio of 1:3 for fertili- zation purposes were randomly divided into 4 groups as follows: i. Control group (n=8) receiving 0.1 ml/mice saline daily by gavage for 30 day, ii. RJ group (n=8) treated with RJ at a dose of 100 mg/kg daily by gavage for 30 days, iii. OXM group (n=8) receiving OXM at the dose of 5 mg/kg daily by gavage for 30 days and iv. RJ+OXM group (n=8) receiving RJ at the dose of 100 mg/kg daily by gavage concomitant with 100 mg/kg OXM adminis- tration for 30 days. Results Analysis revealed a significant reduction in catalase, total antioxidant, as well as embryo development in OXM group (P<0.05). However, RJ group showed a salient recovery in the all of the above mentioned parameters and embryo toxicity. Conclusion The results of this study indicated a partially protective effect of RJ against OXM-induced embryo toxicity. PMID:26464831

  16. Protective effect of Lycium barbarum polysaccharides against cadmium-induced testicular toxicity in male mice.

    PubMed

    Zhang, Lili; Li, Qin; Zheng, Gaoli; Chen, Yunxiang; Huang, Mincong; Zhang, Lijiang; Lin, Xiaoyan

    2017-06-01

    The present study was performed to determine whether Lycium barbarum polysaccharides (LBPs) would protect mice against cadmium (Cd)-induced testicular toxicity. Seventy-two male mice were randomly divided into six groups with twelve mice per group. Four groups were administered orally with cadmium chloride (5.0 mg per kg body weight) for 35 days and treated in combination with LBPs (0, 10.0, 33.3 or 100 mg kg(-1)) from one week before exposure to Cd until the end of the experiment. The other two groups were administered orally with vehicle or LBP (100 mg kg(-1)) only. Pretreatment with LBP ameliorated the Cd-induced reduction in the body weights, sperm motility as well as the level of testosterone in serum. Moreover, Cd-induced increase in the abnormal sperms was reduced and effects of Cd on the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were reversed. Histopathological examination further confirmed that the LBPs effectively attenuated Cd-induced degeneration of seminiferous tubules. Thus, LBPs attenuated Cd-induced testicular injury by improving the activity of antioxidant enzymatic activity and lowering the oxidative stress, so it could be a potential auxiliary therapeutic agent for Cd-induced testicular toxicity.

  17. 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

  18. Rapid CD8+ Function Is Critical for Protection of Neonatal Mice from an Extracellular Bacterial Enteropathogen

    PubMed Central

    Siefker, David T.; Adkins, Becky

    2017-01-01

    Both human and murine neonates are characteristically highly susceptible to bacterial infections. However, we recently discovered that neonatal mice are surprisingly highly resistant to oral infection with Yersinia enterocolitica. This resistance was linked with activation of both innate and adaptive responses, involving innate phagocytes, CD4+ cells, and B cells. We have now extended these studies and found that CD8+ cells also contribute importantly to neonatal protection from Y. enterocolitica. Strikingly, neonatal CD8+ cells in the mesenteric lymph nodes (MLN) are rapidly mobilized, increasing in proportion, number, and IFNγ production as early as 48 h post infection. This early activation appears to be critical for protection since B2m−/− neonates are significantly more susceptible than wt neonates to primary Y. enterocolitica infection. In the absence of CD8+ cells, Y. enterocolitica rapidly disseminated to peripheral tissues. Within 48 h of infection, both the spleens and livers of B2m−/−, but not wt, neonates became heavily colonized, likely leading to their deaths from sepsis. In contrast to primary infection, CD8+ cells were dispensable for the generation of immunological memory protective against secondary infection. These results indicate that CD8+ cells in the neonatal MLN contribute importantly to protection against an extracellular bacterial enteropathogen but, notably, they appear to act during the early innate phase of the immune response. PMID:28119902

  19. Cross-protection induced by Japanese encephalitis vaccines against different genotypes of Dengue viruses in mice

    PubMed Central

    Li, Jieqiong; Gao, Na; Fan, Dongying; Chen, Hui; Sheng, Ziyang; Fu, Shihong; Liang, Guodong; An, Jing

    2016-01-01

    Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) are closely related mosquito-borne flaviviruses that cause very high global disease burdens. Although cross-reactivity and cross-protection within flaviviruses have been demonstrated, the effect of JEV vaccination on susceptibility to DENV infection has not been well elucidated. In this study, we found that vaccination with the JEV inactivated vaccine (INV) and live attenuated vaccine (LAV) could induce cross-immune responses and cross-protection against DENV1-4 in mice. Despite the theoretical risk of immune enhancement, no increased mortality was observed in our mouse model. Additionally, low but consistently detectable cross-neutralizing antibodies against DENV2 and DENV3 were also observed in the sera of JEV vaccine-immunized human donors. The results suggested that both JEV-LAV and JEV-INV could elicit strong cross-immunity and protection against DENVs, indicating that inoculation with JEV vaccines may influence the distribution of DENVs in co-circulated areas and that the cross-protection induced by JEV vaccines against DENVs might provide important information in terms of DENV prevention. PMID:26818736

  20. 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.

  1. Sublingual vaccination with influenza virus protects mice against lethal viral infection.

    PubMed

    Song, Joo-Hye; Nguyen, Huan H; Cuburu, Nicolas; Horimoto, Taisuke; Ko, Sung-Youl; Park, Se-Ho; Czerkinsky, Cecil; Kweon, Mi-Na

    2008-02-05

    We assessed whether the sublingual (s.l.) route would be an effective means of delivering vaccines against influenza virus in mice by using either formalin-inactivated or live influenza A/PR/8 virus (H1N1). Sublingual administration of inactivated influenza virus given on two occasions induced both systemic and mucosal antibody responses and conferred protection against a lethal intranasal (i.n.) challenge with influenza virus. Coadministration of a mucosal adjuvant (mCTA-LTB) enhanced these responses and resulted in complete protection against respiratory viral challenge. In addition, s.l. administration of formalin-inactivated A/PR/8 plus mCTA-LTB induced systemic expansion of IFN-gamma-secreting T cells and virus-specific cytotoxic T lymphocyte responses. Importantly, a single s.l. administration of live A/PR/8 virus was not pathogenic and induced protection mediated by both acquired and innate immunity. Moreover, s.l. administration of live A/PR/8 virus conferred heterosubtypic protection against respiratory challenge with H3N2 virus. Unlike the i.n. route, the A/PR/8 virus, whether live or inactivated, did not migrate to or replicate in the CNS after s.l. administration. Based on these promising findings, we propose that the s.l. mucosal route offers an attractive alternative to mucosal routes for administering influenza vaccines.

  2. Cross-protection induced by Japanese encephalitis vaccines against different genotypes of Dengue viruses in mice.

    PubMed

    Li, Jieqiong; Gao, Na; Fan, Dongying; Chen, Hui; Sheng, Ziyang; Fu, Shihong; Liang, Guodong; An, Jing

    2016-01-28

    Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) are closely related mosquito-borne flaviviruses that cause very high global disease burdens. Although cross-reactivity and cross-protection within flaviviruses have been demonstrated, the effect of JEV vaccination on susceptibility to DENV infection has not been well elucidated. In this study, we found that vaccination with the JEV inactivated vaccine (INV) and live attenuated vaccine (LAV) could induce cross-immune responses and cross-protection against DENV1-4 in mice. Despite the theoretical risk of immune enhancement, no increased mortality was observed in our mouse model. Additionally, low but consistently detectable cross-neutralizing antibodies against DENV2 and DENV3 were also observed in the sera of JEV vaccine-immunized human donors. The results suggested that both JEV-LAV and JEV-INV could elicit strong cross-immunity and protection against DENVs, indicating that inoculation with JEV vaccines may influence the distribution of DENVs in co-circulated areas and that the cross-protection induced by JEV vaccines against DENVs might provide important information in terms of DENV prevention.

  3. Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischaemic injury.

    PubMed

    Pirianov, Grisha; Brywe, Katarina G; Mallard, Carina; Edwards, A David; Flavell, Richard A; Hagberg, Henrik; Mehmet, Huseyin

    2007-05-01

    c-Jun N-terminal kinase 3 (JNK3) is a member of the stress-activated group of mitogen-activated protein kinases. c-Jun N-terminal kinase 3 is a potent mediator of apoptosis and the use of JNK inhibitors or jnk3 gene deletion each protect against brain injury in adults. However, little is known about the role of JNK3 or its mechanism of action in neonatal brain injury. The aim of the present study was to compare the vulnerability of neonatal JNK3 knockout (JNK3 KO) mice and wild-type (WT) mice to cerebral hypoxic-ischaemic injury (HII) using unilateral-carotid occlusion combined with transient hypoxia. The degree of neural tissue loss in JNK3 KO mice was substantially reduced compared with WT mice (JNK3 KO 27.8%+/-2.8% versus WT 48.3%+/-2.0%, Pmice. Hypoxic-ischaemic injury increased JNK phosphorylation and activity, with JNK3 as the major isoform. Significantly, in JNK3 KO animals there was no difference in the activation of the upstream kinases mitogen-activated protein kinase kinase (MKK4) or MKK7. Downstream of JNK3, HII lead to increased phosphorylation of the transcription factors c-Jun and adenovirus transcription factor-2 (ATF-2), which was attenuated in JNK3 KO mice. c-Jun N-terminal kinase 3 deletion also decrease caspase-3 cleavage and Bim/PUMA expression, coupled with a upregulation of AKT/FOXO3a levels, linking JNK3 to apoptosis. These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain.

  4. Fluoxetine Protection in Decompression Sickness in Mice is Enhanced by Blocking TREK-1 Potassium Channel with the "spadin" Antidepressant.

    PubMed

    Vallée, Nicolas; Lambrechts, Kate; De Maistre, Sébastien; Royal, Perrine; Mazella, Jean; Borsotto, Marc; Heurteaux, Catherine; Abraini, Jacques; Risso, Jean-Jacques; Blatteau, Jean-Eric

    2016-01-01

    In mice, disseminated coagulation, inflammation, and ischemia induce neurological damage that can lead to death. These symptoms result from circulating bubbles generated by a pathogenic decompression. Acute fluoxetine treatment or the presence of the TREK-1 potassium channel increases the survival rate when mice are subjected to an experimental dive/decompression protocol. This is a paradox because fluoxetine is a blocker of TREK-1 channels. First, we studied the effects of an acute dose of fluoxetine (50 mg/kg) in wild-type (WT) and TREK-1 deficient mice (knockout homozygous KO and heterozygous HET). Then, we combined the same fluoxetine treatment with a 5-day treatment protocol with spadin, in order to specifically block TREK-1 activity (KO-like mice). KO and KO-like mice were regarded as antidepressed models. In total, 167 mice (45 WTcont 46 WTflux 30 HETflux and 46 KOflux) constituting the flux-pool and 113 supplementary mice (27 KO-like 24 WTflux2 24 KO-likeflux 21 WTcont2 17 WTno dive) constituting the spad-pool were included in this study. Only 7% of KO-TREK-1 treated with fluoxetine (KOflux) and 4% of mice treated with both spadin and fluoxetine (KO-likeflux) died from decompression sickness (DCS) symptoms. These values are much lower than those of WT control (62%) or KO-like mice (41%). After the decompression protocol, mice showed significant consumption of their circulating platelets and leukocytes. Spadin antidepressed mice were more likely to exhibit DCS. Nevertheless, mice which had both blocked TREK-1 channels and fluoxetine treatment were better protected against DCS. We conclude that the protective effect of such an acute dose of fluoxetine is enhanced when TREK-1 is inhibited. We confirmed that antidepressed models may have worse DCS outcomes, but concomitant fluoxetine treatment not only decreased DCS severity but increased the survival rate.

  5. 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

  6. N-acetylcysteine amide protects against methamphetamine-induced tissue damage in CD-1 mice.

    PubMed

    Zhang, X; Tobwala, S; Ercal, N

    2012-09-01

    Methamphetamine (METH), a highly addictive drug used worldwide, induces oxidative stress in various animal organs, especially the brain. This study evaluated oxidative damage caused by METH to tissues in CD-1 mice and identified a therapeutic drug that could protect against METH-induced toxicity. Male CD-1 mice were pretreated with a novel thiol antioxidant, N-acetylcysteine amide (NACA, 250 mg/kg body weight) or saline. Following this, METH (10 mg/kg body weight) or saline intraperitoneal injections were administered every 2 h over an 8-h period. Animals were killed 24 h after the last exposure. NACA-treated animals exposed to METH experienced significantly lower oxidative stress in their kidneys, livers, and brains than the untreated group, as indicated by their levels of glutathione, malondialdehyde, and protein carbonyl and their catalase and glutathione peroxidase activity. This suggests that METH induces oxidative stress in various organs and that a combination of NACA as a neuro- or tissue-protective agent, in conjunction with current treatment, might effectively treat METH abusers.

  7. Hyper-attenuated MTBVAC erp mutant protects against tuberculosis in mice.

    PubMed

    Solans, Luis; Uranga, Santiago; Aguilo, Nacho; Arnal, Carmen; Gomez, Ana Belen; Monzon, Marta; Badiola, Juan Jose; Gicquel, Brigitte; Martin, Carlos

    2014-09-08

    Safety of individuals at risk of immune suppression is an important concern for live vaccines. The new-generation tuberculosis vaccine candidate MTBVAC, a genetically engineered doubly attenuated Mycobacterium tuberculosis mutant with deletions in phoP and fadD26 virulence genes has demonstrated comparable safety in different relevant animal models and superior protection in mice as compared to the only currently licensed tuberculosis vaccine Mycobacterium bovis BCG. Here we describe the construction of a highly attenuated MTBVAC-based live vaccine by an additional gene inactivation generated in erp of MTBVAC. The gene product of erp is an exported repeated protein (Erp), a virulence factor described to be involved in intracellular replication of M. tuberculosis. The resultant strain, MTBVAC erp(-), was tested in severe combined immunodeficiency (SCID) mouse model showing to be severely attenuated when compared to BCG and MTBVAC. Experiments conducted in immunocompetent mice revealed that the hyper-attenuated profile observed with MTBVAC erp(-) strain did not compromise its protective efficacy profile in comparison with BCG. These results postulate MTBVAC erp(-) as a potential tuberculosis vaccine candidate for use in high-risk populations of immune suppression (e.g., due to HIV infection), where the use of BCG is not recommended. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Oral vaccination with a liposome-encapsulated influenza DNA vaccine protects mice against respiratory challenge infection.

    PubMed

    Liu, Jing; Wu, Jianqi; Wang, Bing; Zeng, Sheng; Qi, Feifei; Lu, Changlong; Kimura, Yoshinobu; Liu, Beixing

    2014-05-01

    It is well accepted that vaccination by oral administration has many advantages over injected parenteral immunization. The present study focuses on whether oral vaccination with a DNA vaccine could induce protective immunity against respiratory challenge infection. The M1 gene of influenza A virus was used to construct DNA vaccine using pcDNA 3.1(+) plasmid, a eukaryotic expression vector. The cationic liposomes were used to deliver the constructed DNA vaccine. In vitro and in vivo expression of M1 gene was observed in the cell line and in the intestine of orally vaccinated C57BL/6 mice, respectively. It became clear that this type of oral DNA vaccination was capable of inducing both humoral and cellular immune responses, together with an augmentation of IFN-γ production. In addition, oral vaccination with liposome-encapsulated DNA vaccine could protect the mice against respiratory challenge infection. These results suggest that gastrointestinal tract, a constituent member of the common mucosal immune system, is a potent candidate applicable as a DNA vaccine route against virus respiratory diseases.

  9. Temperature-sensitive mutants of Actinobacillus pleuropneumoniae induce protection in mice.

    PubMed Central

    Byrd, W; Hooke, A M

    1997-01-01

    Temperature-sensitive mutants of Actinobacillus pleuropneumoniae 4074, serotype 1, were isolated after treatment with nitrosoguanidine and enrichment with penicillin and D-cycloserine. Of the four temperature-sensitive mutants evaluated in mice, one (A-1) had a tight phenotype (i.e., it ceased replication immediately after transfer to the nonpermissive temperature [37 degrees C]) and three (1-2, 4-1, and 12-1) were coasters that continued replication for up to three generations after transfer to 37 degrees C. The reversion frequencies ranged from 10(-6) to 10(-9), and cutoff temperatures ranged from 33 to 35 degrees C. No major changes were detected in the biochemical profiles; agglutination reactions; electrophoretic profiles of the lipopolysaccharides, outer membrane proteins, and hemolysin proteins; hemolytic titers; or CAMP factor reactions of the mutants and the wild-type bacteria. Groups of 3- to 5-week-old, female ICR mice were immunized intranasally with three doses of 3.5 x 10(6) CFU of the mutants over 3 weeks and subsequently challenged intranasally with 5 50% lethal doses of the parental wild-type. Protection was induced by both the tight and the coaster mutants, with the 4-1 and 12-1 coasters eliciting greater protection (67 and 82%, respectively) than that induced by the A-1 tight mutant (57%). Intranasal immunization with both phenotypes induced serum antibody responses against the surface antigens and the hemolysin protein. PMID:9169752

  10. Protective effect of tert-butylhydroquinone on cerebral inflammatory response following traumatic brain injury in mice.

    PubMed

    Jin, Wei; Kong, Jie; Wang, Handong; Wu, Jun; Lu, Tianyu; Jiang, Jian; Ni, Hongbin; Liang, Weibang

    2011-07-01

    Antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown in our previous studies to play a crucial role in protection against TBI induced inflammatory response in the brain. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), a novel Nrf2 activator, can protect mice brain against TBI-induced inflammatory damage. Adult male ICR mice were randomly divided into three groups: (1) sham+vehicle group; (2) TBI+vehicle group; and (3) TBI+tBHQ group (n=12 per group). Closed head injury was adopted using Hall's weight-dropping method. We measured Nrf2 and nuclear factor kappa B (NF-κB) binding activities by electrophoretic mobility shift assay (EMSA), concentrations of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay (ELISA), brain oedema by wet/dry weight method, and cortical apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) analysis. Induction of the Nrf2 activity by tBHQ markedly decreased NF-κB activation and inflammatory cytokine production in the injured brain. Administration of tBHQ also significantly attenuated TBI-induced brain oedema and cortical apoptosis. Pre-treatment with tBHQ could attenuate the cerebral inflammatory response after TBI. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. 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.

  12. Protective effects of Fructus sophorae extract on collagen-induced arthritis in BALB/c mice

    PubMed Central

    Han, Hyoung-Min; Hong, Su-Hyun; Park, Heung-Sik; Jung, Jae-Chul; Kim, Jong-Sik; Lee, Yong-Tae; Lee, Eun-Woo; Choi, Yung-Hyun; Kim, Byung-Woo; Kim, Cheol-Min; Kang, Kyung-Hwa

    2017-01-01

    Styphnolobium japonicum (L.) is utilized in Korean medicine for the treatment of various inflammatory diseases. The aim of the present study was to explore the effects of Fructus sophorae extract (FSE) isolated from the dried ripe fruit of S. japonicum (L.) on the development of type II collagen-induced arthritis (CIA) in BALB/c mice. The CIA mice were orally administered FSE or saline daily for 2 weeks. The incidence and severity of disease and the inflammatory response in the serum and the joint tissues were assessed. Macroscopic and histological investigation indicated that FSE protected against CIA development. FSE was associated with a significant reduction in the levels of total immunoglobulin G2a and proinflammatory cytokines and mediators in the serum. In addition, FSE suppressed the gene expression levels of proinflammatory cytokines and mediators, the mediator of osteoclastic bone remodeling, the receptor activator of nuclear factor κ-B ligand and matrix metalloproteinases in the joint tissues. The present results suggest that FSE may protect against inflammation and bone damage, and would be a valuable candidate for further investigation as a novel anti-arthritic agent. PMID:28123483

  13. Protective effect of spermine against pentylenetetrazole kindling epilepsy induced comorbidities in mice.

    PubMed

    Kumar, Mandeep; Kumar, Puneet

    2017-02-14

    Nitric oxide (NO), an important intracellular signaling molecule is involved in modulation of neuronal transmission. The NO level increases during epileptic activity in animal models of epilepsy. However, its role in epileptic activity remains controversial. Spermine is an endogenous polyamine; possesses anti-oxidant property and has ability to modulate ion channels and NO synthase activity. Therefore, the present study was designed to investigate the role of NO pathway in the neuroprotective effect of spermine, in Pentylenetetrazol (PTZ) induced kindling epilepsy in mice. PTZ (35mg/kg; intraperitoneal, i.p.) was administered on every alternate day up to 29days and challenge test was performed on 33rd day. From 15th day, spermine (5 and 10mg/kg; i.p.), L-NAME (10mg/kg; i.p), l-Arginine (50mg/kg; i.p) and sodium valproate (400mg/kg; i.p.) were administered up to 33rd day. Animals were sacrificed on 34th day for estimation of biochemical and neurotransmitters. Pretreatment with spermine, considerably, reversed the PTZ induced alterations. Further, pretreatment of L-NAME and l-Arginine with 5 and 10mg/kg; i.p. spermine, respectively, leads to an increase and decrease in its protective effects. The present study suggests the involvement of NO pathway in the protective effect of spermine against PTZ-induced kindling epilepsy in mice.

  14. 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.

  15. Neurogenic differentiation factor NeuroD confers protection against radiation-induced intestinal injury in mice

    PubMed Central

    Li, Ming; Du, Aonan; Xu, Jing; Ma, Yanchao; Cao, Han; Yang, Chao; Yang, Xiao-Dong; Xing, Chun-Gen; Chen, Ming; Zhu, Wei; Zhang, Shuyu; Cao, Jianping

    2016-01-01

    The gastrointestinal tract, especially the small intestine, is particularly sensitive to radiation, and is prone to radiation-induced injury as a result. Neurogenic differentiation factor (NeuroD) is an evolutionarily-conserved basic helix-loop-helix (bHLH) transcription factor. NeuroD contains a protein transduction domain (PTD), which allows it to be exogenously delivered across the membrane of mammalian cells, whereupon its transcription activity can be unleashed. Whether NeuroD has therapeutic effects for radiation-induced injury remains unclear. In the present study, we prepared a NeuroD-EGFP recombinant protein, and explored its protective effects on the survival and intestinal damage induced by ionizing radiation. Our results showed that NeuroD-EGFP could be transduced into small intestine epithelial cells and tissues. NeuroD-EGFP administration significantly increased overall survival of mice exposed to lethal total body irradiation (TBI). This recombinant NeuroD also reduced radiation-induced intestinal mucosal injury and apoptosis, and improved crypt survival. Expression profiling of NeuroD-EGFP-treated mice revealed upregulation of tissue inhibitor of metalloproteinase 1 (TIMP-1), a known inhibitor of apoptosis in mammalian cells. In conclusion, NeuroD confers protection against radiation-induced intestinal injury, and provides a novel therapeutic clinical option for the prevention of intestinal side effects of radiotherapy and the treatment of victims of incidental exposure. PMID:27436572

  16. 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.

  17. 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.

  18. 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.

  19. BLOCKADE OF PGE2, PGD2 RECEPTORS CONFERS PROTECTION AGAINST PREPATENT SCHISTOSOMIASIS MANSONI IN MICE.

    PubMed

    Abdel-Ghany, Rasha; Rabia, Ibrahim; El-Ahwany, Eman; Saber, Sameh; Gamal, Rasha; Nagy, Faten; Mahmoud, Olaa; Hamad, Rabab Salem; Barakat, Walled

    2015-12-01

    Schistosomiasis is a chronic disease with considerable social impact. Despite the availability of affordable chemotherapy, drug treatment has not significantly reduced the overall number of disease cases. Among other mechanisms, the parasite produces PGE2 and PGD2 to evade host immune defenses. To investigate the role of PGE2 and PGD2 in schistosomiasis, we evaluated the effects of L-161,982, Ah6809 (PGE2 receptor antagonists alone of combined with each other) and MK-0524 (PGD2 receptor antagonist) during prepatent Schistosoma mansoni infection. Drugs were administered intraperitoneally an hour before and 24 hours after infection of C57BL/6 mice with 100 Schistosoma mansoni cercariae. L-161,982, Ah6809, their combination and MK-0524 caused partial protection against pre-patent S. mansoni infection which was mediated by biasing the immune response towards Th1 phenotype. These results showed that blockade of PGE2 and PGD2 receptors confers partial protection against pre-patent S. mansoni infection in mice and that they may be useful as adjunctive therapy to current anti-schistosomal drugs or vaccines.

  20. 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

  1. Immunogenicity and protective efficacy of DNA vaccine against visceral leishmaniasis in BALB/c mice

    PubMed Central

    Kaur, Sukhbir; Kaur, Tejinder; Joshi, Jyoti

    2016-01-01

    Abstract The current study was designed to examine the protective efficacy of DNA vaccines based on gp63 and Hsp70 against murine visceral leishmaniasis. Inbred BALB/c mice were immunized subcutaneously twice at an interval of three weeks with pcDNA3.1(+) encoding T cell epitopes of gp63 and Hsp70 individually and in combination. Animals were challenged intracardially with 107 promastigotes of Leishmania donovani 10 days post immunization and sacrificed 1, 2 and 3 months post challenge. The immunized animals revealed a significant reduction (P < 0.05) in splenic and hepatic parasite burden as compared to the infected controls. Maximum reduction in parasite load (P < 0.05) was observed in animals treated with a combination of pcDNA/gp63 and pcDNA/Hsp70. These animals also showed heightened DTH response, increased IgG2a, elevated Th1 cytokines (IFN-γ and IL-2) and reduced IgG1 and IL-10 levels. Thus, mice immunized with the cocktail vaccine exhibited significantly greater protection in comparison to those immunized with individual antigens. PMID:27533939

  2. Mechanism underlying mitochondrial protection of asiatic acid against hepatotoxicity in mice.

    PubMed

    Gao, Jing; Chen, Jin; Tang, Xinhui; Pan, Liya; Fang, Feng; Xu, Lizhi; Zhao, Xiaoning; Xu, Qiang

    2006-02-01

    Asiatic acid (AA) is one of the triterpenoid components of Terminalia catappa L., which has antioxidative, anti-inflammatory and hepatoprotective activity. This research focused on the mitochondrial protection of AA against acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) in mice. It was found that pretreatment with 25, 50 or 100 mg kg(-1) AA significantly blocked the LPS + D-GalN-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels, which was confirmed by ultrastructural observation under an electron microscope, showing improved nuclear condensation, ameliorated mitochondrion proliferation and less lipid deposition. Meanwhile, different doses of AA could decrease both the transcription and the translation level of voltage-dependent anion channels (VDACs), the most important mitochondrial PTP component protein, and block the translocation of cytochrome c from mitochondria to cytosol. On the other hand, pre-incubation with 25, 50 and 100 microg mL(-1) AA inhibited the Ca(2+)-induced mitochondrial permeability transition (MPT), including mitochondrial swelling, membrane potential dissipation and releasing of matrix Ca(2+) in liver mitochondria separated from normal mice, indicating the direct role of AA on mitochondria. Collectively, the above data suggest that AA could protect liver from damage and the mechanism might be related to up-regulating mitochondrial VDACs and inhibiting the process of MPT.

  3. Renal protective effects of extracts from guava fruit (Psidium guajava L.) in diabetic mice.

    PubMed

    Lin, Chia-Yu; Lin, Chia-Yun; Yin, Mei-Chin

    2012-09-01

    This study analyzed the content of phenolic acids and flavonoids in extracts of guava fruit (Psidium guajava L.), and examined the renal protective effects of guava aqueous extract (GAE) and ethanol extract (GEE) in diabetic mice. GAE had more caffeic acid, myricetin, and quercetin; and GEE had more cinnamic, coumaric and ferulic acids. GAE or GEE at 1 and 2 % was supplied in diet for 12 weeks. GAE or GEE intake at 2 % significantly reduced glucose and blood urea nitrogen levels, increased insulin level in plasma of diabetic mice (p < 0.05). GAE or GEE treatments dose-dependently reserved glutathione content, retained activity of catalase and glutathione peroxidase, and decreased reactive oxygen species, interleukin (IL)-6, tumor necrosis factor-α and IL-1β levels in kidney (p < 0.05). GAE and GEE treatments at 2 % significantly declined renal N (ε)-(carboxymethyl)lysine, pentosidine and fructose levels (p < 0.05), and suppressed renal activity of aldose reductase (p < 0.05). These findings support that guava fruit could protect kidney against diabetic progression via its anti-oxidative, anti-inflammatory and anti-glycative effects.

  4. Protective Effects of Red Guava on Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Mice.

    PubMed

    Li, Pei-Ying; Hsu, Cheng-Chin; Yin, Mei-Chin; Kuo, Yueh-Hsiung; Tang, Feng-Yao; Chao, Che-Yi

    2015-12-12

    Diabetes is an important chronic disease and the 4th leading cause of death in Taiwan. Hyperglycemia-induced oxidative and inflammatory damage are the main causes of chronic complications in diabetic patients. The red guava (red-fleshed guava cultivar of Psidium guajava L.) is a tropical fruit belonging to the Myrtaceae family and an important commercial crop in Taiwan. In this study, the protective effects of a diet containing red guava on inflammation and oxidative stress in streptozotocin (STZ)-induced diabetic mice were examined. The experimental group was divided into seven subgroups: normal (N), diabetes mellitus (DM), diabetes + red guava 1% (L), 2% (M), and 5% (H), diabetes + 5% red guava + anti-diabetic rosiglitazone (HR), and diabetes + anti-diabetic rosiglitazone (R). The mice were fed for 8 weeks and sacrificed by decapitation. Compared with the DM group, the experimental groups with diets containing red guava as well as rosiglitazone all showed significant improvements in blood glucose control, insulin resistance, creatinine, blood urea nitrogen, triglycerides, non-esterified fatty acids, cholesterol, c-reactive protein, TNF-α, and IL-10. Furthermore, the expression of inflammatory proteins, such as iNOS and NF-κB, was suppressed via activated PPARγ, and the expression levels of GPx3 and ACO increased. In summary, red guava can significantly suppress inflammatory and oxidative damage caused by diabetes and alleviate diabetic symptoms; thus, it exerts protective effects and has potential applications for the development of a dietary supplement.

  5. Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice.

    PubMed

    Hohenadl, Christine; Wodal, Walter; Kerschbaum, Astrid; Fritz, Richard; Howard, M Keith; Farcet, Maria R; Portsmouth, Daniel; McVey, John K; Baker, Donald A; Ehrlich, Hartmut J; Barrett, P Noel; Kreil, Thomas R

    2014-04-16

    Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic. Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model.Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001). The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups.

  6. Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice

    PubMed Central

    2014-01-01

    Background Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic. Findings Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model. Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001). Conclusion The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups. PMID:24739285

  7. 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

  8. 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.

  9. 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.

  10. Recombinant tandem multi-linear neutralizing epitopes of human enterovirus 71 elicited protective immunity in mice

    PubMed Central

    2014-01-01

    Background Human Enterovirus 71 (EV71) has emerged as the leading cause of viral encephalitis in children, especially in the Asia-Pacific regions. EV71 vaccine development is of high priority at present, and neutralization antibodies have been documented to play critical roles during in vitro and in vivo protection against EV71 infection. Results In this study, a novel strategy to produce EV71 vaccine candidate based on recombinant multiple tandem linear neutralizing epitopes (mTLNE) was proposed. The three well identified EV71 linear neutralizing epitopes in capsid proteins, VP1-SP55, VP1-SP70 and VP2-SP28, were sequentially linked by a Gly-Ser linker ((G4S)3), and expressed in E.coli in fusion with the Trx and His tag at either terminal. The recombinant protein mTLNE was soluble and could be purified by standard affinity chromatography. Following three dosage of immunization in adult mice, EV71-specific IgG and neutralization antibodies were readily induced by recombinant mTLNE. IgG subtyping demonstrated that lgG1 antibodies dominated the mTLNE-induced humoral immune response. Especially, cytokine profiling in spleen cells from the mTLNE-immunized mice revealed high production of IL-4 and IL-6. Finally, in vivo challenge experiments showed that passive transfer with anti-mTLNE sera conferred full protection against lethal EV71 challenge in neonatal mice. Conclusion Our results demonstrated that this rational designed recombinant mTLNE might have the potential to be further developed as an EV71 vaccine in the future. PMID:24885030

  11. Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

    PubMed Central

    Patial, Sonika; Curtis, Alan D.; Lai, Wi S.; Stumpo, Deborah J.; Hill, Georgette D.; Flake, Gordon P.; Mannie, Mark D.; Blackshear, Perry J.

    2016-01-01

    Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate–rich elements (AREs) in the 3′-untranslated regions (3′UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3′UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases. PMID:26831084

  12. 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

  13. Reactive Oxygen Species Produced by the NOX2 Complex in Monocytes Protect Mice from Bacterial Infections1, 2, 3

    PubMed Central

    Pizzolla, Angela; Hultqvist, Malin; Nilson, Bo; Grimm, Melissa J.; Eneljung, Tove; Jonsson, Ing-Marie; Verdrengh, Margareta; Kelkka, Tiina; Gjertsson, Inger; Segal, Brahm H.; Holmdahl, Rikard

    2012-01-01

    Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent life-threatening bacterial and fungal infections. CGD results from defective production of reactive oxygen species (ROS) by phagocytes caused by mutations in genes encoding the NADPH oxidase 2 (NOX2) complex subunits. Mice with a spontaneous mutation in Ncf1, which encodes the NCF1 (p47phox) subunit of NOX2, have defective phagocyte NOX2 activity. These mice occasionally develop local spontaneous infections by Staphylococcus xylosus or by the common CGD pathogen S. aureus. Ncf1 mutant mice were more susceptible to systemic challenge with these bacteria than wild type mice. Transgenic Ncf1 mutant mice harboring wild type Ncf1 gene under the human CD68 promoter (MN+ mice) gained the expression of NCF1 and functional NOX2 activity specifically in monocyte/macrophages, although minimal NOX2 activity was detected also in some CD11b+Ly6G+ cells defined as neutrophils. MN+ mice did not develop spontaneous infection and were more resistant to administered staphylococcal infections compared to MN− mice. Most strikingly, MN+ mice survived after administered Burkholderia cepacia, an opportunistic pathogen in CGD patients, whereas MN− mice died. Thus, monocyte/macrophage expression of functional NCF1 protected against spontaneous and administered bacterial infections. PMID:22491245

  14. Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.

    PubMed

    Huang, Jing; Li, Xiangming; Coelho-dos-Reis, Jordana G A; Zhang, Min; Mitchell, Robert; Nogueira, Raquel Tayar; Tsao, Tiffany; Noe, Amy R; Ayala, Ramses; Sahi, Vincent; Gutierrez, Gabriel M; Nussenzweig, Victor; Wilson, James M; Nardin, Elizabeth H; Nussenzweig, Ruth S; Tsuji, Moriya

    2015-12-01

    In this study, we developed human immune system (HIS) mice that possess functional human CD4+ T cells and B cells, named HIS-CD4/B mice. HIS-CD4/B mice were generated by first introducing HLA class II genes, including DR1 and DR4, along with genes encoding various human cytokines and human B cell activation factor (BAFF) to NSG mice by adeno-associated virus serotype 9 (AAV9) vectors, followed by engrafting human hematopoietic stem cells (HSCs). HIS-CD4/B mice, in which the reconstitution of human CD4+ T and B cells resembles to that of humans, produced a significant level of human IgG against Plasmodium falciparum circumsporozoite (PfCS) protein upon immunization. CD4+ T cells in HIS-CD4/B mice, which possess central and effector memory phenotypes like those in humans, are functional, since PfCS protein-specific human CD4+ T cells secreting IFN-γ and IL-2 were detected in immunized HIS-CD4/B mice. Lastly, PfCS protein-immunized HIS-CD4/B mice were protected from in vivo challenge with transgenic P. berghei sporozoites expressing the PfCS protein. The immune sera collected from protected HIS-CD4/B mice reacted against transgenic P. berghei sporozoites expressing the PfCS protein and also inhibited the parasite invasion into hepatocytes in vitro. Taken together, these studies show that our HIS-CD4/B mice could mount protective human anti-malaria immunity, consisting of human IgG and human CD4+ T cell responses both specific for a human malaria antigen.

  15. 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.

  16. Mode of action of FK-506 on protective immunity to Hymenolepis nana in mice.

    PubMed

    Asano, K; Taki, M; Matsuo, S; Yamada, K

    1996-01-01

    FK-506 (Tacrolimus) has been shown to block T cell proliferation in vitro by inhibiting the generation of several lymphokines, especially interleukin (IL)-2, but little direct evidence is available to support the view that the immunosuppressive effects of FK-506 in vivo are mediated by a similar inhibition of lymphokine cascade. To investigate the mechanisms of FK-506-induced immunosuppression, the effects of FK-506 on cell-mediated immunity to Hymenolepis nana were examined in mice. FK-506 administration into BALB/c mice daily at a dose of 10.0 mg/kg (but not 5.0 mg/kg) for 5 days caused suppression of protective immunity against H. nana challenge infection. During the infection of mice with H. nana, IL-2 and interferon (IFN)-gama were produced by mesenteric lymph node (MLN) cells with a time course corresponding to that of MLN T cell proliferation. These responses were completely suppressed by repeated administration of FK-506 for 5 days at a dose of 10.0 mg/kg/day (but not 5.0 mg/kg/day). In contrast to the effects of FK-506 on IL-2 and IFN-gamma productions in MLN, IL-1 and tumor necrosis factor-alpha in the intestinal wall, which were enhanced by H. nana infection, were not completely decreased as a result of 10.0 mg/kg FK-506 treatment. The reverse transcriptase-PCR revealed complete inhibition of IL-2 and IFN-gamma mRNA expression on mesenteric L3T4+ cells that were induced by H. nana infection, when mice were given 10.0 mg/kg/day FK-506 for 5 days. These results strongly suggest that FK-506 affects cell-mediated immunity in vivo with mechanisms similar to those observed in vitro.

  17. 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

  18. Regulatory T cells are protective in systemic inflammation response syndrome induced by zymosan in mice.

    PubMed

    Jia, Wenyuan; Cao, Li; Yang, Shuangwen; Dong, Hailong; Zhang, Yun; Wei, Haidong; Jing, Wei; Hou, Lichao; Wang, Chen

    2013-01-01

    Systemic inflammation response syndrome (SIRS) is a key and mainly detrimental process in the pathophysiology of multiple organ dysfunction syndrome. The balance of pro-inflammation and anti-inflammation controls the initiation and development of SIRS. However, the endogenous counterregulatory immune mechanisms that are involved in the development of SIRS are not well understood. CD4(+)CD25(+)Foxp3 (forkhead box P3)(+) regulatory T lymphocytes (Treg cells) play a key role in the immunological balance of the body. Thus, our aim was to investigate the contribution of these key immunomodulators (Treg cells) to the immune dysfunction that is observed in zymosan-induced SIRS in mice. We first evaluated the level of Treg cells in the lung of mice 6 h, 1 d, 2 d, 3 d, 5 d, and 7 d after the injection of zymosan or normal saline by western blot, real-time PCR and flow cytometry. We found that the number of Treg cells and the levels of the Treg cell-related transcription factor (Foxp3) and cytokines (IL-10) in the zymosan-treated group significantly decreased on day 1 and day 2 and significantly increased on day 5 compared with the NS-treated group. In the next experiment, the mice were injected with 200 μg of anti-CD25 mAb (clone PC61) to deplete the Treg cells and then injected with zymosan 2 days later. The number of Treg cells decreased by more than 50% after the injection of the PC61 mAb. In addition, the expression of the anti-inflammatory cytokine IL-10 also decreased. Moreover, the depletion of the Treg cells profoundly increased the mice'mortality and the degree of lung tissue injury. In conclusion, Treg cells tend to play a protective role in pathogenesis of the zymosan-induced generalized inflammation, and IL-10 signaling is associated with their immunomodulatory effect.

  19. 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.

  20. Protective effect of the orientin on noise-induced cognitive impairments in mice.

    PubMed

    Wang, Shuting; Yu, Yinghua; Feng, Yan; Zou, Fang; Zhang, Xiaofei; Huang, Jie; Zhang, Yuyun; Zheng, Xian; Huang, Xu-Feng; Zhu, Yufu; Liu, Yi

    2016-01-01

    There is increasing evidence that chronic noise stress impairs cognition and induces oxidative stress in the brain. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential effects of orientin against chronic noise-induced cognitive decline and its underlying mechanisms. A moderate-intensity noise exposure model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 3 weeks of the noise exposure, the mice were treated with orientin (20mg/kg and 40 mg/kg, oral gavage) for 3 weeks. The chronic noise exposure impaired the learning and memory in mice in the Morris water maze and step-through tests. The noise exposure also decreased exploration and interest in a novel environment in the open field test. The administration of orientin significantly reversed noise-induced alterations in these behavior tests. Moreover, the orientin treatment significantly improved the noise-induced alteration of serum corticosterone and catecholamine levels and oxidative stress in the hippocampus and prefrontal cortex. Furthermore, the orientin treatment ameliorated the noise-induced decrease in brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus and prefrontal cortex. Thus, orientin exerts protective effects on noise-induced cognitive decline in mice, specifically by improving central oxidative stress, neurotransmission, and increases synapse-associated proteins. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic noise-induced cognitive decline.

  1. TLR-Activated Gap Junction Channels Protect Mice against Bacterial Infection through Extracellular UDP Release.

    PubMed

    Qin, Juliang; Zhang, Guangxu; Zhang, Xiaoyu; Tan, Binghe; Lv, Zhangsheng; Liu, Mingyao; Ren, Hua; Qian, Min; Du, Bing

    2016-02-15

    Extracellular UDP (eUDP), released as a danger signal by stressed or apoptotic cells, plays an important role in a series of physiological processes. Although the mechanism of eUDP release in apoptotic cells has been well defined, how the eUDP is released in innate immune responses remains unknown. In this study, we demonstrated that UDP was released in both Escherichia coli-infected mice and LPS- or Pam3CSK4-treated macrophages. Also, LPS-induced UDP release could be significantly blocked by selective TLR4 inhibitor Atractylenolide I and selective gap junction inhibitors carbenoxolone and flufenamic acid (FFA), suggesting the key role of TLR signaling and gap junction channels in this process. Meanwhile, eUDP protected mice from peritonitis by reducing invaded bacteria that could be rescued by MRS2578 (selective P2Y6 receptor inhibitor) and FFA. Then, connexin 43, as one of the gap junction proteins, was found to be clearly increased by LPS in a dose- and time-dependent manner. Furthermore, if we blocked LPS-induced ERK signaling by U0126, the expression of connexin 43 and UDP release was also inhibited dramatically. In addition, UDP-induced MCP-1 secretion was significantly reduced by MRS2578, FFA, and P2Y6 mutation. Accordingly, pretreating mice with U0126 and Gap26 increased invaded bacteria and aggravated mice death. Taken together, our study reveals an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of gap junction channel-mediated UDP release in infectious diseases. Copyright © 2016 by The American Association of Immunologists, Inc.

  2. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice.

    PubMed

    Waidmann, Marc; Bechtold, Oliver; Frick, Julia-Stefanie; Lehr, Hans-Anton; Schubert, Sören; Dobrindt, Ulrich; Loeffler, Jürgen; Bohn, Erwin; Autenrieth, Ingo B

    2003-07-01

    The microflora plays a crucial role in inflammatory bowel diseases (IBDs). Specific pathogen-free (SPF), but not germ-free, interleukin (IL)-2-deficient (IL-2-/-) mice develop colitis. The colitogenicity of commensal bacteria was determined. Gnotobiotic IL-2-/- and IL-2+/+ mice were colonized with Escherichia coli mpk, Bacteroides vulgatus mpk, or both bacterial strains, or with E. coli strain Nissle 1917. DNA arrays were used to characterize E. coli mpk. Colitis was analyzed by histology and real-time reverse-transcription polymerase chain reaction (RT-PCR) for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, and CD14 messenger RNA (mRNA) expression. Bacterial numbers in feces and bacterial localization in the colon was determined by culture and fluorescence in situ hybridization (FISH). IL-2-/- but not IL-2+/+ mice monocolonized with E. coli mpk developed colitis, whereas mono-association with B. vulgatus mpk, or E. coli Nissle, or co-colonization with E. coli mpk and B. vulgatus mpk, did not induce colitis. DNA array experiments and cellular studies revealed that E. coli mpk is a nonpathogenic strain. FISH and culture methods revealed that the anticolitogenic effect of B. vulgatus mpk on E. coli mpk cannot be explained by a significant reduction in numbers of E. coli in the colon. E. coli mpk-induced colitis was associated with increased IFN-gamma, TNF-alpha, CD14, and IL-10 mRNA expression in the colon. In IL-2-/- mice, B. vulgatus mpk protects against E. coli mpk-triggered colitis by an unknown mechanism. E. coli Nissle does not induce colitis. Various bacterial species common to the microflora differ in their ability to trigger IBD.

  3. A peptide mimotope of type 8 pneumococcal capsular polysaccharide induces a protective immune response in mice.

    PubMed

    Buchwald, Ulrike K; Lees, Andrew; Steinitz, Michael; Pirofski, Liise-Anne

    2005-01-01

    Increasing antibiotic resistance and a rising patient population at risk for infection due to impaired immunity underscore the importance of vaccination against pneumococci. However, available capsular polysaccharide vaccines are often poorly immunogenic in patients at risk for pneumococcal disease. The goal of this study was to explore the potential of peptide mimotopes to function as alternative vaccine antigens to elicit a type-specific antibody response to pneumococci. We used a human monoclonal immunoglobulin A (IgA) antibody (NAD) to type 8 Streptococcus pneumoniae capsular polysaccharide (type 8 PS) to screen a phage display library, and the phage PUB1 displaying the peptide FHLPYNHNWFAL was selected after three rounds of biopanning. Inhibition studies with phage-displayed peptide or the peptide PUB1 and type 8 PS showed that PUB1 is a mimetic of type 8 PS. PUB1 conjugated to tetanus toxoid (PUB1-TT) induced a type 8 PS-specific antibody response in BALB/c mice, further defining it as a mimotope of type 8 PS. The administration of immune sera obtained from PUB1-TT-immunized mice earlier (days 14 and 21) and later (days 87 and 100) after primary and reimmunization resulted in a highly significant prolongation of the survival of naive mice after pneumococcal challenge compared to controls. The survival of PUB1-TT-immunized mice was also prolonged after pneumococcal challenge nearly 4 months after primary immunization. The efficacy of PUB1-TT-induced immune sera provides proof of principle that a mimotope-induced antibody response can protect against pneumococci and suggests that peptide mimotopes selected by type-specific human antibodies could hold promise as immunogens for pneumococci.

  4. ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice*

    PubMed Central

    Xiao, Guozhi; Zhang, Ting; Yu, Shibing; Lee, Sojin; Calabuig-Navarro, Virtu; Yamauchi, Jun; Ringquist, Steven; Dong, H. Henry

    2013-01-01

    Hypertriglyceridemia is the most common lipid disorder in obesity and type 2 diabetes. It results from increased production and/or decreased clearance of triglyceride-rich lipoproteins. To better understand the pathophysiology of hypertriglyceridemia, we studied hepatic regulation of triglyceride metabolism by the activating transcription factor 4 (ATF4), a member of the basic leucine zipper-containing protein subfamily. We determined the effect of ATF4 on hepatic lipid metabolism in Atf4−/− mice fed regular chow or provided with free access to fructose drinking water. ATF4 depletion preferentially attenuated hepatic lipogenesis without affecting hepatic triglyceride production and fatty acid oxidation. This effect prevented excessive fat accumulation in the liver of Atf4−/− mice, when compared with wild-type littermates. To gain insight into the underlying mechanism, we showed that ATF4 depletion resulted in a significant reduction in hepatic expression of peroxisome proliferator-activated receptor-γ, a nuclear receptor that acts to promote lipogenesis in the liver. This effect was accompanied by a significant reduction in hepatic expression of sterol regulatory element-binding protein 1c (SREBP-1c), acetyl-CoA carboxylase, and fatty-acid synthase, three key functions in the lipogenic pathway in Atf4−/− mice. Of particular significance, we found that Atf4−/− mice, as opposed to wild-type littermates, were protected against the development of steatosis and hypertriglyceridemia in response to high fructose feeding. These data demonstrate that ATF4 plays a critical role in regulating hepatic lipid metabolism in response to nutritional cues. PMID:23888053

  5. Vitamin D Supplementation Protects against Bone Loss Associated with Chronic Alcohol Administration in Female Mice

    PubMed Central

    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.

    2012-01-01

    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. PMID:22892342

  6. 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.

  7. Immunosuppressive therapy exacerbates autoimmunity in NOD mice and diminishes the protective activity of regulatory T cells.

    PubMed

    Kaminitz, Ayelet; Mizrahi, Keren; Yaniv, Isaac; Stein, Jerry; Askenasy, Nadir

    2010-09-01

    Mounting evidence indicates that immunosuppressive therapy and autologous bone marrow transplantation are relatively inefficient approaches to treat autoimmune diabetes. In this study we assessed the impact of immunosuppression on inflammatory insulitis in NOD mice, and the effect of radiation on immunomodulation mediated by adoptive transfer of various cell subsets. Sublethal radiation of NOD females at the age of 14 weeks (onset of hyperglycemia) delayed the onset of hyperglycemia, however two thirds of the mice became diabetic. Adoptive transfer of splenocytes into irradiated NON and NOD mice precipitated disease onset despite increased contents of CD25(+)FoxP3(+) T cells in the pancreas and regional lymphatics. Similar phenotypic changes were observed when CD25(+) T cells were infused after radiation, which also delayed disease onset without affecting its incidence. Importantly, irradiation increased the susceptibility to diabetes in NOD and NON mice (71-84%) as compared to immunomodulation with splenocytes and CD25(+) T cells in naïve recipients (44-50%). Although irradiation had significant and durable influence on pancreatic infiltrates and the fractions of functional CD25(+)FoxP3(+) Treg cells were elevated by adoptive cell transfer, this approach conferred no protection from disease progression. Irradiation was ineffective both in debulking of pathogenic clones and in restoring immune homeostasis, and the consequent homeostatic expansion evolves as an unfavorable factor in attempts to restore self-tolerance and might even provoke uncontrolled proliferation of pathogenic clones. The obstacles imposed by immunosuppression on abrogation of autoimmune insulitis require replacement of non-specific immunosuppressive therapy by selective immunomodulation that does not cause lymphopenia.

  8. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome

    PubMed Central

    Takemura, Naoki; Kawasaki, Takumi; Kunisawa