Effects of Astrocaryum aculeatum Meyer (Tucumã) on Diet-Induced Dyslipidemic Rats

An in vivo study was conducted to assess the effects of the consumption of Astrocaryum aculeatum Amazon Meyer (tucumã) in the treatment of diet-induced dyslipidemia in sedentary and exercised Wistar rats. With an average weight of 350 grams, 40 male rats were divided into 4 subgroups of 10. The sedentary control group (SCG) was fed with commercial feed, while the sedentary treatment group (STG) was fed with a ration of tucumã. In addition to the sedentary groups, two exercise groups were formed. The Exercised control group (ECG) was fed with commercial food and the exercised treatment group (ETG) was fed with a ration of tucumã. Body weight gain and food intake were monitored during the experiment. Plasma was analyzed for cholesterol, triglycerides, HDL-C, LDL-C, VLDL, total protein, glucose, insulin, and leptin concentrations. Our results show that the ECG group tended to consume more food, while the groups that were fed with tucumã pulp (STG and ETG) presented a greater tendency to gain body mass. ECG group showed a tendency towards a higher concentration of cholesterol in plasma, while STG and ETG presented higher absolute values for triglycerides and VLDL. No hypolipiemic effect was observed related to tucuma ingestion. © 2014 Geórgia Craveiro Holanda Malveira Maia et al

Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged

Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. in the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5- or IL-4-producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. the allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25-treated mice. the exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25(+) CD4(+) T cells expressing high levels of CCR4, but not CCR4KO CD25(+) CD4(+) T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation. the Journal of Immunology, 2013, 190: 2614-2621.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Inst Biomed Sci, Dept Immunol, BR-05508900 São Paulo, BrazilUniv São Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, São Paulo Sch Med, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo Sch Med, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilWeb of Scienc

A Single Dose of a DNA Vaccine Encoding Apa Coencapsulated with 6,6=-Trehalose Dimycolate in Microspheres Confers Long-Term Protection against Tuberculosis in Mycobacterium bovis BCG-Primed Mice

Made available in DSpace on 2015-09-21T17:25:10Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) joseli_vieira_etal_IOC_2013.pdf: 2121105 bytes, checksum: 5ed67f3990f4a296fb8320be5cead158 (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Laboratório de Imunologia e Imunogenética. Rio de Janeiro, RJ, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Instituto Butantã. Centro de Biotecnologia. São Paulo, SP, brasil.Fonte Medicina Diagnóstica. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Escola de Medicina de Ribeirão Preto. Departamento de Bioquímica e Imunologia. Ribeirão Preto, SP, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Laboratório de Imunologia e Imunogenética. Rio de Janeiro, RJ, BrasilMycobacterium bovis BCG prime DNA (Mycobacterium tuberculosis genes)-booster vaccinations have been shown to induce greater protection against tuberculosis (TB) than BCG alone. This heterologous prime-boost strategy is perhaps the most realistic vaccination for the future of TB infection control, especially in countries where TB is endemic. Moreover, a prime-boost regimen using biodegradable microspheres seems to be a promising immunization to stimulate a long-lasting immune response. The alanine proline antigen (Apa) is a highly immunogenic glycoprotein secreted by M. tuberculosis. This study investigated the immune protection of Apa DNA vaccine against intratracheal M. tuberculosis challenge in mice on the basis of a heterologous prime-boost regimen. BALB/c mice were subcutaneously primed with BCG and intramuscularly boosted with a single dose of plasmid carrying apa and 6,6=-trehalose dimycolate (TDM) adjuvant, coencapsulated in microspheres (BCG-APA), and were evaluated 30 and 70 days after challenge. This prime-boost strategy (BCG-APA) resulted in a significant reduction in the bacterial load in the lungs, thus leading to better preservation of the lung parenchyma, 70 days postinfection compared to BCG vaccinated mice. The profound effect of this heterologous prime-boost regimen in the experimental model supports its development as a feasible strategy for prevention of TB

Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection.

Tissue-infiltrating Ly6C(hi) monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function

Functional interferences in host inflammatory immune response by airway allergic inflammation restrain experimental periodontitis development in mice

Aims Periodontal disease (PD) and airway allergic inflammation (AL) present opposing inflammatory immunological features and clinically present an inverse correlation. However, the putative mechanisms underlying such opposite association are unknown. Material and Methods Balb/C mice were submitted to the co-induction of experimental PD (induced by Actinobacillus actinomycetemcomitans oral inoculation) and AL [induced by sensitization with ovalbumin (OVA) and the subsequent OVA challenges], and evaluated regarding PD and AL severity, immune response [cytokine production at periodontal tissues, and T-helper transcription factors in submandibular lymph nodes (LNs)] and infection parameters. Results PD/AL co-induction decreased PD alveolar bone loss and periodontal inflammation while experimental AL parameters were unaltered. An active functional interference was verified, because independent OVA sensitization and challenge not modulate PD outcome. PD+AL group presented decreased tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, -gamma, IL-17A, receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand and matrix metalloproteinase (MMP)-13 levels in periodontal tissues, while IL-4 and IL-10 levels were unaltered by AL co-induction. AL co-induction also resulted in upregulated T-bet and related orphan receptor gamma and downregulated GATA3 levels expression in submandibular LNs when compared with PD group. Conclusion Our results demonstrate that the interaction between experimental periodontitis and allergy involves functional immunological interferences, which restrains experimental periodontitis development by means of a skewed immune response.FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNP

Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation may reveal subclinical alterations in human T-cell lymphotropic virus type 1-associated myelopathy.

BACKGROUND:Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation (galvanic-VEMP) evaluates the motor spinal cord and identifies subclinical myelopathies. We used galvanic-VEMP to compare spinal cord function in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1) from asymptomatic status to HTLV-1-associated myelopathy (HAM). METHODOLOGY/PRINCIPAL FINDINGS:This cross-sectional study with 122 individuals included 26 HTLV-1-asymptomatic carriers, 26 individuals with possible HAM, 25 individuals with HAM, and 45 HTLV-1-seronegative individuals (controls). The groups were similar regarding gender, age, and height. Galvanic stimuli (duration: 400 ms; intensity: 2 mA) were applied bilaterally to the mastoid processes and VEMP was recorded from the gastrocnemius muscle. The electromyographic parameters investigated were the latency and amplitude of the short-latency (SL) and medium-latency (ML) responses. While SL and ML amplitudes were similar between groups, SL and ML latencies were delayed in the HTLV-1 groups compared to the control group (p<0.001). Using neurological examination as the gold standard, ROC curve showed an area under the curve of 0.83 (p<0.001) for SL and 0.86 (p<0.001) for ML to detect spinal cord injury. Sensibility and specificity were, respectively, 76% and 86% for SL and 79% and 85% for ML. Galvanic-VEMP disclosed alterations that were progressive in HTLV-1-neurological disease, ranging from SL delayed latency in HTLV-1-asymptomatic carriers, SL and ML delayed latency in possible HAM group, to absence of VEMP response in HAM group. CONCLUSIONS/SIGNIFICANCE:The worse the galvanic-VEMP response, the more severe the myelopathy. Galvanic-VEMP alteration followed a pattern of alteration and may be a prognostic marker of progression from HTLV-1-asymptomatic carrier to HAM

Protection conferred by heterologous vaccination against tuberculosis is dependent on the ratio of CD4(+)/CD4(+) Foxp3(+) cells

CD4(+) Foxp3(+) regulatory T cells inhibit the production of interferon-?, which is the major mediator of protection against Mycobacterium tuberculosis infection. In this study, we evaluated whether the protection conferred by three different vaccines against tuberculosis was associated with the number of spleen and lung regulatory T cells. We observed that after homologous immunization with the 65 000 molecular weight heat-shock protein (hsp 65) DNA vaccine, there was a significantly higher number of spleen CD4(+) Foxp3(+) cells compared with non-immunized mice. Heterologous immunization using bacillus Calmette Guerin (BCG) to prime and DNA-hsp 65 to boost (BCG/DNA-hsp 65) or BCG to prime and culture filtrate proteins (CFP)-CpG to boost (BCG/CFP-CpG) induced a significantly higher ratio of spleen CD4(+)/CD4(+) Foxp3(+) cells compared with non-immunized mice. In addition, the protection conferred by either the BCG/DNA-hsp 65 or the BCG/CFP-CpG vaccines was significant compared with the DNA-hsp 65 vaccine. Despite the higher ratio of spleen CD4(+)/CD4(+) Foxp3(+) cells found in BCG/DNA-hsp 65-immunized or BCG/CFP-CpG-immunized mice, the lungs of both groups of mice were better preserved than those of DNA-hsp 65-immunized mice. These results confirm the protective efficacy of BCG/DNA-hsp 65 and BCG/CFP-CpG heterologous prime-boost vaccines and the DNA-hsp 65 homologous vaccine. Additionally, the prime-boost regimens assayed here represent a promising strategy for the development of new vaccines to protect against tuberculosis because they probably induce a proper ratio of CD4(+) and regulatory (CD4(+) Foxp3(+)) cells during the immunization regimen. In this study, this ratio was associated with a reduced number of regulatory cells and no injury to the lungs.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2007/02695-5