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1.
J Immunol ; 197(7): 2772-9, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27566825

RESUMO

Among the various hypotheses put forward to explain the modulatory influence of helminth infection on allergic effector responses in humans, the IL-10-induced suppression of Th2-associated responses has been the leading candidate. To explore this helminth/allergy interaction more fully, parasite- and allergen-specific CD4(+) T cell responses in 12 subjects with filarial infections, and coincident allergic sensitization (filarial [Fil](+)allergy [A](+)) were compared with the responses to three appropriate control groups (Fil(-)A(-) [n = 13], Fil(-)A(+) [n = 12], Fil(+)A(-) [n = 11]). The most important findings revealed that Fil(+)A(+) had marked (p < 0.0001 for all cytokines) increases in parasite Ag-driven Th2 (IL-4, IL-5, IL-13), Th9 (IL-9), and the regulatory (IL-10) cytokines when compared with Fil(+)A(-) Moreover, using multiparameter flow cytometry, filarial parasite Ag induced a marked increase in not only the frequency of CD4(+) T cells producing IL-4, IL-5, IL-2, and TNF-α in Fil(+)A(+) when compared with Fil(+)A(-) patients, but also in the frequencies of polyfunctional Th2-like (CD4(+)IL-4(+)IL-5(+) and CD4(+)IL-2(+)IL-4(+)IL-5(+)TNF-α(+)) cells. The Th2-associated responses seen in the Fil(+)A(+) group were correlated with serum IgE levels (p < 0.01, r = 0.5165 for IL-4; p < 0.001, r = 0.5544 for IL-5; and p < 0.001, r = 0.4901 for IL-13) and levels of circulating eosinophils (p < 0.0116, r = 0.5656) and their degranulation/activation products (major basic protein [p < 0.001, r = 0.7353] and eosinophil-derived neurotoxin [p < 0.01, r = 0.7059]). CD4(+) responses to allergen were not different (to a large extent) among the groups. Taken together, our data suggest that allergic sensitization coincident with filarial infection drives parasite Ag-specific T cell hyperresponsiveness, which is characterized largely by an augmented Th2-dominated immune response.


Assuntos
Alérgenos/imunologia , Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Filariose/imunologia , Células Cultivadas , Humanos
2.
Infect Immun ; 84(4): 1123-1136, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26857570

RESUMO

Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80(+)macrophages, and T. cruzi tetramer-specific CD8(+) T lymphocytes capable of producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus,T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses.


Assuntos
Doença de Chagas/patologia , Paralisia/parasitologia , Trypanosoma cruzi , Vasculite/patologia , Vasculite/parasitologia , Animais , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Regulação da Expressão Gênica/fisiologia , Membro Posterior/patologia , Linfócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Paralisia/patologia , Parasitemia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Vasculite/imunologia
3.
J Immunol ; 188(2): 649-60, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22156594

RESUMO

Chagas' disease is a zoonosis prevalent in Latin America that is caused by the protozoan Trypanosoma cruzi. The immunopathogenesis of cardiomyopathy, the main clinical problem in Chagas' disease, has been extensively studied but is still poorly understood. In this study, we systematically compared clinical, microbiologic, pathologic, immunologic, and molecular parameters in two mouse models with opposite susceptibility to acute myocarditis caused by the myotropic Colombiana strain of T. cruzi: C3H/HeSnJ (100% mortality, uncontrolled parasitism) and C57BL/6J (<10% mortality, controlled parasitism). T. cruzi induced differential polarization of immunoregulatory cytokine mRNA expression in the hearts of C57BL/6J versus C3H/HeSnJ mice; however, most differences were small. The difference in IL-10 expression was exceptional (C57BL/6J 8.7-fold greater than C3H/HeSnJ). Consistent with this, hearts from infected C57BL/6J mice, but not C3H/HeSnJ mice, had a high frequency of total IL-10-producing CD8(+) T cells and both CD4(+) and CD8(+) subsets of IFN-γ(+)IL-10(+) double-producing T cells. Furthermore, T. cruzi infection of IL-10(-/-) C57BL/6J mice phenocopied fatal infection in wild-type C3H/HeSnJ mice with complete loss of parasite control. Adoptive transfer experiments indicated that T cells were a source of protective IL-10. Thus, in this system, IL-10 production by T cells promotes T. cruzi control and protection from fatal acute myocarditis.


Assuntos
Doença de Chagas/prevenção & controle , Doença de Chagas/parasitologia , Interleucina-10/fisiologia , Interleucina-10/uso terapêutico , Miocardite/prevenção & controle , Miocardite/parasitologia , Trypanosoma cruzi/imunologia , Doença Aguda , Transferência Adotiva , Animais , Doença de Chagas/mortalidade , Modelos Animais de Doenças , Interleucina-10/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/mortalidade , Parasitemia/imunologia , Parasitemia/mortalidade , Parasitemia/parasitologia , Análise de Sobrevida , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/parasitologia
4.
J Allergy Clin Immunol ; 130(1): 248-56.e9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22541242

RESUMO

BACKGROUND: The extensive similarities between helminth proteins and allergens are thought to contribute to helminth-driven allergic sensitization. OBJECTIVE: The objective of this study was to investigate the cross-reactivity between a major glutathione-S transferase allergen of cockroach (Bla g 5) and the glutathione-S transferase of Wuchereria bancrofti (WbGST), a major lymphatic filarial pathogen of humans. METHODS: We compared the molecular and structural similarities between Bla g 5 and WbGST by in silico analysis and by linear epitope mapping. The levels of IgE, IgG, and IgG(4) antibodies were measured in filarial-infected and filarial-uninfected patients. Mice were infected with Heligmosomoides bakeri, and their skin was tested for cross-reactive allergic responses. RESULTS: These 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG(4) anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST (P< .0003). Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG(4) antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with H bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5. CONCLUSION: These data demonstrate that helminth glutathione-S transferase and the aeroallergen Bla g 5 share epitopes that can induce allergic cross-sensitization.


Assuntos
Anticorpos/sangue , Baratas/enzimologia , Glutationa Transferase/genética , Glutationa Transferase/imunologia , Helmintos/enzimologia , Mimetismo Molecular/imunologia , Sequência de Aminoácidos , Animais , Baratas/genética , Baratas/imunologia , Reações Cruzadas , Filariose Linfática/imunologia , Mapeamento de Epitopos , Feminino , Glutationa Transferase/química , Proteínas de Helminto/química , Proteínas de Helminto/genética , Proteínas de Helminto/imunologia , Helmintos/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Trichostrongyloidea/imunologia , Tricostrongiloidíase/imunologia , Wuchereria bancrofti/enzimologia , Wuchereria bancrofti/genética , Wuchereria bancrofti/imunologia
5.
Life Sci ; 324: 121750, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37142087

RESUMO

AIMS: Millions of people died during the COVID-19 pandemic, but the vast majority of infected individuals survived. Now, some consequences of the disease, known as long COVID, are been revealed. Although the respiratory system is the target of Sars-CoV-2, COVID-19 can influence other parts of the body, including bone. The aim of this work was to investigate the impact of acute coronavirus infection in bone metabolism. MAIN METHODS: We evaluated RANKL/OPG levels in serum samples of patients with and without acute COVID-19. In vitro, the effects of coronavirus in osteoclasts and osteoblasts were investigated. In vivo, we evaluated the bone phenotype in a BSL2 mouse model of SARS-like disease induced by murine coronavirus (MHV-3). KEY FINDINGS: Patients with acute COVID-19 presented decreased OPG and increased RANKL/OPG ratio in the serum versus healthy individuals. In vitro, MHV-3 infected macrophages and osteoclasts, increasing their differentiation and TNF release. Oppositely, osteoblasts were not infected. In vivo, MHV-3 lung infection triggered bone resorption in the femur of mice, increasing the number of osteoclasts at 3dpi and decreasing at 5dpi. Indeed, apoptotic-caspase-3+ cells have been detected in the femur after infection as well as viral RNA. RANKL/OPG ratio and TNF levels also increased in the femur after infection. Accordingly, the bone phenotype of TNFRp55-/- mice infected with MHV-3 showed no signs of bone resorption or increase in the number of osteoclasts. SIGNIFICANCE: Coronavirus induces an osteoporotic phenotype in mice dependent on TNF and on macrophage/osteoclast infection.


Assuntos
Reabsorção Óssea , COVID-19 , Animais , Humanos , Camundongos , Reabsorção Óssea/metabolismo , Diferenciação Celular , COVID-19/metabolismo , Osteoblastos , Osteoclastos/metabolismo , Osteoprotegerina/metabolismo , Pandemias , Fenótipo , Síndrome de COVID-19 Pós-Aguda , Ligante RANK/metabolismo , SARS-CoV-2/metabolismo , Vírus da Hepatite Murina/metabolismo , Vírus da Hepatite Murina/patogenicidade , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo
6.
J Allergy Clin Immunol ; 127(2): 479-86, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21185070

RESUMO

BACKGROUND: The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy. Other data suggest parasitic infections may induce allergic responsiveness. OBJECTIVE: To assess the structural and immunologic relationships between the known Dermatophagoides pteronyssinus (Der p 10) tropomyosin allergen and filarial tropomyosin of Onchocerca volvulus (OvTrop). METHODS: The molecular, structural, and immunologic relationships between OvTrop and Der p 10 were compared. Levels of OvTrop-specific and Der p 10-specific IgE, IgG, and IgG4 in sera of filaria-infected and filarial-uninfected D pteronyssinus-atopic individuals were compared, as were the responses in nonhuman primates infected with the filarial parasite Loa loa. Cross-reactivity was compared by antigen-mediated depletion assays and functionality by passive basophil sensitization. RESULTS: Filarial and mite tropomyosins were very similar, with 72% identity at the amino acid level, and overlapping predicted 3-dimensional structures. The prevalence of IgE and IgG to Der p 10 was increased in filaria-infected individuals compared with uninfected subjects. There was a strong correlation between serum levels of Ov- and Der p 10-tropomyosin-specific IgE, IgG, and IgG4 (P < .0001; r > 0.79). Preincubation of sera from anti-Der p 10-positive subjects with OvTrop completely depleted IgE, IgG, and IgG4 anti-Der p 10. Basophils sensitized with sera from individuals allergic to Der p 10 released histamine similarly when triggered with OvTrop or Der p 10. Primates experimentally infected with L loa developed IgE that cross-reacted with Der p 10. CONCLUSION: Filarial infection induces strong cross-reactive antitropomyosin antibody responses that may affect sensitization and regulation of allergic reactivity.


Assuntos
Antígenos de Plantas/imunologia , Higiene , Hipersensibilidade/etiologia , Onchocerca volvulus/imunologia , Tropomiosina/imunologia , Animais , Antígenos de Dermatophagoides , Proteínas de Artrópodes , Reações Cruzadas , Filariose/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Tropomiosina/química
7.
Pathogens ; 11(3)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35335618

RESUMO

The Zika virus (ZIKV) was first isolated from a rhesus macaque in the Zika forest of Uganda in 1947. Isolated cases were reported until 2007, when the first major outbreaks of Zika infection were reported from the Island of Yap in Micronesia and from French Polynesia in 2013. In 2015, ZIKV started to circulate in Latin America, and in 2016, ZIKV was considered by WHO to be a Public Health Emergency of International Concern due to cases of Congenital Zika Syndrome (CZS), a ZIKV-associated complication never observed before. After a peak of cases in 2016, the infection incidence dropped dramatically but still causes concern because of the associated microcephaly cases, especially in regions where the dengue virus (DENV) is endemic and co-circulates with ZIKV. A vaccine could be an important tool to mitigate CZS in endemic countries. However, the immunological relationship between ZIKV and other flaviviruses, especially DENV, and the low numbers of ZIKV infections are potential challenges for developing and testing a vaccine against ZIKV. Here, we discuss ZIKV vaccine development with the perspective of the immunological concerns implicated by DENV-ZIKV cross-reactivity and the use of a controlled human infection model (CHIM) as a tool to accelerate vaccine development.

8.
PLoS Negl Trop Dis ; 16(5): e0010105, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35499991

RESUMO

BACKGROUND: Epidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms Treg cells exert in the helminth-obesity interface has been poorly investigated. The present study aimed to verify the influence of Heligmosomoides polygyrus infection in early stages of high fat diet-induced obesity. PRINCIPAL FINDINGS: The presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by lower levels of leptin and resistin, lower infiltration of Th1 and Th17 cells in adipose tissue, higher expression of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased Treg frequency in adipose tissue which showed higher expression of cell surface markers of function and activation, like LAP and CD134. The infection could also increase adipose Treg suppressor function in animals on high fat diet. CONCLUSION: These data suggest that H. polygyrus modulates adipose tissue Treg cells with implication for weight gain and metabolic syndrome.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Tecido Adiposo , Animais , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Aumento de Peso
9.
Stem Cell Rev Rep ; 18(2): 732-751, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34780018

RESUMO

Stem cell therapy is an interesting approach for neural repair, once it can improve and increase processes, like angiogenesis, neurogenesis, and synaptic plasticity. In this regard, adult neural stem cells (NSC) are studied for their mechanisms of proliferation, differentiation and functionality in neural repair. Here, we describe novel neural differentiation methods. NSC from adult mouse brains and human adipose-derived stem cells (hADSC) were isolated and characterized regarding their neural differentiation potential based on neural marker expression profiles. For both cell types, their capabilities of differentiating into neuron-, astrocyte- and oligodendrocytes-like cells (NLC, ALC and OLC, respectively) were analyzed. Our methodologies were capable of producing NLC, ALC and OLC from adult murine and human transdifferentiated NSC. NSC showed augmented gene expression of NES, TUJ1, GFAP and PDGFRA/Cnp. Following differentiation induction into NLC, OLC or ALC, specific neural phenotypes were obtained expressing MAP2, GalC/O4 or GFAP with compatible morphologies, respectively. Accordingly, immunostaining for nestin+ in NSC, GFAP+ in astrocytes and GalC/O4+ in oligodendrocytes was detected. Co-cultured NLC and OLC showed excitability in 81.3% of cells and 23.5% of neuron/oligodendrocyte marker expression overlap indicating occurrence of in vitro myelination. We show here that hADSC can be transdifferentiated into NSC and distinct neural phenotypes with the occurrence of neuron myelination in vitro, providing novel strategies for CNS regeneration therapy. Superior Part: Schematic organization of obtaining and generating hNSC from hADSC and differentiation processes and phenotypic expression of neuron, astrocyte and oligodendrocyte markers (MAP2, GFAP and O4, respectively) and stem cell marker (NES) of differentiating hNSC 14 days after induction. The nuclear staining in blue corresponds to DAPI. bar = 100 µm. Inferior part: Neural phenotype fates in diverse differentiation media. NES: nestin; GFAP: Glial fibrillary acidic protein. MAP2: Microtubule-associated protein 2. TUJ1: ß-III tubulin. PDGFRA: PDGF receptor alpha. Two-way ANOVA with Bonferroni post-test with n = 3. * p < 0.05 and ** p < 0.01: (NSCiM1 NSC induction medium 1) vs differentiation media.


Assuntos
Transdiferenciação Celular , Células-Tronco Neurais , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Camundongos , Nestina , Neurogênese , Neurônios , Oligodendroglia
10.
Stem Cell Rev Rep ; 18(8): 2852-2871, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962176

RESUMO

Neurogenesis is a biological process characterized by new neurons formation from stem cells. For decades, it was believed that neurons only multiplied during development and in the postnatal period but the discovery of neural stem cells (NSCs) in mature brain promoted a revolution in neuroscience field. In mammals, neurogenesis consists of migration, differentiation, maturation, as well as functional integration of newborn cells into the pre-existing neuronal circuit. Actually, NSC density drops significantly after the first stages of development, however in specific places in the brain, called neurogenic niches, some of these cells retain their ability to generate new neurons and glial cells in adulthood. The subgranular (SGZ), and the subventricular zones (SVZ) are examples of regions where the neurogenesis process occurs in the mature brain. There, the potential of NSCs to produce new neurons has been explored by new advanced methodologies and in neuroscience for the treatment of brain damage and/or degeneration. Based on that, this review highlights endogenous factors and drugs capable of stimulating neurogenesis, as well as the perspectives for the use of NSCs for neurological and neurodegenerative diseases.


Assuntos
Células-Tronco Neurais , Neurogênese , Animais , Humanos , Recém-Nascido , Adulto , Neurogênese/fisiologia , Ventrículos Laterais , Neurônios , Neuroglia , Mamíferos
11.
Pharmaceutics ; 13(7)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34371713

RESUMO

Doxorubicin (DOX), a chemotherapy drug successfully used in the therapy of various types of cancer, is currently associated with the mucositis development, an inflammation that can cause ulcerative lesions in the mucosa of the gastrointestinal tract, abdominal pain and secondary infections. To increase the safety of the chemotherapy, we loaded DOX into nanostructured lipid carriers (NLCs). The NLC-DOX was characterized by HPLC, DLS, NTA, Zeta potential, FTIR, DSC, TEM and cryogenic-TEM. The ability of NLC-DOX to control the DOX release was evaluated through in vitro release studies. Moreover, the effect of NLC-DOX on intestinal mucosa was compared to a free DOX solution in C57BL/6 mice. The NLC-DOX showed spherical shape, high drug encapsulation efficiency (84.8 ± 4.6%), high drug loading (55.2 ± 3.4 mg/g) and low average diameter (66.0-78.8 nm). The DSC and FTIR analyses showed high interaction between the NLC components, resulting in controlled drug release. Treatment with NLC-DOX attenuated DOX-induced mucositis in mice, improving shortening on villus height and crypt depth, decreased inflammatory parameters, preserved intestinal permeability and increased expression of tight junctions (ZO-1 and Ocludin). These results indicated that encapsulation of DOX in NLCs is viable and reduces the drug toxicity to mucosal structures.

12.
Microbes Infect ; 10(3): 276-84, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18316222

RESUMO

Intracellular replication of Toxoplasma gondii requires cholesterol uptake by host cell low-density lipoprotein receptor (LDLr), a critical element in atherosclerosis. We evaluated host parasitism, inflammatory responses and development of atherosclerosis in LDLr knockout (LDLr(-/-)) and their controls C57BL/6 mice infected with T. gondii. Our results show that T. gondii cysts were reduced in LDLr(-/-) mice when compared to C57BL/6 mice. However, in presence of hypercholesterolemic diet, parasite growth in LDLr(-/-) mice was similar to that seen in infected C57BL/6 mice. In presence of a hypercholesterolemic diet, T. gondii infection leads to a 60% reduction of serum triacylglycerol, total and atherogenic lipoprotein cholesterol. When aortic valve lesion was analyzed, infected mice showed a reduction of atherosclerotic lesion area as well as CD36 expression. MCP-1, SRA-I, SRA-II, ICAM-1 and VCAM-1 mRNA expression was kept similar between infected and control groups. Thus, despite the intense inflammatory process, the drastic reduction in serum lipids seems to limit the development of atherosclerosis in LDLr(-/-) mice infected with T. gondii. In conclusion, our results indicate that T. gondii employs host LDLr to acquire cholesterol and favor its growth. However, in the presence of hypercholesterolemia, T. gondii parasites are able to acquire cholesterol-rich lipoproteins through an alternative host receptor, and overcome LDLr deficiency, favoring host parasitism and impairing lipid loading of foam cells.


Assuntos
Receptores de LDL/fisiologia , Toxoplasma/fisiologia , Toxoplasmose/parasitologia , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/fisiopatologia , Aorta Torácica/imunologia , Aorta Torácica/fisiopatologia , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Aterosclerose/etiologia , Antígenos CD36/metabolismo , Colesterol/sangue , Interações Hospedeiro-Parasita , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/deficiência , Toxoplasmose/complicações , Toxoplasmose/metabolismo , Toxoplasmose/fisiopatologia , Triglicerídeos/sangue
13.
PeerJ ; 5: e2967, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28265495

RESUMO

BACKGROUND: Nowadays, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This leads the body to a pro-inflammatory pattern, which may affect the proper functioning of many tissues. Thus, studying the mechanisms by which obesity induces physiological disorders is necessary, and may be facilitated by the use of animal models, in particular rodents. We sought to characterize the metabolic and adipose tissue changes resulting from a diet rich in fats and simple sugars in gerbils. METHODS: We divided 14 gerbils into two experimental groups that received a diet rich in simple carbohydrates and fats with 5,86 kcal/g (OB, n = 7) or a standard diet with 4.15 kcal/g (CT; n = 7) for 11 weeks. The animals had free access to water and food. The animal weight and food consumption were measured weekly. Blood, adipose tissue and liver of each animal were collected at the end of experiment. The following parameters were determined: cholesterol (COL), triglycerides (TGL) and glycemia (GLI) in the plasma; cytokines (IL-6, IL-10 and TNF-α) and hormones (adiponectin and leptin) in adipose tissue; activity of superoxide dismutase (SOD) and catalase (CAT), extraction and differentiation of fat and histology in liver. RESULTS: The consumption of a diet rich in simple carbohydrates and fats led to increased total body weight and increased relative weights of liver and adipose tissue. In addition, we observed increased fasting glucose levels and circulating triglycerides, along with high TNF-α production in adipose tissue and increased total fat, cholesterol and triglyceride contents in the liver, contributing to higher intensity of hepatic steatosis. On the other hand, the animals of this group showed depletion in the enzyme activity of SOD and CAT in the liver, as well as reduction of IL-10 and adiponectin levels in adipose tissue. DISCUSSION: High intake of saturated fat and simple carbohydrates establish the gerbil as an experimental model for the study of metabolic and hepatic abnormalities resulting from obesity.

14.
Microbes Infect ; 8(11): 2569-77, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16938478

RESUMO

We investigated the role of the platelet activation factor (PAF) receptor (PAFR) in the outcome of infection with Leishmania amazonensis. PAFR deficient (PAFR(-/-)) mice were infected with L. amazonensis and the course of infection was followed. We found that PAFR(-/-) mice in the C57BL/6 background were more susceptible to infection with L. amazonensis than the wild-type controls, as seen both by lesion size and parasite number at the site of infection. Interferon (IFN)-gamma production was delayed in PAFR(-/-) mice, and lower levels of Ccl5 were found in lesions. Expression of nitric oxide synthase-2 mRNA was found impaired in PAFR(-/-) associated with higher levels of arginase-1 mRNA. Moreover, higher levels of antibodies were produced in response to L. amazonensis by PAFR(-/-) mice. We conclude that signaling through the PAFR is essential for the ability of the murine host to control L. amazonensis infection by driving an adequate immune response.


Assuntos
Interferon gama/biossíntese , Leishmania mexicana/imunologia , Leishmaniose Cutânea/imunologia , Glicoproteínas da Membrana de Plaquetas/deficiência , Receptores Acoplados a Proteínas G/deficiência , Animais , Anticorpos Antiprotozoários/sangue , Arginase/biossíntese , Quimiocina CCL1 , Quimiocina CCL5 , Quimiocinas CC/análise , Modelos Animais de Doenças , Suscetibilidade a Doenças , Expressão Gênica , Histocitoquímica , Imunoglobulina G/sangue , Interleucina-10/análise , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/biossíntese , Glicoproteínas da Membrana de Plaquetas/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores Acoplados a Proteínas G/genética , Fator de Necrose Tumoral alfa/análise , Regulação para Cima
15.
Microbes Infect ; 8(12-13): 2745-55, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16979363

RESUMO

Chagas' disease, caused by Trypanosoma cruzi, is a major cause of cardiovascular disease in Latin America. Exacerbated inflammation disproportional to parasite load characterizes chronic myocardial lesions in chagasic patients. Chemokines and their receptors are expected to account for the renewed inflammatory processes after the inoculation of the parasite, but their potential unique functions are far from being clear. Herein, we evaluated the effect of a DNA vaccine encoding CCL4/MIP-1beta, a CC-chemokine, in T. cruzi-elicited myocarditis in rats. Holtzman rats were given intramuscularly cardiotoxin and the CCL4/MIP-1beta DNA-containing plasmid (100microg) was delivered in this muscular site four times. Fourteen days after last immunization, animals were inoculated with a myotropical CL-Brener T. cruzi clone. Peak of parasitism was observed at day 15 after infection, preceding the peak of myocardial inflammation at day 20. Myocarditis was still intense at day 30, but the inflammatory infiltrates showed a more focal distribution. The expression of CCL2/MCP-1 and CCL4/MIP-1beta correlated closely with the kinetics of myocardial inflammation. The CCL4/MIP-1beta DNA vaccine induced an increase of the levels of the anti-CCL4/MIP-1beta observed in T. cruzi-infected animals. This was associated with an exacerbation of myocardial inflammation and fibrosis, although alterations in parasitemia and myocardial parasitism were not observed. Our data suggest that CCL4/MIP-1beta plays a role in preventing excessive inflammation and pathology rather than in controlling parasite replication.


Assuntos
Cardiomiopatia Chagásica/patologia , Quimiocinas CC/imunologia , Trypanosoma cruzi/imunologia , Vacinas de DNA/imunologia , Animais , Cardiomiopatia Chagásica/imunologia , Quimiocina CCL4 , Quimiocinas CC/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Coração/parasitologia , Histocitoquímica , Miocárdio/patologia , Parasitemia , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Trypanosoma cruzi/isolamento & purificação , Vacinas de DNA/genética
16.
Am J Trop Med Hyg ; 95(4): 746-753, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27573628

RESUMO

There is much debate about the interaction between helminths and allergic disease. The "Hygiene Hypothesis," a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti- and pro-allergenic effects that define the helminth/allergy interface.


Assuntos
Alérgenos/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Hipótese da Higiene , Hipersensibilidade/imunologia , Imunidade Adaptativa , Animais , Reações Cruzadas , Helmintíase/parasitologia , Interações Hospedeiro-Parasita , Humanos , Hipersensibilidade/parasitologia , Imunoglobulina E/imunologia , Inflamação/imunologia , Especificidade da Espécie
18.
PLoS Negl Trop Dis ; 6(2): e1492, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22348160

RESUMO

(•)NO is considered to be a key macrophage-derived cytotoxic effector during Trypanosoma cruzi infection. On the other hand, the microbicidal properties of reactive oxygen species (ROS) are well recognized, but little importance has been attributed to them during in vivo infection with T. cruzi. In order to investigate the role of ROS in T. cruzi infection, mice deficient in NADPH phagocyte oxidase (gp91(phox) (-/-) or phox KO) were infected with Y strain of T. cruzi and the course of infection was followed. phox KO mice had similar parasitemia, similar tissue parasitism and similar levels of IFN-γ and TNF in serum and spleen cell culture supernatants, when compared to wild-type controls. However, all phox KO mice succumbed to infection between day 15 and 21 after inoculation with the parasite, while 60% of wild-type mice were alive 50 days after infection. Further investigation demonstrated increased serum levels of nitrite and nitrate (NOx) at day 15 of infection in phox KO animals, associated with a drop in blood pressure. Treatment with a NOS2 inhibitor corrected the blood pressure, implicating NOS2 in this phenomenon. We postulate that superoxide reacts with (•)NO in vivo, preventing blood pressure drops in wild type mice. Hence, whilst superoxide from phagocytes did not play a critical role in parasite control in the phox KO animals, its production would have an important protective effect against blood pressure decline during infection with T. cruzi.


Assuntos
Doença de Chagas/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/imunologia , NADPH Oxidases/deficiência , NADPH Oxidases/imunologia , Fagócitos/enzimologia , Fagócitos/imunologia , Choque , Trypanosoma cruzi/imunologia , Animais , Células Cultivadas , Doença de Chagas/mortalidade , Modelos Animais de Doenças , Feminino , Interferon gama/sangue , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , Parasitemia/imunologia , Baço/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
19.
Eur J Pharmacol ; 633(1-3): 85-92, 2010 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-20152831

RESUMO

Reactive oxygen species, cytokines and chemokines produced at inflammatory sites are pivotal events in the progression of many diseases. Flavonoids are well-known for their antioxidant and anti-inflammatory activities. Here, we investigated the effects of the flavonoid dioclein on the production of mediators of inflammation in vitro and possible underlying mechanisms. Murine macrophages were pretreated with dioclein, rolipram, a PDE4 (cyclic nucleotide phosphosdiesterase type 4) inhibitor, or butylated hydroxytoluene (BHT), an antioxidant, and then activated with LPS or LPS/IFN-gamma. The concentration of TNF-alpha, IL-6, CXCL1/KC, CCL2/JE, and nitric oxide (NO) was determined on culture supernatants. To evaluate potential mechanisms of action, dioclein was tested for inhibition of PDE4 activity and for antioxidant properties by chemiluminescence assays. Dioclein was efficient in reducing the production of cytokines, chemokines and NO in a concentration-dependent manner (from 5 to 50muM). Dioclein was more effective than BHT and rolipram, while having similar inhibitory effects to the combination of BHT plus rolipram. Dioclein inhibited PDE4 activity with an approximate IC(50) of 16.8+/-1.4muM and strongly reduced the concentration of reactive oxygen species in cell and cell-free systems, being more effective than the standard antioxidant BHT. The flavonoid dioclein possesses significant antioxidant and PDE4 inhibitory activity, showing that the substance may have substantial advantages over mechanisms of action already described for many flavonoids. Such effects account for the anti-inflammatory effects of dioclein, mainly by reducing the concentration of mediators of inflammation, such as cytokines, chemokines and reactive oxygen species by macrophages.


Assuntos
Antioxidantes/farmacologia , Flavanonas/farmacologia , Sequestradores de Radicais Livres/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inibidores da Fosfodiesterase 4 , Espécies Reativas de Oxigênio/metabolismo , Animais , Hidroxitolueno Butilado/farmacologia , Células Cultivadas , Citocinas/metabolismo , Interações Medicamentosas , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Explosão Respiratória/efeitos dos fármacos , Rolipram/farmacologia
20.
Microbes Infect ; 12(8-9): 669-76, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20452453

RESUMO

Chagas' disease is caused by Trypanosoma cruzi infection and is characterized by chronic fibrogenic inflammation and heart dysfunction. Chemokines are produced during infection and drive tissue inflammation. In rats, acute infection is characterized by intense myocarditis and regression of inflammation after control of parasitism. We investigated the role of CCL3 and CCL5 during infection by using DNA vaccination encoding for each chemokine separately or simultaneously. MetRANTES treatment was used to evaluate the role of CCR1 and CCR5, the receptors for CCL3 and CCL5. Vaccination with CCL3 or CCL5 increased heart parasitism and decreased local IFN-gamma production, but did not influence intensity of inflammation. Simultaneous treatment with both plasmids or treatment with MetRANTES enhanced cardiac inflammation, fibrosis and parasitism. In conclusion, chemokines CCL3 and CCL5 are relevant, but not essential, for control of T. cruzi infection in rats. On the other hand, combined blockade of these chemokines or their receptors enhanced tissue inflammation and fibrosis, clearly contrasting with available data in murine models of T. cruzi infection. These data reinforce the important role of chemokines during T. cruzi infection but suggest that caution must be taken when expanding the therapeutic modulation of the chemokine system in mice to the human infection.


Assuntos
Cardiomiopatia Chagásica/imunologia , Quimiocina CCL3/imunologia , Quimiocina CCL5/imunologia , Trypanosoma cruzi/imunologia , Animais , Cardiomiopatia Chagásica/patologia , Coração/parasitologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Trypanosoma cruzi/patogenicidade , Vacinas de DNA/administração & dosagem
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