Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
1.
Front Immunol ; 15: 1391949, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38765015

RESUMEN

Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.


Asunto(s)
Dimetilfumarato , Encefalomielitis Autoinmune Experimental , Ganglios Linfáticos , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ratones , Femenino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Mesenterio , Citocinas/metabolismo , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Modelos Animales de Enfermedad
2.
Sci Rep ; 14(1): 7375, 2024 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-38548777

RESUMEN

The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome_App/ ) to enrich and expand this knowledgebase.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Proteómica , Pandemias
3.
Int J Mol Sci ; 24(9)2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37175706

RESUMEN

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.


Asunto(s)
Interleucina-27 , Esclerosis Múltiple , Humanos , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas , Interleucina-27/metabolismo , Leucocitos Mononucleares/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Linfocitos T/metabolismo
4.
Mol Genet Metab ; 138(4): 107552, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36889041

RESUMEN

BACKGROUND AND AIMS: Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes. METHODS: Individuals hospitalized due to COVID-19 (n = 40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n = 13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated. RESULTS: In the first 30 days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p < 0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p < 0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r = 0.65, p < 0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors. CONCLUSIONS: Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa , COVID-19 , Humanos , Lipoproteínas LDL , Biomarcadores , Lisofosfatidilcolinas
5.
Nat Commun ; 13(1): 5722, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36175400

RESUMEN

Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.


Asunto(s)
COVID-19 , SARS-CoV-2 , Tejido Adiposo , Enzima Convertidora de Angiotensina 2 , Citocinas , Humanos
6.
Front Immunol ; 13: 750660, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35197967

RESUMEN

Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-ß (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Antígenos CD19/uso terapéutico , Antígenos CD20 , Linfocitos B/metabolismo , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Humanos , Interferón beta/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Péptidos , Linfocitos T
7.
Viruses ; 13(11)2021 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-34834934

RESUMEN

A SARS-CoV-2 B.1.1.7 variant of concern (VOC) has been associated with increased transmissibility, hospitalization, and mortality. This study aimed to explore the factors associated with B.1.1.7 VOC infection in the context of vaccination. On March 2021, we detected SARS-CoV-2 RNA in nasopharyngeal samples from 14 of 22 individuals vaccinated with a single-dose of ChAdOx1 (outbreak A, n = 26), and 22 of 42 of individuals with two doses of the CoronaVac vaccine (outbreak B, n = 52) for breakthrough infection rates for ChAdOx1 of 63.6% and 52.4% for CoronaVac. The outbreaks were caused by two independent clusters of the B.1.1.7 VOC. The serum of PCR-positive symptomatic SARS-CoV-2-infected individuals had ~1.8-3.4-fold more neutralizing capacity against B.1.1.7 compared to the serum of asymptomatic individuals. These data based on exploratory analysis suggest that the B.1.1.7 variant can infect individuals partially immunized with a single dose of an adenovirus-vectored vaccine or fully immunized with two doses of an inactivated vaccine, although the vaccines were able to reduce the risk of severe disease and death caused by this VOC, even in the elderly.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19/inmunología , COVID-19/virología , SARS-CoV-2/clasificación , SARS-CoV-2/genética , Vacunación , Adenoviridae , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/inmunología , Brasil/epidemiología , COVID-19/prevención & control , Prueba Serológica para COVID-19 , Estudios de Cohortes , Brotes de Enfermedades/estadística & datos numéricos , Femenino , Vectores Genéticos , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , ARN Viral , Vacunas de Productos Inactivados , Secuenciación Completa del Genoma , Adulto Joven
8.
Front Cell Neurosci ; 15: 705618, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34381335

RESUMEN

BACKGROUND: Neurofilament Light (NfL) chain levels in both cerebrospinal fluid (CSF) and serum have been correlated with the reduction of axonal damage in multiple sclerosis (MS) patients treated with Natalizumab (NTZ). However, little is known about the function of plasmacytoid cells in NTZ-treated MS patients. OBJECTIVE: To evaluate CSF NfL, serum levels of soluble-HLA-G (sHLA-G), and eventual tolerogenic behavior of plasmacytoid dendritic cells (pDCs) in MS patients during NTZ treatment. METHODS: CSF NfL and serum sHLA-G levels were measured using an ELISA assay, while pDCs (BDCA-2+) were accessed through flow cytometry analyses. RESULTS: CSF levels of NfL were significantly reduced during NTZ treatment, while the serum levels of sHLA-G were increased. Moreover, NTZ treatment enhanced tolerogenic (HLA-G+, CD274+, and HLA-DR+) molecules and migratory (CCR7+) functions of pDCs in the peripheral blood. CONCLUSION: These findings suggest that NTZ stimulates the production of molecules with immunoregulatory function such as HLA-G and CD274 programmed death-ligand 1 (PD-L1) which may contribute to the reduction of axonal damage represented by the decrease of NfL levels in patients with MS.

9.
Emerg Infect Dis ; 27(6): 1737-1740, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33871331

RESUMEN

We documented 4 cases of severe acute respiratory syndrome coronavirus 2 reinfection by non-variant of concern strains among healthcare workers in Campinas, Brazil. We isolated infectious particles from nasopharyngeal secretions during both infection episodes. Improved and continued protection measures are necessary to mitigate the risk for reinfection among healthcare workers.


Asunto(s)
COVID-19/diagnóstico , Personal de Salud , Reinfección/diagnóstico , Reinfección/virología , SARS-CoV-2/aislamiento & purificación , Esparcimiento de Virus , Adulto , Brasil/epidemiología , COVID-19/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Reinfección/terapia
10.
Viruses ; 13(2)2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669276

RESUMEN

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.


Asunto(s)
Bradiquinina/análogos & derivados , Tratamiento Farmacológico de COVID-19 , Proteína Inhibidora del Complemento C1/uso terapéutico , Sistema Calicreína-Quinina/efectos de los fármacos , Calicreínas/antagonistas & inhibidores , Adulto , Anciano , Bradiquinina/uso terapéutico , Estudios de Casos y Controles , Reposicionamiento de Medicamentos , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Persona de Mediana Edad
11.
Front Immunol ; 12: 806400, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35069589

RESUMEN

Recently, it has been argued that obesity leads to a chronic pro-inflammatory state that can accelerate immunosenescence, predisposing to the early acquisition of an immune risk profile and health problems related to immunity in adulthood. In this sense, the present study aimed to verify, in circulating leukocytes, the gene expression of markers related to early immunosenescence associated with obesity and its possible relationships with the physical fitness in obese adults with type 2 diabetes or without associated comorbidities. The sample consisted of middle-aged obese individuals (body mass index (BMI) between 30-35 kg/m²) with type 2 diabetes mellitus (OBD; n = 17) or without associated comorbidity (OB; n = 18), and a control group of eutrophic healthy individuals (BMI: 20 - 25 kg/m²) of same ages (E; n = 18). All groups (OBD, OB and E) performed the functional analyses [muscle strength (1RM) and cardiorespiratory fitness (VO2max)], anthropometry, body composition (Air Displacement Plethysmograph), blood collections for biochemical (anti-CMV) and molecular (gene expression of leptin, IL-2, IL-4, IL-6, IL-10, TNF-α, PD-1, P16ink4a, CCR7, CD28 and CD27) analyses of markers related to immunosenescence. Increased gene expression of leptin, IL-2, IL-4, IL-10, TNF-α, PD-1, P16ink4a, CCR7 and CD27 was found for the OBD and OB groups compared to the E group. Moreover, VO2max for the OBD and OB groups was significantly lower compared to E. In conclusion, obesity, regardless of associated disease, induces increased gene expression of markers associated with inflammation and immunosenescence in circulating leukocytes in obese middle-aged individuals compared to a eutrophic group of the same age. Additionally, increased adipose tissue and markers of chronic inflammation and immunosenescence were associated to impairments in the cardiorespiratory capacity of obese middle-aged individuals.


Asunto(s)
Biomarcadores , Expresión Génica , Inmunosenescencia/genética , Obesidad/genética , Obesidad/inmunología , Tejido Adiposo/metabolismo , Adulto , Factores de Edad , Envejecimiento , Composición Corporal , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo
12.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32697943

RESUMEN

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Asunto(s)
Betacoronavirus/fisiología , Glucemia/metabolismo , Infecciones por Coronavirus/complicaciones , Complicaciones de la Diabetes/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Monocitos/metabolismo , Neumonía Viral/complicaciones , Adulto , COVID-19 , Línea Celular , Infecciones por Coronavirus/metabolismo , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Femenino , Glucólisis , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/virología , Pandemias , Neumonía Viral/metabolismo , Especies Reactivas de Oxígeno/metabolismo , SARS-CoV-2 , Transducción de Señal
13.
Pediatr Diabetes ; 21(4): 606-614, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32078220

RESUMEN

OBJECTIVE: Characterization of partial remission using the insulin dose-adjusted HbA1c (IDAA1c) ≤ 9 definition in a multiethnic Brazilian population of children and adolescents with type 1 diabetes (T1D), in addition with the determination of both Class II HLA genotype and autoantibodies. METHODS: We analyzed the prevalence of partial remission in 51 new-onset T1D patients with a median time follow-up of 13 months from diagnosis. For this study, anti-GAD65, anti-IA2 and HLA class II genotyping were considered. RESULTS: Partial remission occurred in 41.2% of T1D patients until 3 months after diagnosis, mainly in those aged 5-15 years. We have demonstrated a significant increase in the haplotypes of class II HLA DRB1*0301-DQB1*0201 in children and adolescents with a partial remission phase of the disease (42.9% vs 21.7% in non-remitters, P = .0291). This haplotype was also associated with the reduction of anti-IA2 antibodies production. Homozygote DRB1*03-DQB1*0201/DRB1*03-DQB1*0201 children had the lowest prevalence of IA-2A antibodies (P = .0402). However, this association does not correlate with the time of the remission phase. CONCLUSION: Although the number of patients studied was reduced, our data suggested that the association between genetics and decrease in antibody production to certain islet auto-antigen may contribute, at least in part, to the remission phase of T1D.


Asunto(s)
Autoanticuerpos/biosíntesis , Diabetes Mellitus Tipo 1 , Antígenos de Histocompatibilidad Clase II/genética , Adolescente , Adulto , Autoanticuerpos/genética , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Lactante , Masculino , Remisión Espontánea , Adulto Joven
14.
Brain Behav Immun Health ; 9: 100162, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34589900

RESUMEN

Depression/anxiety (D/A) occurs in up to 50% of multiple sclerosis (MS) patients. Proinflammatory cytokines induce classical symptoms of depression. Activation of the inflammatory response also triggers production of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, the amino acid precursor of serotonin and melatonin. It has been suggested that IDO is the link between the immune and serotonergic systems. This study aimed to quantify the levels of IDO and pro-inflammatory and anti-inflammatory cytokines in patients with MS and depression, according to treatment with interferon-beta (IFN-ß) or fingolimod. The study inclusion criteria were age 18-60 years and a clinical and radiological diagnosis of MS. One hundred and thirty-two patients diagnosed by McDonald's criteria and followed up at Brasília District Hospital, Brazil, with relapsing-remitting MS were identified as potential study participants. Thirty-five of these patients were identified to be receiving treatment with fingolimod or IFN-ß and to have a diagnosis of D/A. IDO and pro-inflammatory and anti-inflammatory cytokine levels were compared between these 35 patients and 18 healthy controls. The level of IL-10 (an anti-inflammatory cytokine) was lower in both the fingolimod-treated (P â€‹< â€‹0.001) and IFN-ß-treated (P â€‹< â€‹0.01) patient groups than in the control group. IFN-ß-treated patients showed increased IDO expression and decreased inflammatory cytokine levels. In contrast, fingolimod-treated patients showed significantly decreased expression of IDO and significantly increased levels of proinflammatory cytokines produced by innate immune cells, including tumor necrosis factor-alpha and interleukin-6. The agents used to treat MS maintain symptoms of D/A in patients with MS via different mechanisms.

15.
Pharmacogenomics J ; 19(1): 72-82, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30131588

RESUMEN

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease that affects approximately 2.5 million people globally. Even though the etiology of MS remains unknown, it is accepted that it involves a combination of genetic alterations and environmental factors. Here, after performing whole exome sequencing, we found a MS patient harboring a rare and homozygous single nucleotide variant (SNV; rs61745847) of the G-protein coupled receptor (GPCR) galanin-receptor 2 (GALR2) that alters an important amino acid in the TM6 molecular toggle switch region (W249L). Nuclear magnetic resonance imaging showed that the hypothalamus (an area rich in GALR2) of this patient exhibited an important volumetric reduction leading to an enlarged third ventricle. Ex vivo experiments with patient-derived blood cells (AKT phosphorylation), as well as studies in recombinant cell lines expressing the human GALR2 (calcium mobilization and NFAT mediated gene transcription), showed that galanin (GAL) was unable to stimulate cell signaling in cells expressing the variant GALR2 allele. Live cell confocal microscopy showed that the GALR2 mutant receptor was primarily localized to intracellular endosomes. We conclude that the W249L SNV is likely to abrogate GAL-mediated signaling through GALR2 due to the spontaneous internalization of this receptor in this patient. Although this homozygous SNV was rare in our MS cohort (1:262 cases), our findings raise the potential importance of impaired neuroregenerative pathways in the pathogenesis of MS, warrant future studies into the relevance of the GAL/GALR2 axis in MS and further suggest the activation of GALR2 as a potential therapeutic route for this disease.


Asunto(s)
Galanina/genética , Esclerosis Múltiple/genética , Receptor de Galanina Tipo 2/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Línea Celular , Femenino , Células HEK293 , Humanos , Fosforilación/genética , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/genética , Adulto Joven
16.
FASEB J ; 32(8): 4470-4481, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29558201

RESUMEN

Cerebral malaria (CM) is a multifactorial syndrome involving an exacerbated proinflammatory status, endothelial cell activation, coagulopathy, hypoxia, and accumulation of leukocytes and parasites in the brain microvasculature. Despite significant improvements in malaria control, 15% of mortality is still observed in CM cases, and 25% of survivors develop neurologic sequelae for life-even after appropriate antimalarial therapy. A treatment that ameliorates CM clinical signs, resulting in complete healing, is urgently needed. Previously, we showed a hyperbaric oxygen (HBO)-protective effect against experimental CM. Here, we provide molecular evidence that HBO targets brain endothelial cells by decreasing their activation and inhibits parasite and leukocyte accumulation, thus improving cerebral microcirculatory blood flow. HBO treatment increased the expression of aryl hydrocarbon receptor over hypoxia-inducible factor 1-α (HIF-1α), an oxygen-sensitive cytosolic receptor, along with decreased indoleamine 2,3-dioxygenase 1 expression and kynurenine levels. Moreover, ablation of HIF-1α expression in endothelial cells in mice conferred protection against CM and improved survival. We propose that HBO should be pursued as an adjunctive therapy in CM patients to prolong survival and diminish deleterious proinflammatory reaction. Furthermore, our data support the use of HBO in therapeutic strategies to improve outcomes of non-CM disorders affecting the brain.-Bastos, M. F., Kayano, A. C. A. V., Silva-Filho, J. L., Dos-Santos, J. C. K., Judice, C., Blanco, Y. C., Shryock, N., Sercundes, M. K., Ortolan, L. S., Francelin, C., Leite, J. A., Oliveira, R., Elias, R. M., Câmara, N. O. S., Lopes, S. C. P., Albrecht, L., Farias, A. S., Vicente, C. P., Werneck, C. C., Giorgio, S., Verinaud, L., Epiphanio, S., Marinho, C. R. F., Lalwani, P., Amino, R., Aliberti, J., Costa, F. T. M. Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria.


Asunto(s)
Encéfalo/metabolismo , Hipoxia/metabolismo , Quinurenina/metabolismo , Malaria Cerebral/metabolismo , Oxígeno/metabolismo , Animales , Circulación Cerebrovascular/fisiología , Células Endoteliales/metabolismo , Femenino , Oxigenoterapia Hiperbárica/métodos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Microcirculación/fisiología
17.
Future Oncol ; 12(20): 2367-78, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27328776

RESUMEN

AIM: This study aimed to evaluate an attenuated Salmonella ihfA-null mutant strain as therapeutic agent to control tumor growth. MATERIALS & METHODS: After bacterial toxicity evaluation, C57BL/6JUnib mice were inoculated with B16F10 cells and treated with two Salmonella strains (LGBM 1.1 and LGBM 1.41). RESULTS: LGBM 1.1 can reduce tumor mass, but it exerts some toxic effects. Although LGBM 1.41 is less toxic than LGBM 1.1, it does not reduce tumor mass significantly. Indeed, animals treated with LGBM 1.41 present only slightly initial delay in tumor progression and increased survival rate as compared with the control. CONCLUSION: The null-mutants of ihfA gene of Salmonella Typhimurium could be a promising candidate for melanoma treatment.


Asunto(s)
Factores de Integración del Huésped/genética , Melanoma/microbiología , Melanoma/patología , Proteínas Mutantes , Infecciones por Salmonella/microbiología , Salmonella typhimurium/genética , Animales , Carga Bacteriana , Modelos Animales de Enfermedad , Femenino , Humanos , Melanoma/mortalidad , Melanoma/terapia , Melanoma Experimental , Ratones , Eliminación de Secuencia , Carga Tumoral
18.
Sci Rep ; 5: 16167, 2015 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-26548646

RESUMEN

The present study investigates the effects of xenotransplantation of Adipose Tissue Mesenchymal Stem Cells (AT-MSCs) in animals after ventral root avulsion. AT-MSC has similar characteristics to bone marrow mesenchymal stem cells (BM-MSCs), such as immunomodulatory properties and expression of neurotrophic factors. In this study, Lewis rats were submitted to surgery for unilateral avulsion of the lumbar ventral roots and received 5 × 10(5) AT-MSCs via the lateral funiculus. Two weeks after cell administration, the animals were sacrificed and the moto neurons, T lymphocytes and cell defense nervous system were analyzed. An increased neuronal survival and partial preservation of synaptophysin-positive nerve terminals, related to GDNF and BDNF expression of AT-MSCs, and reduction of pro-inflammatory reaction were observed. In conclusion, AT-MSCs prevent second phase neuronal injury, since they suppressed lymphocyte, astroglia and microglia effects, which finally contributed to rat motor-neuron survival and synaptic stability of the lesioned motor-neuron. Moreover, the survival of the injected AT- MSCs lasted for at least 14 days. These results indicate that neuronal survival after lesion, followed by mesenchymal stem cell (MSC) administration, might occur through cytokine release and immunomodulation, thus suggesting that AT-MSCs are promising cells for the therapy of neuronal lesions.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Neuronas Motoras/patología , Radiculopatía/terapia , Médula Espinal/trasplante , Tejido Adiposo/citología , Tejido Adiposo/trasplante , Animales , Xenoinjertos , Humanos , Inmunomodulación , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Regeneración Nerviosa , Neuroprotección , Radiculopatía/inmunología , Radiculopatía/metabolismo , Radiculopatía/patología , Ratas , Médula Espinal/fisiopatología , Raíces Nerviosas Espinales/fisiopatología , Sinapsis/inmunología , Sinapsis/metabolismo , Sinapsis/patología , Sinaptofisina/metabolismo , Linfocitos T/inmunología
19.
Proteomics ; 15(19): 3281-2, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26314682

RESUMEN

Multiple sclerosis is an idiopathic demyelinating disease of the CNS. Despite being extensively studied during the last decades, many molecular aspects of the disease are still to be elucidated. Moreover, biomarkers for treatment and early diagnosis are major issues to be tackled. In this edition of Kroksveen et al. (Proteomics 2015, 15, 3361-3369) present biomarker candidates for the early detection of multiple sclerosis. Despite the need for validation in larger sets of samples, this dataset contributes to resolve open questions associated to multiple sclerosis.


Asunto(s)
Cromogranina B/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Femenino , Humanos , Masculino
20.
Infect Immun ; 83(10): 3781-92, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26169268

RESUMEN

Malaria remains a world-threatening disease largely because of the lack of a long-lasting and fully effective vaccine. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of the Duffy binding-like erythrocyte binding protein and apical membrane antigen 1 (AMA1) antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, ectodomains M1 and M2, homologous to AMA1, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. Here, the Plasmodium yoelii MAEBL-M2 domain was expressed in a prokaryotic vector. C57BL/6J mice were immunized with doses of P. yoelii recombinant protein rPyM2-MAEBL. High levels of antibodies, with balanced IgG1 and IgG2c subclasses, were achieved. rPyM2-MAEBL antisera were capable of recognizing the native antigen. Anti-MAEBL antibodies recognized different MAEBL fragments expressed in CHO cells, showing stronger IgM and IgG responses to the M2 domain and repeat region, respectively. After a challenge with P. yoelii YM (lethal strain)-infected erythrocytes (IE), up to 90% of the immunized animals survived and a reduction of parasitemia was observed. Moreover, splenocytes harvested from immunized animals proliferated in a dose-dependent manner in the presence of rPyM2-MAEBL. Protection was highly dependent on CD4(+), but not CD8(+), T cells toward Th1. rPyM2-MAEBL antisera were also able to significantly inhibit parasite development, as observed in ex vivo P. yoelii erythrocyte invasion assays. Collectively, these findings support the use of MAEBL as a vaccine candidate and open perspectives to understand the mechanisms involved in protection.


Asunto(s)
Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Plasmodium yoelii/inmunología , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Animales , Anticuerpos Antiprotozoarios/inmunología , Eritrocitos/parasitología , Femenino , Humanos , Inmunización , Malaria/inmunología , Malaria/mortalidad , Malaria/parasitología , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/química , Vacunas contra la Malaria/genética , Masculino , Merozoítos/química , Merozoítos/crecimiento & desarrollo , Merozoítos/inmunología , Ratones , Ratones Endogámicos C57BL , Plasmodium yoelii/química , Plasmodium yoelii/genética , Plasmodium yoelii/crecimiento & desarrollo , Estructura Terciaria de Proteína , Proteínas Protozoarias/administración & dosificación , Proteínas Protozoarias/genética , Esporozoítos/química , Esporozoítos/crecimiento & desarrollo , Esporozoítos/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA