RESUMEN
Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.
Asunto(s)
Sistema Nervioso , Neurogénesis , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Animales , Sistema Nervioso/metabolismo , Sistema Nervioso/inmunología , Inmunidad Innata , Neuronas/metabolismo , Neuronas/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Transducción de SeñalRESUMEN
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder in children and adolescents. Although increases in oxidative stress and disturbances of neurotransmitter system such as the dopaminergic and abnormalities in several brain regions have been demonstrated, the pathophysiology of ADHD is not fully understood. Nevertheless, ADHD involves several factors that have been associated with an increase in neuroinflammation. This chapter presents an overview of factors that may increase neuroinflammation and play a potential role in the development and pathophysiology of ADHD. The altered immune response, polymorphisms in inflammatory-related genes, ADHD comorbidity with autoimmune and inflammatory disorders and prenatal exposure to inflammation are associated with alterations in offspring brain development and are a risk factor; genetic and environmental risk factors that may increase the risk for ADHD and medications can increase neuroinflammation. Evidence of an association between these factors has been an invaluable tool for research on inflammation in ADHD. Therefore, evidence studies have made it possible to generate alternative therapeutic interventions using natural products as anti-inflammatories that could have great potential against neuroinflammation in ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Adolescente , Niño , Femenino , Humanos , Embarazo , Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo , Inflamación , Enfermedades Neuroinflamatorias , Factores de RiesgoRESUMEN
Acute lymphocytic leukemia is the most common type of cancer in pediatric individuals. Glucose regulated protein (GRP78) is an endoplasmic reticulum chaperone that facilitates the folding and assembly of proteins and regulates the unfolded protein response pathway. GRP78 has a role in survival of cancer and metastasis and cell-surface associated GRP78 (sGRP78) is expressed on cancer cells but not in normal cells. Here, we explored the presence of sGRP78 in pediatric B-ALL at diagnosis and investigated the correlation with bona fide markers of leukemia. By using a combination of flow cytometry and high multidimensional analysis, we found a distinctive cluster containing high levels of sGRP78, CD10, CD19, and CXCR4 in bone marrow samples obtained from High-risk leukemia patients, which was absent in the compartment of Standard-risk leukemia. We confirmed that sGRP78+CXCR4+ blood-derived cells were more frequent in High-risk leukemia patients. Finally, we analyzed the dissemination capacity of sGRP78 leukemia cells in a model of xenotransplantation. sGRP78+ cells emigrated to the bone marrow and lymph nodes, maintaining the expression of CXCR4. Testing the presence of sGRP78 and CXCR4 together with conventional markers may help to achieve a better categorization of High and Standard-risk pediatric leukemia at diagnosis.
Asunto(s)
Chaperón BiP del Retículo Endoplásmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores CXCR4/metabolismo , Adolescente , Animales , Antígenos CD/metabolismo , Línea Celular , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Factores de RiesgoRESUMEN
Medulloblastoma (MB) is the most common and aggressive pediatric intracranial tumor. Estrogen receptor ß (ERß) expression correlates with MB development and its phosphorylation modifies its transcriptional activity in a ligand-dependent or independent manner. Using in silico tools, we have identified several residues in ERß protein as potential targets of protein kinases C (PKCs) α and δ. Using Daoy cells, we observed that PKCα and PKCδ associate with ERß and induce its phosphorylation. The activation of ERß promotes MB cells proliferation and invasion, and PKCs downregulation dysregulates these steroid receptor mediated processes. Our data suggest that these kinases may play a crucial role in the regulation of the ERß transcriptional activity. Overexpression of both PKCα and PKCδ in MB biopsies samples supports their relevance in MB progression.
Asunto(s)
Neoplasias Cerebelosas , Receptor beta de Estrógeno , Meduloblastoma , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C , Línea Celular Tumoral , Proliferación Celular , Niño , Receptor alfa de Estrógeno , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismoRESUMEN
PURPOSE: Medulloblastoma is an embryonal brain tumor that predominantly occurs in childhood with a wide histological and molecular variability. Our aim was to investigate the expression of Toll-like receptors (TLRs), their association with the infiltration of immune cells and with the histological subgroups, and, also, with the overall survival of patients. METHODS: Fifty-six paraffin-preserved biopsies from children with medulloblastoma of the classic, desmoplastic, and anaplastic subtypes were included. Microarrays of tissues were performed, and the infiltration of T and NK cells was quantified, as well as the expression of TLR7, TLR8, and TLR9. For all statistical analyses, significance was p < 0.05. RESULTS: CD4 + and CD8 + T lymphocytes and NK cells were found infiltrating the tumor. The infiltration of NK and CD4 + cells was greater in the classic and desmoplastic subtypes than in anaplastic. We found an important expression of TLRs in all medulloblastomas, but TLR7 and TLR8 were considerably higher in classic and desmoplastic subtypes than in anaplastic. Importantly, we observed that TLR7 was a prognostic factor for survival. CONCLUSIONS: Medulloblastomas present cellular infiltration and a differential expression of TLRs depending on the histological subtype. TLR7 is a prognostic factor of survival that is dependent on treatment and age.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Receptor Toll-Like 7/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Cerebelosas/diagnóstico , Niño , Humanos , Meduloblastoma/diagnóstico , Tasa de Supervivencia , Receptor Toll-Like 8RESUMEN
Bulk atmospheric deposition samples, including wet and dry deposition, were collected during 2004-2006 in four high mountain European lakes: Skalnate Pleso (Tatra mountains, Slovakia), Gossenköllesee (Alps, Austria), Redon (Pyrenees, Spain), and Lochnagar (Grampian Mountains, Scotland). Samples were analysed for polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), endosulfans, and polybromodiphenyl ethers (PBDEs). The deposition of PCBs, HCHs, and low brominated BDEs reflected baseline contributions from long range atmospheric transport. This was also the case for PAHs in Redon and Gossenköllesee, endosulfans in Lochnagar and Gossenköllesee and HCB in these three lakes. However, Skalnate received PAHs, endosulfans, and HCB from regional sources as it was the case for endosulfans in Redon. The distinct origin of these pollutants was reflected in the relative composition of some metabolites such as the proportion of endosulfan sulfate vs α- and ß-endosulfans or the relative composition of BDE47 and BDE99. Wet deposition was the main process for atmospheric removal of PAHs, HCHs, and HCB. In addition, warm season revolatilization from soils and melting snow with subsequent condensation at low temperature were significant for volatile PAHs, HCB, low chlorinated PCBs, and endosulfans. Reaction with OH radicals was not a significant loss process of HCHs and HCB in remote areas, dominated by wet deposition, whereas PCBs and PAHs were significantly removed by both wet deposition and OH radical oxidation, the latter dominating in the highest altitude sites. Photolysis was the main atmospheric removal process of PBDEs, dominating over atmospheric deposition and OH depletion in all sites.
RESUMEN
Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent several pediatric neurological diseases. The present review provides an overview of the most recent research outcomes following quercetin treatment for CNS tumors, ASD and ADHD as well as describes the potential in vitro and in vivo ameliorative effect on oxidative stress of bioactive natural compounds, which seems like a promising future therapy for these diseases. The neuroprotective effects of quercetin against oxidative stress can also be applied in the management of several neurodegenerative disorders with effects such as anti-cancer, anti-inflammatory, anti-viral, anti-obesity and anti-microbial. Therefore, quercetin appears to be a suitable adjuvant for therapy against pediatric neurological diseases.
Asunto(s)
Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Quercetina/uso terapéutico , Niño , HumanosRESUMEN
Psychostimulants and non-psychostimulants are the medications prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, several adverse results have been linked with an increased risk of substance use and side effects. The pathophysiology of ADHD is not completely known, although it has been associated with an increase in inflammation and oxidative stress. This review presents an overview of findings following antioxidant treatment for ADHD and describes the potential amelioration of inflammation and oxidative stress using antioxidants that might have a future as multi-target adjuvant therapy in ADHD. The use of antioxidants against inflammation and oxidative conditions is an emerging field in the management of several neurodegenerative and neuropsychiatric disorders. Thus, antioxidants could be promising as an adjuvant ADHD therapy.
RESUMEN
Patients with advanced stage ovarian clear cell carcinoma (OCCC) have a poor prognosis due to resistance to conventional platinum chemotherapy. Recent studies have demonstrated that PI3K/AKT/mTOR and ERK1/2 signaling pathways are involved in this chemoresistance. Progranulin (PGRN) overexpression contributes to cisplatin resistance of epithelial ovarian cancer cell lines. Also, PGRN expression is regulated by AKT/mTOR and ERK1/2 signaling pathways in different cell types. Thus, the present study was designed to identify if PGRN expression is regulated by AKT, mTOR, and ERK1/2 signaling pathways in the OCCC cell line TOV-21G. Cultured TOV-21G cells were incubated with different concentrations of pharmacological cell signaling inhibitors. PGRN expression and phosphorylation of ERK1/2, AKT, and mTOR were assessed by Western blotting. Inhibition of AKT, mTOR, and ERK1/2 significantly reduced PGRN expression. Cell viability was not affected, while cell proliferation significantly decreased with all inhibitors used in this study. These observations demonstrated that inhibition of PI3K/AKT/mTOR and ERK1/2 signaling pathways reduces PGRN expression in TOV-21G cells. Thus, PGRN could be considered as a candidate for explaining the high resistance to platinum-based treatment and a potential biomarker for therapy response to cell signaling inhibitors in patients with OCCC.
Asunto(s)
Antineoplásicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Progranulinas , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Progranulinas/análisis , Progranulinas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties. METHODS: The present study was aimed to determine the anti-inflammatory potential of M. parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid ß (Aß) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC. RESULTS: MpHE efficiently reduced astrogliosis, the presence of insoluble Aß peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aß plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals. CONCLUSIONS: M. parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M. parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo/efectos de los fármacos , Disfunción Cognitiva/patología , Microglía/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/farmacología , Encéfalo/patología , Disfunción Cognitiva/etiología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Malva , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Microglía/metabolismo , PPAR gamma/metabolismo , Fagocitosis/efectos de los fármacos , Hojas de la PlantaRESUMEN
BACKGROUND AND OBJECTIVES: Substance use disorders (SUDs) have high comorbidities with psychiatric disorders. Childhood and adolescence are particularly vulnerable developmental periods for the onset of SUDs. The objective of this study was to explore the differences, if any, between Mexican adolescents and young adults with respect to the prevalences of groups of psychiatric disorders, the types of substances used and the social factors involved. METHODS: This cross-sectional study included 781 patients evaluated at the Youth Integration Center in Mexico City. The diagnostic criteria for SUDs and psychiatric disorders were defined according to the DSM-IV and ICD-10. Associations between SUDs and psychiatric disorders were evaluated via multivariate analysis using logistic regression models. RESULTS: The adolescents were more frequently substance abusers, whereas the adults had legal problems more often than the adolescents. We showed that adolescents using inhalants or cocaine were 1.62 more likely to have attention deficit hyperactivity disorder (ADHD). Moreover, adults using inhalants were 3.33 times more likely to meet the criteria for a psychotic disorder. DISCUSSION AND CONCLUSIONS: We found that adolescents diagnosed with ADHD were more likely to have problems with use or abuse of or dependence on inhalants, and an elevated prevalence of parental SUDs was found in both the adolescent and adult groups. SCIENTIFIC SIGNIFICANCE: Our findings indicate that earlier diagnosis and intervention are necessary in adolescents with ADHD and/or parental SUDs to prevent more advanced psychiatric diseases and adverse social consequences during adulthood. (Am J Addict 2018;XX:1-7).
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastornos Mentales/epidemiología , Problemas Sociales/prevención & control , Trastornos Relacionados con Sustancias , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Niño , Comorbilidad , Estudios Transversales , Diagnóstico Dual (Psiquiatría)/estadística & datos numéricos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , México/epidemiología , Padres/psicología , Prevalencia , Psicotrópicos/farmacología , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/prevención & control , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
ß-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by ß-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, ß-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the ß-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing ß-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced ß-Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that ß-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Autofagia/genética , Caspasa 1/metabolismo , Regulación de la Expresión Génica/genética , Inflamación/metabolismo , Trastornos de la Memoria , Neuronas/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/patología , Caspasa 1/genética , Modelos Animales de Enfermedad , Inflamación/etiología , Inflamación/patología , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neuronas/ultraestructura , Fragmentos de Péptidos/metabolismo , Presenilina-1/genética , Transducción de Señal/genéticaRESUMEN
TLRs and NLRs participate in the immune system recognition of Helicobacter pylori. However, little is known about the mechanisms leading to inflammasome activation by H. pylori and if NLRs in neutrophils are involved in the process. We studied how NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components are involved in IL-1ß maturation in human neutrophils in response to the infection and if they are dependent on T4SS (type IV secretion system) and TLRs. Human neutrophils were cultured and infected with the 26695 or the VirD4- H. pylori strains; the IL-1ß concentration was analyzed by ELISA, and we also evaluated the activation of TLRs 2 and 4. The infection of neutrophils with both strains of H. pylori induced production of IL-1ß and expression of the NLRP3 inflammasome components such as apoptosis-associated speck-like protein with CARD domain and NLRP3 protein. The infection also increased the activity of caspase-1, which is required for the maturation of IL-1ß. Our study shows, for the first time, that H. pylori infection induces the expression and activation of components of NLRP3 inflammasomes in human neutrophils and that the activation is independent of a functional T4SS and TLR2 and TLR4.
Asunto(s)
Proteínas Portadoras/metabolismo , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Inflamasomas/metabolismo , Neutrófilos/inmunología , Apoptosis , Caspasa 1/metabolismo , Células Cultivadas , Humanos , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Neutrófilos/microbiología , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
The hypothalamus regulates the homeostasis of the organism by controlling hormone secretion from the pituitary. The molecular mechanisms that regulate the differentiation of the hypothalamic thyrotropin-releasing hormone (TRH) phenotype are poorly understood. We have previously shown that Klf10 or TGFß inducible early gene-1 (TIEG1) is enriched in fetal hypothalamic TRH neurons. Here, we show that expression of TGFß isoforms (1-3) and both TGFß receptors (TßRI and II) occurs in the hypothalamus concomitantly with the establishment of TRH neurons during late embryonic development. TGFß2 induces Trh expression via a TIEG1 dependent mechanism. TIEG1 regulates Trh expression through an evolutionary conserved GC rich sequence on the Trh promoter. Finally, in mice deficient in TIEG1, Trh expression is lower than in wild type animals at embryonic day 17. These results indicate that TGFß signaling, through the upregulation of TIEG1, plays an important role in the establishment of Trh expression in the embryonic hypothalamus.
Asunto(s)
Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Hipotálamo/metabolismo , Neuronas/metabolismo , Hormona Liberadora de Tirotropina/metabolismo , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta2/metabolismo , Animales , Proteínas de Unión al ADN/deficiencia , Embrión de Mamíferos , Feto , Hipotálamo/citología , Hipotálamo/crecimiento & desarrollo , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología , Cultivo Primario de Células , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Wistar , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Hormona Liberadora de Tirotropina/genética , Factores de Transcripción/deficiencia , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta2/genética , Factor de Crecimiento Transformador beta3/genética , Factor de Crecimiento Transformador beta3/metabolismoRESUMEN
The purpose of this paper is to review current information about the role of inflammation caused by Helicobacter pylori (H. pylori) infection in neurological diseases such as Parkinson's disease, Alzheimer's disease, Guillain-Barré syndrome, multiple sclerosis, and other inflammatory diseases including ischemic stroke. Infection with H. pylori usually persists throughout life, resulting in a chronic inflammatory response with local secretion of numerous inflammatory mediators including chemokines [interleukin (IL)-8, macrophage chemotactic protein (MCP)-1, growth-regulated oncogene (GRO)-α] and cytokines [IL-1ß, tumor necrosis factor (TNF)-α, IL-6, IL-12, interferon (IFN)-γ], which can pass into the circulation and have a systemic effect. The persistence of detectable systemic and local concentrations of inflammatory mediators is likely to alter the outcome of neurological diseases. These proinflammatory factors can induce brain inflammation and the death of neurons and could eventually be associated to Parkinson's disease and also may be involved in the development of Alzheimer's disease. However, most neurological diseases are the result of a combination of multiple factors, but the systemic inflammatory response is a common component and determinant in the onset, evolution, and outcome of diseases. However, more studies are needed to allow understanding of the effects and mechanisms by which the inflammatory response generated by H. pylori infection affects neurological diseases.
RESUMEN
Helicobacter pylori infection represents one of the most common bacterial infections worldwide. The inflammatory response to this bacterium involves a large influx of neutrophils to the lamina propria of the gastric mucosa. However, little is known about the receptors and molecular mechanisms involved in activation of these neutrophils. In this study, we aimed to determine the role of toll-like receptor 9 (TLR9) in the response of human neutrophils to H. pylori and purified H. pylori DNA (Hp-DNA). Neutrophils were isolated from the blood of adult volunteers and challenged with either H. pylori or Hp-DNA. We found that both, H. pylori and Hp-DNA induced increased expression and release of IL-8. Furthermore, we showed that TLR9 is involved in the induction of IL-8 production by H. pylori and Hp-DNA. IL-8 production induced by H. pylori but not by Hp-DNA was partially mediated by NF-κB. In conclusion, this study showed for first time that both, H. pylori and Hp-DNA activate TLR9 and induce a different inflammatory response that leads to activation of neutrophils.
Asunto(s)
ADN Bacteriano/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , FN-kappa B/inmunología , Neutrófilos/microbiología , Receptor Toll-Like 9/inmunología , Adulto , Células Cultivadas , Humanos , Neutrófilos/inmunologíaRESUMEN
The snow capacity for storage of a large number of pollutants such as polybromodiphenyl ethers (PBDE), including BDE-209, polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), hexachlorocyclohexanes (HCHs; α- and γ-isomers), endosulfans (α- and ß-isomers and the sulphate residue) and hexachlorobenzene (HCB), in a steep altitudinal gradient (1,101-2,500 m above sea level (asl); maximum planar distance 16 km) in a typical European mountain system, the Tyrolean Alps (Austria), was studied here for the first time. Snow samples representing the whole snowpack accumulated at the end of the cold season were collected in all cases. The snow specific surface area (SSA) of these samples, 140-260 cm(2) g(-1), was characteristic of aged snow with low retention capacity. PAHs were the pollutant group in highest concentrations (500-8,400 pg L(-1)). PCBs and PBDEs were found in concentrations of 460-900 and 8.5-290 pg L(-1), respectively. From the fourteen investigated BDE congeners, only BDE-47, BDE-99, BDE-100 and BDE-209 were found above the detection limit, which is consistent with the results found in the only previous study in the Tatra Mountains (Slovakia) which also involved a steep gradient (1,683-2,634 m asl; maximum planar distance 5 km; Arellano et al. 2011) and confirm the capacity of these low-volatile compounds for long-range transport from distant sources. HCB was found in a concentration range of 34-55 pg L(-1). Snow deposition fluxes of PCB-118, PCB-153, γ-HCH, α-endosulfan and BDE-47 showed statistically significant correlations with altitude, involving higher values at higher elevation. This trend may reflect cold trapping effects in view of the snow particle contents and SSA values. However, these gradients were only significant for this limited number of compounds within each pollutant group which may be explained by differences in physical-chemical properties of the compounds and the limited capacity of the aged snow for organic pollutant retention. In some other cases, for example benzo[a]pyrene, the observed vertical gradients may reflect higher preservations at lower temperatures.
Asunto(s)
Contaminantes Ambientales/análisis , Nieve/química , Altitud , Endosulfano/análisis , Monitoreo del Ambiente , Hexaclorociclohexano/análisis , Hidrocarburos Aromáticos/análisis , Estaciones del AñoRESUMEN
Helicobacter pylori contains a pathogenicity island, cagPAI, with genes homologous to components of the type IV secretion system (T4SS) of Agrobacterium tumefaciens. The T4SS components assemble a structure that transfers CagA protein and peptidoglycan into host epithelial cells, causing the increased release of interleukin 8 (IL8) from the cells. The Toll-like receptors on neutrophils recognize H. pylori, initiating signaling pathways that enhance the activation of NF-κB. However, the roles of cagPAI and T4SS in the inflammatory response of neutrophils are unknown. We evaluated the participation of cagPAI and T4SS in the response of human neutrophils to H. pylori infection. Neutrophils were isolated from the blood of healthy donors and infected with H. pylori cagPAI(+), cagPAI(-), and cagPAI mutant strains virB4 (-) and virD4 (-). Whereas cagPAI(+) strain 26695 induced the greatest IL8 production, a proinflammatory response, cagPAI(-) strain 8822 induced the greatest IL10 production, an anti-inflammatory response. In contrast, the virB4 (-) and virD4 (-) mutant strains produced significantly more of the two proinflammatory cytokines IL1ß and tumor necrosis factor αthan the cagPAI(+) strain 26695. We observed that H. pylori downregulated the expression of TLRs 2 and 5 but upregulated TLR9 expression in a cagPAI and T4SS-independent manner. These results show for the first time that the response of human neutrophils to H. pylori may vary from a pro-inflammatory to an anti-inflammatory response, depending on cagPAI and the integrity of T4SS.
Asunto(s)
Sistemas de Secreción Bacterianos/genética , Islas Genómicas/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Inflamación/inmunología , Inflamación/microbiología , Neutrófilos/inmunología , Citocinas/metabolismo , Regulación hacia Abajo , Genotipo , Humanos , Mutación/genética , Receptores Toll-Like/metabolismoRESUMEN
Persistent organic pollutants (POPs), including polychlorobiphenyls (PCB), endosulfans, hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), polybromodiphenyl ethers (PBDEs), and polycyclic aromatic hydrocarbons (PAHs), were analyzed in snowpack samples collected along an altitudinal gradient (1683-2634 meters above sea level) in the High Tatra Mountains (Slovakia). All analyzed compounds were found at all altitudes, pointing to their global distribution. The presence of PBDEs, particularly BDE 209, in the snowpack samples is especially relevant, as it reflects the air transport capacity of this low volatile, very hydrophobic pollutant to remote mountain regions. The most abundant compounds at all altitudes were PAHs, with mean values ranging from 90 to 300 ngL(-1), 1 order of magnitude higher than concentrations of other compounds. PCBs (sum of PCB 28, 52, 101, 118, 153, 138, and 180) and BDE 209 were the dominant organohalogen pollutants, with concentrations from 550 to 1600 pg L(-1) and from 670 to 2000 pgL(-1), respectively. Low brominated PBDEs, endosulfans, HCHs and HCB were consistently found in all samples at lower concentrations. The concentrations of these compounds correlated positively with altitude (i.e., negatively with temperature), which is consistent with cold-trapping effects. The regression coefficients were positive and statistically significant (p < 0.05) for all compounds except BDE 209, endosulfan sulfate, HCB and α-HCH. Contrariwise, the concentrations of BDE 209 and endosulfan sulfate exhibited a statistically significant positive correlation with total particle amount, which agrees with long-range atmospheric transport associated to aerosols according to the physical-chemical properties of these compounds. Snow specific surface area, which determines the maximum amount of each organic compound that can be sorbed by snow, proved utile for describing the distribution of the more volatile compounds, namely α-HCB and HCB, in the snowpack.
Asunto(s)
Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente , Nieve/química , Altitud , Hexaclorociclohexano/análisis , Bifenilos Policlorados/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , EslovaquiaRESUMEN
A sensitive and selective method for the determination of the whole congener distribution of polybromodiphenyl ethers in environmental and biological samples in one single instrumental run is described. The method is based on gas chromatography coupled to low-resolution mass spectrometry in negative ion chemical ionization mode. It allows determination of these compounds at concentration levels lower than 10(-14)g. A programmed temperature vaporization injector has been used to ensure maximum compound transfer to the chromatographic column while maintaining low thermal degradation levels of the more brominated congeners. Selectivity was increased by modification of the MS source parameters for optimization of the abundance of the high mass fragment ions. Under optimized condition, good repeatability (1.7-9.1%) and reproducibility (4.1-20%), and low detection limits, ranging between 1.5 and 15 pg ml(-1), were obtained. These features afforded reliable quantification of these compounds in snow and human samples at the concentrations in which these compounds are found.