RESUMEN
Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), the first soluble chemokine-binding protein to be identified in mammals, inhibits chemotaxis and transendothelial migration of neutrophils and attenuates the inflammatory response of dendritic cells, macrophages, monocytes, and T cells. This immunoregulatory protein is a pivotal mediator of the therapeutic efficacy of mesenchymal stem/stromal cells (MSC) in diverse pathological conditions, including neuroinflammation. However, TSG-6 is also constitutively expressed in some tissues, such as the brain and spinal cord, and is generally upregulated in response to inflammation in monocytes/macrophages, dendritic cells, astrocytes, vascular smooth muscle cells and fibroblasts. Due to its ability to modulate sterile inflammation, TSG-6 exerts protective effects in diverse degenerative and inflammatory diseases, including brain disorders. Emerging evidence provides insights into the potential use of TSG-6 as a peripheral diagnostic and/or prognostic biomarker, especially in the context of ischemic stroke, whereby the pathobiological relevance of this protein has also been demonstrated in patients. Thus, in this review, we will discuss the most recent data on the involvement of TSG-6 in neurodegenerative diseases, particularly focusing on relevant anti-inflammatory and immunomodulatory functions. Furthermore, we will examine evidence suggesting novel therapeutic opportunities that can be afforded by modulating TSG-6-related pathways in neuropathological contexts and, most notably, in stroke.
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Células Madre Mesenquimatosas , Enfermedades Neurodegenerativas , Animales , Humanos , Moléculas de Adhesión Celular/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células Madre Mesenquimatosas/metabolismo , Inflamación/metabolismo , Mamíferos/metabolismoRESUMEN
Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5'-terminal noncoding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, re-endothelialization in the femoral artery injury, and angiogenesis in hind limb ischemia. A Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, re-endothelialization of the injured femoral artery, and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling.
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Histona Desacetilasas/metabolismo , Neovascularización Fisiológica/genética , Animales , Proliferación Celular , Humanos , Masculino , Ratones , Fosforilación , Transducción de SeñalRESUMEN
BACKGROUND: Filmy-ferns (Hymenophyllaceae) are poikilohydric, homoiochlorophyllous desiccation-tolerant (DT) epiphytes. They can colonize lower and upper canopy environments of humid forest. Filmy-ferns desiccate rapidly (hours), contrasting with DT angiosperms (days/weeks). It has been proposed that desiccation tolerance in filmy-ferns would be associated mainly with constitutive features rather than induced responses during dehydration. However, we hypothesize that the inter-specific differences in vertical distribution would be associated with different dynamics of gene expression within the dehydration or rehydration phases. A comparative transcriptomic analysis with an artificial neural network was done on Hymenophyllum caudiculatum (restricted to lower canopy) and Hymenophyllum dentatum (reach upper canopy) during a desiccation/rehydration cycle. RESULTS: Raw reads were assembled into 69,599 transcripts for H. dentatum and 34,726 transcripts for H. caudiculatum. Few transcripts showed significant changes in differential expression (DE). H. caudiculatum had ca. twice DE genes than H. dentatum and higher proportion of increased-and-decreased abundance of genes occurs during dehydration. In contrast, the abundance of genes in H. dentatum decreased significantly when transitioning from dehydration to rehydration. According to the artificial neural network results, H. caudiculatum enhanced osmotic responses and phenylpropanoid related pathways, whilst H. dentatum enhanced its defense system responses and protection against high light stress. CONCLUSIONS: Our findings provide a deeper understanding of the mechanisms underlying the desiccation tolerance responses of two filmy ferns and the relationship between the species-specific response and the microhabitats these ferns occupy in nature.
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Desecación , Ecosistema , Helechos/genética , Expresión Génica , Estrés Fisiológico/genética , Chile , Mapeo Cromosómico , Perfilación de la Expresión GénicaRESUMEN
Background and Purpose- After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting. Methods- Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice. Results- As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1+ cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets. Conclusions- TLR4 deficiency increased the levels of alternative neutrophils (N2)-an effect associated with neuroprotection after stroke-supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke. Visual Overview- An online visual overview is available for this article.
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Infarto de la Arteria Cerebral Media/patología , Infiltración Neutrófila/fisiología , Neutrófilos/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , FenotipoRESUMEN
Ischemic stroke is one of the leading causes of death and disability with an urgent need for innovative therapies, especially targeting the chronic phase. New evidence has emerged showing that Toll-Like Receptor 4 (TLR4), a key mediator of brain damage after stroke, may be involved in brain repair by neurogenesis modulation. The aim of this study is to analyze the role of TLR4 in the different stages of neurogenesis initiated in the subventricular zone (SVZ) over time after stroke in mice. Wildtype and TLR4-deficient mice underwent experimental ischemia, and neural stem/progenitor cells (NSPCs) proliferation and migration were analyzed by using FACS analysis, fluorescence densitometry, RT-qPCR and in vitro assays. Our results show that both groups, wildtype and knock-out animals, present a similar pattern of bilateral cell proliferation at the SVZ, with a decrease in NSPCs proliferation in the acute phase of stroke. We also show that TLR4 activation, very likely mediated by ligands such as HMGB1 released to CSF after stroke, is necessary to keep an increased proliferation of NSCs as well as to promote differentiation from type C cells into neuroblasts promoting their migration. TLR4 activation was also implicated in earlier expression of SDF-1α and faster recovery of BDNF expression after stroke. These results support TLR4 as an important therapeutic target in the modulation of neurogenesis after stroke.
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Ventrículos Laterales/metabolismo , Células-Madre Neurales/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Quimiocina CXCL12/metabolismo , Proteína HMGB1/metabolismo , Ventrículos Laterales/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Neuronas/metabolismo , Transducción de Señal/fisiología , Accidente Cerebrovascular/tratamiento farmacológico , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/fisiologíaRESUMEN
Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect. ApTLR#4F and ApTLR#4FT showed a long-lasting protective effect against brain injury induced by middle cerebral artery occlusion (MCAO), an effect that was absent in TLR4-deficient mice. Similar effects were obtained in other MCAO models, including in rat. Additionally, efficacy of ApTLR#4FT in a model of brain ischemia-reperfusion in rat supports the use of this aptamer in patients undergoing artery recanalization induced by pharmacological or mechanical interventions. The absence of major toxicology aspects and the good safety profile of the aptamers further encourage their future clinical positioning for stroke therapy and possibly other diseases in which TLR4 plays a deleterious role.
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Aptámeros de Nucleótidos/administración & dosificación , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Receptor Toll-Like 4/metabolismo , Animales , Aptámeros de Nucleótidos/farmacología , Modelos Animales de Enfermedad , Humanos , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/etiología , Ratones , Ratas , Técnica SELEX de Producción de Aptámeros , Transducción de Señal , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Hemorrhagic transformation is the main complication of revascularization therapies after stroke. Toll-like receptor 4 (TLR4) is implicated in cerebral damage and inflammation in stroke. This study was designed to determine the role of TLR4 in hemorrhagic transformation development after tissue plasminogen activator (tPA) administration. METHODS: Mice expressing (TLR4+/+) or lacking functional TLR4 (TLR4-/-) were subjected to middle cerebral artery occlusion using an in situ thromboembolic model by thrombin injection into the middle cerebral artery, and tPA (10 mg/kg) was administered 20 minutes or 3 hours after ischemia. Infarct size, hemorrhages, IgG extravasation, matrix metalloproteinase 9 expression, and neutrophil infiltration were assessed 24 hours after ischemia. RESULTS: In TLR4+/+, early reperfusion (tPA at 20 minutes) resulted infarct volume, whereas late recanalization (tPA at 3 hours) did not modify lesion size and increased the rate of the most severe hemorrhages. In TLR4-/- mice, both early and late reperfusion did not modify lesion size. Importantly, late tPA administration did not result in worse hemorrhages and in an increased bleeding area as occurred in TLR4+/+ group. In TLR4-/- animals, late reperfusion produced a lesser increase in matrix metalloproteinase 9 expression when compared with TLR4+/+ animals. CONCLUSIONS: Our results demonstrate TLR4 involvement in hemorrhagic transformation induced by delayed tPA administration, very likely by increasing matrix metalloproteinase 9 expression.
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Isquemia Encefálica/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Fibrinolíticos/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido Plasminógeno/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Hemorragia Cerebral/inducido químicamente , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/metabolismo , Modelos Animales de Enfermedad , Fibrinolíticos/administración & dosificación , Infarto de la Arteria Cerebral Media/complicaciones , Embolia Intracraneal/complicaciones , Trombosis Intracraneal/complicaciones , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/metabolismo , Factores de Tiempo , Activador de Tejido Plasminógeno/administración & dosificaciónRESUMEN
Neuroprotective strategies for ischemic stroke have failed to translate from bench to bedside, possibly due to the lack of consideration of key clinical co-morbidities. Stroke and co-morbidities are associated with raised levels of the pro-inflammatory cytokine interleukin-1 (IL-1). Inhibition of IL-1 by the administration of interleukin-1 receptor antagonist (IL-1Ra) has shown to be neuroprotective after experimental cerebral ischemia. Stroke can also trigger a robust neuroreparative response following injury, yet many of these new born neurons fail to survive or integrate into pre-existing circuits. Thus, we explore here effects of IL-1Ra on post-stroke neurogenesis in young and aged/co-morbid rats. Aged lean, aged Corpulent (a model of atherosclerosis, obesity and insulin resistance) and young Wistar male rats were exposed to transient cerebral ischemia, received subcutaneous IL-1Ra 3 and 6h during reperfusion, and effects on stroke outcome and neurogenesis were analyzed. Our results show that administration of IL-1Ra improves stroke outcome in both young and aged/co-morbid rats. Furthermore, IL-1Ra not only increases stem cell proliferation, but also significantly enhances neuroblast migration and the number of newly born neurons after cerebral ischemia. Overall, our data demonstrate that systemic administration of IL-1Ra improves outcome and promotes neurogenesis after experimental stroke, further highlighting the therapeutic potential of this clinically approved drug.
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Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Movimiento Celular/efectos de los fármacos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Masculino , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
BACKGROUND: Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. METHODS: We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). RESULTS: Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. CONCLUSIONS: Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in the cortical peri-infarct area. Thus, our results highlight the importance of using aged animals for translation to clinical studies.
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Movimiento Celular/fisiología , Proliferación Celular/fisiología , Corteza Cerebral/patología , Infarto de la Arteria Cerebral Media/patología , Microglía/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Envejecimiento , Animales , Células Sanguíneas/patología , Células Sanguíneas/fisiología , Infarto Encefálico/etiología , Infarto Encefálico/patología , Bromodesoxiuridina/metabolismo , Proteínas de Unión al Calcio/metabolismo , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Proteína Doblecortina , Proteína Ácida Fibrilar de la Glía/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Microglía/patología , Neuronas/patología , Infiltración Neutrófila/fisiología , Fosfopiruvato Hidratasa/metabolismoRESUMEN
Toll-like receptor 4 (TLR4) mediates brain damage after stroke. Now our objective is to determine TLR4 involvement in stroke-induced neurogenesis. Stroke was induced by permanent middle cerebral artery occlusion in wild-type and TLR4-deficient mice. Stereological and densitometric analysis of immunofluorescence-labeled brain sections and FACS analysis of cell suspensions were performed. Our results show that subventricular zone (SVZ) cell proliferation after stroke depends on infarct size. Second, when comparing brains with similar lesions, TLR4 attenuated SVZ proliferation, as shown by a decrease in prominin-1(+)/EGFR(+)/nestin(-) cells (type-C cells) at 1-2 d, and in BrdU(+) cells at 7 d, in TLR4(+/+) vs. TLR4(-/-) mice. Interestingly, 7 d after the infarct, neuroblasts in TLR4(+/+) mice migrated farther distances, reaching areas closer to the lesion than those in TLR4-deficient mice. However, at 14 d, TLR4-deficient mice presented a higher number of neuroblasts in all migratory zones than the TLR4(+/+) counterparts, which suggests that TLR4 deficiency delays neuroblast migration. Consistently, TLR4(+/+) mice showed an increased number of interneurons (NeuN(+)/BrdU(+)/GAD67(+) cells) in peri-infarct cortex 14-28 d after stroke. Our data indicate that, despite a negative effect on SVZ cell proliferation, TLR4 plays an important role in stroke-induced neurogenesis by promoting neuroblasts migration and increasing the number of new cortical neurons after stroke.
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Isquemia Encefálica/metabolismo , Movimiento Celular/fisiología , Neurogénesis/fisiología , Neuronas/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Isquemia Encefálica/inmunología , Proliferación Celular/fisiología , Inmunidad Innata/fisiología , Masculino , Ratones Endogámicos C57BL , Receptor Toll-Like 4/inmunologíaRESUMEN
Studies on the low-abundance transcriptome are of paramount importance for identifying the intimate mechanisms of tumor progression that can lead to novel therapies. The aim of the present study was to identify novel markers and targetable genes and pathways in advanced human gastric cancer through analyses of the low-abundance transcriptome. The procedure involved an initial subtractive hybridization step, followed by global gene expression analysis using microarrays. We observed profound differences, both at the single gene and gene ontology levels, between the low-abundance transcriptome and the whole transcriptome. Analysis of the low-abundance transcriptome led to the identification and validation by tissue microarrays of novel biomarkers, such as LAMA3 and TTN; moreover, we identified cancer type-specific intracellular pathways and targetable genes, such as IRS2, IL17, IFNγ, VEGF-C, WISP1, FZD5 and CTBP1 that were not detectable by whole transcriptome analyses. We also demonstrated that knocking down the expression of CTBP1 sensitized gastric cancer cells to mainstay chemotherapeutic drugs. We conclude that the analysis of the low-abundance transcriptome provides useful insights into the molecular basis and treatment of cancer.
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Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Mucosa Gástrica/metabolismo , Perfilación de la Expresión Génica , Neoplasias Gástricas/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Oxidorreductasas de Alcohol/antagonistas & inhibidores , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Western Blotting , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Conectina/genética , Conectina/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Técnicas para Inmunoenzimas , Laminina/genética , Laminina/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Técnica de Sustracción , Análisis de Matrices Tisulares , Células Tumorales CultivadasRESUMEN
The current study isolated and characterized the Lip3F9 polypeptide sequence of Deschampsia antarctica Desv. (GeneBank Accession Number JX846628), which was found to be comprised of 291 base pairs and was, moreover, expressed in Pichia pastoris X-33 cells. The enzyme was secreted after 24 h of P. pastoris culture incubation and through induction with methanol. The expressed protein showed maximum lipase activity (35 U/L) with an optimal temperature of 37 °C. The lipase-expressed enzyme lost 50% of its specific activity at 25 °C, a behavior characteristic of a psychrotolerant enzyme. Recombinant enzyme activity was measured in the presence of ionic and non-ionic detergents, and a decrease in enzyme activity was detected for all concentrations of ionic and non-ionic detergents assessed.
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Expresión Génica , Lipasa/genética , Lipasa/metabolismo , Péptidos/genética , Péptidos/metabolismo , Pichia/genética , Tracheophyta/genética , Secuencia de Aminoácidos , Secuencia de Bases , Detergentes/farmacología , Genes de Plantas , Cinética , Lipasa/antagonistas & inhibidores , Lipasa/química , Lipólisis , Datos de Secuencia Molecular , Péptidos/química , TemperaturaRESUMEN
Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post-stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte-derived macrophages) to central nervous system (CNS)-associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil-dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.
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Enfermedad de Alzheimer , Demencia Vascular , Humanos , Demencia Vascular/tratamiento farmacológico , Células Mieloides , Monocitos , MicroglíaRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2024.1443096.].
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Biomarcadores , Gripe Humana , Interleucina-15 , Interleucina-8 , Humanos , Gripe Humana/inmunología , Gripe Humana/complicaciones , Pronóstico , Interleucina-8/sangreRESUMEN
Introduction: Influenza virus infection can cause a range of clinical symptoms, including respiratory failure (RF) and even death. The mechanisms responsible for the most severe forms of the disease are not yet well understood. The objective is to assess the initial immune response upon admission and its potential impact on infection progression. Methods: We conducted a prospective observational study of patients with influenza virus infection who required admission to a tertiary hospital in the 2017/18 and 2018/19 flu seasons. Immune markers, surrogate markers of neutrophil activation, and blood levels of DNase I and Apolipoprotein-H (ApoH) were determined in the first serum sample available during hospital care. Patients were followed until hospital discharge or death. Initially, 792 patients were included. From this group, 107 patients with poor evolution were selected, and a random control group was matched by day of admission. Results: Patients with poor outcomes had significantly reduced ApoH levels, a soluble protein that regulate both complement and coagulation pathways. In multivariate analysis, low plasma levels of ApoH (OR:5.43; 2.21-13.4), high levels of C- reactive protein (OR:2.73: 1.28-5.4), hyperferritinemia (OR:2.83; 1.28-5.4) and smoking (OR:3.41; 1.04-11.16), were significantly associated with a worse prognosis. RF was independently associated with low levels of ApoH (OR: 5.12; 2.02-1.94), while high levels of IL15 behaved as a protective factor (OR:0.30; 0.12-0.71). Discussion: Therefore, in hospitalized influenza patients, a dysregulated early immune response is associated with a worse outcome. Adequate plasma levels of ApoH are protective against severe influenza and RF and High levels of IL15 protect against RF.
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Biomarcadores , Gripe Humana , Interleucina-15 , Interleucina-8 , Humanos , Gripe Humana/inmunología , Gripe Humana/sangre , Masculino , Femenino , Biomarcadores/sangre , Pronóstico , Persona de Mediana Edad , Interleucina-15/sangre , Anciano , Estudios Prospectivos , Interleucina-8/sangre , AdultoRESUMEN
BACKGROUND AND PURPOSE: Sirtuin 1 (SIRT1) is a member of NAD+-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice. METHODS: Wild-type and Sirt1-/- mice were subjected to permanent focal ischemia by permanent ligature. In another set of experiments, wild-type mice were treated intraperitoneally with vehicle, activator 3 (SIRT1 activator, 10 mg/kg), or sirtinol (SIRT1 inhibitor, 10 mg/kg) for 10 minutes, 24 hours, and 40 hours after ischemia. Brains were removed 48 hours after ischemia for determining the infarct volume. Neurological outcome was evaluated using the modified neurological severity score. RESULTS: Exposure to middle cerebral artery occlusion increased SIRT1 expression in neurons of the ipsilesional mouse brain cortex. Treatment of mice with activator 3 reduced infarct volume, whereas sirtinol increased ischemic injury. Sirt1-/- mice displayed larger infarct volumes after ischemia than their wild-type counterparts. In addition, SIRT1 inhibition/deletion was concomitant with increased acetylation of p53 and nuclear factor κB (p65). CONCLUSIONS: These results support the idea that SIRT1 plays an important role in neuroprotection against brain ischemia by deacetylation and subsequent inhibition of p53-induced and nuclear factor κB-induced inflammatory and apoptotic pathways.
Asunto(s)
Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Sirtuina 1/fisiología , Sirtuinas/fisiología , Acetilación , Alelos , Animales , Proteínas Reguladoras de la Apoptosis/fisiología , Encéfalo/patología , Isquemia Encefálica/patología , Isquemia Encefálica/prevención & control , Infarto de la Arteria Cerebral Media/complicaciones , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/fisiología , Ratones , Ratones Noqueados , FN-kappa B/antagonistas & inhibidores , FN-kappa B/fisiología , Distribución Aleatoria , Transducción de Señal/genética , Método Simple Ciego , Sirtuina 1/deficiencia , Sirtuina 1/genética , Sirtuinas/administración & dosificación , Sirtuinas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/biosíntesis , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND AND PURPOSE: Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome. METHODS: Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed. RESULTS: Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset. CONCLUSIONS: We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.
Asunto(s)
Encéfalo/efectos de los fármacos , Encefalitis/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Neutrófilos/efectos de los fármacos , PPAR gamma/agonistas , Accidente Cerebrovascular/metabolismo , Tiazolidinedionas/farmacología , Encéfalo/metabolismo , Encefalitis/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neutrófilos/metabolismo , Rosiglitazona , Accidente Cerebrovascular/tratamiento farmacológico , Tiazolidinedionas/uso terapéuticoRESUMEN
CDP-choline has shown neuroprotective effects in cerebral ischemia. In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline. We have now studied the participation of Sirtuin1 (SIRT1) in the neuroprotective actions of CDP-choline. Fischer rats and Sirt1â»/â» mice were subjected to permanent focal ischemia. CDP-choline (0.2 or 2 g/kg), sirtinol (a SIRT1 inhibitor; 10 mg/kg), and resveratrol (a SIRT1 activator; 2.5 mg/kg) were administered intraperitoneally. Brains were removed 24 and 48 h after ischemia for western blot analysis and infarct volume determination. Treatment with CDP-choline increased SIRT1 protein levels in brain concomitantly to neuroprotection. Treatment with sirtinol blocked the reduction in infarct volume caused by CDP-choline, whereas resveratrol elicited a strong synergistic neuroprotective effect with CDP-choline. CDP-choline failed to reduce infarct volume in Sirt1â»/â» mice. Our present results demonstrate a robust effect of CDP-choline like SIRT1 activator by up-regulating its expression. Our findings suggest that therapeutic strategies to activate SIRT1 may be useful in the treatment of stroke. Sirtuin 1 (SIRT1) is implicated in a wide range of cellular functions. Regarding stroke, there is no direct evidence. We have demonstrated that citicoline increases SIRT1 protein levels in brain concomitantly to neuroprotection. Citicoline fails to reduce infarct volume in Sirt1â»/â» mice. Our findings suggest that therapeutic strategies acting on SIRT1 may be useful in the treatment of stroke.
Asunto(s)
Citidina Difosfato Colina/farmacología , Fármacos Neuroprotectores , Nootrópicos/farmacología , Sirtuina 1/biosíntesis , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/farmacología , Western Blotting , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Células Cultivadas , Sinergismo Farmacológico , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones , Ratones Noqueados , Monocitos/metabolismo , Naftoles/farmacología , Neuronas/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Resveratrol , Sirtuina 1/antagonistas & inhibidores , Estilbenos/farmacologíaRESUMEN
Tuberculosis (TB) is one of the leading causes of human deaths worldwide caused by infectious diseases. TB infection by Mycobacterium tuberculosis can occur in the lungs, causing pulmonary tuberculosis (PTB), or in any other organ of the body, resulting in extrapulmonary tuberculosis (EPTB). There is no consensus on the genetic determinants of this pathogen that may contribute to EPTB. In this study, we constructed the M. tuberculosis pangenome and used it as a tool to seek genomic signatures associated with the clinical presentation of TB based on its accessory genome differences. The analysis carried out in the present study includes the raw reads of 490 M. tuberculosis genomes (PTB n = 245, EPTB n = 245) retrieved from public databases that were assembled, as well as ten genomes from Mexican strains (PTB n = 5, EPTB n = 5) that were sequenced and assembled. All genomes were annotated and then used to construct the pangenome with Roary and Panaroo. The pangenome obtained using Roary consisted of 2231 core genes and 3729 accessory genes. On the other hand, the pangenome resulting from Panaroo consisted of 2130 core genes and 5598 accessory genes. Associations between the distribution of accessory genes and the PTB/EPTB phenotypes were examined using the Scoary and Pyseer tools. Both tools found a significant association between the hspR, plcD, Rv2550c, pe_pgrs5, pe_pgrs25, and pe_pgrs57 genes and the PTB genotype. In contrast, the deletion of the aceA, esxR, plcA, and ppe50 genes was significantly associated with the EPTB phenotype. Rv1759c and Rv3740 were found to be associated with the PTB phenotype according to Scoary; however, these associations were not observed when using Pyseer. The robustness of the constructed pangenome and the gene-phenotype associations is supported by several factors, including the analysis of a large number of genomes, the inclusion of the same number of PTB/EPTB genomes, and the reproducibility of results thanks to the different bioinformatic tools used. Such characteristics surpass most of previous M. tuberculosis pangenomes. Thus, it can be inferred that the deletion of these genes can lead to changes in the processes involved in stress response and fatty acid metabolism, conferring phenotypic advantages associated with pulmonary or extrapulmonary presentation of TB. This study represents the first attempt to use the pangenome to seek gene-phenotype associations in M. tuberculosis.
RESUMEN
Low fermentation temperatures are usually employed to obtain high-quality wines. This is especially interesting for white wine production since it prevents the loss of volatile compounds and a browning appearance; however, available fermentative yeasts do not usually tolerate low temperatures. Therefore, an interesting place to find new yeasts with cryotolerance is the Antarctic continent. From soil samples collected in Antarctica, 125 yeasts were isolated, of which 25 exhibited fermentative activity at 10 °C. After a fingerprinting assay, we classified the candidates into nine isotypes and sequenced internal transcribed spacer regions for their identification. These yeasts were identified as part of the Mrakia genus. Sugar and alcohol tolerance tests showed that some of these Antarctic soil yeasts were able to grow up to 9% alcohol, and 25% sugar was reached; however, they exhibited longer latency periods compared to the control Saccharomyces cerevisiae. The optimal growing temperature for the isolated Antarctic yeasts was between 10 °C and 15 °C. A comprehensive analysis of the results obtained showed that the isolates 10M3-1, 4M3-6, and 4B1-35 could be good candidates for fermentation purposes due to their alcohol, sugar tolerance, and growth features. Our results prove that it is possible to isolate fermentative yeasts from Antarctic soil with promising characteristics for their potential use in the wine production industry.