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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809077

RESUMEN

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.


Asunto(s)
Vesículas Extracelulares/genética , Inmunidad/genética , Esclerosis Múltiple/genética , Proteoma/genética , Comunicación Celular/genética , Técnicas de Cocultivo , Citocinas/genética , Decidua/inmunología , Decidua/metabolismo , Vesículas Extracelulares/inmunología , Femenino , Humanos , Inmunomodulación/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Placenta/inmunología , Placenta/metabolismo , Embarazo , Linfocitos T Reguladores/inmunología , Trofoblastos/inmunología , Trofoblastos/metabolismo
2.
Glia ; 68(10): 2001-2014, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32163190

RESUMEN

In the last decade, microRNAs have been increasingly recognized as key modulators of glial development. Recently, we identified miR-125a-3p as a new player in oligodendrocyte physiology, regulating in vitro differentiation of oligodendrocyte precursor cells (OPCs). Here, we show that miR-125a-3p is upregulated in active lesions of multiple sclerosis (MS) patients and in OPCs isolated from the spinal cord of chronic experimental autoimmune encephalomyelitis (EAE) mice, but not in those isolated from the spontaneously remyelinating corpus callosum of lysolecithin-treated mice. To test whether a sustained expression of miR-125a-3p in OPCs contribute to defective remyelination, we modulated miR-125a-3p expression in vivo and ex vivo after lysolecithin-induced demyelination. We found that lentiviral over-expression of miR-125a-3p impaired OPC maturation, whereas its downregulation accelerated remyelination. Transcriptome analysis and luciferase reporter assay revealed that these effects are partly mediated by the direct interaction of miR-125a-3p with Slc8a3, a sodium-calcium membrane transporter, and identified novel candidate targets, such as Gas7, that we demonstrated necessary to correctly address oligodendrocytes to terminal maturation. These findings show that miR-125a-3p upregulation negatively affects OPC maturation in vivo, suggest its role in the pathogenesis of demyelinating diseases and unveil new targets for future promyelinating protective interventions.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Silenciador del Gen/fisiología , MicroARNs/biosíntesis , Vaina de Mielina/metabolismo , Remielinización/fisiología , Sustancia Blanca/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Vaina de Mielina/genética , Vaina de Mielina/patología , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Sustancia Blanca/patología
3.
Int J Mol Sci ; 21(8)2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32325694

RESUMEN

The intracellular-ubiquitin-ending-enzyme tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is a potent inhibitor of the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway. Single nucleotide polymorphisms in TNFAIP3 locus have been associated to autoimmune inflammatory disorders, including Multiple Sclerosis (MS). Previously, we reported a TNFAIP3 down-regulated gene expression level in blood and specifically in monocytes obtained from treatment-naïve MS patients compared to healthy controls (HC). Myeloid cells exert a key role in the pathogenesis of MS. Here we evaluated the effect of specific TNFAIP3 deficiency in myeloid cells including monocytes, monocyte-derived cells (M-MDC) and microglia analyzing lymphoid organs and microglia of mice. TNFAIP3 deletion is induced using conditional knock-out mice for myeloid lineage. Flow-cytometry and histological procedures were applied to assess the immune cell populations of spleen, lymph nodes and bone marrow and microglial cell density in the central nervous system (CNS), respectively. We found that TNFAIP3 deletion in myeloid cells induces a reduction in body weight, a decrease in the number of M-MDC and of common monocyte and granulocyte precursor cells (CMGPs). We also reported that the lack of TNFAIP3 in myeloid cells induces an increase in microglial cell density. The results suggest that TNFAIP3 in myeloid cells critically controls the development of M-MDC in lymphoid organ and of microglia in the CNS.


Asunto(s)
Microglía/citología , Monocitos/citología , Mielopoyesis/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/deficiencia , Animales , Peso Corporal/genética , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Femenino , Citometría de Flujo , Células Precursoras de Granulocitos/citología , Células Precursoras de Granulocitos/metabolismo , Inflamación/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Ratones Noqueados , Microglía/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/citología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Bazo/citología , Bazo/inmunología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo
4.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31574937

RESUMEN

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson's disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies.


Asunto(s)
Susceptibilidad a Enfermedades , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Regulación de la Expresión Génica , Humanos , Ratones , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
5.
Clin Immunol ; 181: 83-88, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28642148

RESUMEN

Glatiramer acetate (GA) is a widely used treatment for multiple sclerosis (MS), with incompletely defined mechanism of action. Short-term studies suggested its involvement in the modulation of anti-inflammatory cytokines and regulatory T cells (Treg), while long-term effect is still unknown. To investigate this aspect, we analyzed by flow-cytometry peripheral-blood Treg, natural killer (NK), CD4 and CD8 T-cells and anti-inflammatory CD14+CD163+ monocytes from 37 healthy donor and 90 RRMS patients divided in untreated, treated with GA for 12months and from 34 to 192months. While NK, CD4 and CD8 T-cells did not show any significant differences among groups over time, we demonstrated that GA increased the anti-inflammatory monocytes and restored the Treg level in both GA-treated groups. Both these effects are a characteristic of responder patients and are observed not just in short-term but even after as long as a decade of GA treatment.


Asunto(s)
Acetato de Glatiramer/uso terapéutico , Inmunosupresores/uso terapéutico , Monocitos/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Células Asesinas Naturales/inmunología , Receptores de Lipopolisacáridos/metabolismo , Persona de Mediana Edad , Monocitos/metabolismo , Esclerosis Múltiple Recurrente-Remitente/inmunología , Receptores de Superficie Celular/metabolismo , Resultado del Tratamiento , Adulto Joven
6.
Inflamm Res ; 64(11): 841-4, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26337347

RESUMEN

OBJECTIVE: Nurr1 plays anti-inflammatory functions in astrocytes/microglia. Gene expression analysis reveals Nurr1 down-regulation in PBMCs of MS patients that negatively correlates with disease aggressiveness. This study assesses the consequences of Nurr1 reduction in a MS model represented by EAE. METHODS: EAE was induced in heterozygous Nurr1 knockout mice. Clinical course was evaluated during pre-symptomatic, acute, and chronic phases. Neurohistopathological state was analyzed in spinal cord. RESULTS AND CONCLUSIONS: Nurr1 defect induces early EAE onset and increases inflammatory infiltrates in spinal cord suggesting a Nurr1 role in the early phase of EAE.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones Noqueados , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Médula Espinal/metabolismo , Médula Espinal/patología
7.
Foods ; 12(22)2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-38002189

RESUMEN

The increasing number of food frauds, mainly targeting high quality products, is a rising concern among producers and authorities appointed to food controls. Therefore, the development or implementation of methods to reveal frauds is desired. The genetic traceability of traditional or high-quality dairy products (i.e., products of protected designation of origin, PDO) represents a challenging issue due to the technical problems that arise. The aim of the study was to set up a genetic tool for the origin traceability of dairy products. We investigated the use of Short Tandem Repeats (STRs) to assign milk and cheese to the corresponding producer. Two farms were included in the study, and the blood of the cows, bulk milk, and derived cheese were sampled monthly for one year. Twenty STRs were selected and Polymerase Chain Reactions for each locus were carried out. The results showed that bulk milk and derived cheese express an STR profile composed of a subset of STRs of the lactating animals. A bioinformatics tool was used for the exclusion analysis. The study allowed the identification of a panel of 20 markers useful for the traceability of milk and cheeses, and its effectiveness in the traceability of dairy products obtained from small producers was demonstrated.

8.
Mult Scler ; 18(10): 1484-92, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22562951

RESUMEN

BACKGROUND: Glatiramer acetate (GA) in multiple sclerosis acts through the induction of GA-specific T-helper 2 cells. Nevertheless, the phenomenon is not universal in patients, explaining individual differences in clinical response. OBJECTIVE: The objective of this article was to categorize GA-treated patients. METHOD: An enhanced quantitative PCR assay was used for measuring ex-vivo GA-induced IFNγ and IL4 mRNA responses in mononuclear cells from 23 healthy donors, 27 untreated patients, 33 short-term (≤6 months) and 77 long-term (>6 months) GA-treated patients. Thresholds for IFNγ and IL4 transcriptional response were calculated by ROC analysis and long-term treated patients were compared in terms of prognostic stratification. RESULTS: Thresholds for IFNγ and IL4 transcriptional response were calculated at 5.36 and 1.41 relative expression (RE). Finally, 67% of long-term treated patients scored above both response thresholds. These patients had a higher proportion of relapse-free subjects (74% vs 40% when compare to patients who scored below both thresholds) and a significantly better relapse-free survival rate (p=0.006; CI 0.29-0.75). The negative predictive value to predict adverse clinical outcome was 79% (CI 0.63-0.90), meaning that by a positive response, there is a 79% chance that the patient will not experience a negative outcome at 3 years. CONCLUSIONS: Our enhanced quantitative PCR assay produced clinically significant results for GA-treated patients. As such, if patients have a positive response, it means they have less chance of a relapse, while patients with a negative response have a greater probability of a worse outcome.


Asunto(s)
Interferón gamma/inmunología , Interleucina-4/inmunología , Esclerosis Múltiple Recurrente-Remitente/clasificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adolescente , Adulto , Femenino , Acetato de Glatiramer , Humanos , Inmunosupresores/uso terapéutico , Interferón gamma/sangre , Interleucina-4/sangre , Masculino , Persona de Mediana Edad , Péptidos/uso terapéutico , Reacción en Cadena de la Polimerasa/métodos , Curva ROC , Adulto Joven
9.
Brain Pathol ; 31(2): 283-296, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33051914

RESUMEN

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) in which inflammation plays a key pathological role. Recent evidences showed that systemic inflammation induces increasing cell infiltration within meninges and perivascular spaces in the brain parenchyma, triggering resident microglial and astrocytic activation. The anti-inflammatory enzyme A20, also named TNF associated protein 3 (TNFAIP3), is considered a central gatekeeper in inflammation and peripheral immune system regulation through the inhibition of NF-kB. The TNFAIP3 locus is genetically associated to MS and its transcripts is downregulated in blood cells in treatment-naïve MS patients. Recently, several evidences in mouse models have led to hypothesize a function of A20 also in the CNS. Thus, here we aimed to unveil a possible contribution of A20 to the CNS human MS pathology. By immunohistochemistry/immunofluorescence and biomolecular techniques on post-mortem brain tissue blocks obtained from control cases (CC) and progressive MS cases, we demonstrated that A20 is present in CC brain tissues in both white matter (WM) regions, mainly in few parenchymal astrocytes, and in grey matter (GM) areas, in some neuronal populations. Conversely, in MS brain tissues, we observed increased expression of A20 by perivascular infiltrating macrophages, resident-activated astrocytes, and microglia in all the active and chronic active WM lesions. A20 was highly expressed also in the majority of active cortical lesions compared to the neighboring areas of normal-appearing grey matter (NAGM) and control GM, particularly by activated astrocytes. We demonstrated increased A20 expression in the active MS plaques, particularly in macrophages and resident astrocytes, suggesting a key role of this molecule in chronic inflammation.


Asunto(s)
Encéfalo/inmunología , Encéfalo/patología , Esclerosis Múltiple Crónica Progresiva/inmunología , Esclerosis Múltiple Crónica Progresiva/patología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Masculino , Persona de Mediana Edad
10.
J Genet Genomics ; 48(6): 497-507, 2021 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-34353742

RESUMEN

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c+, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Alelos , Femenino , Expresión Génica , Estudios de Asociación Genética , Genotipo , Humanos , Intrones/genética , Italia , Masculino , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
11.
Electrophoresis ; 31(17): 2882-93, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20715125

RESUMEN

Plasma acute-phase proteins (APPs) glyco-isoforms are important biomarkers of inflammatory processes such as those occurring in multiple sclerosis (MS). Specific analysis of these proteins is often hampered by sample biochemical complexity. The aim of our study was to set up a method to accurately visualize, identify and quantify APPs glyco-isoforms in human serum. An enrichment strategy based on affinity chromatography using the carbohydrate-binding proteins concanavalin A (ConA) and erythrina cristagalli lectin (ECL) was applied to pooled serum samples from 15 patients and 9 healthy individuals. Image analysis of 2-DE detected 30 spots with a fold change higher than 1.5. A total of 14 were statistically significant (p value<0.05): 7 up-regulated and 7 down-regulated in MS samples. ESI LC-Nanospray IT mass spectrometry analysis confirmed that all of them were APPs isoforms supporting the idea that the accurate analysis of differential glycosylation profiles in these biomarkers is instrumental to distinguish between MS patients and healthy subjects. Additionally, overlaps in ConA/ECL maps protein patterns suggest how the used lectins are able to bind sugars harbored by the same oligosaccharide structure. Among identified proteins, the presence of complex and/or hybrid type N-linked sugar structures is well known. Performing galectin-3 binding and Western blotting, we were able to demonstrate a correlation between hybrid type glyco-isoforms of ß-haptoglobin and MS. In conclusion, although the patho-physiological role of the identified species still remains unclear and further validations are needed, these findings may have a relevant impact on disease-specific marker identification approaches.


Asunto(s)
Proteínas de Fase Aguda/química , Electroforesis en Gel Bidimensional/métodos , Glicoproteínas/química , Lectinas/metabolismo , Esclerosis Múltiple/metabolismo , Proteómica/métodos , Proteínas de Fase Aguda/metabolismo , Adulto , Western Blotting , Concanavalina A/metabolismo , Femenino , Galectina 3/metabolismo , Glicoproteínas/sangre , Glicoproteínas/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Lectinas de Plantas/metabolismo , Isoformas de Proteínas/sangre , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Reproducibilidad de los Resultados , Suero/química , Espectrometría de Masa por Ionización de Electrospray
12.
Dis Model Mech ; 13(5)2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32188741

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Superóxido Dismutasa-1/genética , Factores de Transcripción/genética , Regulación hacia Arriba/genética , Esclerosis Amiotrófica Lateral/sangre , Animales , Astrocitos/metabolismo , Astrocitos/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/sangre , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Factores de Transcripción/metabolismo , Activación Transcripcional/genética
13.
J Cell Biol ; 167(5): 953-60, 2004 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-15583033

RESUMEN

Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its beta-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1-APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/biosíntesis , Membrana Celular/metabolismo , Colesterol/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Biomarcadores/metabolismo , Compartimento Celular/fisiología , Células Cultivadas , Colesterol/deficiencia , Endopeptidasas , Hipocampo/citología , Hipocampo/fisiopatología , Humanos , Microdominios de Membrana/metabolismo , Ratones , Ratones Transgénicos , Neuronas/citología , Ratas , Fracciones Subcelulares/metabolismo , Antígenos Thy-1/metabolismo , Regulación hacia Arriba/fisiología
14.
Transl Psychiatry ; 9(1): 207, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31455763

RESUMEN

The transcription factor NURR1 regulates the dopamine (DA) signaling pathway and exerts a critical role in the development of midbrain dopaminergic neurons (mDA). NURR1 alterations have been linked to DA-associated brain disorders, such as Parkinson's disease and schizophrenia. However, the association between NURR1 defects and the attention-deficit hyperactivity disorder (ADHD), a DA-associated brain disease characterized by hyperactivity, impulsivity and inattention, has never been demonstrated. To date, a comprehensive murine model of ADHD truly reflecting the whole complex human psychiatric disorder still does not exist. NURR1-knockout (NURR1-KO) mice have been reported to exhibit increased spontaneous locomotor activity, but their complete characterization is still lacking. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. As a result, their hyperactive phenotype was confirmed, while their impulsive behavior was reported for the first time. On the other hand, no anxiety and alterations in motor coordination, sociability and memory were observed. Also, the number of mDA expressing tyrosine hydroxylase, a rate-limiting enzyme of catecholamines biosynthesis, and DA level in brain were not impaired in NURR1-KO mice. Finally, hyperactivity has been shown to be recovered by treatment with methylphenidate, the first line psychostimulant drug used for ADHD. Overall, our study suggests that the NURR1 deficient male mouse may be a satisfactory model to study some ADHD behavioral phenotypes and to test the clinical efficacy of potential therapeutic agents.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Conducta Animal/fisiología , Conducta Impulsiva/fisiología , Actividad Motora/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Masculino , Ratones , Ratones Noqueados , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiología , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo
15.
Front Immunol ; 10: 1935, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31474999

RESUMEN

Pregnancy is a naturally occurring disease modifier of multiple sclerosis (MS) associated with a substantial reduction in relapse rate. To date, attempts to explain this phenomenon have focused on systemic maternal immune cell composition, with contradictory results. To address this matter, we compared the immunomodulatory effects of pregnancy on five leukocyte populations (i.e., CD4+ and CD8+ T cells, CD4+CD127-CD25high regulatory T cells, CD56brightCD16- NK cells, and CD14+CD163+ monocytes) in peripheral blood from different cohorts of MS patients and healthy women at different times of gestation, as well as in decidual samples from the placenta of MS patients and healthy women collected after delivery. For the first time to our knowledge, we observed that the frequency of these cell populations in the decidua is not different between MS patients and healthy women, suggesting that a physiological immune regulation may occur at the fetal-maternal interface. In peripheral blood, however, contrary to healthy women, in MS patients cell frequencies were not significantly altered by gestation. In particular, CD8+ T cells did not show differences between groups. CD4+ T cells were higher in non-pregnant MS compared to healthy women, while during pregnancy they remained constant in MS and increased in healthy women. Regulatory T cells were higher in non-pregnant controls compared to MS women, while the difference was reduced during gestation due to the decrease of regulatory T cell levels in healthy women. CD14+CD163+ monocytes did not show differences between groups. CD56brightCD16- NK cells were not significantly different in non-pregnant MS compared to controls and increased in healthy women during gestation. In conclusion, our findings support the hypothesis that disease amelioration in MS patients during pregnancy may be due to a modulation of the immune cells functional activity rather than their frequency. Further studies exploring functional changes of these cells would be crucial to bring light into the complex mechanisms of pregnancy-induced tolerance and autoimmunity overall.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Decidua/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Femenino , Humanos , Inmunomodulación/inmunología , Recuento de Linfocitos , Circulación Placentaria , Embarazo , Adulto Joven
16.
Front Immunol ; 9: 311, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29527211

RESUMEN

Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto's thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg) percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity.


Asunto(s)
Autoinmunidad , Regulación de la Expresión Génica/inmunología , Enfermedad de Hashimoto/inmunología , Factores Inmunológicos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Femenino , Enfermedad de Hashimoto/patología , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Linfocitos T Reguladores/patología
17.
Neurotox Res ; 32(1): 1-7, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28337659

RESUMEN

Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro-inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy.


Asunto(s)
Esclerosis Múltiple/sangre , Enfermedad de Parkinson/sangre , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Esclerosis Amiotrófica Lateral/sangre , Femenino , Expresión Génica , Humanos , Italia , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética
18.
J Neuroimmunol ; 292: 34-9, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26943956

RESUMEN

We studied the baseline expression level of 25 interferon-regulated genes (MxA, GPR3, IL17RC, ISG15, TRAIL, OASL, IFIT1, IFIT2, RSAD2, OAS3, IFI44L, TRIM22, IL10, CXCL10, STAT1, OAS1, OAS2, IFNAR1, IFNAR2, IFNß, ISG20, IFI6, PKR, IRF7, USP18), recurrently proposed in the literature as predictive biomarkers of interferon-beta treatment response, in whole blood of 10 "responders" and 10 "non-responders" multiple sclerosis relapsing-remitting patients, retrospectively selected on the basis of stringent clinical criteria after a five years follow-up. However, we cannot confirm the predictive value of these candidate biomarkers.


Asunto(s)
Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Adolescente , Adulto , Biomarcadores/sangre , Citocinas/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , ARN Mensajero/metabolismo , Estudios Retrospectivos , Estadísticas no Paramétricas , Adulto Joven
19.
Neurotox Res ; 30(3): 338-44, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27159982

RESUMEN

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.


Asunto(s)
Enfermedad de Alzheimer/sangre , Proteínas de Unión al ADN/sangre , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/sangre , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/sangre , Enfermedad de Parkinson/sangre , Receptores de Esteroides/sangre , Receptores de Hormona Tiroidea/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/tratamiento farmacológico , Biomarcadores/sangre , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico
20.
PLoS One ; 10(6): e0129291, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26046356

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a heterogeneous and unpredictable course. To date there are no prognostic biomarkers even if they would be extremely useful for early patient intervention with personalized therapies. In this context, the analysis of inter-individual differences in cerebrospinal fluid (CSF) proteome may lead to the discovery of biological markers that are able to distinguish the various clinical forms at diagnosis. METHODS: To this aim, a two dimensional electrophoresis (2-DE) study was carried out on individual CSF samples from 24 untreated women who underwent lumbar puncture (LP) for suspected MS. The patients were clinically monitored for 5 years and then classified according to the degree of disease aggressiveness and the disease-modifying therapies prescribed during follow up. RESULTS: The hierarchical cluster analysis of 2-DE dataset revealed three protein spots which were identified by means of mass spectrometry as Apolipoprotein E (ApoE) and two isoforms of vitamin D binding protein (DBP). These three protein spots enabled us to subdivide the patients into subgroups correlated with clinical classification (MS aggressive forms identification: 80%). In particular, we observed an opposite trend of values for the two protein spots corresponding to different DBP isoforms suggesting a role of a post-translational modification rather than the total protein content in patient categorization. CONCLUSIONS: These findings proved to be very interesting and innovative and may be developed as new candidate prognostic biomarkers of MS aggressiveness, if confirmed.


Asunto(s)
Apolipoproteínas E/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Proteína de Unión a Vitamina D/líquido cefalorraquídeo , Adolescente , Adulto , Western Blotting , Análisis por Conglomerados , Electroforesis en Gel Bidimensional , Femenino , Humanos , Espectrometría de Masas , Persona de Mediana Edad , Esclerosis Múltiple/clasificación , Esclerosis Múltiple/diagnóstico , Pronóstico , Isoformas de Proteínas/líquido cefalorraquídeo , Proteoma/clasificación , Proteoma/metabolismo , Proteómica/métodos , Adulto Joven
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