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Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1ß in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1ß expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1ß-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1ß-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS.
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BACKGROUND AND OBJECTIVES: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. METHODS: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. RESULTS: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. CONCLUSIONS: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.
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Catepsina D , Cirrosis Hepática , Macrófagos , Ratones Noqueados , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Animales , Catepsina D/metabolismo , Catepsina D/genética , Macrófagos/metabolismo , Ratones , Humanos , Masculino , Ratones Endogámicos C57BL , Matriz Extracelular/metabolismo , Hepatocitos/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fnins.2020.577666.].
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BACKGROUND: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches. RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA. CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
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Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.
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Multiple sclerosis (MS) is an autoimmune chronic disease characterized by inflammation and demyelination of the central nervous system (CNS). Despite numerous studies conducted, valid biomarkers enabling a definitive diagnosis of MS are not yet available. The aim of our study was to identify a marker from a blood sample to ease the diagnosis of MS. In this study, since there is evidence connecting the serotonin pathway to MS, we used an ELISA (Enzyme-Linked Immunosorbent Assay) to detect serum MS-specific auto-antibodies (auto-Ab) against the extracellular loop 1 (ECL-1) of the 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A). We utilized an ELISA format employing poly-D-lysine as a pre-coating agent. The binding of 208 serum samples from controls, both healthy and pathological, and of 104 serum samples from relapsing-remitting MS (RRMS) patients was tested. We observed that the serum-binding activity in control cohort sera, including those with autoimmune and neurological diseases, was ten times lower compared to the RRMS patient cohort (p = 1.2 × 10-47), with a sensitivity and a specificity of 98% and 100%, respectively. These results show that in the serum of patients with MS there are auto-Ab against the serotonin receptor type 2A which can be successfully used in the diagnosis of MS due to their high sensitivity and specificity.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Polilisina , Humanos , Sistema Nervioso Central , Anticuerpos , Pruebas Hematológicas , BiomarcadoresRESUMEN
PURPOSE: The use of topological metrics to derive quantitative descriptors from structural connectomes is receiving increasing attention but deserves specific studies to investigate their reproducibility and variability in the clinical context. This work exploits the harmonization of diffusion-weighted acquisition for neuroimaging data performed by the Italian Neuroscience and Neurorehabilitation Network initiative to obtain normative values of topological metrics and to investigate their reproducibility and variability across centers. METHODS: Different topological metrics, at global and local level, were calculated on multishell diffusion-weighted data acquired at high-field (e.g. 3 T) Magnetic Resonance Imaging scanners in 13 different centers, following the harmonization of the acquisition protocol, on young and healthy adults. A "traveling brains" dataset acquired on a subgroup of subjects at 3 different centers was also analyzed as reference data. All data were processed following a common processing pipeline that includes data pre-processing, tractography, generation of structural connectomes and calculation of graph-based metrics. The results were evaluated both with statistical analysis of variability and consistency among sites with the traveling brains range. In addition, inter-site reproducibility was assessed in terms of intra-class correlation variability. RESULTS: The results show an inter-center and inter-subject variability of <10%, except for "clustering coefficient" (variability of 30%). Statistical analysis identifies significant differences among sites, as expected given the wide range of scanners' hardware. CONCLUSIONS: The results show low variability of connectivity topological metrics across sites running a harmonised protocol.
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Conectoma , Adulto , Humanos , Conectoma/métodos , Reproducibilidad de los Resultados , Benchmarking , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagenRESUMEN
Previous studies indicated that spatial neglect is characterized by widespread alteration of resting-state functional connectivity and changes in the functional topology of large-scale brain systems. However, whether such network modulations exhibit temporal fluctuations related to spatial neglect is still largely unknown. This study investigated the association between brain states and spatial neglect after the onset of focal brain lesions. A cohort of right-hemisphere stroke patients (n = 20) underwent neuropsychological assessment of neglect as well as structural and resting-state functional MRI sessions within 2 weeks from stroke onset. Brain states were identified using dynamic functional connectivity as estimated by the sliding window approach followed by clustering of seven resting state networks. The networks included visual, dorsal attention, sensorimotor, cingulo-opercular, language, fronto-parietal, and default mode networks. The analyses on the whole cohort of patients, i.e., with and without neglect, identified two distinct brain states characterized by different degrees of brain modularity and system segregation. Compared to non-neglect patients, neglect subjects spent more time in less modular and segregated state characterized by weak intra-network coupling and sparse inter-network interactions. By contrast, patients without neglect dwelt mainly in more modular and segregated states, which displayed robust intra-network connectivity and anti-correlations among task-positive and task-negative systems. Notably, correlational analyses indicated that patients exhibiting more severe neglect spent more time and dwelt more often in the state featuring low brain modularity and system segregation and vice versa. Furthermore, separate analyses on neglect vs. non-neglect patients yielded two distinct brain states for each sub-cohort. A state featuring widespread strong connections within and between networks and low modularity and system segregation was detected only in the neglect group. Such a connectivity profile blurred the distinction among functional systems. Finally, a state exhibiting a clear separation among modules with strong positive intra-network and negative inter-network connectivity was found only in the non-neglect group. Overall, our results indicate that stroke yielding spatial attention deficits affects the time-varying properties of functional interactions among large-scale networks. These findings provide further insights into the pathophysiology of spatial neglect and its treatment.
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Initiatives for the collection of harmonized MRI datasets are growing continuously, opening questions on the reliability of results obtained in multi-site contexts. Here we present the assessment of the brain anatomical variability of MRI-derived measurements obtained from T1-weighted images, acquired according to the Standard Operating Procedures, promoted by the RIN-Neuroimaging Network. A multicentric dataset composed of 77 brain T1w acquisitions of young healthy volunteers (mean age = 29.7 ± 5.0 years), collected in 15 sites with MRI scanners of three different vendors, was considered. Parallelly, a dataset of 7 "traveling" subjects, each undergoing three acquisitions with scanners from different vendors, was also used. Intra-site, intra-vendor, and inter-site variabilities were evaluated in terms of the percentage standard deviation of volumetric and cortical thickness measures. Image quality metrics such as contrast-to-noise and signal-to-noise ratio in gray and white matter were also assessed for all sites and vendors. The results showed a measured global variability that ranges from 11% to 19% for subcortical volumes and from 3% to 10% for cortical thicknesses. Univariate distributions of the normalized volumes of subcortical regions, as well as the distributions of the thickness of cortical parcels appeared to be significantly different among sites in 8 subcortical (out of 17) and 21 cortical (out of 68) regions of i nterest in the multicentric study. The Bland-Altman analysis on "traveling" brain measurements did not detect systematic scanner biases even though a multivariate classification approach was able to classify the scanner vendor from brain measures with an accuracy of 0.60 ± 0.14 (chance level 0.33).
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Encéfalo , Imagen por Resonancia Magnética , Humanos , Adulto Joven , Adulto , Reproducibilidad de los Resultados , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Neuroimagen , Relación Señal-RuidoRESUMEN
BACKGROUND: TNF-dependent synaptotoxicity contributes to the neuronal damage occurring in patients with Multiple Sclerosis (pwMS) and its mouse model Experimental Autoimmune Encephalomyelitis (EAE). Here, we investigated miR-142-3p, a synaptotoxic microRNA induced by inflammation in EAE and MS, as a potential downstream effector of TNF signalling. METHODS: Electrophysiological recordings, supported by molecular, biochemical and histochemical analyses, were performed to explore TNF-synaptotoxicity in the striatum of EAE and healthy mice. MiR-142 heterozygous (miR-142 HE) mice and/or LNA-anti miR-142-3p strategy were used to verify the TNF-miR-142-3p axis hypothesis. The cerebrospinal fluid (CSF) of 151 pwMS was analysed to evaluate possible correlation between TNF and miR-142-3p levels and their impact on clinical parameters (e.g. progression index (PI), age-related clinical severity (gARMSS)) and MRI measurements at diagnosis (T0). RESULTS: High levels of TNF and miR-142-3p were detected in both EAE striatum and MS-CSF. The TNF-dependent glutamatergic alterations were prevented in the inflamed striatum of EAE miR-142 HE mice. Accordingly, TNF was ineffective in healthy striatal slices incubated with LNA-anti miR- 142-3p. However, both preclinical and clinical data did not validate the TNF-miR-142-3p axis hypothesis, suggesting a permissive neuronal role of miR-142-3p on TNF-signalling. Clinical data showed a negative impact of each molecule on disease course and/or brain lesions and unveiled that their high levels exert a detrimental synergistic effect on disease activity, PI and white matter lesion volume. CONCLUSION: We propose miR-142-3p as a critical modulator of TNF-mediated neuronal toxicity and suggest a detrimental synergistic action of these molecules on MS pathology.
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Encefalomielitis Autoinmune Experimental , MicroARNs , Esclerosis Múltiple , Animales , Humanos , Ratones , Antagomirs , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Inflamación , MicroARNs/genéticaRESUMEN
BACKGROUND: Individual genetic variability may influence the course of multiple sclerosis (MS). The interleukin (IL)-8C>T rs2227306 single nucleotide polymorphism (SNP) regulates IL-8 activity in other clinical conditions; however, its role in MS has never been investigated. OBJECTIVES: To explore the association between IL-8 SNP rs2227306, cerebrospinal fluid (CSF) IL-8 concentrations, clinical, and radiological characteristics in a group of newly diagnosed MS patients. METHODS: In 141 relapsing-remitting (RR)-MS patients, rs2227306 polymorphism, CSF levels of IL-8, clinical, and demographical characteristics were determined. In 50 patients, structural magnetic resonance imaging (MRI) measures were also assessed. RESULTS: An association between CSF IL-8 and Expanded Disability Status Scale (EDSS) at diagnosis was found in our set of patients (r = 0.207, p = 0.014). CSF IL-8 concentrations were significantly higher in patients carrying the T variant of rs2227306 (p = 0.004). In the same group, a positive correlation emerged between IL-8 and EDSS (r = 0.273, p = 0.019). Finally, a negative correlation between CSF levels of IL-8 and cortical thickness emerged in rs2227306T carriers (r = -0.498, p = 0.005). CONCLUSION: We describe for the first time a role of SNP rs2227306 of IL-8 gene in regulating the expression and the activity of this inflammatory cytokine in MS.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico , Interleucina-8/genética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Citocinas , Imagen por Resonancia MagnéticaRESUMEN
Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist. Here, we report the ability of N-substituted l-iminosugars to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype. Particularly, we found that they increase the levels of defective α-N-acetylglucosaminidase and correct its proper sorting toward the lysosomal compartment. Furthermore, l-iminosugars reduce HS accumulation by downregulating protein levels of exostosin glycosyltransferases. These results highlight an interesting pharmacological potential of these glycomimetics in Sanfilippo syndrome, paving the way for the development of novel therapeutic approaches for the treatment of such incurable disease.
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Mucopolisacaridosis III , Humanos , Mucopolisacaridosis III/tratamiento farmacológico , Mucopolisacaridosis III/metabolismo , Heparitina Sulfato/metabolismo , Lisosomas/metabolismo , Fibroblastos/metabolismo , Neuronas/metabolismoRESUMEN
Background/Purpose: To investigate the association between the degree of spatial neglect and the changes of brain system segregation (SyS; i.e., the ratio of the extent to which brain networks interact internally and with each other) after stroke. Methods: A cohort of 20 patients with right hemisphere lesion was submitted to neuropsychological assessment as well as to resting-state functional magnetic resonance imaging session at acute stage after stroke. The severity of spatial neglect was quantified using the Center of Cancellation (CoC) scores of the Bells cancellation test. For each patient, resting-state functional connectivity (FC) matrices were assessed by implementing a brain parcellation of nine networks that included the visual network, dorsal attention network (DAN), ventral attention network (VAN), sensorimotor network (SMN), auditory network, cingulo-opercular network, language network, frontoparietal network, and default mode network (DMN). For each patient and each network, we then computed the SyS derived by subtracting the between-network FC from the within-network FC (normalized by the within-network FC). Finally, for each network, the CoC scores were correlated with the SyS. Results: The correlational analyses indicated a negative association between CoC and SyS in the DAN, VAN, SMN, and DMN (q < 0.05 false discovery rate [FDR]-corrected). Patients with more severe spatial neglect exhibited lower SyS and vice versa. Conclusion: The loss of segregation in multiple and specific networks provides a functional framework for the deficits in spatial and nonspatial attention and motor/exploratory ability observed in neglect patients.
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Background/Purpose: To identify brain hubs that are behaviorally relevant for neglect after stroke as well as to characterize their functional architecture of communication. Methods: Twenty acute right hemisphere damaged patients underwent neuropsychological and resting-state functional magnetic resonance imaging sessions. Spatial neglect was assessed by means of the Center of Cancellation on the Bells Cancellation Test. For each patient, resting-state functional connectivity matrices were derived by adopting a brain parcellation scheme consisting of 153 nodes. For every node, we extracted its betweenness centrality (BC) defined as the portion of all shortest paths in the connectome involving such node. Then, neglect hubs were identified as those regions showing a high correlation between their BC and neglect scores. Results: A first set of neglect hubs was identified in multiple systems including dorsal attention and ventral attention, default mode, and frontoparietal executive-control networks within the damaged hemisphere as well as in the posterior and anterior cingulate cortex. Such cortical regions exhibited a loss of BC and increased (i.e., less efficient) weighted shortest path length (WSPL) related to severe neglect. Conversely, a second group of neglect hubs found in visual and motor networks, in the undamaged hemisphere, exhibited a pathological increase of BC and reduction of WSPL associated with severe neglect. Conclusion: The topological reorganization of the brain in neglect patients might reflect a maladaptive shift in processing spatial information from higher level associative-control systems to lower level visual and sensory-motor processing areas after a right hemisphere lesion.
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Conectoma , Trastornos de la Percepción , Accidente Cerebrovascular , Humanos , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Trastornos de la Percepción/etiología , Trastornos de la Percepción/complicaciones , Mapeo EncefálicoRESUMEN
Quantitative Susceptibility Mapping (QSM) is an MRI-based technique allowing the non-invasive quantification of iron content and myelination in the brain. The RIN - Neuroimaging Network established an optimized and harmonized protocol for QSM across ten sites with 3T MRI systems from three different vendors to enable multicentric studies. The assessment of the reproducibility of this protocol is crucial to establish susceptibility as a quantitative biomarker. In this work, we evaluated cross-vendor reproducibility in a group of six traveling brains. Then, we recruited fifty-one volunteers and measured the variability of QSM values in a cohort of healthy subjects scanned at different sites, simulating a multicentric study. Both voxelwise and Region of Interest (ROI)-based analysis on cortical and subcortical gray matter were performed. The traveling brain study yielded high structural similarity (â¼0.8) and excellent reproducibility comparing maps acquired on scanners from two different vendors. Depending on the ROI, we reported a quantification error ranging from 0.001 to 0.017 ppm for the traveling brains. In the cohort of fifty-one healthy subjects scanned at nine different sites, the ROI-dependent variability of susceptibility values, of the order of 0.005-0.025 ppm, was comparable to the result of the traveling brain experiment. The harmonized QSM protocol of the RIN - Neuroimaging Network provides a reliable quantification of susceptibility in both cortical and subcortical gray matter regions and it is ready for multicentric and longitudinal clinical studies in neurological and pychiatric diseases.
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Encéfalo , Imagen por Resonancia Magnética , Humanos , Reproducibilidad de los Resultados , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Sustancia Gris/diagnóstico por imagen , Mapeo Encefálico/métodosRESUMEN
Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.
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Calcio , Enfermedades por Almacenamiento Lisosomal , Humanos , Calcio/metabolismo , Lisosomas/metabolismo , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Autofagia/fisiología , HidrolasasRESUMEN
In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity.
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Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases.
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Catepsinas , Virosis , Catepsinas/metabolismo , Endopeptidasas , Humanos , Lisosomas/metabolismo , Péptido HidrolasasRESUMEN
Introduction: The plasticity of the neural circuits after injuries has been extensively investigated over the last decades. Transcallosal microsurgery for lesions affecting the third ventricle offers an interesting opportunity to investigate the whole-brain white matter reorganization occurring after a selective resection of the genu of the corpus callosum (CC). Method: Diffusion MRI (dMRI) data and neuropsychological testing were collected pre- and postoperatively in six patients with colloid cysts, surgically treated with a transcallosal-transgenual approach. Longitudinal connectometry analysis on dMRI data and graph analysis on structural connectivity matrix were implemented to analyze how white matter pathways and structural network topology reorganize after surgery. Results: Although a significant worsening in cognitive functions (e.g., executive and memory functioning) at early postoperative, a recovery to the preoperative status was observed at 6 months. Connectometry analysis, beyond the decrease of quantitative anisotropy (QA) near the resection cavity, showed an increase of QA in the body and forceps major CC subregions, as well as in the left intra-hemispheric corticocortical associative fibers. Accordingly, a reorganization of structural network topology was observed between centrality increasing in the left hemisphere nodes together with a rise in connectivity strength among mid and posterior CC subregions and cortical nodes. Conclusion: A structural reorganization of intra- and inter-hemispheric connective fibers and structural network topology were observed following the resection of the genu of the CC. Beyond the postoperative transient cognitive impairment, it could be argued anterior CC resection does not preclude neural plasticity and may subserve the long-term postoperative cognitive recovery.
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BACKGROUND: The development of automated seizure detection methods using EEG signals could be of great importance for the diagnosis and the monitoring of patients with epilepsy. These methods are often patient-specific and require high accuracy in detecting seizures but also very low false-positive rates. The aim of this study is to evaluate the performance of a seizure detection method using EEG signals by investigating its performance in correctly identifying seizures and in minimizing false alarms and to determine if it is generalizable to different patients. METHODS: We tested the method on about two hours of preictal/ictal and about ten hours of interictal EEG recordings of one patient from the Freiburg Seizure Prediction EEG database using machine learning techniques for data mining. Then, we tested the obtained model on six other patients of the same database. RESULTS: The method achieved very high performance in detecting seizures (close to 100% of correctly classified positive elements) with a very low false-positive rate when tested on one patient. Furthermore, the model portability or transfer analysis revealed that the method achieved good performance in one out of six patients from the same dataset. CONCLUSIONS: This result suggests a strategy to discover clusters of similar patients, for which it would be possible to train a general-purpose model for seizure detection.