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1.
Int J Mol Sci ; 25(3)2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38338973

RESUMEN

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.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Polilisina , Humanos , Sistema Nervioso Central , Anticuerpos , Pruebas Hematológicas , Biomarcadores
2.
Mult Scler ; 29(4-5): 512-520, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36803228

RESUMEN

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.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico , Interleucina-8/genética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Citocinas , Imagen por Resonancia Magnética
3.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-36012353

RESUMEN

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.


Asunto(s)
Catepsinas , Virosis , Catepsinas/metabolismo , Endopeptidasas , Humanos , Lisosomas/metabolismo , Péptido Hidrolasas
4.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34207476

RESUMEN

Heparan sulfate proteoglycans (HSPGs) encompass a group of glycoproteins composed of unbranched negatively charged heparan sulfate (HS) chains covalently attached to a core protein. The complex HSPG biosynthetic machinery generates an extraordinary structural variety of HS chains that enable them to bind a plethora of ligands, including growth factors, morphogens, cytokines, chemokines, enzymes, matrix proteins, and bacterial and viral pathogens. These interactions translate into key regulatory activity of HSPGs on a wide range of cellular processes such as receptor activation and signaling, cytoskeleton assembly, extracellular matrix remodeling, endocytosis, cell-cell crosstalk, and others. Due to their ubiquitous expression within tissues and their large functional repertoire, HSPGs are involved in many physiopathological processes; thus, they have emerged as valuable targets for the therapy of many human diseases. Among their functions, HSPGs assist many viruses in invading host cells at various steps of their life cycle. Viruses utilize HSPGs for the attachment to the host cell, internalization, intracellular trafficking, egress, and spread. Recently, HSPG involvement in the pathogenesis of SARS-CoV-2 infection has been established. Here, we summarize the current knowledge on the molecular mechanisms underlying HSPG/SARS-CoV-2 interaction and downstream effects, and we provide an overview of the HSPG-based therapeutic strategies that could be used to combat such a fearsome virus.


Asunto(s)
COVID-19/patología , Proteoglicanos de Heparán Sulfato/metabolismo , SARS-CoV-2/metabolismo , COVID-19/virología , Proteoglicanos de Heparán Sulfato/química , Heparina de Bajo-Peso-Molecular/química , Heparina de Bajo-Peso-Molecular/metabolismo , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Sulfotransferasas/metabolismo , Virosis/tratamiento farmacológico , Virosis/patología , Virosis/virología , Internalización del Virus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19
5.
Int J Mol Sci ; 21(18)2020 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-32916872

RESUMEN

In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.


Asunto(s)
Carcinogénesis , Proteoglicanos de Heparán Sulfato/metabolismo , Sistema de Señalización de MAP Quinasas , Microambiente Tumoral , Proteoglicanos de Heparán Sulfato/química , Humanos , Estructura Molecular , Terapia Molecular Dirigida
6.
Int J Mol Sci ; 21(12)2020 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-32545699

RESUMEN

Mucopolysaccharidoses (MPSs) are inherited disorders of the glycosaminoglycan (GAG) metabolism. The defective digestion of GAGs within the intralysosomal compartment of affected patients leads to a broad spectrum of clinical manifestations ranging from cardiovascular disease to neurological impairment. The molecular mechanisms underlying the progression of the disease downstream of the genetic mutation of genes encoding for lysosomal enzymes still remain unclear. Here, we applied a targeted metabolomic approach to a mouse model of PS IIIB, using a platform dedicated to the diagnosis of inherited metabolic disorders, in order to identify amino acid and fatty acid metabolic pathway alterations or the manifestations of other metabolic phenotypes. Our analysis highlighted an increase in the levels of branched-chain amino acids (BCAAs: Val, Ile, and Leu), aromatic amino acids (Tyr and Phe), free carnitine, and acylcarnitines in the liver and heart tissues of MPS IIIB mice as compared to the wild type (WT). Moreover, Ala, Met, Glu, Gly, Arg, Orn, and Cit amino acids were also found upregulated in the liver of MPS IIIB mice. These findings show a specific impairment of the BCAA and fatty acid catabolism in the heart of MPS IIIB mice. In the liver of affected mice, the glucose-alanine cycle and urea cycle resulted in being altered alongside a deregulation of the BCAA metabolism. Thus, our data demonstrate that an accumulation of BCAAs occurs secondary to lysosomal GAG storage, in both the liver and the heart of MPS IIIB mice. Since BCAAs regulate the biogenesis of lysosomes and autophagy mechanisms through mTOR signaling, impacting on lipid metabolism, this condition might contribute to the progression of the MPS IIIB disease.


Asunto(s)
Hígado/química , Metabolómica/métodos , Mucopolisacaridosis III/metabolismo , Miocardio/química , Aminoácidos Aromáticos/análisis , Aminoácidos de Cadena Ramificada/análisis , Animales , Carnitina/análogos & derivados , Carnitina/análisis , Modelos Animales de Enfermedad , Humanos , Metabolismo de los Lípidos , Masculino , Ratones
7.
Int J Mol Sci ; 21(1)2019 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-31878257

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.


Asunto(s)
Esclerosis Múltiple/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Inflamación/metabolismo , Potenciación a Largo Plazo/genética , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología
8.
Gen Comp Endocrinol ; 242: 66-73, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-26631456

RESUMEN

The peptides orexin A (OxA) and orexin B (OxB) deriving from a common precursor molecule, prepro-orexin, by proteolytic cleavage, bind the two G-coupled OX1 and OX2 receptors. While OX1 selectively binds OxA, OX2 shows similar affinity for both orexins. Firstly discovered in the hypothalamus, orexins and their receptors have been found in other brain regions as well as in peripheral tissues of mammals, thus resulting involved in the regulation of a broad variety of physiological functions. While the functional localization of OxA and OX1 in the mammalian genital tract has been already described, the expression of OxB and OX2 and their potential role in the reproductive functions remain to be explored. Here, we investigated the presence of OxB and OX2 in the rat testis by immunohistochemical and biochemical analyses. The results definitely demonstrated the localization of OxB and OX2 in pachytene and second spermatocytes as well as in spermatids at all stages of the cycle of the seminiferous epithelium. The expression of both OX2 mRNA and protein in the rat testis was also established by RT-PCR and Western blotting, respectively. The analysis of the molecular mechanism of action of OxB in the rat testis showed that OxB, in contrast with OxA, is unable to promote steroidogenesis. These results translate into the regulation of diverse biological actions by OxA and OxB in the male gonad.


Asunto(s)
Receptores de Orexina/metabolismo , Orexinas/metabolismo , Testículo/metabolismo , Animales , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Neuropéptidos/metabolismo , Receptores de Orexina/genética , Orexinas/genética , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropéptido/metabolismo , Espermátides/metabolismo
9.
Biochem Biophys Res Commun ; 464(4): 1290-1296, 2015 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-26220343

RESUMEN

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A in human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer.


Asunto(s)
Receptores de Orexina/metabolismo , Orexinas/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Testosterona/metabolismo , Transporte Activo de Núcleo Celular , Anciano , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Células Tumorales Cultivadas
10.
Am J Med Genet A ; 164A(10): 2627-32, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25044788

RESUMEN

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme, iduronate-2-sulfatase (IDS). Phenotypic expression of MPS II in female patients rarely occurs and may be the result of (i) structural abnormalities of the X chromosome, (ii) homozygosity for disease-causing mutations, or (iii) skewed X-chromosome inactivation, in which the normal IDS allele is preferentially inactivated and the abnormal IDS allele is active. We report here on a female patient with clinical MPS II manifestations, deficiency of IDS enzyme activity and a de novo balanced reciprocal X;9 translocation. As our patient has a skewed XCI pattern, but neither genomic IDS mutations nor abnormal IDS transcripts were detected, we speculate about the possible role of the chromosomal rearrangement in reducing the IDS translation efficiency.


Asunto(s)
Mucopolisacaridosis II/genética , Translocación Genética/genética , Inactivación del Cromosoma X/genética , Alelos , Niño , Femenino , Humanos , Iduronato Sulfatasa/genética , Mutación/genética , Fenotipo
11.
Front Neurosci ; 18: 1426471, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38826776

RESUMEN

[This corrects the article DOI: 10.3389/fnins.2020.577666.].

12.
Cell Biosci ; 14(1): 63, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760822

RESUMEN

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.

13.
iScience ; 27(3): 108959, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38361619

RESUMEN

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.

14.
Front Mol Neurosci ; 17: 1430080, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39169949

RESUMEN

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.

15.
Mol Metab ; 87: 101989, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39019115

RESUMEN

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.


Asunto(s)
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/metabolismo
16.
J Med Chem ; 66(3): 1790-1808, 2023 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-36696678

RESUMEN

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.


Asunto(s)
Mucopolisacaridosis III , Humanos , Mucopolisacaridosis III/tratamiento farmacológico , Mucopolisacaridosis III/metabolismo , Heparitina Sulfato/metabolismo , Lisosomas/metabolismo , Fibroblastos/metabolismo , Neuronas/metabolismo
17.
Brain Connect ; 13(8): 464-472, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36128806

RESUMEN

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.

18.
Front Syst Neurosci ; 17: 1163147, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37205053

RESUMEN

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.

19.
Brain Connect ; 13(8): 473-486, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-34269620

RESUMEN

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.


Asunto(s)
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 Encefálico
20.
Phys Med ; 112: 102610, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37331082

RESUMEN

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.


Asunto(s)
Conectoma , Adulto , Humanos , Conectoma/métodos , Reproducibilidad de los Resultados , Benchmarking , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen
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