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1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199295

RESUMO

Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.


Assuntos
Autofagia , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/patologia , Anidridos Ftálicos/uso terapêutico , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/metabolismo , Animais , Ataxina-3/genética , Autofagia/efeitos dos fármacos , Cerebelo/patologia , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doença de Machado-Joseph/fisiopatologia , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Mutação/genética , Anidridos Ftálicos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Acta Biomed ; 92(3): e2021108, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212924

RESUMO

OBJECTIVE: Diffuse glioma arises anywhere in the CNS, but most frequent in the cerebral hemispheres. The tumor tends to be seen in children and in younger adults aged 20-30. We report one such case in an older female patient presenting the intraoperative cytology of the tumor. CASE REPORT: A 48-year-old female was diagnosed by MRI with a tumor of cerebellum. Cytologic material was obtained during the resection of the tumor and diagnosed cytologically as glioma. CONCLUSION: This case is presented to focus the ability of the intraoperative cytology in diagnosis of the glioma, using immunocytology and confirmed by histo- immunohistology.


Assuntos
Glioma , Adulto , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Citodiagnóstico , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade
3.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068922

RESUMO

INTRODUCTION: AQP4 (aquaporin-4)-immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4-IgG in cell differentiation. MATERIAL AND METHODS: We included three groups-a group of patients with AQP4-IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. RESULTS AND CONCLUSIONS: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.


Assuntos
Aquaporina 4/imunologia , Autoanticorpos/imunologia , Diferenciação Celular , Sistema Nervoso Central/patologia , Imunoglobulina G/imunologia , Neuromielite Óptica/imunologia , Células Precursoras de Oligodendrócitos/patologia , Animais , Autoanticorpos/sangue , Estudos de Casos e Controles , Sistema Nervoso Central/imunologia , Cerebelo/imunologia , Cerebelo/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/patologia , Células Precursoras de Oligodendrócitos/imunologia
4.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068557

RESUMO

Depression is a prominent complex psychiatric disorder, usually complicated through expression of comorbid conditions, with chronic pain being among the most prevalent. This comorbidity is consistently associated with a poor prognosis and has been shown to negatively impact patient outcomes. With a global rise in this condition presenting itself, the importance of discovering long-term, effective, and affordable treatments is crucial. Electroacupuncture has demonstrated renowned success in its use for the treatment of pain and is a widely recognized therapy in clinical practice for the treatment of various psychosomatic disorders, most notably depression. Our study aimed to investigate the effects and mechanisms of Acid-Saline (AS) inducing states of chronic pain and depression comorbidity in the cerebellum, using the ST36 acupoint as the therapeutic intervention. Furthermore, the role of TRPV1 was relatedly explored through the use of TRPV1-/- mice (KO). The results indicated significant differences in the four behavioral tests used to characterize pain and depression states in mice. The AS and AS + SHAM group showed significant differences when compared to the Control and AS + EA groups in the von Frey and Hargreaves's tests, as well as the Open-Field and Forced Swimming tests. This evidence was further substantiated in the protein levels observed in immunoblotting, with significant differences between the AS and AS + SHAM groups when compared to the AS + EA and AS + KO groups being identified. In addition, immunofluorescence visibly served to corroborate the quantitative outcomes. Conclusively these findings suggest that AS-induced chronic pain and depression comorbidity elicits changes in the cerebellum lobules VI, VII, VIII, which are ameliorated through the use of EA at ST36 via its action on TRPV1 and related molecular pathways. The action of TRPV1 is not singular in CPDC, which would suggest other potential targets such as acid-sensing ion channel subtype 3 (ASIC3) or voltage-gated sodium channels (Navs) that could be explored in future studies.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Dor Crônica/genética , Depressão/genética , Canais de Cátion TRPV/genética , Ácidos/toxicidade , Pontos de Acupuntura , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/efeitos da radiação , Dor Crônica/induzido quimicamente , Dor Crônica/complicações , Dor Crônica/terapia , Comorbidade , Depressão/complicações , Depressão/patologia , Modelos Animais de Doenças , Eletroacupuntura , Humanos , Camundongos , Camundongos Knockout , Solução Salina/toxicidade , Natação
5.
J Clin Neurosci ; 87: 80-83, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33863540

RESUMO

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by slowly progressive cerebellar ataxia. Previously, autonomic symptoms or dysfunction have not been reported. To evaluate subclinical autonomic dysfunction regarding thermoregulatory function in SCA, we recorded sympathetic outflow to skin in a DRPLA patient confirmed by genetic analysis. We recorded skin sympathetic nerve activity (SSNA), which was elicited and recorded by using the microneurographical technique. In results, the resting frequency of SSNA bursts was very low (8.2 ± 0.4 bursts/min [institutional normal range: 20.8 ± 2.4 bursts/min]). However, acceleration of SSNA bursts induced by mental arithmetic stress was confirmed. The amplitude of reflex bursts induced by electrical stimuli was slightly low (9.6 ± 1.6 µV [institutional normal range: 10.9 ± 2.2 µV]), and the reflex latency was mildly prolonged (872 ± 23.7 msec [institutional normal range: 761.9 ± 51.7 msec]). These results suggest potentially central autonomic dysfunction in this patient with DRPLA. To our knowledge, this is the first report to record SSNA and confirm subclinical autonomic dysfunction in a case with DRPLA.


Assuntos
Fibras Adrenérgicas/fisiologia , Epilepsias Mioclônicas Progressivas/diagnóstico , Epilepsias Mioclônicas Progressivas/fisiopatologia , Condução Nervosa/fisiologia , Fenômenos Fisiológicos da Pele , Pele/inervação , Atrofia , Cerebelo/patologia , Estimulação Elétrica/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Reflexo/fisiologia
6.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918525

RESUMO

The deuterium content modification in an organism has a neuroprotective effect during the hypoxia model, affecting anxiety, memory and stress resistance. The aim of this work was to elucidate the possible mechanisms of the medium D/H composition modification on nerve cells. We studied the effect of an incubation medium with a 50 ppm deuterium content compared to a medium with 150 ppm on: (1) the activity of Wistar rats' hippocampus CA1 field neurons, (2) the level of cultured cerebellar neuron death during glucose deprivation and temperature stress, (3) mitochondrial membrane potential (MMP) and the generation of reactive oxygen species in cultures of cerebellar neurons. The results of the analysis showed that the incubation of hippocampal sections in a medium with a 50 ppm deuterium reduced the amplitude of the pop-spike. The restoration of neuron activity was observed when sections were returned to the incubation medium with a 150 ppm deuterium content. An environment with a 50 ppm deuterium did not significantly affect the level of reactive oxygen species in neuron cultures, while MMP decreased by 16-20%. In experiments with glucose deprivation and temperature stress, the medium with 50 ppm increased the death of neurons. Thus, a short exposure of nerve cells in the medium with 50 ppm deuterium acts as an additional stressful factor, which is possibly associated with the violation of the cell energy balance. The decrease in the mitochondrial membrane potential, which is known to be associated with ATP synthesis, indicates that this effect may be associated with the cell energy imbalance. The decrease in the activity of the CA1 field hippocampal neurons may reflect reversible adaptive changes in the operation of fast-reacting ion channels.


Assuntos
Meios de Cultura/química , Deutério/análise , Fenômenos Eletrofisiológicos , Hidrogênio/análise , Tecido Nervoso/fisiopatologia , Animais , Região CA1 Hipocampal/patologia , Morte Celular , Cerebelo/patologia , Masculino , Neurônios/patologia , Ratos Wistar , Ácido Succínico/análise , Temperatura
7.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805296

RESUMO

The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I-IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder.


Assuntos
Transtorno Bipolar/patologia , Doenças Cerebelares/patologia , Cerebelo/patologia , Substância Cinzenta/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Transtorno Bipolar/diagnóstico por imagem , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia
8.
Life Sci ; 277: 119386, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33774024

RESUMO

AIMS: Homocysteine has been linked to neurodegeneration and motor function impairments. In the present study, we evaluate the effect of chronic mild hyperhomocysteinemia on the motor behavior (motor coordination, functional performance, and muscular force) and biochemical parameters (oxidative stress, energy metabolism, gene expression and/or protein abundance of cytokine related to the inflammatory pathways and acetylcholinesterase) in the striatum and cerebellum of Wistar male rats. MAIN METHODS: Rodents were submitted to one injection of homocysteine (0.03 µmol Hcy/g of body weight) between 30th and 60th postnatal days twice a day. After hyperhomocysteinemia induction, rats were submitted to horizontal ladder walking, beam balance, suspension, and vertical pole tests and/or euthanized to brain dissection for biochemical and molecular assays. KEY FINDINGS: Chronic mild hyperhomocysteinemia did not alter motor function, but induced oxidative stress and impaired mitochondrial complex IV activity in both structures. In the striatum, hyperhomocysteinemia decreased TNF-α gene expression and increased IL-1ß gene expression and acetylcholinesterase activity. In the cerebellum, hyperhomocysteinemia increased gene expression of TNF-α, IL-1ß, IL-10, and TGF-ß, while the acetylcholinesterase activity was decreased. In both structures, hyperhomocysteinemia decreased acetylcholinesterase protein abundance without altering total p-NF-κB, NF-κB, Nrf-2, and cleaved caspase-3. SIGNIFICANCE: Chronic mild hyperhomocysteinemia compromises several biochemical/molecular parameters, signaling pathways, oxidative stress, and chronic inflammation in the striatum and cerebellum of rats without impairing motor function. These alterations may be related to the mechanisms in which hyperhomocysteinemia has been linked to movement disorders later in life and neurodegeneration.


Assuntos
Cerebelo/patologia , Corpo Estriado/patologia , Citocinas/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hiper-Homocisteinemia/fisiopatologia , Estresse Oxidativo , Animais , Cerebelo/metabolismo , Corpo Estriado/metabolismo , Citocinas/genética , Metabolismo Energético , Regulação da Expressão Gênica , Homocisteína/metabolismo , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Ratos , Ratos Wistar
9.
J Neuroimaging ; 31(3): 524-531, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33565204

RESUMO

BACKGROUND AND PURPOSE: Patients with pulmonary arterial hypertension (PAH) frequently present with anxiety, depression, autonomic, and cognitive deterioration, which may indicate brain changes in regions that control these functions. However, the precise regional brain-injury in sites that regulate cognitive, autonomic, and mood functions in PAH remains unclear. We examined the shifts in regional gray matter (GM) volume, using high-resolution T1-weighted images, and brain tissue alterations, using T2-relaxometry procedures, in PAH compared to healthy subjects. METHODS: We collected two high-resolution T1-weighted series, and proton-density and T2-weighted images using a 3.0-Tesla magnetic resonance imaging scanner from 9 PAH and 19 healthy subjects. Both high-resolution T1-weighted images were realigned and averaged, partitioned to GM tissue type, normalized to a common space, and smoothed. Using proton-density and T2-weighted images, T2-relaxation maps were calculated, normalized to a common space, and smoothed. Whole-brain GM volume and T2-relaxation maps were compared between PAH and controls using analysis of covariance (covariates, age, sex, and total-brain-volume; false discover rate corrections). RESULTS: Significantly decreased GM volumes, indicating tissue injury, emerged in multiple brain regions, including the hippocampus, insula, cerebellum, parahippocampus, temporal, frontal, and occipital gyri, cingulate, amygdala, and thalamus. Higher T2-relaxation values, suggesting tissue damage, appeared in the cerebellum, hippocampus, parahippocampus, frontal, lingual, and temporal and occipital gyri, and cingulate areas in PAH compared to healthy subjects. CONCLUSIONS: PAH patients showed significant GM injury and brain tissue changes in sites that regulate cognition, autonomic, and mood functions. These findings indicate a brain structural basis for functional deficits in PAH patients.


Assuntos
Lesões Encefálicas/patologia , Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Hipertensão Arterial Pulmonar/patologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Lesões Encefálicas/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Cognição/fisiologia , Feminino , Substância Cinzenta/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Tálamo/patologia
10.
Int J Rehabil Res ; 44(2): 104-109, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481455

RESUMO

Sporadic spinocerebellar degenerative diseases such as multiple system atrophy (cerebellar type) and cortical cerebellar atrophy typically present with cerebellar ataxia. Multiple system atrophy is characterized by ataxia, with parkinsonism, dysautonomia and neuropsychiatric symptoms, resulting in reduced quality of life. Effects of physical rehabilitation focused on motor symptoms with ataxia in nonmultiple system atrophy patients have been reported; however, without addressing concomitant nonmotor symptoms. Here, we examined the motor, nonmotor and quality of life effects of inpatient physical rehabilitation in 15 multiple systems atrophy and nine cortical cerebellar atrophy patients without dementia. Rehabilitation involved a 4-week hospitalization with physical, occupational and speech therapy. The following assessments were conducted at admission and discharge: the scale for the assessment and rating of ataxia for ataxia; Montreal cognitive assessment for cognition, hospital anxiety and depression scale for emotion and medical outcomes study short-form for health-related quality of life. Data were analyzed for statistical significance (P < 0.05) using the Wilcoxon signed-rank test. In patients with multiple system atrophy, rehabilitation significantly improved ataxia, cognition with mild cognitive impairment (73.3%) and health-related quality of life; however, patients with depression (86.7%) showed no improvement in emotional health and quality of life. Similar effects on motor and nonmotor symptoms were observed in patients with cortical cerebellar atrophy. This suggests that inpatient rehabilitation could not only improve motor and nonmotor functions, but also the quality of life in patients with spinocerebellar degenerative disease.


Assuntos
Atrofia/patologia , Cerebelo/patologia , Atrofia de Múltiplos Sistemas/terapia , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/patologia , Estudos Retrospectivos
11.
FASEB J ; 35(2): e21329, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33484186

RESUMO

L1 syndrome is a rare developmental disorder characterized by hydrocephalus of varying severity, intellectual deficits, spasticity of the legs, and adducted thumbs. Therapy is limited to symptomatic relief. Numerous gene mutations in the L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in L1 syndrome patients, and those affecting the extracellular domain of this transmembrane type 1 glycoprotein show the most severe phenotypes. Previously analyzed rodent models of the L1 syndrome focused on L1-deficient animals or mouse mutants with abrogated cell surface expression of L1, making it difficult to test L1 function-triggering mimetic compounds with potential therapeutic value. To overcome this impasse, we generated a novel L1 syndrome mouse with a mutation of aspartic acid at position 201 in the extracellular part of L1 (p.D201N, hereafter termed L1-201) that displays a cell surface-exposed L1 accessible to the L1 mimetics. Behavioral assessment revealed an increased neurological deficit score and increased locomotor activity in male L1-201 mice carrying the mutation on the X-chromosome. Histological analyses of L1-201 mice showed features of the L1 syndrome, including enlarged ventricles and reduced size of the corpus callosum. Expression levels of L1-201 protein as well as extent of cell surface biotinylation and immunofluorescence labelling of cultured cerebellar neurons were normal. Importantly, treatment of these cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine rescued impaired cell migration and survival as well as neuritogenesis. Altogether, the novel L1 syndrome mouse model provides a first experimental proof-of-principle for the potential therapeutic value of L1 mimetic compounds.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Peptidomiméticos/uso terapêutico , Paraplegia Espástica Hereditária/tratamento farmacológico , Animais , Células Cultivadas , Cerebelo/citologia , Cerebelo/metabolismo , Cerebelo/patologia , Ventrículos Cerebrais/metabolismo , Ventrículos Cerebrais/patologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cloridrato de Duloxetina/farmacologia , Cloridrato de Duloxetina/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Molécula L1 de Adesão de Célula Nervosa/genética , Neurogênese , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peptidomiméticos/farmacologia , Fenótipo , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologia , Toluidinas/farmacologia , Toluidinas/uso terapêutico , Trimebutina/farmacologia , Trimebutina/uso terapêutico
12.
Environ Toxicol ; 36(4): 491-505, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33219756

RESUMO

Valproic acid (VPA)-a short branched chain fatty acid (BCFA), is widely recognized as an anticonvulsant and a mood-stabilizing drug, but various adverse effects of VPA have also been investigated. However, the impact of BCFAs aggregation on brain cells, in the pathogenesis of neurodegeneration remains elusive. The objective of this study is to understand the cellular mechanisms underlying VPA-induced neuronal cell death mediated by oxidative stress, and the neuroprotective role of exogenous melatonin treatment on VPA-induced cell death. Neurotoxicity of VPA and protective role exerted by melatonin were assessed in vitro in SH-SY5Y cells and in vivo in the cerebral cortex and cerebellum regions of Wistar rat brain. The results show that melatonin pre-treatment protects the cells from VPA-induced toxicity by exerting an anti-apoptotic and anti-inflammatory effect by regulating apoptotic proteins and pro-inflammatory cytokines. The findings of the present study emphasize novel insights of melatonin as a supplement for the prevention and treatment of neuronal dysfunction induced by VPA.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Graxos/metabolismo , Melatonina/farmacologia , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Humanos , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Ácido Valproico/metabolismo , Ácido Valproico/toxicidade
13.
Cancer Lett ; 499: 188-200, 2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33253789

RESUMO

The deregulation of epigenetic pathways has been implicated as a critical step in tumorigenesis including in childhood brain tumor medulloblastoma. The H3K27me3 demethylase UTX/KDM6A plays important roles in development and is frequently mutated in various types of cancer. However, how UTX regulates tumor development remains largely unclear. Here, we report the generation of a UTX-deleted mouse model of SHH medulloblastoma that demonstrates the tumor suppressor functions of UTX, which could be antagonized by the deletion of another H3K27me3 demethylase JMJD3/KDM6B. Intriguingly, UTX deletion in cancerous cerebellar granule neuron precursors (CGNPs) resulted in the impaired recruitment of host CD8+ T cells to the tumor microenvironment through a non-cell autonomous mechanism. In both mouse medulloblastoma models and in human medulloblastoma cells, we showed that UTX activates Th1-type chemokines, which are responsible for T cell migration. Surprisingly, our results showed that the depletion of cytotoxic CD8+ T cells did not affect mouse medulloblastoma growth. Nevertheless, the UTX/chemokine/T cell recruitment pathway we identified may be applied to many other cancers and may be important for improving cancer immunotherapy. In addition, UTX is required for the expression of NeuroD2 in precancerous progenitors, which encodes a potent proneural transcription factor. Overexpression of NEUROD2 in CGNPs decreased cell proliferation and increased neuron differentiation. We showed that UTX deletion led to impaired neural differentiation, which could coordinate with active SHH signaling to accelerate medulloblastoma development. Thus, UTX regulates both cell-intrinsic oncogenic processes and the tumor microenvironment in medulloblastoma. Our study provides insights into both medulloblastoma development and context dependent functions of UTX in tumorigenesis.


Assuntos
Neoplasias Cerebelares/genética , Histona Desmetilases/metabolismo , Meduloblastoma/genética , Proteínas Supressoras de Tumor/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Histona Desmetilases/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Masculino , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/patologia , Neurônios/patologia , Neuropeptídeos/genética , Cultura Primária de Células , Receptor Smoothened/genética , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Proteínas Supressoras de Tumor/genética
15.
Anat Sci Int ; 96(1): 87-96, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32789737

RESUMO

Cerebellar abnormalities are commonly associated with hydrocephalus. However, the effect of hydrocephalus on the otherwise normal cerebellum has been largely neglected. This study assesses the morphological changes in the Purkinje cells in relation to cerebellar dysfunction observed in juvenile hydrocephalic rats. Fifty-five three-week old albino Wistar rats were used, hydrocephalus was induced by intracisternal injection of kaolin (n = 35) and others served as controls (n = 20). Body weight measurements, hanging wire, negative geotaxis, and open field tests were carried out at the onset and then weekly for 4 weeks, rats were killed, and their cerebella processed for Hematoxylin and Eosin, Cresyl violet and Golgi staining. Qualitative and quantitative studies were carried out; quantitative data were analyzed using two-way ANOVA and independent T tests at p < 0.05. Hydrocephalic rats weighed less than controls (p = 0.0247) but their cerebellar weights were comparable. The hydrocephalic rats had a consistently shorter latency to fall in the hanging wire test (F(4,112) = 18.63; p < 0.0001), longer latency to turn in the negative geotaxis test (F(4,112) = 22.2; p < 0.0001), and decreased horizontal (F(4,112) = 4.172, p = 0.0035) and vertical movements (F(4,112) = 4.397; p = 0.0024) in the open field test than controls throughout the 4 weeks post-induction. Cellular compression in the granular layer, swelling of Purkinje cells with vacuolations, reduced dendritic arborization and increased number of pyknotic Purkinje cells were observed in hydrocephalic rats. Hydrocephalus caused functional and morphological changes in the cerebellar cortex. Purkinje cell loss, a major pathological feature of hydrocephalus, may be responsible for some of the motor deficits observed in this condition.


Assuntos
Cerebelo/patologia , Cerebelo/fisiopatologia , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Caulim/efeitos adversos , Desempenho Psicomotor , Células de Purkinje/fisiologia , Animais , Cerebelo/citologia , Modelos Animais de Doenças , Hidrocefalia/induzido quimicamente , Movimento , Ratos Wistar
16.
Mol Genet Genomics ; 296(1): 33-40, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32944789

RESUMO

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Síndrome de Dandy-Walker/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Lisencefalia/genética , Mutação de Sentido Incorreto , Proteínas/genética , Retina/anormalidades , Tetralogia de Fallot/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Tronco Encefálico/anormalidades , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Vermis Cerebelar/anormalidades , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Cerebelo/patologia , Pré-Escolar , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/metabolismo , Síndrome de Dandy-Walker/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Família , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Proteínas Hedgehog/deficiência , Proteínas Hedgehog/genética , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Lisencefalia/diagnóstico por imagem , Lisencefalia/metabolismo , Lisencefalia/patologia , Masculino , Linhagem , Fenótipo , Proteínas/metabolismo , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores Sexuais , Transdução de Sinais , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/metabolismo , Tetralogia de Fallot/patologia , Proteína GLI1 em Dedos de Zinco/deficiência , Proteína GLI1 em Dedos de Zinco/genética
18.
Pediatr Blood Cancer ; 68(2): e28770, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33063942

RESUMO

Retinoblastoma survivors with a germline RB1 mutation are at elevated risk for secondary (nonocular) malignancy, but their risk for low-grade glioma (LGG) is unknown. We performed a retrospective review of the Memorial Sloan Kettering Cancer Center and the NCI databases that revealed that three of the 837 5-year survivors of hereditary retinoblastoma were diagnosed with an LGG and a fourth patient (but unilateral and without a germline mutation) was identified at another center. Retinoblastoma survivors may be at increased risk for LGG.


Assuntos
Glioma/genética , Segunda Neoplasia Primária/genética , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Cerebelo/patologia , Feminino , Predisposição Genética para Doença/genética , Glioma/patologia , Humanos , Masculino , Segunda Neoplasia Primária/diagnóstico , Neoplasias da Retina/patologia , Neoplasias da Retina/terapia , Retinoblastoma/patologia , Retinoblastoma/terapia , Lobo Temporal/patologia , Adulto Jovem
19.
Exp Neurol ; 335: 113516, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33172833

RESUMO

The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.


Assuntos
Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Cerebelo/patologia , Hipocampo/patologia , Transcriptoma , Animais , Peso Corporal , Lesões Encefálicas Traumáticas/psicologia , Corticosterona/sangue , Lesão Axonal Difusa/genética , Lesão Axonal Difusa/patologia , Lobo Frontal/lesões , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/patologia , Masculino , Aprendizagem em Labirinto , Análise em Microsséries , Desempenho Psicomotor , Ratos , Ratos Wistar , Recuperação de Função Fisiológica
20.
Biochim Biophys Acta Mol Basis Dis ; 1867(1): 165976, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33011198

RESUMO

BACKGROUND: There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia and dystonia share common biological pathways. We therefore aimed to increase our understanding of their shared pathophysiology by investigating their shared biological pathways and molecular networks. METHODS: We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology database and genome-wide association studies, and identified shared genes between the three diseases. We then assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression profiles and brain-tissue-specific gene co-expression networks. RESULTS: The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein-protein interaction networks. Biological processes common/shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic transmission, synaptic plasticity and nervous system development. The average expression of shared genes was significantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinct cerebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development. CONCLUSIONS: The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cerebellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing.


Assuntos
Ataxia , Encéfalo , Cerebelo , Depressão , Distonia , Plasticidade Neuronal , Transmissão Sináptica , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Depressão/genética , Depressão/metabolismo , Depressão/patologia , Distonia/genética , Distonia/metabolismo , Distonia/patologia , Estudo de Associação Genômica Ampla , Humanos , Mapas de Interação de Proteínas
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