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1.
Virus Res ; 342: 199325, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38309472

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 becomes a serious threat to global health and requires the development of effective antiviral therapies. Current therapies that target viral proteins have limited efficacy with side effects. In this study, we investigated the antiviral activity of MIT-001, a small molecule reactive oxygen species (ROS) scavenger targeting mitochondria, against SARS-CoV-2 and other zoonotic viruses in vitro. The antiviral activity of MIT-001 was quantified by RT-qPCR and plaque assay. We also evaluated the functional analysis of MIT-001 by JC-1 staining to measure mitochondrial depolarization, total RNA sequencing to investigate gene expression changes, and immunoblot to quantify protein expression levels. The results showed that MIT-001 effectively inhibited the replication of B.1.617.2 and BA.1 strains, Zika virus, Seoul virus, and Vaccinia virus. Treatment with MIT-001 restored the expression of heme oxygenase-1 (HMOX1) and NAD(P)H: quinone oxidoreductase 1 (NqO1) genes, anti-oxidant enzymes reduced by SARS-CoV-2, to normal levels. The presence of MIT-001 also alleviated mitochondrial depolarization caused by SARS-CoV-2 infection. These findings highlight the potential of MIT-001 as a broad-spectrum antiviral compound that targets for zoonotic RNA and DNA viruses, providing a promising therapeutic approach to combat viral infection.


Assuntos
COVID-19 , Infecção por Zika virus , Zika virus , Humanos , Animais , SARS-CoV-2 , Espécies Reativas de Oxigênio , Pandemias , Peixes , Antivirais/farmacologia
2.
Acta Biomater ; 151: 561-575, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35931279

RESUMO

The efficient production of dopaminergic neurons via the direct conversion of other cell types is of interest as a potential therapeutic approach for Parkinson's disease. This study aimed to investigate the use of elongated porous gold nanorods (AuNpRs) as an enhancer of cell fate conversion. We observed that AuNpRs promoted the direct conversion of fibroblasts into dopaminergic neurons in vivo and in vitro. The extent of conversion of fibroblasts into dopaminergic neurons depended on the porosity of AuNpRs, as determined by their aspect ratio. The mechanism underlying these results involves specific AuNpR-induced transcriptional changes that altered the expression of antioxidant-related molecules. The generation of dopaminergic neurons via the direct conversion method will open a new avenue for developing a therapeutic platform for Parkinson's disease treatment. STATEMENT OF SIGNIFICANCE: In this study, we applied modified gold nanoporous materials (AuNpRs) to the direct lineage reprogramming of dopaminergic neurons. The cell reprogramming process is energy-intensive, resulting in an excess of oxidative stress. AuNpRs facilitated the direct conversion of dopaminergic neurons by ameliorating oxidative stress during the reprogramming process. We have found this mechanistic clue from high throughput studies in this research work.


Assuntos
Nanoporos , Doença de Parkinson , Antioxidantes/metabolismo , Reprogramação Celular , Neurônios Dopaminérgicos/metabolismo , Ouro/metabolismo , Ouro/farmacologia , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia
3.
Nat Neurosci ; 23(12): 1555-1566, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33199896

RESUMO

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Peróxido de Hidrogênio/metabolismo , Doença de Alzheimer/psicologia , Animais , Atrofia , Encéfalo/patologia , Morte Celular , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Humanos , Ativação de Macrófagos , Camundongos , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Monoaminoxidase/metabolismo , Degeneração Neural/patologia , Neuroglia , Neurônios/patologia , Memória Espacial , Tauopatias/patologia
4.
Curr Biol ; 30(2): 276-291.e9, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31928877

RESUMO

Current pharmacological treatments for Parkinson's disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.


Assuntos
Astrócitos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Degeneração Neural/fisiopatologia , Doença de Parkinson/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Resposta de Imobilidade Tônica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , Doença de Parkinson/terapia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Ácido gama-Aminobutírico/biossíntese
5.
Biochim Biophys Acta Mol Basis Dis ; 1865(7): 1938-1945, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481590

RESUMO

Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.


Assuntos
Envelhecimento , Encefalopatias/genética , Epigênese Genética , Mutação , Proteína EWS de Ligação a RNA/genética , Animais , Autofagia , Humanos , MicroRNAs/genética
6.
Exp Neurobiol ; 27(2): 103-111, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29731676

RESUMO

A recent study reveals that missense mutations of EWSR1 are associated with neurodegenerative disorders such as amyotrophic lateral sclerosis, but the function of wild-type (WT) EWSR1 in the central nervous system (CNS) is not known yet. Herein, we investigated the neuroanatomical and motor function changes in Ewsr1 knock out (KO) mice. First, we quantified neuronal nucleus size in the motor cortex, dorsal striatum and hippocampus of three different groups: WT, heterozygous Ewsr1 KO (+/-), and homozygous Ewsr1 KO (-/-) mice. The neuronal nucleus size was significantly smaller in the motor cortex and striatum of homozygous Ewsr1 KO (-/-) mice than that of WT. In addition, in the hippocampus, the neuronal nucleus size was significantly smaller in both heterozygous Ewsr1 KO (+/-) and homozygous Ewsr1 KO (-/-) mice. We then assessed motor function of Ewsr1 KO (-/-) and WT mice by a tail suspension test. Both forelimb and hindlimb movements were significantly increased in Ewsr1 KO (-/-) mice. Lastly, we performed immunohistochemistry to examine the expression of TH, DARPP-32, and phosphorylated (p)-DARPP-32 (Thr75) in the striatum and substantia nigra, which are associated with dopaminergic signaling. The immunoreactivity of TH and DARPP-32 was decreased in Ewsr1 KO (-/-) mice. Together, our results suggest that EWSR1 plays a significant role in neuronal morphology, dopaminergic signaling pathways, and motor function in the CNS of mice.

7.
Aging Cell ; 17(1)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29130578

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD-dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac-p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53-induced mitochondrial dysfunction and neuronal damage in a deacetylase activity-dependent manner. Notably, mitochondrially targeted p53 (mito-p53) directly reduced mitochondria DNA-encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53-ChIP analysis verified the presence of p53-binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito-p53 activity. Our results indicate that SIRT3 dysfunction leads to p53-mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.


Assuntos
Doença de Alzheimer/metabolismo , Mitocôndrias/metabolismo , Sirtuína 3/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Doença de Alzheimer/patologia , Animais , Camundongos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/metabolismo
8.
Exp Neurobiol ; 25(5): 233-240, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27790057

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that leads to a progressive muscle wasting and paralysis. The pathological phenotypes are featured by severe motor neuron death and glial activation in the lumbar spinal cord. Proposed ALS pathogenic mechanisms include glutamate cytotoxicity, inflammatory pathway, oxidative stress, and protein aggregation. However, the exact mechanisms of ALS pathogenesis are not fully understood yet. Recently, a growing body of evidence provides a novel insight on the importance of glial cells in relation to the motor neuronal damage via the non-cell autonomous pathway. Accordingly, the aim of the current paper is to overview the role of astrocytes and microglia in the pathogenesis of ALS and to better understand the disease mechanism of ALS.

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