RESUMO
Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 µM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1-/- mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Cardiomiopatias , Doxorrubicina , Ferroptose , Heme Oxigenase-1 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos , Estresse Oxidativo , Animais , Ferroptose/efeitos dos fármacos , Doxorrubicina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Masculino , Camundongos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Linhagem Celular , Ratos , Cardiotoxicidade , Antibióticos Antineoplásicos/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Protoporfirinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cicloexilaminas , Proteínas de Membrana , FenilenodiaminasRESUMO
Paraneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Síndromes Paraneoplásicas do Sistema Nervoso/induzido quimicamente , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , China , Etoposídeo/uso terapêutico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Microglia-mediated inflammation plays an important role in the pathogenesis of several neurodegenerative diseases including Parkinson's disease (PD). Recently, autophagy has been linked to the regulation of the inflammatory response. However, the potential role of microglial autophagy in the context of PD pathology has not been characterized. In the present study, we investigated whether impaired microglial autophagy would affect dopaminergic neurodegeneration and neuroinflammation both in vivo and in vitro. In vitro, BV2 microglial cells were exposed to LPS in the presence or absence of autophagy-related gene 5 (Atg5) small interference RNA (Atg5-siRNA). For in vivo study, microglial Atg5 conditional knockout (Atg5flox/flox; CX3CR1-Cre) mice and their wild-type littermates (Atg5flox/flox) were intraperitoneally injected with MPTP to induce experimental PD model. Our results revealed that disruption of autophagy by Atg5-siRNA aggravated LPS-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2 conditioned medium. In mice, impaired autophagy in microglia exacerbated dopaminergic neuron loss in response to MPTP. The mechanism by which the deficiency of microglial autophagy promoted neuroinflammation and dopaminergic neurodegeneration was related to the regulation of NLRP3 inflammasome activation. These findings demonstrate that impairing microglial autophagy aggravates pro-inflammatory responses to LPS and exacerbates MPTP-induced neurodegeneration by modulating NLRP3 inflammasome responses. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for PD.
Assuntos
Microglia , Doença de Parkinson , Animais , Autofagia , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Inflamassomos , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.
Assuntos
Inflamação/etiologia , Glicoproteínas de Membrana/fisiologia , Microglia/fisiologia , Doença de Parkinson/etiologia , Receptores Imunológicos/fisiologia , alfa-Sinucleína/farmacologia , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Feminino , Masculino , Glicoproteínas de Membrana/deficiência , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , Receptores Imunológicos/deficiência , Transdução de SinaisRESUMO
INTRODUCTION: Allergic bronchopulmonary aspergillosis (ABPA) has been regarded as a rare disease in China due to the lack of quantitative detection of Aspergillus fumigatus-specific IgE (sIgE). We compared the diagnostic rate of ABPA among asthma patients with or without A. fumigatus-sIgE screening tests to evaluate the benefit of the tests in diagnosing ABPA. METHODS: We reviewed the detection rate of A. fumigatus-sIgE and the diagnostic rate of ABPA in 1842 asthma patients in the First Affiliated Hospital of Zhejiang University from 2014 to 2016. Additionally, we collected 144 asthma cases from November 2016 to March 2017 to detect the total serum IgE, A. fumigatus-sIgE and sIgE against mixed mold extract, the ABPA diagnostic rate of these patients was then compared with the total cohort. Total serum IgE, A. fumigatus-sIgE and sIgE against mixed mold extract were also tested in 30 patients identified with Aspergillus-positive sputum culture to analyze the incidence of ABPA. RESULTS: Among the 1,842 asthma cases, 566 were inspected for total IgE; 308 (55.40%) were total IgE-positive and 58 (10.43%) had total IgE > 1,000 IU/mL. In contrast, only 126 cases were tested for A. fumigatus-sIgE (6.84%), and 28 had A. fumigatus-sIgE > 0.35 kUA/L (22.22%). Eleven patients were finally diagnosed with ABPA. Of 1,842 asthma patients, only 0.6% were diagnosed with ABPA if the A. fumigatus-sIgE was not detected at first. Moreover, among the 144 asthma cases that were selected for total IgE, A. fumigatus-sIgE, and sIgE against mixed mold extract screening tests, 12 had total IgE > 1,000 IU/mL (8.33%), 11 had A. fumigatus-sIgE > 0.35 kUA/L (7.64%), and 14 had sIgE against mixed mold extract > 0.35 (9.72%); 7 of these patients were confirmed as having ABPA according to the ISHAM guidelines (4.86%) but only 2 without A. fumigatus-sIgE screening test were diagnosed with ABPA (1.39%) (p = 0.000). Of the 30 Aspergillus-positive sputum culture cases, 4 had A. fumigatus-sIgE > 0.35 kUA/L (13.33%), but none was diagnosed with ABPA. CONCLUSIONS: Routine A. fumigatus-sIgE screening for asthma patients can significantly improve the diagnostic rate of ABPA.
Assuntos
Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus fumigatus/imunologia , Asma/complicações , Imunoglobulina E/sangue , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergilose Broncopulmonar Alérgica/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escarro/microbiologiaRESUMO
FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Cloridrato de Fingolimode/uso terapêutico , Degeneração Neural/metabolismo , Degeneração Neural/prevenção & controle , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamenteRESUMO
Recent laboratory and gene sequencing data suggest that variations in receptors called the "triggering-receptors-expressed-on-myeloid-cells" (TREMs) are implicated in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and frontotemporal lobar degeneration. TREM receptors are thought to play a critical role in regulating the immune system, inflammation, and certain cellular functions. One TREM, in particular, TREM2, is highly expressed on cells of the myeloid lineage. The binding of TREM2 to the adapter protein, DNAX activating protein of 12 kD (DAP12), in microglial cells has been shown to modulate phagocytosis within the nervous system. This review highlights the role of TREM2 in neurological diseases. Moreover, here we consider potential contributions of TREM2 and mechanisms underlying TREM2 activity as contributing to neurodegeneration. These findings may provide novel insights and opportunities to consider, especially for clinicians, as they diagnose and treat certain neurological diseases.
Assuntos
Glicoproteínas de Membrana/metabolismo , Doenças do Sistema Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/patologiaRESUMO
In this study, we investigated whether tanshinone I (T-I) has therapeutic effects in cellular and animal model of Parkinson's disease (PD), and explore its possible mechanism. For this purpose, human neuroblastoma SH-SY5Y cells were cultured and exposed to 100 µM 6-hydroxydopamine (6-OHDA) in the absence or presence of T-I (1, 2.5 and 5 µM). The results revealed that 6-OHDA-induced cell death was reduced by T-I pretreatment as measured by MTT assay, lactate dehydrogenase release and flow cytomety analysis of cell apoptosis. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by T-I in SH-SY5Y cells. T-I pretreatment was also shown to result in an increase in nuclear factor erythroid-2-related factor 2 (Nrf2) protein levels and its transcriptional activity as well as the upregulation of Nrf2-dependent genes encoding the antioxidant enzymes heme oxygenase-1, glutathione cysteine ligase regulatory subunit and glutathione cysteine ligase modulatory subunit in SH-SY5Y cells. Moreover, in the in vivo experiment, T-I treatment significantly attenuated 6-OHDA-induced striatal oxidative stress and ameliorated dopaminergic neurotoxicity in 6-OHDA-lesioned mice, as evidenced by western blot analysis of tyrosine hydroxylase (TH) and TH immunostaining of dopaminergic neurons in the substantia nigra and the striatum. Taken together, the results suggest that T-I may be beneficial for the treatment of neurodegenerative diseases like PD.
Assuntos
Abietanos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Doença de Parkinson/prevenção & controle , Abietanos/uso terapêutico , Animais , Elementos de Resposta Antioxidante , Morte Celular , Linhagem Celular Tumoral , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Transcrição Gênica , Regulação para CimaRESUMO
Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. S-allyl cysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has been reported to possess neuroprotective effects against stroke. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study tests the hypothesis that SAC attenuates ischemic neuronal injury by activating the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response in both in vitro and in vivo models. Our findings demonstrate that SAC treatment resulted in an increase in Nrf2 protein levels and subsequent activation of antioxidant response element pathway genes in primary cultured neurons and mice. Exposure of primary neurons to SAC provided protection against oxygen and glucose deprivation-induced oxidative insults. In wild-type (Nrf2(+/+) ) mice, systemic administration of SAC attenuated middle cerebral artery occlusion-induced ischemic damage, a protective effect not observed in Nrf2 knockout (Nrf2(-/-) ) mice. Taken together, these findings provide the first evidence that activation of the Nrf2 antioxidant response by SAC is strongly associated with its neuroprotective effects against experimental stroke and suggest that targeting the Nrf2 pathway may provide therapeutic benefit for the treatment of stroke. The transcription factor Nrf2 is involved in cerebral ischemic disease and may be a promising target for the treatment of stroke. We provide novel evidence that SAC confers neuroprotection against ischemic stroke by activating the antioxidant Nrf2 signaling pathway. ARE, antioxidant response element; GCLC, glutathione cysteine ligase regulatory subunit; GCLM, glutathione cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; Maf, musculoaponeurotic fibrosarcoma; Nrf2, nuclear factor erythroid-2-related factor 2; SAC, S-allyl cysteine; ROS, reactive oxygen species.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Cisteína/análogos & derivados , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Infarto Encefálico/etiologia , Infarto Encefálico/prevenção & controle , Células Cultivadas , Córtex Cerebral/citologia , Cisteína/farmacologia , Cisteína/uso terapêutico , Modelos Animais de Doenças , Embrião de Mamíferos , Glucose/deficiência , Hipóxia/tratamento farmacológico , Marcação In Situ das Extremidades Cortadas , L-Lactato Desidrogenase/metabolismo , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Exame Neurológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Eriodictyol, a flavonoid isolated from the Chinese herb Dracocephalum rupestre, has long been established as an antioxidant. The present study was designed to investigate the effect of eriodictyol on ß-amyloid 25-35 peptide (Aß25-35)-induced oxidative cell death in primary neurons and to explore the role of the nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway in this process. For this purpose, primary cultures of cortical neurons were exposed to 15 µM Aß25-35 in the absence or presence of eriodictyol (20, 40 and 80 µM). The results revealed that Aß25-35-induced cytotoxicity and apoptotic characteristics such as activation of JNK/p38 apoptotic signaling pathway were effectively attenuated by eriodictyol pretreatment. Eriodictyol treatment also resulted in an increase in Nrf2 protein levels and subsequent activation of ARE pathway genes in primary cultured neurons. The protective effects of eriodictyol were attenuated by RNA interference-mediated knockdown of Nrf2 expression. Taken together, these results clearly demonstrate that eriodictyol protects neurons against Aß25-35-induced cell death partially through Nrf2/ARE signaling pathway, which further supports that eriodictyol might be a promising novel therapeutic agent for AD.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Morte Celular/efeitos dos fármacos , Flavanonas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Fragmentos de Peptídeos/toxicidade , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Neurônios/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: A large cranial defect following decompressive craniectomy (DC) is a common sequela in patients with severe traumatic brain injury (TBI). Such a defect can cause severe disturbance of cerebral blood flow (CBF) regulation. This study investigated the impact of cranioplasty on CBF in these patients. METHODS: Patients who underwent DC and secondary cranioplasty were prospectively studied for a severe TBI. CT perfusion was used to measure CBF before and after cranioplasty. The basal ganglia, parietal lobe and occipital lobe on the decompressed side were chosen as zones of interest for CBF evaluation. RESULTS: Nine patients representing nine cranioplasty procedures were included in the study. Before cranioplasty, CBF on the decompressed side was lower than that on the contralateral side. During the early stage (10 days) after cranioplasty, CBF on the decompressed side was increased and this increase was significant in the parietal and occipital lobe. CBF was also increased on the contralateral side. In addition, the difference in CBF between the contralateral side and the decompressed side was reduced after cranioplasty. Further, the CT perfusion showed that the CBFs decreased again 3 months post-cranioplasty among four cases, but was still higher than those before cranioplasty. CONCLUSIONS: This study indicates that cranioplasty may increase CBF and benefit the recovery in patients with DC for TBI.
Assuntos
Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/cirurgia , Circulação Cerebrovascular/fisiologia , Craniectomia Descompressiva/métodos , Adulto , Feminino , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Procedimentos de Cirurgia Plástica/métodos , Crânio/cirurgia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Aging, the main risk factor for Parkinson's disease (PD), is associated with increased α-synuclein levels in substantia nigra pars compacta (SNc). Excess α-synuclein spurs Lewy-like pathology and dysregulates the activity of protein phosphatase 2A (PP2A). PP2A dephosphorylates many neuroproteins, including the catecholamine rate-limiting enzyme, tyrosine hydroxylase (TH). A loss of nigral dopaminergic neurons induces PD movement problems, but before those abnormalities occur, behaviors such as olfactory loss, anxiety, and constipation often manifest. Identifying mouse models with early PD behavioral changes could provide a model in which to test emerging therapeutic compounds. To this end, we evaluated mice expressing A53T mutant human (A53T) α-synuclein for behavior and α-synuclein pathology in olfactory bulb, adrenal gland, and gut. Aging A53T mice exhibited olfactory loss and anxiety that paralleled olfactory and adrenal α-synuclein aggregation. PP2A activity was also diminished in olfactory and adrenal tissues harboring insoluble α-synuclein. Low adrenal PP2A activity co-occurred with TH hyperactivity, making this the first study to link adrenal synucleinopathy to anxiety and catecholamine dysregulation. Aggregated A53T α-synuclein recombinant protein also had impaired stimulatory effects on soluble recombinant PP2A. Collectively, the data identify an excellent model in which to screen compounds for their ability to block the spread of α-synuclein pathology associated with pre-motor stages of PD.
Assuntos
Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , alfa-Sinucleína/genética , Glândulas Suprarrenais/enzimologia , Glândulas Suprarrenais/metabolismo , Envelhecimento/patologia , Animais , Ansiedade/genética , Ansiedade/psicologia , Western Blotting , Química Encefálica/fisiologia , Progressão da Doença , Alimentos , Trato Gastrointestinal/enzimologia , Trato Gastrointestinal/metabolismo , Genótipo , Hipercinese/genética , Hipercinese/psicologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Neurônios/fisiologia , Transtornos Parkinsonianos/enzimologia , Proteína Fosfatase 2/metabolismo , Olfato/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
(-)-Epigallocatechin gallate (EGCG) has recently been shown to exert neuroprotection in a variety of neurological diseases; however, its role and the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the potential neuroprotective effects of EGCG and the possible role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in the putative neuroprotection against experimental stroke in rats. The results revealed that EGCG exhibit significant neuroprotection, as evidenced by reduced infarction size and the decrease in transferase dUTP nick end labeling-positive neurons. Furthermore, EGCG also enhanced levels of Nrf2 and its downstream ARE pathway genes such as heme oxygenase-1, glutamate-cysteine ligase modulatory subunit and glutamate-cysteine ligase regulatory subunit, as compared to control groups. In accordance with its induction of Nrf2 activation, EGCG exerted a robust attenuation of reactive oxygen species generation and an increase in glutathione content in ischemic cortex. Taken together, these results demonstrated that EGCG exerted significant antioxidant and neuroprotective effects following focal cerebral ischemia, possibly through the activation of the Nrf2/ARE signaling pathway.
Assuntos
Elementos de Resposta Antioxidante/fisiologia , Isquemia Encefálica/metabolismo , Catequina/análogos & derivados , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Isquemia Encefálica/prevenção & controle , Catequina/farmacologia , Catequina/uso terapêutico , Masculino , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis in PLWH.
RESUMO
Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Flavanonas/farmacologia , Glucosídeos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Recent emerging evidence reveals that cGAS-STING-mediated Type I interferon (IFN) signaling axis takes part in the microglial-associated neuroinflammation. However, the potential role of pharmacological inhibition of STING on neuroinflammation and dopaminergic neurodegeneration remains unknown. In the present study, we investigated whether pharmacological inhibition of STING attenuates neuroinflammation and neurodegeneration in experimental models of Parkinson's disease. We report that therapeutic inhibition of STING with C-176 significantly inhibited the activation of downstream signaling pathway, suppressed neuroinflammation, and ameliorated MPTP-induced dopaminergic neurotoxicity and motor deficit. Furthermore, pharmacological inhibition of STING with C-176 attenuated proinflammatory response in BV2 microglial cells exposed to LPS/MPP+. More importantly, C-176 also reduced NLRP3 inflammasome activation both in vitro and in vivo. The results of our study suggest that pharmacologic inhibition of STING protects against dopaminergic neurodegeneration and neuroinflammation that may act at least in part through suppressing NLRP3 inflammasome activation. STING signaling may hold great promise for the development of new treatment strategy for PD.
RESUMO
BACKGROUND: Crigler-Najjar syndrome type I (CNS I) is a very rare autosomal recessive inherited disease that liver transplantation can properly deal with. METHODS: We present one case of an 18-month-old child with CNS I diagnosed by clinical findings and genetic detecting. LTx was performed 5 days after kernicterus broke out and neurological symptoms were successfully reversed. RESULT: Magnetic resonance imaging and magnetic resonance spectroscopy showed encouraging results that brain pathology had a trend to return to normal in 1-year follow-up, combined with electroencephalogram and motor development estimate studies. CONCLUSIONS: Liver transplantation can cure CNS I with reversible neurological symptoms to some extent in time. Magnetic resonance spectroscopy may be a future option of predicting brain conditions and selecting suitable patients with CNS I for transplantation.
Assuntos
Síndrome de Crigler-Najjar/cirurgia , Transplante de Fígado/métodos , Bilirrubina/sangue , Síndrome de Crigler-Najjar/sangue , Síndrome de Crigler-Najjar/patologia , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , MasculinoRESUMO
Microglia-mediated neuroinflammation and mitochondrial dysfunction play critical role in the pathogenic process of Parkinson's disease (PD). Mitophagy plays central role in mitochondrial quality control. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia-mediated neurodegeneration and neuroinflammation. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Several preclinical studies have reported the beneficial effects of UA on age-related conditions by increasing mitophagy and blunting excessive inflammatory responses. However, the specific role of UA in pathology of PD remains unknown. In this study, we showed that treatment with UA reduced the loss of dopaminergic neurons, ameliorated behavioral deficits and neuroinflammation in MPTP mouse model of PD. Further study revealed that UA promotes mitophagy, restores mitochondrial function and attenuate proinflammatory response in BV2 microglial cells exposed to LPS. Moreover, UA also reduced NLRP3 inflammasome activation both in vitro and in vivo. Importantly, disruption of microglial mitophagy with pharmacological or genetic approach partly blunted the neuroprotective effects of UA in MPTP mouse model of PD. Collectively, these results provide strong evidence that UA protects against dopaminergic neurodegeneration and neuroinflammation. The mechanism may be related with its inhibition of NLRP3 inflammasome activation via promoting mitophagy in microglia.
Assuntos
Cumarínicos/farmacologia , Inflamassomos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of PD. Recent reports have highlighted the protective role of urolithin A (UA), a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries and walnuts, in several neurological disorders including Alzheimer's disease and ischemic stroke. However, the potential role of UA in PD has not been characterized. In this study, we investigated the underlying mechanisms for role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mice model of PD. Our results revealed that UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells. Meanwhile, administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-striatal dopaminergic neurotoxicity. More important, UA treatment significantly attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogenesis. Mechanistically, we demonstrated that UA exerts neuroprotective effects by promoting mitochondrial biogenesis via SIRT1-PGC-1α signaling pathway. Taken together, these data provide new insights into the novel role of UA in regulating mitochondrial dysfunction and suggest that UA may have potential therapeutic applications for PD.
Assuntos
Cumarínicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Células PC12 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismoRESUMO
Objective: Brain atrophy is an important imaging characteristic of cerebral small vascular disease (CSVD). Our study explores the linear measurement application on CT images of CSVD patients and develops a fully automatic brain atrophy classification model. The second aim was to compare it with the end-to-end Convolutional Neural Networks (CNNs) model. Methods: A total of 385 subjects such as 107 no-atrophy brain, 185 mild atrophy, and 93 severe atrophy were collected and randomly separated into training set (n = 308) and test set (n = 77). Key slices for linear measurement were manually identified and used to annotate nine linear measurements and a binary classification of cerebral sulci widening. A linear-measurement-based pipeline (2D model) was constructed for two-types (existence/non-existence brain atrophy) or three-types classification (no/mild atrophy/severe atrophy). For comparison, an end-to-end CNN model (3D-deep learning model) for brain atrophy classification was also developed. Furthermore, age and gender were integrated to the 2D and 3D models. The sensitivity, specificity, accuracy, average F1 score, receiver operating characteristics (ROC) curves for two-type classification and weighed kappa for three-type classification of the two models were compared. Results: Automated measurement of linear measurements and cerebral sulci widening achieved moderate to almost perfect agreement with manual annotation. In two-type atrophy classification, area under the curves (AUCs) of the 2D model and 3D model were 0.953 and 0.941 with no significant difference (p = 0.250). The Weighted kappa of the 2D model and 3D model were 0.727 and 0.607 according to standard classification they displayed, mild atrophy and severe atrophy, respectively. Applying patient age and gender information improved classification performances of both 2D and 3D models in two-type and three-type classification of brain atrophy. Conclusion: We provide a model composed of different modules that can classify CSVD-related brain atrophy on CT images automatically, using linear measurement. It has similar performance and better interpretability than the end-to-end CNNs model and may prove advantageous in the clinical setting.