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BACKGROUND: Tocilizumab has been proposed as an effective treatment for severe COVID-19. We aimed to investigate whether tocilizumab administration is associated with increased availability of serum iron which may possibly be associated with adverse effects on clinical outcomes. METHODS: We performed an observational, retrospective cohort study. We included adults, who were hospitalized in ICU with the diagnosis of severe COVID-19 infection eligible for tocilizumab treatment. Laboratory data including serum iron, ferritin, transferrin saturation, hemoglobin, and C-reactive protein levels of all patients were collected shortly before and 24 h, 48 h, and 72 h after tocilizumab administration. RESULTS: During the study period, 15 patients fulfilled the inclusion criteria and were eligible to receive tocilizumab treatment. Tocilizumab therapy was associated with a prominent increase in serum iron and transferrin saturation levels (26 ± 13 µg/dL and 15 ± 8% before treatment and 79 ± 32 µg/dL and 41 ± 15% 72 h after treatment, respectively, p < 0.001) and decrease in serum ferritin levels (1,921 ± 2,071 ng/mL before and 1,258 ± 1,140 ng/mL 72 h after treatment, p = 0.027). CONCLUSION: Treatment of severe COVID-19 patients with tocilizumab is associated with a profound increase in serum iron and ferritin saturation levels along with a decrease in ferritin levels. This may represent an undesirable side effect that may potentiate viral replication.
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Anticorpos Monoclonais Humanizados , Tratamento Farmacológico da COVID-19 , Ferro , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Ferritinas/sangue , Homeostase , Humanos , Ferro/sangue , Estudos Retrospectivos , Transferrinas/sangueRESUMO
Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.
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Cerebelo/efeitos dos fármacos , Doença de Machado-Joseph/tratamento farmacológico , Trealose/efeitos adversos , Trealose/uso terapêutico , Adolescente , Adulto , Idoso , Cerebelo/fisiopatologia , Progressão da Doença , Feminino , Humanos , Israel , Doença de Machado-Joseph/fisiopatologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Adulto JovemRESUMO
Neuroinflammation contributes to amyotrophic lateral sclerosis (ALS) progression. TLR4, a transmembrane protein that plays a central role in activation of the innate immune system, has been shown to induce microglial activation in ALS models. TLR4 is up-regulated in the spinal cords of hSOD1G93A mice. We aimed to examine the effects of specific TLR4 inhibition on disease progression and survival in the hSOD1G93A mouse model of ALS. Immunologic effect of TLR4 inhibition in vitro was measured by the effect of TAK-242 treatment on LPS-induced splenocytes proliferation. hSOD1G93A transgenic mice were treated with TAK-242, a selective TLR4 inhibitor, or vehicle. Survival, body weight, and motor behavior were monitored. To evaluate in vivo immunologic modifications associated with TAK-242 treatment, we measured serum IL-1ß in the plasma, as well as IL-1ß and TNF-α mRNAs in the spinal cord in wild-type mice and in TAK-242-treated and vehicle-treated early symptomatic hSOD1G93A mice. Immunohistochemical analysis of motor neurons, astrocytes, and microglial reactivity in the spinal cords were performed on symptomatic (100 days old) TAK-242-treated and vehicle-treated hSOD1G93A mice. In vitro, splenocytes taken from 100 days old hSOD1G93A mice showed significantly increased proliferation when exposed to LPS (p = 0.0002), a phenomenon that was reduced by TAK-242 (p = 0.0179). TAK-242 treatment did not attenuate body weight loss or significantly affect survival. However, TAK-242-treated hSOD1G93A mice showed temporary clinical delay in disease progression evident in the ladder test and hindlimb reflex measurements. Plasma IL-1ß levels were significantly reduced in TAK-242-treated compared to vehicle-treated hSOD1G93A mice (p = 0.0023). TAK-242 treatment reduced spinal cord astrogliosis and microglial activation and significantly attenuated spinal cord motor neuron loss at early disease stage (p = 0.0259). Compared to wild-type animals, both IL-1ß and TNF-α mRNAs were significantly upregulated in the spinal cords of hSOD1G93A mice. Spinal cord analysis in TAK-242-treated hSOD1G93A mice revealed significant attenuation of TNF-α mRNA (p = 0.0431), but no change in IL-1ß mRNA. TLR4 inhibition delayed disease progression, attenuated spinal cord astroglial and microglial reaction, and reduced spinal motor neuron loss in the ALS hSOD1G93A mouse model. However, this effect did not result in increased survival. To our knowledge, this is the first report on TAK-242 treatment in a neurodegenerative disease model. Further studies are warranted to assess TLR4 as a therapeutic target in ALS.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/fisiopatologia , Atividade Motora , Medula Espinal/patologia , Sulfonamidas/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Comportamento Animal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Interleucina-1beta/sangue , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Baço/patologia , Sulfonamidas/farmacologia , Superóxido Dismutase-1/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND AIMS: Mesenchymal stromal cells (MSC) may be useful in a range of clinical applications. The placenta has been suggested as an abundant, ethically acceptable, less immunogenic and easily accessible source of MSC. The aim of this study was to evaluate the capacity of induced placental MSC to differentiate into neurotrophic factor-producing cells (NTF) and their protective effect on neuronal cells. METHODS: MSC were isolated from placentas and characterized by fluorescence-activated cell sorting (FACS). The cells underwent an induction protocol to differentiate them into NTF. Analysis of the cellular differentiation was done using polymerase chain reactions (PCR), immunocytochemical staining and enzyme-linked immunosorbent assays (ELISA). Conditioned media from placental MSC (PL-MSC) and differentiated MSC (PL-DIFF) were collected and examined for their ability to protect neural cells. RESULTS: The immunocytochemical studies showed that the cells displayed typical MSC membrane markers. The cells differentiated into osteoblasts and adipocytes. PCR and immunohistology staining demonstrated that the induced cells expressed typical astrocytes markers and neurotrophic factors. Vascular endothelial growth factor (VEGF) levels were higher in the conditioned media from PL-DIFF compared with PL-MSC, as indicated by ELISA. Both PL-DIFF and PL-MSC conditioned media markedly protected neural cells from oxidative stress induced by H(2)O(2) and 6-hydroxydopamine. PL-DIFF conditioned medium had a superior effect on neuronal cell survival. Anti-VEGF antibodies (Bevacizumab) reduced the protective effect of the conditioned media from differentiated and undifferentiated MSC. CONCLUSIONS: This study has demonstrated a neuroprotective effect of MSC of placental origin subjected to an induction differentiation protocol. These data offer the prospect of using placenta as a source for stem cell-based therapies.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Fatores de Crescimento Neural/biossíntese , Neurônios/metabolismo , Estresse Oxidativo , Placenta/citologia , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular , Separação Celular , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Imuno-Histoquímica , Células-Tronco Mesenquimais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Gravidez , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND AND PURPOSE: Elevated blood pressure (BP) in acute ischemic stroke is common. A raised BP is related to mortality and disability, yet excessive BP lowering can be detrimental. The optimal BP management in acute ischemic stroke remains insufficient and relies on expert consensus statements. Permissive hypertension is recommended during the first 24-h after stroke onset, yet there is ongoing uncertainty regarding the most appropriate blood BP management in the acute phase of ischemic stroke. This study aims to develop a decision support tool for improving the management of extremely high BP during the first 24 h after acute ischemic stroke by using machine learning (ML) tools. METHODS: This diagnostic accuracy study used retrospective data from MIMIC-III and eICU databases. Decision trees were constructed by a hierarchical binary recursive partitioning algorithm to predict the BP-lowering of 10-30% off the maximal value when antihypertensive treatment was given in patients with an extremely high BP (above 220/110 or 180/105 mmHg for patients receiving thrombolysis), according to the American Heart Association/American Stroke Association (AHA/ASA), the European Society of Cardiology, and the European Society of Hypertension (ESC/ESH) guidelines. Regression trees were used to predict the time-weighted average BP. Implementation of synthetic minority oversampling technique was used to balance the dataset according to different antihypertensive treatments. The model performance of the decision tree was compared to the performance of neural networks, random forest, and logistic regression models. RESULTS: In total, 7,265 acute ischemic stroke patients were identified. Diastolic BP (DBP) is the main variable for predicting BP reduction in the first 24 h after a stroke. For patients receiving thrombolysis with DBP <120 mmHg, Labetalol and Amlodipine are effective treatments. Above DBP of 120 mmHg, Amlodipine, Lisinopril, and Nicardipine are the most effective treatments. However, successful treatment depends on avoiding hyponatremia and on kidney functions. CONCLUSION: This is the first study to address BP management in the acute phase of ischemic stroke using ML techniques. The results indicate that the treatment choice should be adjusted to different clinical and BP parameters, thus, providing a better decision-making approach.
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Real-world healthcare data hold the potential to identify therapeutic solutions for progressive diseases by efficiently pinpointing safe and efficacious repurposing drug candidates. This approach circumvents key early clinical development challenges, particularly relevant for neurological diseases, concordant with the vision of the 21st Century Cures Act. However, to-date, these data have been utilized mainly for confirmatory purposes rather than as drug discovery engines. Here, we demonstrate the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects, specifically candidate marketed drugs that exhibit beneficial effects on Parkinson's disease (PD) progression. We performed an observational study in cohorts of ascertained PD patients extracted from two large medical databases, Explorys SuperMart (N = 88,867) and IBM MarketScan Research Databases (N = 106,395); and applied two conceptually different, well-established causal inference methods to estimate the effect of hundreds of drugs on delaying dementia onset as a proxy for slowing PD progression. Using this approach, we identified two drugs that manifested significant beneficial effects on PD progression in both datasets: rasagiline, narrowly indicated for PD motor symptoms; and zolpidem, a psycholeptic. Each confers its effects through distinct mechanisms, which we explored via a comparison of estimated effects within the drug classification ontology. We conclude that analysis of observational healthcare data, emulating otherwise costly, large, and lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials, beneficial against common, late-onset progressive diseases for which disease-modifying therapeutic solutions are scarce.
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INTRODUCTION: Remote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans. METHODS: This was an open-label, single-arm, dual-center study conducted on adults with chronic migraine. Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 min within 1 h of attack onset. Pain levels were recorded at baseline, 2 h, and 24 h post-treatment. Efficacy outcomes (pain relief and pain-free responses at 2 h, sustained pain relief and sustained pain-free responses at 24 h) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments. RESULTS: Forty-two participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 h, 26.3% (10/38) were pain-free at 2 h, 84.4% (27/32) had sustained pain relief response at 24 h and 45.0% (9/20) had sustained pain relief response at 24 h in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent. The incidence of device-related adverse events was low (1.8%). CONCLUSIONS: REN used for a series of migraine attacks was effective and well tolerated across attacks. REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04161807. Retrospectively registered on November 13, 2019.
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Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder. The causes of ALS are still obscure. Accumulating evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. DJ-1 plays an important role in the oxidative stress response. The aim of this study was to discover whether there are changes in DJ-1 expression or in DJ-1-oxidized isoforms in an animal model of ALS. We used mutant SOD1(G93A) transgenic mice, a commonly used animal model for ALS. Upregulation of DJ-1 mRNA and protein levels were identified in the brains and spinal cords of SOD1(G93A) transgenic mice as compared to wild-type controls, evident from an early disease stage. Furthermore, an increase in DJ-1 acidic isoforms was detected, implying that there are more oxidized forms of DJ-1 in the CNS of SOD1(G93A) mice. This is the first report of possible involvement of DJ-1 in ALS. Since DJ-1 has a protective role against oxidative stress, it may suggest a possible therapeutic target in ALS.
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Esclerose Lateral Amiotrófica/metabolismo , Proteínas Oncogênicas/metabolismo , Estresse Oxidativo , Isoformas de Proteínas/metabolismo , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas/genética , Peroxirredoxinas , Mutação Puntual , Proteína Desglicase DJ-1 , Isoformas de Proteínas/genética , Teste de Desempenho do Rota-Rod , Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1RESUMO
Parkinson's disease (PD) is not a simple movement disorder induced just by loss of dopaminergic neurons in the substantia nigra pars compacta. Apparently, the substantia nigra is not the only or the first brain region damaged in PD. Moreover, older and recent studies have shown that the degenerative process in PD is much more extensive and affects not only the central nervous system (CNS) but also the peripheral autonomic nervous system and the organs outside the brain that the latter innervates. These include mainly the gastrointestinal tract, the heart, kidneys, urogenital system, and skin. Additional extra-CNS organs that are involved in PD include the eye and the adrenal gland. This article reviews the anatomical, physiological, and clinical features of extracerebral manifestations of PD, and describes their relevance to the etiology and pathogenesis of the disease. It establishes this illness as a systemic CNS and peripheral disorder that warrants new hypotheses regarding its causation and progression.
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Olho/fisiopatologia , Trato Gastrointestinal/fisiopatologia , Coração/fisiopatologia , Doença de Parkinson/patologia , Sistema Nervoso Periférico/patologia , Pele/fisiopatologia , Bexiga Urinária/fisiopatologia , Olho/patologia , Trato Gastrointestinal/patologia , Humanos , Sistema Nervoso Periférico/fisiopatologia , Pele/patologia , Bexiga Urinária/patologiaRESUMO
The involvement of environmental heavy metals in Parkinson's disease (PD) has been suggested by epidemiologic studies; however, the mechanism of this effect is unknown. PD is characterized by the aggregation of alpha-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on alpha-synuclein in human SH-SY5Y cells. The heavy metals induced an increase in heme-oxygenase-1 levels without significant cell death or ROS generation. The metals inhibited ALA-dehydratase, which is the inhibitory subunit of the proteasome, thereby accelerating proteasomal activity and decreasing protein levels of CDK-1 and PBGD. However, alpha-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that alpha-synuclein is inaccessible to proteasomal degradation. Indeed, electron microscopy revealed the formation of aggresomes in Pb2+- or hemin-treated cells. Thus, although heavy metals enhance proteasomal activity, alpha-synuclein is protected from degradation, and its protein levels and aggregation are increased.
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Cobre/toxicidade , Gálio/toxicidade , Chumbo/toxicidade , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Estruturas Citoplasmáticas/efeitos dos fármacos , Estruturas Citoplasmáticas/ultraestrutura , Heme Oxigenase-1/metabolismo , Hemina/farmacologia , Humanos , Mutação , Sintase do Porfobilinogênio/antagonistas & inibidores , Sintase do Porfobilinogênio/metabolismo , Complexo de Endopeptidases do Proteassoma/ultraestrutura , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Iron supplementation, is recommended for the treatment of restless legs syndrome (RLS). We gathered evidence for the efficacy and safety of iron supplementation for RLS. METHODS: A systematic review and meta-analysis of randomized controlled trials that compared iron supplementation versus no iron for patients with RLS was performed. Multiple databases were searched. The primary outcome was the effect of iron on the International Restless Legs Syndrome score (IRLSS) at 4â¯weeks after treatment. For dichotomous data, risk ratios (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous data, weighted mean differences (WMD) were calculated. RESULTS: Ten trials fulfilled the inclusion criteria. Iron therapy was associated with a significant decrease of the IRLSS of -3.55 [95% CI (-5.41) - (-1.68)] points and an increase in the percentage of patients with improvement of the IRLSS score, RR of 2.16 [95% CI 1.56-2.98]. IV FCM was associated with improvement in both the IRLSS (WMD of -2.79 (95% CI (-4.62) - (-0.96), 4 trials, I2â¯=â¯0%) and on the RLS-QOL by WMD of 8.67 (95% CI 1.68-15). Iron was associated with an increased rate of adverse events RR 2.04 (95% CI 1.46-2.85), which were not severe and not associated with increased rate of treatment discontinuation. CONCLUSION: Iron supplementation is associated with improvement of the IRLSS score. Our meta-analysis supports the use of iron, oral or IV, as effective therapy for patients with RLS. Further studies should assess subgroups of patients most likely to benefit from iron supplementation.
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Suplementos Nutricionais , Compostos Férricos/administração & dosagem , Síndrome das Pernas Inquietas/tratamento farmacológico , Administração Intravenosa , Administração Oral , Compostos Férricos/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Oxidative stress is implicated in the pathogenesis of central nervous system damage in neurodegenerative diseases as well as in normal aging. Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases caused by both environmental and inherited factors. DJ-1 mutations were recently identified in familial PD. The aim of this study was to elucidate the effects of the neurotoxins rotenone and 6-hydroxydopamine that lead to intracellular reactive oxygen species (ROS) on DJ-1 expression levels and intracellular distribution. The sensitivity to oxidative insults induced by rotenone, 6-hydroxydopamine and hydrogen peroxide of transfected human neuroblastoma cells that were engineered to have increased or decreased DJ-1 levels was also examined. Overexpression of DJ-1 resulted in increased cellular resistance to these insults and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Exposure of naïve neuroblastoma cells to rotenone or 6-hydroxydopamine induced upregulation of DJ-1 mRNA and protein levels. Pretreatment with an antioxidant abolished these changes, implying that the upregulation of DJ-1 resulted from oxidative stress. Neurotoxins exposure not only induced upregulation of DJ-1, but also induced cellular redistribution of DJ-1 manifested by translocation of DJ-1 into the mitochondria. These results may imply that DJ-1 plays an important role in the neuronal defense mechanism against oxidative insults.
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Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/metabolismo , Estresse Oxidativo/fisiologia , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA Complementar/biossíntese , DNA Complementar/genética , Humanos , Peróxido de Hidrogênio/toxicidade , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microscopia Confocal , Mutação , Proteínas do Tecido Nervoso/biossíntese , Proteínas Oncogênicas/genética , Oxidantes/toxicidade , Estresse Oxidativo/genética , Oxidopamina/toxicidade , Proteína Desglicase DJ-1 , RNA/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rotenona/toxicidade , Simpatolíticos/toxicidade , Transfecção , Desacopladores/toxicidade , Regulação para Cima/efeitos dos fármacosRESUMO
DJ-1 plays an important role in oxidative stress, and is involved in various neurodegenerative diseases. Accumulating evidence suggests a central role for oxidative stress in multiple sclerosis (MS). The aim of this study was to examine whether changes occur in DJ-1 expression in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found upregulation of DJ-1 mRNA and protein expression levels in EAE and a correlation between disease severity and increased DJ-1 levels. Although DJ-1 isoforms were more alkaline in controls, in EAE, a shift was noted toward acidic isoforms. ROS induced by SIN-I exposure led to an increase in DJ-1 mRNA and protein levels in human glioma U-87 cells. Immunocytochemical staining demonstrated that DJ-1 is present both in the cytoplasm and the nuclei of these cells. This is the first report of modulation of DJ-1 expression in EAE. Upregulation of DJ-1 was noted in EAE, and similar results were observed in glioma cells exposed to ROS. In view of the accumulating evidence on the central role of oxidative stress in MS, and the importance of DJ-1 in oxidative stress management by the CNS, we believe that DJ-1 will be found to have a central role in MS.
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Encefalomielite Autoimune Experimental/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Esclerose Múltipla/metabolismo , Proteínas Oncogênicas/metabolismo , Estresse Oxidativo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C3H , Morfolinas/química , Morfolinas/farmacologia , Proteínas Oncogênicas/genética , Peroxirredoxinas , Proteína Desglicase DJ-1 , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sidnonas/química , Sidnonas/farmacologia , Regulação para CimaRESUMO
Parkinson's disease (PD), one of the most common neurodegenerative diseases, is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years, including alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1. DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. Moreover, DJ-1 immunoreactive inclusions are found in other alpha-synucleopathies and tauopathies, indicating that different neurodegenerative diseases might share a common mechanism in which DJ-1 might play a key role. The function of DJ-1 is still unknown; however, it is associated with various cellular processes, including response to oxidative stress, cellular transformation, RNAbinding, androgen-receptor signaling, spermatogenesis, and fertilization. This article reviews the current knowledge on DJ-1, focusing on its importance in the pathogenesis of PD.
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Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Oncogênicas/fisiologia , Transtornos Parkinsonianos/genética , Animais , Transformação Celular Viral/fisiologia , Dopamina/fisiologia , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/genética , Genes Recessivos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Mutação , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Proteínas Oncogênicas/análise , Proteínas Oncogênicas/deficiência , Proteínas Oncogênicas/genética , Estresse Oxidativo/fisiologia , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/fisiopatologia , Peroxirredoxinas , Proteína Desglicase DJ-1 , Tauopatias/genética , Tauopatias/fisiopatologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/fisiologia , alfa-Sinucleína/genética , alfa-Sinucleína/fisiologiaRESUMO
Parkinson's disease (PD) is a multifactorial disease caused by both genetic and environmental factors. Alpha-synuclein is of particular interest in PD since it is a major component of Lewy bodies and mutations in the alpha-synuclein gene were identified in familial PD. Oxidative stress and proteasomal dysfunction are implicated in the pathogenesis of PD but their interactions as well as their effect on aggregates formation are not yet clear. We therefore examined the roles of oxidative stress and proteasomal inhibition on protein aggregates induction in naïve and neuronally differentiated neuroblastoma SH-SY5Y cells. Neuroblastoma cells were stably transfected with wild type (WT) and A53T mutant alpha-synuclein. Naïve and transfected cells were exposed to oxidative stress induced by rotenone, SIN-I, FeCl(2,) and to proteasomal inhibition by lactacystin. Proteasomal inhibition caused a dose-dependent decrease in viability and induced protein aggregates formation containing alpha-synuclein and ubiquitin. Proteasomal inhibition induced significantly increased alpha-synuclein aggregation in cells expressing mutant alpha-synuclein. Exposure to reactive oxygen species (ROS) combined with proteasomal inhibition increased aggregates formation. Inclusion body formation and cell death of differentiated neuroblastoma cells overexpressing alpha-synuclein can serve as a valuable model for elucidating the molecular components that cause neurodegeneration in PD as well as evaluating pharmacological interventions.
Assuntos
Diferenciação Celular , Estresse Oxidativo , Doença de Parkinson/metabolismo , Inibidores de Proteassoma , Benzotiazóis , Linhagem Celular Tumoral , Citoplasma/metabolismo , Compostos Ferrosos/farmacologia , Humanos , Imuno-Histoquímica , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Mutação , Neuroblastoma , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia , Tiazóis/metabolismo , Ubiquitina/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
We previously reported that acute agonist activation of G(i/o)-coupled receptors inhibits adenylate cyclase (AC) type VIII activity, whereas agonist withdrawal following chronic activation of these receptors induces AC-VIII superactivation. Three splice variants of AC-VIII have been identified, which are called AC-VIII-A, -B and -C (with AC-VIII-B missing the glycosylation domain and AC-VIII-C lacking most of the C1b area). We report here that AC-VIII-A and -B, but not -C, are inhibited by acute mu-opioid and dopaminergic type D2 receptor activation, indicating that the C1b area of AC-VIII has an important role in AC inhibition by G(i/o)-coupled receptor activation. On the other hand the glycosylation sites in AC-VIII did not play a role in AC-VIII regulation. Although AC-VIII-A and -C differed in their capacity to be inhibited by acute agonist exposure, agonist withdrawal after prolonged treatment led to a similar superactivation of all three splice variants, with no significant change in AC-VIII expression. AC-VIII superactivation was not affected by pre-incubation with a cell permeable cAMP analogue, indicating that the superactivation does not depend on the agonist-induced reduction in cAMP levels. The superactivated AC-VIII-A, -B and -C were similarly re-inhibited by re-application of agonist (morphine or quinpirole), returning the activity to control levels. These results demonstrate marked differences in the agonist inhibition of the AC-VIII splice variants before, but not after, superactivation.
Assuntos
Adenilil Ciclases/fisiologia , Processamento Alternativo/fisiologia , Variação Genética/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Adenilil Ciclases/metabolismo , Animais , Células COS/química , Células COS/efeitos dos fármacos , Células COS/enzimologia , Células COS/metabolismo , Chlorocebus aethiops , Colforsina/farmacologia , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Vetores Genéticos , Ionomicina/farmacologia , Morfina/antagonistas & inibidores , Morfina/farmacologia , Toxina Pertussis/farmacologia , Receptores de Dopamina D2 , Fatores de TempoRESUMO
Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using ß-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.
Assuntos
Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , beta-Sinucleína/metabolismo , Humanos , Doença de Parkinson/terapiaRESUMO
BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is a stereotypic condition characterized by anterograde and retrograde amnesia that typically resolves within 24 hours. The pathophysiology of TGA is still unclear. We noted that patients hospitalized with TGA tend to appear in seasonal clusters, and decided to investigate this phenomenon. METHODS: Every patient with acute presentation of amnesia at our medical center is hospitalized for observation and evaluation. We reviewed the monthly occurrence of TGA in our patient population between 2000 and 2014, and compared this to non-TGA hospitalizations during the same time period. RESULTS: During the analysis period, 154 patients who met the criteria for TGA were hospitalized, as well as 259,007 non-TGA hospitalizations. The annual occurrence of TGA ranged from 5 to 16 hospitalizations. There were 91 TGA events in women and 63 in men, in subjects aged 62.8±10.6 years (mean±SD). The incidence was maximal during December [odds ratio (OR)=2.83, 95% confidence interval (CI)=1.20-6.67] and March (OR=2.77, 95% CI=1.17-6.56), and minimal from April to August. The incidence exhibited an increase followed by a decrease from October to February. A seasonal trend was observed as well, with incidence peaks occurring in winter (OR=1.82, 95% CI=1.12-2.96) and spring (OR=1.80, 95% CI=1.10-2.94). CONCLUSIONS: Our findings suggest that the incidence of TGA exhibits seasonal variations. This observation may help to improve the understanding of the pathophysiology underlying TGA.
RESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson's disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS.