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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.
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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
Objective: Human adenovirus (HAdV) coinfection with other respiratory viruses is common, but adenovirus infection combined with human coronavirus-229E (HCoV-229E) is very rare. Study design and setting: Clinical manifestations, laboratory examinations, and disease severity were compared between three groups: one coinfected with HAdV-Ad7 and HCoV-229E, one infected only with adenovirus (mono-adenovirus), and one infected only with HCoV-229E (mono-HCoV-229E). Results: From July to August 2019, there were 24 hospitalized children: two were coinfected with HAdV-Ad7 and HCoV-229E, and 21 were infected with a single adenovirus infection. Finally, one 14-year-old boy presented with a high fever, but tested negative for HAdV-Ad7 and HCoV-229E. Additionally, three adult asymptotic cases with HCoV-229E were screened. No significant difference in age was found in the coinfection and mono-adenovirus groups (11 vs. 8 years, p = 0.332). Both groups had the same incubation period (2.5 vs. 3 days, p = 0.8302), fever duration (2.5 vs. 2.9 days, p = 0.5062), and length of hospital stay (7 vs. 6.76 days, p = 0.640). No obvious differences were found in viral loads between the coinfection and mono-adenovirus groups (25.4 vs. 23.7, p = 0.570), or in the coinfection and mono-HCoV-229E groups (32.9 vs. 30.06, p = 0.067). All cases recovered and were discharged from the hospital. Conclusion: HAdV-Ad7 and HCoV-229E coinfection in healthy children may not increase the clinical severity or prolong the clinical course. The specific interaction mechanism between the viruses requires further study.
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Adenovírus Humanos , Coinfecção , Coronavirus , Adulto , Criança , Humanos , Masculino , Hospitais , Carga Viral , AdolescenteRESUMO
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.
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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
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.
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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
The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.
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Hipertermia Induzida , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Tretinoína/uso terapêuticoRESUMO
BACKGROUND: Delayed cerebral ischemia (DCI) is a primary cause of poor prognosis after aneurysmal subarachnoid hemorrhage (aSAH) and needs close medical attention in clinical practice. Homocysteine (Hcy) has been implicated in cerebrovascular diseases. This study aimed to investigate whether serum Hcy could help to predict the occurrence of DCI in aSAH patients, and compare its diagnostic value with traditional methods. METHODS: We enrolled 241 aSAH patients in this study. Serum Hcy levels were collected from each patient. The baseline information was reviewed and analyzed. The binary logistic regression was used to explore the relation of serum Hcy levels with occurrence of DCI, and diagnostic performance of serum Hcy for predicting DCI was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: The admission serum Hcy levels were found significantly higher in aSAH patients with DCI than those without (P < 0.001). The serum Hcy levels were positively correlated with the World Federation of Neurosurgical Societies (WFNS) scores, modified Fisher scores as well as Hunt and Hess scores at admission. Multivariate analysis revealed that occurrence of DCI was associated with serum Hcy levels (Odds Ratio [OR] = 1.257; 95% Confidence Interval [CI], 1.133-1.396, P < 0.001), modified Fisher scores (OR = 1.871; 95%CI, 1.111-3.150, P = 0.018) and Hunt and Hess scores (OR = 2.581; 95%CI, 1.222-5.452, P = 0.013) after adjusting for the significant variables in univariate analysis. Meanwhile, serum Hcy levels achieved good performance for DCI prediction (area under the curve [AUC], 0.781; 95%CI, 0.723-0.831, P < 0.001). CONCLUSION: Serum homocysteine might have the potential to be a useful and cost-effective biomarker for predicting the occurrence of DCI in aSAH patients.
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RATIONALE: Intrasellar cavernous hemangiomas (ICHs) are rare vascular lesions that arise in the sellar region. ICHs are usually misdiagnosed and treated as pituitary adenomas. Therefore, a preoperative diagnosis is particularly important, especially when the goal is complete resection. PATIENT CONCERNS: A 55-year-old woman presented with a 1-month history of intermittent dizziness. Magnetic resonance imaging (MRI) revealed a well-demarcated abnormal ellipsoid signal in the sellar region (size: 2.7âcmâ×â1.7âcm), with a mulberry-like enhancement after gadolinium injection. Computed tomography revealed an intrasellar mass without calcification that extended into the left cavernous sinus and was faintly contrast-enhanced. Angiography revealed a tumor with mildly delayed staining fed by the C5 segment of the right internal carotid artery. DIAGNOSIS: An intrasellar cavernous hemangioma based on neuroradiological examinations. INTERVENTIONS: The patient underwent surgery with an endoscopic endonasal transsphenoidal approach to debulk the lesion and obtain tissue for the pathological diagnosis. OUTCOMES: Blood spurting was observed after puncture, and the capsule was stained blue. Lesion removal was stopped, and the patient underwent gamma knife surgery 1 week later. She remained in good condition during the follow-up. LESSONS: Sponge-like or mulberry-like lesions can be identified on MRI after gadolinium injection and can facilitate a preoperative diagnosis of ICH. Currently, surgical debulking with cranial nerve decompression during the acute stage and subsequent gamma knife radiosurgery are considered to be a safe and effective treatment.
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Hemangioma Cavernoso/diagnóstico por imagem , Sela Túrcica/diagnóstico por imagem , Angiografia Cerebral , Angiografia por Tomografia Computadorizada , Meios de Contraste , Diagnóstico Diferencial , Endoscopia , Feminino , Hemangioma Cavernoso/cirurgia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-IdadeRESUMO
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.
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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
Triggering receptor expressed on myeloid cells-2 (TREM2) was a newly identified receptor expressed on microglia. Several observations support the hypothesis that TREM2 variation may confer susceptibility to Parkinson's disease (PD). Therefore, in this paper, we explored the role of TREM2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results revealed that overexpression of TREM2 remarkably reduced MPTP-induced neuropathology including the dopaminergic neurodegeneration and neuroinflammation in vivo. Further mechanistic study revealed that TREM2 inhibited neuroinflammation by negatively regulating the TRAF6/TLR4-mediated activation of the MAPK and NF-κB signaling pathways. Taken together, our data suggest that TREM2 may have important neuroprotective effects against PD by critically modulating neuroinflammatory responses. These findings provide insights into the role of TREM2 in PD pathogenesis, and highlight TREM2 as a potential therapeutic target for this kind of disease.
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Neurônios Dopaminérgicos/metabolismo , Inflamação/metabolismo , Glicoproteínas de Membrana/metabolismo , Transtornos Parkinsonianos/patologia , Receptores Imunológicos/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Adenoviridae/genética , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Transtornos Parkinsonianos/complicações , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
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.
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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
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.
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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
BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is an infrequent disease characterized by severe headaches with or without focal neurological deficits or seizures and a reversible vasoconstriction of cerebral arteries. The Orpha number for RCVS is ORPHA284388. However, RCVS triggered by blood transfusion is rare. Here we provided the clinical, neuroimaging and outcome data of patients diagnosed with RCVS resulting from red blood cells transfusion. METHODS: We retrospectively identified 7 patients presenting with RCVS after red blood cells transfusion from January 2010 to May 2014. The information on clinical features, neuroimaging and outcome were collected and analyzed. RESULTS: All 7 patients were Chinese women, with a mean age of 42 years (38-46). All the patients had severe anemia (Hb level < 6 g/dl) caused by primary menorrhagia due to uterine myoma (n = 5) or end-stage renal disease (n = 2) and severe anemia persisted for a average period of 4 months (2-6). Each patient received packed red blood cells transfusion (average: 1580 ml) over a period of 2-5 days. Blood transfusion increased the hemoglobin level by at least 4.5 g/dL from baseline. The neurological symptoms appeared a mean of 6.3 days (2-13) after the last blood transfusion. Headache was the most frequent symptom and seizure, transient or persistent neurological disorders were observed. Neuroimaging showed cortical subarachnoid hemorrhage (n = 2), focal intracerebral hemorrhage (n = 2), localized brain edema (n = 3), cerebral infarction (n = 1), and posterior reversible encephalopathy syndrome (n = 2). Cerebral vasoconstrictions were demonstrated by magnetic resonance angiography or cerebral angiography. Arterial constriction reversed in all patients within 1 to 3 months of follow-up after disease onset and no relapse was observed up to a mean of 17.1 ± 4.8 months of follow-up. CONCLUSIONS: RCVS is a rare complication as a result of blood transfusion in patients with chronic severe anemia and should be considered in patients who show severe headache or neurologic deficits after transfusion.
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Transfusão de Eritrócitos/efeitos adversos , Vasoespasmo Intracraniano/diagnóstico , Vasoespasmo Intracraniano/etiologia , Adulto , Feminino , Cefaleia/diagnóstico , Cefaleia/etiologia , Humanos , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Retrospectivos , Vasoconstrição/fisiologiaRESUMO
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.
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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
α-Synuclein is a chaperone-like protein implicated in Parkinson's disease (PD). Among α-synuclein's normal functions is an ability to bind to and stimulate the activity of the protein phosphatase 2A (PP2A) catalytic subunit in vitro and in vivo. PP2A activity is impaired in PD and in dementia with Lewy Bodies in brain regions harboring α-synuclein aggregates. Using PP2A as the readout, we measured PP2A activity in response to α-synuclein, ceramides, and FTY720, and then on the basis of those results, we created new FTY720 compounds. We then measured the effects of those compounds in dopaminergic cells. In addition to stimulating PP2A, all three compounds stimulated the expression of brain derived neurotrophic factor and protected MN9D cells against tumor-necrosis-factor-α-associated cell death. FTY720-C2 appears to be more potent while FTY720-Mitoxy targets mitochondria. Importantly, FTY720 is already FDA approved for treating multiple sclerosis and is used clinically worldwide. Our findings suggest that FTY720 and our new FTY720-based compounds have considerable potential for treating synucleinopathies such as PD.
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(-)-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.
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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
There is increasing evidence that oxidative stress is critically involved in the pathogenesis of Parkinson's disease (PD), suggesting that pharmacological targeting of the antioxidant machinery may have therapeutic value. Naringenin, a natural flavonoid compound, has been reported to possess neuroprotective effect against PD related pathology; however the mechanisms underlying its beneficial effects are poorly defined. Thus, the purpose of the present study was to investigate the potential neuroprotective role of naringenin and to delineate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in models of PD both in vitro and in vivo. Naringenin treatment resulted in an increase in nuclear factor E2-related factor 2 (Nrf2) protein levels and subsequent activation of antioxidant response element (ARE) pathway genes in SH-SY5Y cells and in mice. Exposure of SH-SY5Y cells to naringenin provided protection against 6-OHDA-induced oxidative insults that was dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity or induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In mice, oral administration of naringenin resulted in significant protection against 6-OHDA-induced nigrostriatal dopaminergic neurodegeneration and oxidative damage. Our results indicate that activation of Nrf2/ARE signaling by naringenin is strongly associated with its neuroprotective effects against 6-OHDA neurotoxicity and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in PD.
Assuntos
Elementos de Resposta Antioxidante/fisiologia , Flavanonas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/fisiologia , Flavanonas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Transdução de Sinais/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiologiaRESUMO
Eriodictyol, a flavonoid isolated from the Chinese herb Dracocephalum rupestre has long been established as an antioxidant. The present study was designed to explore the protective effects of eriodictyol against hydrogen peroxide (H(2)O(2))-induced neurotoxicity with cultured rat pheochromocytoma cells (PC12 cells) and the possible mechanisms involved. For this purpose, differentiated PC12 cells were cultured and exposed to 200 µM H(2)O(2) in the absence or presence of eriodictyol (20, 40 and 80 µM). In addition, the potential contribution of the Nrf2/ARE neuroprotective pathway in eriodictyol-mediated protection against H(2)O(2)-induced neurotoxicity was also investigated. The results showed that H(2)O(2)-induced cell death can be inhibited in the presence of eriodictyol as measured by assays for MTT and apoptosis. Further study revealed that eriodictyol induced the nuclear translocation of Nrf2, enhanced the expression of heme oxygenase (HO-1) and γ-glutamylcysteine synthetase (γ-GCS), and increased the levels of intracellular glutathione. Treatment of PC12 cells with Nrf2 small interference RNA abolished eriodictyol-induced HO-1 and γ-GCS expression and its protective effects. In conclusion, these results suggest that eriodictyol upregulates HO-1 and γ-GCS expression through the activation of Nrf2/ARE pathway and protects PC12 cells against H(2)O(2)-induced oxidative stress.
Assuntos
Elementos de Resposta Antioxidante , Antioxidantes , Morte Celular , Flavanonas , Peróxido de Hidrogênio , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Oxidantes , Animais , Ratos , Elementos de Resposta Antioxidante/fisiologia , Apoptose/efeitos dos fármacos , Western Blotting , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Flavanonas/farmacologia , Glutationa/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/toxicidade , Indicadores e Reagentes , Neurônios/efeitos dos fármacos , Oxidantes/toxicidade , Células PC12 , Espécies Reativas de Oxigênio/metabolismo , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/fisiologiaRESUMO
Clinical data have shown that survival rates vary considerably among brain tumor patients, according to the type and grade of the tumor. Metabolite profiles of intact tumor tissues measured with high-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy (HRMAS (1)H NMRS) can provide important information on tumor biology and metabolism. These metabolic fingerprints can then be used for tumor classification and grading, with great potential value for tumor diagnosis. We studied the metabolic characteristics of 30 neuroepithelial tumor biopsies, including two astrocytomas (grade I), 12 astrocytomas (grade II), eight anaplastic astrocytomas (grade III), three glioblastomas (grade IV) and five medulloblastomas (grade IV) from 30 patients using HRMAS (1)H NMRS. The results were correlated with pathological features using multivariate data analysis, including principal component analysis (PCA). There were significant differences in the levels of N-acetyl-aspartate (NAA), creatine, myo-inositol, glycine and lactate between tumors of different grades (P<0.05). There were also significant differences in the ratios of NAA/creatine, lactate/creatine, myo-inositol/creatine, glycine/creatine, scyllo-inositol/creatine and alanine/creatine (P<0.05). A soft independent modeling of class analogy model produced a predictive accuracy of 87% for high-grade (grade III-IV) brain tumors with a sensitivity of 87% and a specificity of 93%. HRMAS (1)H NMR spectroscopy in conjunction with pattern recognition thus provides a potentially useful tool for the rapid and accurate classification of human brain tumor grades.
Assuntos
Neoplasias Encefálicas/patologia , Diagnóstico por Imagem/métodos , Espectroscopia de Ressonância Magnética/métodos , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Humanos , Neoplasias Neuroepiteliomatosas/classificação , Neoplasias Neuroepiteliomatosas/diagnóstico , Neoplasias Neuroepiteliomatosas/metabolismo , Análise de Componente Principal , Sensibilidade e EspecificidadeRESUMO
PURPOSE: The aim of the present study was to evaluate both the in vitro and in vivo antitumor activity of an oridonin nanosuspension (ORI-N) relative to efficacy of bulk oridonin delivery. METHODS: ORI-N with a particle size of 897.2±14.2 nm and a zeta potential of -21.8±0.8 mV was prepared by the high-pressure homogenization (HPH) technique. The in vitro cytotoxicity of ORI-N against SMMC-7721 cells was evaluated by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, the effects of ORI-N on cell cycle and cell apoptosis was analyzed by flow cytometry; the in vivo anti-tumor activity was observed in H22 tumor bearing mice. RESULTS: ORI-N effectively inhibited the proliferation of SMMC-7721 cells. Flow cytometric analysis demonstrated that ORI-N arrested SMMC-7721 cells in the G2/M cycle, and furthermore, that ORI-N induced a higher apoptotic rate than the bulk ORI solution. In vivo studies ORI-N also showed higher antitumor efficacy as measured by reduced tumor volume and tumor weight, as well as lower toxicity in H22 solid tumor bearing mice compared to free ORI at the same concentration. CONCLUSIONS: These results suggest that the delivery of ORI-N as a nanosuspension is a promising approach for treating tumors.
Assuntos
Antineoplásicos Fitogênicos , Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Sarcoma/tratamento farmacológico , Animais , Anexina A5/análise , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Feminino , Citometria de Fluxo , Camundongos , Microscopia de Fluorescência , Nanopartículas , Tamanho da Partícula , Sarcoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Linarin, a natural occurring flavanol glycoside derived from Mentha arvensis and Buddleja davidii is known to have anti-acetylcholinesterase effects. The present study intended to explore the neuroprotective effects of linarin against Aß(25-35)-induced neurotoxicity with cultured rat pheochromocytoma cells (PC12 cells) and the possible mechanisms involved. For this purpose, PC12 cells were cultured and exposed to 30 µM Aß(25-35) in the absence or presence of linarin (0.1, 1.0 and 10 µM). In addition, the potential contribution of the PI3K/Akt neuroprotective pathway in linarin-mediated protection against Aß(25-35)-induced neurotoxicity was also investigated. The results showed that linarin dose-dependently increased cell viability and reduced the number of apoptotic cells as measured by MTT assay, Annexin-V/PI staining, JC-1 staining and caspase-3 activity assay. Linarin could also inhibit acetylcholinesterase activity induced by Aß(25-35) in PC12 cells. Further study revealed that linarin induced the phosphorylation of Akt dose-dependently. Treatment of PC12 cells with the PI3K inhibitor LY294002 attenuated the protective effects of linarin. Furthermore, linarin also stimulated phosphorylation of glycogen synthase kinase-3ß (GSK-3ß), a downstream target of PI3K/Akt. Moreover, the expression of the anti-apoptotic protein Bcl-2 was also increased by linarin treatment. These results suggest that linarin prevents Aß(25-35)-induced neurotoxicity through the activation of PI3K/Akt, which subsequently inhibits GSK-3ß and up-regulates Bcl-2. These findings raise the possibility that linarin may be a potent therapeutic compound against Alzheimer's disease acting through both acetylcholinesterase inhibition and neuroprotection.