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1.
Acta Histochem ; 124(2): 151856, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35077998

RESUMO

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.


Assuntos
Neuroblastoma , Ligante Indutor de Apoptose Relacionado a TNF , Alcinos , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligopeptídeos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
2.
Virol J ; 19(1): 151, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127711

RESUMO

BACKGROUND: ß-Amyloid (Aß) protein is a pivotal pathogenetic factor in Alzheimer's disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aß to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aß exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aß and other virus infections, this study aimed to investigate the potent activity of Aß on EV-A71 infection and extended the potential function of Aß in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases. METHODS: Aß peptides 1-42 are a major pathological factor of senile plaques in Alzheimer's disease (AD). Thus, we utilized Aß1-42 as a test subject to perform our study. The production of monomer Aß1-42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aß1-42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aß1-42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay. RESULTS: We found that EV-A71 infection induced Aß production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aß1-42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aß1-42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aß1-42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aß1-42 to prevent viruses from infecting cells. CONCLUSIONS: Our findings unveiled that Aß1-42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aß in other non-envelope viruses linked to infectious neurological diseases.


Assuntos
Doença de Alzheimer , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Neuroblastoma , Peptídeos beta-Amiloides , Antígenos Virais/genética , Proteínas do Capsídeo/genética , Enterovirus/genética , Enterovirus Humano A/genética , Humanos , Fragmentos de Peptídeos , RNA , Receptores Depuradores/metabolismo
3.
Cell Death Dis ; 13(9): 809, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130928

RESUMO

The small nucleolar RNA host gene 1 (SNHG1) is a novel oncogenic long non-coding RNA (lncRNA) aberrantly expressed in different tumor types. We previously found highly expressed SNHG1 was associated with poor prognosis and MYCN status in neuroblastoma (NB). However, the molecular mechanisms of SNHG1 in NB are still unclear. Here, we disrupted endogenous SNHG1 in the MYCN-amplified NB cell line SK-N-BE(2)C using the CRISPR/Cas9 system and demonstrated the proliferation and colony formation ability of SNHG1-knowndown cells were suppressed. The transcriptome analysis and functional assays of SNHG1-knockdown cells revealed SNHG1 was involved in various biological processes including cell growth, migration, apoptosis, cell cycle, and reactive oxygen species (ROS). Interestingly, the expression of core regulatory circuitry (CRC) transcription factors in MYCN-amplified NB, including PHOX2B, HAND2, GATA3, ISL1, TBX1, and MYCN, were decreased in SNHG1-knockdown cells. The chromatin-immunoprecipitation sequencing (ChIP-seq) and transposase-accessible chromatin using sequencing (ATAC-seq) analyses showed that chromatin status of these CRC members was altered, which might stem from interactions between SNHG1 and HDAC1/2. These findings demonstrate that SNHG1 plays a crucial role in maintaining NB identity via chromatin regulation and reveal the function of the lncRNA SNHG1 in NB.


Assuntos
MicroRNAs , Neuroblastoma , RNA Longo não Codificante , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromatina , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Humanos , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Nucleolar Pequeno , Espécies Reativas de Oxigênio/metabolismo , Transposases/metabolismo
4.
Curr Oncol ; 29(9): 6508-6522, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36135081

RESUMO

The Raf-MEK-ERK signaling network has been the subject of intense research due to its role in the development of human cancers, including pediatric neuroblastoma (NB). MEK and ERK are the central components of this signaling pathway and are attractive targets for cancer therapy. Approximately 3-5% of the primary NB samples and about 80% of relapsed samples contain mutations in the Raf-MEK-ERK pathway. In the present study, we analyzed the NB patient datasets and revealed that high RAF and MEK expression leads to poor overall survival and directly correlates with cancer progression and relapse. Further, we repurposed a specific small-molecule MEK inhibitor CI-1040 to inhibit the Raf-MEK-ERK pathway in NB. Our results show that CI-1040 potently inhibits NB cell proliferation and clonogenic growth in a dose-dependent manner. Inhibition of the Raf-MEK-ERK pathway by CI-1040 significantly enhances apoptosis, blocks cell cycle progression at the S phase, inhibits expression of the cell cycle-related genes, and significantly inhibits phosphorylation and activation of the ERK1/2 protein. Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB.


Assuntos
Sistema de Sinalização das MAP Quinases , Neuroblastoma , Benzamidas , Criança , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêutico , Recidiva Local de Neoplasia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Transdução de Sinais
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1134-1142, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073211

RESUMO

OBJECTIVE: To investigate the role of long non-coding RNA ZEB1-AS1 in cerebral ischemia/reperfusion injury (CI/RI). METHODS: We detected the temporal changes of ZEB1-AS1 and HMGB1 expression using qPCR and Western blotting in SD rats following CI/RI induced by middle cerebral artery occlusion (MCAO). The rat models of CI/RI were subjected to injections of vectors for ZEB1-AS1 overexpression or knockdown into the lateral ventricle, and the changes in cognitive function, brain water content, blood-brain barrier integrity, and IL-1ß and TNF-α levels in the cerebrospinal fluid (CSF) and serum were observed. Neuronal loss and cell apoptosis in the cortex of the rat models were detected by FJC and TUNEL methods, and HMGB1 and TLR-4 expressions were analyzed with Western blotting. We also examined the effects of ZEB1-AS1 knockdown on apoptosis and expressions of HMGB1 and TLR-4 in SH-SY5Y cells with oxygen-glucose deprivation/reoxygenation (OGD/R). RESULTS: In CI/RI rats, the expressions of ZEB1-AS1 and HMGB1 in the brain tissue increased progressively with the extension of reperfusion time, reaching the peak levels at 24 h followed by a gradual decline. ZEB1-AS1 overexpression significantly aggravated icognitive impairment and increased brain water content, albumin content in the CSF, and IL-1ß and TNF-α levels in the CSF and serum in CI/RI rats (P < 0.05), while ZEB1-AS1 knockdown produced the opposite effects (P < 0.05 or 0.01). ZEB1-AS1 overexpression obviously increased the number of FJC-positive neurons in the cortex and enhanced the expressions of HMGB1 and TLR-4 in the rat models (P < 0.01); ZEB1-AS1 knockdown significantly reduced the number of FJC-positive neurons and lowered HMGB1 and TLR-4 expressions (P < 0.01). In SH-SY5Y cells with OGD/R, ZEB1-AS1 knockdown significantly suppressed cell apoptosis and lowered the expressions of HMGB1 and TLR-4 (P < 0.01). CONCLUSION: ZEB1-AS1 overexpression aggravates CI/RI in rats through the HMGB1/TLR-4 signaling axis.


Assuntos
Proteína HMGB1 , RNA Longo não Codificante , Traumatismo por Reperfusão , Receptor 4 Toll-Like , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína HMGB1/metabolismo , Humanos , Infarto da Artéria Cerebral Média , Neuroblastoma , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa , Água
6.
Sci Rep ; 12(1): 15509, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109577

RESUMO

To investigate the value of the radiomic models for differentiating parasellar cavernous hemangiomas from meningiomas and to compare the classification performance with different MR sequences and classifiers. A total of 96 patients with parasellar tumors (40 cavernous hemangiomas and 56 meningiomas) were enrolled in this retrospective multiple-center study. Univariate and multivariate analyses were performed to identify the clinical factors and semantic features of MRI scans. Radiomics features were extracted from five MRI sequences using radiomics software. Three feature selection methods and six classifiers were evaluated in the training cohort to construct favorable radiomic machine-learning classifiers. The performance of different classifiers was evaluated using the AUC and compared to neuroradiologists. The detection rates of T1WI, T2WI, and CE-T1WI for parasellar cavernous hemangiomas and meningiomas were approximately 100%. In contrast, the ADC maps had the detection rate of 18/22 and 19/25, respectively, (AUC, 0.881) with 2.25 cm as the critical value diameter. Radiomics models with the SVM and KNN classifiers based on T2WI and ADC maps had favorable predictive performances (AUC > 0.90 and F-score value > 0.80). These models outperformed MRI model (AUC 0.805) and neuroradiologists (AUC, 0.756 and 0.545, respectively). Radiomic models based on T2WI and ADC and combined with SVM and KNN classifiers have the potential to be a viable method for differentiating parasellar hemangiomas from meningiomas. T2WI is more universally applicable than ADC values due to its higher detection rate for parasellar tumors.


Assuntos
Hemangioma Cavernoso , Neoplasias Meníngeas , Meningioma , Neuroblastoma , Humanos , Aprendizado de Máquina , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico por imagem , Meningioma/patologia , Estudos Retrospectivos
7.
Zhonghua Bing Li Xue Za Zhi ; 51(9): 838-842, 2022 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-36097899

RESUMO

Objective: To investigate the expression of Ki-67 and CD34 in the differential diagnosis of ductal carcinoma in situ (DCIS) and DCIS-like invasive breast cancer (DLIBC). Methods: A total of 100 cases of DCIS and 150 cases of DLIBC diagnosed pathologically in Yantai Yuhuangding Hospital from January 2019 to March 2022 were collected. The expression of p63, CK5/6, Ki-67 and CD34 in both groups were detected by immunohistochemical (IHC) staining and evaluated. Results: The 100 cases of DCIS included 11 cases of low-grade DCIS, 28 cases of intermediate-grade DCIS and 61 cases of high-grade DCIS. IHC staining of p63 and CK5/6 showed the myoepithelial cells around cancerous duct were complete or partial absence. Ki-67 expression showed two patterns: high expression in the basal layers and scattered expression within the tumor. Most cases showed mainly high basal expression (77/100, 77%), and the proportion of this pattern was significantly different between low grade and high grade DCIS (P<0.05). All cases showed complete CD34 expression surrounding the cancerous duct with different proportion (vascular necklace) suggested small vessels proliferation. The 150 cases of DLIBC included 142 cases of invasive ductal carcinoma (IDC) (three cases of basal-like breast cancer was included), two cases of secretory carcinoma, three cases of solid papillary carcinoma, two cases of adenoid cystic carcinoma and one case of acinar cell carcinoma. Among 142 cases of IDC, 13 cases were grade Ⅰ, 77 were grade Ⅱ and 52 were grade Ⅲ. IHC staining of p63 showed complete absence of myoepithelium. CK5/6 was negative in most cases and only positively expressed within the tumor in 3 cases of basal-like breast cancer. Ki-67 indicated a scattered expression pattern within the tumor. In most cases, CD34 immunostaining showed scattered positive blood vessels within the tumor while only two cases showed incomplete expression of CD34 around the tumor (2/150, 1.3%). The different expression patterns of Ki-67 and CD34 in DCIS and DLIBC was statistically significant (P<0.05). Conclusions: The different expression patterns of Ki-67 and CD34 are helpful to distinguish DLIBC from DCIS. The appearance of "vascular necklace" with CD34 and the high expression of Ki-67 around the cancerous duct highly support the diagnosis of DCIS, and the scattered expression pattern of CD34 supports DLIBC.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Neuroblastoma , Antígenos CD34 , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Moléculas de Adesão Celular , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67
8.
Sci Rep ; 12(1): 15425, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104347

RESUMO

Multi-omics data are increasingly being gathered for investigations of complex diseases such as cancer. However, high dimensionality, small sample size, and heterogeneity of different omics types pose huge challenges to integrated analysis. In this paper, we evaluate two network-based approaches for integration of multi-omics data in an application of clinical outcome prediction of neuroblastoma. We derive Patient Similarity Networks (PSN) as the first step for individual omics data by computing distances among patients from omics features. The fusion of different omics can be investigated in two ways: the network-level fusion is achieved using Similarity Network Fusion algorithm for fusing the PSNs derived for individual omics types; and the feature-level fusion is achieved by fusing the network features obtained from individual PSNs. We demonstrate our methods on two high-risk neuroblastoma datasets from SEQC project and TARGET project. We propose Deep Neural Network and Machine Learning methods with Recursive Feature Elimination as the predictor of survival status of neuroblastoma patients. Our results indicate that network-level fusion outperformed feature-level fusion for integration of different omics data whereas feature-level fusion is more suitable incorporating different feature types derived from same omics type. We conclude that the network-based methods are capable of handling heterogeneity and high dimensionality well in the integration of multi-omics.


Assuntos
Neuroblastoma , Algoritmos , Humanos , Aprendizado de Máquina , Redes Neurais de Computação , Neuroblastoma/genética , Prognóstico
9.
Molecules ; 27(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36080159

RESUMO

The aim of this study was to investigate the cytotoxic activity of the Coriandrum sativum (C. sativum) ethanolic extract (CSEE) in neuroblastoma cells, chemically characterize the compounds present in the CSEE, and predict the molecular interactions and properties of ADME. Thus, after obtaining the CSEE and performing its chemical characterization through dereplication methods using UPLC/DAD-ESI/HRMS/MS, PM6 methods and the SwissADME drug design platform were used in order to predict molecular interactions and ADME properties. The CSEE was tested for 24 h in neuroblastoma cells to the establishment of the IC50 dose. Then, the cell death was evaluated, using annexin-PI, as well as the activity of the effector caspase 3, and the protein and mRNA levels of Bax and Bcl-2 were analyzed by ELISA and RT-PCR, respectively. By UHPLC/DAD/HRMS-MS/MS analysis, the CSEE showed a high content of isocoumarins-dihydrocoriandrin, coriandrin, and coriandrones A and B, as well as nitrogenated compounds (adenine, adenosine, and tryptophan). Flavonoids (apigenin, hyperoside, and rutin), phospholipids (PAF C-16 and LysoPC (16:0)), and acylglicerol were also identified in lower amount as important compounds with antioxidant activity. The in silico approach results showed that the compounds 1 to 6, which are found mostly in the C. sativum extract, obey the "Five Rules" of Lipinski, suggesting a good pharmacokinetic activity of these compounds when administered orally. The IC50 dose of CSEE (20 µg/mL) inhibited cell proliferation and promoted cell death by the accumulation of cleaved caspase-3 and the externalization of phosphatidylserine. Furthermore, CSEE decreased Bcl-2 and increased Bax, both protein and mRNA levels, suggesting an apoptotic mechanism. CSEE presents cytotoxic effects, promoting cell death. In addition to the promising results predicted through the in silico approach for all compounds, the compound 6 showed the best results in relation to stability due to its GAP value.


Assuntos
Coriandrum , Neuroblastoma , Linhagem Celular Tumoral , Coriandrum/química , Humanos , Neuroblastoma/tratamento farmacológico , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2 , RNA Mensageiro , Espectrometria de Massas em Tandem , Proteína X Associada a bcl-2/genética
10.
Epileptic Disord ; 24(5): 1-11, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36117315

RESUMO

Objective: Epilepsy is a chronic brain disease with recurrent seizures. Autophagy plays a crucial role in the progression of epilepsy. This study aimed to explore the function and intrinsic mechanism of the long non-coding RNA (lncRNA) UCA1/miR-132-3p/ATG16L1 axis in epilepsy via regulation of autophagy. Methods: The expression of lncRNA UCA1, miR-132-3p and ATG16L1 was measured in serum from epileptic patients by quantitative RT-PCR. A SH-SY5Y cell model was further constructed using retinoic acid to investigate the UCA1/ miR-132-3p/ATG16L1 axis by quantitative RT-PCR, western blotting, fluorescence in situ hybridisation, RNA immunoprecipitation, chromatin immunoprecipitation, and a dual-luciferase reporter gene assay. Results: In the serum of epileptic patients, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated, compared to controls. Similarly, in the SH-SY5Y cell model, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated in retinoic acid-treated cells; lncRNA UCA1 was mainly located in the cytoplasm. lncRNA UCA1 overexpression was shown to promote autophagic gene expression, which was reversed by miR-132-3p overexpression. Moreover, autophagic gene expression induced by miR-132-3p knockdown was reversed by ATG16L1 knockdown. Based on precipitation assays, lncRNA UCA1 and miR-132-3p were shown to form a complex with the transcription factor, EZH2, and miR-132-3p was shown to interact with ATG16L1 based on a luciferase assay. Finally, lncRNA UCA1 was shown to negatively regulate miR-132-3p expression, and miR-132-3p was shown to negatively regulate ATG16L1. Significance: In this cell model, lncRNA UCA1 promotes autophagic gene expression via epigenetic regulation mediated by ATG16L1 and miR-132-3p.


Assuntos
MicroRNAs , Neuroblastoma , RNA Longo não Codificante , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Epigênese Genética , Expressão Gênica , Humanos , MicroRNAs/genética , Neuroblastoma/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Tretinoína/farmacologia
11.
Comput Math Methods Med ; 2022: 1949344, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118839

RESUMO

Alzheimer's disease (AD) is the most commonly seen neurodegenerative brain disorder. The paracrine effects of mesenchymal stem cells (MSCs) signify to trigger immunomodulation and neural regeneration. However, the role and mechanism of bone marrow MSC- (BMSC-) derived CX3CL1 in AD remains elusive. In this study, Aß 1-42-intervened SH-SY5Y cells were used for AD cell model construction. pcDNA-ligated CX3CL1 overexpression plasmids were transfected into BMSCs. The levels of soluble and membrane-bound CX3CL1 were detected by ELISA and Western blotting (WB), respectively. The growth, apoptosis, and pathology of AD model cells were evaluated by CCK-8, flow cytometry, immunofluorescence, morphology observation, biochemical examination, and WB. It was found that Aß 1-42 significantly reduced CX3CL1 expression either in soluble or membrane-bound form, cell viability, relative protein expression of synaptic markers, SOD, CAT, and GSH-Px contents, as well as Trx protein expression; in addition, it enhanced the apoptosis rate, the relative expression of cleaved caspase-3, Aß, tau, p-Tau, Iba1, MDA, TXNIP, and NLRP3 in SH-SY5Y cells; however, the above effects were prominently reversed by the coculture of BMSCs. Moreover, overexpression of CX3CL1 in BMSCs observably strengthened the corresponding tendency caused by BMSCs. In conclusion, through the TXNIP/NLRP3 pathway, CX3CL1 derived from BMSCs inhibited pathological damage in Aß 1-42-induced SH-SY5Y.


Assuntos
Doença de Alzheimer , Células-Tronco Mesenquimais , Neuroblastoma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspase 3/metabolismo , Caspase 3/farmacologia , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/farmacologia , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Sincalida/metabolismo , Sincalida/farmacologia , Superóxido Dismutase
12.
Mol Med Rep ; 26(5)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36052865

RESUMO

The purpose of the present study was to explore the functional role of microRNA (miR)­363­3p and related regulatory mechanisms in cerebral ischemia/reperfusion (I/R) injury. The neuronal cell line SH­SY5Y was exposed to 4 h of oxygen and glucose deprivation (OGD), followed by 6, 12, 24 and 48 h of re­oxygenation to mimic I/R injury in vitro. Cell viability, apoptosis and inflammation were assessed by CCK­8, lactate dehydrogenase (LDH), flow cytometry and ELISA assays. The association between miR­363­3p and programmed cell death 6­interacting protein (PDCD6IP) was further confirmed using luciferase reporter assay. Our data revealed that the expression level of miR­363­3p was significantly downregulated after OGD/R induction. Overexpression of miR­363­3p markedly suppressed OGD/R­induced cell injury, as reflected by attenuated cell viability, reduced apoptosis, LDH activity and pro­inflammatory cytokine levels. Mechanistically, PDCD6IP was confirmed as the target of miR­363­3p. Furthermore, PDCD6IP knockdown imitated, while overexpression reversed the effects of miR­363­3p overexpression on OGD/R­induced cell injury. Collectively, miR­363­3p could attenuate OGD/R­induced cell injury by alleviating apoptosis and inflammation, which may be mediated, at least in part, via inhibition of PDCD6IP.


Assuntos
Proteínas de Ligação ao Cálcio , Proteínas de Ciclo Celular , Complexos Endossomais de Distribuição Requeridos para Transporte , MicroRNAs , Neuroblastoma , Traumatismo por Reperfusão , Apoptose/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Glucose , Humanos , Inflamação/genética , MicroRNAs/metabolismo , Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo
13.
Medicine (Baltimore) ; 101(37): e30353, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123911

RESUMO

OBJECTIVES: The present study aimed to conduct a meta-analysis of previously published studies in order to clarify the association of long noncoding RNA (lncRNAs) LINC00673 rs11655237 C> T polymorphism with cancer risk. DESIGN: Systematic review and meta-analysis. SETTING: Electronic databases of PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang Database were used to search relevant studies. Studies published up to October 20, 2019 were included. The included studies were assessed in the following genetic model: allelic model, homozygote model, Heterozygote model, dominant model, recessive model. Data syntheses were conducted using STATA 12.0. PARTICIPANTS: Participants with various types cancers were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Odds ratio (ORs) and 95% confidence interval (CIs) were calculated to assess the risk of tumor. RESULTS: Seven articles including 7 case-control studies, 7423 cases and 11,049 controls were adopted for meta-analysis. Our result demonstrated that LINC00673 rs11655237 C> T was related to the cancer among all model including allelic model (T vs C: pooled OR = 1.24, 95% CI = 1.16-1.41, P < .001), homozygous model (TT vs CC: pooled OR=1.54, 95% CI = 1.36-1.76, P < .001), heterozygous model (CT vs CC: pooled OR=1.24, 95% CI = 1.16-1.32, P < .001), dominant model (CT + TT vs CC: pooled OR=1.28, 95% CI = 1.20-1.36, P < .001) and recessive model (TT vs CT+ CC: pooled OR=1.42, 95% CI = 1.25-1.61, P < .001). Subgroup analysis also demonstrated that polymorphisms at this site also increased the risk of neuroblastoma. CONCLUSIONS: Our results find that rs11655237 contributed to occurrence of cancer in all models in Chinese population.


Assuntos
Neuroblastoma , RNA Longo não Codificante , China , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética
14.
ACS Chem Neurosci ; 13(18): 2728-2742, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36094343

RESUMO

Transient receptor potential canonical 5 (TRPC5) channels are predominantly expressed in the striatum and substantia nigra of the brain. These channels are permeable to calcium ions and are activated by oxidative stress. The physiological involvement of TRPC5 channels in temperature and mechanical sensation is well documented; however, evidence for their involvement in the pathophysiology of neurodegenerative disorders like Parkinson's disease (PD) is sparse. Thus, in the present study, the role of TRPC5 channels and their associated downstream signaling was elucidated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) model of PD. Bilateral intranigral administration of MPTP and 24 h MPP+ exposure were performed to induce PD in the Sprague-Dawley rats and SH-SY5Y cells, respectively. MPTP led to behavioral anomalies and TRPC5 overexpression accompanied by increased calcium influx, apoptosis, oxidative stress, and mitochondrial dysfunctions. In addition, tyrosine hydroxylase (TH) expression was significantly lower in the midbrain and substantia nigra compared to sham animals. Intraperitoneal administration of potent and selective TRPC5 inhibitor, HC070 (0.1 and 0.3 mg/kg) reversed the cognitive and motor deficits seen in MPTP-lesioned rats. It also restored the TH and TRPC5 expression both in the striatum and midbrain. Furthermore, in vitro and in vivo studies suggested improvements in mitochondrial health along with reduced oxidative stress, apoptosis, and calcium-mediated excitotoxicity. Together, these results showed that inhibition of TRPC5 channels plays a crucial part in the reversal of pathology in the MPTP/MPP+ model of Parkinson's disease.


Assuntos
Intoxicação por MPTP , Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Canais de Potencial de Receptor Transitório , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Humanos , Intoxicação por MPTP/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Methods Mol Biol ; 2546: 185-194, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36127589

RESUMO

Neuroblastoma and other neural crest tumors can be characterized by the increased production and excretion of catecholamines and their metabolites. Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are important catecholamine metabolites that can be measured to provide relatively rapid laboratory diagnosis and clinical follow-up of neuroblastoma. We present a procedure to quantify HVA and VMA in urine samples which have been diluted to a creatinine concentration of 2 mg/dL. Diluted samples are spiked with deuterated internal standards, acidified, and extracted with an organic solvent. A bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) and pyridine mixture is added to the dried extract to create trimethylsilyl derivatives of HVA and VMA. The derivatized compounds are measured using gas chromatography-mass spectrometry (GC/MS).


Assuntos
Neuroblastoma , Ácido Vanilmandélico , Biomarcadores , Catecolaminas , Creatinina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Ácido Homovanílico/urina , Humanos , Neuroblastoma/diagnóstico , Piridinas , Solventes , Ácido Vanilmandélico/urina
16.
J Int Adv Otol ; 18(5): 392-398, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36063095

RESUMO

BACKGROUND: This study aimed to compare the cytotoxic, cytostatic, and ototoxic effects of lipoplatin compared to cisplatin application in the subcutaneous xenograft nude mouse neuroblastoma tumor model. METHODS: In this study, C1300 neuroblastoma cells were administered subcutaneously to 21 male nude mice. When the tumor reached 150 mm3 diameter, mice were randomized into 3 groups. Saline, cisplatin, and lipoplatin were given intraperitoneally. The auditory function tests were performed before administration and 72 hours after administration. Mice were sacrificed and the tumor and cochlea were removed after 72 hours. Histopathologic evaluation of necrosis and apoptosis was determined by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. Cyclooxygenase 2, superoxide dismutase 2, and inducible nitric oxide synthase levels were determined by immunohistochemistry in tissue samples. RESULTS: Apoptosis and necrosis rates were higher in lipoplatin group than in cisplatin group (P=.035 and P=.010, respectively) in tumor tissue. In the spiral ganglion, apoptosis and necrosis were lower in the lipoplatin group than in cisplatin group (P=.002 and P=.002, respectively). Cyclooxygenase 2 pattern in the cochlea was positive in both control and lipoplatin group and negative in cisplatin group (P=.001). Superoxide dismutase 2 and inducible nitric oxide synthase 2 protein expressions showed no difference between groups. The auditory functions were similar to baseline values and had a better threshold value in lipoplatin group than cisplatin group. CONCLUSION: For the treatment of neuroblastoma, the use of lipoplatin seems to be beneficial in reducing side effects of cisplatin. We recommend that the mechanism of these properties of lipoplatin should be evaluated in further studies.


Assuntos
Antineoplásicos , Neuroblastoma , Ototoxicidade , Animais , Antineoplásicos/farmacologia , Cisplatino/uso terapêutico , Ciclo-Oxigenase 2 , Masculino , Camundongos , Camundongos Nus , Necrose/induzido quimicamente , Neuroblastoma/tratamento farmacológico , Óxido Nítrico Sintase Tipo II
17.
Nutrients ; 14(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36079767

RESUMO

Rosmarinic acid (RA) is a natural polyphenolic compound with antioxidative property. With the present study, we aimed to evaluate the neuroprotective role of RA on Parkinson's disease using rotenone induced SH-SY5Y cell model of Parkinson's disease, the underlying mechanism of action of RA was also investigated. Cell viability, cell morphology, apoptosis, signaling protein phosphorylation and expression, cellular reactive oxygen species (ROS) production, ATP content, and mitochondrial membrane potential were tested in SH-SY5Y cells. RA showed a neuroprotective effect in a rotenone-induced SH-SY5Y cell model of Parkinson's disease with dose-dependent manner, it reduced cell apoptosis and restored normal cell morphology. RA not only decreased levels of α-synuclein and Tau phosphorylation but also elevated the contents of AMPK phosphorylation, Akt phosphorylation, and PGC-1α. RA restored the reduced mitochondrial membrane potential and ATP content as well as inhibited rotenone-induced ROS overproduction. Further findings demonstrated that the neuroprotective role of RA was partially due to the inhibition of Abl tyrosine kinase. RA treatment suppressed the hyperphosphorylation of Abl Y412 and CrkII Y221 induced by rotenone. Nilotinib, a specific inhibitor of Abl, elicited a similar neuroprotective effect as that of RA. The present study indicates that RA has a property of neuroprotection against rotenone, and the neuroprotective effect is partially attributed to the inhibition of Abl.


Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Doença de Parkinson , Trifosfato de Adenosina/farmacologia , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Cinamatos , Depsídeos , Humanos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Rotenona/toxicidade
18.
J Enzyme Inhib Med Chem ; 37(1): 2348-2356, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36050834

RESUMO

Multitarget drugs are a promising therapeutic approach against Alzheimer's disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1-4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1-4 and 6) effects against Aß-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.


Assuntos
Doença de Alzheimer , Neuroblastoma , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Aspártico Endopeptidases/metabolismo , Inibidores da Colinesterase , Humanos , Indazóis/farmacologia , Neuroblastoma/tratamento farmacológico , Relação Estrutura-Atividade
19.
Bioorg Chem ; 128: 106112, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36070628

RESUMO

Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2'-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid 10a exhibited good inhibitory activity against HDAC8 (IC50 = 117 nM) with 50-fold and 42-fold high selectivity relative to HDAC1 and HDAC6, respectively. Meanwhile, 10a disrupted tubulin polymerization effectively and exhibited potent antiproliferative activity against BE-(2)-C cell line, with IC50 value of 17 nM. Mechanism studies revealed that 10a blocked cell cycle, induced cellular apoptosis and suppressed colony formation. Moreover, 10a possessed good physicochemical properties and metabolic stability. Importantly, 10a exhibited better antitumor effects in human neuroblastoma xenograft mice model than those of clinical HDAC inhibitor and tubulin inhibitor, whether used alone or in combination. These results highlighted the advantages of the HDAC8/tubulin dual inhibitor 10a as an outstanding antitumor agent.


Assuntos
Antineoplásicos , Neuroblastoma , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Camundongos , Neuroblastoma/tratamento farmacológico , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico
20.
J Pediatr Hematol Oncol Nurs ; 39(5): 304-316, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36129889

RESUMO

Background: Administration of 131I-metaiodobenzylguanidine (131I-MIBG) for neuroblastoma requires hospitalization in single-room isolation and limits caregiver physical contact due to the child's radioactive burden. Though used for decades, there is a dearth of research on the experiences of children and their parents while isolated. Methods: This qualitative descriptive study evaluated the experience of children with neuroblastoma undergoing single-room isolation for 131I-MIBG therapy and their parents. Ten nurses, nine parents, and five children were interviewed; transcripts were analyzed applying a conventional content analysis approach. Results: Child themes included overall experiences ranging from positive to negative; emotional stress was common; symptoms were common but mostly managed; the children were adequately prepared for isolation; and audiovisual technology and entertainment helped. The indwelling urinary catheter was a source of emotional stress and/or pain for several children. Parent themes included I thought it was going to be a lot worse; it gets better with time; feeling concerned and overwhelmed; prepared as much as you can be; and you feel like you're not alone. Discussion: Findings suggest that children and parents would benefit from additional coping support interventions to address emotional distress. Efforts should be made to identify other sources of technology or room designs that can maximize the child's sense of connection with parents and healthcare professionals. Additional research is needed to examine the impact of this isolation experience on the long-term psychological outcomes of children and parents.


Assuntos
3-Iodobenzilguanidina , Neuroblastoma , 3-Iodobenzilguanidina/uso terapêutico , Criança , Humanos , Radioisótopos do Iodo , Neuroblastoma/radioterapia , Pais/psicologia
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