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1.
ISA Trans ; 141: 20-29, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37059673

RESUMEN

Powered by the rapid progress of analytics techniques and the increasing availability of healthcare data, artificial intelligence (AI) is bringing a paradigm shift to healthcare applications. AI techniques offer considerable advantages for the evaluation and assimilation of large amounts of complex healthcare data. However, to effectively use AI tools in healthcare, key issues need to be considered and several limitations must be addressed, such as privacy-preserving and authentication of the healthcare data for analysis in training and inference procedures. Although various techniques ranging from cryptographic tools to obfuscation mechanisms have been proposed to provide privacy guarantees for data in AI-based services, none of them is applicable to online AI-driven healthcare applications. For they require a heavy computational cost on protecting privacy without offering authentication services for third parties. In this paper, we present RASS, an efficient privacy-preserving and authentication scheme for securing analyzed data in an AI-driven healthcare system. The security proofs of our construction indicate that its unforgeability and multi-show unlinkability can defend against the tempering and collusion attacks respectively. Finally, we conduct sufficient efficiency analysis, and the results show that RASS achieves the above security demands without introducing complex computation and communication costs.

2.
Behav Sleep Med ; 21(5): 529-539, 2023 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-36263691

RESUMEN

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.


Asunto(s)
Terapia Cognitivo-Conductual , Trastornos del Sueño del Ritmo Circadiano , Trastornos del Inicio y del Mantenimiento del Sueño , Adolescente , Humanos , Femenino , Adulto Joven , Masculino , Sueño , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Resultado del Tratamiento
3.
Hum Cell ; 35(6): 1785-1796, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36006565

RESUMEN

Ribosomal protein L34-antisense RNA 1 (RPL34-AS1), one of the long non-coding RNAs (lncRNAs), plays an important function in regulating diverse human malignant tumors. Nevertheless, the functions of RPL34-AS1 in ischemic stroke remain unclear. The present work focused on determining the candidate targets of RPL34-AS1 and its related mechanism in ischemic injury. The oxygen-glucose deprivation (OGD/R) in vitro cell model and middle cerebral artery occlusion (MCAO) in vivo rat model were utilized to simulate the pathological process of ischemic stroke. Additionally, the CCK8, WB (detecting Bcl-2 and Bax protein levels), and caspase-3 activity assays were done to investigate the anti-apoptotic functions of RPL34-AS1. The relationship among RPL34-AS1, insulin-like growth factor 1 receptor (IGF1R), and microRNA-223-3p (miR-223-3p) was determined through luciferase reporter assay. In this study, RPL34-AS1 expression was reduced in patients suffering from ischemic stroke. The overexpression of RPL34-AS1 reduced ischemic brain damage. However, the cell viability and glucose uptake were increased, and the apoptosis rate was decreased in the OGD/R-induced neurons. Further, miR-223-3p resulted in the decreased cell viability and glucose uptake and the increased cell apoptosis to cause ischemic brain damage. Besides, the neuroprotective effects of RPL34-AS1 on OGD/R injury were partly reversed by miR-223-3p. Mechanistically, lncRNA RPL34-AS1 could function as the competing endogenous RNA (ceRNA) of miR-223-3p to regulate IGF1R. Collectively, our study demonstrated that lncRNA RPL34-AS1 attenuated OGD/R-induced neuronal injury by mediating miR-223-3p/IGF1R axis. This discovery might serve as the candidate therapeutic target for ischemic stroke.


Asunto(s)
Accidente Cerebrovascular Isquémico , MicroARNs , Fármacos Neuroprotectores , ARN Largo no Codificante , Animales , Apoptosis/genética , Caspasa 3/metabolismo , Glucosa/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratas , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Proteína X Asociada a bcl-2/metabolismo
5.
Front Pharmacol ; 13: 708610, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35571087

RESUMEN

Tremors have been reported even with a low dose of tacrolimus in patients with nephrotic syndrome and are responsible for hampering the day-to-day work of young active patients with nephrotic syndrome. This study proposes a neural network model based on seven variables to predict the development of tremors following tacrolimus. The sensitivity and specificity of this algorithm are high. A total of 252 patients were included in this study, out of which 39 (15.5%) experienced tremors, 181 patients (including 32 patients who experienced tremors) were randomly assigned to a training dataset, and the remaining were assigned to an external validation set. We used a recursive feature elimination algorithm to train the training dataset, in turn, through 10-fold cross-validation. The classification performance of the classifer was then used as the evaluation criterion for these subsets to find the subset of optimal features. A neural network was used as a classification algorithm to accurately predict tremors using the subset of optimal features. This model was subsequently tested in the validation dataset. The subset of optimal features contained seven variables (creatinine, D-dimer, total protein, calcium ion, platelet distribution width, serum kalium, and fibrinogen), and the highest accuracy obtained was 0.8288. The neural network model based on these seven variables obtained an area under the curve (AUC) value of 0.9726, an accuracy of 0.9345, a sensitivity of 0.9712, and a specificity of 0.7586 in the training set. Meanwhile, the external validation achieved an accuracy of 0.8214, a sensitivity of 0.8378, and a specificity of 0.7000 in the validation dataset. This model was capable of predicting tremors caused by tacrolimus with an excellent degree of accuracy, which can be beneficial in the treatment of nephrotic syndrome patients.

6.
Front Cell Neurosci ; 16: 888836, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35558879

RESUMEN

Neurovascular system plays a vital role in controlling the blood flow into brain parenchymal tissues. Additionally, it also facilitates the metabolism in neuronal biological activities. Cerebral microvascular endothelial cells (MECs) are involved in mediating progression of the diseases related to cerebral vessels, including stroke. Arachidonic acid can be transformed into epoxyeicosatrienoic acids (EETs) under the catalysis by cytochrome P450 epoxygenase. We have reported that EETs could protect neuronal function. In our research, the further role of 14,15-EET in the protective effects of cerebral MECs and the potential mechanisms involved in oxygen glucose deprivation and reperfusion (OGD/R) were elucidated. In our study, we intervened the SIRT1/FOXO3a pathway and established a TSPO knock down model by using RNA interference technique to explore the cytoprotective role of 14,15-EET in OGD/R injury. Cerebral MECs viability was remarkably reduced after OGD/R treatment, however, 14,15-EET could reverse this effect. To further confirm whether 14,15-EET was mediated by SIRT1/FOXO3a signaling pathway and translocator protein (TSPO) protein, we also detected autophagy-related proteins, mitochondrial membrane potential, apoptosis indicators, oxygen free radicals, etc. It was found that 14,15-EET could regulate the mitophagy induced by OGD/R. SIRT1/FOXO3a signaling pathway and TSPO regulation were related to the protective role of 14,15-EET in cerebral MECs. Moreover, we also explored the potential relationship between SIRT1/FOXO3a signaling pathway and TSPO protein. Our study revealed the protective role and the potential mechanisms of 14,15-EET in cerebral MECs under OGD/R condition.

7.
Int J Biol Macromol ; 202: 102-111, 2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35038464

RESUMEN

Stem cell transplantation technology provides the cell reconstruction of damaged heart a completely new therapy approach. Due to the inappropriate microenvironment such as reactive oxygen radicals caused by ischemic infarct, the survival and retention rates of cell transplantation are not desirable. A thermo sensitive chitosan-vitamin C (CSVC) hydrogel scaffold was developed to reduce oxidative stress injury after myocardial infarction, thereby increasing the cell survival rate of cell transplantation. Vitamin C was conjugated on the chitosan chain by electrostatic adsorption. Compared to chitosan, CSVC complex had a higher solubility and stronger antioxidant property. CSVC hydrogel has suitable gelation time and injectable properties. Scanning electron microscopy showed that chitosan hydrogels had three-dimensional porous structure with irregular pores interconnected throughout the construct. Live/dead and H&E staining results showed that CSVC hydrogel can support the survival and adhesion of cardiomyocytes. Compared with chitosan hydrogel, CSVC hydrogel can clearly improve the survival of cardiomyocytes and reduce the ROS level under H2O2-induced oxidative stress conditions. These results suggest that CSVC hydrogel has the potential to support the survival of cardiomyocytes in tissue engineering.


Asunto(s)
Quitosano , Hidrogeles , Ácido Ascórbico/farmacología , Supervivencia Celular , Quitosano/química , Hidrogeles/química , Hidrogeles/farmacología , Peróxido de Hidrógeno , Estrés Oxidativo , Ingeniería de Tejidos/métodos
8.
Biomed Res Int ; 2021: 5213550, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34414235

RESUMEN

In order to evaluate the importance of deep learning techniques in stroke diseases, this paper systematically reviews the relevant literature. Deep learning techniques have a significant impact on the diagnosis, treatment, and prediction of stroke. In addition, this study also discusses the current bottlenecks and the future development prospects of deep learning technology.


Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/prevención & control , Algoritmos , Aprendizaje Profundo , Humanos , Redes Neurales de la Computación
9.
Int Immunopharmacol ; 99: 108040, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34435586

RESUMEN

Despite advances in the understanding of the pathophysiology of ischemic stroke, therapeutic options remain limited. Methylcobalamin is an endogenous vitamin B12 that exhibits anti-inflammatory and antiapoptotic activities in a variety of diseases. In this study, we aimed to explore the neuroprotective effects and mechanism of action of methylcobalamin on cerebral ischemic injury in vitro and in vivo. The oxygen and glucose deprivation/reperfusion model and middle cerebral artery occlusion model were used to simulate cerebral ischemic injury in vitro and in vivo. Cell viability, inflammatory factors, cell apoptosis, and protein expression levels were determined. Further, autophagy flux and the cerebral infarction volume were measured. The modified neurological severity score, Longa score, Rotarod assay, and foot-fault test were used to evaluate behavioral changes and neurological deficits in rats. In vitro, methylcobalamin significantly increased cell viability, decreased lactate dehydrogenase release, attenuated inflammatory cytokine expression, reduced the apoptotic proportion, and enhanced autophagy flux after OGD treatment. In addition, Bcl-2 and Beclin1 expression levels and the LC3 II/I ratio were increased, whereas levels of Bax and cleaved caspase-3 were decreased. In vivo, methylcobalamin significantly reduced the cerebral infarction volume and neurological deficits in the rats. Furthermore, methylcobalamin activated the ERK1/2 pathway, whereas ERK1/2 inhibitors diminished its effects in the in vitro and in vivo models. In conclusion, methylcobalamin may exert a neuroprotective effect on cerebral ischemia and is a promising drug candidate for developing novel neuroprotective therapies.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Vitamina B 12/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Fármacos Neuroprotectores/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Vitamina B 12/farmacología , Vitamina B 12/uso terapéutico
10.
Sensors (Basel) ; 21(10)2021 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-34064942

RESUMEN

The fast proliferation of edge computing devices brings an increasing growth of data, which directly promotes machine learning (ML) technology development. However, privacy issues during data collection for ML tasks raise extensive concerns. To solve this issue, synchronous federated learning (FL) is proposed, which enables the central servers and end devices to maintain the same ML models by only exchanging model parameters. However, the diversity of computing power and data sizes leads to a significant difference in local training data consumption, and thereby causes the inefficiency of FL. Besides, the centralized processing of FL is vulnerable to single-point failure and poisoning attacks. Motivated by this, we propose an innovative method, federated learning with asynchronous convergence (FedAC) considering a staleness coefficient, while using a blockchain network instead of the classic central server to aggregate the global model. It avoids real-world issues such as interruption by abnormal local device training failure, dedicated attacks, etc. By comparing with the baseline models, we implement the proposed method on a real-world dataset, MNIST, and achieve accuracy rates of 98.96% and 95.84% in both horizontal and vertical FL modes, respectively. Extensive evaluation results show that FedAC outperforms most existing models.

11.
Neuroscience ; 455: 212-222, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33197503

RESUMEN

Status epilepticus (SE) leads to irreversible neuronal damage and consists of a complex pathogenesis that involves oxidative stress and subsequent autophagy. Rosiglitazone has recently been considered as a potential neuroprotective factor in epilepsy because of its antioxidative function. The aim of this study was to assess the effects of rosiglitazone in SE rat models and investigate whether its mechanisms of action involve autophagy via the antioxidant factor, nuclear factor erythroid 2-related factor 2 (Nrf2). The male Sprague-Dawley rats (200-220 g) were used to establish lithium-pilocarpine-induced SE model. We found that rosiglitazone markedly improved neuronal survival at 24-h post-SE as indicated via Hematoxylin-Eosin and Nissl staining. Furthermore, along with a reduction in reactive oxygen species, rosiglitazone pretreatment enhanced the antioxidative activity of superoxide dismutase and the expression level of Nrf2, as detected via chemical assay kits and Western blotting, respectively. In addition, the microtubule-associated protein light chain 3II (LC3II)/LC3I ratio was increased and peaked at 24 h after SE, whereas p62 mRNA levels were sharply elevated at 72 h after SE, both SE-induced increases of which were reversed via rosiglitazone pretreatment. To further test our hypothesis of the key role of Nrf2 in this process, small-interfering RNA for Nrf2 (siNrf2) was then transfected into SE rats to knockdown Nrf2 expression. We found that siNrf2 partially blocked the above effects of rosiglitazone on autophagy-related proteins in SE rats. Taken together, our findings suggest that rosiglitazone attenuates oxidative-stress-induced autophagy via increasing Nrf2 in SE rats and may be used as a promising therapeutic strategy for SE treatment.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Pilocarpina , Rosiglitazona , Estado Epiléptico , Animales , Elementos de Respuesta Antioxidante , Autofagia , Litio/farmacología , Masculino , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Pilocarpina/toxicidad , Ratas , Ratas Sprague-Dawley , Rosiglitazona/farmacología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico
12.
J Neurosci ; 40(16): 3142-3151, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32152200

RESUMEN

Prohibitin (PHB) is a critical protein involved in many cellular activities. In brain, PHB resides in mitochondria, where it forms a large protein complex with PHB2 in the inner TFmembrane, which serves as a scaffolding platform for proteins involved in mitochondrial structural and functional integrity. PHB overexpression at moderate levels provides neuroprotection in experimental brain injury models. In addition, PHB expression is involved in ischemic preconditioning, as its expression is enhanced in preconditioning paradigms. However, the mechanisms of PHB functional regulation are still unknown. Observations that nitric oxide (NO) plays a key role in ischemia preconditioning compelled us to postulate that the neuroprotective effect of PHB could be regulated by NO. Here, we test this hypothesis in a neuronal model of ischemia-reperfusion injury and show that NO and PHB are mutually required for neuronal resilience against oxygen and glucose deprivation stress. Further, we demonstrate that NO post-translationally modifies PHB through protein S-nitrosylation and regulates PHB neuroprotective function, in a nitric oxide synthase-dependent manner. These results uncover the mechanisms of a previously unrecognized form of molecular regulation of PHB that underlies its neuroprotective function.SIGNIFICANCE STATEMENT Prohibitin (PHB) is a critical mitochondrial protein that exerts a potent neuroprotective effect when mildly upregulated in mice. However, how the neuroprotective function of PHB is regulated is still unknown. Here, we demonstrate a novel regulatory mechanism for PHB that involves nitric oxide (NO) and shows that PHB and NO interact directly, resulting in protein S-nitrosylation on residue Cys69 of PHB. We further show that nitrosylation of PHB may be essential for its ability to preserve neuronal viability under hypoxic stress. Thus, our study reveals a previously unknown mechanism of functional regulation of PHB that has potential therapeutic implications for neurologic disorders.


Asunto(s)
Neuronas/metabolismo , Neuroprotección/fisiología , Óxido Nítrico/metabolismo , Daño por Reperfusión/metabolismo , Proteínas Represoras/metabolismo , Animales , Muerte Celular/fisiología , Células Cultivadas , GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Ratones , NG-Nitroarginina Metil Éster/farmacología , Neuronas/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Prohibitinas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
13.
Curr Drug Deliv ; 16(8): 751-758, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31722658

RESUMEN

BACKGROUND: Curcumin has shown considerable pharmacological activity, including antiinflammatory activity. Nevertheless, the pharmacological effect of curcumin may be limited because of poor water solubility, metabolizing rapidly and systemic elimination. OBJECTIVE: In the current research, a novel curcumin nanoemulsion (Cur-NE) was developed for improving in vitro permeability and bioavailability via pulmonary administration. METHODS: The Cur-NE was prepared by a modified emulsification-evaporation method and its surfac morphology, particles size and distribution, and encapsulation efficiencies of drug in NE were characterized. In vitro transmembrane transport experiment was performed to investigate the transport profile of curcumin across Xenopus alveolar membrane. The pharmacokinetics of Cur-NE in rabbits was evaluated. RESULTS: The average particles size, zeta potential, polydispersity index of Cur-NE were 234.8±1.08 nm, -19.5±0.2 mV and 0.10, respectively. Xenopus alveolar membrane was used in the transmembrane transport study, the cumulative amount of curcumin was 6.6% for curcumin suspensions, but nearly 50% for Cur-NE at the time of 8 h (P<0.05). The pharmacokinetic study in rabbits, the absolute bioavailability of curcumin for Cur-NE was 24.11%. CONCLUSION: Thus, a novel Cur-NE for pulmonary drug delivery was developed for improving in vitro permeability and bioavailability, which can be an alternate to the oral administration.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/farmacocinética , Nanopartículas/administración & dosificación , Nanopartículas/química , Alveolos Pulmonares/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Curcumina/química , Sistemas de Liberación de Medicamentos , Emulsiones , Tamaño de la Partícula , Permeabilidad , Conejos , Solubilidad , Xenopus
14.
Cell Physiol Biochem ; 52(4): 708-727, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30921509

RESUMEN

BACKGROUND/AIMS: With advances in RNA-sequencing (RNA-seq), exploring the expression and transcripts of different classes of genes are now possible. Our purpose was to analyse to the long non-coding RNAs (lncRNAs) in mouse brain microvascular endothelial cells (bEnd.3) after oxygen-glucose deprivation/re-oxygenation (OGD/R). METHODS: RNA-seq was employed to explore the expression of lncRNAs, and quantitative real-time PCR (qRT-PCR) was used to identify the results of RNA-seq. Furthermore, the biological functions of the lncRNAs were identified by cell viability, wound healing, transwell, tube formation and immunofluorescent staining assays. Finally, the molecular mechanisms involving the differentially expressed lncRNAs were further explored by bioinformatics and Western blotting (WB). RESULTS: In total, 2710 lncRNAs were found, 33 of which were significantly differentially expressed, with 18 upregulated lncRNAs and 15 downregulated lncRNAs in brain microvascular endothelial cells following OGD/R. Among the dysregulated genes, G protein-coupled receptor 137b-pseudogene (Gpr137b-ps), predicted gene 32856 (Gm32856), small nucleolar RNA host gene 17 (snhg17), chaperonin containing Tcp1 and subunit 6a (Cct6a) were significantly upregulated lncRNAs; this finding was further validated using qRT-PCR. Moreover, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes (KEGG) pathway analyses were employed to decipher the potential target genes and signaling pathways of the differentially expressed lncRNAs. Finally, we selected pseudogene-expressed lncRNA Gpr137b-ps as a candidate gene, and report for the first time that pseudogenes can mediate angiogenesis and their potential target genes, namely, 15-lipoxygenase1 (15-LOX1), Signal Transducer and Activator of Transcription 3 (S TAT3) and vascular endothelial growth factor (VEGF). CONCLUSION: Therefore, our study revealed that Gpr137b-ps plays critical roles in the process of angiogenesis, suggesting avenues for the development of future therapeutic strategies that contribute to promoting angiogenesis following I/R.


Asunto(s)
Hipoxia de la Célula , Glucosa/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/metabolismo , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/metabolismo , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Oxígeno/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transcriptoma/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
J Cell Mol Med ; 23(4): 2970-2983, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30784209

RESUMEN

Long non-coding RNAs (lncRNAs) have been identified as playing critical roles in multiple diseases. However, little is known regarding their roles and mechanisms in post-stroke angiogenesis. Our studies focused on deciphering the functional roles and the underlying mechanisms of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the process of angiogenesis following oxygen-glucose deprivation/reoxygenation (OGD/R). We characterized the up-regulation of MALAT1 expression in the process of angiogenesis after hypoxic injury in vivo and in vitro. We further showed that compared with the empty vector, MALAT1 knockdown had significantly reduced the capacity for angiogenesis, which was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), scratching, cell cycle and immunofluorescent staining. Thus, our findings suggest that MALAT1 may mediate proangiogenic function in OGD/R. To further explore the potential mechanisms, we used lentiviruses expressing shMALAT1 and empty vector; the results revealed that shMALAT1 reduced the expression of 15-lipoxygenase 1 (15-LOX1), vascular endothelial growth factor (VEGF) and the phosphorylation of signal transducers and activators of transcription 3 (pSTAT3). Taken together, our results are the first to propose that MALAT1 may regulate angiogenesis through the 15-LOX1/STAT3 signalling pathway, and they may provide a critical target for the treatment of hypoxic injury and an avenue for therapeutic angiogenesis.


Asunto(s)
Isquemia Encefálica/complicaciones , Endotelio Vascular/patología , Glucosa/deficiencia , Neovascularización Patológica/patología , Oxígeno/metabolismo , ARN Largo no Codificante/genética , Daño por Reperfusión/complicaciones , Animales , Apoptosis , Hipoxia de la Célula , Movimiento Celular , Endotelio Vascular/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/etiología , Neovascularización Patológica/metabolismo , Transducción de Señal
16.
Int J Biol Macromol ; 125: 1192-1202, 2019 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-30227207

RESUMEN

Myocardial infarction (MI) continues to be a major contributor to the morbidity and mortality across the globe. Injectable hydrogel, a tissue-engineered scaffold, recently demonstrated very promising in myocardial repair. However, the undesirable retention and survival of transplanted cells has limited their applications due to the oxidative stress microenvironment of MI lesions. In this work, a thermosensitive α-tocopherol (AT) liposome loaded chitosan hydrogel was developed to suppress the oxidative stress injury in cardiomyocytes. AT was embedded in the liposomes to improve its solubility and stability. The innovative AT liposome loaded chitosan hydrogel (AT-LCH) system had an appropriate sol-to-gel transition temperature. Hydrogels possessed a highly porous structure with irregular pores interconnected throughout the construct as shown by SEM, and liposomes distributed uniformly in the porous structure. A sustained AT release was observed in AT-LCH. In addition, AT-LCH has shown an excellent biocompatibility to support the adhesion and survival of cardiomyocytes. Moreover, it can resist the oxidative stress environment and improve the survival of cardiomyocytes. In general, this work suggests that AT-LCH may present an ideal scaffold material for injectable cardiac tissue engineering.


Asunto(s)
Antioxidantes/administración & dosificación , Quitosano/química , Hidrogeles , Liposomas , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , alfa-Tocoferol/administración & dosificación , Animales , Antioxidantes/química , Adhesión Celular , Línea Celular , Supervivencia Celular , Humanos , Hidrogeles/química , Enlace de Hidrógeno , Ratas , Especies Reactivas de Oxígeno/metabolismo , Reología , Análisis Espectral , Temperatura , alfa-Tocoferol/química
17.
ACS Chem Neurosci ; 10(1): 507-517, 2019 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-30346717

RESUMEN

As an important protective mechanism against cerebral ischemia, angiogenesis has become a topic of interest in the treatment of ischemic stroke with the challenge that few drugs promote angiogenesis. Previous studies of the identification of drug-target interactions mainly focused on the overall structures of drugs and proteins, which limited the discovery of novel structure drugs. In this article, we proposed a new strategy for discovering proangiogenic drugs based on the assumption that drug-protein interaction is mediated by substructure and domain. First, we identified substructure-domain relationships according to the known drug-protein interactions and established the drug-substructure-domain-protein relationships of genes that are proangiogenic in brain tissue and expressed significantly during ischemic stroke. Then we quantified the intensity of interaction between each drug and each protein. Finally, we obtained 540 interactive relationships between 238 drugs and 54 genes, establishing a drug-gene network with two patterns of independent and complex drug-gene interactions. Both of the patterns facilitated finding not only drugs with the same overall structure but also drugs with a different overall structure based on the same or a similar protein spectrum. In addition, we analyzed the mechanism of action of each predicted drug and extracted drugs with similar mechanisms. In vitro, our results showed that azelnidipine, azilsartan, lercanidipine, nafcillin, and vortioxetine enhanced bEnd.3 cell proliferation, migration, tube formation, and the expression of angiogenic marker PCNA. Azelnidipine, azilsartan, lercanidipine, and nafcillin increased the level of expression of proangiogenic factor VEGF. Unlike previous studies focusing on the overall structures of drugs, our research highlighted local structural similarity, which has great potential in the search for more proangiogenic drugs with novel structures.


Asunto(s)
Inductores de la Angiogénesis/administración & dosificación , Isquemia Encefálica/genética , Descubrimiento de Drogas/métodos , Dominios Proteicos/genética , Accidente Cerebrovascular/genética , Inductores de la Angiogénesis/química , Isquemia Encefálica/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Bases de Datos Genéticas/tendencias , Humanos , Dominios Proteicos/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad
18.
Neurol Res ; 40(3): 211-220, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29334873

RESUMEN

Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b.wt) orally through the study period. Results Cd-induced ROS levels and malondialdehyde (MDA) content were inhibited by nobiletin and improved glutathione levels. Nobiletin reduced neuronal apoptosis induced by Cd and raised cleaved caspase-3 levels. Intriguingly, nobiletin blocked JNK and Erk1/2 phosphorylation and down-regulated the pathways. Raised expression of kinases - MKK and ASK1 were reduced by nobiletin. Discussion The suppressed expression of phosphatases - PP2A and PP5 were up-regulated on nobiletin treatment. Nobiletin significantly blocked the activation of Akt/mTOR signaling. Enhanced phosphorylation of S6K1, Akt, and 4E-BP1 induced by Cd was significantly inhibited by nobiletin. The raised levels of raptor and rictor proteins were remarkably down-regulated on nobiletin treatment. Collectively, the observations of this study indicate protective effects of nobiletin against Cd-induced neurotoxicity.


Asunto(s)
Apoptosis/efectos de los fármacos , Flavonas/uso terapéutico , Enfermedades Neurodegenerativas/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Cadmio/toxicidad , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Glutatión/metabolismo , Etiquetado Corte-Fin in Situ , MAP Quinasa Quinasa 4/metabolismo , Masculino , Malondialdehído/metabolismo , Enfermedades Neurodegenerativas/inducido químicamente , Neuronas/efectos de los fármacos , Neuronas/patología , Proteína Oncogénica v-akt/metabolismo , Ratas , Ratas Sprague-Dawley
19.
Open Life Sci ; 13: 22-27, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33817063

RESUMEN

AIM: The aim of the study is to investigate a variation in the gene SLC6A19 in a female patient with Hartnup disorder manifested only by seizure. METHODS: DNA samples collected from the patient and her parents were analyzed and twelve exons of the SLC6A19 gene were amplified and sequenced. RESULTS: We found c.47C>T and c.1522G>A mutations in the gene SLC6A19 belonging to the patient, which are missense mutations inherited from her parents. The c.47C>T mutation is from her father and c.1522G>A is inherited from her mother. The parents are both heterozygous healthy carriers. CONCLUSION: Two novel mutations of the SLC6A19 gene are revealed in the female patient with Hartnup disorder, exhibiting no typical dermatologic problems, but having dramatic neurological symptoms.

20.
Mol Cells ; 40(11): 837-846, 2017 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-29081082

RESUMEN

As a component of the neurovascular unit, cerebral smooth muscle cells (CSMCs) are an important mediator in the development of cerebral vascular diseases such as stroke. Epoxyeicosatrienoic acids (EETs) are the products of arachidonic acid catalyzed by cytochrome P450 epoxygenase. EETs are shown to exert neuroprotective effects. In this article, the role of EET in the growth and apoptosis of CSMCs and the underlying mechanisms under oxygen glucose deprivation (OGD) conditions were addressed. The viability of CMSCs was decreased significantly in the OGD group, while different subtypes of EETs, especially 14,15-EET, could increase the viability of CSMCs under OGD conditions. RAPA (serine/threonine kinase Mammalian Target of Rapamycin), a specific mTOR inhibitor, could elevate the level of oxygen free radicals in CSMCs as well as the anti-apoptotic effects of 14,15-EET under OGD conditions. However, SP600125, a specific JNK (c-Jun N-terminal protein kinase) pathway inhibitor, could attenuate oxygen free radicals levels in CSMCs as well as the anti-apoptotic effects of 14,15-EET under OGD conditions. These results strongly suggest that EETs exert protective functions during the growth and apoptosis of CSMCs, via the JNK/c-Jun and mTOR signaling pathways in vitro. We are the first to disclose the beneficial roles and underlying mechanism of 14,15-EET in CSMC under OGD conditions.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/farmacología , Corteza Cerebral/irrigación sanguínea , Glucosa/metabolismo , Microvasos/citología , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Antracenos/farmacología , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , MAP Quinasa Quinasa 4/metabolismo , Masculino , Microvasos/efectos de los fármacos , Microvasos/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismo
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