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As a precursor of protoporphyrin IX (PpIX), an endogenous pro-apoptotic and fluorescent molecule, 5-Aminolevulinic acid (5-ALA) has gained substantial attention for its potential in fluorescence-guided surgery as well as photodynamic therapy (PDT). Moreover, 5-ALA-PDT has been suggested as a promising chemo-radio sensitization therapy for various cancers. However, insufficient 5-ALA-induced PpIX fluorescence and the induction of multiple resistance mechanisms may hinder the 5-ALA-PDT clinical outcome. Reduced efficacy and resistance to 5-ALA-PDT can result from genomic alterations, tumor heterogeneity, hypoxia, activation of pathways related to cell surveillance, production of nitric oxide, and most importantly, deregulated 5-ALA transporter proteins and heme biosynthesis enzymes. Understanding the resistance regulatory mechanisms of 5-ALA-PDT may allow the development of effective personalized cancer therapy. Here, we described the mechanisms underlying resistance to 5-ALA-PTD across various tumor types and explored potential strategies to overcome this resistance. Furthermore, we discussed future approaches that may enhance the efficacy of treatments using 5-ALA-PDT.
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Ácido Aminolevulínico , Resistencia a Antineoplásicos , Neoplasias , Fotoquimioterapia , Fármacos Fotosensibilizantes , Ácido Aminolevulínico/farmacología , Humanos , Fotoquimioterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Protoporfirinas/farmacología , Protoporfirinas/metabolismoRESUMEN
Glioblastoma is a rare and deadly malignancy with a low survival rate. Emerging evidence has shown that aberrantly expressed circular RNAs (circRNAs) play a critical role in the initiation and progression of GBM tumorigenesis. The oncogenic function of circZNF609 and circNFIX is involved in several types of cancer, but the role and underlying mechanism of these circRNAs in glioblastoma remain unclear. In this study, we hypothesized that circZNF609 and circNFIX may regulate EGFR through sponging miR-145-5p. Herein, we assessed the expression levels of circZNF609, circNFIX, miR-145-5p, and EGFR using quantitative polymerase chain reaction in glioblastoma patients and normal brain samples. The results showed that circZNF609, circNFIX, and EGFR expression levels were upregulated and miR145-5p was downregulated (p = 0.001, 0.06, 0.002, and 0.0065, respectively), while there was no significant association between clinicopathological features of the patients and the level of these genes expression. We also found a significant inverse correlation between miR145-5p and the expression of cZNF609, cNFIX and EGFR (p = 0.0003, 0.0006, and 0.009, respectively). These findings may open a new window for researchers to better understand the potential pathways involved in GBM pathogenesis. In conclusion, it may provide a new potential pathway for the development of effective drugs for the treatment of GBM patients.
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Neoplasias Encefálicas , Receptores ErbB , Regulación Neoplásica de la Expresión Génica , Glioblastoma , MicroARNs , Factores de Transcripción NFI , ARN Circular , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , ARN Circular/genética , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Factores de Transcripción NFI/genética , Factores de Transcripción NFI/metabolismo , Adulto , Anciano , Línea Celular TumoralRESUMEN
Objectives: Esophageal cancer stem cells (ECSCs) have been identified as the subset of cells within esophageal squamous cell carcinoma that possess tumorigenic, invasive, and metastatic properties. One important aspect of cancer metastasis is the binding of sialyl-Lewis X (CD15s) with E- or P-selectin, which facilitates the adhesion and migration of cancer cells to distant sites. This study was conducted to investigate the impact of fucosylation processes on the metastatic behavior of ECSCs. Materials and Methods: The esophageal cancer cell line (KYSE-30) was cultured and divided into control and 2F-peracetyl fucose (2F-PerAcFuc) treated groups. Spheres were harvested from these cultures. Cell invasion assay and qPCR were conducted to examine migration and marker expression in both groups. Cancer cell line-derived xenografts were established in nude mice to validate findings in vivo. Results: Our results initially indicated that the addition of 2F-PerAcFuc, an inhibitor of fucosylation, resulted in the down-regulation of the Fut3/CD15s pathway in both cancer stem-like cells and the xenograft model. Measurements of subcutaneous xenograft tumor volume revealed a significant decrease in tumor size among nude mice after treatment with 2F-PerAcFuc. Additionally, a reduction in Fut8/E-cadherin levels was observed in the xenograft model of nude mice. Furthermore, the administration of 2F-PerAcFuc lowered the levels of fucosylated glycoconjugates in nude mice. Conclusion: Our data suggest that inhibition of fucosyltransferase 3 and 8 can reduce the metastatic capacity of cancer stem-like cells by down-regulating CD15s and E-cadherin in a mouse model of esophageal cancer.
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NAD(P)H Quinone Dehydrogenase 1 (NQO1) plays a pivotal role in the regulation of neuronal function and synaptic plasticity, cellular adaptation to oxidative stress, neuroinflammatory and degenerative processes, and tumorigenesis in the central nervous system (CNS). Impairment of the NQO1 activity in the CNS can result in abnormal neurotransmitter release and clearance, increased oxidative stress, and aggravated cellular injury/death. Furthermore, it can cause disturbances in neural circuit function and synaptic neurotransmission. The abnormalities of NQO1 enzyme activity have been linked to the pathophysiological mechanisms of multiple neurological disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, cerebrovascular disease, traumatic brain injury, and brain malignancy. NQO1 contributes to various dimensions of tumorigenesis and treatment response in various brain tumors. The precise mechanisms through which abnormalities in NQO1 function contribute to these neurological disorders continue to be a subject of ongoing research. Building upon the existing knowledge, the present study reviews current investigations describing the role of NQO1 dysregulations in various neurological disorders. This study emphasizes the potential of NQO1 as a biomarker in diagnostic and prognostic approaches, as well as its suitability as a target for drug development strategies in neurological disorders.
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Enfermedad de Alzheimer , Encefalopatías , Neoplasias Encefálicas , NAD(P)H Deshidrogenasa (Quinona) , Humanos , Carcinogénesis , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Neuronas/patología , Estrés Oxidativo , Encefalopatías/metabolismoRESUMEN
Background: Long contact of UV causes skin damage. Glycolic acid (GA) as an alpha hydroxy acid is used to treat photodamaged skin. However, GA leads to side effects including; burning, erythema and peeling.Purpose: The aim of this study was to develop a controlled delivery systems loading GA in order to increasing its efficacy and lowering its side effects.Methods: Liposomes were evaluated for encapsulation efficiency, size and morphology. Optimized formulation was dispersed in HPMC gel bases and drug release kinetics were also studied. Clinical efficacy and safety of GA-loaded liposomal gel and GA gel formulation were evaluated in patients with photodamaged skin.Results: The EE% and average particle size of liposomes were 64 ±2.1 % and 317±3.6 nm, respectively. SEM image showed that liposomes were spherical in shape. In vitro release kinetics of GA from both formulations followed Weibull model. Clinical evaluation revealed that GA-loaded liposomal gel was more effective than GA gel formulation. Treatment with GA-loaded liposomal gel resulted in a statistically significant reduction in the scores of hyperpigmentation, fine wrinkling and lentigines. Moreover, liposomal gel formulation was able to minimize side effects of GA.Conclusion: According to the obtained results, the liposome-based gel formulation can be used as potential drug delivery system to enhance permeation of GA through skin layers and also reduce its side effects.
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Glicolatos , Liposomas , Absorción Cutánea , Humanos , Liposomas/metabolismo , Piel/metabolismo , Sistemas de Liberación de Medicamentos , Tamaño de la PartículaRESUMEN
There is growing evidence that the long noncoding RNAs (lncRNAs) contribute to the pathogenesis of various neurodegenerative diseases such as multiple sclerosis (MS). The role of lncRNAs nuclear repressor of NFAT (NRON) and Taurine up-regulated 1 (TUG1) in the inflammatory processes occurring in the experimental autoimmune encephalomyelitis (EAE) model of MS is yet to be investigated. Transcript levels of NRON and TUG1 in acute and chronic phases of EAE and cultured macrophages as well as the correlation between NRON and TUG1 expression with inflammatory cytokines, were evaluated in this study. EAE experimental model was induced in female C57BL/6 mice with subcutaneous injection of MOG35-55/CFA. Mice were scored for 28 days and then sacrificed. The expression of lncRNAs TUG1 and NRON in lumbar spinal cords, activated and controlled macrophages as well as the expression of IL-1, IL-6, and CDe-3 inflammatory cytokines, were assayed by real-time RT-PCR. The lncRNAs TUG1 and NRON were significantly down-regulated in lumbar spinal cords tissues in the acute phase of EAE compared to the control group. TUG1 and NRON were significantly down-regulated in macrophages treated with 10 ng lipopolysaccharide (LPS) compared to the control macrophages. A negative correlation was identified between NRON and TUG1 expression and IL-1, IL-6, and CDe-3 inflammatory cytokines. The present study demonstrates the dysregulation of lncRNAs TUG1 and NRON in spinal cord tissue lesions of EAE and activated macrophages, pointing to their potential role in the pathogenesis of EAE.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , ARN Largo no Codificante , Animales , Femenino , Ratones , Citocinas/genética , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Inflamación/genética , Inflamación/patología , Interleucina-1 , Interleucina-6 , Ratones Endogámicos C57BL , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Widespread alterations in the expression of various genes could contribute to the pathogenesis of epilepsy. The expression levels of various genes, including major inhibitory and excitatory receptors, ion channels, cell type-specific markers, and excitatory amino acid transporters, were assessed and compared between the human epileptic hippocampus and amygdala, and findings from autopsy controls. Moreover, the potential correlation between molecular alterations in epileptic brain tissues and the clinical characteristics of patients undergoing epilepsy surgery was evaluated. Our findings revealed significant and complex changes in the expression of several key regulatory genes in both the hippocampus and amygdala of patients with intractable epilepsy. The expression changes in various genes differed considerably between the epileptic hippocampus and amygdala. Different correlation patterns were observed between changes in gene expression and clinical characteristics, depending on whether the patients were considered as a whole or were subdivided. Altered molecular signatures in different groups of epileptic patients, defined within a given category, could be viewed as diagnostic biomarkers. Distinct patterns of molecular changes that distinguish these groups from each other appear to be associated with epilepsy-specific functional consequences.
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Epilepsia , Humanos , Epilepsia/metabolismo , Hipocampo/metabolismo , Canales Iónicos/metabolismo , Amígdala del Cerebelo/metabolismoRESUMEN
Spreading depression (SD), a pathological cortical negative DC potential, is caused by an elevation of potassium ions in the extracellular space. This leads to a transient relocation of ions within neurons and a slow spread through brain tissue. Our previous research established a correlation between scalp SD and seizures in patients with intractable epilepsy using our novel electroencephalography (EEG). In this study, we enhanced our EEG system by incorporating a Near-infrared spectroscopy (NIRS) module for multi-modal EEG-NIRS measurements. The aim is to provide an investigation into the defining characteristics and methods for detecting SD.Clinical Relevance-: The detection of SD serves as a novel biomarker for epilepsy, capable of forewarning seizures within a time range from 10 secs to 30 min. This detection plays a crucial role in predicting and preventing seizures and providing diagnostic information for drug-resistant epilepsy patients.
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Epilepsia Refractaria , Epilepsia , Humanos , Cuero Cabelludo , Depresión , Epilepsia/diagnóstico , Convulsiones , Electroencefalografía/métodos , IonesRESUMEN
Objective: Despite 6%-20% of the adult population suffering from tinnitus, there is no standard treatment for it. Placenta extract has been used for various therapeutic purposes, including hearing loss. Here, we evaluate the effect of a novel neuroprotective protein composition (NPPC) extract on electrophysiological and molecular changes in the medial geniculate body (MGB) of tinnitus-induced rats. Methods: To evaluate the protein analysis by western blot, the rats were divided into three groups: (1) saline group (intraperitoneal injection of 200 mg/kg saline twice a day for 28 consecutive days, (2) chronic Na-Sal group received sodium salicylate as in the first group, and (3) chronic treatment group (received salicylate 200 mg/kg twice daily for 2 weeks, followed by 0.4 mg NPPC daily from day 14 to day 28). Single-unit recordings were performed on a separate group that was treated as in group 4. Gap-prepulse inhibition of the acoustic startle (GPIAS) and pre-pulse inhibition (PPI) was performed to confirm tinnitus in all groups at the baseline, 14th and 28th days. Results: Western blot analysis showed that the expression of γ-Aminobutyric acid Aα1 subunit (GABA Aα1), N-methyl-d-aspartate receptor subtype 2B (NR2B or NMDAR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR1 (GluR1), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR2 (GluR2) decreased after Na-Sal injection, while NPPC upregulated their expression. MGB units in rats with tinnitus showed decreased spontaneous firing rate, burst per minute, and a spike in a burst. After NPPC administration, neural activity patterns showed a significant positive effect of NPPC on tinnitus. Conclusion: NPPC can play an effective role in the treatment of tinnitus in salicylate-induced rats, and MGB is one of the brain areas involved in these processes. Level of Evidence: NA.
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Adult neural stem/progenitor cells (NSPCs) in two neurogenic areas of the brain, the dentate gyrus and the subventricular zone, are major players in adult neurogenesis. Addressing specific questions regarding NSPCs outside of their niche entails in vitro studies through isolation and culture of these cells. As there is heterogeneity in their morphology, proliferation, and differentiation capacity between these two neurogenic areas, NSPCs should be isolated from each area through specific procedures and media. Identifying region-specific NPSCs provides an accurate pathway for assessing the effects of extrinsic factors and drugs on these cells and investigating the mechanisms of neurogenesis in both healthy and pathologic conditions. A great number of isolation and expansion techniques for NSPCs have been reported. The growth and expansion of NSPCs obtained from the dentate gyrus of aged rats are generally difficult. There are relatively limited data and protocols about NSPCs isolation and their culture from aged rats. Our approach is an efficient and reliable strategy to isolate and expand NSPCs obtained from young adult and aged rats. NSPCs isolated by this method maintain their self-renewal and multipotency. Key features ⢠NSPCs isolated from the hippocampal dentate gyrus of young adult and aged rats, based on Kempermann et al. (2014) and Aligholi et al. (2014). ⢠Maintenance of NSPCs isolated from the dentate gyrus of aged rats (20-24 months) in our culture condition is feasible. ⢠According to our protocol, maximum growth of primary neurospheres obtained from isolated NSPCs of young and aged rats took 15 and 35 days, respectively.
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The effect of neuroprotective placental protein composition (NPPC) on the suppression of tinnitus and the restoration of the auditory brainstem response (ABR) characteristics was explored in tinnitus-induced rats. The animals were placed into two groups: (1) the study group, rats received sodium salicylate (SS) at the dose of 200 mg/kg twice a day for two weeks, and then 0.4 mg of the NPPC per day, between the 14th and 28th days, (2) the placebo group, rats received saline for two weeks, and then the NPPC alone between the 14th and 28th days. The gap pre-pulse inhibition of the acoustic startle (GPIAS), the pre-pulse inhibition (PPI), and the ABR assessments were performed on animals in both groups three times (baseline, day 14, and 28). The GPIAS value declined after 14 consecutive days of the SS injection, while NPPC treatment augmented the GPIAS score in the study group on the 28th day. The PPI outcomes revealed no significant changes, indicating hearing preservation after the SS and NPPC administrations. Moreover, some changes in ABR characteristics were observed following SS injection, including (1) higher ABR thresholds, (2) lowered waves I and II amplitudes at the frequencies of 6, 12, and 24 kHz and wave III at the 12 kHz, (3) elevated amplitude ratios, and (4) prolongation in brainstem transmission time (BTT). All the mentioned variables returned to their normal values after applying the NPPC. The NPPC use could exert positive therapeutic effects on the tinnitus-induced rats and improve their ABR parameters.
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Methadone (Met) is the most common treatment for opioid addiction. Although Met is effective for treatment of opioid dependence, sexual dysfunctions and infertility have been reported as a major problem in patients under Met treatment. The present study aimed to evaluate the effect of melatonin and N-acetylcysteine (N) on morphine and Met-induced oxidative stress, apoptosis, suppression of blood sexual hormones, impairment in sperm parameters, and sexual dysfunction. Adult male Wistar rats (n = 66) were randomly divided into 11 equal groups (n = 6) as follows: control, sham, morphine, Met, Met+N, Met+ melatonin, Met+melatonin+N, morphine+ Met, morphine+Met+ melatonin, morphine+Met+N, and morphine+Met+ melatonin+N groups. On day 56 post-treatment, the blood was collected from the tail and the serum levels of sex hormones were evaluated, then the rats were sacrificed, and their bilateral testes and epididymis were retrieved for histological, immunohistochemical, molecular, testicular tissue stress oxidative status, and sperm parameters assays. Exposure to morphine, Met, and shift of morphine to Met resulted in testicular degeneration that can be attributed to generating the stress oxidative-induced- apoptotic testicular cell death and impairing spermatogenesis. Melatonin and N alone and particularly, in combination with each other improved testicular degeneration, sex hormone suppression, and testicular function mediated by increasing the testicular antioxidant capacity and inhibition of the apoptosis pathway. It's suggested that oral administration of antioxidants may be an effective treatment for attenuating some opioid-related testicular dysfunction and degeneration.
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Melatonina , Enfermedades Testiculares , Animales , Masculino , Ratas , Acetilcisteína/farmacología , Analgésicos Opioides/toxicidad , Antioxidantes/farmacología , Antioxidantes/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Melatonina/metabolismo , Melatonina/farmacología , Derivados de la Morfina/metabolismo , Derivados de la Morfina/toxicidad , Estrés Oxidativo , Ratas Wistar , Semen/metabolismo , Enfermedades Testiculares/patología , TestículoRESUMEN
Due to the increasing emission of greenhouse gases and global warming, the development of renewable energy has become very important. The availability of fossil fuels and the low cost of their extraction compared to renewable energy projects reduce the motivation of countries, especially countries that have abundant natural resources, to develop this technology. Renewable energy deployment has become crucial in response to rising greenhouse gas emissions and global warming. Policies supporting renewable energy play a significant role in this. This study examines the effect of such policies on the deployment of renewable energy technologies, considering the role of natural resources. Two groups of countries were analysed: 20 oil developed countries and 20 oil developing countries. Given the availability of data and the achievement of balanced panels to evaluate short-term and long-term relationships between variables, in current research Data from 2010 to 2020 was used, and various panel data estimators such as Feasible Generalized Least Squares and Generalized Method of Moments were employed. The Quantile estimator was also used to assess the accuracy of the results. The findings suggest that renewable energy policies consistently lead to increased deployment of renewable energy technologies, regardless of a country's group. Of course, this positive effect is different according to the level of development in countries. Due to the higher efficiency of renewable energy policy, developed oil countries have more capacity to support renewable energy projects than oil developing countries. The abundance of natural resources in oil developed countries did not negatively impact renewable energy capacity, but in oil developing countries, the "resource curse" hindered the development of installed renewable energy.
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Gases de Efecto Invernadero , Política Pública , Combustibles Fósiles , Calentamiento Global , Energía Renovable , TecnologíaRESUMEN
Ionic currents within the brain generate voltage oscillations. These bioelectrical activities include ultra-low frequency electroencephalograms (DC-EEG, frequency less than 0.1 Hz) and conventional clinical electroencephalograms (AC-EEG, 0.5-70 Hz). Although AC-EEG is commonly used for diagnosing epilepsy, recent studies indicate that DC-EEG is an essential frequency component of EEG and can provide valuable information for analyzing epileptiform discharges. During conventional EEG recordings, DC-EEG is censored by applying high-pass filtering to i) obliterate slow-wave artifacts, ii) eliminate the bioelectrodes' half-cell potential asymmetrical changes in ultralow-low frequency, and iii) prevent instrument saturation. Spreading depression (SD), which is the most prolonged fluctuation in DC-EEG, may be associated with epileptiform discharges. However, recording of SD signals from the scalp's surface can be challenging due to the filtering effect and non-neuronal slow shift potentials. In this study, we describe a novel technique to extend the frequency bandwidth of surface EEG to record SD signals. The method includes novel instrumentation, appropriate bioelectrodes, and efficient signal-processing techniques. To evaluate the accuracy of our approach, we performed a simultaneous surface recording of DC- and AC-EEG from epileptic patients during long-term video EEG monitoring, which provide a promising tool for diagnosis of epilepsy. DATA AVAILABILITY STATEMENT: The data presented in this study are available on request.
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Electroencefalografía , Epilepsia , Humanos , Electroencefalografía/métodos , Epilepsia/diagnóstico , Encéfalo/fisiología , Potenciales de la Membrana , Procesamiento de Señales Asistido por ComputadorRESUMEN
In this study, CO2 solubility in different choline chloride-based deep eutectic solvents (DESs) has been investigated using the Quantitative Structure-Property Relationship (QSPR). In this regard, the effect of different structures of the hydrogen bond donor (HBD) in choline chloride (ChCl) based deep eutectic solvents (DESs) has been studied in different temperatures and different molar ratios of ChCl as hydrogen bond acceptor (HBA) to HBD. 12 different datasets with 390 data on the CO2 solubility were chosen from the literature for the model development. Eight predictive models, which contain the pressure and one structural descriptor, have been developed at the fixed temperature (i.e. 293, 303, 313, or 323 K), and the constant molar ratio of ChCl to HBD equal to 1:3 or 1:4. Moreover, two models were also introduced, which considered the effects of pressure, temperature, and HBD structures, simultaneously in the molar ratios equal to 1:3 or 1:4. Two additional datasets were used only for the further external validation of these two models at new temperatures, pressures, and HBD structures. It was identified that CO2 solubility depends on the "EEig02d" descriptor of HBD. "EEig02d" is a molecular descriptor derived from the edge adjacency matrix of a molecule that is weighted by dipole moments. This descriptor is also related to the molar volume of the structure. The statistical evaluation of the proposed models for the unfixed and fixed temperature datasets confirmed the validity of the developed models.
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Glioblastoma multiforme (GBM) is the most malignant type of cerebral neoplasm in adults with a poor prognosis. Currently, combination therapy with different anti-cancer agents is at the forefront of GBM research. Hence, this study aims to evaluate the potential anti-cancer synergy of a clinically approved neurokinin-1 receptor antagonist, aprepitant, and 5-aminolevulinic acid (5-ALA), a prodrug that elicits fluorescent porphyrins in gliomas on U-87 human GBM cells. We found that aprepitant and 5-ALA effectively inhibited GBM cell viability. The combinatorial treatment of these drugs exerted potent synergistic growth inhibitory effects on GBM cells. Moreover, aprepitant and 5-ALA induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax and P53 along with downregulation of Bcl-2). Furthermore, aprepitant and 5-ALA increased the accumulation of protoporphyrin IX, a highly pro-apoptotic and fluorescent photosensitizer. Aprepitant and 5-ALA significantly inhibited GBM cell migration and reduced matrix metalloproteinases (MMP-2 and MMP-9) activities. Importantly, all these effects were more prominent following aprepitant-5-ALA combination treatment than either drug alone. Collectively, the combination of aprepitant and 5-ALA leads to considerable synergistic anti-proliferative, pro-apoptotic, and anti-migratory effects on GBM cells and provides a firm basis for further evaluation of this combination as a novel therapeutic approach for GBM.
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Ácido Aminolevulínico , Glioblastoma , Adulto , Humanos , Ácido Aminolevulínico/farmacología , Ácido Aminolevulínico/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Aprepitant/farmacología , Aprepitant/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/farmacología , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Línea Celular TumoralRESUMEN
Hyperexcitability is associated with neuronal dysfunction, cellular death, and consequently neurodegeneration. Redox disbalance can contribute to hyperexcitation and increased reactive oxygen species (ROS) levels are observed in various neurological diseases. NOX4 is an NADPH oxidase known to produce ROS and might have a regulating function during oxidative stress. We, therefore, aimed to determine the role of NOX4 on neuronal firing, hyperexcitability, and hyperexcitability-induced changes in neural network function. Using a multidimensional approach of an in vivo model of hyperexcitability, proteomic analysis, and cellular function analysis of ROS, mitochondrial integrity, and calcium levels, we demonstrate that NOX4 is neuroprotective by regulating ROS and calcium homeostasis and thereby preventing hyperexcitability and consequently neuronal death. These results implicate NOX4 as a potential redox regulator that is beneficial in hyperexcitability and thereby might have an important role in neurodegeneration.
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Calcio , Proteómica , Humanos , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Estrés Oxidativo , Especies Reactivas de OxígenoRESUMEN
Traumatic brain injury (TBI) causes long-term disability and mortality worldwide. The prime pathological players in TBI are neuroinflammation and apoptosis. These pathological changes lead to a limited capacity of regeneration after TBI. To alleviate inflammatory responses and apoptosis triggered by TBI, developing bioactive scaffolds conjoined with stem cells is a decisive approach in neural tissue engineering. The aim of this study was to fabricate a novel nano-scaffold made of RADA-16 with a bioactive motif of stromal cell-derived factor-1 α (SDF-1α) and evaluate its effects with stem cell transplantation on inflammatory pathways, reactive gliosis, and apoptosis after TBI. Co-transplantation of Nano-SDF and human neural stem cells (hNSCs) derived from fetus brain in adult rats subjected to TBI led to the improvement of motor activitycompared with the control group. The treated animals with hNSCs + Nano-SDF had a significantly lower expression of toll-like receptor 4 and nuclear factor-kappa B at the injury site than the control animals. A significant reduction in the number of reactive astrocytes was also observed in rats that received hNSCs + Nano-SDF compared with the vehicle and Nano-SDF groups. Furthermore, the TUNEL assay indicated a significant reduction in TUNEL positive cells in the hNSCs + Nano-SDF group compared with the TBI, vehicle, and Nano-SDF groups. These data demonstrated co-transplantation of hNSCs with Nano-SDF can reduce inflammatory responses and cell death after TBI via creating a more supportive microenvironment. Further research is required to establish the therapeutic efficacy of Nano-SDF with stem cells for TBI.