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The increasing prevalence of endocrine-disrupting chemicals (EDCs) in our environment is a growing concern, with numerous studies highlighting their adverse effects on the human endocrine system. Among the EDCs, estrogenic endocrine-disrupting chemicals (eEDCs) are exogenous compounds that perturb estrogenic hormone function by interfering with estrogen receptor (ER) homo (α/α, ß/ß) or hetero (α/ß) dimerization. To date, a comprehensive screening approach for eEDCs affecting all ER dimer forms in live cells is lacking. Here, we developed ER dimerization-detecting biosensors (ERDDBs), based on bioluminescence resonance energy transfer, for dimerization detection and rapid eEDC identification. To enhance the performance of these biosensors, we determined optimal donor and acceptor locations using computational analysis. Additionally, employing HaloTag as the acceptor and incorporating the P2A peptide as a linker yielded the highest sensitivity among the prototypes. We also established stable cell lines to screen potential ER dimerization inducers among estrogen analogs (EAs). The EAs were categorized through cross-comparison of ER dimer responses, utilizing EC values derived from a standard curve established with 17ß-estradiol. We successfully classified 26 of 72 EAs, identifying which ER dimerization types they induce. Overall, our study underscores the effectiveness of the optimized ERDDB for detecting ER dimerization and its applicability in screening and identifying eEDCs.
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Cranial irradiation is used for prophylactic brain radiotherapy as well as the treatment of primary brain tumors. Despite its high efficiency, it often induces unexpected side effects, including cognitive dysfunction. Herein, we observed that mice exposed to cranial irradiation exhibited cognitive dysfunction, including altered spontaneous behavior, decreased spatial memory, and reduced novel object recognition. Analysis of the actin cytoskeleton revealed that ionizing radiation (IR) disrupted the filamentous/globular actin (F/G-actin) ratio and downregulated the actin turnover signaling pathway p21-activated kinase 3 (PAK3)-LIM kinase 1 (LIMK1)-cofilin. Furthermore, we found that IR could upregulate microRNA-206-3 p (miR-206-3 p) targeting PAK3. As the inhibition of miR-206-3 p through antagonist (antagomiR), IR-induced disruption of PAK3 signaling is restored. In addition, intranasal administration of antagomiR-206-3 p recovered IR-induced cognitive impairment in mice. Our results suggest that cranial irradiation-induced cognitive impairment could be ameliorated by regulating PAK3 through antagomiR-206-3 p, thereby affording a promising strategy for protecting cognitive function during cranial irradiation, and promoting quality of life in patients with radiation therapy.
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Disfunción Cognitiva , MicroARNs , Animales , Humanos , Ratones , Actinas/metabolismo , Antagomirs , Disfunción Cognitiva/genética , Irradiación Craneana/efectos adversos , Regulación hacia Abajo , Quinasas Lim/metabolismo , MicroARNs/genética , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Calidad de VidaRESUMEN
Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Ácido Glutámico , Tolerancia a Radiación/genética , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Mitocondrias/metabolismo , Prolina , Proteínas de Transporte de Membrana MitocondrialRESUMEN
The Warburg effect is a phenomenon in which cancer cells rely primarily on glycolysis rather than oxidative phosphorylation, even in the presence of oxygen. Although evidence of its involvement in cell proliferation has been discovered, the advantages of the Warburg effect in cancer cell survival under treatment have not been fully elucidated. In recent years, the metabolic characteristics of radioresistant cancer cells have been evaluated, enabling an extension of the original concept of the Warburg effect. In this review, we focused on the role of the Warburg effect in redox homeostasis and DNA damage repair, two critical factors contributing to radioresistance. In addition, we highlighted the metabolic involvement in the radioresistance of cancer stem cells, which is the root cause of tumor recurrence. Finally, we summarized radiosensitizing drugs that target the Warburg effect. Insights into the molecular mechanisms underlying the Warburg effect and radioresistance can provide valuable information for developing strategies to enhance the efficacy of radiotherapy and provide future directions for successful cancer therapy.
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Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/radioterapia , Glucólisis , Fosforilación Oxidativa , Oxígeno/metabolismoRESUMEN
Glioblastoma (GBM) currently has a dismal prognosis. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic advantages. Here, we show that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in radioresistant GBM cells. The downregulation of DGKB increases DAG accumulation and decreases fatty acid oxidation, contributing to radioresistance by reducing mitochondrial lipotoxicity. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is increased after ionizing radiation. Genetic inhibition of DGAT1 using short hairpin RNA (shRNA) or microRNA-3918 (miR-3918) mimic suppresses radioresistance. We discover that cladribine, a clinical drug, activates DGKB, inhibits DGAT1, and sensitizes GBM cells to radiotherapy in vitro and in vivo. Together, our study demonstrates that DGKB downregulation and DGAT1 upregulation confer radioresistance by reducing mitochondrial lipotoxicity and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance.
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Diacilglicerol Quinasa , Glioblastoma , Humanos , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Diacilglicerol O-Acetiltransferasa/genética , Diacilglicerol O-Acetiltransferasa/metabolismo , Glioblastoma/genética , Glioblastoma/radioterapia , Lípidos/toxicidad , Triglicéridos/metabolismo , Regulación hacia ArribaRESUMEN
Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.
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Proteínas Relacionadas con la Autofagia , Autofagia , Neoplasias Encefálicas , Glioblastoma , Tolerancia a Radiación , Transactivadores , Animales , Humanos , Ratones , Proteínas Relacionadas con la Autofagia/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Supervivencia Celular , Modelos Animales de Enfermedad , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Transactivadores/metabolismo , Lidoflazina/uso terapéuticoRESUMEN
Cancer cachexia is a muscle-wasting syndrome that leads to a severely compromised quality of life and increased mortality. A strong association between cachexia and poor prognosis has been demonstrated in intractable cancers, including glioblastoma (GBM). In the present study, it was demonstrated that ionizing radiation (IR), the first-line treatment for GBM, causes cancer cachexia by increasing the exosomal release of plasminogen activator inhibitor-1 (PAI-1) from glioblastoma cells. Exosomal PAI-1 delivered to the skeletal muscle is directly penetrated in the muscles and phosphorylates STAT3 to intensify muscle atrophy by activating muscle RING-finger protein-1 (MuRF1) and muscle atrophy F-box (Atrogin1); furthermore, it hampers muscle protein synthesis by inhibiting mTOR signaling. Additionally, pharmacological inhibition of PAI-1 by TM5441 inhibited muscle atrophy and rescued muscle protein synthesis, thereby providing survival benefits in a GBM orthotopic xenograft mouse model. In summary, our data delineated the role of PAI-1 in the induction of GBM cachexia associated with radiotherapy-treated GBM. Our data also indicated that targeting PAI-1 could serve as an attractive strategy for the management of GBM following radiotherapy, which would lead to a considerable improvement in the quality of life of GBM patients undergoing radiotherapy.
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Caquexia , Glioblastoma , Animales , Caquexia/etiología , Caquexia/metabolismo , Glioblastoma/complicaciones , Glioblastoma/radioterapia , Humanos , Ratones , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Inhibidor 1 de Activador Plasminogénico , Calidad de Vida , Radiación Ionizante , Serina-Treonina Quinasas TORRESUMEN
Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.
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(1) Background: The impairment of language function after a stroke is common. It is unclear how the brain reorganizes for language function after cerebral infarction. The aim of this observational study is to investigate the association of structural integrity and functional neural activity with language function in aphasic patients with middle cerebral artery infarction. (2) Methods: Magnetic resonance images and scores from the Western Aphasia Battery on 20 patients were retrieved from medical records. A Voxel-wise linear regression analysis was performed using fractional anisotropy maps or the fractional amplitude of low-frequency fluctuation maps as dependent variables and scores of oral language function as independent variables while controlling for age and time elapsed after stroke. (3) Results: Spontaneous speech was positively associated with fractional anisotropy in the left dorsal stream and the right posterior corpus callosum and with the fractional amplitude of the low-frequency fluctuation of cranial nuclei in the pontomedullary junction. Comprehension was positively associated with the left ventral stream. Naming was positively associated with the left ventral stream and the bilateral occipitofrontal fasciculus, as well as with the fractional amplitude of low-frequency fluctuation of the supramarginal gyrus in the left hemisphere. (4) Conclusions: The dorsal and ventral streams are important for articulation and meaning after the reorganization of neural circuits following stroke. Subdomains of oral language function with a visual component are dependent on the visual association areas located in the right hemisphere.
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Selective serotonin reuptake inhibitors (SSRIs) are effective first line therapies for treating depression, but are plagued by undesirable side effects and are not effective in all patients. Because SSRIs effectively deplete the neuronal releasable serotonin (5-HT) pool, gaining a deeper understanding of intracellular mechanisms regulating 5-HT pools can help us understand the shortcomings of SSRIs and develop more effective therapies. In this study, we found that BAIAP3 (brain-specific angiogenesis inhibitor 1-associated protein 3) is significantly downregulated in two mouse models of depression (the IR- and CUMS-induced depressive mouse models). In BAIAP3 downregulated models (in vitro and in vivo), we discovered that trafficking of dense core vesicle (DCV), organelles that store, transport and release cargo via exocytosis, was reduced. Accordingly, 5-HT exocytosis and levels in the synapse were lowered, causing defective post-synaptic neurotransmission. In a screen of natural products, we identified eucalyptol, the active components of Eucalyptus, as uniquely capable of increasing neuronal Baiap3 expression and elevate synaptic 5-HT levels. Moreover, eucalyptol treatment relieved depressive behavioral symptoms and restored serotonin levels in mice. Mechanistically, eucalyptol restores Baiap3 expression by reducing inhibitory microRNAs (miR-329, miR-362). These findings illuminate how Baiap3 depletion propagates neurotransmission dysfunction and point to eucalyptol as a novel agent for restoring serotonin exocytosis, suggesting potential for developing eucalyptol as a therapy for treating depression.
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This study investigated the changes in the structural connectivity of the bilateral hemispheres over time following a middle cerebral artery infarction. Eighteen patients in the subacute group and nine patients in the chronic group with mild upper extremity motor impairment (Fugl-Meyer motor assessment score for the upper limb > 43) following middle cerebral artery infarction were retrospectively evaluated in this study. All the patients underwent T1-weighted and diffusion tensor imaging. Tract-based statistical analyses of fractional anisotropy were used to compare the changes in the bilateral structural connectivity with those of age-matched normal controls. The corticospinal tract pathway of the affected hemisphere, corpus callosum, and corona radiata of the unaffected hemisphere had decreased structural connectivity in the subacute group, while the motor association area and anterior corpus callosum in the bilateral frontal lobes had increased structural connectivity in the chronic group. The bilateral hemispheres were influenced even in patients with mild motor impairment following middle cerebral artery infarction, and the structural connectivity of the bilateral hemispheres changed according to the time following the stroke.
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Aspiration after stroke is associated with pneumonia and mortality. In this study, we investigated brain structural connectivity associated with aspiration after unilateral supratentorial stroke. Patients on oral feeding after stroke were divided into liquid aspiration (22 patients) and normal (18 patients) groups based on videofluoroscopic swallowing studies. Voxel-based lesion-symptom mapping and voxel-wise group comparison of fractional anisotropy, mode of anisotropy, and mean diffusivity maps were conducted. Voxel-based lesion-symptom mapping revealed no significant lesion differences between groups. The aspiration group showed significantly increased fractional anisotropy and mode of anisotropy in the anterior limb and the genu of the internal capsule in the right hemisphere. In contrast, the normal group showed significantly increased mean diffusivity, mainly in the superior longitudinal fasciculus in the right hemisphere (P < 0.05). Degeneration of the internal capsule in the right hemisphere was found to affect aspiration after stroke.
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Accidente Cerebrovascular , Anisotropía , Encéfalo , Imagen de Difusión por Resonancia Magnética , Humanos , Red Nerviosa , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patologíaRESUMEN
BACKGROUND: Glioblastoma Multiforme (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM harbors glioblastoma stem-like cells (GSCs), which play a crucial role in therapeutic resistance and recurrence. METHODS: Patient-derived GSCs, GBM cell lines, intracranial GBM xenografts, and GBM sections were used to measure mRNA and protein expression and determine the related molecular mechanisms by qRT-PCR, immunoblot, immunoprecipitation, immunofluorescence, OCR, ECAR, live-cell imaging, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate tumor inhibitory effects of glimepiride combined with radiotherapy. RESULTS: We report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain containing linker protein 3 (CLIP3, also known as CLIPR-59). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model. CONCLUSIONS: Our data suggest that radioresistant GBM cells exhibit enhanced stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Thus, glimepiride could be an attractive strategy for overcoming radioresistance and recurrence by rescuing CLIP3 expression.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación hacia Abajo , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/radioterapia , Glucólisis , Humanos , Masculino , Ratones , Ratones Desnudos , Proteínas Asociadas a Microtúbulos/genética , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/efectos de la radiación , Tolerancia a Radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
GBM is a high-grade cancer that originates from glial cells and has a poor prognosis. Although a combination of surgery, radiotherapy, and chemotherapy is prescribed to patients, GBM is highly resistant to therapies, and surviving cells show increased aggressiveness. In this study, we investigated the molecular mechanism underlying GBM progression after radiotherapy by establishing a GBM orthotopic xenograft mouse model. Based on transcriptomic analysis, we found that the expression of BEX1 and BEX4 was upregulated in GBM cells surviving radiotherapy. We also found that upregulated expression of BEX1 and BEX4 was involved in the formation of the filamentous cytoskeleton and altered mechanotransduction, which resulted in the activation of the YAP/TAZ signaling pathway. BEX1- and BEX4-mediated YAP/TAZ activation enhanced the tumor formation, growth, and radioresistance of GBM cells. Additionally, latrunculin B inhibited GBM progression after radiotherapy by suppressing actin polymerization in an orthotopic xenograft mouse model. Taken together, we suggest the involvement of cytoskeleton formation in radiation-induced GBM progression and latrunculin B as a GBM radiosensitizer.
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Actinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glioblastoma/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Oncogénicas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Actinas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Línea Celular Tumoral , Glioblastoma/genética , Glioblastoma/patología , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Asociadas a Microtúbulos/genética , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/genética , Proteínas Oncogénicas/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
Wind power forecasting plays a key role in the design and maintenance of wind power generation which can directly help to enhance environment resilience. Offshore wind power forecasting has become more challenging due to their operation in a harsh and multi-faceted environment. In this paper, the data generated from offshore wind turbines are used for power forecasting purposes. First, fragmented data is filtered and Deep Auto-Encoding is used to select high dimensional features. Second, a mixture of the CNN and LSTM models is used to train prominent wind features and further improve forecasting accuracy. Finally, the CNN-LSTM deep learning hybrid model is fine-tuned with various parameters for reliable forecasting of wind energy on three different offshore Windfarms. A state-of-the-art comparison against existing models is presented based on root mean square error (RMSE) and mean absolute error (MAE) respectively. The forecasting analyses indicate that the proposed CNN-LSTM strategy is quite successful for offshore wind turbines by retaining the lowest RMSE and MAE along with high forecasting accuracy. The experimental findings will be helpful to design environment resilient energy transition pathways.
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Energía Renovable , Predicción , Redes Neurales de la ComputaciónRESUMEN
Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Compuestos de Platino/uso terapéutico , Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/metabolismo , Humanos , Compuestos de Platino/farmacología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.
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Proteínas Adaptadoras Transductoras de Señales/genética , Dinaminas/genética , Glioblastoma/radioterapia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Mitocondrias/genética , Mitocondrias/patología , Mitocondrias/efectos de la radiación , Fosforilación Oxidativa/efectos de la radiación , Proteínas Proto-Oncogénicas c-akt/genética , Tolerancia a Radiación/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Increased triglyceride, cholesterol, and low-density lipoprotein (LDL) levels cause hyperlipidemia. Despite the availability of statin-based drugs to reduce LDL levels, additional effective treatments for reducing blood lipid concentrations are required. Herein, soybean hydrolysate prepared via peptic and tryptic hydrolysis promoted trans-intestinal cholesterol excretion (TICE) by increasing ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8 expression. The peptide sequence capable of promoting TICE was determined via HPLC and LC-MS/MS. Based on this, pure artificial peptides were synthesized, and the efficacy of the selected peptides was verified using cellular and hyperlipidemic mouse models. Soybean hydrolysates, including two bioactive peptides (ALEPDHRVESEGGL and SLVNNDDRDSYRLQSGDAL), promoted TICE via the expression of ABCG5 and ABCG8 in enterocytes. They downregulated expression of hepatic cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1 via expression of fibroblast growth factor 19 (FGF19) in a liver X receptor α (LXRa)-dependent pathway. Administration of bioactive peptides to hyperlipidemic mouse models by oral gavage reduced cholesterol levels in serum via upregulation of ABCG5 and ABCG8 expression in the proximal intestine and through fecal cholesterol excretion, upregulated FGF 15/19 expression, and suppressed hepatic bile acid synthesis. Oral administration of soybean-derived bioactive peptides elicited hypolipidemic effects by increasing TICE and decreasing hepatic cholesterol synthesis.
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Ácidos y Sales Biliares/biosíntesis , Colesterol/metabolismo , Glycine max/química , Hepatocitos/efectos de los fármacos , Hiperlipidemias/tratamiento farmacológico , Proteínas de Plantas/farmacología , Animales , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hidrólisis , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Plantas/químicaRESUMEN
PURPOSE: To compare the image quality of brain computed tomography (CT) images reconstructed with deep learning-based image reconstruction (DLIR) and adaptive statistical iterative reconstruction-Veo (ASIR-V). METHODS: Sixty-two patients underwent routine noncontrast brain CT scans and datasets were reconstructed with 30% ASIR-V and DLIR with three selectable reconstruction strength levels (low, medium, high). Objective parameters including CT attenuation, noise, noise reduction rate, artifact index of the posterior cranial fossa, and contrast-to-noise ratio (CNR) were measured at the levels of the centrum semiovale and basal ganglia. Subjective parameters including gray matter-white matter differentiation, sharpness, and overall diagnostic quality were also assessed and compared with the interobserver agreement. RESULTS: There was a gradual reduction in the image noise and artifact index of the posterior cranial fossa as the strength levels of DLIR increased (all P < 0.001) compared with that of ASIR-V. CNR in both the centrum semiovale and basal ganglia levels also improved from the low to high strength levels of DLIR compared with that of ASIR-V (all P < 0.001). DLIR images with medium and high strength levels demonstrated the best subjective image quality scores among the reconstruction datasets. There was moderate to good interobserver agreement for the subjective image quality assessments with ASIR-V and DLIR. CONCLUSION: On routine brain CT scans, optimized protocols with DLIR allowed significant reduction of noise and artifacts with improved subjective image quality compared with ASIR-V.
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Aprendizaje Profundo , Algoritmos , Encéfalo/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Dosis de Radiación , Interpretación de Imagen Radiográfica Asistida por Computador , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Susceptibility-weighted imaging (SWI) is occasionally performed with intravenous gadolinium (Gd). It was reported that SWI can be performed after Gd injection without information loss or signal change. PURPOSE: To investigate the diagnostic value of contrast-enhanced SWI (CE-SWI) in the assessment of intracranial brain neoplasm. MATERIAL AND METHODS: After obtaining the approval of the local ethics committee, 35 brain neoplasm patients (24 with metastasis and 11 with glioblastoma multiforme [GBM]) were enrolled. In order to investigate the value of using CE-SWI, two neuroradiologists performed an evaluation of the frequency of the intratumoral susceptibility signals (ITSS) in SWI and CE-SWI with visual assessment using 5-grade scales. We evaluated the visibility of the tumor margins and the internal architecture of tumors on T1-weighted imaging (T1WI), contrast-enhanced T1 (CE-T1), SWI, and CE-SWI. RESULTS: The contrast-enhanced scans (CE-T1 and CE-SWI) showed statistically significant higher scores compared to non-enhanced scans (T1WI and SWI) for the analysis of the tumor margin in GBM and metastasis (P < 0.05, Wilcoxon signed rank test). Statistically significant higher scores are noted in GBMs compared to metastases in the visibility of the internal architecture of tumors on CE-SWI and the visibility of the tumor margin on CE-T1 (P < 0.05, Mann-Whitney test). CONCLUSION: Based on our results, SWI can be performed after gadolinium injection without information loss or signal change. CE-SWI is useful in evaluating intracranial neoplasm due to its ability to simultaneously demonstrate both ITSS that are not visible with conventional magnetic resonance sequences and contrast enhancement.