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Glioblastoma (GBM) poses a significant therapeutic challenge due to its invasive nature and limited drug penetration through the blood-brain barrier (BBB). In response, here we present an innovative biomimetic approach involving the development of genetically engineered exosome nanocatalysts (Mn@Bi2Se3@RGE-Exos) for efficient GBM therapy via improving the BBB penetration and enzyme-like catalytic activities. Interestingly, a photothermally activatable multiple enzyme-like reactivity is observed in such a nanosystem. Upon NIR-II light irradiation, Mn@Bi2Se3@RGE-Exos are capable of converting hydrogen peroxide into hydroxyl radicals, oxygen, and superoxide radicals, providing a peroxidase (POD), oxidase (OXD), and catalase (CAT)-like nanocatalytic cascade. This consequently leads to strong oxidative stresses to damage GBM cells. In vitro, in vivo, and proteomic analysis further reveal the potential of Mn@Bi2Se3@RGE-Exos for the disruption of cellular homeostasis, enhancement of immunological response, and the induction of cancer cell ferroptosis, showcasing a great promise in anticancer efficacy against GBM with a favorable biosafety profile. Overall, the success of this study provides a feasible strategy for future design and clinical study of stimuli-responsive nanocatalytic medicine, especially in the context of challenging brain cancers like GBM.
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Exosomas , Glioblastoma , Rayos Infrarrojos , Fototerapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Humanos , Exosomas/química , Exosomas/metabolismo , Animales , Fototerapia/métodos , Ratones , Catálisis , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Antineoplásicos/química , Antineoplásicos/farmacología , Manganeso/química , Manganeso/farmacología , Barrera Hematoencefálica/metabolismoRESUMEN
The past decades have witnessed a rapid expansion in investigations of two-dimensional (2D) monoelemental materials (Xenes), which are promising materials in various fields, including applications in optoelectronic devices, biomedicine, catalysis, and energy storage. Apart from graphene and phosphorene, recently emerging 2D Xenes, specifically graphdiyne, borophene, arsenene, antimonene, bismuthene, and tellurene, have attracted considerable interest due to their unique optical, electrical, and catalytic properties, endowing them a broader range of intriguing applications. In this review, the structures and properties of these emerging Xenes are summarized based on theoretical and experimental results. The synthetic approaches for their fabrication, mainly bottom-up and top-down, are presented. Surface modification strategies are also shown. The wide applications of these emerging Xenes in nonlinear optical devices, optoelectronics, catalysis, biomedicine, and energy application are further discussed. Finally, this review concludes with an assessment of the current status, a description of existing scientific and application challenges, and a discussion of possible directions to advance this fertile field.
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CatálisisRESUMEN
BACKGROUND: The Longshi Scale is a pictorial assessment tool for evaluating activities of daily living (ADL) in patients with stroke. The paper-based version presents challenges; thus, the WeChat version was created to enhance accessibility. Herein, we aimed to validate the inter-rater and test-retest reliabilities of the WeChat version of the Longshi Scale and explore its potential clinical applications. METHODS: We recruited 115 patients with stroke in the study. The ADL results of each patient were assessed using both the WeChat and paper-based version of the Longshi Scale; each evaluation was conducted by 28 health professionals and 115 caregivers separately. To explore the test-retest reliability of the WeChat version, 22 patients were randomly selected and re-evaluated by health professionals using the WeChat version. All evaluation criteria were recorded, and all evaluators were surveyed to indicate their preference between the two versions. RESULTS: Consistency between WeChat and the paper-based Longshi Scale was high for ADL scores by health professionals (ICC2,1 = 0.803-0.988) and caregivers (ICC2,1 = 0.845-0.983), as well as for degrees of disability (κw = 0.870 by professionals; κw = 0.800 by caregivers). Bland-Altman analysis showed no significant discrepancies. The WeChat version exhibited good test-retest reliability (κw = 0.880). The WeChat version showed similar inter-rater reliability in terms of the ADL score evaluated using the paper-based version (ICC2,1 = 0.781-0.941). The time to complete assessments did not differ significantly, although the WeChat version had a shorter information entry time (P < 0.001, 95% confidence interval: -43.463 to -15.488). Health professionals favored the WeChat version (53.6%), whereas caregivers had no significant preference. CONCLUSIONS: The WeChat version of the Longshi Scale is reliable and serves as a suitable alternative for health professionals and caregivers to assess ADL levels in patients with stroke. The WeChat version of the Longshi Scale is considered user-friendly by health professionals, although it is not preferred by caregivers. TRIAL REGISTRATION: This study was approved by the Ethics Committee of the Second People's Hospital of Shenzhen (approval number: 20210812003-FS01) and registered on the Clinical Trial Register Center website: clinicaltrials.gov on January 31, 2022 (registration no.: NCT05214638).
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Actividades Cotidianas , Accidente Cerebrovascular , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de la Discapacidad , Reproducibilidad de los ResultadosRESUMEN
Multiple resonance (MR) boron-nitrogen doped polycyclic aromatic hydrocarbons (BN-PAHs) showed compelling thermally activated delayed fluorescence (TADF), surpassing those of their hydrocarbon analogs. However, the structural variety of π-extended BN-PAHs remains narrow. In this study, we synthesized three double helical BN-doped nanographenes (BN-NGs), 2a-2c, via the π-extension of the MR core. During the formation of 2a, a nanographene with one heptagon (1a) was obtained, whereas subsequent dehydrocyclization of the [6]helicene units within 2b-2c led to heptagon structures, yielding other two BN-NGs containing double heptagons (1b-1c). These BN-NGs (2a-2c and 1a-1c) showed pronounced redshifts of 100-190 nm compared to the parent MR core while preserving the TADF characteristics and prolonging the delayed fluorescence lifetime to the millisecond level. Furthermore, the integration of heptagon ring into 1a-1c expanded the conjugation, reduced the oxidation potentials, and yielded a more flexible framework compared to those of 2a-2c. The enantiomers of 2a-2c, 1a, and 1c were resolved and their chiroptical properties were studied. Notably, 1a and 1c exhibited the increased chiroptical dissymmetry factors.
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The incorporation of pentagon-heptagon pairs into helical nanographenes lacks a facile synthetic route, and the impact of these pairs on chiroptical properties remains unclear. In this study, a method for the stepwise construction of pentagon-heptagon pairs in helical nanographenes by the dehydrogenation of [6]helicene units was developed. Three helical nanographenes containing pentagon-heptagon pairs were synthesized and characterized using this approach. A wide variation in the molecular geometries and photophysical properties of these helical nanographenes was observed, with changes in the helical length of these structures and the introduction of the pentagon-heptagon pairs. The embedded pentagon-heptagon pairs reduced the oxidation potential of the synthesized helical nanographenes. The high isomerization energy barriers enabled the chiral resolution of the helicene enantiomers. Chiroptical investigations revealed remarkably enhanced circularly polarized luminescence and luminescence dissymmetry factors with an increasing number of the pentagon-heptagon pairs.
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INTRODUCTION: The aim of this study was to summarize the incidence, risk factors, and prognostic factors of distant metastasis of sinonasal carcinoma. METHODS: We collected data for patients diagnosed with sinonasal carcinoma from 2010 to 2015 from the SEER database and analyzed the risk factors for distant metastasis via univariate and multivariate logistic regression analysis. In addition, univariate and multivariate Cox regression analysis models were used to describe the factors related to the overall survival of patients with distant metastasis. RESULTS: A total of 2,255 patients were included in the study, including 86 in the distant metastasis group and 2,169 in the nondistant metastasis group. In the univariate and multivariate logistic regression analyses, we found that the risk factors affecting distant metastasis were poorly differentiated tumor grade (HR = 1.932, 95% CI: 1.082-3.452, p = 0.026), advanced T stage (T3-T4) (HR = 4.302, 95% CI: 2.047-9.039, p < 0.001), and advanced N stage (HR = 3.093, 95% CI: 1.911-5.005, p < 0.001). Moreover, elderly patients had a poorer prognosis than young patients (HR = 1.792, 95% CI: 1.096-2.931, p = 0.02) and that surgical treatment improved the survival rate of tumor patients with distant metastasis (HR = 0.450, 95% CI: 0.247-0.821, p = 0.009). CONCLUSION: Tumor grade, T stage, and N stage are risk factors for distant metastasis in sinonasal carcinoma, while an age of less than 65 years and surgery were positive prognostic factors for sinonasal carcinoma patients with distant metastasis.
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Carcinoma , Neoplasias de los Senos Paranasales , Humanos , Anciano , Estadificación de Neoplasias , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Questionnaires have been used in the past 2 decades to predict the diagnosis of vertigo and assist clinical decision-making. A questionnaire-based machine learning model is expected to improve the efficiency of diagnosis of vestibular disorders. OBJECTIVE: This study aims to develop and validate a questionnaire-based machine learning model that predicts the diagnosis of vertigo. METHODS: In this multicenter prospective study, patients presenting with vertigo entered a consecutive cohort at their first visit to the ENT and vertigo clinics of 7 tertiary referral centers from August 2019 to March 2021, with a follow-up period of 2 months. All participants completed a diagnostic questionnaire after eligibility screening. Patients who received only 1 final diagnosis by their treating specialists for their primary complaint were included in model development and validation. The data of patients enrolled before February 1, 2021 were used for modeling and cross-validation, while patients enrolled afterward entered external validation. RESULTS: A total of 1693 patients were enrolled, with a response rate of 96.2% (1693/1760). The median age was 51 (IQR 38-61) years, with 991 (58.5%) females; 1041 (61.5%) patients received the final diagnosis during the study period. Among them, 928 (54.8%) patients were included in model development and validation, and 113 (6.7%) patients who enrolled later were used as a test set for external validation. They were classified into 5 diagnostic categories. We compared 9 candidate machine learning methods, and the recalibrated model of light gradient boosting machine achieved the best performance, with an area under the curve of 0.937 (95% CI 0.917-0.962) in cross-validation and 0.954 (95% CI 0.944-0.967) in external validation. CONCLUSIONS: The questionnaire-based light gradient boosting machine was able to predict common vestibular disorders and assist decision-making in ENT and vertigo clinics. Further studies with a larger sample size and the participation of neurologists will help assess the generalization and robustness of this machine learning method.
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Aprendizaje Automático , Encuestas y Cuestionarios , Vértigo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Vértigo/diagnósticoRESUMEN
Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.
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Nanocompuestos/uso terapéutico , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Animales , Humanos , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
BACKGROUND: The development of tumor tissue-infiltrating regulatory T cell (Treg) is incompletely understood. This study investigates the role of retinoblastoma cell (Rbc)-derived Twistrelated protein 1 (Twist) in the Treg development. METHODS: The surgically removed Rb tissues were collected. Rbcs were cultured with CD4+ T cells to assess the role of Rbc-derived Twist in the Treg generation. RESULTS: We found that more than 90% Rbcs expressed Twist. Foxp3+ Tregs were detected in the Rb tissues that were positively correlated with the Twist expression in Rbcs, negatively associated with Rb patient survival and sight survival. Treating Rbcs with hypoxia promoted the Twist expression that could be detected in the cytoplasm, nuclei and on the cell surface. Twist activated CD4+ T cells by binding the TLR4/myeloid differentiation factor 2 complex and promoted the transforming growth factor-ß-inducible early gene 1 product and Foxp3 expression. These Rbc-induced Foxp3+ Tregs showed immune-suppressive function on CD8+ T cell proliferation. CONCLUSIONS: Rbcs express Twist, that induces IL-4+ Foxp3+ Tregs; the latter can inhibit CD8+ cytotoxic T cell activities. Therefore, Twist may play an important role in the pathogenesis of Rb.
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Biomarcadores de Tumor/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias de la Retina/inmunología , Proteína de Retinoblastoma/metabolismo , Retinoblastoma/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Proteína 1 Relacionada con Twist/metabolismo , Biomarcadores de Tumor/genética , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas Nucleares/genética , Pronóstico , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/patología , Retinoblastoma/metabolismo , Retinoblastoma/patología , Proteína de Retinoblastoma/genética , Células Tumorales Cultivadas , Proteína 1 Relacionada con Twist/genéticaRESUMEN
BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. METHODS: Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure. RESULTS: The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses. CONCLUSIONS: This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. Graphical Headlights ⢠RG108 protected against noise-induced hearing loss ⢠RG108 administration protected against noise-induced hair cell loss and auditory neural damage. ⢠RG108 administration attenuated oxidative stress-induced DNA damage and subsequent apoptosis-mediated cell loss in the cochlea after noise exposure.
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Pérdida Auditiva Provocada por Ruido , Animales , Umbral Auditivo , Metilación de ADN , Pérdida Auditiva Provocada por Ruido/prevención & control , Ratones , Ftalimidas , Calidad de Vida , Triptófano/análogos & derivadosRESUMEN
BACKGROUND: Ability in the activities of daily life is often impaired in the older adults with a neurological disease. The Barthel Index is an instrument used worldwide to assess such ability. The Longshi Scale is a picture-based alternative, but its effectiveness has not been evaluated with older adult subjects. This study was to determine whether the Longshi Scale can effectively quantify the ability of older adults in the activities of daily living by comparing its ratings with those using the Barthel Index. METHODS: A multi-center cross-sectional study was conducted among patients over 65 years. A total of 2438 patients were divided into three groups, including bedridden, domestic, or community group based on their ability to go out of bed, move outdoors, and return indoors. Their ability in the activities of daily living among three groups was evaluated using both the Longshi Scale and the Barthel Index, and the results were compared. RESULTS: There was a significant difference in the average Barthel Index scores of three groups classified using the Longshi Scale. The average Longshi Scale scores also showed significant differences between the four groups classified using the Barthel Index. Spearman correlation coefficients showed strong correlation(>0.83) between the Longshi Scale and Barthel Index scores. CONCLUSIONS: The Longshi Scale can efficiently distinguish the ability in the activities of daily living of people with a neurological disease. Its rating correlate well with those using the Barthel Index.
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Actividades Cotidianas , Personas con Discapacidad , Anciano , China/epidemiología , Estudios Transversales , HumanosRESUMEN
Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.
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Nanomedicina , Neoplasias/terapia , Fototerapia , Animales , HumanosRESUMEN
Spinal fusion is a standard operation for treating moderate and severe intervertebral disc diseases. In recent years, the proportion of three-dimensional printing interbody fusion cage in spinal fusion surgery has gradually increased. In this paper, the research progress of molding technology and materials used in three-dimensional printing interbody fusion cage at present is summarized. Then, according to structure layout, three-dimensional printing interbody fusion cages are classified into five types: solid-porous-solid (SPS) type, solid-porous-frame (SPF) type, frame-porous-frame (FPF) type, whole porous cage (WPC) type and others. The optimization process of three-dimensional printing interbody fusion cage and the advantages and disadvantages of each type are analyzed and summarized in depth. The clinical application of various types of 3D printed interbody fusion cage was introduced and summarized later. Lastly, combined with the latest research progress and achievements, the future research direction of three-dimensional printing interbody fusion cage in molding technology, application materials and coating materials is prospected in order to provide some reference for scholars engaged in interbody fusion cage research and application.
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Degeneración del Disco Intervertebral , Desplazamiento del Disco Intervertebral , Fusión Vertebral , Humanos , Porosidad , Impresión TridimensionalRESUMEN
Cisplatin is used in a wide variety of malignancies, but cisplatin-induced ototoxicity remains a major issue in clinical practice. Experimental evidence indicates that ferroptosis plays a key role in mediating the unwanted cytotoxicity effect caused by cisplatin. However, the role of ferroptosis in cisplatin-induced ototoxicity requires elucidation. Ferrostatin-1 (Fer-1) was identified as a potent inhibitor of ferroptosis and radical-trapping antioxidant with its ability to reduce the accumulation of lipid peroxides and chain-carrying peroxyl radicals. In the current study, we investigated the effects of Fer-1 in cisplatin-induced ototoxicity in in vitro, ex vivo, and in vivo models. We found, for the first time that Fer-1 efficiently alleviated cisplatin-induced cytotoxicity in HEI-OC1 cells via a concentration-dependent manner. Furthermore, Fer-1 mitigated cisplatin cytotoxicity in transgenic zebrafish sensory hair cells. In HEI-OC1 cells, Fer-1 pretreatment not only drastically reduced the generation of intracellular reactive oxygen species but also remarkably decreased lipid peroxidation levels induced by cisplatin. This was not only ascribed to the inhibition of 4-hydroxynonenal, the final product of lipid peroxides, but also to the promotion of glutathione peroxidase 4, the protein marker of ferroptosis. MitoTracker staining and transmission electron microscopy of mitochondrial morphology suggested that in HEI-OC1 cells, Fer-1 can effectively abrogate mitochondrial damage resulting from the interaction with cisplatin. In addition, Fer-1 pretreatment of cochlear explants substantially protected hair cells from cisplatin-induced damage. Therefore, our results demonstrated that ferroptosis might be involved in cisplatin ototoxicity. Fer-1 administration mitigated cisplatin-induced hair cell damage, further investigations are required to elucidate the molecular mechanisms of its otoprotective effect.
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Cisplatino/efectos adversos , Ciclohexilaminas/farmacología , Células Ciliadas Auditivas/efectos de los fármacos , Ototoxicidad/tratamiento farmacológico , Fenilendiaminas/farmacología , Animales , Animales Modificados Genéticamente , Células Cultivadas , Cóclea/citología , Cóclea/efectos de los fármacos , Ciclohexilaminas/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Humanos , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Técnicas de Cultivo de Órganos , Ototoxicidad/etiología , Fenilendiaminas/administración & dosificación , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Pez Cebra/genéticaRESUMEN
Long-term uninterrupted therapy is essential for maximizing clinical benefits of antiangiogenic drugs (AADs) in cancer patients. Unfortunately, nearly all clinically available AADs are delivered to cancer patients using disrupted regimens. We aim to develop lifetime, nontoxic, effective, orally active, and low-cost antiangiogenic and antitumor drugs for treatment of cancer patients. Here we report our findings of long-term maintenance therapy with orally active, nontoxic, low cost antiangiogenic chemotherapeutics for effective cancer treatment. In a sequential treatment regimen, robust antiangiogenic effects in tumors were achieved with an anti-VEGF drug, followed by a low-dose chemotherapy. The nontoxic, low dose of the orally active prodrug capecitabine was able to sustain the anti-VEGF-induced vessel regression for long periods. In another experimental setting, maintenance of low-dose capecitabine produced greater antiangiogenic and antitumor effects after AAD plus chemotherapy. No obvious adverse effects were developed after more than 2-mo of consecutive treatment with a low dose of capecitabine. Together, our findings provide a rationalized concept of effective cancer therapy by long-term maintenance of AAD-triggered antiangiogenic effects with orally active, nontoxic, low-cost, clinically available chemotherapeutics.
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Capecitabina/farmacología , Neoplasias Experimentales , Neovascularización Patológica , Células A549 , Administración Oral , Animales , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Factores de TiempoRESUMEN
Photoacoustic imaging (PAI) is an attractive imaging modality, which is promising for clinical cancer diagnosis due to its advantages on deep tissue penetration and fine spatial resolution. However, few tumor catalytic/responsive PAI strategies are developed. Here, we design an exosome-like nanozyme vesicle for in vivo H2O2-responsive PAI of nasopharyngeal carcinoma (NPC). The intrinsic peroxidase-like activity of graphene quantum dot nanozyme (GQDzyme) effectively converts the 2,2'-azino- bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form in the presence of H2O2. The oxidized ABTS exhibits strong near-infrared (NIR) absorbance, rendering it to be an ideal contrast agent for PAI. Thus, GQDzyme/ABTS nanoparticle is a novel type of catalytic PAI contrast agent, which is sensitive to H2O2 produced from NPC cells. Furthermore, we develop an approach to construct exosome-like nanozyme vesicle via biomimetic functionalization of GQDzyme/ABTS nanoparticle with natural erythrocyte membrane modified with folate acid. In vivo animal experiments demonstrated that this exosome-like nanozyme vesicle effectively accumulated in NPC and selectively triggered catalytic PAI for NPC. In addition, our nanozyme vesicle exhibits excellent biocompatibility and stealth ability for long blood circulation. Together, we demonstrate that GQDzyme/ABTS based exosome-like nanozyme vesicle is an ideal nanoplatform for developing deep-tissue tumor-targeted catalytic PAI in vivo.
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Exosomas/química , Nanopartículas/administración & dosificación , Carcinoma Nasofaríngeo/tratamiento farmacológico , Técnicas Fotoacústicas , Animales , Benzotiazoles/química , Benzotiazoles/farmacología , Catálisis , Exosomas/efectos de los fármacos , Xenoinjertos , Humanos , Peróxido de Hidrógeno/química , Ratones , Nanopartículas/química , Carcinoma Nasofaríngeo/patología , Peroxidasa/química , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacologíaRESUMEN
BACKGROUND: Intake of trans fatty acids (TFAs) from partially hydrogenated vegetable oil is associated with a variety of adverse outcomes, but little is known about the health effects of ruminant trans fats. Trans-vaccenic acid (TVA) is a naturally occurring TFA found in the fat of ruminants and in human dairy products. The present study was conducted to investigate the anticancer activity and underlying mechanisms of TVA on human nasopharyngeal carcinoma (NPC) 5-8F and CNE-2 cells. METHODS: A CCK8 assay was used to determine the effect of TVA and the Mcl-1 inhibitor S63845 on the proliferation of NPC cells. Apoptosis was measured using flow cytometry. Western blotting was used to detect the protein expression levels of factors associated with Bcl-2-family protein signaling and Akt signaling. RESULTS: TVA significantly inhibited cell proliferation in a dose-dependent manner. Mechanistic investigation demonstrated that TVA significantly decreased p-Akt levels and Bad phosphorylation on Ser-136 and Ser-112. More importantly, we discovered that the Mcl-1 inhibitor S63845 synergistically sensitized NPC cells to apoptosis induction by TVA. CONCLUSION: TVA can inhibit NPC cell growth and induced apoptosis through the inhibition of Bad/Akt phosphorylation. The combined use of TVA and Mcl-1 inhibitors offers a potential advantage for nasopharyngeal cancer treatment.
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Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Antineoplásicos/farmacología , Western Blotting , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Humanos , Ácidos Oléicos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Letal Asociada a bcl/antagonistas & inhibidores , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Multifunctional nanodots represent an emerging platform for overcoming the delivery challenges of poorly water-soluble drugs for use in the diagnosis and treatment of cancer. The authors describe the preparation of nanocrystallites composed of the water-insoluble photosensitizer zinc(II)-phthalocyanine in the form of nanodots by applying a cryodesiccation-driven crystallization approach. Modification of the surface of the nanodots with Pluronic F127 and folic acid endows them with excellent water solubility and stealth properties in blood. Under near-infrared (NIR) photoexcitation at 808 nm, the nanodots are shown to produce singlet oxygen, which is widely used in photodynamic therapy of cancer. The nanodots exhibit strong NIR absorbance at 808 nm and can be used as a non-toxic contrast agent for photoacoustic imaging of tissue. Graphical abstract Schematic presentation of the preparation of ZnPcNDs by droplet-confined/cryodesiccation-driven crystallization.
Asunto(s)
Medios de Contraste/uso terapéutico , Portadores de Fármacos/uso terapéutico , Indoles/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Puntos Cuánticos/uso terapéutico , Animales , Línea Celular Tumoral , Medios de Contraste/efectos de la radiación , Medios de Contraste/toxicidad , Cristalización , Portadores de Fármacos/efectos de la radiación , Portadores de Fármacos/toxicidad , Ácido Fólico/química , Humanos , Indoles/efectos de la radiación , Indoles/toxicidad , Rayos Infrarrojos , Isoindoles , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/efectos de la radiación , Compuestos Organometálicos/toxicidad , Técnicas Fotoacústicas/métodos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/efectos de la radiación , Fármacos Fotosensibilizantes/toxicidad , Poloxámero/química , Puntos Cuánticos/efectos de la radiación , Puntos Cuánticos/toxicidad , Oxígeno Singlete/uso terapéutico , Compuestos de ZincRESUMEN
Nanobodies consist of a single domain variable fragment of a camelid heavy-chain antibody. Nanobodies have potential applications in biomedical fields because of their simple production procedures and low cost. Occasionally, nanobody clones of interest exhibit low affinities for their target antigens, which, together with their short half-life limit bioanalytical or therapeutic applications. Here, we developed a novel platform we named fenobody, in which a nanobody developed against H5N1 virus is displayed on the surface of ferritin in the form of a 24mer. We constructed a fenobody by substituting the fifth helix of ferritin with the nanobody. TEM analysis showed that nanobodies were displayed on the surface of ferritin in the form of 6 × 4 bundles, and that these clustered nanobodies are flexible for antigen binding in spatial structure. Comparing fenobodies with conventional nanobodies currently used revealed that the antigen binding apparent affinity of anti-H5N1 fenobody was dramatically increased (â¼360-fold). Crucially, their half-life extension in a murine model was 10-fold longer than anti-H5N1 nanobody. In addition, we found that our fenobodies are highly expressed in Escherichia coli, and are both soluble and thermo-stable nanocages that self-assemble as 24-polymers. In conclusion, our results demonstrate that fenobodies have unique advantages over currently available systems for apparent affinity enhancement and half-life extension of nanobodies. Our fenobody system presents a suitable platform for various large-scale biotechnological processes and should greatly facilitate the application of nanobody technology in these areas.
Asunto(s)
Antivirales/química , Ferritinas/química , Anticuerpos de Dominio Único/química , Animales , Antivirales/farmacología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Ferritinas/farmacología , Semivida , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Ratones , Microscopía Electrónica de Transmisión , Modelos Moleculares , Peso Molecular , Tamaño de la Partícula , Anticuerpos de Dominio Único/farmacología , Propiedades de SuperficieRESUMEN
BACKGROUND/AIMS: Hearing and balance deficits are mainly caused by loss of sensory inner ear hair cells. The key signals that control hair cell regeneration are of great interest. However, the molecular events by which the cellular signals mediate hair cell regeneration in the mouse utricle are largely unknown. METHODS: In the present study, we investigated gene expression changes and related molecular pathways using RNA-seq and qRT-PCR in the newborn mouse utricle in response to neomycin-induced damage. RESULTS: There were 302 and 624 genes that were found to be up-regulated and down-regulated in neomycin-treated samples. GO and KEGG pathway analyses of these genes revealed many deregulated cellular components, molecular functions, biological processes and signaling pathways that may be related to hair cell development. More importantly, the differentially expressed genes included 9 transcription factors from the zf-C2H2 family, and eight of them were consistently down-regulated during hair cell damage and subsequent regeneration. CONCLUSION: Our results provide a valuable source for future studies and highlighted some promising genes, pathways or processes that may be useful for therapeutic applications.