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1.
ACS Biomater Sci Eng ; 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38722972

RESUMEN

It still remains challenging to design multifunctional therapeutic reagents for effective cancer therapy under a unique tumor microenvironment including insufficient endogenous H2O2 and O2, low pH, and a high concentration of glutathione (GSH). In this work, a CO-based phototherapeutic system triggered by photogenerated holes, which consisted of ionic liquid (IL), the CO prodrug Mn2(CO)10, and iridium(III) porphyrin (IrPor) modified carbonized ZIF-8-doped graphitic carbon nitride nanocomposite (IL/ZCN@Ir(CO)), was designed for cascade hypoxic tumors. Upon light irradiation, the photogenerated holes on IL/ZCN@Ir(CO) oxidize water into H2O2, which subsequently induces Mn2(CO)10 to release CO. Meanwhile, IrPor can convert H2O2 to hydroxyl radical (•OH) and subsequent singlet oxygen (1O2), which further triggers CO release. Moreover, the degraded MnO2 shows activity for glutathione (GSH) depletion and mimics peroxidase, leading to GSH reduction and •OH production in tumors. Thus, this strategy can in situ release high concentrations of CO and reactive oxygen species (ROS) and deplete GSH to efficiently induce cell apoptosis under hypoxic conditions, which has a high inhibiting effect on the growth of tumors, offering an attractive strategy to amplify CO and ROS generation to meet therapeutic requirements in cancer treatment.

2.
Nano Lett ; 24(19): 5920-5928, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38708934

RESUMEN

A significant challenge in direct seawater electrolysis is the rapid deactivation of the cathode due to the large scaling of Mg(OH)2. Herein, we synthesized a Pt-coated highly disordered NiCu alloy (Pt-NiCu alloy) electrode with superior solidophobic behavior, enabling stable hydrogen generation (100 mA cm-2, >1000 h durability) and simultaneous production of Mg(OH)2 (>99.0% purity) in electrolyte enriched with Mg2+ and Ca2+. The unconventional solidophobic property primarily stems from the high surface energy of the NiCu alloy substrate, which facilitates the adsorption of surface water and thereby compels the bulk formation of Mg(OH)2 via homogeneous nucleation. The discovery of this solidophobic electrode will revolutionarily simplify the existing techniques for seawater electrolysis and increase the economic viability for seawater electrolysis.

3.
Front Immunol ; 15: 1364957, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38650932

RESUMEN

Introduction: CARD11 is a lymphoid lineage-specific scaffold protein regulating the NF-κB activation downstream of the antigen receptor signal pathway. Defective CARD11 function results in abnormal development and differentiation of lymphocytes, especially thymic regulatory T cells (Treg). Method: In this study, we used patients' samples together with transgenic mouse models carrying pathogenic CARD11 mutations from patients to explore their effects on Treg development. Immunoblotting and a GFP receptor assay were used to evaluate the activation effect of CARD11 mutants on NF-κB signaling. Then the suppressive function of Tregs carrying distinct CARD11 mutations was measured by in vitro suppression assay. Finally, we applied the retroviral transduced bone marrow chimeras to rescue the Treg development in an NF-κB independent manner. Results and discuss: We found CARD11 mutations causing hyper-activated NF-κB signals also gave rise to compromised Treg development in the thymus, similar to the phenotype in Card11 deficient mice. This observation challenges the previous view that CARD11 regulates Treg lineage dependent on the NF-kB activation. Mechanistic investigations reveal that the noncanonical function CARD11, which negatively regulates the AKT/ FOXO1 signal pathway, is responsible for regulating Treg generation. Moreover, primary immunodeficiency patients carrying CARD11 mutation, which autonomously activates NF-κB, also represented the reduced Treg population in their peripheral blood. Our results propose a new regulatory function of CARD11 and illuminate an NF-κB independent pathway for thymic Treg lineage commitment.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD , Guanilato Ciclasa , Mutación , FN-kappa B , Transducción de Señal , Linfocitos T Reguladores , Timo , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , FN-kappa B/metabolismo , Humanos , Ratones , Timo/inmunología , Timo/citología , Timo/metabolismo , Ratones Transgénicos , Diferenciación Celular/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Masculino
4.
Nat Commun ; 15(1): 3531, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38670961

RESUMEN

E6AP dysfunction is associated with Angelman syndrome and Autism spectrum disorder. Additionally, the host E6AP is hijacked by the high-risk HPV E6 to aberrantly ubiquitinate the tumor suppressor p53, which is linked with development of multiple types of cancer, including most cervical cancers. Here we show that E6AP and the E6AP/E6 complex exist, respectively, as a monomer and a dimer of the E6AP/E6 protomer. The short α1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended α1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two α1-helices to promote the attachment and detachment of substrates to the catalytic C-lobe of E6AP, thus facilitating ubiquitin transfer. These findings, complemented by mutagenesis analysis, suggest that the α1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP.


Asunto(s)
Multimerización de Proteína , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/genética , Humanos , Ubiquitina/metabolismo , Ubiquitina/química , Ubiquitinación , Modelos Moleculares , Cristalografía por Rayos X , Proteínas Oncogénicas Virales/metabolismo , Proteínas Oncogénicas Virales/química , Proteínas Oncogénicas Virales/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética , Unión Proteica , Conformación Proteica en Hélice alfa
5.
Neuroimage ; 291: 120586, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38548039

RESUMEN

Creativity, a high-order cognitive ability, has received wide attention from researchers and educators who are dedicated to promoting its development throughout one's lifespan. Currently, creativity is commonly assessed with divergent thinking tasks, such as the Alternative Uses Task. Recent advancements in neuroimaging techniques have enabled the identification of brain markers for high-order cognitive abilities. One such brain structure of interest in this regard is the hippocampus, which has been found to play an important role in generating creative thoughts in adulthood. However, such role of the hippocampus in childhood is not clear. Thus, this study aimed to investigate the associations between creativity, as measured by divergent thinking, and both the volume of the hippocampus and its resting-state functional connectivity in 116 children aged 8-12 years. The results indicate significant relations between divergent thinking and the volume of the hippocampal head and the hippocampal tail, as well as the volume of a subfield comprising cornu ammonis 2-4 and dentate gyrus within the hippocampal body. Additionally, divergent thinking was significantly related to the differences between the anterior and the posterior hippocampus in their functional connectivity to other brain regions during rest. These results suggest that these two subregions may collaborate with different brain regions to support diverse cognitive processes involved in the generation of creative thoughts. In summary, these findings indicate that divergent thinking is significantly related to the structural and functional characteristics of the hippocampus, offering potential insights into the brain markers for creativity during the developmental stage.


Asunto(s)
Encéfalo , Imagen por Resonancia Magnética , Niño , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Creatividad , Cognición , Mapeo Encefálico/métodos , Hipocampo/diagnóstico por imagen
6.
Front Immunol ; 15: 1295472, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38500883

RESUMEN

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.


Asunto(s)
COVID-19 , Miositis , Humanos , Estudios Retrospectivos , Ligasas , COVID-19/terapia , COVID-19/complicaciones , SARS-CoV-2 , China/epidemiología , Miositis/complicaciones , Miositis/epidemiología , Oxígeno
7.
Comput Biol Med ; 171: 108137, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38447499

RESUMEN

Lesion segmentation in ultrasound images is an essential yet challenging step for early evaluation and diagnosis of cancers. In recent years, many automatic CNN-based methods have been proposed to assist this task. However, most modern approaches often lack capturing long-range dependencies and prior information making it difficult to identify the lesions with unfixed shapes, sizes, locations, and textures. To address this, we present a novel lesion segmentation framework that guides the model to learn the global information about lesion characteristics and invariant features (e.g., morphological features) of lesions to improve the segmentation in ultrasound images. Specifically, the segmentation model is guided to learn the characteristics of lesions from the global maps using an adversarial learning scheme with a self-attention-based discriminator. We argue that under such a lesion characteristics-based guidance mechanism, the segmentation model gets more clues about the boundaries, shapes, sizes, and positions of lesions and can produce reliable predictions. In addition, as ultrasound lesions have different textures, we embed this prior knowledge into a novel region-invariant loss to constrain the model to focus on invariant features for robust segmentation. We demonstrate our method on one in-house breast ultrasound (BUS) dataset and two public datasets (i.e., breast lesion (BUS B) and thyroid nodule from TNSCUI2020). Experimental results show that our method is specifically suitable for lesion segmentation in ultrasound images and can outperform the state-of-the-art approaches with Dice of 0.931, 0.906, and 0.876, respectively. The proposed method demonstrates that it can provide more important information about the characteristics of lesions for lesion segmentation in ultrasound images, especially for lesions with irregular shapes and small sizes. It can assist the current lesion segmentation models to better suit clinical needs.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Nódulo Tiroideo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Ultrasonografía , Mama
8.
Biomed Pharmacother ; 174: 116460, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38520864

RESUMEN

Ischemic stroke is a common intravascular disease and one of the leading causes of death and disability. The salidroside derivative SHPL-49, which we previously synthesized, significantly attenuates cerebral ischemic injury in a rat model of permanent middle cerebral artery occlusion. To explore the neuroprotective mechanism of SHPL-49, the effects of SHPL-49 on the expression levels of neurotrophic factors in neurons and microglia and the polarization of microglia were investigated in the present study. SHPL-49 activated the brain-derived neurotrophic factor (BDNF) pathway, decreased the number of degenerated neurons, and accelerated neurogenesis in rats with cerebral ischemia. In addition, SHPL-49 promoted the polarization of microglia toward the M2 phenotype to alleviate neuroinflammation. In BV2 cells, SHPL-49 upregulated CD206 mRNA and protein levels and inhibited CD86 mRNA and protein levels. SHPL-49 also increased neurotrophic factor secretion in BV2 cells, which indirectly promoted the survival of primary neurons after oxygen-glucose deprivation (OGD). Proteomics analysis revealed that SHPL-49 promoted growth-associated protein 43 (Gap43) expression. SHPL-49 enhanced synaptic plasticity and increased Gap43 protein levels via activation of the BDNF pathway in the OGD primary neuron model. These results indicate that SHPL-49 prevents cerebral ischemic injury by activating neurotrophic factor pathways and altering microglial polarization. Thus, SHPL-49 is a potential neuroprotective agent.


Asunto(s)
Isquemia Encefálica , Factor Neurotrófico Derivado del Encéfalo , Proteína GAP-43 , Glucósidos , Microglía , Neuronas , Fármacos Neuroprotectores , Fenoles , Ratas Sprague-Dawley , Receptor trkB , Transducción de Señal , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Glucósidos/farmacología , Fenoles/farmacología , Masculino , Ratas , Proteína GAP-43/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Transducción de Señal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Receptor trkB/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Neurogénesis/efectos de los fármacos , Ratones
9.
Adv Mater ; : e2311322, 2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38299450

RESUMEN

Seawater electrolysis for hydrogen production is a sustainable and economical approach that can mitigate the energy crisis and global warming issues. Although various catalysts/electrodes with excellent activities have been developed for high-efficiency seawater electrolysis, their unsatisfactory durability, especially for anodes, severely impedes their industrial applications. In this review, attention is paid to the factors that affect the stability of anodes and the corresponding strategies for designing catalytic materials to prolong the anode's lifetime. In addition, two important aspects-electrolyte optimization and electrolyzer design-with respect to anode stability improvement are summarized. Furthermore, several methods for rapid stability assessment are proposed for the fast screening of both highly active and stable catalysts/electrodes. Finally, perspectives on future investigations aimed at improving the stability of seawater electrolysis systems are outlined.

10.
Small ; : e2311087, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38335310

RESUMEN

Herein, a type of light- and heat-driven flexible supramolecular polymer with reversibly long-lived phosphorescence and photochromism is constructed from acrylamide copolymers with 4-phenylpyridinium derivatives containing a cyano group (P-CN, P-oM, P-mM), sulfobutylether-ß-cyclodextrin (SBCD), and polyvinyl alcohol (PVA). Compared to their parent solid polymers, these flexible supramolecules based on the non-covalent cross-linking of copolymers, SBCD, and PVA efficiently boost the phosphorescence lifetimes (723.0 ms for P-CN, 623.0 ms for P-oM, 945.8 ms for P-mM) through electrostatic interaction and hydrogen bonds. The phosphorescence intensity/lifetime, showing excellent responsiveness to light and heat, sharply decreased after irradiation with a 275 nm flashlight or sunlight and gradually recovered through heating. This is accompanied by the occurrence and fading of visible photochromism, manifesting as dark green for P-CN and pink for P-oM and P-mM. These reversible photochromism and phosphorescence behaviors are mainly attributed to the generation and disappearance of organic radicals in the 4-phenylpyridinium derivatives with a cyano group, which can guide tunable luminescence and photochromism.

11.
Adv Healthc Mater ; : e2302767, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38381808

RESUMEN

Low immunogenicity, absence of tumor-infiltrating lymphocytes and immunosuppressive microenvironment of immune cold tumors are the main bottlenecks leading to unfavorable prognosis. Here, an integrated tumor bioimaging and multimodal therapeutic strategy is developed, which converts immune cold into hot by modulating oxidative stress levels, enhancing photo-killing efficacy, inducing immunogenic cell death and inhibiting the immune checkpoint. On that occasion, the unique tumor microenvironment can be harnessed to biosynthesize in situ self-assembly iron complexes and fluorescent gold nanoclusters from metal ions Fe(II) and Au(III) for active targeting and real-time visualization of the tumors, simultaneously regulating reactive oxygen species levels within tumors via peroxidase-like activity. Furthermore, methylene blue (MB)-mediated photodynamic therapy promotes the release of damage-associated molecular patterns (DAMPs), which acts as in situ tumor vaccine and further induces dendritic cells maturation, augments the infiltration of antitumor T cells and significantly impedes the primary tumor growth and proliferation. More strikingly, by synergizing with the programmed cell death receptor-1 (PD-1) checkpoint inhibitor, the immunosuppressive microenvironment is remodeled and the survival time of model mice is prolonged. In summary, this paradigm utilizes the tumor-specific microenvironment to boost robust and durable systemic antitumor immunity, providing a novel opportunity for precision cancer theranostics.

12.
Med Educ Online ; 29(1): 2303209, 2024 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-38194435

RESUMEN

Medical professionalism and ethics (MPE) are critical components influencing how medical practitioners provide patients with the highest standard of care. As a result, a structured attempt has been undertaken to enhance the content and teaching delivery of the medical professionalism and ethics education (MPEE) in the undergraduate medical curriculum. Guided by Vygotsky's sociocultural learning theory, Harre and Van Langenhove's positioning theory and Taba's principles of curriculum development, a curriculum co-creation project was organized with the aim of developing a socio-culturally responsive MPEE. A total of fifteen medical students agreed to participate in the project where they co-created MPE curriculum with a medical educator over the course of three months. Upon completion of the project, a co-created, socio-culturally responsive MPE curriculum was presented. The thematic analysis revealed positive changes in the participants' attitudes, skills, and behaviors towards co-creating the MPE curriculum. They also reported feeling a sense of fulfilment after having a transformative experience as curriculum co-creators and after receiving positive feedback from the faculty, staff, and other students on the co-created MPE curriculum. The project's success demonstrates the importance of curriculum co-creation as a strategy to promote co-creation efforts among students and educators in developing a socio-culturally responsive curriculum. The project's framework and practical recommendations can be adopted by other medical educators and faculties to encourage students' participation and their role on curriculum development using the co-creation approach.


Asunto(s)
Educación Médica , Estudiantes de Medicina , Humanos , Profesionalismo , Ética Médica , Curriculum
13.
BMC Genomics ; 25(1): 117, 2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38279081

RESUMEN

BACKGROUND: In cellular activities, essential proteins play a vital role and are instrumental in comprehending fundamental biological necessities and identifying pathogenic genes. Current deep learning approaches for predicting essential proteins underutilize the potential of gene expression data and are inadequate for the exploration of dynamic networks with limited evaluation across diverse species. RESULTS: We introduce ECDEP, an essential protein identification model based on evolutionary community discovery. ECDEP integrates temporal gene expression data with a protein-protein interaction (PPI) network and employs the 3-Sigma rule to eliminate outliers at each time point, constructing a dynamic network. Next, we utilize edge birth and death information to establish an interaction streaming source to feed into the evolutionary community discovery algorithm and then identify overlapping communities during the evolution of the dynamic network. SVM recursive feature elimination (RFE) is applied to extract the most informative communities, which are combined with subcellular localization data for classification predictions. We assess the performance of ECDEP by comparing it against ten centrality methods, four shallow machine learning methods with RFE, and two deep learning methods that incorporate multiple biological data sources on Saccharomyces. Cerevisiae (S. cerevisiae), Homo sapiens (H. sapiens), Mus musculus, and Caenorhabditis elegans. ECDEP achieves an AP value of 0.86 on the H. sapiens dataset and the contribution ratio of community features in classification reaches 0.54 on the S. cerevisiae (Krogan) dataset. CONCLUSIONS: Our proposed method adeptly integrates network dynamics and yields outstanding results across various datasets. Furthermore, the incorporation of evolutionary community discovery algorithms amplifies the capacity of gene expression data in classification.


Asunto(s)
Mapas de Interacción de Proteínas , Saccharomyces cerevisiae , Animales , Ratones , Humanos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Algoritmos , Proteínas/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo
15.
Adv Mater ; 36(2): e2306062, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37907201

RESUMEN

Although hydrogen gas (H2 ) storage might enable offshore renewable energy to be stored at scale, the commercialization of technology for H2 generation by seawater electrolysis depends upon the development of methods that avoid the severe corrosion of anodes by chloride (Cl- ) ions. Here, it is revealed that the stability of an anode used for seawater splitting can be increased by more than an order of magnitude by loading Ag nanoparticles on the catalyst surface. In experiments, an optimized NiFe-layered double hydroxide (LDH)@Ag electrode displays stable operation at 400 mA cm-2 in alkaline saline electrolyte and seawater for over 5000 and 2500 h, respectively. The impressive long-term durability is more than 20 times that of an unmodified NiFe-LDH anode. Meticulous characterization and simulation reveals that in the presence of an applied electric field, free Cl- ions react with oxidized Ag nanoparticles to form stable AgCl species, giving rise to the formation of a Cl- -free layer near the anode surface. Because of its simplicity and effectiveness, it is anticipated that the proposed strategy to immobilize chloride ions on the surface of an anode has the potential to become a crucial technology to control corrosion during large-scale electrolysis of seawater to produce hydrogen.

16.
Eur J Pharm Sci ; 194: 106653, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38006986

RESUMEN

As a widely used antidepressant that works by inhibiting the reuptake of serotonin, sertraline exerts an antidepressant effect depending on its concentration in the brain, which might be limited by the blood-brain barrier (BBB). It is highly possible to combine proton pump inhibitors (PPIs) with sertraline in clinical trials. Nevertheless, the role played by PPIs in regulating the transport of sertraline across the BBB remains unclear. Here, the impact of PPIs on the distribution of sertraline in the brain and the mechanisms involved were investigated. A mouse brain distribution study showed that Omeprazole (OME), Pantoprazole (PAN), Ilaprazole (ILA), and Esomeprazole (ESO) increased the area under the brain concentration-time curves (AUC) for sertraline by 2.02-, 3.18-, 3.04-, and 4.21-fold, respectively, after the 14-day administration of PPIs. Besides, PPIs significantly increased the permeability of sertraline in brain perfusion experiments, with PAN having the highest rank order, followed by ILA, OME, and ESO. In the tail suspension test (TST), co-administration PPI groups showed significantly shorter immobility time than the control group. In vitro, four PPIs inhibited sertraline efflux in breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and showed a mixed inhibition type. In this study, PPIs were further found to inhibit the mRNA and protein expression of brain BCRP. To sum up, the findings of this study revealed that PPIs could enhance the brain distribution and antidepressant effect of sertraline, which may be attributed to the inhibition of BCRP expression at the BBB by PPIs.


Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles , Inhibidores de la Bomba de Protones , Sertralina , Animales , Ratones , Inhibidores de la Bomba de Protones/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Sertralina/farmacología , Barrera Hematoencefálica/metabolismo , Proteínas de Neoplasias/metabolismo , Omeprazol/farmacología , Esomeprazol , Antidepresivos/farmacología , Pantoprazol/farmacología
17.
Am J Cancer Res ; 13(11): 5254-5270, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38058806

RESUMEN

Hepatocellular carcinoma (HCC) represents a lethal cancer, and most HCC cases occur in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret biological contents to maintain liver inflammation. Herein, we aimed to identify the key transcription factor secreted by extracellular vesicles (EVs) derived from HSCs and explored its oncogenic mechanism. The activated HSC cell line LX-2 was co-cultured with HCC cells with or without the EVs release inhibitor GW4869. The effects of co-culture with HSC on HCC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition were analyzed. Co-culture with activated LX-2 enhanced HCC cell growth and motility, while GW4869 inhibited the pro-carcinogenic effect of HSC, suggesting that HSC promoted HCC progression through the secretion of EVs. HSC-derived EVs carried the key oncogenic transcription factor PRDM16, and uptake of EVs-derived PRDM16 by HCC cells activated the NOTCH1-mediated Notch signaling pathway. Knocking down PRDM16 in EVs or blocking Notch signaling in HCC cells significantly inhibited the tumor-promoting effects of HSC-derived EVs. Our study demonstrates that HSC-derived EVs activate the NOTCH1-mediated Notch signaling pathway in HCC cells by carrying PRDM16, leading to HCC progression.

18.
Pharmaceutics ; 15(12)2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38140044

RESUMEN

Triple-negative breast cancer (TNBC) is a highly aggressive disease with rapid progression and poor prognosis due to multidrug resistance (MDR). Piperine (PIP) shows promise as a P-gp inhibitor, capable of sensitizing chemotherapeutic drugs and exhibiting antitumor properties. This study explores the inhibitory mechanism of PIP on P-glycoprotein (P-gp) and its capacity to enhance the sensitivity of paclitaxel (PTX). We subsequently evaluated the efficacy and safety of albumin nanoparticles that co-encapsulate PTX and PIP (PP@AN). The results demonstrated that PIP enhanced the accumulation of PTX intracellularly, as determined with HPLC/MS/MS analysis. PIP was also found to increase cell sensitivity to PTX. Furthermore, we explored the inhibitory mechanism of PIP on P-gp, utilizing molecular docking simulations, RT-qPCR, and Western blot analysis. PIP appears to compete with the active paclitaxel binding site on P-gp, affecting ATPase activity and downregulating the MDR1 gene and P-gp expression. In summary, PIP could inhibit P-gp and act as a sensitizer in the treatment of TNBC with PTX. Moreover, stable and uniform PP@AN was successfully formulated, resulting in a significant increase in drug accumulation within cells as well as the downregulation of P-gp in tumors at the optimal ratio (PTX:PIP = 1:2). This led to an improvement in the antitumor effect in vivo while also reducing hepatotoxicity and hemototoxicity following chemotherapy. This study comprehensively investigated PIP's inhibitory effect and mechanism on P-gp. We present a new approach for co-delivering PIP and PTX using albumin nanoparticles, which reduced toxicity and improved therapeutic efficacy both in vivo and in vitro.

19.
Heliyon ; 9(11): e21480, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38027756

RESUMEN

The new energy automobile industry is a comprehensive system that contains Exploration and Manufacture, Consumption and Promotion, Infrastructure Construction and Supporting Industries, which coordinate and supplement with each other. Accordingly, from the perspective of policy object, NEVs policies since 1991 to 2022 could be divided into four fields in China. With policy bibliometric analysis and social network analysis, in each field of policies, its policy networks can be drawn, with statistic of policies released separately, in order to comprehensively analyse the features of NEVs policy making. It is found that: (1) The structure of policy system is balanced among four fields of NEVs policies in China, though with a bias towards Consumption & Promotion, Exploration & Manufacture. (2) Policy makers in all four fields of NEVs policies preferred slightly to formulate policies jointly, rather than acting alone. While policies made by sole actors are part of policy system. (3) GOOSC, MIIT and MOT, as sole actor, played more significant roles in industry-wide, supply-side and demand-side of NEVs industry respectively. (4) Policy networks of all four fields started with the "iron four" (MIIT, NDRC, MOF, MOST), ultimately forming two different ways of development, specialization and sociability. (5) In addition to the government departments, social organizations and enterprises also influenced the policy network, at the edge of network. This paper is of positive significance for understanding the current status and characteristics of policy making in different fields of the NEV industry, beneficial to distinguish potential effective ways to impact on NEVs policy system in China.

20.
ACS Appl Bio Mater ; 6(12): 5708-5715, 2023 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-37990995

RESUMEN

Recently, various nanomaterials have drawn increasing attention for enhanced tumor therapy. However, a lack of tumor uptake and insufficient generation of cytotoxic agents have largely limited the antitumor efficacy in vivo. Herein, a multifunctional nanoplatform (IL@CPPor(CO)) was constructed with pH-responsive copper peroxide nanoparticles (CPNP) that are capable of self-supplying H2O2, a radical-sensitive carbonic oxide (CO) donor (Fe3(CO)12), photosensitizer Iridium(III) meso-tetra (N-methyl-4-pyridyl)porphyrin pentachloride (IrPor), and ionic liquid (IL) for enhanced oncotherapy. Under acidic conditions, the CPNP could decompose to release H2O2 and Cu2+. The concomitant generation of H2O2 could efficiently trigger Fe3(CO)12 to release the CO in situ. On the other hand, Cu2+ possesses both glutathione depletion and Fenton-like properties. In addition, IrPor has both peroxidase-like activity and photosensitizer properties to produce reactive oxygen species (ROS) in tumors. The released ROS could trigger the rapid intracellular release of CO. More importantly, released CO and ROS could promote cell apoptosis and improve the therapeutic efficacy. Moreover, due to the pH-dependent ROS generation property, the IL@CPPor(CO) exhibited high tumor accumulation, low toxicity, and good biocompatibility, which enabled effective tumor growth inhibition with minimal side effects in vivo. This work provides a novel multifunctional nanoplatform that combined photodynamic therapy with CDT and CO to improve therapeutic efficacy.


Asunto(s)
Neoplasias , Fármacos Fotosensibilizantes , Humanos , Especies Reactivas de Oxígeno , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Cobre , Preparaciones de Acción Retardada/farmacología , Óxidos , Peróxido de Hidrógeno , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Concentración de Iones de Hidrógeno
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