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1.
Front Psychol ; 15: 1455005, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39351108

RESUMEN

Environmental serious games aim to heighten players' awareness and comprehension of environmental issues, thus fostering pro-environmental decision-making. Research to date has affirmed these games' effectiveness in enhancing environmental knowledge and abilities, elevating consciousness regarding environmental matters, and promoting pro-environmental behavioral intentions and actions. Nonetheless, a detailed exploration into the precise mechanisms facilitating these impacts remains scarce. Leveraging theories of motivation, cognition, affect, and behavior, this paper outlines four hypothesized mechanisms of influence and introduces an Embodied-Enactive Cognition Model as a novel perspective. It suggests that future research should expand its inquiry into the multifaceted factors that influence pro-environmental decision-making, deepen the comprehension of the intrinsic mechanisms at play, pioneer novel research methodologies, and diversify the array of categories and contextual applications of environmental serious games.

2.
BMC Plant Biol ; 24(1): 930, 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39370516

RESUMEN

BACKGROUND: Wheat is one of major sources of human cadmium (Cd) intake. Reducing the grain Cd concentrations in wheat is urgently required to ensure food security and human health. In this study, we performed a field experiment at Wenjiang experimental field of Sichuan Agricultural University (Chengdu, China) to reveal the effects of FeCl3 and Fe2(SO4)3 on reducing grain Cd concentrations in dwarf Polish wheat (Triticum polonicum L., 2n = 4x = 28, AABB). RESULTS: Soil application of FeCl3 and Fe2(SO4)3 (0.04 M Fe3+/m2) significantly reduced grain Cd concentration in DPW at maturity by 19.04% and 33.33%, respectively. They did not reduce Cd uptake or root-to-shoot Cd translocation, but increased Cd distribution in lower leaves, lower internodes, and glumes. Meanwhile, application of FeCl3 and Fe2(SO4)3 up-regulated the expression of TpNRAMP5, TpNRAMP2 and TpYSL15 in roots, and TpYSL15 and TpZIP3 in shoots; they also downregulated the expression of TpZIP1 and TpZIP3 in roots, and TpIRT1 and TpNRAMP5 in shoots. CONCLUSIONS: The reduction in grain Cd concentration caused by application of FeCl3 and Fe2(SO4)3 was resulted from changes in shoot Cd distribution via regulating the expression of some metal transporter genes. Overall, this study reports the physiological pathways of soil applied Fe fertilizer on grain Cd concentration in wheat, suggests a strategy for reducing grain Cd concentration by altering shoot Cd distribution.


Asunto(s)
Cadmio , Compuestos Férricos , Triticum , Triticum/metabolismo , Triticum/genética , Cadmio/metabolismo , Compuestos Férricos/metabolismo , Cloruros/metabolismo , Fertilizantes , Suelo/química , Contaminantes del Suelo/metabolismo , Raíces de Plantas/metabolismo , Grano Comestible/metabolismo , Grano Comestible/genética , China , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética
3.
Adv Ther ; 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39230871

RESUMEN

INTRODUCTION: SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis. RESULTS: Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity. CONCLUSIONS: SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab. TRIAL REGISTRATION: NCT03792074.

4.
Brain Imaging Behav ; 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39269599

RESUMEN

Insomnia is a widespread health problem among adults, and it impairs cognitive control and emotional regulation functions. Stress and insomnia are positively correlated, and their vicious cycle has been widely reported. In this study, we explore the neural biomarkers of insomnia from the perspective of whole-brain functional connectivity and investigate the neural mechanisms underlying the association between stress and insomnia. The current study was conducted on a cross-sectional sample (N = 430). First, we investigated the correlation between perceived stress and insomnia. Second, we applied connectome-based predictive modeling (CPM) to determine the neuromarkers of insomnia. Finally, we explored the neural basis underlying the association between perceived stress and insomnia. A significant positive correlation was found between perceived stress and insomnia in the present research. Results of CPM revealed the following as the neural substrates supporting insomnia: the emotion regulation circuit involving repetitive negative thinking and the cognitive control circuit involving attention control. According to further results from mediation analysis, the frontoparietal network supporting cognitive emotion regulation is an important neural mechanism that maintains the correlation between stress and insomnia. The present study offers a profound insight into the alterations of brain activity related to insomnia, and it further investigates the neural underpinnings of the robust association between stress and insomnia. This study also opens new avenues for neural interventions to alleviate stress-related insomnia.

5.
J Mater Chem B ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39311835

RESUMEN

Dipeptidyl peptidase IV (DPPIV) is an enzyme belonging to the type II transmembrane serine protease family that has gained wide interest in the fields of hematology, immunology, and cancer biology. Moreover, DPPIV has emerged as a promising target for therapeutic intervention in type II diabetes. Due to its biological limitations, traditional strategies cannot meet the requirements of low abundance DPPIV analysis in complex environments. In this work, combining the high programmability of DNA and the chemical diversity of peptides, we designed DNA-peptide conjugates that can be specifically recognized, polypeptides as specific substrates for target DPPIV and DNA probes as primers for catalytic hairpin assembly (CHA), recycling a large amount of DNAzymes by triggering CHA amplification. The DNAzyme substrate modified with the FAM fluorescent group was immobilized on the surface of gold nanoparticles by S-Au chemical bonds to form a signal output probe. The DNAzymes enzyme cleaved the substrate of the signal outputs probe, yielding a double-amplified fluorescence signal. This method has a detection limit as low as 0.18 mU mL-1 and a linear range of 0-5 mU mL-1 in serum samples, showing high stability and good potential for practical applications.

6.
Elife ; 132024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39259216

RESUMEN

Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE), and dorsal pallium in the mouse brain. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.


Asunto(s)
Oligodendroglía , Prosencéfalo , Animales , Oligodendroglía/metabolismo , Oligodendroglía/citología , Prosencéfalo/embriología , Prosencéfalo/citología , Ratones , Linaje de la Célula/genética
7.
Ibrain ; 10(3): 366-374, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39346789

RESUMEN

Delayed neurocognitive recovery after surgery is associated with increased morbidity and mortality. However, its mechanism of action remains controversial and complex. A prospective, double-blind, randomized controlled trial was performed at the Affiliated Hospital of Zunyi Medical University. Older patients (aged 65 years and older) who underwent gastrointestinal surgery were randomly divided into sevoflurane-based or propofol-based anesthesia groups. The Mini-Mental State Examination was performed to evaluate cognitive function. Peripheral venous blood was collected to test the levels of choline acetyltransferase and acetylcholinesterase. A total of 75 patients were enrolled and 30 patients in each group completed the study. On Day 1 postoperation, patients in the sevoflurane group showed worse performance on the Mini-Mental State Examination than patients in the propofol group. Lower blood choline acetyltransferase concentrations and higher acetylcholinesterase concentrations were observed in patients who had sevoflurane anesthesia than in patients who had propofol anesthesia 1 day postoperative. At 3 days postoperation, patients with sevoflurane- or propofol-based general anesthesia did not differ regardless of Mini-Mental State Examination score or choline acetyltransferase and acetylcholinesterase levels. Sevoflurane-based anesthesia has short-term delayed neurocognitive recovery in older surgical patients, which may be related to central cholinergic system degeneration.

8.
Eur J Pharmacol ; 983: 176994, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39271040

RESUMEN

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts.


Asunto(s)
Ansiolíticos , Trastornos de Ansiedad , Modelos Animales de Enfermedad , Animales , Humanos , Ansiolíticos/uso terapéutico , Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología
9.
J Mater Chem B ; 12(39): 9930-9937, 2024 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-39263860

RESUMEN

The detection of a single biomarker is prone to false negative or false positive results. Simultaneous analysis of two biomarkers can greatly improve the accuracy of diagnosis. In this work, we designed a new method for coinstantaneous detection of two breast cancer biomarkers miRNA-21 and HER2 using the properties of duplex-specific nuclease (DSN). Cy5-labeled DNA1 and FAM-labeled DNA2 are used as signal probes to distinguish the two signals. When the sample contains the targets HER2 and miRNA-21, HER2 binds to the HER2 aptamer on the double-stranded DNA2, while miRNA-21 binds to the complementary DNA1. Then, DSN enzyme is added to cut the DNA probes adsorbed on the HER2 aptamer and miRNA-21, releasing the fluorescent groups, which can be readsorbed to the empty sites, thus repeating the cutting of the probes and producing an exponential signal amplification with two distinct fluorescent signals. The detection limits of miRNA-21 and HER2 are 1.12 pM and 0.36 ng mL-1, respectively, with linear ranges of 5 pM to 50 pM and 1 ng mL-1 to 15 ng mL-1. The method was validated in real biological samples, providing a new approach for synchronous analysis of important markers in breast cancer.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , MicroARNs , Receptor ErbB-2 , Humanos , MicroARNs/análisis , MicroARNs/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Femenino
10.
Cancer Control ; 31: 10732748241284535, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39292867

RESUMEN

OBJECTIVE: To retrospectively analyze the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) on the progression free survival (PFS) of advanced gastric cancer (GC) and colorectal cancer (CRC). METHOD: We retrospectively collected all the HIPEC data of GC and CRC in the Chongqing University Cancer Hospital from August 2018 to April 2023. Data were extracted from inpatient records and outpatient examination records. The IBM SPSS statistics 23.0 software was used to analyze the data. We mainly compared the PFS of HIPEC cases with that of non-HIPEC cases (both from our center and from the literature). PFS was analyzed with the Kaplan-Meier method. Log Rank (Mantel Cox), Breslow (Generalized Wilcoxon), and Tarone-Ware were used for univariate analyses. RESULT: A total of 342 HIPEC cases were analyzed in this study. Stage IV GC and CRC accounted for 48.5% of the total number of cases. Abdominal pain and distension (47.4%) were the most common side effects from HIPEC. Serious complications were rare (1.8%, including bleeding, perforation, obstruction, and death). The PFS and disease-free survival (DFS) of abdominal malignancy treated with HIPEC were significantly associated with the TNM stage, but not HIPEC numbers nor HIPEC drugs. In stage IV HIPEC cases, adding adjuvant chemotherapy after HIPEC resulted in better PFS. In addition, the association between peritoneal carcinomatosis index (PCI) and PFS of stage IV HIPEC cases was close to significant. Compared with the 33 stage IV (with peritoneal metastases) GC cases without HIPEC in our center from the last 15 years, the PFS of the 56 stage Ⅳ GC cases with HIPEC was not improved significantly (median PFS: 6 ± 2.92 months vs 7 ± 1.63 months for with vs without HIPEC in stage IV GC, respectively; P ≥ 0.05). Compared with the 58 stage IV (with peritoneal metastases) CRC cases without HIPEC in our center from the last 15 years, the PFS of the 86 stage IV CRC cases with HIPEC was not improved significantly either (median PFS: 7 ± 1.68 months vs 7 ± 0.62 months for with vs without HIPEC in stage IV CRC, respectively; P ≥ 0.05). When comparing our HIPEC data with the non-HIPEC data reported by other scholars for the PFS of advanced GC and CRC, the negative results were similar. CONCLUSION: The PFS/DFS of HIPEC cases was associated with the TNM stage, but not with the HIPEC numbers or HIPEC drugs. PCI may be related to the PFS of stage IV HIPEC cases. Adding chemotherapy or targeted therapy after HIPEC may improve the PFS of stage IV cases. HIPEC did not significantly improve the PFS of stage IV GC or CRC cases in our center.


Asunto(s)
Neoplasias Colorrectales , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Masculino , Femenino , Quimioterapia Intraperitoneal Hipertérmica/métodos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Anciano , Adulto , Supervivencia sin Progresión
11.
Mol Cell ; 84(18): 3513-3529.e5, 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39255795

RESUMEN

Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.


Asunto(s)
Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales , Inmunidad Innata , Factor 3 Regulador del Interferón , Lipoilación , Ácido Palmítico , Transducción de Señal , Inmunidad Innata/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/inmunología , Humanos , Animales , Ácido Palmítico/farmacología , Ratones , Células HEK293 , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/inmunología , Aciltransferasas/genética , Aciltransferasas/inmunología , Aciltransferasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones Endogámicos C57BL , Antivirales/farmacología , Proteínas de Neoplasias , Péptidos y Proteínas de Señalización Intracelular
12.
Sci Adv ; 10(31): eadk4331, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093969

RESUMEN

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here, we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels.


Asunto(s)
Segmento Inicial del Axón , Axones , Homeostasis , Plasticidad Neuronal , Sinapsis , Animales , Plasticidad Neuronal/fisiología , Segmento Inicial del Axón/metabolismo , Axones/fisiología , Axones/metabolismo , Ratones , Sinapsis/fisiología , Potenciales de Acción , Masculino , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo
13.
Biomedicines ; 12(8)2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39200116

RESUMEN

Store-operated Ca2+ entry (SOCE) is a ubiquitous cellular mechanism that cells use to activate extracellular Ca2+ entry when intracellular Ca2+ stores are depleted. In skeletal muscle, SOCE occurs within Ca2+ entry units (CEUs), intracellular junctions between stacks of SR membranes containing STIM1 and transverse tubules (TTs) containing ORAI1. Gain-of-function mutations in STIM1 and ORAI1 are linked to tubular aggregate (TA) myopathy, a disease characterized by the atypical accumulation of tubes of SR origin. Moreover, SOCE and TAs are increased in the muscles of aged male mice. Here, we assessed the longitudinal effects (from 4-6 months to 10-14 months of age) of constitutive, muscle-specific Orai1 knockout (cOrai1 KO) on skeletal muscle structure, function, and the assembly of TAs and CEUs. The results from these studies indicate that cOrai1 KO mice exhibit a shorter lifespan, reduced body weight, exercise intolerance, decreased muscle-specific force and rate of force production, and an increased number of structurally damaged mitochondria. In addition, electron microscopy analyses revealed (i) the absence of TAs with increasing age and (ii) an increased number of SR stacks without adjacent TTs (i.e., incomplete CEUs) in cOrai1 KO mice. The absence of TAs is consistent with TAs being formed as a result of excessive ORAI1-dependent Ca2+ entry.

14.
Sci Total Environ ; 951: 175423, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39134267

RESUMEN

Ecological drought is a complex process in terrestrial ecosystems where vegetation's eco-physiological functions are impaired due to water stress. However, there is currently a lack of long-term assessment of ecological drought from an eco-physiological perspective. In this study, the standardized ecological drought index (SESNDI) was developed using actual evaporation, root soil moisture, and kernel normalized difference vegetation index via the Euclidean distance method, reflecting ecosystem physiology, water supply capacity, and vegetation status. Solar-induced chlorophyll fluorescence validated SESNDI by reflecting vegetation photosynthesis. Using China as an example, severely impacted by climate change and ecological restoration, ecological drought's spatio-temporal variation and propagation characteristics was evaluated using clustering algorithms. The results demonstrated that (1) SESNDI showed superior performance over several other drought indices. (2) During 1982-2020, ecological drought was prevalent from 1990 to 2010, especially in the central and northeastern regions. (3) Compared to 1982-2000, the median duration and affected area of ecological drought events during 2001-2020 reduced by four months and 1.51 × 105 km2, respectively, while the median intensity increased by 0.06. (4) Decreased precipitation and increased temperature were the primary factors contributing to the frequent occurrence of ecological drought in China from 1990 to 2010. This study offers a crucial methodology for evaluating ecological drought, serving as a reference for developing effective terrestrial restoration strategies.


Asunto(s)
Cambio Climático , Sequías , Ecosistema , Monitoreo del Ambiente , China , Monitoreo del Ambiente/métodos
15.
Proc Natl Acad Sci U S A ; 121(36): e2410564121, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39190359

RESUMEN

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.


Asunto(s)
Disfunción Cognitiva , ARN Mensajero , Encefalopatía Asociada a la Sepsis , Animales , Masculino , Ratones , Acetilación , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Sepsis/metabolismo , Sepsis/complicaciones , Sepsis/genética , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/genética , Receptores de GABA-B
16.
J Control Release ; 374: 293-311, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39151831

RESUMEN

The persistent presence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei poses a significant obstacle to achieving a comprehensive cure for hepatitis B virus (HBV). Current applications of CRISPR/Cas9 for targeting and eliminating cccDNA have been confined to in vitro studies due to challenges in stable cccDNA expression in animal models and the limited non-immunogenicity of delivery systems. This study addresses these limitations by introducing a novel non-viral gene delivery system utilizing Gemini Surfactant (GS). The developed system creates stable and targeted CRISPR/Cas9 nanodrugs with a negatively charged surface through modification with red blood cell membranes (RBCM) or hepatocyte membranes (HCM), resulting in GS-pDNA@Cas9-CMs complexes. These GS-pDNA complexes demonstrated complete formation at a 4:1 w/w ratio. The in vitro transfection efficiency of GS-pDNA-HCM reached 54.61%, showing homotypic targeting and excellent safety. Additionally, the study identified the most effective single-guide RNA (sgRNA) from six sequences delivered by GS-pDNA@Cas9-HCM. Using GS-pDNA@Cas9-HCM, a significant reduction of 96.47% in in vitro HBV cccDNA and a 52.34% reduction in in vivo HBV cccDNA were observed, along with a notable decrease in other HBV-related markers. The investigation of GS complex uptake by AML-12 cells under varied time and temperature conditions revealed clathrin-mediated endocytosis (CME) for GS-pDNA and caveolin-mediated endocytosis (CVME) for GS-pDNA-HCM and GS-pDNA-RBCM. In summary, this research presents biomimetic gene-editing nanovectors based on GS (GS-pDNA@Cas9-CMs) and explores their precise and targeted clearance of cccDNA using CRISPR/Cas9, demonstrating good biocompatibility both in vitro and in vivo. This innovative approach provides a promising therapeutic strategy for advancing the cure of HBV.


Asunto(s)
Sistemas CRISPR-Cas , Técnicas de Transferencia de Gen , Virus de la Hepatitis B , Hepatitis B , Nanopartículas , Hepatitis B/terapia , Virus de la Hepatitis B/genética , Humanos , Nanopartículas/química , Animales , Células Hep G2 , Terapia Genética/métodos , Materiales Biomiméticos/química , ADN Circular , Plásmidos/genética , Plásmidos/administración & dosificación , Hepatocitos/metabolismo , Biomimética/métodos , Tensoactivos/química , ADN Viral/genética , Ratones
17.
Biomed Pharmacother ; 179: 117371, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39216447

RESUMEN

The continuous activation of macrophages play a critical role in the pathogenesis of cytokine storm (CS). Considering that CS results from the participation of multiple cytokines, the therapeutic effect of a single cytokine or its receptor-targeted blockade therapy remains uncertain. Melittin, which can systematically suppress the overexpression of proinflammatory mediators via inhibiting the mitogen-activated protein kinase and nuclear factor kappa-B pathways in activated macrophages, shows great potential in alleviating CS and acute inflammatory injury (AII). However, its clinical application is limited by its hemolytic activity, non-specific cytotoxicity and lack of targeting. In this study, a folic acid-modified and melittin stable-loaded solid lipid nanoparticle (Fa-MpG@LNP) with a core-shell structure was developed for CS control via targeted inhibition of the overproduction of proinflammatory mediators in activated macrophages with specific expression of folate receptor-ß. The resultant Fa-MpG@LNP showed ideal physicochemical properties and stability, low hemolytic activity and non-specific cytotoxicity, and it can specifically bind to lipopolysaccharide (LPS)-stimulated macrophages and effectively reduce the elevated levels of proinflammatory mediators. After intravenous administration, the Fa-MpG@LNP accumulated at inflamed tissue and significantly downregulate the overproduction of proinflammatory cytokines in tissue-infiltrated macrophages, resulting in a significant decrease of cytokine concentration in inflamed tissue and serum in LPS-induced acute pneumonia mice, and finally alleviate AII with undetectable toxic side effects. These results indicate the clinical application potential of Fa-MpG@LNP in alleviating CS and its related symptoms.


Asunto(s)
Síndrome de Liberación de Citoquinas , Citocinas , Macrófagos , Meliteno , Nanopartículas , Animales , Meliteno/farmacología , Meliteno/administración & dosificación , Ratones , Nanopartículas/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Citocinas/metabolismo , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Células RAW 264.7 , Masculino , Lipopolisacáridos , Inflamación/tratamiento farmacológico , Inflamación/patología , Lípidos/química , Ácido Fólico/química , Ratones Endogámicos C57BL , Mediadores de Inflamación/metabolismo , Liposomas
18.
Chem Commun (Camb) ; 60(73): 9962-9965, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39171778

RESUMEN

Functional composite layers composed of an amino-functionalized zirconium 1,4-dicarboxybenzene metal-organic framework were constructed on zinc anodes to mitigate the interface disturbances in aqueous batteries. These layers enable robust Zn2+ adsorption and homogenized Zn2+ transport and deposition kinetics, facilitating achieving high stability in a symmetric cell (3500 h) and a full cell (35 000 cycles, 96.7%).

19.
Chem Sci ; 15(30): 12108-12117, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39092122

RESUMEN

In situ polymerized 1,3-dioxolane (PDOL) is widely utilized to construct solid polymer electrolytes because of its high room-temperature ionic conductivity and good compatibility with lithium metal. However, the current polymerization additives used in PDOL do not effectively contribute to the formation of a robust solid electrolyte interphase (SEI), leading to decreased cycle life. Herein, a film-forming Lewis acid, tris(hexafluoroisopropyl) borate (THB), is demonstrated not only to be a catalyst for the ring-opening polymerization of DOL, but also an additive for the formation of a stable fluorine- and boron-rich SEI to improve the interfacial stability and suppress the Li dendrite growth. Moreover, molecular dynamics simulations and experimental results demonstrate that the introduction of THB can promote the dissociation of lithium salt and release more Li+ while the boron site can effectively restrict the free movement of TFSI- anion, thus increasing Li+ transference numbers (0.76) and ensuring the long-term cycling stability of cells. By using THB-PDOL, a stable cycling of Li‖Li symmetric cell for 600 h at a capacity of 0.5 mA h cm-2 can be achieved. Furthermore, employing THB-PDOL in Li‖LiFePO4 full cell enables a capacity retention of 98.64% after 300 cycles at 1C and a capacity retention of 95.39% after 200 cycles at a high temperature (60 °C). At the same time, this electrolyte is also suitable for the Li‖NCM523 full cell, which also achieves excellent stability of more than 180 cycles. This film-forming Lewis acid additive provides ideas for designing low-cost, high-performance PDOL-based lithium metal batteries.

20.
J Orthop Surg Res ; 19(1): 477, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39138567

RESUMEN

BACKGROUND: This study investigates the effectiveness of a self-developed intelligent monitoring system for home-based knee rehabilitation following total knee arthroplasty (TKA). METHODS: In this randomized controlled trial, 120 patients undergoing TKA were divided using random digit allocation. Preoperative and one-month postoperative assessments of knee function, quality of life, and isometric knee extension strength were conducted with the Intelligent Monitoring System. Patients received group-specific rehabilitation instructions pre-discharge and performed exercises for one month. RESULTS: Changes in isometric knee extensor strength on the affected side within one month post-surgery for the brace-monitored rehabilitation group showed a significant decrease three days after surgery compared to one day before surgery. Subsequent measurements taken at postoperative days 5, 7, 14, and 21 indicated a gradual increase in strength, although these increases did not reach statistical significance when compared with previous measurements. One month post-surgery, all groups demonstrated significant improvements in knee joint function and mobility compared to pre-surgery levels. Notably, the brace-monitored group showed statistically significant improvements in 36-Item Short-Form Health Survey (SF-36) scores over the conventional rehabilitation group. CONCLUSIONS: The Intelligent Monitoring System provides effective real-time monitoring and guidance for home-based knee rehabilitation post-TKA. It significantly enhances knee joint function, isometric knee extension strength, and quality of life shortly after surgery compared to traditional rehabilitation methods. This system offers a promising approach for improving postoperative recovery in TKA patients. TRIAL REGISTRATION: This study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (Ethics Approval Number 202209008-2). It was registered with the China Clinical Trial Registry, a primary registry of the World Health Organization's International Clinical Trials Registry Platform (Registration Number ChiCTR2300068852).


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Calidad de Vida , Humanos , Artroplastia de Reemplazo de Rodilla/rehabilitación , Artroplastia de Reemplazo de Rodilla/métodos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Articulación de la Rodilla/fisiopatología , Articulación de la Rodilla/cirugía , Fuerza Muscular , Resultado del Tratamiento , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/instrumentación , Terapia por Ejercicio/métodos , Terapia por Ejercicio/instrumentación , Recuperación de la Función
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