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1.
CNS Neurosci Ther ; 30(7): e14777, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38958388

RESUMEN

A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within 7 days prior to hospital admission. Through this retrospective, observational cohort study, they found prior VKA use did not increase the risk of symptomatic intracranial hemorrhage (sICH) overall. However, recent VKA use with a presenting international normalized ratio (INR) > 1.7 was associated with a significantly increased risk of sICH. Future large-scale randomized controlled trials should be conducted to further clarify the effects and feasibility of EVT therapy in ischemic stroke patients under anticoagulation.


Asunto(s)
Anticoagulantes , Procedimientos Endovasculares , Trombectomía , Vitamina K , Humanos , Vitamina K/antagonistas & inhibidores , Trombectomía/métodos , Trombectomía/efectos adversos , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Procedimientos Endovasculares/métodos , Procedimientos Endovasculares/efectos adversos , Accidente Cerebrovascular Isquémico/cirugía , Estudios Retrospectivos
2.
CNS Neurosci Ther ; 30(7): e14747, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38973085

RESUMEN

AIM: To explore the regulatory mechanisms of microglia-mediated cytotoxic CD8+ T-cell infiltration in the white matter injury of perioperative stroke (PIS). METHODS: Adult male C57BL/6 mice were subjected to ileocolic bowel resection (ICR) 24 h prior to permanent distant middle cerebral artery occlusion (dMCAO) to establish model PIS. White matter injury, functional outcomes, peripheral immune cell infiltration, and microglia phenotype were assessed up to 28 days after dMCAO using behavioral phenotyping, immunofluorescence staining, transmission electron microscopy, western blot, and FACS analysis. RESULTS: We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8+ T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8+ T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor-interacting protein kinase 1 (RIPK1) activity could alleviate CD8+ T-cell infiltration and demyelination in PIS mice. CONCLUSION: Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8+ T cells and microglia necroptosis, suggesting that modulating interactions of CD8+ T cells and microglia could be a novel therapeutic target of long-term neurological deficits of PIS.


Asunto(s)
Linfocitos T CD8-positivos , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Sustancia Blanca , Animales , Masculino , Ratones , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/inmunología , Sustancia Blanca/patología , Sustancia Blanca/inmunología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/inmunología , Microglía/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Activación de Linfocitos , Modelos Animales de Enfermedad
3.
Int J Surg ; 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833358

RESUMEN

BACKGROUND: Liver transplantation (LT) is the most efficient treatment for pediatric patients with end-stage liver diseases, while bacterial infection is the leading reason for posttransplant mortality. The present study is to explore the outcomes and risk factors of early bacterial infection (within 1 mo) after pediatric LT. METHODS: In this prospective cohort study, 1316 pediatric recipients (median [IQR] age: 9.1 [6.3-28.0] months; male: 48.0%; median [IQR] follow-up time: 40.6 [29.1-51.4] months) who received LT from September 2018 to April 2022 were included. Bacterial culture samples such as sputum, abdominal drainage, blood and so on were collected when recipients were presented with infective symptoms. Kaplan-Meier analysis was applied to estimate the long-term survival rates and logistic regression was used to identify independent risk factors. To explore the role of pretransplant rectal swab culture (RSC) in reducing posttransplant bacterial infection rate, 188 infant LT recipients (median [IQR] age: 6.8 [5.5-8.1] months; male: 50.5%) from May 2022 to September 2023 were included. Log-binomial regression was used to measure the association of pretransplant RSC screening and posttransplant bacterial infection. The "Expectation Maximization" algorithm was used to impute the missing data. RESULTS: Bacterial infection was the primary cause for early (38.9%) and overall mortality (35.6%) after pediatric LT. Kaplan-Meier analysis revealed inferior 1- and 5-year survival rates for recipients with posttransplant bacterial infection (92.6% vs. 97.1%, 91.8% vs. 96.4% respectively; P<0.001). Among all detected bacteria, Staphylococcus spp. (34.3%) and methicillin-resistant coagulase-negative Staphylococci (43.2%) were the dominant species and multi-drug resistant organisms, respectively. Multivariable analysis revealed that infant recipients (adjusted odds ratio [aOR], 1.49; 95% CI, 1.01-2.20), male recipients (aOR, 1.43; 95% CI, 1.08-1.89), high graft-to-recipient weight ratio (aOR, 1.64; 95% CI, 1.17-2.30), positive posttransplant RSC (aOR, 1.45; 95% CI, 1.04-2.02) and nasopharyngeal swab culture (aOR 2.46; 95% CI, 1.72-3.52) were independent risk factors for early bacterial infection. Furthermore, RSC screening and antibiotic prophylaxis before transplantation could result in a relatively lower posttransplant infection rate, albeit without statistical significance (adjusted RR, 0.53; 95% CI, 0.25-1.16). CONCLUSION: In this cohort study, posttransplant bacterial infection resulted in an inferior long-term patient survival rate. The five identified independent risk factors for posttransplant bacterial infection could guide the prophylaxis strategy of posttransplant bacterial infection in the future. Additionally, pretransplant RSC might decrease posttransplant bacterial infection rate.

4.
Ecotoxicol Environ Saf ; 281: 116638, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38944013

RESUMEN

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40-69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5-10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles. Three CSVD markers were used: white matter hyper-intensity (WMH), mean diffusivity (MD), and fractional anisotropy (FA). The first principal components of the MD and FA measures in the 48 white matter tracts were analysed. The sample consisted of 44,470 participants from the UK Biobank. The median (T1-T3) concentrations of pollutants were as follows: NO2, 25.5 (22.4-28.7) µg/m3; NOx, 41.3 (36.2-46.7) µg/m3; PM10, 15.9 (15.4-16.4) µg/m3; PM2.5, 9.9 (9.5-10.3) µg/m3; PM2.5 absorbance, 1.1 (1.0-1.2) per metre; and PM2.5-10, 6.1 (5.9-6.3) µg/m3. Compared with the low group, the high group's APEX, NOX, and PM2.5 levels were associated with increased WMH volumes, and the estimates (95 %CI) were 0.024 (0.003, 0.044), 0.030 (0.010, 0.050), and 0.032 (0.011, 0.053), respectively, after adjusting for potential confounders. APEX, PM10, PM2.5 absorbance, and PM2.5-10 exposure in the high group were associated with increased FA values compared to that in the low group. Sex-specific analyses revealed associations only in females. Regarding the combined associations of air pollutant exposure and PRS-defined genetic susceptibility with CSVD markers, the associations of NO2, NOX, PM2.5, and PM2.5-10 with WMH were more profound in females with low PRS-defined genetic susceptibility, and the associations of PM10, PM2.5, and PM2.5 absorbance with FA were more profound in females with higher PRS-defined genetic susceptibility. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Enfermedades de los Pequeños Vasos Cerebrales , Exposición a Riesgos Ambientales , Predisposición Genética a la Enfermedad , Material Particulado , Humanos , Persona de Mediana Edad , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/inducido químicamente , Femenino , Masculino , Contaminantes Atmosféricos/toxicidad , Anciano , Estudios Transversales , Adulto , Contaminación del Aire/efectos adversos , Contaminación del Aire/estadística & datos numéricos , Reino Unido , Biomarcadores
5.
Cancer Lett ; 592: 216934, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38710299

RESUMEN

The Staphylococcal nuclease and Tudor domain containing 1 (SND1) has been identified as an oncoprotein. Our previous study demonstrated that SND1 impedes the major histocompatibility complex class I (MHC-I) assembly by hijacking the nascent heavy chain of MHC-I to endoplasmic reticulum-associated degradation. Herein, we aimed to identify inhibitors to block SND1-MHC-I binding, to facilitate the MHC-I presentation and tumor immunotherapy. Our findings validated the importance of the K490-containing sites in SND1-MHC-I complex. Through structure-based virtual screening and docking analysis, (-)-Epigallocatechin (EGC) exhibited the highest docking score to prevent the binding of MHC-I to SND1 by altering the spatial conformation of SND1. Additionally, EGC treatment resulted in increased expression levels of membrane-presented MHC-I in tumor cells. The C57BL/6J murine orthotopic melanoma model validated that EGC increases infiltration and activity of CD8+ T cells in both the tumor and spleen. Furthermore, the combination of EGC with programmed death-1 (PD-1) antibody demonstrated a superior antitumor effect. In summary, we identified EGC as a novel inhibitor of SND1-MHC-I interaction, prompting MHC-I presentation to improve CD8+ T cell response within the tumor microenvironment. This discovery presents a promising immunotherapeutic candidate for tumors.


Asunto(s)
Presentación de Antígeno , Linfocitos T CD8-positivos , Catequina , Endonucleasas , Ratones Endogámicos C57BL , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Humanos , Presentación de Antígeno/inmunología , Endonucleasas/metabolismo , Catequina/análogos & derivados , Catequina/farmacología , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Simulación del Acoplamiento Molecular , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/metabolismo , Melanoma Experimental/terapia , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo
6.
ACS Appl Mater Interfaces ; 16(15): 19699-19710, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38588069

RESUMEN

Self-assembly of peptides on layered nanomaterials such as graphite and MoS2 in the formation of long-range ordered two-dimensional nanocrystal patterns leading to its potential applications for biosensing and bioelectronics has attracted significant interest in nanoscience and nanotechnology. However, controlling the self-assembly of peptides on nanomaterials is still challenging due to the unclear role of nanomaterials in steering self-assembly. Here, we used the in-situ AFM technique to capture different changes of peptide coverage as well as lengthening and widening rates depending on peptide concentrations, show the distinct boundary dynamics of two stabilized peptide domains, and resolve the molecular resolution structural differences and specific orientation of peptide on both nanomaterials. Moreover, ex-situ results showed that the nanomaterial layers tuned the opposite changes of nanowire heights and densities and displayed the different water-resistance stabilities on both nanomaterials. This work provides a basis for understanding nanomaterials steering peptide self-assembly and using hybrid bionanomaterials as a scaffold, enabling for potential biosensing and bioelectronics applications.

8.
PLoS One ; 19(4): e0302026, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38683853

RESUMEN

The current robot path planning methods only use global or local methods, which is difficult to meet the real-time and integrity requirements, and can not avoid dynamic obstacles. Based on this, this study will use the improved A-star global planning algorithm to design a hybrid robot obstacle avoidance path planning algorithm that integrates sliding window local planning methods to solve related problems. Specifically, A-star is optimized by evaluation function, sub node selection mode and path smoothness, and fuzzy control is introduced to optimize the sliding window algorithm. The study conducted algorithm validation on the TurtleBot3 mobile robot, with data sourced from experimental data from a certain college. The results showed that hybrid algorithm enabled the planned path to effectively navigate around dynamic obstacles and reach the target point accurately. When compared with traditional methods, path length reduced by 9.6%, path planning time decreased by 29% with an approximate 26.7% increase in the average speed of the robot. Compared with the traditional methods, the research algorithm has greatly improved in avoiding dynamic obstacles, path planning efficiency, model adaptability and so on, which has important value for relevant research. It can be seen that the algorithm proposed in the study has performance advantages, demonstrating the effectiveness and advantages of robot path planning, and can provide reference for robot obstacle avoidance optimization. Research can complete tasks for robots in practical environments, which has certain reference value for the research of robots in path planning and the development of path obstacle avoidance planning.


Asunto(s)
Algoritmos , Robótica , Robótica/métodos , Lógica Difusa , Modelos Teóricos
9.
J Cereb Blood Flow Metab ; 44(7): 1246-1249, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38629577

RESUMEN

Cell therapy and regenerative medicine have made remarkable progress in treating neurodegenerative disorders. Induced pluripotent stem cells (iPSCs) offer a promising source for cell replacement therapies, but their practical application faces challenges due to poor survival and integration after transplantation. Park et al. propose a novel therapeutic strategy involving the co-transplantation of regulatory T cells (Tregs) and iPSC-derived dopamine neurons. This combined approach enhances the survival of transplanted cells and protects against neuroinflammation-induced damage. In PD animal models, the co-transplantation approach significantly suppressed the host immune response, resulting in improved behavioral recovery. Additionally, Tregs demonstrate acute neuroprotection and contribute to delayed neuro-restoration in ischemic stroke. This combined approach of cell therapy with immunomodulation offers a promising avenue for advancing our understanding of neurological diseases and promoting the development of novel treatments.


Asunto(s)
Encefalopatías , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Humanos , Animales , Encefalopatías/terapia , Encefalopatías/inmunología , Células Madre Pluripotentes Inducidas/trasplante , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Trasplante Autólogo/métodos
10.
Curr Med Chem ; 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38584558

RESUMEN

BACKGROUND: Pathogenic viruses that cause large-scale global or regional outbreaks almost always contain class I fusion proteins. Although the viruses differ in morphology, they all require fusion protein-mediated virus-host cell membranes during the early stages of host cell invasion. METHOD: The CHR region and NHR region of fusion proteins can form the 6-HB structure to drive the fusion pore formation between viruses and host cells through metastable interactions. Here, we obtained bifunctional N-peptides with inhibitory activities against two viruses, HIV-1 and MERS-CoV, based on the sequences in the HIV-1 NHR region by constructing N-trimer conformation interacting with the CHR region. RESULT: This study demonstrates that N-peptides with the coiled triple helix structure obtained from the NHR region in 6-HB are able to target the CHR region and exhibit inhibitory activity against a variety of viruses. CONCLUSION: Moreover, this strategy can be used to investigate antivirals against unknown viruses for future outbreaks.

11.
J Food Drug Anal ; 32(1): 103-111, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38526588

RESUMEN

Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague-Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC0-t and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.


Asunto(s)
Compuestos Alílicos , Compuestos de Bifenilo , Interacciones de Hierba-Droga , Lignanos , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Fenoles , Ratas , Animales , Ratas Sprague-Dawley , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Metotrexato/farmacología , Proteínas de Neoplasias
12.
CNS Neurosci Ther ; 30(3): e14619, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38532275

RESUMEN

BACKGROUND: Patients with malignancies have an increased risk of suffering ischemic stroke via several mechanisms such as coagulation dysfunction and other malignancy-related effects as well as iatrogenic causes. Moreover, stroke can be the first sign of an occult malignancy, termed as malignancy-associated ischemic stroke (MAS). Therefore, timely diagnostic assessment and targeted management of this complex clinical situation are critical. FINDINGS: Patients with both stroke and malignancy have atypical ages, risk factors, and often exhibit malignancy-related symptoms and multiple lesions on neuroimaging. New biomarkers such as eicosapentaenoic acid and blood mRNA profiles may help in distinguishing MAS from other strokes. In terms of treatment, malignancy should not be considered a contraindication, given comparable rates of recanalization and complications between stroke patients with or without malignancies. CONCLUSION: In this review, we summarize the latest developments in diagnosing and managing MAS, especially stroke with occult malignancies, and provide new recommendations from recently emerged clinical evidence for diagnostic and therapeutic workup strategies.


Asunto(s)
Accidente Cerebrovascular Isquémico , Neoplasias , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Neoplasias/complicaciones , Accidente Cerebrovascular/complicaciones , Factores de Riesgo , Neuroimagen
13.
Gen Psychiatr ; 37(1): e101317, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38313394

RESUMEN

Background: In early adolescence, youth are highly prone to suicidal behaviours. Identifying modifiable risk factors during this critical phase is a priority to inform effective suicide prevention strategies. Aims: To explore the risk and protective factors of suicidal behaviours (ie, suicidal ideation, plans and attempts) in early adolescence in China using a social-ecological perspective. Methods: Using data from the cross-sectional project 'Healthy and Risky Behaviours Among Middle School Students in Anhui Province, China', stratified random cluster sampling was used to select 5724 middle school students who had completed self-report questionnaires in November 2020. Network analysis was employed to examine the correlates of suicidal ideation, plans and attempts at four levels, namely individual (sex, academic performance, serious physical illness/disability, history of self-harm, depression, impulsivity, sleep problems, resilience), family (family economic status, relationship with mother, relationship with father, family violence, childhood abuse, parental mental illness), school (relationship with teachers, relationship with classmates, school-bullying victimisation and perpetration) and social (social support, satisfaction with society). Results: In total, 37.9%, 19.0% and 5.5% of the students reported suicidal ideation, plans and attempts in the past 6 months, respectively. The estimated network revealed that suicidal ideation, plans and attempts were collectively associated with a history of self-harm, sleep problems, childhood abuse, school bullying and victimisation. Centrality analysis indicated that the most influential nodes in the network were history of self-harm and childhood abuse. Notably, the network also showed unique correlates of suicidal ideation (sex, weight=0.60; impulsivity, weight=0.24; family violence, weight=0.17; relationship with teachers, weight=-0.03; school-bullying perpetration, weight=0.22), suicidal plans (social support, weight=-0.15) and suicidal attempts (relationship with mother, weight=-0.10; parental mental illness, weight=0.61). Conclusions: This study identified the correlates of suicidal ideation, plans and attempts, and provided practical implications for suicide prevention for young adolescents in China. Firstly, this study highlighted the importance of joint interventions across multiple departments. Secondly, the common risk factors of suicidal ideation, plans and attempts were elucidated. Thirdly, this study proposed target interventions to address the unique influencing factors of suicidal ideation, plans and attempts.

14.
Int J Neuropsychopharmacol ; 27(3)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38408281

RESUMEN

BACKGROUND: The efficacy of pharmacological and nutritional interventions in individuals at clinical high risk for psychosis (CHR-P) remains elusive. This study aims to investigate the efficacy of pharmacological and nutritional interventions in CHR-P and whether these interventions can enhance the efficacy of psychological treatments. METHODS: We systematically reviewed data from 5 databases until July 24, 2021: PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, and WanFang Data. The primary outcome was the transition to psychosis. Network meta-analyses were conducted at 3 time points (6, 12, and ≥24 months) considering both pharmacological/nutritional interventions alone and its combination with psychotherapy. RESULTS: Out of 11 417 identified references, 21 studies were included, comprising 1983 participants. CHR-P participants receiving omega-3 polyunsaturated fatty acids treatment were associated with a lower probability of transition compared with placebo/control at 6 months (odds ratio [OR] = 0.07, 95% confidence interval [CI] = .01 to .054), 12 months (OR = 0.14, 95% CI = .03 to .66), and ≥24 months (OR = 0.16, 95% CI = .05 to .54). Moreover, risperidone plus psychotherapy was associated with a lower likelihood of transition at 6 months compared with placebo/control plus psychotherapy, but this result was not sustained over longer durations. CONCLUSION: Omega-3 polyunsaturated fatty acids helped in preventing transitions to psychosis compared with controls. PROSPERO REGISTRATION NUMBER: CRD42021256209.


Asunto(s)
Ácidos Grasos Omega-3 , Trastornos Psicóticos , Humanos , Metaanálisis en Red , Trastornos Psicóticos/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Risperidona , Oportunidad Relativa
15.
ACS Nano ; 18(4): 3260-3275, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38227975

RESUMEN

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Microglía/patología , Microglía/fisiología , Barrera Hematoencefálica/patología , Isquemia Encefálica/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología
16.
Sci Rep ; 13(1): 20791, 2023 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-38012244

RESUMEN

Bladder cancer is the most common malignant tumor of urinary system, and its morbidity and mortality are increasing rapidly. Although great advances have been made in medical technology in recent years, there is still a lack of effective prognostic and therapeutic methods for bladder cancer. NETs are reticulated DNA structures decorated with various protein substances released extracellularly by neutrophils stimulated by strong signals. Recently, it has been found that NETs are closely related to the growth, metastasis and drug resistance of many types of cancers. However, up to now, the research on the relationship between NETs and bladder cancer is still not enough. In this study, we aimed to conduct a comprehensive analysis of NRGs in bladder cancer tissues to evaluate the relationship between NRGs and prognosis prediction and sensitivity to therapy in patients with bladder cancer. We scored NRGs in each tissue by using ssGSEA, and selected gene sets that were significantly associated with NRGs scores by using the WCGNA algorithm. Based on the expression profiles of NRGs-related genes, NMF clustering analysis was performed to identify different BLCA molecular subtypes. For the differentially expressed genes between subtypes, we used univariate COX regression, LASSO regression and multivariate COX regression to further construct a hierarchical model of BLCA patients containing 10 genes. This model and the nomogram based on this model can accurately predict the prognosis of BLCA patients in multiple datasets. Besides, BLCA patients classified based on this model differ greatly in their sensitivity to immunotherapy and targeted therapies, which providing a reference for individualized treatment of patients with bladder cancer.


Asunto(s)
Trampas Extracelulares , Neoplasias de la Vejiga Urinaria , Humanos , Inmunoterapia , Pronóstico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Nomogramas , Proteínas Tirosina Quinasas Receptoras
17.
Xenobiotica ; 53(5): 454-464, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37728540

RESUMEN

1. Two curcumin analogs, (1E,6E)-1,7-bis(3,5-diethyl-4-hydroxyphenyl)hepta-1,6-diene-3,5- dione (N17) and its prodrug ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2,6-diethyl-4,1- phenylene)bis(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate) (N17'), were evaluated as breast cancer resistance protein (BCRP) inhibitors.2. MDCKII-BCRP and MDCKII-WT were used to evaluate the modulation effects of N17 and N17' on BCRP and to explore the relevant mechanism. Sprague-Dawley rats were orally administered rosuvastatin (ROS), a probe substrate of BCRP, without and with N17' (100 mg/kg) to investigate the effect of N17' on ROS pharmacokinetics.3. In cell studies, N17 and N17' were substrates of BCRP, and they decreased the activity and protein expression of BCRP. In rat study, N17' increased the systemic exposure of ROS by 218% (p = 0.058).4. N17 and N17' are potential BCRP inhibitors and will be promising candidates for overcoming the BCRP-mediated multidrug resistance.

18.
Angew Chem Int Ed Engl ; 62(38): e202309613, 2023 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-37555781

RESUMEN

In situ polymerization of liquid electrolytes is currently the most feasible way for constructing solid-state batteries, which, however, is affected by various interfering factors of reactions and so the electrochemical performance of cells. To disclose the effects from polymerization conditions, two types of generally used in situ polymerizing reactions of ring-opening polymerization (ROP) and double bond radical polymerization (DBRP) were investigated on the aspects of monomer conversion and electrochemical properties (Li+ -conductivity and interfacial stability). The ROP generated poly-ester and poly-carbonate show a high monomer conversion of ≈90 %, but suffer a poor Li+ -conductivity of lower than 2×10-5  S cm-1 at room temperature (RT). Additionally, the terminal alkoxy anion derived from the ROP is not resistant to high-voltage cathodes. While, the DBRP produced poly-VEC(vinyl ethylene carbonate) and poly-VC(vinylene carbonate) show lower monomer conversions of 50-80 %, delivering relatively higher Li+ -conductivities of 2×10-4  S cm-1 at RT. Compared two polymerizing reactions and four monomers, the VEC-based F-containing copolymer possesses advantages in Li+ -conductivity and antioxidant capacity, which also shows simultaneous stability towards Li-metal with the help of LiF-based passivating layer, allowing a long-term stable cycling of high-voltage quasi solid-state cells.

19.
J Cereb Blood Flow Metab ; 43(2_suppl): 4-7, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37589500

RESUMEN

Cerebrovascular dysfunction and diseases are major causes of mortality, morbidity, and poor quality of patient life. Despite the enormous socioeconomic burden imposed by these conditions, therapeutic options remain scarce. However, rigorous preclinical and clinical research has augmented our mechanistic understanding of cerebrovascular diseases and underlying pathophysiological processes, and there is some optimism that novel therapeutic strategies may be developed in the next decade. This special collection comprises preclinical and clinical studies from investigators who presented their work at the Brain & BrainPET 2022 conference. It highlights recent research on cerebrovascular disease mechanisms, diagnosis, and treatments. A focus is set on cerebroprotective strategies during acute and chronic cerebral ischemia and predicting stroke risk and unfavorable outcomes. The special collection also sheds light on emerging novel treatment targets and management strategies in the pursuit of better clinical outcomes for patients with cerebrovascular diseases.


Asunto(s)
Isquemia Encefálica , Trastornos Cerebrovasculares , Accidente Cerebrovascular , Humanos , Encéfalo/metabolismo , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/metabolismo , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/metabolismo
20.
Patterns (N Y) ; 4(4): 100709, 2023 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-37123440

RESUMEN

It is critical to accurately predict the rupture risk of an intracranial aneurysm (IA) for timely and appropriate treatment because the fatality rate after rupture is 50 % . Existing methods relying on morphological features (e.g., height-width ratio) measured manually by neuroradiologists are labor intensive and have limited use for risk assessment. Therefore, we propose an end-to-end deep-learning method, called TransIAR net, to automatically learn the morphological features from 3D computed tomography angiography (CTA) data and accurately predict the status of IA rupture. We devise a multiscale 3D convolutional neural network (CNN) to extract the structural patterns of the IA and its neighborhood with a dual branch of shared network structures. Moreover, we learn the spatial dependence within the IA neighborhood with a transformer encoder. Our experiments demonstrated that the features learned by TransIAR are more effective and robust than handcrafted features, resulting in a 10 % - 15 % improvement in the accuracy of rupture status prediction.

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