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ABSTRACT: Although it is caused by a single-nucleotide mutation in the ß-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization, we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)-cleaving protease ADAMTS13 alleviated vaso-occlusive episode in mice with SCA. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in mice with SCA. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.
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Anemia de Células Falciformes , Enfermedades Vasculares , Ratones , Animales , Factor de von Willebrand/genética , Hibridación Fluorescente in Situ , Anemia de Células Falciformes/patología , Macrófagos/patología , Proteína ADAMTS13/genéticaRESUMEN
The liquid-like feature of thermoelectric superionic conductors is a double-edged sword: the long-range migration of ions hinders the phonon transport, but their directional segregation greatly impairs the service stability. We report the synergetic enhancement in figure of merit (ZT) and stability in Cu1.99Se-based superionic conductors enabled by ion confinement effects. Guided by density functional theory and nudged elastic band simulations, we elevated the activation energy to restrict ion migrations through a cation-anion co-doping strategy. We reduced the carrier concentration without sacrificing the low thermal conductivity, obtaining a ZT of â¼3.0 at 1,050 K. Notably, the fabricated device module maintained a high conversion efficiency of up to â¼13.4% for a temperature difference of 518 K without obvious degradation after 120 cycles. Our work could be generalized to develop electrically and thermally robust functional materials with ionic migration characteristics.
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Single-cell studies have delineated cellular diversity and uncovered increasing numbers of previously uncharacterized cell types in complex tissues. Thus, synthesizing growing knowledge of cellular characteristics is critical for dissecting cellular heterogeneity, developmental processes and tumorigenesis at single-cell resolution. Here, we present Cell Taxonomy (https://ngdc.cncb.ac.cn/celltaxonomy), a comprehensive and curated repository of cell types and associated cell markers encompassing a wide range of species, tissues and conditions. Combined with literature curation and data integration, the current version of Cell Taxonomy establishes a well-structured taxonomy for 3,143 cell types and houses a comprehensive collection of 26,613 associated cell markers in 257 conditions and 387 tissues across 34 species. Based on 4,299 publications and single-cell transcriptomic profiles of â¼3.5 million cells, Cell Taxonomy features multifaceted characterization for cell types and cell markers, involving quality assessment of cell markers and cell clusters, cross-species comparison, cell composition of tissues and cellular similarity based on markers. Taken together, Cell Taxonomy represents a fundamentally useful reference to systematically and accurately characterize cell types and thus lays an important foundation for deeply understanding and exploring cellular biology in diverse species.
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Effective bimetallic nanoelectrocatalysis demands precise control of composition, structure, and understanding catalytic mechanisms. To address these challenges, we employ a two-in-one approach, integrating online synthesis with real-time imaging of bimetallic Au@Metal core-shell nanoparticles (Au@M NPs) via electrochemiluminescence microscopy (ECLM). Within 120 s, online electrodeposition and in situ catalytic activity screening alternate. ECLM captures transient faradaic processes during potential switches, visualizes electrochemical processes in real-time, and tracks catalytic activity dynamics at the single-particle level. Analysis using ECL photon flux density eliminates size effects and yields quantitative electrocatalytic activity results. Notably, a nonlinear activity trend corresponding to the shell metal to Au surface atomic ratio is discerned, quantifying the optimal surface component ratio of Au@M NPs. This approach offers a comprehensive understanding of catalytic behavior during the deposition process with high spatiotemporal resolution, which is crucial for tailoring efficient bimetallic nanocatalysts for diverse applications.
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Spin-crossover (SCO) materials exhibit remarkable potential as bistable switches in molecular devices. However, the spin transition temperatures (Tc) of known compounds are unable to cover the entire ambient temperature spectrum, largely limiting their practical utility. This study reports an exemplary two-dimensional SCO solid solution system, [FeIII(H0.5LCl)2-2x(H0.5LF)2x]·H2O (H0.5LX = 5-X-2-hydroxybenzylidene-hydrazinecarbothioamide, X = F or Cl, x = 0 to 1), in which the adjacent layers are adhered via hydrogen bonding. Notably, the Tc of this system can be fine-tuned across 90 K (227-316 K) in a linear manner by modulating the fraction x of the LF ligand. Elevating x results in strengthened hydrogen bonding between adjacent layers, which leads to enhanced intermolecular interactions between adjacent SCO molecules. Single-crystal diffraction analysis and periodic density functional theory calculations revealed that such a special kind of alteration in interlayer interactions strengthens the FeIIIN2O2S2 ligand field and corresponding SCO energy barrier, consequently resulting in increased Tc. This work provides a new pathway for tuning the Tc of SCO materials through delicate manipulation of molecular interactions, which could expand the application of bistable molecular solids to a much wider temperature regime.
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Copper is a trace element required by the organism, but once the level of copper exceeds the threshold, it becomes toxic and even causes death. The underlying mechanisms of copper-induced death are inconclusive, with different studies showing different opinions on the mechanism of copper-induced death. Multiple investigations have shown that copper induces oxidative stress, endoplasmic reticulum stress, nucleolar stress, and proteasome inhibition, all of which can result in cell death. The latest research elucidates a copper-dependent death and denominates it as cuproptosis. Cuproptosis takes place through the combination of copper and lipoylated proteins of the tricarboxylic acid cycle, triggering agglomeration of lipoylated proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress and ultimately death. Given the toxicity and necessity of copper, abnormal levels of copper lead to diseases such as neurological diseases and cancer. The development of cancer has a high demand for copper, neurological diseases involve the change of copper contents and the binding of copper to proteins. There is a close relationship between these two kinds of diseases and copper. Here, we summarize the mechanisms of copper-related death, and the association between copper and diseases, to better figure out the influence of copper in cell death and diseases, thus advancing the clinical remedy of these diseases.
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Cobre , Neoplasias , Humanos , Cobre/metabolismo , Animales , Neoplasias/metabolismo , Neoplasias/patología , Estrés Oxidativo , Estrés del Retículo Endoplásmico , Muerte Celular , Apoptosis , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patologíaRESUMEN
While three-dimensional (3D) DNA walking amplifiers hold considerable promise in the construction of advanced DNA-based fluorescent biosensors for bioimaging, they encounter certain difficulties such as inadequate sensitivity, premature activation, the need for exogenous propelling forces, and low reaction rates. In this contribution, a variety of profitable solutions have been explored. First, a catalytic hairpin assembly (CHA)-achieved nonenzymatic isothermal nucleic acid amplification is integrated to enhance sensitivity. Subsequently, one DNA component is simply functionalized with a photocleavage-bond to conduct a photoresponsive manner, whereby the target recognition occurs only when the biosensor is exposed to an external ultraviolet light source, overcoming premature activation during biodelivery. Furthermore, a special self-propelling walking mechanism is implemented by reducing biothiols to MnO2 nanosheets, thereby propelling forces that are self-supplied to a Mn2+-reliant DNAzyme. By carrying the biosensing system with a DNA molecular framework to induce a unique concentration localization effect, the nucleic acid contact reaction rate is notably elevated by 6 times. Following these, an ultrasensitive in vitro detection performance with a limit of detection down to 2.89 fM is verified for a cancer-correlated microRNA biomarker (miRNA-21). Of particular importance, our multiple concepts combined 3D DNA walking amplifier that enables highly efficient fluorescence bioimaging in live cells and even bodies, exhibiting a favorable application prospect in disease analysis.
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Técnicas Biosensibles , ADN Catalítico , MicroARNs , ADN Catalítico/química , Compuestos de Manganeso , Óxidos , ADN/química , MicroARNs/análisis , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
BACKGROUND: Patients with diabetes have an increased risk of developing heart failure with preserved ejection fraction (HFpEF). This study aimed to compare indices of myocardial deformation and perfusion between patients with type 2 diabetes mellitus (T2DM) with and without HFpEF and to investigate the relationship between myocardial strain and perfusion reserve. METHODS: This study included 156 patients with T2DM without obstructive coronary artery disease (CAD) and 50 healthy volunteers who underwent cardiac magnetic resonance (CMR) examination at our center. Patients with T2DM were subdivided into the T2DM-HFpEF (n = 74) and the T2DM-non-HFpEF (n = 82) groups. The parameters of left ventricular (LV) and left atrial (LA) strain as well as stress myocardial perfusion were compared. The correlation between myocardial deformation and perfusion parameters was also assessed. Mediation analyses were used to evaluate the direct and indirect effects of T2DM on LA strain. RESULTS: Patients with T2DM and HFpEF had reduced LV radial peak systolic strain rate (PSSR), LV circumferential peak diastolic strain rate (PDSR), LA reservoir strain, global myocardial perfusion reserve index (MPRI), and increased LA booster strain compared to patients with T2DM without HFpEF (all P < 0.05). Furthermore, LV longitudinal PSSR, LA reservoir, and LA conduit strain were notably impaired in patients with T2DM without HFpEF compared to controls (all P < 0.05), but LV torsion, LV radial PSSR, and LA booster strain compensated for these alterations (all P < 0.05). Multivariate linear regression analysis demonstrated that LA reservoir and LA booster strain were independently associated with global MPRI (ß = 0.259, P < 0.001; ß = - 0.326, P < 0.001, respectively). Further, the difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI. Global stress PI, LA booster, global rest PI, and global MPRI showed high accuracy in diagnosing HFpEF among patients with T2DM (areas under the curve [AUC]: 0.803, 0.790, 0.740, 0.740, respectively). CONCLUSIONS: Patients with T2DM and HFpEF exhibited significant LV systolic and diastolic deformation, decreased LA reservoir strain, severe impairment of myocardial perfusion, and elevated LA booster strain that is a compensatory response in HFpEF. Global MPRI was identified as an independent influencing factor on LA reservoir and LA booster strain. The difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI, suggesting a possible mechanistic link between microcirculation impairment and cardiac dysfunction in diabetes. Myocardial perfusion and LA strain may prove valuable for diagnosing and managing HFpEF in the future.
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Función del Atrio Izquierdo , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Imagen por Resonancia Cinemagnética , Imagen de Perfusión Miocárdica , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular Izquierda , Humanos , Masculino , Femenino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Imagen de Perfusión Miocárdica/métodos , Anciano , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/diagnóstico , Circulación Coronaria , Estudios de Casos y Controles , Contracción MiocárdicaRESUMEN
BACKGROUND: Remnant cholesterol (RC) is implicated in the risk of cardiovascular disease. However, comprehensive population-based studies elucidating its association with aortic valve calcium (AVC) progression are limited, rendering its precise role in AVC ambiguous. METHODS: From the Multi-Ethnic Study of Atherosclerosis database, we included 5597 individuals (61.8 ± 10.1 years and 47.5% men) without atherosclerotic cardiovascular disease at baseline for analysis. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as estimated by the Martin/Hopkins equation. Using the adjusted Cox regression analyses, we examined the relationships between RC levels and AVC progression. Furthermore, we conducted discordance analyses to evaluate the relative AVC risk in RC versus LDL-C discordant/concordant groups. RESULTS: During a median follow-up of 2.4 ± 0.9 years, 568 (10.1%) participants exhibited AVC progression. After adjusting for traditional cardiovascular risk factors, the HRs (95% CIs) for AVC progression comparing the second, third, and fourth quartiles of RC levels with the first quartile were 1.195 (0.925-1.545), 1.322 (1.028-1.701) and 1.546 (1.188-2.012), respectively. Notably, the discordant high RC/low LDL-C group demonstrated a significantly elevated risk of AVC progression compared to the concordant low RC/LDL-C group based on their medians (HR, 1.528 [95% CI 1.201-1.943]). This pattern persisted when clinical LDL-C threshold was set at 100 and 130 mg/dL. The association was consistently observed across various sensitivity analyses. CONCLUSIONS: In atherosclerotic cardiovascular disease-free individuals, elevated RC is identified as a residual risk for AVC progression, independent of traditional cardiovascular risk factors. The causal relationship of RC to AVC and the potential for targeted RC reduction in primary prevention require deeper exploration.
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Aterosclerosis , Enfermedades Cardiovasculares , Hipercolesterolemia , Masculino , Humanos , Femenino , Calcio , LDL-Colesterol , Válvula Aórtica/diagnóstico por imagen , Colesterol , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiologíaRESUMEN
This study aimed to assess the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computer tomography (18F-FDG PET/CT) in patients with relapsed multiple myeloma (MM). Fifty-one consecutive patients with relapsed MM were enrolled in this retrospective study. 18F-FDG parameters based on the Italian Myeloma Criteria for PET Use (IMPeTUs) and clinical data were analyzed for overall survival (OS) and progression-free survival (PFS). The Cox proportional risk model was used for univariate and multivariate analysis, and Kaplan-Meier survival curves were used for survival analysis. The median length of follow-up was 20 months (IQR, 5-29 months), the median PFS for the entire cohort was 8 months (IQR, 3-17 months) and the median OS was 21 months (IQR, 8-49 months). Multivariate survival analysis demonstrated that the Deauville score of BM > 3 [HR 2.900, 95% CI (1.011, 8.319), P = 0.048] and the presence of EMD [HR 3.134, 95% CI (1.245, 7.891), P = 0.015] were independent predictors of poor PFS. The presence of EMD [HR 12.777, 95% CI (1.825, 89.461), P = 0.010] and the reduced platelets count [HR 7.948, 95% CI (1.236, 51.099), P = 0.029] were adversely associated with OS. 18F-FDG PET/CT parameters based on IMPeTUs have prognostic significance in patients with relapsed MM.
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OBJECTIVES: To explore the added value of arterial enhancement fraction (AEF) derived from dual-energy computed tomography CT (DECT) to conventional image features for diagnosing cervical lymph node (LN) metastasis in papillary thyroid cancer (PTC). METHODS: A total of 273 cervical LNs (153 non-metastatic and 120 metastatic) were recruited from 92 patients with PTC. Qualitative image features of LNs were assessed. Both single-energy CT (SECT)-derived AEF (AEFS) and DECT-derived AEF (AEFD) were calculated. Correlation between AEFD and AEFS was determined using Pearson's correlation coefficient. Multivariate logistic regression analysis with the forward variable selection method was used to build three models (conventional features, conventional features + AEFS, and conventional features + AEFD). Diagnostic performances were evaluated using receiver operating characteristic (ROC) curve analyses. RESULTS: Abnormal enhancement, calcification, and cystic change were chosen to build model 1 and the model provided moderate diagnostic performance with an area under the ROC curve (AUC) of 0.675. Metastatic LNs demonstrated both significantly higher AEFD (1.14 vs 0.48; p < 0.001) and AEFS (1.08 vs 0.38; p < 0.001) than non-metastatic LNs. AEFD correlated well with AEFS (r = 0.802; p < 0.001), and exhibited comparable performance with AEFS (AUC, 0.867 vs 0.852; p = 0.628). Combining CT image features with AEFS (model 2) and AEFD (model 3) could significantly improve diagnostic performances (AUC, 0.865 vs 0.675; AUC, 0.883 vs 0.675; both p < 0.001). CONCLUSIONS: AEFD correlated well with AEFS, and exhibited comparable performance with AEFS. Integrating qualitative CT image features with both AEFS and AEFD could further improve the ability in diagnosing cervical LN metastasis in PTC. CLINICAL RELEVANCE STATEMENT: Arterial enhancement fraction (AEF) values, especially AEF derived from dual-energy computed tomography, can help to diagnose cervical lymph node metastasis in patients with papillary thyroid cancer, and complement conventional CT image features for improved clinical decision making. KEY POINTS: ⢠Metastatic cervical lymph nodes (LNs) demonstrated significantly higher arterial enhancement fraction (AEF) derived from dual-energy computed tomography (DECT) and single-energy CT (SECT)-derived AEF (AEFS) than non-metastatic LNs in patients with papillary thyroid cancer. ⢠DECT-derived AEF (AEFD) correlated significantly with AEFS, and exhibited comparable performance with AEFS. ⢠Integrating qualitative CT images features with both AEFS and AEFD could further improve the differential ability.
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Neoplasias de la Tiroides , Tomografía Computarizada por Rayos X , Humanos , Cáncer Papilar Tiroideo/patología , Metástasis Linfática/patología , Tomografía Computarizada por Rayos X/métodos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Neoplasias de la Tiroides/patología , Estudios RetrospectivosRESUMEN
AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etiología , Reino Unido/epidemiología , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Adulto , Factores de Riesgo , Índice de Masa Corporal , Fumar/efectos adversos , Fumar/epidemiología , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Ejercicio Físico , Estudios de Seguimiento , Presión Sanguínea , IncidenciaRESUMEN
BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.
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MicroARNs , ARN Largo no Codificante , Calcificación Vascular , Humanos , Ratas , Animales , MicroARNs/metabolismo , Aldosterona/toxicidad , ARN Largo no Codificante/metabolismo , Osteogénesis , Calcificación Vascular/inducido químicamente , Calcificación Vascular/genética , Calcificación Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismoRESUMEN
Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.
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Sistemas CRISPR-Cas , Edición Génica , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Edición Génica/métodos , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , AnimalesRESUMEN
BACKGROUND: Epilepsy is a very common neurological disease, and it is important to focus on both controlling seizures and alleviating the psychological problems associated with this disease.Anxiety is an important risk factor for epilepsy and seriously affects the quality of life of patients with epilepsy (PWE). However, several risk factors for anxiety in PWE are relatively controversial and understudied. This meta-analysis was performed to identify potential risk factors for anxiety in PWE with the aim of reducing the incidence of anxiety and improving the quality of life among the individuals. METHOD: The PubMed, Embase and Cochrane Library databases were systematically searched up to July 2023 to find eligible original English studies. All the search results were reviewed based on our inclusion and exclusion criteria. We calculated the combined odds ratios (ORs), standard mean differences (SMDs) and their corresponding 95% confidence intervals (CIs) to evaluate the effect of the included risk factors on anxiety in PWE. RESULTS: Twenty-four studies involving 5,403 PWE were ultimately included. The pooled results of our meta-analysis showed that female sex (OR = 1.67; 95 % CI: 1.30,2.15; p < 0.001), unmarried/divorced/widowed (OR = 0.83; 95 % CI: 0.72,0.96; p = 0.011), low socioeconomic status (OR = 0.47; 95 % CI: 0.33,0.67; p < 0.001), education levels below high school (OR = 1.74; 95 % CI: 1.36,2.23; p < 0.001), a history of trauma (OR = 2.53; 95 % CI: 1.69,3.78; p < 0.001), monotherapy (OR = 0.49; 95 % CI: 0.39,0.62; p < 0.001), AED-induced psychiatric side effects (OR = 2.45; 95 % CI: 1.20,4.98); p = 0.014), depression (OR = 5.45 95 % CI: 2.49,11.94; p < 0.001), a history of suicide (OR = 3.56; 95 % CI: 1.72,7.38; p = 0.001), and illness-related shame (OR = 2.76; 95 % CI: 2.17,3.52; p < 0.001) were risk factors for anxiety. CONCLUSION: This meta-analysis showed that female, unmarried, low socioeconomic status, education level below senior high school, a history of trauma, monotherapy, AED-induced psychiatric side effects, depression, a history of suicide, and shame were risk factors for anxiety in PWE. However, further research is needed to determine the effect of other potential risk factors on anxiety in PWE. In addition, most of the studies included in this meta-analysis were not uniform in scale, and the risk factors were not comprehensive; therefore, larger prospective studies in different countries are needed to further investigate these risk factors.
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Ansiedad , Epilepsia , Humanos , Epilepsia/psicología , Epilepsia/epidemiología , Epilepsia/complicaciones , Factores de Riesgo , Ansiedad/epidemiología , Ansiedad/etiología , Calidad de Vida/psicologíaRESUMEN
A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.
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BACKGROUND AND AIM: The present study aimed to investigate whether the mitochondrial KATP channel contributes to angiotensin II (Ang II)-induced vascular dysfunction, the development of hypertension, and atherosclerosis. METHODS AND RESULTS: ApoE (-/-) mice fed a high-fat diet were chronically infused with Ang II for eight weeks and concomitantly treated with losartan (ARB), apocynin, or 5-hydroxy decanoate (5-HD), or 3-methyladenine (3-MA). Systolic blood pressure was measured, and pathological changes of aortic or liver tissue were observed. Nitric oxide (NO), superoxide dismutase 2 (SOD2) levels and vasorelaxation rate were measured, and protein and mRNA expressions were examined by western blot and RT-PCR. Ang II-induced development of hypertension was suppressed not only by ARB, and apocynin but also by 5-HD or 3-MA. Ang II infusion decreased aortic NO production and relaxation, as well as SOD2 activity in liver, which were improved by all treatments. In addition, Ang II-induced activation of autophagy was suppressed by 5-HD in aortic tissue, furthermore, Ang II increases the atherosclerotic index in plasma and exacerbates the development of atherosclerosis by increases of fat deposition in the aorta and liver. Lipid metabolism-related mRNA expressions (LXR-α, LDLR, SRBI, Acca, and FASN) were changed by Ang II. Similarly, not only ARB, and apocynin, but also 5-HD and 3-MA suppressed Ang II-induced these changes. CONCLUSIONS: Our present findings evidence that mitochondrial KATP channel-mediated autophagy contributes to Ang II-induced vascular dysfunction, development of hypertension, and atherosclerosis.
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Angiotensina II , Aterosclerosis , Autofagia , Hipertensión , Óxido Nítrico , Superóxido Dismutasa , Animales , Autofagia/efectos de los fármacos , Masculino , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Hipertensión/fisiopatología , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/patología , Óxido Nítrico/metabolismo , Aterosclerosis/inducido químicamente , Aterosclerosis/patología , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/fisiopatología , Ratones Noqueados para ApoE , Ratones Endogámicos C57BL , Aorta/efectos de los fármacos , Aorta/patología , Aorta/metabolismo , Aorta/fisiopatología , Presión Sanguínea/efectos de los fármacos , Ratones , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Dieta Alta en Grasa , Canales de PotasioRESUMEN
BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.
Asunto(s)
Aneurisma de la Aorta , Disección Aórtica , Ácido Ascórbico , Factores Protectores , Vitamina E , Humanos , Masculino , Estudios Prospectivos , Persona de Mediana Edad , Femenino , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Vitamina E/administración & dosificación , Factores de Riesgo , Anciano , Incidencia , Disección Aórtica/epidemiología , Disección Aórtica/prevención & control , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/prevención & control , Medición de Riesgo , Reino Unido/epidemiología , Factores de Tiempo , Dieta/efectos adversos , AdultoRESUMEN
Sustainable production of pome fruit crops is dependent upon having virus-free planting materials. The production and distribution of plants derived from virus- and viroid-negative sources is necessary not only to control pome fruit viral diseases but also for sustainable breeding activities, as well as the safe movement of plant materials across borders. With variable success rates, different in vitro-based techniques, including shoot tip culture, micrografting, thermotherapy, chemotherapy, and shoot tip cryotherapy, have been employed to eliminate viruses from pome fruits. Higher pathogen eradication efficiencies have been achieved by combining two or more of these techniques. An accurate diagnosis that confirms complete viral elimination is crucial for developing effective management strategies. In recent years, considerable efforts have resulted in new reliable and efficient virus detection methods. This comprehensive review documents the development and recent advances in biotechnological methods that produce healthy pome fruit plants. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
Asunto(s)
Productos Agrícolas , Frutas , Enfermedades de las Plantas , Viroides , Enfermedades de las Plantas/virología , Enfermedades de las Plantas/prevención & control , Frutas/virología , Productos Agrícolas/virología , Viroides/genética , Viroides/fisiología , Virus de Plantas/fisiología , Biotecnología/métodos , Prunus domestica/virologíaRESUMEN
Severe tissue injuries pose a significant risk to human health. Conventional wound dressings fall short in achieving effective tissue regeneration, resulting in suboptimal postoperative healing outcomes. In this study, an asymmetric adhesive wound dressing (marked as SIS/PAA/LAP) was developed, originating from acrylate acid (AA) solution with laponite (LAP) nanoparticles polymerization and photo-crosslinked on the decellularized extracellular matrix small intestinal submucosa (SIS) patch. Extensive studies demonstrated that the SIS/PAA/LAP exhibited higher tissue adhesion strength (~ 33 kPa) and burst strength (~ 22 kPa) compared to conventional wound dressings like Tegaderm and tissue adhesive products. Importantly, it maintained favorable cell viability and demonstrated robust angiogenic capacity. In animal models of full-thickness skin injuries in rats and skin injuries in Bama miniature pigs, the SIS/PAA/LAP could be precisely applied to wound sites. By accelerating the formation of tissue vascularization, it displayed superior tissue repair outcomes. This asymmetrically adhesive SIS-based patch would hold promising applications in the field of wound dressings.