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BACKGROUND: Finerenone was approved for the treatment of type 2 diabetes patients with chronic kidney disease. However, the post-marketing safety of finerenone in the real world is unknown. METHODS: The quarterly reported data related to finerenone from the third quarter of 2021 to the second quarter of 2023 were collected by using the FAERS database. Two disproportionality analysis methods were estimated by using Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN). RESULTS: A total of 1067 adverse events (AEs) were included. Twenty-four kinds of system organ classes (SOCs) were classified for the organs and systems involved and 39 AEs with significant safety signals were identified using ROR and BCPNN at the preferred terms (PTs) level. Most AEs originated from the United States, and the median time to onset of AEs was 13 days. Three hundred and fifty-one (55.5%) reported serious outcome. The proportion of medication combinations was 29.0%. The most commonly reported AEs were the glomerular filtration rate decreased. Safety signals have also been observed in new and unexpected AEs. CONCLUSION: The analysis of the AE signals may contribute to minimizing the risks associated with its use.
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Heavy metal pollutants are important abiotic environmental factors affecting pest habitats. In this study, Cd pre-exposure significantly increased the tolerance of Lymantria dispar larvae to ß-cypermethrin, but did not significantly alter their tolerance to λ-cyhalothrin and bifenthrin. The activation of P450 by Cd exposure is the key mechanism that induces insecticide cross-tolerance in L. dispar larvae. Both before and after ß-cypermethrin treatment, Cd exposure significantly increased the expression of CYP6AB224 and CYP6AB226 in L. dispar larvae. Silencing CYP6AB224 and CYP6AB226 reduced the tolerance of Cd-treated L. dispar larvae to ß-cypermethrin. Transgenic CYP6AB224 and CYP6AB226 genes significantly increased the tolerance of Drosophila and Sf9 cells to ß-cypermethrin, and the recombinant proteins of both genes could significantly metabolise ß-cypermethrin. Cd exposure significantly increased the expression of CnCC and Maf. CnCC was found to be a key transcription factor regulating CYP6AB224- and CYP6AB226-activated insecticide cross-tolerance in Cd-treated larvae. Decreasing reactive oxygen species (ROS) levels in the Cd-treated larvae or increasing ROS levels in the untreated larvae reduced or enhanced the expression of CnCC, CYP6AB224 and CYP6AB226 and ß-cypermethrin tolerance in L. dispar larvae, respectively. Collectively, Cd exposure confers ß-cypermethrin tolerance in L. dispar larvae through the ROS/CnCC signalling pathway-mediated P450 detoxification.
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A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.
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Enfermedad de Alzheimer , Cromonas , Deferiprona , Quelantes del Hierro , Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Quelantes del Hierro/farmacología , Quelantes del Hierro/química , Quelantes del Hierro/síntesis química , Deferiprona/farmacología , Deferiprona/química , Monoaminooxidasa/metabolismo , Humanos , Cromonas/química , Cromonas/farmacología , Cromonas/síntesis química , Relación Estructura-Actividad , Animales , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Ferroptosis/efectos de los fármacos , Estructura Molecular , Simulación del Acoplamiento Molecular , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
Surface chemistry of carriers plays a key role in enzyme loading capacity, structure rigidity, and thus catalyze activity of immobilized enzymes. In this work, the two model enzymes of horseradish peroxidase (HRP) and glucose oxidase (GOx) are co-immobilized on the lysozyme functionalized magnetic core-shell nanocomposites (LYZ@MCSNCs) to enhance their stability and activity. Briefly, the HRP and GOx aggregates are firstly formed under the crosslinker of trimesic acid, in which the loading amount and the rigidity of the enzyme can be further increased. Additionally, LYZ easily forms a robust anti-biofouling nanofilm on the surface of SiO2@Fe3O4 magnetic nanoparticles with abundant functional groups, which facilitate chemical crosslinking of HRP and GOx aggregates with minimized inactivation. The immobilized enzyme of HRP-GOx@LYZ@MCSNCs exhibited excellent recovery activity (95.6 %) higher than that of the free enzyme (HRP&GOx). Specifically, 85 % of relative activity was retained after seven cycles, while 73.5 % of initial activity was also remained after storage for 33 days at 4 °C. The thermal stability and pH adaptability of HRP-GOx@LYZ@MCSNCs were better than those of free enzyme of HRP&GOx. This study provides a mild and ecofriendly strategy for multienzyme co-immobilization based on LYZ functionalized magnetic nanoparticles using HRP and GOx as model enzymes.
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Estabilidad de Enzimas , Enzimas Inmovilizadas , Nanopartículas de Magnetita , Reactivos de Enlaces Cruzados/química , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Peroxidasa de Rábano Silvestre/química , Peroxidasa de Rábano Silvestre/metabolismo , Concentración de Iones de Hidrógeno , Nanopartículas de Magnetita/química , Muramidasa/química , Muramidasa/metabolismo , Agregado de Proteínas , Dióxido de Silicio/química , TemperaturaRESUMEN
Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.
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A facile and mild method based on self-assembled lysozyme (LYZ) to fabricate bifunctional MNPs@UIO-66-Arg core-shell-satellite nanocomposites (CSSNCs) is reported for the high-efficiency enrichment of phosphopeptides. Under physiological conditions, LYZ rapidly self-assembled into a robust coating on Fe3O4@SiO2 magnetic nanoparticles (MNPs) with abundant surface functional groups, which effectively mediate heterogeneous nucleation and growth of UIO-66 nanocrystals. Well-defined MNPs@UIO-66 CSSNCs with stacked pores, showing high specific surface area (333.65 m2 g- 1) and low mass transfer resistance, were successfully fabricated by fine-tuning of the reaction conditions including reaction time and acetic acid content. Furthermore, the UIO-66 shells were further modified with arginine to obtain bifunctional MNPs@UIO-66-Arg CSSNCs. Thanks to the unique morphology and synergistic effect of Zr-O clusters and guanidine groups, the bifunctional MNPs@UIO-66-Arg CSSNCs exhibited outstanding enrichment performance for phosphopeptides, delivering a low limit of detection (0.1 fmol), high selectivity (ß-casein/BSA, mass ratio 1:2000), and good capture capacity (120 mg g- 1). The mechanism for phosphopeptides capture may attribute to the hydrogen bonds, electrostatic interactions, and Zr-O-P bonds between phosphate groups in peptides and guanidyl/Zr-O clusters on bifunctional MNPs@UIO-66-Arg CSSNCs. In addition, the small stacking pores on the core-shell-satellite architecture may selectively capture phosphopeptides with low molecular weight, eliminating interference of other large molecular proteins in complex biological samples.
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Estructuras Metalorgánicas , Nanocompuestos , Ácidos Ftálicos , Fosfopéptidos/química , Dióxido de Silicio , Estructuras Metalorgánicas/química , Nanocompuestos/químicaRESUMEN
In this study, titanium (IV)-immobilized magnetic nanoparticles (Ti4+-PTL-MNPs) were firstly synthesized via a one-step aqueous self-assembly of lysozyme nanofilms for efficient phosphopeptide enrichment. Under physiological conditions, lysozymes readily self-organized into phase-transitioned lysozyme (PTL) nanofilms on Fe3O4@SiO2 and Fe3O4@C MNP surfaces with abundant functional groups, including -NH2, -COOH, -OH, and -SH, which can be used as multiple linkers to efficiently chelate Ti4+. The obtained Ti4+-PTL-MNPs possessed high sensitivity of 0.01 fmol µL-1 and remarkable selectivity even at a mass ratio of ß-casein to BSA as low as 1:400 for phosphopeptide enrichment. Furthermore, the synthesized Ti4+-PTL-MNPs can also selectively identify low-abundance phosphopeptides from extremely complicated human serum samples and their rapid separation, good reproducibility, and excellent recovery were also proven. This one-step self-assembly of PTL nanofilms facilitated the facile and efficient surface functionalization of various nanoparticles for proteomes/peptidomes.
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Nanopartículas de Magnetita , Fosfopéptidos , Humanos , Titanio , Muramidasa , Dióxido de Silicio , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: A novel automated method for measuring left ventricular (LV) global longitudinal strain (GLS) along the endocardium has advantages in terms of its rapid application and excellent reproducibility. However, it remains unclear whether the available normal range for conventional GLS using the manual method is applicable to the automated GLS method. This study aimed to compare automated GLS head-to-head with manual layer-specific GLS, and to identify whether a specialized normal reference range for automated GLS is needed and explore the main determinants. METHODS: In total, 1683 healthy volunteers (men, 43%; age, 18-80 years) were prospectively enrolled from 55 collaborating laboratories. LV GLS was measured using both manual layer-specific and automated methods. RESULTS: Automated GLS was higher than endocardial, mid-myocardial, and epicardial GLS. Women had a higher automated GLS than men. GLS had no significant age dependency in men, but first increased and then decreased with age in women. Accordingly, sex- and age-specific normal ranges for automated GLS were proposed. Moreover, GLS appeared to have different burdens in relation to dominant determinants between the sexes. GLS in men showed no dominant determinants; however, GLS in women correlated with age, body mass index, and heart rate. CONCLUSIONS: Using the novel automated method, was LV GLS higher than when using the manual GLS method. The normal ranges of automated GLS stratified according to sex and age were provided, with dominant determinants showing sex disparities that require full consideration in clinical practice.
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Ecocardiografía , Tensión Longitudinal Global , Masculino , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Valores de Referencia , Ecocardiografía/métodos , Función Ventricular Izquierda/fisiología , Reproducibilidad de los ResultadosRESUMEN
Both acute cerebral infarction and malignant tumors are prevalent in the elderly. However, acute cerebral infarction is rarely present as the first clinical manifestation of malignant tumors. By searching the Picture Archiving and Communication System from 2010 to 2022 and the medical record database from 2003 to 2022, we found three cases of Trousseau syndrome, one male and two females with an average age of 69.3 ± 3.2 years, presenting with acute cerebral infarction. Two patients denied having hypertension, diabetes, and coronary heart disease. The average value of the D-dimer was 17.83 ± 12.39 mg/L (normal range, 0 to 0.55 mg/L). Magnetic resonance imaging (MRI) of the brain showed scattered and multiple small infarcts in the watershed area. The sites of infarction were not those that are typically caused by vascular atherosclerosis. One of the females was diagnosed with pancreatic cancer (T2N2M1, stage IV), the male was diagnosed with gastric cancer (T4N3M1, stage IV), and the other female was diagnosed with lung adenocarcinoma (rTxN3M1b, stage IV). The patient with pancreatic cancer underwent a comprehensive geriatric assessment, which revealed that she had a disability, dementia, malnutrition, short life expectancy, and high chemotherapy risk. Ultimately, the patient opted for conservative care, and 3 months after being discharged, she passed away from an acute upper gastrointestinal hemorrhage. Elderly patients with unexplained D-dimer elevation, multiple cerebral vascular lesions detected on MRI, and an absence of typical stroke risk factors need to be monitored for Trousseau syndrome. To screen for cancer, tumor markers and related imaging should be performed first. Trousseau syndrome is primarily treated with chemotherapy, radiotherapy and anticoagulant therapy. The risk of bleeding should be assessed carefully when using anticoagulant therapy in the elderly. Comprehensive geriatric assessment can assist in weighing the benefits and side effects of cancer treatment, making correct medical choices, and improving patients' quality of life.
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Two undescribed steroids, named (15 R)-2,15-dihydroxypregna-1,4-dien-3,16-dione (1) and 2,15-dihydroxypregna-1,4,14-trien-3,16-dione (2), were isolated from the aerial parts of Munronia pinnata (Wall.) W. Theob. The structure elucidation of two compounds was performed by using spectroscopic methods and comparing the literature. Compound 2 exhibited inhibitory effect against PTP-1B with an IC50 value of 152.07 ± 3.33 µM, and compound 1 was inactive.
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Fluopyram, a SDH inhibitor fungicide, is widely used in agriculture to control fungi and nematodes. However, fluopyram has been proved toxic that caused damage to organs through oxidative stress. The development of natural extracts that can reduce oxidative damage is a promising method. Lentinan is isolated from Lentinus edodes and has been verified its antioxidant activity. In this study, Caenorhabditis elegans was used to evaluate the protective effects of lentinan against fluopyram-induced toxicity and the possible mechanisms. Results showed that lentinan pretreatment notably increased the survival rate of N2 nematodes by 15.0 % and extended the lifespan by 91.5 %, compared with the fluopyram treatment. Lentinan pretreatment reverted the inhibition of the locomotion and reproduction of C. elegans under the fluopyram stress. In addition, lentinan pretreatment significantly decreased the contents of ROS and MDA in N2 nematodes. Moreover, pretreated with lentinan significantly recovered the decreased activities of CAT, SOD, GST and SDH induced by fluopyram. Lentinan pretreatment enhanced the mRNA levels of daf-16 and skn-1 and their downstream genes in the nematodes compared with the fluopyram group. In daf-16 and skn-1 mutants, the lifespan, ROS and related genes expression were not significantly changed in lentinan pretreatment. Pretreated with lentinan significantly enhanced the fluorescence intensity of SOD-3::GFP and GST-4::GFP, and promoted the nuclear translocation of DAF-16 and SKN-1 under the fluopyram stress. In summary, these findings indicated that lentinan protected C. elegans from fluopyram-induced toxicity via DAF-16 and SKN-1.
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BACKGROUND & AIMS: Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota. METHODS: CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apcmin/+ mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion. RESULTS: PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apcmin/+ mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice. CONCLUSIONS: PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.
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Neoplasias Colorrectales , Microbioma Gastrointestinal , Ratones , Animales , Transducción de Señal , Sulfato de Dextran/toxicidad , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis , Medicina Tradicional , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/metabolismo , Carcinogénesis , Azoximetano/toxicidadRESUMEN
AIMS: Mitral annular plane systolic excursion (MAPSE) is a simple and reliable index for evaluating left ventricular (LV) systolic function, particularly in patients with poor image quality; however, the lack of reference values limits its widespread use. This study aimed to establish the normal ranges for MAPSE measured using motion-mode (M-mode) and two-dimensional speckle tracking echocardiography (2D-STE) and to explore its principal determinants. METHODS AND RESULTS: This multicentre, prospective, cross-sectional study included 1952 healthy participants [840 men (43%); age range, 18-80 years] from 55 centres. MAPSE was measured using M-mode echocardiography and 2D-STE. The results showed that women had a higher MAPSE than men and MAPSE decreased with age. The age- and sex-specific reference values for MAPSE were established for these two methods. Multiple linear regression analyses revealed that MAPSE on M-mode echocardiography correlated with age and MAPSE on 2D-STE with age, blood pressure (BP), heart rate, and LV volume. Moreover, MAPSE measured by 2D-STE correlated more strongly with global longitudinal strain compared with that measured using M-mode echocardiography. CONCLUSION: Normal MAPSE reference values were established based on age and sex. BP, heart rate, and LV volume are potential factors that influence MAPSE and should be considered in clinical practice. Normal values are useful for evaluating LV longitudinal systolic function, especially in patients with poor image quality, and may further facilitate the use of MAPSE in routine assessments.
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Ecocardiografía , Válvula Mitral , Masculino , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Valores de Referencia , Estudios Prospectivos , Estudios Transversales , Válvula Mitral/diagnóstico por imagen , Ecocardiografía/métodos , Función Ventricular Izquierda/fisiologíaRESUMEN
Desensitization therapy for iodinated contrast media (ICM) aims to induce drug tolerance in patients with a history of severe allergic reactions to ICM in a short time. Currently, there is no widely accepted consensus on inducing desensitization to avoid severe allergic responses to ICM. The clinically successful cases have shown that prophylactic use of antihistamines and glucocorticoids can increase the desensitization effect; repeatedly desensitizing and gradually increasing the dose can be conducive to establishing better tolerance to ICM. Most desensitization effects, including stress resistance, can endure 24-48 h. The mechanisms of desensitization therapy remain unclear, the initial dose, administration interval and dose gradient are largely based on clinical experiences and the reaction of patients. This article reviews the current research progress on ICM-related allergies, desensitization methods and related mechanisms, as well as the benefits and hazards of desensitization, to provide a reference for desensitization treatment of hypersensitivity to ICM .
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Medios de Contraste , Hipersensibilidad , Humanos , Medios de Contraste/efectos adversos , Consenso , GlucocorticoidesRESUMEN
OBJECTIVE: The small intestinal bacterial overgrowth (SIBO) in acute pancreatitis correlates with the severity of the disease. However, corresponding studies on the microbial composition of the duodenal mucosa of patients are uncommon. METHODS: Duodenal mucosal biopsies were collected by gastroscopy from 16 patients with mild acute pancreatitis (the Ap group) and 16 healthy individuals (the control group) and subjected to histological studies as well as bacterial 16S rRNA gene sequencing. Caerulein and L-arginine were used to induce mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) in mice, respectively, and their pancreas and duodenum were collected for histological studies. RESULTS: H&E analysis displayed no significant pathological damage in the descending duodenum of patients with acute pancreatitis compared with that of the controls. Immunofluorescence and Real-time PCR revealed that the expressions of tight junction proteins (TJPs) in duodenal mucosa were decreased in acute pancreatitis. The results of the alpha diversity analysis revealed no significant difference between the two groups, while LEfSe and the random forest revealed a few differences, indicating that the descending duodenum mucosal microbiota changed slightly in patients with mild acute pancreatitis. We observed the pathological changes and the expression of TJPs in the duodenum in the three groups of mice and found that SAP mice had more severe pathological damage in the duodenum. Furthermore, the expression of TJPs in the duodenum was lower in the MAP and SAP groups of mice compared to control mice, but it was similar in both groups. CONCLUSION: Patients with mild acute pancreatitis had mild duodenal barrier dysfunction and slight changes in duodenal mucosal microbiota.
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Microbiota , Pancreatitis , Humanos , Enfermedad Aguda , ARN Ribosómico 16S/genética , Pancreatitis/metabolismo , Duodeno/patología , Mucosa Intestinal/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
Objective: The impact of the aging population in China varies between regions. It is because regions with different resource endowments, such as those related to economy, population, and medical care, have different degrees of disability risk in the face of the increases in the disabled and semi-disabled older population caused by the overall aging of the population. This study aimed to construct an evaluation system to monitor and measure the degree of social disability risk in different regions in China and to evaluate and compare the degree of social disability risk in different regions using empirical data. Method: This study used the Delphi method to construct a social disability risk measurement index system with macro, meso, and micro dimensions. At the same time, based on the data of CHARLS2018, an AHP-entropy method was used to calculate the index's total weight, and the standard deviation classification method was used to classify the total and criterion-level measurement scores of 28 provinces. Results: The regional degree of social disability risk was analyzed in subdimensions. Our research indicates that China's social disability risk situation is not promising, with a general medium to high-risk level. The score of degree of social disability risk among provinces is consistent with the regional economic development level to a large extent. The risk of social disability varies significantly among the eastern and central, and western regions of China and the provinces within the three regions. Discussion: Currently, the situation facing the degree of social disability risk in China is that the overall risk level of the country is higher, and the difference between regions is significant. It is necessary to take measures to meet better the needs of the aging population and the disabled and semi-disabled older populations in a large-range, large-scale, multilevel way.
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Desarrollo Económico , China/epidemiologíaRESUMEN
OBJECTIVE@#To explore whether the protein Deglycase protein 1 (DJ1) can ameliorate Alzheimer's disease (AD)-like pathology in Amyloid Precursor Protein/Presenilin 1 (APP/PS1) double transgenic mice and its possible mechanism to provide a theoretical basis for exploring the pathogenesis of AD.@*METHODS@#Adeno-associated viral vectors (AAV) of DJ1-overexpression or DJ1-knockdown were injected into the hippocampus of 7-month-old APP/PS1 mice to construct models of overexpression or knockdown. Mice were divided into the AD model control group (MC), AAV vector control group (NC), DJ1-overexpression group (DJ1 +), and DJ1-knockdown group (DJ1 -). After 21 days, the Morris water maze test, immunohistochemistry, immunofluorescence, and western blotting were used to evaluate the effects of DJ1 on mice.@*RESULTS@#DJ1 + overexpression decreased the latency and increased the number of platform traversals in the water maze test. DJ1 - cells were cured and atrophied, and the intercellular structure was relaxed; the number of age spots and the expression of AD-related proteins were significantly increased. DJ1 + increased the protein expression of Nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), light chain 3 (LC3), phosphorylated AMPK (p-AMPK), and B cell lymphoma-2 (BCL-2), as well as the antioxidant levels of total superoxide dismutase (T-SOD), total antioxidant capacity (T-AOC), and Glutathione peroxidase (GSH-PX), while decreasing the levels of Kelch-like hydrates-associated protein 1 (Keap1), mammalian target of rapamycin (mTOR), p62/sequestosome1 (p62/SQSTM1), Caspase3, and malondialdehyde (MDA).@*CONCLUSION@#DJ1-overexpression can ameliorate learning, memory, and AD-like pathology in APP/PS1 mice, which may be related to the activation of the NRF2/HO-1 and AMPK/mTOR pathways by DJ1.
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Animales , Ratones , Enfermedad de Alzheimer/terapia , Proteínas Quinasas Activadas por AMP/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Mamíferos/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 2 Relacionado con NF-E2/metabolismo , Presenilina-1/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Flower-like phosphorus-doped nickel oxide (P-NiO) is proposed as a counter electrode (CE) for dye-sensitized solar cells (DSSCs). The flower-like nickel oxide essentially serves as the matrix for the CE, which is expected to promote a two-dimensional electron transport pathway. The phosphorus is intended to improve the catalytic ability by creating more active sites in the NiO for the catalysis of triiodide ions (I3-) to iodide ions (I-) on the surface of the CE. The P-NiO is controlled by a sequencing of precursor concentration, which allows the P-NiO to possess different features. The debris aggregation occurs in the P-NiO-1, while the P-NiO-0.75 leads to the incomplete flower-like nanosheets. The complete flower-like morphology can be observed in the P-NiO-0.5, P-NiO-0.25 and P-NiO-0.1 catalytic electrodes. The DSSC with the P-NiO-0.5 CE achieves a power conversion efficiency (η) of 9.05%, which is better than that of the DSSC using a Pt CE (η = 8.51%); it also performs better than that with the Pt CE, even under rear illumination and dim light conditions. The results indicate the promising potential of the P-NiO CE to replace the expensive Pt CE.
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Cancer patients often face severe organ toxicity caused by chemotherapy. Among these, chemotherapy-induced hepatotoxicity and cardiotoxicity are the main causes of death of cancer patients. Chemotherapy-induced cardiotoxicity even creates a new discipline termed "cardio-oncology". Therefore, relieving toxicities induced by chemotherapy has become a key issue for improving the survival and quality of life in cancer patients. In this work, mesenchymal stem cell exosomes with the "G-C" abundant tetrahedral DNA nanostructure (TDN) are modified to form a decoy exosome (Exo-TDN). Exo-TDN reduces DOX-induced hepatotoxicity as the "G-C" base pairs scavenge DOX. Furthermore, Exo-TDN with cardiomyopathic peptide (Exo-TDN-PCM) is engineered for specific targeting to cardiomyocytes. Injection of Exo-TDN-PCM significantly reduces DOX-induced cardiotoxicity. Interestingly, Exo-TDN-PCM can also promote macrophage polarization into the M2 type for tissue repair. In addition, those decoy exosomes do not affect the anticancer effects of DOX. This decoy exosome strategy serves as a promising therapy to reduce chemo-induced toxicity.
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Antineoplásicos , Enfermedad Hepática Inducida por Sustancias y Drogas , Exosomas , Neoplasias , Humanos , Exosomas/genética , Exosomas/metabolismo , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Cardiotoxicidad/metabolismo , Calidad de Vida , Antineoplásicos/toxicidad , Antineoplásicos/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoRESUMEN
Background: As reflected in the WHO classification of glioma since 2020, genomic information has been an important criterion in addition to histology for glioma classification. There is a significant intergrade difference as well as intragrade difference of survival probability among glioma patients. Except the molecular criteria used in the WHO classification, few studies have explored other genomic factors that may be underlying these survival differences, especially in Chinese populations. Here, we used integrative genomic approaches to characterize a Chinese glioma cohort to search for potential prognostic biomarkers. Methods: We recruited 46 Chinese patients with primary malignant glioma. All the patients were analyzed with whole-exome sequencing (WES) and 27 of them were analyzed with RNA-seq. We compared the molecular features between patients in different WHO grades. We classified the glioblastoma (GBM) patients into two groups (good vs poor survival) using six-month progression-free survival (PFS6) status and compared the genomic profiles between the two groups. Results: We found grade II and grade III patients cluster together (LGG) and they are different from GBM in unsupervised clustering analysis with RNA-seq data. Gene set enrichment analysis (GSEA) comparing GBM and the LGG group suggested that GBM had upregulation of multiple pathways related to genome integrity and immune cell infiltration. Further comparison of somatic mutations between the two groups revealed TOPAZ1 as a novel mutation associated with GBM and prevalence of CNV in multiple genes in GBM. Comparison between PFS6 good and poor GBM patients revealed six genes (TRIML2, ROCK1, PKD1, OBSCN, HECTD4, and ADCY7) were significantly mutated and two genes (NTRK1 and B2M) had more CNV alterations in the poor prognosis group. Conclusion: Taken together, our molecular data revealed that GBM patient showed distinct characteristics related to individual gene, chromosome integrity, and infiltrating immune cells compared to LGG (grade II/III) patients. We also identified few novel genes with SNV or CNV, which might be the potential markers for clinical outcome of GBM.