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Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Sorafenibe , Colágeno/metabolismo , Microambiente TumoralRESUMO
Thermoset polymers have become integral to our daily lives due to their exceptional durability, making them feasible for a myriad of applications; however, this ubiquity also raises serious environmental concerns. Covalent adaptable networks (CANs) with dynamic covalent linkages that impart efficient reprocessability and recyclability to thermosets have garnered increasing attention. While various dynamic exchange reactions have been explored in CANs, many rely on the stimuli of active nucleophilic groups and/or catalysts, introducing performance instability and escalating the initial investment. Herein, we propose a new direct and catalyst-free CâC/CâN metathesis reaction between α-cyanocinnamate and aldimine as a novel dynamic covalent motif for constructing recyclable thermosets. This chemistry offers mild reaction conditions (room temperature and catalyst-free), ensuring high yields and simple isolation procedures. By incorporating dynamic CâC/CâN linkages into covalently cross-linked polymer networks, we obtained dynamic thermosets that exhibit both malleability and reconfigurability. The resulting tunable dynamic properties, coupled with the high thermal stability and recyclability of the CâC/CâN linkage-based networks, enrich the toolbox of dynamic covalent chemistry.
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The presence of butylparaben (BP), a prevalent pharmaceutical and personal care product, in surface waters has raised concerns regarding its impact on aquatic ecosystems. Despite its frequent detection, the toxicity of BP to the cyanobacterium Microcystis aeruginosa remains poorly understood. This study investigates the influence of BP on the growth and physiological responses of M. aeruginosa. Results indicate that low concentrations of BP (below 2.5 mg/L) have negligible effects on M. aeruginosa growth, whereas higher concentrations (5 mg/L and 10 mg/L) lead to significant growth inhibition. This inhibition is attributed to the severe disruption of photosynthesis, evidenced by decreased Fv/Fm values and chlorophyll a content. BP exposure also triggers the production of reactive oxygen species (ROS), resulting in elevated activity of antioxidant enzymes. Excessive ROS generation stimulates the production of microcystin-LR (MC-LR). Furthermore, lipid peroxidation and cell membrane damage indicate that high BP concentrations cause cell membrane rupture, facilitating the release of MC-LR into the environment. Transcriptome analysis reveals that BP disrupts energy metabolic processes, particularly affecting genes associated with photosynthesis, carbon fixation, electron transport, glycolysis, and the tricarboxylic acid cycle. These findings underscore the profound physiological impact of BP on M. aeruginosa and highlight its role in stimulating the production and release of MC-LR, thereby amplifying environmental risks in aquatic systems.
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Microcystis , Microcystis/efeitos dos fármacos , Microcystis/crescimento & desenvolvimento , Microcystis/metabolismo , Microcistinas/biossíntese , Biomassa , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Toxinas Marinhas/biossíntese , Parabenos/farmacologia , Antioxidantes/metabolismoRESUMO
BACKGROUND: Although prior research has estimated the overarching cost burden of heart failure (HF), a thorough analysis examining medical expense differences and trends, specifically among commercially insured patients with heart failure, is still lacking. Thus, the study aims to examine historical trends and differences in medical costs for commercially insured heart failure patients in the United States from 2006 to 2021. METHODS: A population-based, cross-sectional analysis of medical and pharmacy claims data (IQVIA PharMetrics® Plus for Academic) from 2006 to 2021 was conducted. The cohort included adult patients (age > = 18) who were enrolled in commercial insurance plans and had healthcare encounters with a primary diagnosis of HF. The primary outcome measures were the average total annual payment per patient and per cost categories encompassing hospitalization, surgery, emergency department (ED) visits, outpatient care, post-discharge care, and medications. The sub-group measures included systolic, diastolic, and systolic combined with diastolic, age, gender, comorbidity, regions, states, insurance payment, and self-payment. RESULTS: The study included 422,289 commercially insured heart failure (HF) patients in the U.S. evaluated from 2006 to 2021. The average total annual cost per patient decreased overall from $9,636.99 to $8,201.89, with an average annual percentage change (AAPC) of -1.11% (95% CI: -2% to -0.26%). Hospitalization and medication costs decreased with an AAPC of -1.99% (95% CI: -3.25% to -0.8%) and - 3.1% (95% CI: -6.86-0.69%). On the other hand, post-discharge, outpatient, ED visit, and surgery costs increased by an AAPC of 0.84% (95% CI: 0.12-1.49%), 4.31% (95% CI: 1.03-7.63%), 7.21% (95% CI: 6.44-8.12%), and 9.36% (95% CI: 8.61-10.19%). CONCLUSIONS: The study's findings reveal a rising trend in average total annual payments per patient from 2006 to 2015, followed by a subsequent decrease from 2016 to 2021. This decrease was attributed to the decline in average patient costs within the Medicare Cost insurance category after 2016, coinciding with the implementation of the Medicare Access and CHIP Reauthorization Act (MACRA) of 2015. Additionally, expenses related to surgical procedures, emergency department (ED) visits, and outpatient care have shown substantial growth over time. Moreover, significant differences across various variables have been identified.
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Insuficiência Cardíaca , Seguro Saúde , Humanos , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/economia , Estados Unidos , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Idoso , Adulto , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Custos de Cuidados de Saúde/tendências , Revisão da Utilização de Seguros , Hospitalização/economia , Gastos em Saúde/estatística & dados numéricos , Gastos em Saúde/tendênciasRESUMO
BACKGROUND: An accurate perception of death risk is a prerequisite for advanced cancer patients to make informed end-of-life care decisions. However, there is to date no suitable scale to measure death risk perception. This study was to develop and psychometrically test the death risk perception scale (DRPS) for advanced cancer patients. METHODS: Process of instrument development and psychometric evaluation were used. First, qualitative research, a literature review, brainstorming, a Delphi study, and cognitive interviews were conducted to construct a pretest scale of death risk perception. Second, a scale-based survey was administered to 479 advanced cancer patients. Item, exploratory factor, and confirmatory factor analyses were employed to optimize the scale. The Cronbach's alpha was calculated as a reliability analysis. The validity analysis included construct, convergent, discriminant, and content validity values. RESULTS: A three-dimension, 12-item scale was developed, including deliberative, affective, and experiential risk perception. The confirmatory factor analysis supported the three-factor model with satisfactory convergent and discriminant validity levels. The Cronbach's alpha coefficient for internal consistency was 0.807 and scale-level content validity index was 0.98. CONCLUSIONS: The 12-item DRPS is a reliable and valid instrument for assessing the level of death risk perception in advanced cancer patients. More studies are needed to examine its structure and robustness prior to use.
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Atitude Frente a Morte , Neoplasias , Percepção , Psicometria , Humanos , Psicometria/instrumentação , Psicometria/métodos , Neoplasias/psicologia , Neoplasias/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Inquéritos e Questionários , Reprodutibilidade dos Testes , Idoso , Adulto , Pesquisa Qualitativa , Medição de Risco/métodos , Medição de Risco/normas , Técnica Delphi , Análise Fatorial , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Advanced cancer patients often experience existential distress (ED). However, the factors associated with ED remain unclear. This study investigated the current state of ED and identified the associated factors in Chinese patients with advanced cancer. METHODS: A cross-sectional study was conducted among 352 advanced cancer patients from 3 tertiary hospitals in Fujian, China. Participants were invited to complete the Existential Distress Scale, Number Rating Scale, Self-Perceived Burden Scale, Quality of Life Concerns in the End-of-Life Questionnaire, and Hospital Anxiety and Depression Scale. OBJECTIVES: This study aimed to investigate the level of existential distress among advanced cancer patients in China and identify the associated factors. RESULTS: A total of 352 advanced cancer patients were recruited for this study. The average score for ED was 8.48 ± 7.12 among the advanced cancer patients. Multiple regression showed that the associated factors included depression (ß = 0.32, p = 0.000), self-perceived burden (SPB) (ß = 0.18, p = 0.001), the presence of a spouse (ß = -0.10, p = 0.050), and reception of government subsidies (ß = 0.17, p = 0.001). The factors accounted for 30.1% of the total variance in ED (F = 8.472, p < 0.001). SIGNIFICANCE OF RESULTS: Among the advanced cancer patients queried, ED was found to be positively influenced by depression, SPB, and reception of government subsidies and negatively influenced by the presence of a spouse. Depression was the most important risk factor, and thus future ED interventions should target depression.
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BACKGROUND: Conus, a highly diverse species of venomous predators, has attracted significant attention in neuroscience and new drug development due to their rich collection of neuroactive peptides called conotoxins. Recent advancements in transcriptome, proteome, and genome analyses have facilitated the identification of conotoxins within Conus' venom glands, providing insights into the genetic features and evolutionary patterns of conotoxin genes. However, the underlying mechanism behind the extraordinary hypervariability of conotoxins remains largely unknown. RESULTS: We analyzed the transcriptomes of 34 Conus species, examining various tissues such as the venom duct, venom bulb, and salivary gland, leading to the identification of conotoxin genes. Genetic variation analysis revealed that a subset of these genes (15.78% of the total) in Conus species underwent positive selection (Ka/Ks > 1, p < 0.01). Additionally, we reassembled and annotated the genome of C. betulinus, uncovering 221 conotoxin-encoding genes. These genes primarily consisted of three exons, with a significant portion showing high transcriptional activity in the venom ducts. Importantly, the flanking regions and adjacent introns of conotoxin genes exhibited a higher prevalence of transposon elements, suggesting their potential contribution to the extensive variability observed in conotoxins. Furthermore, we detected genome duplication in C. betulinus, which likely contributed to the expansion of conotoxin gene numbers. Interestingly, our study also provided evidence of introgression among Conus species, indicating that interspecies hybridization may have played a role in shaping the evolution of diverse conotoxin genes. CONCLUSIONS: This study highlights the impact of adaptive evolution and introgressive hybridization on the genetic diversity of conotoxin genes and the evolution of Conus. We also propose a hypothesis suggesting that transposable elements might significantly contribute to the remarkable diversity observed in conotoxins. These findings not only enhance our understanding of peptide genetic diversity but also present a novel approach for peptide bioengineering.
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Conotoxinas , Caramujo Conus , Animais , Conotoxinas/genética , Caramujo Conus/genética , Peptídeos/genética , Genoma , GenômicaRESUMO
Examples of self-assembled multiple emulsion droplets on the nanometre scale are very rare. In this work, we use coarse-grained (CG) molecular dynamics simulations to study the self-assembly of ternary mixtures consisting of water, n-heptane, and nonionic surfactant tetraethylene glycol monododecyl ether (C12E4). The water volume fractions studied are 1%, 3%, and 5%, respectively. Various nanoscale emulsions are obtained in a spontaneous process. When the water/surfactant volume ratio vm/s = 1.0/1.0, the obtained emulsion droplets are identified as oil-in-water-in-oil (O/W/O) double types, consisting of an oil core, an inner surfactant layer, a water layer, and an outer surfactant layer. The water molecules are distributed around the hydrophilic ends of the surfactants, while the hydrophobic ends of the surfactants wrap the oil cores and penetrate into the oil bulk. Hydrogen-bond interactions among water and the hydrophilic ends of the surfactants form cross-links that stabilize the double emulsion droplets. The sizes of all the oil cores inside the droplets are <6 nm in diameter, even with the highest water volume fraction of 5%. Both the concentration of free water molecules on the order of 10-6 mol/cm3 and the favourable energy change during emulsion formation indicate that the emulsion droplets are thermodynamically stable. In contrast, for vm/s = 1.0/5.5, no double emulsion but a simple water-in-oil emulsion was observed, with morphologies evolving from oblate to bicontinuous phases with an increase in the water volume fraction from 1% to 5%. Our coarse-grained molecular dynamics simulations provide valuable insight for the preparation of nanoscale double emulsions and the characterization of their structures.
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The case highlights an available method to minimize the target volume and reduce the radiation dose by using a temporary catheter, to reduce the long-term risk of radiotherapy for ventricular arrhythmias.
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Ablação por Cateter , Radiocirurgia , Taquicardia Ventricular , Complexos Ventriculares Prematuros , Humanos , Complexos Ventriculares Prematuros/radioterapia , Complexos Ventriculares Prematuros/cirurgia , Ventrículos do Coração , Resultado do TratamentoRESUMO
PURPOSE: Cancer patients undergoing chemotherapy are prone to suffering a higher incidence rate of depression, leading to poor quality of life. However, how cancer affects depression is unclear. This study aimed to examine whether the relationship between cognitive appraisal and depression is mediated by perceived stress and self-efficacy in cancer patients undergoing chemotherapy. METHODS: A total of 421 cancer patients undergoing chemotherapy participated in this cross-sectional survey. Cognitive appraisal of cancer, perceived stress, self-efficacy, and depression were measured with the Perceived Life Threat Scale, Perceived Stress Scale, General Self-efficacy Scale and Hospital Anxiety, and Depression Scale-Depression Scale, respectively. Path analysis was performed to analyze the mediating effects of perceived stress and self-efficacy on the relationship between cognitive appraisal of cancer and depression. RESULTS: Cognitive appraisal of cancer exerted direct (b = 0.066, SE = 0.020, p < 0.001, bias-corrected 95% CI = [0.027, 0.106]) and indirect (mediated by depression and insomnia) (b = 0.136, SE = 0.015, p < 0.001, bias-corrected 95% CI = [0.107, 0.167]) effects on depression. Perceived stress and self-efficacy were significant in mediating the relationship between cognitive appraisal of cancer and depression (b = 0.101, SE = 0.014, p < 0.001, bias-corrected 95% CI = [0.074, 0.132]; b = 0.021, SE = 0.006, p < 0.001, bias-corrected 95% CI = [0.006, 0.028], respectively). Additionally, a sequential mediating effect of perceived stress via self-efficacy was found, and the mediating effect size was 0.014 (p < 0.01, bias-corrected 95% CI = [0.010,0.034]). CONCLUSIONS: This study suggests that medical staff could prevent or relieve depression through improving self-efficacy or reducing perceived stress in cancer patients undergoing chemotherapy.
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Neoplasias , Autoeficácia , Humanos , Estudos Transversais , Qualidade de Vida/psicologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Neoplasias/tratamento farmacológico , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia , CogniçãoRESUMO
Okadaic acid (OA) is one of the most prevalent marine phycotoxin with complex toxicity, which can lead to toxic symptoms such as diarrhea, vomiting, nausea, abdominal pain, and gastrointestinal discomfort. Studies have shown that the main affected tissue of OA is digestive tract. However, its toxic mechanism is not yet fully understood. In this study, we investigated the changes that occurred in the epithelial microenvironment following OA exposure, including the epithelial barrier and gut bacteria. We found that impaired epithelial cell junctions, mucus layer destruction, cytoskeletal remodeling, and increased bacterial invasion occurred in colon of rats after OA exposure. At the same time, the gut bacteria decreased in the abundance of beneficial bacteria and increased in the abundance of pathogenic bacteria, and there was a significant negative correlation between the abundance of pathogenic bacteria represented by Escherichia/Shigella and animal body weight. Metagenomic analysis inferred that Escherichia coli and Shigella spp. in Escherichia/Shigella may be involved in the process of cytoskeletal remodeling and mucosal layer damage caused by OA. Although more evidence is needed, our results suggest that opportunistic pathogens may be involved in the complex toxicity of OA during OA-induced epithelial barrier damage.
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Animais , Ratos , Ácido Okadáico/toxicidade , Peso Corporal , Colo , Escherichia coli/genéticaRESUMO
BACKGROUND: Cancer not only affects cancer patients' quality of life but also their family caregivers'. A WeChat-based Dyadic Life Review Program was developed by our research team for people with advanced cancer and their family caregivers to improve their quality of life. AIM: To explore the feasibility and preliminary effects of the WeChat-based Dyadic Life Review Program on people with advanced cancer and their family caregivers. METHODS: A feasibility randomized controlled trial was conducted. Both quantitative and qualitative data were collected. A total of 47 advanced cancer patient-family caregiver dyads was recruited. Twenty-six dyads were randomized into the experimental group, and 21 dyads into the control group. The experimental group engaged in the WeChat-based Dyadic Life Review Program twice a week for 4 weeks. RESULTS: For qualitative results, five themes emerged: (1) accepting and enjoying the program; (2) increasing communication with one another; (3) feeling grateful for each other; (4) providing emotional support to each other; and (5) releasing caregivers' stress. In terms of quantitative results, quality of life (Z = -4.06, p < 0.001; t = 4.30, p < 0.001), family adaptability(Z = -3.01, p = 0.003; Z = -3.29, p = 0.001), and family cohesion(Z = -4.14, p < 0.001; Z = -3.88, p < 0.001) of people with advanced cancer and family caregivers were improved, and family caregivers' care burden (t = -2.50, p = .018) was decreased in the experimental group compared with the control group post-test. CONCLUSIONS: The WeChat-based Dyadic Life Review Program is feasible and acceptable for people with advanced cancer and their family caregivers. It has the potential to improve their quality of life, adaptability and cohesion, and reduce family caregivers' care burden.
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Cuidadores , Neoplasias , Cuidadores/psicologia , Comunicação , Estudos de Viabilidade , Humanos , Neoplasias/psicologia , Qualidade de VidaRESUMO
Zeolites have found tremendous applications in the chemical industry. However, the dynamic nature of their active sites under the flow of adsorbate molecules for adsorption and catalysis is unclear, especially in operando conditions, which could be different from the as-synthesized structures. In the present study, we report a structural transformation of the adsorptive active sites in SAPO-34 zeolite by using acetone as a probe molecule under various temperatures. The combination of solid-state nuclear magnetic resonance, in situ variable-temperature synchrotron X-ray diffraction, and in situ diffuse-reflectance infrared Fourier-transform spectroscopy allow a clear identification and quantification that the chemisorption of acetone can convert the classical Brønsted acid site adsorption mode to an induced Frustrated Lewis Pairs adsorption mode at increasing temperatures. Such facile conversion is also supported by the calculations of ab-initio molecular-dynamics simulations. This work sheds new light on the importance of the dynamic structural alteration of active sites in zeolites with adsorbates at elevated temperatures.
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Transition metal doped chalcogenides are one of the most important classes of catalysts that have been attracting increasing attention for petrochemical and energy related chemical transformations due to their unique physiochemical properties. For practical applications, achieving maximum atom utilization by homogeneous dispersion of metals on the surface of chalcogenides is essential. Herein, we report a detailed study of a deposition method using thiourea coordinated transition metal complexes. This method allows the preparation of a library of a wide range of single atoms including both noble and non-noble transition metals (Fe, Co, Ni, Cu, Pt, Pd, Ru) with a metal loading as high as 10 wt % on various ultrathin 2D chalcogenides (MoS2, MoSe2, WS2 and WSe2). As demonstrated by the state-of-the-art characterization, the doped single transition metal atoms interact strongly with surface anions and anion vacancies in the exfoliated 2D materials, leading to high metal dispersion in the absence of agglomeration. Taking Fe on MoS2 as a benchmark, it has been found that Fe is atomically dispersed until 10 wt %, and beyond this loading, formation of coplanar Fe clusters is evident. Atomic Fe, with a high electron density at its conduction band, exhibits a superior intrinsic activity and stability in CO2 hydrogenation to CO per Fe compared to corresponding surface Fe clusters and other Fe catalysts reported for reverse water-gas-shift reactions.
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It has only recently been established that doping light elements (lithium, boron, and carbon) into supported transition metals can fill interstitial sites, which can be observed by the expanded unit cell. As an example, interstitial lithium (int Li) can block H filling octahedral interstices of palladium metal lattice, which improves partial hydrogenation of alkynes to alkenes under hydrogen. In contrast, herein, we report int Li is not found in the case of Pt/C. Instead, we observe for the first time a direct 'substitution' of Pt with substitutional lithium (sub Li) in alternating atomic columns using scanning transmission electron microscopy-annular dark field (STEM-ADF). This ordered substitutional doping results in a contraction of the unit cell as shown by high-quality synchrotron X-ray diffraction (SXRD). The electron donation of d-band of Pt without higher orbital hybridizations by sub Li offers an alternative way for ultra-selectivity in catalytic hydrogenation of carbonyl compounds by suppressing the facile CO bond breakage that would form alcohols.
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A novel armor-type composite of metal-organic framework (MOF)-encapsulated CoCu nanoparticles with a Fe3 O4 core (Fe3 O4 @SiO2 -NH2 -CoCu@UiO-66) has been designed and synthesized by the half-way injection method, which successfully serves as an efficient and recyclable catalyst for the selective transfer hydrogenation. In this half-way injection approach, the pre-synthetic Fe3 O4 @SiO2 -NH2 -CoCu was injected into the UiO-66 precursor solution halfway through the MOF budding period. The formed MOF armor could play a role of providing significant additional catalytic sites besides CoCu nanoparticles, protecting CoCu nanoparticles, and improving the catalyst stability, thus facilitating the selective transfer hydrogenation of nitrobenzaldehydes into corresponding nitrobenzyl alcohols in high selectivity (99 %) and conversion (99 %) rather than nitro group reduction products. Notably, this method achieves the precise assembly of a MOF-encapsulated composite, and the ingenious combination of MOF and nanoparticles exhibits excellent catalytic performance in the selective hydrogen transfer reaction, implementing a "1+1>2" strategy in catalysis.
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Core-shell nanocomposites with a catalytic metal-organic framework (MOF) shell are more effective and stable than bare MOF. We have successfully designed an effective heterogeneous catalyst for the synthesis of benzimidazole by integrating acidic catalytic activity, and promoted the aerobic oxidation and magnetic recyclability of core-shell nanocomposite Fe3O4@SiO2@UiO-66. The Fe3O4@SiO2 core is encapsulated by the in situ-grown UiO-66 shell, and the UiO-66 shell retains the porous structure and crystallinity of UiO-66 with abundant exposed Lewis acid sites. It shows high catalytic ability for the synthesis of various benzimidazoles through the acid-catalyzed condensation and aerobic oxidation with in situ oxygen. The Fe3O4@SiO2 core provides magnetic recyclability of Fe3O4@SiO2@UiO-66, and maintains high catalytic ability and stability over six cycles.
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Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study evaluated the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. All the tested compounds at the concentrations from 10-9 M to 10-6 M did not show cytotoxicity in endothelial cells by MTT assay. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated ß-galactosidase, downregulated p21 and p53, and increased the production of nitric oxide (NO) in both angiotensin II - and hydrogen peroxide - induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations, which were attenuated in the presence of endothelial NO synthase (eNOS) inhibitor L-NAME or sirtuin 1 (SIRT1) inhibitor sirtinol. Pts and Pts nicotinate did not alter SIRT1 expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1, according to surface plasmon resonance results and the molecular docking analysis. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. Moreover, Pts and Pts nicotinate shared similar ADME (absorption, distribution, metabolism, excretion) profiles and physiochemical properties. This study suggests that the Pts and Pts nicotinate ameliorate vascular endothelial senescence and elicit endothelium-dependent relaxations via activation of SIRT1. These two compounds may be potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.
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Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Resveratrol/análogos & derivados , Sirtuína 1/fisiologia , Estilbenos/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Células Cultivadas , Células Endoteliais/fisiologia , Humanos , Masculino , Niacina/análogos & derivados , Ratos , Ratos Sprague-DawleyRESUMO
Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin α4ß7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4ß7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6-into-B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4ß7+ -donor T cells in mesenteric lymph nodes and spleen. Furthermore, we found that the RA pathway modulates the ability of dendritic cells to imprint gut-homing specificity on alloreactive T cells. We also showed that host dendritic cell RA signaling influences GVHD risk. Our studies identified radiation and recipient RA signaling as 2 primary factors that dictate the magnitude of gut-homing donor T cell induction after allogeneic HSCT. Attenuating radiation-associated inflammation and modulating host RA signaling represent feasible strategies to mitigate intestinal GVHD by reducing gut-seeking pathogenic donor T cells.
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Família Aldeído Desidrogenase 1/metabolismo , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Retinal Desidrogenase/metabolismo , Linfócitos T/imunologia , Tretinoína/metabolismo , Irradiação Corporal Total , Família Aldeído Desidrogenase 1/genética , Animais , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Retinal Desidrogenase/genética , Transdução de Sinais , Transplante HomólogoRESUMO
OBJECTIVES: To evaluate the effects of a mind map-based life review programme (MBLRP) on psychological distress, hope, meaning in life and self-transcendence in cancer patients undergoing chemotherapy. METHODS: Eighty-four cancer patients undergoing chemotherapy from a university-affiliated hospital in Fujian, China. The participants were randomly allocated to a MBLRP group (n = 40) or usual care group (n = 44). Data were collected at baseline (T0), on the second day (T1) and four weeks after the programme (T2) using the Distress Thermometer, Meaning in Life Questionnaire, Herth Hope Scale and Self-transcendence Scale. RESULTS: No significant interaction effects for time and group membership were found for psychological distress either at T1 (t = -1.707, p = .090) or at T2 (t = -1.123, p = .263). The interaction effects for T1 and group membership were statistically significant for meaning in life (t = 3.487, p = .001) and hope (t = 5.313, p < .001), but not statistically significant for self-transcendence (t = 0.148, p = .882). The interaction effects for T2 and group membership were statistically significant for meaning in life (t = 2.592, p = .01), hope (t = 5.215, p < .001) and self-transcendence (t = 2.843, p = .005). CONCLUSIONS: The MBLRP could improve hope, meaning in life and self-transcendence in cancer patients undergoing chemotherapy.