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2.
JACC Heart Fail ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34509408

RESUMO

OBJECTIVES: The authors sought to investigate associations between sacubitril/valsartan adherence and clinical outcomes after hospitalization for heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Sacubitril/valsartan improves outcomes in HFrEF, though the extent to which medication adherence is associated with outcomes in routine care is less well characterized. METHODS: The authors analyzed patients aged ≥65 years hospitalized for HFrEF within the Get With the Guidelines-Heart Failure registry linked with Medicare claims between October 2015 and September 2018 who were discharged with sacubitril/valsartan. Sacubitril/valsartan adherence was assessed using medication fills to calculate proportion of days covered (PDC) through 90 days postdischarge. Associations between postdischarge adherence (PDC < or ≥80%) and risk of readmission and death within 1 year were examined by comparing cumulative incidences and adjusted event rates. RESULTS: Among 897 patients prescribed sacubitril/valsartan at discharge, 295 (32.9%) had PDC ≥80% and 602 (67.1%) had PDC <80%. Baseline characteristics were balanced between groups. Compared with patients with PDC <80%, patients with PDC ≥80% had a significantly lower adjusted hazard of all-cause re-hospitalization (HR: 0.66; [95% CI: 0.48-0.89]) and death (HR: 0.42; [0.22-0.79]) at 90 days and at 1 year (HR: 0.69; [0.56-0.86] and HR: 0.53; [0.38-0.74], respectively). For every 5 percentage point increase in PDC, patients experienced a significant reduction in rehospitalization (HR: 0.98; [0.97-0.99]) and death (HR: 0.96; [0.94-0.97]) at 1 year. CONCLUSIONS: In patients hospitalized for HFrEF and discharged on sacubitril/valsartan, high adherence to sacubitril/valsartan within 90 days after discharge was associated with substantially lower rates of readmission and death. Additional efforts to improve adherence with sacubitril/valsartan and other guideline-directed medical therapies in HFrEF are warranted.

3.
Talanta ; 235: 122788, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517646

RESUMO

A thermal desorption associative ionization time-of-flight mass spectrometer was developed for ultrasensitive detection of semi-volatile chemical warfare agents (CWAs). The excited-state CH2Cl2-induced associative ionization method presented a soft ionization characterization and an excellent sensitivity towards CWAs. The detection sensitivities of the investigated nine CWA-related substances were 2.56 × 105-5.01 × 106 counts ng-1 in a detection cycle (30 s or 100 s). The corresponding 3σ limits of detection (LODs) were 0.08-3.90 pg. Compared with the best-documented LODs via the dielectric barrier discharge ionization (DBDI) and secondary electrospray ionization (SESI), the obtained LODs of the investigated compounds were improved by 2-76 times. Additionally, the measured sensitivity of 2-Chloroethyl ethyl, a proxy for mustard gas, is 550 counts pptv-1, which exceeds the DBDI and SESI's corresponding values (4.4 counts pptv-1 and 6.5 counts pptv-1) nearly by two orders of magnitude. A field application simulation was conducted by putting a strip of PTFE film contaminated with the CWA-related agent into the thermal desorption unit. The simulation showed that the sensitivities of the instrument via swipe surveying could achieve 2.19 × 105 to 5.23 × 106 counts ng-1. The experimental results demonstrate that the excited-state CH2Cl2-induced associative ionization is an ultrasensitive ionization method for CWAs and reveal a prospect for improving the detection of CWA species future.


Assuntos
Substâncias para a Guerra Química , Gás de Mostarda , Substâncias para a Guerra Química/análise , Limite de Detecção , Espectrometria de Massas , Gás de Mostarda/análise , Espectrometria de Massas por Ionização por Electrospray
4.
Sci Rep ; 11(1): 18403, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526541

RESUMO

The sex-specific physical and biochemical responses in dioecious plants to abiotic stresses could result in gender imbalance, and how to ease the current situation by microorganisms is still unclear. Using native soil where poplars were grown, growth parameters, soil physicochemical properties in the rhizosphere soil of different sexes of Populus cathayana exposed to salt stress and exogenous arbuscular mycorrhizal (AM) inoculation were tested. Besides, the sex-specific microbial community structures in the rhizosphere soil of different sexes of Populus cathayana were compared under salt stress. To identify the sex-specific microbial community characteristics related to salinity and AM symbiosis, a combined qPCR and DGGE method was used to monitor microbial community diversity. Seedlings suffered severe pressure by salt stress, reflected in limited growth, biomass, and nutrient element accumulation, especially on females. Exogenous AM inoculation treatment alleviated these negative effects, especially under salt treatment of 75 mM. Compared with salt effect, exogenous AM inoculation treatment showed a greater effect on soil physical-chemical properties of both sexes. Based on DGGE results, salt stress negatively affected fungal richness but positively affected fungal Simpson diversity index, while exogenous AM inoculation treatment showed the opposite effect. Structural equation modeling (SEM) was performed to show the causal relationships between salt and exogenous AM inoculation treatments with biomass accumulation and microbial community: salt and exogenous AM inoculation treatment showed complicated effects on elementary concentrations, soil properties, which resulted in different relationship with biomass accumulation and microbial community. Salt stress had a negative effect on soil properties and microbial community structure in the rhizosphere soil of P. cathayana, whereas exogenous AM inoculation showed positive impacts on most of the soil physical-chemical properties and microbial community status.

5.
Nat Plants ; 7(9): 1162-1163, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475527
6.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2603-2613, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472281

RESUMO

Porcine epidemic diarrhea (PED) is a major disease of pigs that inflicts heavy losses on the global pig industry. The etiologic agent is the porcine epidemic diarrhea virus (PEDV), which is assigned to the genus Alphacoronavirus in the family Coronaviridae. This review consists of five parts, the first of which provides a brief introduction to PEDV and its epidemiology. Part two outlines the passive immunity in new born piglets and the important role of colostrum, while the third part summarizes the characteristics of the immune systems of pregnant sows, discusses the concept of the "gut-mammary gland-secretory IgA(sIgA) axis" and the possible underpinning mechanisms, and proposes issues to be addressed when designing a PEDV live vaccine. The final two parts summarizes the advances in the R&D of PEDV vaccines and prospects future perspectives on prevention and control of PEDV, respectively.


Assuntos
Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Doenças dos Suínos , Vacinas Virais , Animais , Anticorpos Antivirais , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Feminino , Imunização , Gravidez , Suínos , Doenças dos Suínos/prevenção & controle
7.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2924-2935, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472309

RESUMO

The ß2m (Beta-2-microglobin) gene encodes a non-glycosylated protein that functions as an important component of major histocompatibility complexⅠ(MHCⅠ) for antigen presentation. To evade immune mediated clearance, human tumors and pathogens have adopted different strategies, including loss of MHCⅠexpression. Appropriate animal models are essential for understanding the mechanisms underpinning the clinical treatment of tumor and other human diseases. We constructed ß2m knockout mice using CRISPR/Cas9 gene editing tool through embryo microinjection. Subsequently, genotyping and phenotyping of knockout mice were performed by PCR, qPCR, and flow cytometry. Mice genotyping showed that the coding region of the target gene was absent in the knockout mice. Real time PCR showed that mRNA level of ß2m was significantly downregulated. Flow cytometry showed that the proportions of CD8+ killer T cells was significantly reduced in a variety of tissues and organs of the immune system. Taken together, we have successfully constructed a strain of ß2m knockout mice, which will facilitate subsequent in vivo study on the function and mechanism of the ß2m gene.


Assuntos
Linfócitos T Citotóxicos , Microglobulina beta-2 , Animais , Antígenos de Histocompatibilidade Classe I , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglobulina beta-2/genética
8.
Eur Radiol ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477909

RESUMO

OBJECTIVES: To investigate the feasibility of automatic machine learning (autoML) based on native T1 mapping to predict late gadolinium enhancement (LGE) status in hypertrophic cardiomyopathy (HCM). METHODS: Ninety-one HCM patients and 44 healthy controls who underwent cardiovascular MRI were enrolled. The native T1 maps of HCM patients were classified as LGE ( +) or LGE (-) based on location-matched LGE images. An autoML pipeline was implemented using the tree-based pipeline optimization tool (TPOT) for 3 binary classifications: LGE ( +) and LGE (-), LGE (-) and control, and HCM and control. TPOT modeling was repeated 10 times to obtain the optimal model for each classification. The diagnostic performance of the best models by slice and by case was evaluated using sensitivity, specificity, accuracy, and microaveraged area under the curve (AUC). RESULTS: Ten prediction models were generated by TPOT for each of the 3 binary classifications. The diagnostic accuracy obtained with the best pipeline in detecting LGE status in the testing cohort of HCM patients was 0.80 by slice and 0.79 by case. In addition, the TPOT model also showed discriminability between LGE (-) patients and control (accuracy: 0.77 by slice; 0.78 by case) and for all HCM patients and controls (accuracy: 0.88 for both). CONCLUSIONS: Native T1 map analysis based on autoML correlates with LGE ( +) or (-) status. The TPOT machine learning algorithm could be a promising method for predicting myocardial fibrosis, as reflected by the presence of LGE in HCM patients without the need for late contrast-enhanced MRI sequences. KEY POINTS: • The tree-based pipeline optimization tool (TPOT) is a machine learning algorithm that could help predict late gadolinium enhancement (LGE) status in patients with hypertrophic cardiomyopathy. • The TPOT could serve as an adjuvant method to detect LGE by using information from native T1 maps, thus avoiding the need for contrast agent. • The TPOT also detects native T1 map alterations in LGE-negative patients with hypertrophic cardiomyopathy.

9.
Am J Hosp Palliat Care ; : 10499091211046236, 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538119

RESUMO

OBJECTIVES: This study investigated institutional and personal barriers to and facilitators of neonatal palliative care facing neonatal professionals in China. METHODS: A cross-sectional questionnaire surveyed 231 neonatal clinicians employed in 5 neonatal intensive care units from 2 children's hospitals and 3 medical centers in China. MEASUREMENTS: The translated modified version of the Neonatal Palliative Care Attitude Scale was used to survey neonatal clinicians' attitudes and beliefs regarding neonatal palliative care. RESULTS: Findings highlight 4 facilitators and 5 barriers among participating clinicians. Participants gave contradictory responses regarding the relative importance of curative treatment versus palliative care in the NICU. Negatively traumatic feelings, cultural issues and moral distress may impact this contradictory response and discourage clinicians from providing neonatal palliative care. Additionally, neonatologists and nurses held differing attitudes on several topics (p < 0.05). CONCLUSION: Further research should address strategies to improve knowledge and attitudes and relieve moral distress in NICU clinicians. Neonatal clinicians providing neonatal palliative care should receive regular palliative care training addressing culture-specific issues and communication skills. PRACTICE IMPLICATIONS: Study findings will be beneficial to inform clinical education and practice. Regular interdisciplinary team training is needed to enhance support for palliative care and decrease clinicians' moral distress during end-of-life care.

10.
Aquac Int ; : 1-31, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34539102

RESUMO

With the continuous expansion of aquaculture scale and density, contemporary aquaculture methods have been forced to overproduce resulting in the accelerated imbalance rate of water environment, the frequent occurrence of fish diseases, and the decline of aquatic product quality. Moreover, due to the fact that the average age profile of agricultural workers in many parts of the world are on the higher side, fishery production will face the dilemma of shortage of labor, and aquaculture methods are in urgent need of change. Modern information technology has gradually penetrated into various fields of agriculture, and the concept of intelligent fish farm has also begun to take shape. The intelligent fish farm tries to deal with the precise work of increasing oxygen, optimizing feeding, reducing disease incidences, and accurately harvesting through the idea of "replacing human with machine," so as to liberate the manpower completely and realize the green and sustainable aquaculture. This paper reviews the application of fishery intelligent equipment, IoT, edge computing, 5G, and artificial intelligence algorithms in modern aquaculture, and analyzes the existing problems and future development prospects. Meanwhile, based on different business requirements, the design frameworks for key functional modules in the construction of intelligent fish farm are proposed.

11.
Mater Horiz ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533547

RESUMO

A series of triphenylethylene derivatives exhibited multi-photoresponsive properties, including photochromism, photodeformation and room temperature phosphorescence (RTP), which are strongly related to molecular conformations and packing in the aggregated states. Accordingly, these properties can be subtly adjusted by substituents to the center double bond and/or peripheral phenyl moieties. The introduction of bromine atom was beneficial to photochromism and photodeformation properties as a result of the additional C-H⋯Br interactions and electron-withdrawing property. Also, it can promote the RTP effect via heavy atom effect, resulting in persistent afterglow lasting up to 150 min as detected by chemiluminescent imaging system.

12.
Phys Chem Chem Phys ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533560

RESUMO

The Y-family DNA polymerases specialize in translesion DNA synthesis, which is essential for replicating damaged DNA. The Y-family polymerases, which are made up of four stable domains, exhibit extensive distributions of charged residues, and are responsible for the tight formation of the protein-DNA complex. However, it is still unclear how the electrostatic interactions influence the conformational dynamics of the polymerases. Here, we focus on the case of a prototype Y-family DNA polymerase, Dpo4. Using coarse-grained models including a salt-dependent electrostatic potential, we investigate the effects of the electrostatic interactions on the folding process of Dpo4. Our simulations show that strong electrostatic interactions result in a three-state folding of Dpo4, consistent with the experimental observations. This folding process exhibits low cooperativity led by low salt concentration, where the individual domains fold one by one through one single pathway. Since the refined folding order of domains in multidomain proteins can shrink the configurational space, we suggest that the electrostatic interactions facilitate the Dpo4 folding. In addition, we study the local conformational dynamics of Dpo4 in terms of fluctuation and frustration analyses. We show that the electrostatic interactions can exaggerate the local conformational properties, which are in favor of the large-scale conformational transition of Dpo4 during the functional DNA binding. Our results underline the importance of electrostatic interactions in the conformational dynamics of Dpo4 at both the global and local scale, providing useful guidance in protein engineering at the multidomain level.

13.
BMC Pulm Med ; 21(1): 292, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525985

RESUMO

BACKGROUND: Asthma is a chronic inflammatory disorder of the airways involving many different factors. This study aimed to screen for the critical genes using DNA methylation/CpGs and miRNAs involved in childhood atopic asthma. METHODS: DNA methylation and gene expression data (Access Numbers GSE40732 and GSE40576) were downloaded from the Gene Expression Omnibus database. Each set contains 194 peripheral blood mononuclear cell (PBMC) samples of 97 children with atopic asthma and 97 control children. Differentially expressed genes (DEGs) with DNA methylation changes were identified. Pearson correlation analysis was used to select genes with an opposite direction of expression and differences in methylation levels, and then Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Protein-protein interaction network and miRNA-target gene regulatory networks were then constructed. Finally, important genes related to asthma were screened. RESULTS: A total of 130 critical DEGs with DNA methylation changes were screened from children with atopic asthma and compared with control samples from healthy children. GO and KEGG pathway enrichment analysis found that critical genes were primarily related to 24 GO terms and 10 KEGG pathways. In the miRNA-target gene regulatory networks, 9 KEGG pathways were identified. Analysis of the miRNA-target gene network noted an overlapping KEGG signaling pathway, hsa04060: cytokine-cytokine receptor interaction, in which the gene CCL2, directly related to asthma, was involved. This gene is targeted by eight asthma related miRNAs (hsa-miR-206, hsa-miR-19a, hsa-miR-9,hsa-miR-22, hsa-miR-33b, hsa-miR-122, hsa-miR-1, and hsa-miR-23b). The genes IL2RG and CCl4 were also involved in this pathway. CONCLUSIONS: The present study provides a novel insight into the underlying molecular mechanism of childhood atopic asthma.

14.
Adv Mater ; : e2104002, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499382

RESUMO

Photoresponsive materials have drawn much attention and are widely applied in daily life for their reversible changes in luminous color or appearance color under light irradiation. In this work, a new photoresponsive system based on triarylamine derivatives is developed. With the changed aryl substituents, adjustable photoresponsive properties, including photoactivated phosphorescence and photochromism after being dispersed into the poly(methyl methacrylate) (PMMA) matrix, are demonstrated. According to the theoretical calculations and experimental data, the competition between the formations of triplet excitons and cationic radicals under photoirradiation should be the main reason for their different photoresponsive properties. Excitingly, the applications of rewritable photopatterning, anticounterfeiting, information encryption, and decryption are realized conveniently, in addition to the successful model of sunglasses to protect eyes away from ultraviolet radiation and strong light in the sunlight. These studies present a simple and efficient design strategy for the development of photoresponsive materials on modulating the phosphorescence and photochromic property.

15.
Plant Cell ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469582

RESUMO

Verticillium wilt is a severe plant disease that causes massive losses in multiple crops. Increasing the plant resistance to Verticillium wilt is a critical challenge worldwide. Here, we report that the hemibiotrophic Verticillium dahliae (V. dahliae)-secreted Asp f2-like protein VDAL causes leaf wilting when applied to cotton leaves in vitro but enhances the resistance to V. dahliae when overexpressed in Arabidopsis or cotton without affecting the plant growth and development. VDAL protein interacts with Arabidopsis E3 ligases PUB25 and PUB26 (PUBs) and is ubiquitinated by PUBs in vitro. However, VDAL is not degraded by PUB25 or PUB26 in planta. Besides, the pub25 pub26 double mutant shows higher resistance to V. dahliae than the wild type. PUBs interact with the transcription factor MYB6 in a yeast two-hybrid screen. MYB6 promotes plant resistance to Verticillium wilt while PUBs ubiquitinate MYB6 and mediate its degradation. VDAL competes with MYB6 for binding to PUBs, and the role of VDAL in increasing Verticillium wilt resistance depends on MYB6. Taken together, these results suggest that plants evolute a strategy to utilize the invaded effector protein VDAL to resist the V. dahliae infection without causing a hypersensitive response (HR); alternatively, hemibiotrophic pathogens may use some effectors to keep plant cells alive during its infection in order to take nutrients from host cells. This study provides the molecular mechanism for plants increasing disease resistance when overexpressing some effector proteins without inducing HR, and may promote searching for more genes from pathogenic fungi or bacteria to engineer plant disease resistance.

16.
J Voice ; 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34470707

RESUMO

OBJECTIVES: The purpose of this study was to adapt and validate the Mandarin Chinese version of the pediatric Voice Handicap Index-10 (pVHI-10). METHODS: A cross-sectional study was conducted from January 2018 to December 2019. A total of 422 parents completed the questionnaire, including 283 parents of children with voice disorders (dysphonic group) and 139 parents of children without voice disorders (control group). Internal consistency, test-retest reliability, clinical effectiveness, and cut-off value were evaluated. RESULTS: In the dysphonic group, the internal consistency of the Mandarin Chinese version of pVHI-10 was excellent (Cronbach's α = 0.95). The test-retest reliability was excellent for the total score of the Mandarin Chinese version of pVHI-10 (interclass correlation coefficient = 0.916). The total scores as well as scores on individual items were significantly higher in the dyphonic group compared to those in the control group (P <0.001). In addition, the optimum cut-off value for the Mandarin Chinese version of pVHI-10 was 6.5 (87% sensitivity and 86.3% specificity, respectively). CONCLUSION: The Mandarin Chinese version of the pVHI-10 is a valid tool that evaluates the quality of life of children with voice disorders from the parents' perspective.

17.
Eur Radiol ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342693

RESUMO

OBJECTIVES: To evaluate the feasibility of high b-value diffusion-weighted imaging (DWI) for distinguishing non-muscle-invasive bladder cancer (NMIBC) from muscle-invasive bladder cancer (MIBC) and low- from high-grade bladder urothelial carcinoma using a fractional-order calculus (FROC) model as well as a combination of FROC DWI and bi-parametric Vesical Imaging-Reporting and Data System (VI-RADS). METHODS: Fifty-eight participants with bladder urothelial carcinoma were included in this IRB-approved prospective study. Diffusion-weighted images, acquired with 16 b-values (0-3600 s/mm2), were analyzed using the FROC model. Three FROC parameters, D, ß, and µ, were used for delineating NMIBC from MIBC and for tumor grading. A receiver operating characteristic (ROC) analysis was performed based on the individual FROC parameters and their combinations, followed by comparisons with apparent diffusion coefficient (ADC) and bi-parametric VI-RADS based on T2-weighted images and DWI. RESULTS: D and µ were significantly lower in the MIBC group than in the NMIBC group (p = 0.001 for each), and D, ß, and µ all exhibited significantly lower values in the high- than in the low-grade tumors (p ≤ 0.011). The combination of D, ß, and µ produced the highest specificity (85%), accuracy (78%), and the area under the ROC curve (AUC, 0.782) for distinguishing NMIBC and MIBC, and the best sensitivity (89%), specificity (86%), accuracy (88%), and AUC (0.892) for tumor grading, all of which outperformed the ADC. The combination of FROC parameters with bi-parametric VI-RADS improved the AUC from 0.859 to 0.931. CONCLUSIONS: High b-value DWI with a FROC model is useful in distinguishing NMIBC from MIBC and grading bladder tumors. KEY POINTS: • Diffusion parameters derived from a FROC diffusion model may differentiate NMIBC from MIBC and low- from high-grade bladder urothelial carcinomas. • Under the condition of a moderate sample size, higher AUCs were achieved by the FROC parameters D (0.842) and µ (0.857) than ADC (0.804) for bladder tumor grading with p ≤ 0.046. • The combination of the three diffusion parameters from the FROC model can improve the specificity over ADC (85% versus 67%, p = 0.031) for distinguishing NMIBC and MIBC and enhance the performance of bi-parametric VI-RADS.

18.
Microb Ecol ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342699

RESUMO

Host-parasite co-evolution is a process of reciprocal, adaptive genetic change. In natural conditions, parasites can shift to other host species, given both host and parasite genotypes allow this. Even though host-parasite co-evolution has been extensively studied both theoretically and empirically, few studies have focused on parasite gene flow between native and novel hosts. Nosema ceranae is a native parasite of the Asian honey bee Apis cerana, which infects epithelial cells of mid-guts. This parasite successfully switched to the European honey bee Apis mellifera, where high virulence has been reported. In this study, we used the parasite N. ceranae and both honey bee species as model organisms to study the impacts of two-host habitat sharing on parasite diversity and virulence. SNVs (Single Nucleotide Variants) were identified from parasites isolated from native and novel hosts from sympatric populations, as well as novel hosts from a parapatric population. Parasites isolated from native hosts showed the highest levels of polymorphism. By comparing the parasites isolated from novel hosts between sympatric and parapatric populations, habitat sharing with the native host significantly enhanced parasite diversity, suggesting there is continuing gene flow of parasites between the two host species in sympatric populations.

19.
Int J Pharm ; 607: 120979, 2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371151

RESUMO

The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (~30 nm) and a weak negative zeta potential of around -5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. Furthermore, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy.

20.
Biochem Biophys Res Commun ; 575: 1-7, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34454174

RESUMO

The pathogenesis of atherosclerosis is closely related to endothelial cell injury caused by lipid peroxidation-induced ferroptosis. Tanshinone IIA (TSA) protects endothelial tissues from damage. In this study, we investigated whether TSA exerts its protective effect on endothelial cells by inhibiting ferroptosis. Ferroptosis was induced in human coronary artery endothelial cells (HCAECs), and cells were treated with TSA. Morphological examination indicated that TSA exerted a significant protective effect on the HCAECs. This was further confirmed by LDH release and cell death detection assays. Flow cytometry revealed that TSA significantly reduced the excessive accumulation of total cellular ROS and lipid ROS caused by ferroptosis inducers. TSA also restored the reduction of glutathione (GSH), a potent and abundant reductant in cells. In addition, we found that TSA promoted the expression of NRF2, an essential player in response to oxidative stress, and its downstream genes. Immunofluorescent staining revealed that TSA promoted the nuclear translocation of NRF2. Increased nuclear translocation of NRF2 was validated by Western blot evaluation of cytoplasmic and nuclear protein extracts. Furthermore, NRF2 inhibition abolished the protective effects of TSA on HCAECs. These data demonstrate that TSA represses ferroptosis via activation of NRF2 in HCAECs.

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