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1.
Comput Struct Biotechnol J ; 23: 1477-1488, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38623562

RESUMO

Mycobacteria are causative agents of tuberculosis (TB), which is a global health concern. Drug-resistant TB strains are rapidly emerging, thereby necessitating the urgent development of new drugs. Two-component signal transduction systems (TCSs) are signaling pathways involved in the regulation of various bacterial behaviors and responses to environmental stimuli. Applying specific inhibitors of TCSs can disrupt bacterial signaling, growth, and virulence, and can help combat drug-resistant TB. We conducted a comprehensive pharmacophore-based inhibitor screening and biochemical and biophysical examinations to identify, characterize, and validate potential inhibitors targeting the response regulators PhoP and MtrA of mycobacteria. The constructed pharmacophore model Phar-PR-n4 identified effective inhibitors of formation of the PhoP-DNA complex: ST132 (IC50 = 29 ± 1.6 µM) and ST166 (IC50 = 18 ± 1.3 µM). ST166 (KD = 18.4 ± 4.3 µM) and ST132 (KD = 14.5 ± 0.1 µM) strongly targeted PhoP in a slow-on, slow-off manner. The inhibitory potency and binding affinity of ST166 and ST132 for MtrAC were comparable to those of PhoP. Structural analyses and molecular dynamics simulations revealed that ST166 and ST132 mainly interact with the α8-helix and C-terminal ß-hairpin of PhoP, with functionally essential residue hotspots for structure-based inhibitor optimization. Moreover, ST166 has in vitro antibacterial activity against Macrobacterium marinum. Thus, ST166, with its characteristic 1,2,5,6-tetrathiocane and terminal sulphonic groups, has excellent potential as a candidate for the development of novel antimicrobial agents to combat pathogenic mycobacteria.

2.
Obes Rev ; : e13748, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38590187

RESUMO

Adipose tissue is the first and primary target organ of obesity and the main source of circulating miRNAs in patients with obesity. This systematic review aimed to analyze and summarize the generation and mechanisms of adipose-derived miRNAs and their role as early predictors of various obesity-related complications. Literature searches in the PubMed and Web of Science databases using terms related to miRNAs, obesity, and adipose tissue. Pre-miRNAs from the Human MicroRNA Disease Database, known to regulate obesity-related metabolic disorders, were combined for intersection processing. Validated miRNA targets were sorted through literature review, and enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes via the KOBAS online tool, disease analysis, and miRNA transcription factor prediction using the TransmiR v. 2.0 database were also performed. Thirty miRNAs were identified using both obesity and adipose secretion as criteria. Seventy-nine functionally validated targets associated with 30 comorbidities of these miRNAs were identified, implicating pathways such as autophagy, p53 pathways, and inflammation. The miRNA precursors were analyzed to predict their transcription factors and explore their biosynthesis mechanisms. Our findings offer potential insights into the epigenetic changes related to adipose-driven obesity-related comorbidities.

3.
Nat Commun ; 15(1): 2552, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38514649

RESUMO

Sulfide electrolytes represent a crucial category of superionic conductors for all-solid-state lithium metal batteries. Among sulfide electrolytes, glassy sulfide is highly promising due to its long-range disorder and grain-boundary-free nature. However, the lack of comprehension regarding glass formation chemistry has hindered their progress. Herein, we propose interstitial volume as the decisive factor influencing halogen dopant solubility within a glass matrix. We engineer a Li3PS4-Li4SiS4 complex structure within the sulfide glassy network to facilitate the release of interstitial volume. Consequently, we increase the dissolution capacity of LiI to 40 mol% in 75Li2S-25P2S5 glass. The synthesized glass exhibits one of the highest ionic conductivities among reported glass sulfides. Furthermore, we develop a glassy/crystalline composite electrolyte to mitigate the shortcomings of argyrodite-type sulfides by utilizing our synthesized glass as the filler. The composite electrolytes effectively mitigate Li intrusion. This work unveils a protocol for the dissolution of halogen dopants in glass electrolytes.

4.
J Ethnopharmacol ; 328: 118097, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38531432

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa (CT) is the dried fleshy stem with scaly leaves of Cistanche tubiflora (Schenk) Wight, which has the effects of tonifying the kidney-yang, benefiting the vital essence and blood, and moisturizing the intestines and laxatives. There are differences in the activity of CT before and after processing, but the mechanism of processing is not clear. AIM OF THE STUDY: The study aimed to compare the strength of action of CT before and after yellow-wine processing in the treatment of constipation and kidney yang deficiency and to identify the active ingredients responsible for the differences in activity before and after yellow-wine processing. MATERIALS AND METHODS: This study established the fingerprints of CT and PCT using HPLC to identify their shared components. Then efficacy of KYDS and FC were carried out to compare the differences between CT and PCT in terms of efficacy. Next, this study established the spectrum-effect relationship between the shared chemical components and the medical effects of CT and PCT using the gray correlation analysis and entropy methods. Ultimately, the activity of the analyzed chemical components was verified using the zebrafish model. RESULTS: CT was more effective than PCT in promoting intestinal peristalsis, regulating gastrointestinal hormone levels, and thus treating FC. PCT was more effective than CT in improving the level of hormone indexes of the hypothalamus-pituitary-target gland axis, replenishing blood, and enhancing immunity. Through the analysis of the spectrum-effect relationship, it was finally found that 5, 6, 12 (tubuloside A), and 13 (isoacteoside) might be more closely related to the activity of tonifying kidney yang, and peaks 9, 10, and 11 (acteoside) are more closely associated with the treatment of constipation, and peaks 3 (salidroside), 4, 1, 2 (geniposidic acid), and 8 (echinacoside) were associated with both kidney yang tonic and treatment of constipation. At the same time, an activity verification experiment showed that echinacoside, geniposidic acid, and salidroside were effective in the treatment of FC and KYDS, while acteoside was very effective in the treatment of FC, and tubuloside A was significant in supplementing the blood, which validated the spectrum-effect relationship analysis. CONCLUSION: This study proved that the raw CT had a better laxative effect, while the yellow-wine processed CT had a better kidney-yang tonic effect; moreover, spectrum-effect relationships were established to analyze the chemical components leading to changes in the activity of CT before and after yellow-wine processing.


Assuntos
Cistanche , Glucosídeos , Glucosídeos Iridoides , Fenóis , Polifenóis , Animais , Quimiometria , Peixe-Zebra , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Constipação Intestinal
5.
J Ethnopharmacol ; 327: 118020, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38458341

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala tenuifilia Willd (Polygalaceae), a traditional Chinese medicine, has been used for a long time to treat various illnesses with serious adverse reactions. Glycyrrhizae radix et rhizoma processing is generally used to reduce the adverse reactions. AIM OF THE STUDY: The aim of this study was to validate the irritation caused by raw Polygalaceae (RPA), to investigate whether processed Polygalaceae (PGA) was less irritating, and to screen and validate irritant properties of virgaureagenin G (polygala acid, PA), 3,6'-disinapoylsucrose (DSS), Tenuifolia (TEN) and polygalaxanthone III (POL), which had pharmacologically active in Polygalaceae. Zebrafish model, Draize test and High-Performance Liquid Chromatography (HPLC) were utilized to achieve the aim. MATERIALS AND METHODS: Scanning Electron Microscopy (SEM) and optical microscope were used to determine the presence of calcium oxalate needle crystal in RPA and PGA. Zebrafish egg spinning changes and zebrafish embryo behavior were used for irritation validation, irritation comparison and irritant screening. For additional evidence, the Draize test, HE staining of rabbit eyes and ELISA kit were used. Finally, changes in the composition of RPA and PGA were investigated using HPLC. RESULTS: SEM and optical microscopy revealed no calcium oxalate needle crystals in Polygalaceae. RPA, PGA, PA and DSS were able to accelerate the spinning of zebrafish eggs and the movement of embryos, while TEN and POL were not. RPA, PGA, DSS and PA may cause rabbit eyes to become hyperemic and swollen, resulting in damage to the iris, cornea and conjunctiva and increased levels of interleukin-6 (IL-6) and interleukin-10 (IL-10). Comparatively, the effects caused by PGA were less severe than those caused by RPA. In addition, compared to RPA, PGA had lower levels of DSS and PA. CONCLUSIONS: RPA, PGA, DSS, and PA were irritating. However, processing and curing could reduce the irritation by reducing the levels of DSS and PA. DSS and PA could be two potential irritants of Polygalaceae.


Assuntos
Medicamentos de Ervas Chinesas , Glycyrrhiza , Polygala , Animais , Coelhos , Peixe-Zebra , Irritantes , Medicamentos de Ervas Chinesas/química , Raízes de Plantas/química , Polygala/química , Oxalato de Cálcio
6.
Lett Appl Microbiol ; 77(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38366661

RESUMO

This study aims to isolate microbial strains for producing mono-rhamnolipids with high proportion. Oily sludge is rich in petroleum and contains diverse biosurfactant-producing strains. A biosurfactant-producing strain LP20 was isolated from oily sludge, identified as Pseudomonas aeruginosa based on phylogenetic analysis of 16S rRNA. High-performance liquid chromatography-mass spectrometry results indicated that biosurfactants produced from LP20 were rhamnolipids, mainly containing Rha-C8-C10, Rha-C10-C10, Rha-Rha-C8-C10, Rha-Rha-C10-C10, Rha-C10-C12:1, and Rha-C10-C12. Interestingly, more mono-rhamnolipids were produced by strain LP20 with a relative abundance of 64.5%. Pseudomonas aeruginosa LP20 optimally produced rhamnolipids at a pH of 7.0 and a salinity of 0.1% using glycerol and nitrate. The culture medium for rhamnolipids by strain LP20 was optimized by response surface methodology. LP20 produced rhamnolipids up to 6.9 g L-1, increased by 116%. Rhamnolipids produced from LP20 decreased the water surface tension to 28.1 mN m-1 with a critical micelle concentration of 60 mg L-1. The produced rhamnolipids emulsified many hydrocarbons with EI24 values higher than 56% and showed antimicrobial activity against Staphylococcus aureus and Cladosporium sp. with inhibition rates 48.5% and 17.9%, respectively. Pseudomonas aeruginosa LP20 produced more proportion of mono-rhamnolipids, and the LP20 rhamnolipids exhibited favorable activities and promising potential in microbial-enhanced oil recovery, bioremediation, and agricultural biocontrol.


Assuntos
Decanoatos , Pseudomonas aeruginosa , Ramnose/análogos & derivados , Esgotos , Pseudomonas aeruginosa/genética , Filogenia , RNA Ribossômico 16S/genética , Glicolipídeos , Tensoativos/farmacologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-38334008

RESUMO

To move away from linear system mining-manufacture-production-disposal, most countries have been trying to establish a circular economy, by reusing waste as resources. Responding to this paradigm change, the Ministry of Environment of Korea amended the Wastes Control Act in the 2010s. To increase the recycling rate in Korea, the environmental assessment of recycling (EAR) has been introduced to improve the Wastes Control Act. The whole process of new recycling technologies can be assessed in terms of environmental or technical aspects by assessment institutes of the EAR. Finally, the governmental research institute can approve of an application case, which proves environmental friendliness, even if the technology is not defined in the current act. Recently, 17 companies have been coassessed and approved to recycle steel codes in waste tires as resources for iron smelting via assessments of the whole process, such as environmental analysis and quality assessment. The EAR has been enforcing recycling materials for six years, and the total profit of the companies that were approved was estimated to be approximately 55 million USD. However, many amendments to the EAR continue to be requested by stakeholders. In this study, the effect of the EAR was evaluated, and additional tasks were found to enhance the EAR. Integr Environ Assess Manag 2024;00:1-13. © 2024 SETAC.

8.
Sci Data ; 11(1): 206, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355745

RESUMO

The water footprint of a crop (WF) is a common metric for assessing agricultural water consumption and productivity. To provide an update and methodological enhancement of existing WF datasets, we apply a global process-based crop model to quantify consumptive WFs of 175 individual crops at a 5 arcminute resolution over the 1990-2019 period. This model simulates the daily crop growth and vertical water balance considering local environmental conditions, crop characteristics, and farm management. We partition WFs into green (water from precipitation) and blue (from irrigation or capillary rise), and differentiate between rainfed and irrigated production systems. The outputs include gridded datasets and national averages for unit water footprints (expressed in m3 t-1 yr-1), water footprints of production (m3 yr-1), and crop water use (mm yr-1). We compare our estimates to other global studies covering different historical periods and methodological approaches. Provided outputs can offer insights into spatial and temporal patterns of agricultural water consumption and serve as inputs for further virtual water trade studies, life cycle and water footprint assessments.

9.
Mo Med ; 121(1): 87-92, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38404440

RESUMO

Optic atrophy 1(OPA1) is a GTPase protein that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), the mitochondrial network morphology is compromised. Studies on TAR-DNA binding protein 43 (TDP-43) has been the focus in our lab. OPA1 and TDP-43 interaction may shed a light on how aberrant TDP-43 interacts with OPA1, which will lead to mitochondrial dysfunction. The preliminary study tested the idea of whether OPA1 and TDP-43 are physically interacting in human platelet derived mitochondria obtained from healthy human subjects.


Assuntos
Esclerose Amiotrófica Lateral , Proteínas de Ligação a DNA , GTP Fosfo-Hidrolases , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Isoformas de Proteínas/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo
10.
Mol Metab ; 81: 101892, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38331318

RESUMO

BACKGROUND: Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of Atg7 gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity remain uncertain. The study aimed to elucidate the role and underly mechanism of Atg7 action in the context of obesity-induced muscle mass decline. METHODS: In this study, we established a murine model of high-fat diet-induced obesity (DIO) and introduced adeno-associated virus delivery of short hairpin RNA to knock down Atg7 (shAtg7) into the gastrocnemius muscle. We then examined the expressions of Atg7 and myoprotein degradation markers in the gastrocnemius tissues of obese patients and mice using immunofluorescence and western blotting techniques. To further investigate the effects of Atg7, we assessed skeletal muscle cell diameter and the myoprotein degradation pathway in C2C12 and HSkMC cells in the presence or absence of Atg7. Immunofluorescence staining for MyHC and western blotting were utilized for this purpose. To understand the transcriptional regulation of Atg7 in response to myoprotein degradation, we conducted luciferase reporter assays and chromatin immunoprecipitation experiments to examine whether FoxO3a enhances the transcription of Atg7. Moreover, we explored the role of Akt in Atg7-mediated regulation and its relevance to obesity-induced muscle mass decline. This was accomplished by Akt knockdown, treatment with MK2206, and GST pulldown assays to assess the interaction between Atg7 and Akt. RESULTS: After 20 weeks of being on a high-fat diet, obesity was induced, leading to a significant decrease in the gastrocnemius muscle area and a decline in muscle performance. This was accompanied by a notable increase in Atg7 protein expression (p < 0.01). Similarly, in gastrocnemius tissues of obese patients when compared to nonobese individuals, there was a significant increase in both Atg7 (p < 0.01) and TRIM63 (p < 0.01) levels. When palmitic acid was administered to C2C12 cells, it resulted in increased Atg7 (p < 0.01), LC3Ⅱ/Ⅰ (p < 0.01), and p62 levels (p < 0.01). Additionally, it promoted FoxO3a-mediated transcription of Atg7. The knockdown of Atg7 in the gastrocnemius partially reversed DIO-induced muscle mass decline. Furthermore, when Atg7 was knocked down in C2C12 and HSkMC cells, it mitigated palmitic acid-induced insulin resistance, increased the p-Akt/Akt ratio (p < 0.01), and reduced TRIM63 (p < 0.01). Muscular atrophy mediated by Atg7 was reversed by genetic knockdown of Akt and treatment with the p-Akt inhibitor MK2206. Palmitic acid administration increased the binding between Atg7 and Akt (p < 0.01) while weakening the binding of PDK1 (p < 0.01) and PDK2 (p < 0.01) to Akt. GST pulldown assays demonstrated that Atg7 directly interacted with the C-terminal domain of Akt. CONCLUSION: The consumption of a high-fat diet, along with lipid-induced effects, led to the inhibition of Akt signaling, which, in turn, promoted FoxO3a-mediated transcription, increasing Atg7 levels in muscle cells. The excess Atg7 inhibited the phosphorylation of Akt, leading to a cyclic activation of FoxO3a and exacerbating the decline in muscle mass regulated by obesity. Consequently, Atg7 serves as a regulatory point in determining the decline in muscle mass induced by obesity.


Assuntos
Ácido Palmítico , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Transdução de Sinais , Fibras Musculares Esqueléticas/metabolismo , Obesidade/metabolismo , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo
11.
Environ Pollut ; 345: 123561, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38355081

RESUMO

Tire wear particles (TWPs), abundant in the aquatic environment, pose potential ecological risks, yet their implications have not been extensively studied. Rolling friction TWPs, sliding friction TWPs (S-TWPs) and cryogenically milled tire treads were used as research objects to study the ecotoxicity and difference of the above materials before and after aging in natural water (AS-TWPs) to the periphytic biofilm. The results showed that there were significant differences in the microstructure, surface elements, size, functional groups and environmentally persistent free radicals (EPFRs) of the three TWPs. After aging in natural water, the properties of the three TWPs mentioned above showed homogenization, but the EPFRs and reactive oxygen species (ROS) yield were different. After exposure to TWPs (10 mg L-1), total organic carbon and adenosine triphosphate decreased significantly (p < 0.05), and the production of extracellular polymeric substances (EPS) in the periphytic biofilm increased, in which the content of humic-like substance and proteins (tryptophan protein and humic acid-like substances) increased obviously. The increment of TB-EPS was higher than that of LB-EPS, and S-TWPs and AS-TWPs had the strongest promoting effect on EPS secretion. In addition, 10 mg L-1 TWPs caused massive cell death in the periphytic biofilm, which was more obvious in the S-TWPs and AS-TWPs exposure group. The toxic mechanism of TWPs promotes intracellular ROS accumulation and leads to the release of lactate dehydrogenase, which was attributed to the formation of EPFRs on the surface of TWPs and an increase in EPFRs intensity after aging in natural water. TWPs at environmentally relevant concentrations (0.1 mg L-1) had no biological toxicity to periphytic biofilms. This study fills the gap in the study of the surface structure characteristics of TWPs on the toxicity of periphytic biofilms, and is of great significance to the study of the aquatic toxicity mechanism of TWPs.


Assuntos
Biofilmes , Água , Espécies Reativas de Oxigênio , Matriz Extracelular de Substâncias Poliméricas
12.
Sci Total Environ ; 920: 170765, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38340839

RESUMO

Nutrient runoff into rivers caused by human activity has led to global eutrophication issues. The Nakdong River in South Korea is currently facing significant challenges related to eutrophication and harmful algal blooms, underscoring the critical importance of managing total nitrogen (T-N) levels. However, traditional methods of indoor analysis, which depend on sampling, are labor-intensive and face limitations in collecting high-frequency data. Despite advancements in sensor allowing for the measurement of various parameters, sensors still cannot directly measure T-N, necessitating surrogate regression methods. Therefore, we conducted T-N predictions using a water quality dataset collected from 2018 to 2022 at 157 observatories within the Nakdong River basin. To account for the water quality characteristics of each location, we employed a clustering technique to divide the basin and compared a Gaussian mixture model with K-means clustering. Moreover, optimal regressor for each cluster was selected by comparing multiple linear regression (MLR), random forest, and XGBoost. The results showed that forming four clusters via K-means clustering was the most suitable approach and MLR was reasonably accurate for all clusters. Subsequently, recursive feature elimination cross-validation was used to identify suitable parameters for T-N prediction, thus leading to the construction of high-accuracy T-N prediction models. Clustering was useful not only for improving the regressors but also for spatially analyzing the water quality characteristics of the Nakdong River. The MLR model can reveal causal relationships and thus is useful for decision-making. The results of this study revealed that the combination of a simple linear regression model and clustering method can be applied to a wide watershed. The clustering-based regression model showed potential for accurately predicting T-N at the basin level and is expected to contribute to nationwide water quality management through future applications in various fields.

13.
Sci Total Environ ; 914: 169807, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38211873

RESUMO

China has formulated several policies to alleviate the water pollution load, but few studies have quantitatively analyzed their impacts on future water pollution loads in China. Based on grey water footprint (GWF) assessment and scenario simulation, we analyze the water pollution (including COD, NH3-N, TN and TP) in China from 2021 to 2035 under different scenarios for three areas: consumption-side, production-side and terminal treatment. We find that under the current policy scenario, the GWF of COD, NH3-N, TN, and TP in China could be reduced by 15.0 % to 39.9 %; the most effective measures for GWF reduction are diet structure change (in the consumption-side area), and the wastewater treatment rate and livestock manure utilization improvement (in the terminal treatment area). However, the GWF will still increase in 8 provinces, indicating that the current implemented policy is not universally effective in reducing GWF across all provinces. Under the technical improvement scenario, the GWF of the four pollutants will decrease by 54.9 %-71.1 % via improvements in the current measures related to current policies and new measures in the production-side area and the terminal treatment area; thus, GWF reduction is possible in all 31 provinces. However, some policies face significant challenges in achieving full implementation, and certain policies are only applicable to a subset of provinces. Our detailed analysis of future water pollution scenarios and response options to reduce pollution loads can help to inform the protection of freshwater resources in China and quantitatively assess the effectiveness of policies in other fields.

15.
Angew Chem Int Ed Engl ; 63(12): e202316360, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38243690

RESUMO

Halide solid electrolytes (SEs) have attracted significant attention due to their competitive ionic conductivity and good electrochemical stability. Among typical halide SEs (chlorides, bromides, and iodides), substantial efforts have been dedicated to chlorides or bromides, with iodide SEs receiving less attention. Nevertheless, compared with chlorides or bromides, iodides have both a softer Li sublattice and lower reduction limit, which enable iodides to possess potentially high ionic conductivity and intrinsic anti-reduction stability, respectively. Herein, we report a new series of iodide SEs: Lix YI3+x (x=2, 3, 4, or 9). Through synchrotron X-ray/neutron diffraction characterizations and theoretical calculations, we revealed that the Lix YI3+x SEs belong to the high-symmetry cubic structure, and can accommodate abundant vacancies. By manipulating the defects in the iodide structure, balanced Li-ion concentration and generated vacancies enables an optimized ionic conductivity of 1.04 × 10-3  S cm-1 at 25 °C for Li4 YI7 . Additionally, the promising Li-metal compatibility of Li4 YI7 is demonstrated via electrochemical characterizations (particularly all-solid-state Li-S batteries) combined with interface molecular dynamics simulations. Our study on iodide SEs provides deep insights into the relation between high-symmetry halide structures and ionic conduction, which can inspire future efforts to revitalize halide SEs.

16.
Adv Healthc Mater ; 13(2): e2301124, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37820720

RESUMO

A nanopatterned interdigitated electrode array (nanoIEA)-based impedance assay is developed for quantitative real-time measurement of aligned endothelial cell (EC) barrier functions in vitro. A bioinspired poly(3,4-dihydroxy-L-phenylalanine) (poly (l-DOPA)) coating is applied to improve the human brain EC adhesion onto the Nafion nanopatterned surfaces. It is found that a poly (l-DOPA)-coated Nafion grooved nanopattern makes the human brain ECs orient along the nanopattern direction. Aligned human brain ECs on Nafion nanopatterns exhibit increased expression of genes encoding tight and adherens junction proteins. Aligned human brain ECs also have enhanced impedance and resistance versus unaligned ones. Treatment with a glycogen synthase kinase-3 inhibitor (GSK3i) further increases impedance and resistance, suggesting synergistic effects occur on the cell-cell tightness of in vitro human brain ECs via a combination of anisotropic matrix nanotopography and GSK3i treatment. It is found that this enhanced cell-cell tightness of the combined approach is accompanied by increased expression of claudin protein. These data demonstrate that the proposed nanoIEA assay integrated with poly (l-DOPA)-coated Nafion nanopatterns and interdigitated electrode arrays can make not only biomimetic aligned ECs, but also enable real-time measurement of the enhanced barrier functions of aligned ECs via tighter cell-cell junctions.


Assuntos
Células Endoteliais , Polímeros de Fluorcarboneto , Levodopa , Humanos , Impedância Elétrica , Levodopa/metabolismo , Levodopa/farmacologia , Endotélio
17.
Int Immunopharmacol ; 127: 111437, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38150882

RESUMO

OBJECTIVES: Myocardial inflammation underlies a broad spectrum of conditions that cause damage to the myocardium and lead to structural and functional defects. Homocysteine (Hcy) is closely related to the occurrence and development of cardiovascular diseases. We investigated the mechanism underlying the effects of vitamin D as a prophylactic treatment for Hcy-induced cardiac inflammation. METHODS: The levels of 25(OH)D3 and Hcy were assessed using ELISA kits. Expression levels of the vitamin D receptor (VDR), NFE2 like bZIP transcription factor 2 (NFE2L2), methylenetetrahydrofolate reductase (MTHFR) and inflammatory factors were examined by Western blotting, immunohistochemistry and real time polymerase chain reaction. NFE2L2/MTHFR-knockdown HL-1 cells and NFE2L2+/- mouse were used to test the effects of vitamin D. RESULTS: We found the levels of Hcy in the serum and myocardial tissue of mice in the Hcy + CCE group were lower than in the Hcy groups, which was opposed to the trend exhibited by the serum 25(OH)D3 level of mice. The mRNA and protein expression levels of the inflammatory factors in cardiac tissues and cardiomyocytes were strongly decreased by the Hcy treatment, compared to the Hcy + CCE/Hcy + 1,25(OH)2D3 groups. Moreover, the results revealed that the level of nuclear NFE2L2 in Hcy + CCE/Hcy + 1,25(OH)2D3 group was increased compared to Hcy group with a reciprocal decrease in the level of cytosolic NFE2L2 in vivo and in vitro. Similarly, the MTHFR mRNA and protein expression in the Hcy + CCE group was higher than the Hcy group. We determined that NFE2L2 promoted the expression of MTHFR. However, based on Hcy treatment, the combination of 1,25(OH)2D3 and MTHFR-/- reversed the decline in IL-6 and TNFα expression caused by 1,25(OH)2D3 alone. Chromatin immunoprecipitation and luciferase reporter assays showed the up-regulation effect of VDR on NFE2L2 and NFE2L2 on MTHFR. CONCLUSIONS: Our findings indicate that vitamin D/VDR could improve Hcy-induced myocardial inflammation through activation of NFE2L2 mediated MTHFR.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2) , Vitamina D , Camundongos , Animais , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Calcitriol/farmacologia , Vitaminas , RNA Mensageiro/metabolismo , Inflamação/tratamento farmacológico
18.
Transplant Cell Ther ; 30(3): 314.e1-314.e12, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38103787

RESUMO

Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.


Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células-Tronco de Sangue Periférico , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Adulto Jovem , Alemtuzumab/uso terapêutico , Medula Óssea , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T , Doadores não Relacionados
19.
Oral Dis ; 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38135895

RESUMO

OBJECTIVE: Midpalatal expansion (MPE) is routinely employed to treat transverse maxillary arch deficiency. Neutrophils are indispensable for recruiting bone marrow stromal cells (BMSCs) at the initial stage of bone regeneration. This study aimed to explore whether neutrophils participate in MPE and how they function during bone formation under mechanical stretching. MATERIALS AND METHODS: The presence and phenotype of neutrophils in the midpalatal suture during expansion were detected by flow cytometry and immunofluorescence staining. The possible mechanism of neutrophil recruitment and polarization was explored in vitro by exposing vascular endothelial cells (VECs) to cyclic tensile strain. RESULTS: The number of neutrophils in the distracted suture peaked on Day 3, and N2-type neutrophils significantly increased on Day 5 after force application. The depletion of circulatory neutrophils reduced bone volume by 43.6% after 7-day expansion. The stretched VECs recruited neutrophils via a CXCR2 mechanism in vitro, which then promoted BMSC osteogenic differentiation through the VEGFA/VEGFR2 axis. Consistently, these neutrophils showed higher expression of canonical N2 phenotype genes, including CD206 and Arg1. CONCLUSIONS: These results suggested that neutrophils participated in early bone formation during MPE. Based on these findings, we propose that stretched VECs recruited and polarized neutrophils, which, in turn, induced BMSC osteogenic differentiation.

20.
Clin Park Relat Disord ; 9: 100225, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965070

RESUMO

Introduction: Motor and nonmotor Parkinson's disease (PD) symptoms can negatively influence employment, which may contribute to financial hardship. This article explores the association between financial hardship, employment challenges, and quality of life in people with early PD. Methods: We measured financial hardship with a validated summary item (5-point scale, lower score - less hardship) and the Comprehensive Score for Financial Toxicity (0-44, lower score worse toxicity) in a cohort of 60 employed individuals with early PD (<5 years). We used Spearman's Correlations and nonparametric tests to identify associations between financial hardship, demographic characteristics, PD-related factors, employment factors, and quality of life (Neuro-QOL computer adapted measures). Results: The sample was mostly white (93 %) and male (65 %). The plurality were highly-educated with graduate degrees (42 %). Of the 60 participants, 23 (38 %) reported a little bit and 14 (23 %) reported somewhat or more hardship. Comprehensive financial toxicity (22.0 ± 8.7) was correlated moderately (ρ = -0.56) with the single-item summary score. High financial hardship was associated with reduced confidence in job retention (ρ = -0.43, p = 0.001) and reduced perceived workplace success (ρ = -0.352, p = 0.006). Financial hardship was also associated with poorer quality of life in five Neuro-QOL domains: lower extremity function, satisfaction with social roles and activities, depression, anxiety, and stigma (p < 0.05). Conclusion: Financial hardship was common and was associated with employment challenges and poor quality of life. Further work should explore the effects of medical and psychosocial interventions to alleviate financial and employment challenges in individuals with early PD.

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