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OBJECTIVE: This study aimed to apply music therapy as a clinical treatment for patients with breast cancer (BC) experiencing mild or moderate depression during hospitalization and observe any improvements in their depression and quality of life. METHODS: A total of 102 patients who had mild-to-moderate depression, were diagnosed with BC, and were admitted to our hospital from October 2022 to October 2023 were selected as the subjects of a retrospective analysis. According to their participation in short-term music therapy, they were divided into a control group (routine nursing treatment n = 45) and an observation group (routine nursing treatment + music therapy n = 57). Self-rating depression (SDS) scale and functional assessment of cancer therapy-breast (FACT-B) scale Chinese version 4.0 scores and patient satisfaction after treatment were compared between the two groups. RESULTS: After treatment, the SDS scale scores and FACT-B scores of the observation group were significantly better than those of the control group (P < 0.001). The patient satisfaction in the observation group was higher than in the control group (P < 0.05). CONCLUSION: Music therapy is a highly safe method to improve the depression and quality of life of patients with BC. It also provides a simple and convenient nondrug clinical treatment with broad application prospects.
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Neoplasias da Mama , Depressão , Musicoterapia , Qualidade de Vida , Humanos , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Musicoterapia/métodos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Depressão/terapia , Depressão/psicologia , Satisfação do Paciente , Hospitalização , Emoções , IdosoRESUMO
Objectives: Magnetic resonance imaging (MRI) is increasingly used to detect knee osteoarthritis (KOA). In this study, we aimed to systematically examine the global research status on the application of medical knee MRI in the treatment of KOA, analyze research hotspots, explore future trends, and present results in the form of a knowledge graph. Methods: The Web of Science core database was searched for studies on medical knee MRI scans in patients with KOA between 2004 and 2023. CiteSpace, SCImago Graphica, and VOSviewer were used for the country, institution, journal, author, reference, and keyword analyses. Results: A total of 2,904 articles were included. The United States and Europe are leading countries. Boston University is the main institution. Osteoarthritis and cartilage is the main magazine. The most frequently cocited article was "Radiological assessment of osteoarthrosis". Guermazi A was the author with the highest number of publications and total references. The keywords most closely linked to MRI and KOA were "cartilage", "pain", and "injury". Conclusions: The application of medical knee MRI in KOA can be divided into the following parts: (1). MRI was used to assess the relationship between the characteristics of local tissue damage and pathological changes and clinical symptoms. (2).The risk factors of KOA were analyzed by MRI to determine the early diagnosis of KOA. (3). MRI was used to evaluate the efficacy of multiple interventions for KOA tissue damage (e.g., cartilage defects, bone marrow edema, bone marrow microfracture, and subchondral bone remodeling). Artificial intelligence, particularly deep learning, has become the focus of research on MRI applications for KOA.
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Objective: To explore the relationship between the exposure level of particulate matter 2.5 (PM2.5) and particulate matter 10 (PM10) in the air of pregnant women during preconception and first trimester of pregnancy and the risk of gestational diabetes mellitus (GDM). Methods: The data of pregnant women delivered in 22 monitoring hospitals in Hebei Province from 2019 to 2021 were collected, and the daily air quality data of their cities were used to calculate the exposure levels of PM2.5 and PM10 in different pregnancy stages, and logistic regression model was used to analyze the impact of exposure levels of PM2.5 and PM10 on GDM during preconception and first trimester of pregnancy. Results: 108,429 singleton live deliveries were included in the study, of which 12,967 (12.0%) women had a GDM diagnosis. The prevalence of GDM increased over the course of the study from 10.2% (2019) to 14.9% (2021). From 2019 to 2021, the average exposure of PM2.5 and PM10 was relatively 56.67 and 103.08µg/m3 during the period of preconception and first trimester of pregnancy in Hebei Province. Handan, Shijiazhuang, and Xingtai regions had the most severe exposure to PM2.5 and PM10, while Zhangjiakou, Chengde, and Qinhuangdao had significantly lower exposure levels than other regions. The GDM group had statistically higher exposure concentrations of PM2.5 and PM10 during the period of preconception, first trimester, preconception and first trimester (P<0.05). Multivariate logistic regression analysis showed that the risk of GDM increases by 4.5%, 6.0%, and 10.6% for every 10ug/m3 increase in the average exposure value of PM2.5 in preconception, first trimester, preconception and first trimester, and 1.7%, 2.1%, and 3.9% for PM10. Moreover, High exposure to PM2.5 in the first, second, and third months of preconception and first trimester is associated with the risk of GDM. And high exposure to PM10 in the first, second, and third months of first trimester and the first, and third months of preconception is associated with the risk of GDM. Conclusion: Exposure to high concentrations of PM2.5 and PM10 during preconception and first trimester of pregnancy can significantly increase the risk of GDM. It is important to take precautions to prevent exposure to pollutants, reduce the risk of GDM, and improve maternal and fetal outcomes.
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Poluição do Ar , Diabetes Gestacional , Exposição Materna , Material Particulado , Primeiro Trimestre da Gravidez , Humanos , Feminino , Gravidez , Diabetes Gestacional/epidemiologia , China/epidemiologia , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Adulto , Material Particulado/análise , Material Particulado/efeitos adversos , Exposição Materna/efeitos adversos , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/efeitos adversos , Estudos de Coortes , Exposição Ambiental/efeitos adversos , Adulto JovemRESUMO
Ray parenchyma cells are involved in the initiation of heartwood formation. The position within a ray influences the timing of ray parenchyma cell differentiation and function; however, there is little information concerning the positional influence on the cellular changes of ray parenchyma cells from sapwood and heartwood. In this study, radial variations in morphology, size, and ultrastructure of ray parenchyma cells were studied by combined transmission electron microscopy and optical microscopy. Results showed that cellular traits of ray parenchyma cells in Populus tomentosa were all affected by both radial position in the secondary xylem and position within a ray. Specifically, radial variations in cellular traits were more evident in isolation cells, which were not adjacent to vessel elements. Both cell length and cell width/length ratio of isolation cells were bigger than contact cells, which contacted adjacent vessel elements via pits. Moreover, the secondary wall thickening and lignification of contact cells developed in the current-year xylem, much earlier than isolation cells. Secondary walls in contact cells were in a polylamellate structure with a protective layer on the inner side. No alteration in the ultrastructure of contact cells occurred in the sapwood-heartwood transition zone, except that most contact cells died. By contrast, in the transition zone, isolation cells still lived. A thin secondary wall began to deposit on the thick primary wall of isolation cells, with two isotropic layers on the inner side of the primary wall and secondary wall respectively being characteristic. Meanwhile, starch grains in isolation cells were depleted, and dark polyphenolic droplets lost their spherical shape and flowed together. Furthermore, the intercellular spaces of isolation cells became densified in the transition zone. Overall, cellular changes suggested that the positional information of ray parenchyma cells appeared to be an important factor in the transformation from sapwood to heartwood. Unlike contact cells, isolation cells were more elongated, specialized in radial transport, had a delayed formation of secondary walls, and were involved in the synthesis of heartwood substances. Our result promotes the elucidation of the involvement of xylem rays in heartwood formation.
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This study introduces an improved Ski Climate Index (SCI) designed to assess skiing suitability in China by applying fuzzy logic. Using daily meteorological data from 733 weather stations for the periods 1961-1990 and 1991-2020, the study identifies significant changes in SCI distribution over time. Additionally, a coupled analysis is performed, integrating the SCI results with the distribution and spatial vitality of 389 ski resorts in China. This analysis provides a comprehensive understanding of the interplay between actual ski resources and the ongoing evolution of the skiing industry in China and three significant results:1) The snow module has a major impact on SCI distribution, while other non-snow natural elements, such as sunshine duration, wind speed, and thermal comfort, influence the overall SCI assessment less; 2) High SCI values are concentrated in Northwestern and Northeastern China, with increased ski climate resources being observed in Shaanxi-Gansu-Ningxia, Southwest Tibet, and Sichuan due to climate change and noticeable declines in the Southern regions of Northeast China.; 3) In terms of the distribution and vitality of ski resorts, the SCI also partially reflects the development of ski resorts. This skiing suitability model uses climate resources to offer valuable insights for key decision-making in resort development and operation, thereby supporting advancement of the ice-snow economy.
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Bacterial resistance poses a significant threat to both human and animal health. N-acetylcysteine (NAC), which is used as an anti-inflammatory, has been shown to have distinct and contrasting impacts on bacterial resistance. However, the precise mechanism underlying the relationship between NAC and bacterial resistance remains unclear and requires further investigation. In this study, we study the effect of NAC on bacterial resistance and the underlying mechanisms. Specifically, we examine the effects of NAC on Edwardsiella tarda ATCC15947, a pathogen that exhibits resistance to many antibiotics. We find that NAC can promote resistance of E. tarda to many antibiotics, such as doxycycline, resulting in an increase in the bacterial survival rate. Through proteomic analysis, we demonstrate that NAC activates the amino acid metabolism pathway in E. tarda, leading to elevated intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS). Additionally, NAC reduces antibiotic influx while enhancing efflux, thus maintaining low intracellular antibiotic concentrations. We also propose that NAC promotes protein aggregation, thus contributing to antibiotic resistance. Our study describes the mechanism underlying E. tarda resistance to doxycycline and cautions against the indiscriminate use of metabolite adjuvants.
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Acetilcisteína , Antibacterianos , Doxiciclina , Farmacorresistência Bacteriana , Edwardsiella tarda , Edwardsiella tarda/efeitos dos fármacos , Edwardsiella tarda/genética , Doxiciclina/farmacologia , Antibacterianos/farmacologia , Acetilcisteína/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Animais , Glutationa/metabolismo , Proteômica , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Testes de Sensibilidade MicrobianaRESUMO
With the rapid development of information technology (e.g., Internet of Things (IoT) and artificial intelligence (AI)), piezoelectric sensor (i.e., piezoelectric nanogenerator, PENG) receives an increasing number attention in the field of self-powered wearable devices. Taking piezoelectric fiber as an example, it shows promising application for wearable devices owing to its light weight and high flexibility compared with block electronic devices. However, it still remains a challenge to fabricate low-cost and high-performance piezoelectric fiber via a large-scale but efficient method. In this study, via extrusion molding and leaching, a core-sheath piezoelectric sensor is facilely fabricated, whose core and sheath layer are respectively slender steel wire (i.e., electrode) and PVDF microfibrillar bundle (PMB) (i.e., piezoelectric layer). Such piezoelectric sensor shows decent output performance in both pressing (12.3 V) and bending (0.32 V) mode. Meanwhile, it possesses sensitive stress responsiveness when serving for self-powered sensing. Furthermore, such piezoelectric sensors can realize wearable signal transmission and human motion monitoring, showing promising potential for wearable devices in the future. This work proposes a large-scale but efficient method for fabricating high-performance PVDF microfibril based piezoelectric fiber, opening a new pathway to develop self-powered sensors following the concept of polymer "structuring" processing.
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BACKGROUND: Idiopathic ventricular arrhythmias (IVAs) arising from different portions of the communicating vein of the left ventricular summit (summit-CV) are not a rare phenomenon. Whereas its electrocardiographic (ECG) and electrophysiological characteristics are not fully investigated. OBJECTIVE: This study aimed to identify distinct ECG and electrophysiological features of IVAs originating from different portions of summit-CV. METHODS: Nineteen patients confirmed arising from summit-CV were included in this study. RESULTS: The 19 patients were divided into proximal and distal portion groups based on their target sites in summit-CV. In the proximal portion group, 100% (11/11) VAs showed dominant negative (rs or QS) waves in lead I, while in the distal portion group, 87.5% (7/8) showed dominant positive waves (R, Rs or r) (p < 0.000). In lead V1, 100% (11/11) of the proximal portion group showed dominant positive waves (R or Rs), while 62.50% (5/8) of the distal portion group showed positive and negative bidirectional or negative waves (RS or rS) (p < 0.005). RI>4mV, SI<3.5mV, RV1<13mV, SV1>3.5mV, RI/SI>0.83, and RV1/SV1< 2.6 indicated a distal portion of summit-CV with the predictive value of 0.909, 1.000, 0.653, 0.972, 0.903, 0.966, respectively. A more positive wave in lead I and a more negative wave in lead V1 indicated more distal origin in summit-CV. Target sites in proximal and distal summit-CV groups showed similar electrophysiological characteristics during mapping. CONCLUSIONS: There were significant differences in ECG characteristics of VAs at different portions of summit-CV, which could aid pre-procedure planning and facilitate radiofrequency catheter ablation (RFCA) procedures.
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Potenciais de Ação , Ablação por Cateter , Eletrocardiografia , Frequência Cardíaca , Ventrículos do Coração , Valor Preditivo dos Testes , Humanos , Ablação por Cateter/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/cirurgia , Taquicardia Ventricular/diagnóstico , Técnicas Eletrofisiológicas Cardíacas , Estudos Retrospectivos , IdosoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a prevalent stress disorder, yet the underlying physiological mechanisms linking stress to appetite and weight loss remain elusive. While most antidepressants are associated with excessive weight and appetite gain, sertraline (SER) exhibits a lower risk of these side effects. Metacinnabar (ß-HgS), the primary component of Tibetan medicine Zuotai, has been shown to enhance mice's resilience against external stress without causing excessive increases in weight or appetite. However, the precise physiological pathway through which ß-HgS restores appetite and weight in stressed mice remains unclear. AIM OF THE STUDY: The objective of this study is to assess the efficacy of ß-HgS in ameliorating weight loss and appetite suppression induced by pressure stimulation in mice, as well as elucidate its potential mechanisms of action. METHODS: The present study employed chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) as experimental models to simulate environmental stress encountered in daily life. Subsequently, a series of experiments were conducted, including behavior tests, HE staining of rectal and hippocampal pathological sections, detection of depression-related biological indicators, analysis of intestinal flora diversity, as well as metabolomics analysis of hippocampal and intestinal contents. RESULT: Dysregulation of glycerophospholipid metabolism may represent the principal pathway underlying reduced appetite, body weight, neurotransmitter and appetite hormone levels, heightened inflammatory response, hippocampal and rectal tissue damage, as well as altered composition of intestinal microbiota in stressed mice. Following intervention with SER and ß-HgS in stressed mice, the deleterious effects induced by stress can be ameliorated, in which the medium-dose ß-HgS exhibited superior performance. CONCLUSION: The aforementioned research findings suggest that the stress-induced decrease in appetite and body weight in mice may be associated with dysregulation in glycerophospholipid metabolism connecting the gut-brain axis. ß-HgS exhibits potential in ameliorating depressive-like symptoms in mice subjected to stress, while concurrently restoring their body weight and appetite without inducing excessive augmentation. Its therapeutic effect may also be attributed to its ability to modulate glycerophospholipid metabolism status and exert influence on the gut-brain axis.
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Apetite , Microbioma Gastrointestinal , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/tratamento farmacológico , Camundongos , Apetite/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Comportamento Animal/efeitos dos fármacosRESUMO
Mogrosides are natural compounds highly valued in the food sector for their exceptional sweetness. Here, we report a novel O-glycosyltransferase (UGT74DD1) from Siraitia grosvenorii that catalyzes the conversion of mogrol to mogroside IIE. Site-directed mutagenesis yielded the UGT74DD1-W351A mutant, which exhibited the new capability to transform mogroside IIE into the valuable sweetener mogroside III, but with low catalytic activity. Subsequently, using structure-guided directed evolution with combinatorial active-site saturation testing, the superior mutant M6 (W351A/Q373 K/E49H/Q335W/S278C/D17F) were obtained, which showed a 46.1-fold increase in catalytic activity compared to UGT74DD1-W351A. Molecular dynamics simulations suggested that the enhanced activity and extended substrate profiles of M6 are due to its enlarged substrate-binding pocket and strengthened enzyme-substrate hydrogen bonding interactions. Overall, we redesigned UGT74DD1, yielding mutants that catalyze the conversion of mogrol into mogroside III. This study thus broadens the toolbox of UGTs capable of catalyzing the formation of valuable polyglycoside compounds.
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Glicosiltransferases , Edulcorantes , Glicosiltransferases/genética , Glicosiltransferases/química , Glicosiltransferases/metabolismo , Edulcorantes/química , Edulcorantes/metabolismo , Cucurbitaceae/química , Cucurbitaceae/enzimologia , Cucurbitaceae/genética , Cucurbitaceae/metabolismo , Mutagênese Sítio-Dirigida , Proteínas de Plantas/genética , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Biocatálise , Domínio Catalítico , Engenharia de Proteínas , Especificidade por Substrato , CinéticaRESUMO
Aporphine alkaloids have diverse pharmacological activities; however, our understanding of their biosynthesis is relatively limited. Previous studies have classified aporphine alkaloids into two categories based on the configuration and number of substituents of the D-ring and have proposed preliminary biosynthetic pathways for each category. In this study, we identified two specific cytochrome P450 enzymes (CYP80G6 and CYP80Q5) with distinct activities toward (S)-configured and (R)-configured substrates from the herbaceous perennial vine Stephania tetrandra, shedding light on the biosynthetic mechanisms and stereochemical features of these two aporphine alkaloid categories. Additionally, we characterized two CYP719C enzymes (CYP719C3 and CYP719C4) that catalyzed the formation of the methylenedioxy bridge, an essential pharmacophoric group, on the A- and D-rings, respectively, of aporphine alkaloids. Leveraging the functional characterization of these crucial cytochrome P450 enzymes, we reconstructed the biosynthetic pathways for the two types of aporphine alkaloids in budding yeast (Saccharomyces cerevisiae) for the de novo production of compounds such as (R)-glaziovine, (S)-glaziovine, and magnoflorine. This study provides key insight into the biosynthesis of aporphine alkaloids and lays a foundation for producing these valuable compounds through synthetic biology.
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Aporfinas , Sistema Enzimático do Citocromo P-450 , Saccharomyces cerevisiae , Aporfinas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Saccharomyces cerevisiae/metabolismo , Stephania/metabolismo , Stephania/química , Alcaloides/biossíntese , Alcaloides/metabolismo , Vias BiossintéticasRESUMO
Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Canais de Cátion TRPC , Infecção por Zika virus , Zika virus , Infecção por Zika virus/virologia , Infecção por Zika virus/metabolismo , Animais , Humanos , Zika virus/fisiologia , Zika virus/efeitos dos fármacos , Camundongos , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Células HEK293 , Proteínas Virais/metabolismo , Convulsões/virologia , Convulsões/metabolismo , Convulsões/tratamento farmacológico , Proteases Virais , Serina Endopeptidases , Nucleosídeo-Trifosfatase , RNA Helicases DEAD-boxRESUMO
Artificial photoenzymes with novel catalytic modes not found in nature are in high demand; yet, they also present significant challenges in the field of biocatalysis. In this study, a chemogenetic modification strategy is developed to facilitate the rapid diversification of photoenzymes. This strategy integrates site-specific chemical conjugation of various artificial photosensitizers into natural protein cavities and the iterative mutagenesis in cell lysates. Through rounds of directed evolution, prominent visible-light-activatable photoenzyme variants were developed, featuring a thioxanthone chromophore. They successfully enabled the enantioselective [2 + 2] photocycloaddition of 2-carboxamide indoles, a class of UV-sensitive substrates that are traditionally challenging for known photoenzymes. Furthermore, the versatility of this photoenzyme is demonstrated in enantioselective whole-cell photobiocatalysis, enabling the efficient synthesis of enantioenriched cyclobutane-fused indoline tetracycles. These findings significantly expand the photophysical properties of artificial photoenzymes, a critical factor in enhancing their potential for harnessing excited-state reactivity in stereoselective transformations.
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Reação de Cicloadição , Estereoisomerismo , Indóis/química , Indóis/síntese química , Indóis/metabolismo , Processos Fotoquímicos , Biocatálise , Evolução Molecular Direcionada , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Luz , Escherichia coli/enzimologia , Estrutura MolecularRESUMO
This study aims to predict the possible targets and related signaling pathways of Modified Huoluo Xiaoling Pills against colorectal cancer(CRC) by both network pharmacology and molecular docking and verify the mechanism of action by experiments. TCMSP was used to obtain the active ingredients and targets of Modified Huoluo Xiaoling Pills, and GeneCards, DrugBank, OMIM, and TTD were employed to acquire CRC-related targets. Cytoscape software was utilized to construct the drug-active ingredient-target network, and the STRING database was applied to establish the protein-protein interaction(PPI) network. DAVID platform was adopted to investigate the targets in terms of GO function and KEGG pathway enrichment analysis. Molecular docking was performed in AutoDock Vina. HCT 116 cells were intervened by different concentrations of Modified Huoluo Xiaoling Pills-containing serum, and CCK-8 was used to detect the proliferation inhibition of HCT 116 cells in each group. Transwell was employed to show the invasive abi-lity of HCT 116 cells, and Western blot was taken to reveal the expression levels of ß-catenin, cyclinD1, c-Myc, as well as epithelial-mesenchymal transition(EMT) marker proteins E-cadherin, N-cadherin, vimentin, MMP2, MMP7, MMP9, and TWIST in HCT 116 cells. The network pharmacological analysis yielded 242 active ingredients of Modified Huoluo Xiaoling Pills, 1 844 CRC targets, and 127 overlapping targets of CRC and Modified Huoluo Xiaoling Pills, and the signaling pathways related to CRC involved PI3K-Akt, TNF, HIF-1, IL-17, Wnt, etc. Molecular docking showed that the key active ingredients had a stable binding conformation with the core proteins. CCK-8 indicated that Modified Huoluo Xiaoling Pills significantly inhibited the proliferation of HCT 116 cells. Transwell assay showed that with increasing concentration of Modified Huoluo Xiaoling Pills containing serum, the invasive ability of HCT 116 cells was more obviously inhibited. The expression of ß-catenin, cyclinD1, c-Myc, N-cadherin, vimentin, MMP2, MMP7, MMP9, and TWIST proteins were suppressed, and the expression of E-cadherin was improved by the intervention of drug-containing serum. Thus, it can be seen that Modified Huoluo Xiaoling Pills restrains the proliferation, invasion, and metastasis of CRC cells through multiple components, multiple targets, and multiple pathways, and the mechanism of action may be related to the inhibition of the activation of the Wnt/ß-catenin signaling pathway, thereby affecting the occurrence of EMT.
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Proliferação de Células , Neoplasias Colorretais , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Glabridin (Gla) has been reported to have significant effects in scar treatment, and however, the water insolubility of Gla leads to its poor transdermal absorption ability, which affects its bioactivities. Therefore, we attempted to prepare the Gla dissolving microneedles (Gla-MN) to improve the absorbtion of Gla. After investigation of the 3 factors including the needle tip matrix concentration, the prescription concentration of backing material, and the dissolution method of Gla, we finally determined the process parameters of 10% hyaluronic acid (HA) as the needle tip and 5% polyvinyl alcohol (PVA) as the backing, according to which the Gla-MN was prepared with the good characteristics of high hardness, complete appearance and good in vitro dissolution ability. We then loaded Gla onto the microneedles and measured that the average drug loading of Gla-MN was 2.26 ± 0.11 µg/mg and the cumulative transdermal release of Gla-MN was up to 76.9% after 24 h. In addition, Gla-MN had good skin penetration properties, with Gla-MN penetrating at least 4 to 5 layers of parafilm. And the skin basically could return to normal after 4 h of piercing. Importantly, our results showed that Gla-MN had higher transdermal delivery and therapeutic effects against keloid than that of Gla at the same dosage.
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Ultrasound (US) generates toxic reactive oxygen species (ROS) by acting on sonosensitizers for cancer treatment, and the mechanical damage induced by cavitation effects under US is equally significant. Therefore, designing a novel sonosensitizer that simultaneously possesses efficient ROS generation and enhanced mechanical effects is promising. In this study, carbon-doped zinc oxide nanoparticles (C-ZnO) are constructed for mechano-sonodynamic cancer therapy. The presence of carbon (C) doping optimizes the electronic structure, thereby enhancing the ROS generation triggered by US, efficiently inducing tumor cell death. On the other hand, the high specific surface area and porous structure brought about by C doping enable C-ZnO to enhance the mechanical stress induced by cavitation bubbles under US irradiation, causing severe mechanical damage to tumor cells. Under the dual effects of sonodynamic therapy (SDT) and mechanical therapy mediated by C-ZnO, excellent anti-tumor efficacy is demonstrated both in vitro and in vivo, along with a high level of biological safety. This is the first instance of utilizing an inorganic nanomaterial to achieve simultaneous enhancement of ROS production and US-induced mechanical effects for cancer therapy. This holds significant importance for the future development of novel sonosensitizers and advancing the applications of US in cancer treatment.
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Estruturas Metalorgânicas , Nanopartículas , Espécies Reativas de Oxigênio , Terapia por Ultrassom , Óxido de Zinco , Óxido de Zinco/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Animais , Terapia por Ultrassom/métodos , Linhagem Celular Tumoral , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Camundongos , Carbono/química , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
The global surge in multidrug-resistant bacteria owing to antibiotic misuse and overuse poses considerable risks to human and animal health. With existing antibiotics losing their effectiveness and the protracted process of developing new antibiotics, urgent alternatives are imperative to curb disease spread. Notably, improving the bactericidal effect of antibiotics by using non-antibiotic substances has emerged as a viable strategy. Although reduced nicotinamide adenine dinucleotide (NADH) may play a crucial role in regulating bacterial resistance, studies examining how the change of metabolic profile and bacterial resistance following by exogenous administration are scarce. Therefore, this study aimed to elucidate the metabolic changes that occur in Edwardsiella tarda (E. tarda), which exhibits resistance to various antibiotics, following the exogenous addition of NADH using metabolomics. The effects of these alterations on the bactericidal activity of neomycin were investigated. NADH enhanced the effectiveness of aminoglycoside antibiotics against E. tarda ATCC15947, achieving bacterial eradication at low doses. Metabolomic analysis revealed that NADH reprogrammed the ATCC15947 metabolic profile by promoting purine metabolism and energy metabolism, yielding increased adenosine triphosphate (ATP) levels. Increased ATP levels played a crucial role in enhancing the bactericidal effects of neomycin. Moreover, exogenous NADH promoted the bactericidal efficacy of tetracyclines and chloramphenicols. NADH in combination with neomycin was effective against other clinically resistant bacteria, including Aeromonas hydrophila, Vibrio parahaemolyticus, methicillin-resistant Staphylococcus aureus, and Listeria monocytogenes. These results may facilitate the development of effective approaches for preventing and managing E. tarda-induced infections and multidrug resistance in aquaculture and clinical settings.
Assuntos
Aminoglicosídeos , Antibacterianos , Edwardsiella tarda , NAD , Edwardsiella tarda/efeitos dos fármacos , Antibacterianos/farmacologia , NAD/metabolismo , Aminoglicosídeos/farmacologia , Animais , Doenças dos Peixes/microbiologia , Doenças dos Peixes/tratamento farmacológico , Testes de Sensibilidade Microbiana , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Neomicina/farmacologia , Sinergismo Farmacológico , Metabolômica , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacosRESUMO
Negative thermal expansion (NTE) compounds provide a solution for the mismatch of coefficients of thermal expansion in highly integrated device design. However, the current NTE compounds are rare, and how to effectively design new NTE compounds is still challenging. Here, a new concept is proposed to design NTE compounds, that is, to increase the flexibility of framework structure by expanding the space in framework structure compounds. Taking the parent compound NaZr2(PO4)3 as a case, a new NTE system AIBIICIII(MoO4)3 (A = Li, Na, K, and Rb; B = Mg and Mn; C = Sc, In, and Lu) is designed. In these compounds, the large volume of MoO4 tetrahedron is used to replace the small volume of PO4 tetrahedron in NaZr2(PO4)3 to enhance structural space and NTE performance. Simultaneously, a joint study of temperature-dependent X-ray diffraction, Raman spectroscopy, and the first principles calculation reveals that the NTE in AIBIICIII(MoO4)3 series compounds arise from the coupled oscillation of polyhedral. Large-radius ions are conducive to enhancing the space and softening the framework structure to achieve the enhancement of NTE. The current strategy for designing NTE compounds is expected to be adopted in other compounds to obtain more NTE compounds.
RESUMO
The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.
Assuntos
Apoptose , Proteínas de Drosophila , Fatores de Transcrição Forkhead , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Histona Acetiltransferases/metabolismo , Histona Acetiltransferases/genética , Drosophila/genética , Drosophila/metabolismo , Sistema de Sinalização das MAP Quinases , Humanos , Transdução de Sinais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly used antibiotics and is often incidentally killed during treatment. We attempted to identify a means to protect L. plantarum ATCC14917 from the metabolic changes caused by two commonly used antibiotics, ampicillin, and doxycycline. We examined the metabolic changes under ampicillin and doxycycline treatment and assessed the protective effects of adding key exogenous metabolites. RESULTS: Using metabolomics, we found that under the stress of ampicillin or doxycycline, L. plantarum ATCC14917 exhibited reduced metabolic activity, with purine metabolism a key metabolic pathway involved in this change. We then screened the key biomarkers in this metabolic pathway, guanine and adenosine diphosphate (ADP). The exogenous addition of each of these two metabolites significantly reduced the lethality of ampicillin and doxycycline on L. plantarum ATCC14917. Because purine metabolism is closely related to the production of reactive oxygen species (ROS), the results showed that the addition of guanine or ADP reduced intracellular ROS levels in L. plantarum ATCC14917. Moreover, the killing effects of ampicillin and doxycycline on L. plantarum ATCC14917 were restored by the addition of a ROS accelerator in the presence of guanine or ADP. CONCLUSIONS: The metabolic changes of L. plantarum ATCC14917 under antibiotic treatments were determined. Moreover, the metabolome information that was elucidated can be used to help L. plantarum cope with adverse stress, which will help probiotics become less vulnerable to antibiotics during clinical treatment.