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Objective:To explore the possible mechanism of Bupiwei Xieyinhuo Shengyang Prescription on gastroesophageal reflux disease (GERD) based on network pharmacology and molecular docking technology.Methods:The main active components and target information of Bupiwei Xieyinhuo Shengyang Prescription were screened by TCMSP database, and targets were identified by GeneCards, OMIM, TTD and PharmGKB databases. The intersection of active ingredient components and disease targets was selected to construct PPI network by STRING. Cytoscape CytoNCA plug-in was used to extract core targets for analysis. GO function enrichment and KEGG pathway enrichment analysis were performed using Metascape. Cytoscape 3.7.2 was used to construct the "component-target-signal pathway" network, and Autodock was used to complete molecular docking verification. Animal experiments were further used for verification. SPF SD male rats were selected and GERD model was established by esophageal stent implantation. After 14 days of intervention, serum TNF-α and COX-2 levels of rats in each group were detected for verification.Results:A total of 215 effective compounds were screened from Bupiwei Xieyinhuo Shengyang Prescription. The main targets of GERD were TNF, IL6, CASP3, TP53 and PTGS2, which mainly focused on cancer pathway, AGE-RAGE signaling pathway, calcium signaling pathway and NF-κB signaling pathway. The results of molecular docking showed that the binding potential and activity of the key active components of Bupiwei Xieyinhuo Shengyang Prescription and the core target were better. Compared with the model group, Bupiwei Xieyinhuo Shengyang Prescription could reduce the serum expression levels of TNF-α and COX-2 ( P<0.01). Conclusions:By regulating TNF, IL6, CASP3, TP53, PTGS2 and other core targets, Bupiwei Xieyinhuo Shengyang Prescription can regulate NF-κB signaling pathway, calcium signaling pathway and other signaling pathways to play a role in the treatment of GERD.
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OBJECTIVE@#To explore the specific pharmacological molecular mechanisms of Kai Xin San (KXS) on treating Alzheimer's disease (AD) based on network pharmacology and experimental validation.@*METHODS@#The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine (ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway.@*RESULTS@#In total, 38 active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta (A β)-glycogen synthase kinase-3 beta (GSK3 β)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo, KXS treatment significantly improved cognitive deficits in AD rats induced by Aβ1-42, decreased the levels of Aβ, p-GSK3β, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1 alpha (PP1A) and PP2A (P<0.05 or P<0.01).@*CONCLUSION@#KXS exerted neuroprotective effects by regulating the Aβ -GSK3β-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.
Subject(s)
Rats , Animals , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Glycogen Synthase Kinase 3 beta , Network Pharmacology , Molecular Docking Simulation , Glycogen Synthase Kinase 3/therapeutic use , Drugs, Chinese Herbal/therapeutic useABSTRACT
ObjectiveTo explore the active ingredients， therapeutic targets， and relative signaling pathways of Tripterygium wilfordii in the treatment of triple negative breast cancer （TNBC） based on network pharmacology， and to verify the mechanism through in vitro cell model. MethodThe active ingredients of T. wilfordii were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. The targets of TNBC were obtained from DisGeNET and GeneCards. Venny was used to identify the potential therapeutic targets of T. wilfordii against TNBC. Protein-protein interaction （PPI） network was constructed with String database. Gene ontology （GO） annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were carried out with DAVID to predict the mechanisms of potential targets. The molecular docking between triptolide and key targets were performed with AutoDock Vina. The effect of triptolide （0， 5， 10， 20， 30， 40， 50， 60， 80 nmol·L-1） on the proliferation of MDA-MB-231 cells was determined through methyl thiazolyl tetrazolium （MTT） assay. The effect of triptolide （0， 12.5， 25， 50 nmol·L-1） on the apoptosis of MDA-MB-231 cells was detected with Hoechst 33342 staining. Western blot was performed to detect the effect of triptolide （0， 25， 50 nmol·L-1） on the expression levels of key targets. ResultT. wilfordii had 23 active ingredients related to 55 potential targets of TNBC. GO and KEGG enrichment revealed that the potential targets were associated with 103 biological processes， 15 cellular components， and 35 molecular functions， and were involved in 140 signaling pathways including atherosclerosis and apoptosis. The results of molecular docking demonstrated that triptolide could bind with the targets including threonine kinase 1 （Akt1）， vascular endothelial growth factor A （VEGFA）， cellular tumor antigen p53 （p53）， transcription factor AP-1 （JUN）， signal transducer and activator of transcription 3 （STAT3）， tumor necrosis factor （TNF）， mitogen-activated protein kinase 8 （MAPK8）， prostaglandin G/H synthase 2 （PTGS2）， and Caspase-3. According to the results of MTT assay， triptolide （20， 30， 40， 50， 60， 80 nmol·L-1） inhibited the proliferation of MDA-MB-231 cells compared with blank control （P<0.05， P<0.01）. Hoechst 33342 staining showed that triptolide （12， 25， 50 nmol·L-1） induced the apoptosis of MDA-MB-231 cells compared with black control （P<0.05， P<0.01）. Western blot showcased that 50 nmol·L-1 triptolide down-regulated the relative expression levels of p-Akt， TNF-α， and VEGFA， while 25 and 50 nmol·L-1 triptolide up-regulated the relative expression level of p53 in a dose-dependent manner compared with the blank control （P<0.05， P<0.01）. ConclusionT. wilfordii has multiple ingredients， targets， and pathways in the treatment of TNBC. It may regulate p53， VEGFA， TNF-α and other key targets to induce cell apoptosis and suppress angiogenesis and inflammatory response， which provides a scientific basis for the further investigation and clinical application of T. wilfordii.
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A computational study of the pulsating jet in a squared channel with a dynamic glottal-shaped constriction is presented. It follows the model experiments of Triep and Brücker (J Acoust Soc Am 127(2):1537–1547, 2010) with the cam-driven model that replicates the dynamic glottal motion in the process of human phonation. The boundary conditions are mapped from the model experiment onto the computational model and the three dimensional time resolved velocity and pressure fields are numerically calculated. This study aims to provide more details of flow separation and pressure distribution in the glottal gap and in the supraglottal flow field. Within the glottal gap a ‘vena contracta’ effect is generated in the mid-sagittal plane. The flow separation in the mid-coronal plane is therefore delayed to larger diffuser angles which leads to an ‘axisswitching’ effect from mid-sagittal to mid-coronal plane. The location of flow separation in mid-sagittal cross section moves up- and downwards along the vocal folds surface in streamwise direction. The generated jet shear layer forms a chain of coherent vortex structures within each glottal cycle. These vortices cause characteristic velocity and pressure fluctuations in the supraglottal region, that are in the range of 10–30 times of the fundamental frequency.
Subject(s)
Humans , Constriction , Phonation , Vocal CordsABSTRACT
El Instrumento de Temor a la Evaluación Social Negativa (ITESN) ha mostrado evidencias de validez y confiabilidad al utilizarse en muestras culturalmente distintas y al traducirse a diferentes idiomas (Duke et al., 2006; Gallego, 2010; Gallego et al., 2007; Weeks et al., 2005; Tavoli et al., 2009). Dada la relevancia del estudio de la ansiedad y fobia social, y con la intención de aportar herramientas para estudiar estas variables en muestras mexicanas, este proyecto presenta evidencias de validez y confiabilidad de una traducción al castellano del ITESN (Leary, 1983) en una muestra de estudiantes universitarios de Ciudad de México. Se realizaron análisis de discriminación de reactivos, factoriales exploratorios y factoriales confirmatorios mediante modelamiento de ecuaciones estructurales. Los resultados muestran una estructura unifactorial que agrupa ocho de los doce reactivos del instrumento original, explica el 53.8 % de la varianza total y muestra consistencia interna adecuada (α = 0.88). Se obtienen evidencias de validez de criterio del ITESN, así: a) se asocia positivamente con el Instrumento de Ansiedad Rasgo y b) mediante un procedimiento experimental, se observan asociaciones positivas entre el ITESN y mediciones de ansiedad estado y motivación de autopresentación ante la expectativa de conocer a otra persona. Se discute el funcionamiento de los cuatro reactivos redactados de forma negativa y la interpretación teórica de las relaciones que respaldan la validez de criterio.
The Brief fear of Negative Evaluation Scale (BFNE) has shown good validity and reliability properties in different cultural samples, as well as when it has been translated to other languages (Duke et al., 2006; Gallego, 2010; Gallego et al., 2007; Weeks et al., 2005; Tavoli et al., 2009). Given the relevance of the study of anxiety and social phobia and the need for research tools for Mexican samples, this study presents validity and reliability evidences for a translation to Spanish language of the BFNE (Leary, 1983) in a sample of undergraduate students from Mexico City. Psychometric tests included discrimination analysis for each item, principal component factorial analysis, and confirmatory factor analysis through structural equation modeling. Results show a one factor structure with just eight of the 12 original items. It explains 53.8% of total variance and has good reliability ( α = 0.88). In addition, evidence was found concerning criterion validity for the BFNE: a) It correlates positively with a Trait Anxiety Scale; and b) through an experimental procedure, positive correlations for the BFNE with a State Anxiety Scale and a Self-Presentation Motivation Scale when participants had the expectation of being introduced to another person. The discussion verses in relation to the performance of score reversed items and the theoretical meaning of items and to the observed relationships that support the criterion validity of this translation to Spanish language of the BFNE scale.