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1.
Braz. j. biol ; 83: e247604, 2023. tab, graf
Article in English | MEDLINE, LILACS, VETINDEX | ID: biblio-1339370

ABSTRACT

Abstract In the current report, we studied the possible inhibitors of COVID-19 from bioactive constituents of Centaurea jacea using a threefold approach consisting of quantum chemical, molecular docking and molecular dynamic techniques. Centaurea jacea is a perennial herb often used in folk medicines of dermatological complaints and fever. Moreover, anticancer, antioxidant, antibacterial and antiviral properties of its bioactive compounds are also reported. The Mpro (Main proteases) was docked with different compounds of Centaurea jacea through molecular docking. All the studied compounds including apigenin, axillarin, Centaureidin, Cirsiliol, Eupatorin and Isokaempferide, show suitable binding affinities to the binding site of SARS-CoV-2 main protease with their binding energies -6.7 kcal/mol, -7.4 kcal/mol, -7.0 kcal/mol, -5.8 kcal/mol, -6.2 kcal/mol and -6.8 kcal/mol, respectively. Among all studied compounds, axillarin was found to have maximum inhibitor efficiency followed by Centaureidin, Isokaempferide, Apigenin, Eupatorin and Cirsiliol. Our results suggested that axillarin binds with the most crucial catalytic residues CYS145 and HIS41 of the Mpro, moreover axillarin shows 5 hydrogen bond interactions and 5 hydrophobic interactions with various residues of Mpro. Furthermore, the molecular dynamic calculations over 60 ns (6×106 femtosecond) time scale also shown significant insights into the binding effects of axillarin with Mpro of SARS-CoV-2 by imitating protein like aqueous environment. From molecular dynamic calculations, the RMSD and RMSF computations indicate the stability and dynamics of the best docked complex in aqueous environment. The ADME properties and toxicity prediction analysis of axillarin also recommended it as safe drug candidate. Further, in vivo and in vitro investigations are essential to ensure the anti SARS-CoV-2 activity of all bioactive compounds particularly axillarin to encourage preventive use of Centaurea jacea against COVID-19 infections.


Resumo No presente relatório, estudamos os possíveis inibidores de Covid-19 de constituintes bioativos de Centaurea jacea usando uma abordagem tripla que consiste em técnicas de química quântica, docking molecular e dinâmica molecular. Centaurea jacea é uma erva perene frequentemente usada em remédios populares de doenças dermatológicas e febre. Além disso, as propriedades anticâncer, antioxidante, antibacteriana e antiviral de seus compostos bioativos também são relatadas. A Mpro (proteases principais) foi acoplada a diferentes compostos de Centaurea jacea por meio de docking molecular. Todos os compostos estudados, incluindo apigenina, axilarina, Centaureidina, Cirsiliol, Eupatorina e Isokaempferide, mostram afinidades de ligação adequadas ao sítio de ligação da protease principal SARS-CoV-2 com suas energias de ligação -6,7 kcal / mol, -7,4 kcal / mol, - 7,0 kcal / mol, -5,8 kcal / mol, -6,2 kcal / mol e -6,8 kcal / mol, respectivamente. Dentre todos os compostos estudados, a axilarina apresentou eficiência máxima de inibidor, seguida pela Centaureidina, Isokaempferida, Apigenina, Eupatorina e Cirsiliol. Nossos resultados sugeriram que a axilarina se liga aos resíduos catalíticos mais cruciais CYS145 e HIS41 do Mpro, além disso a axilarina mostra 5 interações de ligações de hidrogênio e 5 interações hidrofóbicas com vários resíduos de Mpro. Além disso, os cálculos de dinâmica molecular em uma escala de tempo de 60 ns (6 × 106 femtossegundos) também mostraram percepções significativas sobre os efeitos de ligação da axilarina com Mpro de SARS-CoV-2 por imitação de proteínas como o ambiente aquoso. A partir de cálculos de dinâmica molecular, os cálculos RMSD e RMSF indicam a estabilidade e dinâmica do melhor complexo ancorado em ambiente aquoso. As propriedades ADME e a análise de previsão de toxicidade da axilarina também a recomendaram como um candidato a medicamento seguro. Além disso, as investigações in vivo e in vitro são essenciais para garantir a atividade anti-SARS-CoV-2 de todos os compostos bioativos, particularmente a axilarina, para encorajar o uso preventivo de Centaurea jacea contra infecções por Covid-19.


Subject(s)
Humans , Pharmaceutical Preparations , Centaurea , COVID-19 , Protease Inhibitors , Molecular Dynamics Simulation , Molecular Docking Simulation , SARS-CoV-2
2.
J. Health Biol. Sci. (Online) ; 10(1): 1-6, 01/jan./2022. tab, ilus
Article in English | LILACS | ID: biblio-1370924

ABSTRACT

Objective: to evaluate the molecular interaction of silibinin with the targets ALS3 and SAP5. Methodology: Molecular docking protocols were conducted to analyze the binding interaction of silibinin with ALS3 and SAP5. Results: Eleven interactions of ALS3 with silibinin and four with fluconazole were found, while six interactions were observed of SAP5 with silibinin and four with fluconazole. Conclusion: Molecular docking between silibinin and ALS3 identified important interactions, but no significant interactions were observed with SAP5, even though silibinin can exhibit affinity and interactions with other SAP5 sites.


Objetivo: Avaliar a interação molecular da silibinina com os alvos ALS3 e SAP5. Metodologia: Protocolos de docking molecular foram conduzidos para analisar a interação de ligação da silibinina com ALS3 e SAP5. Resultados: Foram encontradas onze interações de ALS3 com silibinina e quatro com fluconazol, enquanto seis interações foram observadas de SAP5 com silibinina e quatro com fluconazol. Conclusão: Docking molecular entre silibinina e ALS3 identificou interações importantes, mas não foram observadas interações significativas com SAP5, embora a silibinina possa apresentar afinidade e interações com outros sítios SAP5.


Subject(s)
Candida albicans , Silymarin , Proteins , Invasive Fungal Infections
3.
Article in Chinese | WPRIM | ID: wpr-907149

ABSTRACT

Objective To explore the potential mechanism of Erchen decoction in the treatment of obese polycystic ovary syndrome and obese infertility, in order to provide theoretical basis for “treating different diseases with same method”. Methods The active ingredients and targets of Erchen decoction were obtained from TCMSP database, and the targets of obese polycystic ovary syndromes and obese infertility were obtained from GeneCard database. Active ingredient-target network was constructed by Cytoscape 3.7.1, and protein-protein interaction network and core target were obtained from STRING. GO and KEGG enrichment analysis were performed by Cytoscape 3.7.1 and online software. Results 125 ingredients and 218 targets of Erchen decoction were obtained. There were 2 783 target genes for obese infertility and 2 962 target genes for obese polycystic ovary syndrome. Erchen decoction has a total of 117 target genes in the treatment of obese infertility and obese polycystic ovary syndromes, which proves the principle of “treating different diseases with same method”. Potential active ingredients include quercetin, kaempferol, naringin, baicalin and formononetin. PPI showed that STAT3, JUN, AKT1, MAPK3, MAPK1, MAPK14, IL-6 and FOS were the core targets of “treating different diseases with same method”. Molecular docking results showed that quercetin, kaempferol, etc. had good binding ability with JUN. GO and KEGG enrichment analysis showed that AGE-RAGE signaling pathway, IL-17 signaling pathway and endocrine resistance might be the key pathways for the “treating different diseases with same method” of Erchen decoction. Conclusion Erchen decoction treating "different diseases with same method" involves same targets and same pathways, which can provide reference for future experimental research.

4.
Acta Pharmaceutica Sinica ; (12): 724-730, 2022.
Article in Chinese | WPRIM | ID: wpr-922899

ABSTRACT

The α-conotoxins are peptide toxins that are identified from the venom of marine cone snails and they hold outstanding potency on various subtypes of nicotinic acetylcholine receptors (nAChRs). nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, so nAChR dysfunctions have been involved in a variety of severe pathologies. Four types of α-3/5 conotoxins MI, MIA, MIB and MIC have been found from Conus magus. Among them, the activity and selectivity of MIA and MIB have not been well studied. In this study, four α-3/5 conotoxins MI, MIA, MIB and MIC were synthesized by solid peptide synthesis method, and the bioactivities of them were screened by double electrode voltage clamp electrophysiology. The results showed that MIA and MIB selectively inhibited muscle type acetylcholine receptors with IC50 values of 14.45 and 72.78 nmol·L-1, respectively, which are slightly weaker than MI and MIC. Molecular docking results have shown MIA and MIB interact with muscle-type nAChRs with similar mechanism. The reasons for activity differences may relate to the size of the N-terminal amino acids. Together, the conotoxins MIA and MIB may have the potential to develop as a tool for detect the function of muscle type nAChRs, as well as the diagnosis or treat of related diseases.

5.
Acta Pharmaceutica Sinica ; (12): 716-723, 2022.
Article in Chinese | WPRIM | ID: wpr-922896

ABSTRACT

This study identified the exact molecular mechanisms of baicalein on neuroinflammation in lipopolysaccharide (LPS)-induced BV-2 cells. Bioinformatics methods and molecular docking were integrated for predicting the potential targets and mechanisms of baicalein. Immunofluorescence staining and Western blot were used to analyze the predicted key targets [inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)], the expression level of protein related to signal transducer and activator of transcription 1/nuclear factor kappa-B (STAT1/NF-‍κB) signaling pathway and its upstream regulator NADPH oxidase-2 (NOX2), and then the mechanism of baicalein in alleviating neuroinflammation was explored. The results showed that iNOS and COX-2 were predicted as the key targets and NF-κB signaling pathway was one of the important pathways by bioinformatics methods and molecular docking. Experimental verification showed that baicalein could significantly reduce the expression of iNOS and COX-2, inhibit the phosphorylation of NF-κB and STAT1 and the production of NOX2 in LPS-induced BV-2 cells. To sum up, baicalein could effectively inhibit the inflammatory reaction in LPS-induced BV-2 cells through regulating NOX2 (gp91phox/p47phox)/STAT1/NF-κB pathway.

6.
Medicina (Ribeirão Preto) ; 54(1)jul, 2021. fig.
Article in Portuguese | LILACS | ID: biblio-1353725

ABSTRACT

RESUMO: Modelo do estudo: Trata-se de um estudo experimental in vitro com abordagem computacional. Objetivo: Ana-lisar a existência de interação entre as drogas hidrofóbicas bezafibrato e hidroclorotiazida com a hemoglobina a fim de prever alterações na biodisponibilidade das drogas, bem como na função proteica. Metodologia: Testes de interação in vitro entre a hemoglobina bovina e bezafibrato ou hidroclorotiazida foram realizados por espectrofo-tometria; análises dos sítios de interação e extrapolações para a hemoglobina humana foram feitas por técnicas de bioinformática. Resultados: Os testes in vitro demonstraram diminuição de absorbância (k) em 405 nm igual a 8,75 x 10-4 min-1 para o bezafibrato e 6,25 x 10-4 min--1 para a hidroclorotiazida. A diminuição sugere interação das drogas com a hemoglobina, sendo que o bezafibrato parece interagir com afinidade ligeiramente maior. As análises in silico mostraram que as drogas se ligam à porção proteica da hemoglobina. A constante de afinidade de ligação obtida por ancoragem molecular para o bezafibrato com a hemoglobina bovina (-8,3 kcal/mol) corrobora com o valor experimental de k e com o maior número de interações observadas, em relação à hidroclorotiazida (-6,6 kcal/mol). O mesmo padrão é observado para a interação do bezafibrato (-7,6 kcal/mol) e da hidroclorotiazida (-6,7 kcal/mol) com a hemoglobina humana. Conclusão: As técnicas de espectrofotometria e bioinformática utilizadas sugerem a possibilidade de interação da hemoglobina com drogas de natureza hidrofóbica, como bezafibrato e hi-droclorotiazida, sendo que essa interação pode afetar a função normal da hemoglobina e alterar a farmacodinâmica e farmacocinética das drogas prejudicando sua eficiência terapêutica. (AU)


ABSTRACT: Study model: It is an in vitro experimental study with a computational approach. Objective: Analyze the presence of interaction between hydrophobic drugs bezafibrate and hydrochlorothiazide and hemoglobin to predict bioavailability changes as well as in the protein function. Metodology: The in vitro tests to evaluate the interaction between the bovine hemoglobin and bezafibrate and hydrochlorothiazide were perfomed by spectrophotometry; bioinformatic tools made interaction analysis and extrapolation for human hemoglobin. Results: The in vitro tests showed a decrease in the absorbance (k) at 405 nm equal to 8.75 x 10-4 min-1 for bezafibrate and 6.25 x 10-4 min-1 for hydrochlorothiazide. The decrease suggests an interaction between the drugs and hemoglobin, for bezafibrate this interaction seems to be stronger than hydrochlorothiazide. The in silico analysis showed that the drugs bind to the protein portion of the hemoglobin. The binding affinity constant obtained by molecular docking from bezafibrate and bovine hemoglobin (-8.3 Kcal/mol) sustain the experimental value of k and the greater number of interactions observed in relation to hydrochlorothiazide (-6.6 kcal/mol). The same pattern was observed for interaction of bezafibrate (-7.6 kcal/mol) and hydrochlorothiazide (-6.7 kcal/mol) with human hemoglobin. Conclusion: The spectrophotometry and bioinformatic methods suggested the possibility of hemoglobin interaction with hydrophobic drugs such as bezafibrate and hydrochlorothiazide; this interaction could affect the normal function of hemoglobin and change the pharmacodynamics and pharmacokinetics of drugs impairing their therapeutic efficiency. (AU)


Subject(s)
Spectrophotometry , Hemoglobins , Computational Biology , Molecular Docking Simulation
7.
Rev. Assoc. Med. Bras. (1992) ; 67(2): 195-199, Feb. 2021. graf
Article in English | LILACS | ID: biblio-1287817

ABSTRACT

SUMMARY OBJECTIVE: Free intra-abdominal fluid describes an accumulation of free fluid in the peritoneal cavity. It has different etiologies, but it frequently constitutes a meaningful clinical sign. In this study, the authors interrogate whether abdominal ultrasound augments the medical students' ability to identify free intra-abdominal fluid. METHODS: Thirty-one medical students without any previous formal ultrasound training were subjected to cognitive assessment before and after four and a half-hour of theoretical lecture and hands-on course about the diagnosis of free intra-abdominal fluid by physical examination and abdominal ultrasound. The hands-on sessions were done in healthy volunteers with a simulated peritoneal catheter and in patients treated with peritoneal dialysis with different amounts of dialysate in their cavity. RESULTS: The cognitive assessment before and after the course increased from 6.7±2.3 to 11.6±1.1 points (p<0.0001). The sensitivity, specificity, and accuracy in the diagnosis of free intra-abdominal fluid were higher when students used abdominal ultrasound. The students agree with the inclusion of abdominal ultrasound in the diagnose of free intra-abdominal fluid in the undergraduate curriculum. CONCLUSIONS: This study demonstrates that incorporating abdominal ultrasound is feasible and improves medical students' short-time competency in performing and interpreting the findings diagnostic of free intra-abdominal fluid.


Subject(s)
Humans , Students, Medical , Education, Medical, Undergraduate , Ultrasonography , Clinical Competence , Curriculum
8.
Article in Chinese | WPRIM | ID: wpr-909584

ABSTRACT

OBJECTIVE Since the coronavirus disease 2019 (COVID-19) outbreak in December 2019, the search for a potential treatment for COVID-19 has been a constant focus. Therefore, we identified potential treatments for COVID-19 from Hippophae Fructus, a Tibetan medicine that may act on COVID-19, using a network pharmacology approach. METHODS We collected the chemical constituents and corresponding targets of Hippophae Fructus from traditional Chinese medicine system pharmacology (TCMSP). COVID-19 related genes were predicted in pubmed-Gene, OMIM and GeneCards databases. Then, protein-protein interactions (PPIs) of key genes were analyzed by STRING database. Compound-target-diseases network was constructed using Cytoscape software. The potential pathways were deter?mined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Additionally, molecular docking was used to verify the binding effect between the active component and the target. RESULTS A total of 33 components and 192 corresponding targets in Hippophae Fructus were found. 50 genes were obtained from the intersection of component targets and disease targets. These genes include IL-6, TNF, MAPK8 and PTGS2, which regu?late several pathways associated with COVID-19, involving Hepatitis B, Influenza A, TNF signaling pathway and Tuber?culosis. More importantly, high-node compounds such as quercetin and beta-sitosterol can well bind to key targets. CONCLUSION Some components in Hippophae Fructus can act on COVID-19 related genes and regulate multiple pathways. Perhaps Hippophae Fructus has the effect in treating COVID-19.

9.
Article in Chinese | WPRIM | ID: wpr-907683

ABSTRACT

Objective:To analize the mechanism of Xiaoxianxiong Decoction on myocardial ischemiareperfusion injury by network pharmacological method and molecular docking technology. Methods:The effective components and corresponding target proteins of Xiaoxianxiong Decoction were screened by TCMSP, and the predicted target protein names were converted to gene names in UniProt database. The gene target of myocardial ischemia reperfusion injury was screened through the GeneCards and OMIM database. Venn online software was used to obtain the common target of drugs and diseases, then the visual analysis and the "compound-target" network diagram was constructed by using Cytoscape software. The protein interaction network was made by using STRING database and Cytoscape software, and the network topology was analyzed. Molecular docking software (autodock Vina) was used to verify the molecular docking between the top five active components and the top ten core targets, and the GO function of target genes and enrichment analysis of KEGG pathway were analyzed by Bioconductor R software package. Results:After the screening, 38 effective chemical components and 187 target genes of Xiaoxianxiong Decoction and 511 disease-related target genes were obtained. 72 common target genes of drug diseases were obtained. The core targets involved AKT1, MMP9, IL1B, EGF, etc. Go function analysis showed 1 095 biological processes, 24 cell components, 61 molecular functions, and KEGG pathway analysis found 111 related signal pathways. Conclusion:This study predicted that Xiaoxianxiong Decoction could treat myocardial ischemia-reperfusion injury through multiple targets such as AKT1, MMP9, IL1B, EGF, and multiple pathways such as IL-17 signaling pathway and PI3K-Akt signaling pathway, which laid a foundation for further study on the material basis and molecular mechanism of this compound.

10.
China Pharmacy ; (12): 2987-2993, 2021.
Article in Chinese | WPRIM | ID: wpr-906779

ABSTRACT

OBJECTIVE:To investigate the potential mechanism of Salvia miltiorrhiza in the treatment of postoperative abdominal adhesion (PAA). METHODS :Active components and target genes of S. miltiorrhiza were retrieved from TCMSP database,SwissADME database ,Perl database ,UniProt database and other databases. GeneCards ,OMIM and PubMed database were used to retrieve target genes related to PAA. Venn diagram was drawn by using mapping tool of bioinformatic online database so as to screen the intersecting targets of active component-PAA. STRING platform was adopted to establish target network related to active component-PAA and protein-protein interaction (PPI)network of intersecting targets ,etc.,and to screen hub genes. Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genom es(KEGG)pathway enrichment were carried out by using R 3.6.1 software. Using the protein encoded by hub gene as receptor and tanshinone Ⅱ A as ligand ,the molecular docking was carried out with AutoDock 1.5.6 tool. RESULTS :A total of 38 active components of S. miltiorrhiza with high gastrointestinal absorption and their corresponding 72 targets,755 PAA-related target genes were identified. Results of Venn diagram showed that there were 33 intersecting targets of active components of chuqi90@163.com S. miltiorrhiza with PAA. Tanshinone ⅡA,dihydrotanshinolac- tone and other components may be important nodes of the target network related to active component-PAA. FOS,APP,ACHE, CASP3 and PTGS2 may be the hub genes in PPI network of intersecting targets. Results of GO enrichment showed that the intersecting targets were mainly concentrated in adrenergic receptor activity ,catecholamine binding ,G protein-coupled amine receptor activity and so on ;KEGG pathway enrichment analysis showed that the intersecting targets were mainly enriched in neuroactive ligand-receptor interaction ,cGMP-PKG signaling pathway ,endocrine resistance ,EGFR-tyrosine kinase inhibitor resistance and calcium signaling pathway.Molecular docking analysis showed that tanshinone ⅡA could form hydrogen bonds with many amino acid residues such as VAL- 580 of proto oncogenes c-Fos ,amyloid precursor protein ,acetylcholinesterase,caspase 3 and prostaglandin G/H synthase 2. CONCLUSIONS :The active components of S. miltiorrhiza play a role in the treatment of PAA by directly or indirectly acting on neuroactive ligand-receptor interaction ,cGMP-PKG signaling pathway ,endocrine resistance , EGFR-tyrosine kinase inhibitor resistance resistance and calcium signaling pathway.

11.
Article in Chinese | WPRIM | ID: wpr-906339

ABSTRACT

Objective:Combined with high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) and network pharmacology, to predict the target and potential mechanism of Gardeniae Fructus in the treatment of cerebral ischemia. Method:HPLC-Q-TOF-MS/MS was used to identify the chemical constituents of Gardeniae Fructus according to the retention time, relative molecular weight, secondary mass spectrometry fragmentation and other information of chromatographic peaks, and combined with literature data. The targets of main active ingredients in Gardeniae Fructus were predicted by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction database. The potential targets of Gardeniae Fructus against cerebral ischemia were obtained through Online Mendelian Inheritance in Man (OMIM), GeneCards and Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene ontology (GO) function enrichment and KEGG pathway analysis of potential targets were analyzed with the DAVID 6.8. Cytoscape 3.6.0 software was used to construct the network of active components-targets-pathways. At last, Discovery Studio 2016 software was applied in the molecular docking verification between the key active ingredients and potential protein targets. Result:A total of 40 chemical constituents in Gardeniae Fructus were identified, including iridoids, diterpenoid pigments, organic acids, monoterpenoids and other components. According to the main active ingredients, 208 potential targets were predicted, 560 disease targets related to cerebral ischemia were retrieved, 59 key targets were selected by mapping component targets with disease targets. These targets could act on key target proteins such as tumor necrosis factor (TNF), Caspase-3 (CASP3) and CASP8, and participate in the regulation of TNF, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), hypoxia inducible factor 1 (HIF-1) and other signal pathways. Molecular docking results showed that geniposide could interact with targets of prostaglandin G/H synthase 2 (PTGS2), TNF<italic> </italic>and nuclear transcription factor-<italic>κ</italic>B p65 (RELA), crocin Ⅰ could interact with interleukin-2 (IL-2). Conclusion:Geniposide, crocin Ⅰ and other ingredients in Gardeniae Fructus can play a role of anti-inflammatory and inhibiting apoptosis to prevent or treat cerebral ischemic diseases by up-regulating protein expression level of RELA and IL-2, down-regulating protein expression level of TNF, CASP8, CASP3 and matrix metalloproteinase 2 (MMP2), and regulating TNF, PI3K/Akt and HIF-1 signaling pathways.

12.
Article in Chinese | WPRIM | ID: wpr-906282

ABSTRACT

Objective:To explore the molecular mechanism of Jiangtang Xiaozhi tablets (JTXZT) in the treatment of non-alcoholic fatty liver disease (NAFLD) by means of network pharmacology and molecular docking. Method:With the help of traditional Chinese medicine (TCM) Systems Pharmacology Database and Analysis Platform (TCMSP), TCMs Integrated Database (TCMID), Encyclopedia of TCM (ETCM) and Bioinformatics Analysis Tool for Molecular Mechanism of TCM (BATMAN-TCM), the chemical compositions of medicinal materials in JTXZT were obtained, the compound targets were predicted in SwissTargetPrediction database and STITCH database. The targets of NAFLD were searched by The Human Gene Database (GeneCards), Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD) and DisGeNET, and intersection analysis was performed with the targets of the active ingredients to obtain the targets of JTXZT for treatment of NAFLD. Based on STRING 11.0 database, the protein-protein interaction (PPI) network of therapeutic targets was constructed, and the enrichment analysis of therapeutic targets was carried out by DAVID 6.8. Finally, the interaction characteristics of key components and core therapeutic targets of JTXZT for treatment of NAFLD were verified based on molecular docking. Result:The key components of JTXZT for treatment of NAFLD were quercetin, luteolin, kaempferol, berberine, isorhamnetin, betulinic acid, oleanolic acid, ursolic acid. formononetin and hexitol, and the core targets of JTXZT for treatment of NAFLD were mitogen-activated protein kinase 1 (MAPK1), Jun proto-oncogene, activator protein-1 (AP-1) transcription factor subunit (JUN), MAPK3, protein kinase B1 (AKT1 or Akt1), tumor protein p53 (TP53), E1A binding protein p300 (EP300), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), tumor necrosis factor (TNF),amyloid beta precursor protein (APP) and cytochrome P450 family 2 subfamily E member 1 (CYP2E1). Biological function and pathway enrichment analysis showed that JTXZT mainly through xenobiotic metabolic process, oxidation-reduction process, cholesterol metabolic process and other biological processes, regulating phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, MAPK signaling pathway, NAFLD and insulin signaling pathway to play a role in the treatment of NAFLD. The results of molecular docking showed that the active components of JTXZT had a good affinity with the core targets of JTXZT for the treatment of NAFLD. Conclusion:JTXZT treats NAFLD through multiple active components, multiple key targets and multiple action pathways.

13.
Article in Chinese | WPRIM | ID: wpr-906252

ABSTRACT

Objective:To study the mechanism of astragaloside Ⅳ in the treatment of ischemic stroke by means of network pharmacology. Method:The targets of astragaloside Ⅳ were predicted using Swiss Target Prediction platform, and the targets of ischemic stroke were retrieved using GeneCards, Therapeutic Target Database (TTD), Traditional Chinese Medicine Integrated Database (TCMID) and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) databases. The potential targets of astragaloside Ⅳ acting on ischemic stroke were obtained by the intersection of the targets of astragaloside Ⅳ and ischemic stroke. STRING platform was used to build protein-protein interaction (PPI) network, and eigenvalues were calculated through network topology analysis to screen core targets. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the related targets in DAVID database. Finally, molecular docking verification was conducted to further clarify the core targets of astragaloside Ⅳ acting on ischemic stroke. Result:The 44 common targets were obtained after the intersection of the targets of astragaloside Ⅳ and ischemic stroke. PPI network topology analysis showed that RAC-alpha serine/threonine-protein kinase (Akt1), renin (REN), epidermal growth factor receptor (EGFR), vascular endothlial growth factor A (VEGFA) and neuronal proto-oncogene tyrosine-protein kinase (SRC) were the core targets of astragaloside Ⅳ in the treatment of ischemic stroke. Enrichment analysis results of KEGG pathway showed that the pathways of astragaloside Ⅳ acting on ischemic stroke involved the neuroactive ligand-receptor interaction pathway, cGMP-PKG signaling pathway, calcium signaling pathway, Rap1 signaling pathway, PI3K/Akt signaling pathway, etc. Conclusion:Astragaloside Ⅳ may promote angiogenesis and inhibit platelet activity by acting on Akt1, REN, EGFR, VEGFA, SRC, thus improving cerebral blood flow. It can also inhibit the apoptosis of ischemic brain tissue cells and inflammation to reduce the damage of nerve function, and finally treat ischemic stroke. This study provides ideas and guidance for further exploring the mechanism of astragaloside Ⅳ in the treatment of ischemic stroke.

14.
Article in Chinese | WPRIM | ID: wpr-905974

ABSTRACT

Objective:To explore the mechanism of Xiaojinwan in treating breast cancer bone metastases through cell experiments and bioinformatic analysis. Method:The inhibitory effect of Xiaojinwan on MCF-7 cell viability was detected by cell counting kit-8 (CCK-8) assay. The key components and targets responsible for Xiaojinwan in inhibiting breast cancer bone metastases were predicted by network pharmacology and molecular docking. The active components and targets of Xiaojinwan were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCSMP) and SwissTarget Prediction, and the breast cancer bone metastases-related targets from GeneCards and DisGeNET. The results were imported into STRING for constructing a protein-protein interaction (PPI) network, followed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using DAVID. A network of the active components of Xiaojinwan-breast cancer bone metastases-related targets-pathways was constructed using Cytoscape 3.7.2. AutoDock 4 was employed for molecular docking. The protein expression levels of matrix metallopmteinase-9 (MMP-9), hypoxia-inducible factor 1<italic>α </italic>(HIF1A), and androgen receptor (AR) were assayed by Western blot. Result:Xiaojinwan inhibited the viability of MCF-7 cells and acted on breast cancer bone metastases through such processes as redox and protein autophosphorylation. KEGG enrichment analysis showed that HIF-1, vascular endothelial growth factor (VEGF) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathways were involved. As verified by molecular docking, the active components such as eucalyptin stably bound to AR and MMP-9. Western blot indicated that Xiaojinwan dose-dependently inhibited the expression of MMP-9 and HIF1A proteins in MCF-7 cells. Conclusion:Xiaojinwan acts on AR and MMP-9 through HIF, VEGF and other related signaling pathways, thereby improving hypoxia in tumor microenvironment, inhibiting angiogenesis, and reducing cell invasion and viability.

15.
Article in Chinese | WPRIM | ID: wpr-905958

ABSTRACT

Objective:To explore the possible mechanism of Astragali Radix-Curcumae Rhizoma (AC) in inhibiting tumor growth in the orthotopic transplantation model of colon cancer in mice. Method:The molecular docking technology was used to predict the intermolecular interaction between the main active components of AC and the pathway target proteins, such as stromal cell-derived factor-1 (SDF-1), C-X-C motif chemokine receptor 4 (CXCR4), and nuclear factor kappa-B p65 (NF-<italic>κ</italic>B p65). The orthotopic transplantation model of CT26.WT colon cancer was established in mice for <italic>in vivo</italic> experimental verification. Sixty BALB/c male mice were randomly divided into a sham operation group, a model group, a 5-fluorouracil (5-Fu, 30 mg·kg<sup>-1</sup>) group,and low- (0.32 g·kg<sup>-1</sup>), medium- (0.64 g·kg<sup>-1</sup>), and high-dose (1.28 g·kg<sup>-1</sup>) AC groups, with 10 mice in each group. The sham operation group and the model group received normal saline by gavage. The corresponding drugs were administered by gavage in the 5-Fu group and by intraperitoneal injection in the AC groups. After intervention for 15 days, the tumor <italic>in situ</italic> was completely stripped, and the colon tissues 5-6 cm in length adjacent to the tumor were taken. The tumor volume was measured and calculated. The pathological changes of tumor tissues and colon tissues were observed by Hematoxylin-Eosin (HE) staining. Western blot was used to detect the protein expression of SDF-1, CXCR4, p-NF-<italic>κ</italic>B p65 in colon tissues. Western blot and Real-time quantitative polymerase chain reaction (Real-time PCR) were used to detect SDF-1, CXCR4, NF-<italic>κ</italic>B p65, Cyclin D<sub>1</sub>, oncogene c-Myc protein and mRNA expression in tumor tissues. Result:Compared with the model group, 5-Fu and AC groups showed reduced tumor volumes <italic>in situ</italic> (<italic>P</italic><0.05, <italic>P</italic><0.01), with the tumor inhibition rate in the 5-Fu group as high as (61.38±2.34)%. The tumor-inhibiting effect was optimal in the medium-dose AC group, with the tumor inhibition rate of (43.43±3.71)%. Compared with the model group, 5-Fu and AC groups showed relieved pathological changes of tumor and colon tissues. Specifically, AC down-regulated the protein expression levels of SDF-1, CXCR4, and p-NF-<italic>κ</italic>B p65 in colon tissues (<italic>P</italic><0.01), and down-regulated the protein and mRNA expression levels of SDF-1, CXCR4, NF-<italic>κ</italic>B p65, Cyclin D<sub>1</sub>, and c-Myc in tumor tissues (<italic>P</italic><0.05, <italic>P</italic><0.01). Conclusion:AC can inhibit the growth of orthotopic transplantation tumor of colon cancer, and its intervention mechanism may be related to the regulation of related protein and mRNA expression in the SDF-1/CXCR4/NF-<italic>κ</italic>B signaling pathway.

16.
Article in Chinese | WPRIM | ID: wpr-905937

ABSTRACT

Objective:To investigate the effects of polyethylene glycol 400 (PEG400) on the pharmacokinetics and anti-inflammatory effect of baicalin, and to preliminarily explore the anti-inflammatory effects of baicalin and its main metabolite baicalein 6-<italic>O</italic>-<italic>β</italic>-<italic>D</italic>-glucuronide (B6G) by molecular docking. Method:Rats were randomly divided into two groups with water and PEG400 as the dissolving matrix, and rats were administrated the equal dose of baicalin aqueous solution (baicalin+water group) and baicalin PEG400 solution (baicalin+PEG400 group). After the plasma samples were processed at different time periods, the concentrations of baicalin and B6G in rat plasma were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and pharmacokinetic parameters were processed by DAS 3.2.2 software. Mice were randomly divided into a blank group (normal saline, 20 mL·kg<sup>-1</sup>), aspirin group (dose of 0.2 g·kg<sup>-1</sup>), baicalin/baicalin+PEG400 high and low dose (3.0, 1.5 g·kg<sup>-1</sup>) groups, after continuous administration for 7 days, the mouse ear swelling and foot swelling models were established, and the swelling degree and swelling inhibition rate were calculated. Result:The pharmacokinetic study showed that compared with baicalin+water group, the plasma concentrations of baicalin and B6G increased after administration of baicalin PEG400 solution, and the area under the curve (AUC<sub>0-</sub><italic><sub>t</sub></italic>) increased by 2.36, 1.97 times, and the peak concentration (<italic>C</italic><sub>max</sub>) increased by 2.12, 1.65 times, respectively. The results of mouse ear and foot swelling inflammation models showed that the anti-inflammatory effect was enhanced after intragastric administration of baicalin PEG400 solution. In addition, molecular docking results showed that baicalin and B6G could site bind to multiple target proteins [tumor necrosis factor (TNF)-<italic>α</italic>, interleukin (IL)-6, IL-1<italic>β</italic>, prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) and nuclear transcription factor-<italic>κ</italic>B (NF-<italic>κ</italic>B)] with higher affinity, which was superior to the positive drug aspirin. Conclusion:PEG400 can increase the plasma concentration of baicalin and its main metabolite B6G, and enhance the anti-inflammatory effect. Baicalin and B6G can form strong hydrogen bonds with various inflammatory factors and of nuclear transcription factors, it is speculated that baicalin and B6G jointly play an anti-inflammatory role.

17.
Article in Chinese | WPRIM | ID: wpr-904625

ABSTRACT

Objective To explore the potential targets and synergistic mechanisms of Kushen Decoction for the treatment of cryptosporidiosis using network pharmacology and molecular docking methods. Methods The main active ingredients of Kushen Decoction were captured from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TC-MSP) and the Universal Protein Resource (UniProt) database, and the potential targets were predicted. In addition, the active ingredients of Kushen Decoction that were not included in the TCMSP database were retrieved in CNKI, WanFang Data, CBM, PubMed and Web of Science databases, and the target genes of all supplemented active ingredients were predicted using the online TargetNet database. Network construction and analysis were performed using the Cytoscape software, and cryptosporidiosis-related targets were retrieved in the Comparative Toxicogenomics Database and GeneCards database. The protein-protein interaction (PPI) network was created using the STRING database, and the DAVID database was used for GO enrichment and KEGG pathway analyses. The tissue distribution of key targets was investigated using the BioGPS database, and the AutoDockTools software was employed to verify the molecular docking results. Results A total of 38 active ingredients of Kushen Decoction were screened, and the core ingredients included quercetin, (+)-14α-hydroxymatrine and apigenin. A total of 831 targets of Kushen Decoction and 512 cryptosporidiosis-related targets were predicted, and PPI network analysis revealed 69 key targets, including AKT1, TNF and IL-6. There were 303 biological processes, 46 molecular functions and 29 cellular components involved in the treatment of cryptosporidiosis with Kushen Decoction, and 13 KEGG pathways played a therapeutic role in the synergistic mechanisms of multiple targets, such as Toll-like receptor (TLR), nuclear factor kappa B(NF)-κB, nucleotide binding oligomerization domain like receptor (NLR) signal pathways. The core targets were mainly distributed in the hematologic and immune systems. Molecular docking analysis showed that the binding energy between active ingredients and key targets were all less than 0 kJ/mol, indicating the strong binding of ligands to receptors. Conclusions The active ingredients of Kushen Decoction, such as quercetin, (+)-14α-hydroxymatrine and apigenin, may act on targets like AKT1, TNF, IL-6 to modulate TLR, NLR and NF-κB signaling pathways to play a synergistic role in the treatment of cryptosporidiosis in the hematologic and immune system.

18.
Article in English | WPRIM | ID: wpr-922772

ABSTRACT

Buxue Yimu Pill (BYP) is a classic gynecological medicine in China, which is composed of Angelica sinensis (Oliv.) Diels, Leonurus japonicus Houtt, Astragalus membranaceus (Fisch.) Bunge, Colla corii asini and Citrus reticulata Blanco. It has been widely used in clinical therapy with the function of enriching Blood, nourishing Qi, and removing blood stasis. The current study was designed to determine the bioactive molecules and therapeutic mechanism of BYP against hemorrhagic anemia. Herein, GC-MS and UPLC/Q-TOF-MS/MS were employed to identify the chemical compounds from BYP. The genecards database (https: //www.genecards.org/) was used to obtain the potential target proteins related to hemorrhagic anemia. Autodock/Vina was adopted to evaluate the binding ability of protein receptors and chemical ligands. Gene ontology and KEGG pathway enrichment analysis were conducted using the ClusterProfiler. As a result, a total of 62 candidate molecules were identified and 152 targets related to hemorrhagic anemia were obtained. Furthermore, 34 active molecules and 140 targets were obtained through the virtual screening experiment. The data of molecular-target (M-T), target-pathway (T-P), and molecular-target-pathway (M-T-P) network suggested that 32 active molecules enhanced hematopoiesis and activated the immune system by regulating 57 important targets. Pharmacological experiments showed that BYP significantly increased the counts of RBC, HGB, and HCT, and significantly down-regulated the expression of EPO, IL-6, CSF3, NOS2, VEGFA, PDGFRB, and TGFB1. The results also showed that leonurine, leonuriside B, leosibiricin, ononin, rutin, astragaloside I, riligustilide and levistolide A, were the active molecules closely related to enriching Blood. In conclusion, based on molecular docking, network pharmacology and validation experiment results, the enriching blood effect of BYP on hemorrhagic anemia may be associated with hematopoiesis, anti-inflammation, and immunity enhancement.


Subject(s)
Anemia/drug therapy , Drugs, Chinese Herbal , Humans , Molecular Docking Simulation , Tandem Mass Spectrometry
19.
Article in English | WPRIM | ID: wpr-922768

ABSTRACT

Chansu has demonstrated adverse reactions in clinical settings, which is associated with its toxicity and limits its clinical applications. But there are methodological limitations for drug safety evaluation. In the current study, ultra-high performance liquid chromatography, lipidomic profiling, and molecular docking were used to systemically assess Chansu-induced acute inflammatory irritation and further identify the underlying drug targets. Compared with the EtOAc extract, Chansu water fraction containing indolealkylamines caused acute inflammatory irritation in rats, including acute pain (spontaneous raising foot reaction), and inflammation (paw edema). At the molecular level, lipids analysis revealed significantly higher levels of pro-inflammatory mediators of the COX and LOX pathways. However, anti-inflammatory mediators from the CYP 450, ALA, and DHA pathways markedly decreased after exposure to Chansu water fraction. Moreover, four indolealkylamines from Chansu showed a high theoretical affinity to a known irritation target, 5-HT


Subject(s)
Animals , Bufanolides , Edema/drug therapy , Inflammation , Lipidomics , Molecular Docking Simulation , Rats , Water
20.
Article in Chinese | WPRIM | ID: wpr-921807

ABSTRACT

The active ingredients of Ficus hirta and Hypericum perforatum were collected from Traditional Chinese Medicine Database and Analysis Platform(TCMSP) and related papers. The potential targets of these two medicinal herbs were searched from HERB database, and those associated with microvascular angina were screened out from GeneCards, Online Mendelian Inheritance in Man(OMIM), Therapeutic Target Database(TTD), and HERB. Cytoscape was used to construct a protein-protein interaction(PPI) network of the common targets shared by the two herbs and microvascular angina based on the data of String platform. Metascape was employed to identify the involved biological processes and pathways enriched with the common targets. Cytoscape was used to draw the "active ingredient-target-pathway" network. AutoDock Vina was used to dock the core ingredients with the key targets. A total of 19 potential active ingredients and 71 potential targets were identified to be associated with microvascular angina. Bioinformatics analysis showed that phosphatidylinositol-3-kinase/protein kinase B(PI3 K-AKT), interleukin-17(IL17), hypoxia-inducible factor 1(HIF-1) and other signaling pathways were related to the treatment of microvascular angina by F. hirta and H. perforatum. Molecular docking results showed that β-sitosterol, luteolin and other ingredients had strong affinity with multiple targets including mitogen-associated protein kinase 1(MAPK1), epidermal growth factor receptor(EGFR) and so on. These findings indicated that F. hirta and H. perforatum may regulate PI3 K-AKT, IL17, HIF-1 and other signaling pathways by acting on multiple targets to alleviate oxidative stress, inhibit inflammatory response, regulate angiogenesis, and improve vascular endothelium and other functions. This study provides reference for in vitro and in vivo studies of the treatment of microvascular angina.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Ficus , Humans , Hypericum , Medicine, Chinese Traditional , Microvascular Angina , Molecular Docking Simulation
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