Chemical composition and therapeutic mechanism of Xuanbai Chengqi Decoction in the treatment of COVID-19 by network pharmacology, molecular docking and molecular dynamic analysis.

Xuanbai Chengqi Decoction (XBCQD), a classic traditional Chinese medicine, has been widely used to treat COVID-19 in China with remarkable curative effect. However, the chemical composition and potential therapeutic mechanism is still unknown. Here, we used multiple open-source databases and literature mining to select compounds and potential targets for XBCQD. The COVID-19 related targets were collected from GeneCards and NCBI gene databases. After identifying putative targets of XBCQD for the treatment of COVID-19, PPI network was constructed by STRING database. The hub targets were extracted by Cytoscape 3.7.2 and MCODE analysis was carried out to extract modules in the PPI network. R 3.6.3 was used for GO enrichment and KEGG pathway analysis. The effective compounds were obtained via network pharmacology and bioinformatics analysis. Drug-likeness analysis and ADMET assessments were performed to select core compounds. Moreover, interactions between core compounds and hub targets were investigated through molecular docking, molecular dynamic (MD) simulations and MM-PBSA calculations. As a result, we collected 638 targets from 61 compounds of XBCQD and 845 COVID-19 related targets, of which 79 were putative targets. Based on the bioinformatics analysis, 10 core compounds and 34 hub targets of XBCQD for the treatment of COVID-19 were successfully screened. The enrichment analysis of GO and KEGG indicated that XBCQD mainly exerted therapeutic effects on COVID-19 by regulating signal pathways related to viral infection and inflammatory response. Meanwhile, the results of molecular docking showed that there was a stable binding between the core compounds and hub targets. Moreover, MD simulations and MM-PBSA analyses revealed that these compounds exhibited stable conformations and interacted well with hub targets during the simulations. In conclusion, our research comprehensively explained the multi-component, multi-target, and multi-pathway intervention mechanism of XBCQD in the treatment of COVID-19, which provided evidence and new insights for further research.

Network pharmacology of iridoid glycosides from Eucommia ulmoides Oliver against osteoporosis.

Eucommia ulmoides Oliver is one of the commonly used traditional Chinese medicines for the treatment of osteoporosis, and iridoid glycosides are considered to be its active ingredients against osteoporosis. This study aims to clarify the chemical components and molecular mechanism of iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis by integrating network pharmacology and molecular simulations. The active iridoid glycosides and their potential targets were retrieved from text mining as well as Swiss Target Prediction, TargetNet database, and STITCH databases. At the same time, DisGeNET, GeneCards, and Therapeutic Target Database were used to search for the targets associated with osteoporosis. A protein-protein interaction network was built to analyze the interactions between targets. Then, DAVID bioinformatics resources and R 3.6.3 project were used to carry out Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Moreover, interactions between active compounds and potential targets were investigated through molecular docking, molecular dynamic simulation, and binding free energy analysis. The results showed that a total of 12 iridoid glycosides were identified as the active iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis. Among them, aucubin, reptoside, geniposide and ajugoside were the core compounds. The enrichment analysis suggested iridoid glycosides of Eucommia ulmoides Oliver prevented osteoporosis mainly through PI3K-Akt signaling pathway, MAPK signaling pathway and Estrogen signaling pathway. Molecular docking results indicated that the 12 iridoid glycosides had good binding ability with 25 hub target proteins, which played a critical role in the treatment of osteoporosis. Molecular dynamic and molecular mechanics Poisson-Boltzmann surface area results revealed these compounds showed stable binding to the active sites of the target proteins during the simulations. In conclusion, our research demonstrated that iridoid glycosides of Eucommia ulmoides Oliver in the treatment of osteoporosis involved a multi-component, multi-target and multi-pathway mechanism, which provided new suggestions and theoretical support for treating osteoporosis.

Exploring the potential therapeutic effect of Eucommia ulmoides-Dipsaci Radix herbal pair on osteoporosis based on network pharmacology and molecular docking technology.

Eucommia ulmoides-Dipsaci Radix (EU-DR) is a commonly used herbal pair for the treatment of osteoporosis (OP) in China. The purpose of this study was to investigate the potential mechanism of EU-DR on OP through network pharmacology and molecular docking approaches. Combining data from multiple open-source databases and literature mining, the active compounds and potential targets of EU-DR were screened out. The OP related targets were identified from the interactive web tool GEO2R. The shared targets were obtained by intersecting the targets of EU-DR and OP. The protein-protein interaction (PPI) network was constructed via the STRING database and Cytoscape 3.7.2 software. GO and KEGG enrichment analysis were conducted using R 3.6.3 software with adjusted p-value < 0.05. Sybyl-x 2.1.1 and Autodock Vina 1.1.2 software were used to cross validate the affinity between active compounds and target proteins. Our results showed that a total of 50 active compounds were screened, corresponding to 895 EU-DR targets, 2202 OP targets and 144 shared targets. The flavonoids in EU-DR played an important role in anti-OP. The enrichment analysis of GO and KEGG suggested EU-DR exerted a therapeutic effect on OP mainly by regulating the osteoclast differentiation related signaling pathway. Meanwhile, molecular docking results showed that most active compounds in EU-DR had strong binding efficiency to the target proteins. In conclusion, this study elaborated the multi-component, multi-target, and multi-pathway interaction mechanism of the EU-DR herbal pair in the treatment of OP for the first time, which also provided a pharmacological basis for treating OP.

Using open-tubular capillary electrochromatography with part-coating column for binding constants determination of ß2 -adrenergic receptor with seven drugs.

An open-tubular capillary electrochromatography method has been developed for the determination of binding constants between ß2 -adrenergic receptor (ß2 -AR) and seven drugs. ß2 -AR was oriented immobilized onto one part of inner surface of capillary via microwave-assisted technical synthesis. According to the linear relationship between coating length and the apparent mobility of analyte, the binding constant (Kb ) can be obtained by related theories and equations. The order of Kb values between drugs such as adrenaline hydrochloride, norepinephrine bitartrate, and propranolol hydrochloride with ß2 -AR is well consistent with that reported in the literature. By the method, Kb values between four extracts of Radix Paeoniae Rubra and ß2 -AR were also successfully obtained. Subsequently, computer models were applied to interpret the CEC experiments. And the results proved to be in good agreement with the method. The work, herein, demonstrates the potential of the method in drug-receptor affinity interactions evaluation and screening of lead compounds from natural sources.

Molecular Modeling Study for the Design of Novel Peroxisome Proliferator-Activated Receptor Gamma Agonists using 3D-QSAR and Molecular Docking.

Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of PPARγ agonists represents a valuable research tool for diabetes therapy. To explore the structural requirements of PPARγ agonists, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were performed on a series of N-benzylbenzamide derivatives employing comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and surflex-dock techniques. The generated models of CoMFA and CoMSIA exhibited a high cross-validation coefficient (q²) of 0.75 and 0.551, and a non-cross-validation coefficient (r²) of 0.958 and 0.912, respectively. The predictive ability of the models was validated using external validation with predictive factor (r²pred) of 0.722 and 0.682, respectively. These results indicate that the model has high statistical reliability and good predictive power. The probable binding modes of the best active compounds with PPARγ active site were analyzed, and the residues His323, Tyr473, Ser289 and Ser342 were found to have hydrogen bond interactions. Based on the analysis of molecular docking results, and the 3D contour maps generated from CoMFA and CoMSIA models, the key structural features of PPARγ agonists responsible for biological activity could be determined, and several new molecules, with potentially higher predicted activity, were designed thereafter. This work may provide valuable information in further optimization of N-benzylbenzamide derivatives as PPARγ agonists.

An Optimized and Feasible Preparation Technique for the Industrial Production of Hydrogel Patches.

For hydrogel patches, the laboratory tests could not fully reveal the existing problems of full scale of industrial production, and there are few studies about the preparation technique for the industrial manufacturing process of hydrogel patches. So, the purpose of this work was to elucidate the effects of mainly technological operation and its parameters on the performance of hydrogel patches at the industrial-scale production. The results revealed the following: (1) the aqueous phase was obtained by polyvinylpyrrolidone (PVP) along with tartaric acid dissolved in purified water, then feeding this into a vacuum mixer as a whole in one batch, thus extended the crosslinking reaction time of hydrogel paste (matrix) and allowed the operation of coating/cutting-off to be carried out easily, and there was no permeation of backing layer; (2) the gel strength of the hydrogel patches increased with the increase of working temperature, however, once the temperature exceeded 35 ± 2 °C, the hydrogel paste would lose water severely and the resultant physical crosslinking structure which has lower gel/cohesive strength would easily bring gelatinization/residues during application; (3) the relative humidity (RH) of the standing-workshop was dynamically controlled (namely at 35 ± 2 °C, keeping the RH at 55 ± 5% for 4 days, then 65 ± 5% for 2 days), which would make patches with satisfactory characteristics such as better flexibility, higher adhesive force, smooth flat matrix surface, and without gelatinization/residues and warped edge during the using process; (4) the aging of the packaged hydrogel patches was very sensitive to storage temperature, higher temperature, higher gel strength and lower adhesiveness. The storage temperature of 10 ± 2 °C could effectively prevent matrix aging and adhesion losing, which would also facilitate the expiration date of patches extended obviously. In conclusion, this work provides an optimized and feasible preparation technique for the industrial production of the hydrogel patches and establishes the hydrogel patches as a novel carrier for transdermal drug delivery.

Preparation and characterisation of solid dispersions of tanshinone IIA, cryptotanshinone and total tanshinones.

Total tanshinones are lipophilic active constituents extracted from Salvia miltiorrhiza Bge. Tanshinone IIA and cryptotanshinone are the major components in total tanshinones. However, the bioavailability of both compounds is low due to poor water solubility. To enhance the solubility and dissolution rate of tanshinone IIA, cryptotanshinone and total tanshinones, three common used hydrophilic carriers including PEG 6000, poloxamer 188 and PVP K30 were used to prepare the solid dispersions at different ratios, respectively. The solid dispersions were characterised by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). The results of powder X-ray diffraction confirmed the microcrystal state of total tanshinones in solid dispersions and no chemical interaction between total tanshinones and carriers was observed in FTIR spectra. The solubility and dissolution rate of tanshinone IIA and cryptotanshinone were significantly increased in all solid dispersions. Regarding tanshinone IIA, the solubility and dissolution rate of in solid dispersions prepared with poloxamer 188 were significantly higher than that with PEG 6000 and PVP K30. The higher solubility and dissolution rate of cryptotanshinone were obtained in solid dispersion of PVP K30 than that of PEG 6000 solid dispersions but no significant difference from poloxamer 188 solid dispersions. The results indicate that the superior carrier for preparation of tanshinone IIA and total tanshinones solid dispersions is poloxamer 188, and that for cryptotanshinone is PVP K30.

Euonymus alatus: A Review on Its Phytochemistry and Antidiabetic Activity.

Euonymus alatus (E. alatus) is a medicinal plant used in some Asian countries for treating various conditions including cancer, hyperglycemia, and diabetic complications. This review outlines the phytochemistry and bioactivities of E. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified from E. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studies in vitro and in vivo have demonstrated the hypoglycemic activity of E. alatus extracts and its certain constituents. The hypoglycemic activity of E. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPARγ and aldose reductase pathways. Further studies on E. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.

Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications.

The purpose of this work was to develop and characterize the fibrauretine (FN) loaded propylene glycol-embodying deformable liposomes (FDL), and evaluate the pharmacokinetic behavior and safety of FDL for vaginal drug delivery applications. FDL was characterized for structure, particle size, zeta potential, deformability and encapsulation efficiency; the ability of FDL to deliver FN across vagina tissue in vitro and the distribution behavior of FN in rat by vaginal drug delivery were investigated, the safety of FDL to the vagina of rabbits and rats as well as human vaginal epithelial cells (VK2/E6E7) were also evaluated. Results revealed that: (i) the FDL have a closed spherical shape and lamellar structure with a homogeneous size of 185±19nm, and exhibited a negative charge of -53±2.7mV, FDL also have a good flexibility with a deformability of 92±5.6 (%phospholipids/min); (ii) the dissolving capacity of inner water phase and hydrophilicity of phospholipid bilayers of deformable liposomes were increased by the presence of propylene glycol, this may be elucidated by the fluorescent probes both lipophilic Nile red and hydrophilic calcein that were filled up the entire volume of the FDL uniformly, so the FDL with a high entrapment capacity (were calculated as percentages of total drug) for FN was 78±2.14%; (iii) the permeability of FN through vaginal mucosa was obviously improved by propylene glycol-embodying deformable liposomes, no matter whether the FN loaded in liposomes or not, although FN loaded in liposomes caused the highest permeability and drug reservoir in vagina; (iv) the FN mainly aggregated in the vagina and uterus, then the blood, spleen, liver, kidney, heart and lungs for vaginal drug delivery, this indicating vaginal delivery of FDL have a better 'vaginal local targeting effect'; and (v) the results of safety evaluation illustrate that the FDL is non-irritant and well tolerated in vivo, thereby establishing its vaginal drug delivery potential. These results indicate that the propylene glycol-embodying deformable liposomes may be a promising drug delivery carrier for vaginal delivery of fibrauretine.

[Content comparison of pinoresinol diglucoside in original and reborn bark of Eucommia ulmoides].

OBJECTIVE: To evaluate the reborn barks quality, antihypertensive effective component of pinoresnol diglucoside (PDG) in three times reborn barks were determined. METHODS: A YWG C18 column (10 microm, 250 x 4.6 mm) was used with a mobile phase of methanol-water (30:75) and flow rate of 1.0 (ml/min). The detective wave-length was set at 277nm and the column temperature at room temperature. RESULTS: PDG in the first reborn barks are slightly higher than the original ones, and in the second reborn barks are similar with the barks before girdling (the fist reborn barks), but in the third reborn barks, PDG are much lower than the barks before girdling (the second reborn barks). CONCLUSION: In order to ensure reborn barks quality, we suggest that the girdling bark regeneration can be made two times, the time between the first and the second girdling is not less than five years. PDG in the third reborn barks should be enhanced.