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The complex chemical composition and limited research ideas of traditional Chinese medicine （TCM） have led to the unclear material basis and mechanism of the medicinal effects， which is a common problem hindering the modernization of TCM in China. The introduction of computer virtual technology has provided a new perspective for TCM research. In this study， we established the research method of structure-activity omics to study the relationships between the structures and effects of different compounds in TCM based on the chemical structures of TCM components and to analyze and predict the material basis and multitarget synergistic mechanism of TCM. Furthermore， a structure-activity omics study was carried out with the anti-inflammatory and analgesic effects of Qizhi Weitong granules as an example. This study provides support for screening the pharmacodynamic components and analyzing the active ingredients of TCM and gives insights into the research on the material basis and mechanism of compound efficacy and the development of lead compounds of TCM， thus promoting the modern research and the innovative development of TCM.
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ObjectiveTo explain the anti-inflammatory and analgesic effects of Corydalis Rhizoma by the means of structure-activity omics. MethodOn the basis of the previous in vitro screening study， we studied the in vivo efficacy of the alkaloids in Corydalis Rhizoma. With the targets as a bridge， the structures of chemical components in Corydalis Rhizoma were connected with the efficacy. The molecular docking of the alkaloids in Corydalis Rhizoma with the targets of inflammation and pain was carried out. According to the docking scores and the differences in the structural nucleus of Corydalis Rhizoma alkaloids， a study of structure-activity omics was carried out to summarize the rules of their connection. ResultThe alkaloids in Corydalis Rhizoma had good anti-inflammatory and analgesic effects in vivo， involving 53 chemical components and 73 targets. There were 3 074 targets associated with inflammation and pain， and 42 targets of direct action were shared by the chemical components and the disease. The protein-protein interaction （PPI） and molecular docking analysis predicted that the main active components of Corydalis Rhizoma were tetrahydropalmatine and palmatine， and the core targets were prostaglandin endoperoxide synthase 2 （PTGS2）， glutamate receptor metabotropic 5 （GRM5）， estrogen receptor 1 （ESR1）， solute carrier family 6 member 4 （SLC6A4）， and fusion oncoproteins （FOS）. According to the differences of mother nucleus， the 53 alkaloid components of Corydalis Rhizoma were classified into 8 categories， including protoberberine， berberine， and aporphine， which had high binding affinities with PTGS2， GRM5 and other targets. The relationship between the structures of Corydalis Rhizoma alkaloids and docking scores in each group showed the same law. In protoberberine， appropriate substituents with hydroxyl， alkoxy or methyl groups on the A and D rings of the parent ring were conducive to enhancing the binding activities with the two targets. In berberine， the structure containing a methyl group on position 13 had strong binding affinities with the two targets. It is hypothesized that the methyl fragment changes the binding mode between the component structure and amino acid residues， which greatly improves the binding affinity. ConclusionThis study employs the method of structure-activity omics to analyze the material basis for the anti-inflammatory and analgesic effects of alkaloids in Corydalis Rhizoma， and the structure-activity omics provides new ideas for revealing the pharmacodynamic substances of traditional Chinese medicine.
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ObjectiveTo explain the pharmacodynamic substances of Aurantii Fructus flavonoids that exert anti-inflammatory and analgesic effects using a structure-activity omics approach. MethodOn the basis of the previous in vitro pharmacological screening conducted by the research team， an in vivo pharmacological study of Aurantii Fructus flavonoids was carried out. Core targets of the anti-inflammatory and analgesic active components of flavonoids of Aurantii Fructus were identified using various network databases， including the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， the Online Mendelian Inheritance in Man （OMIM）， and the Search Tool for the Retrieval of Interacting Genes/Proteins （STRING）. Computer-aided virtual screening technology was used to dock different types of Aurantii Fructus flavonoids with core targets. The key core targets with high binding activity were selected based on the comprehensive scores of each target and the active structures. Using these targets as bridges， the structures of one or more types of chemical components in Aurantii Fructus were closely linked to pharmacological effects. The structure-activity relationship between the clear pharmacodynamic compounds and their effects was explored through the binding patterns of various structures with pharmacodynamic targets. ResultAurantii Fructus flavonoids demonstrated significant anti-inflammatory and analgesic effects on dextran sulfate sodium （DSS）-induced colitis in mice， which could improve symptoms and significantly reduce the levels of inflammatory factors interleukin-6 （IL-6） and interleukin-1β （IL-1β）（P<0.05）. Twelve active components of Aurantii Fructus flavonoids were identified and categorized into nine dihydroflavonoids and three flavonoids based on their structures of the parent nuclei. Through Venn analysis， 167 anti-inflammatory and analgesic targets for Aurantii Fructus were identified. Based on degree value and molecular docking comprehensive scores， prostaglandin-endoperoxide synthase 2（PTGS2） and mitogen-activated protein kinase 3（MAPK3） were selected for further structural analysis. Structural analysis revealed that components containing glycoside structures exhibited higher binding activity with anti-inflammatory and analgesic targets. ConclusionThis study utilized a structure-activity omics approach based on in vivo pharmacodynamic experiments to analyze the material basis of the anti-inflammatory and analgesic effects of Aurantii Fructus flavonoids. The structure-activity omics approach provides new ideas and methods for elucidating the pharmacodynamic substances of Chinese medicine.
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ObjectiveT o explore the influence of patch shape for intraventricular tunnel (IVT) construction on biomechanical performance of the double outlet right ventricle after correction. Methods Based on the idealized IVT model, a two-dimensional IVT patch was designed. Six groups of patch models with the rhombic long-to-short axis ratio of 1∶0.625, 1∶0.3, 1∶0.2, 1∶0.15, 1∶0.125, 1∶0.1 were established according to the difference between the long and short axis of the rhombus patch in the turning part, and finite element analysis method was used to numerically simulate the process of stitching, holding and propping up the patch into a three-dimensional (3D) IVT model. Results The maximum stresses on suture line of 6 patch models were mainly concentrated at acute-angle corners of the rhombus. As rhombic long-to-short axis ratio of the patch increased, the maximum stress of the IVT suture line first decreased and then increased, and the volume showed an increasing trend. The pressure difference between two ends of the tunnel first decreased and then increased. The patch with the long-to-short axis ratio of 1∶0.15 had a uniform surface stress distribution, and the maximum stress on the suture line was the smallest. Meanwhile the right ventricular volume was less encroached on, and the pressure difference at both ends of the tunnel was small. Conclusions The IVT shape can influence stresses of suture line, the right ventricle volume and the pressure difference of IVT with non-monotonic variations. The suture effect of the patch with the long-to-short axis ratio of 1∶0.15 is relatively better among the constructed models.
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Objective To explore the biomechanical mechanism of aortic insufficiency (AI) after single aortic valve replacement (SAVR) in children and propose the corresponding countermeasures. Methods The idealized aortic valve model and postoperative growth model were constructed. By changing the length of leaflet free edge, leaflet height as well as improving the design with a concave structure, the effects of different structure dimensions on movement synchronization and closing performance of the aortic valve after surgery were compared. Results The closure of the replacement leaflet lagged behind the autologous leaflet, which fitted 2 mm below free edge of the replacement leaflet. AI occurred 6 years after operation. Increasing leaflet height could not improve the postoperative effect and would increase the maximum stress of the leaflet. Increasing free edge length by 10% could improve the postoperative outcomes, while increasing free edge length by 15% would cause the leaflet to be too long, hence resulting in a poor fit of the aortic valve. Compared with the traditional structure, the concave structure was more beneficial for closing performance of the aortic valve, and it could effectively reduce the maximum stress by 20% with the best effect. Conclusions The leaflet movement will be out of synchronization after SAVR, the point of convergence will be shifted, and AI will appear 6 years after surgery. It is recommended to use a concave structure with free edge length increased by 10%, while increasing leaflet height is not recommended.
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To solve the problem of stent malapposition of intravascular stents, explore the design method of intravascular body-fitted stent structure and to establish an objective apposition evaluation method, the support and apposition performance of body-fitted stent in the stenotic vessels with different degrees of calcified plaque were simulated and analyzed. The traditional tube-mesh-like stent model was constructed by using computational aided design tool SolidWorks, and based on this model, the body-fitted stent model was designed by means of projection algorithm. Abaqus was used to simulate the crimping-expansion-recoil process of the two stents in the stenotic vessel with incompletely calcified plaque and completely calcified plaque respectively. A comprehensive method for apposition evaluation was proposed considering three aspects such as separation distance, fraction of non-contact area and residual volume. Compared with the traditional stent, the separation distances of the body-fitted stent in the incompletely calcified plaque model and the completely calcified plaque model were decreased by 21.5% and 22.0% respectively, the fractions of non-contact areas were decreased by 11.3% and 11.1% respectively, and the residual volumes were decreased by 93.1% and 92.5% respectively. The body-fitted stent improved the apposition performance and was effective in both incompletely and completely calcified plaque models. The established apposition performance evaluation method of stent considered more geometric factors, and the results were more comprehensive and objective.