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Based on the research system of computer-aided drug design combined with complex network analysis, the potential mechanism of Dunhuang Dabupi Decoction in preventing and treating gastric cancer (GC) is analyzed, and the scientific connotation of its prescription rules is explored through the efficacy grouping. To study the effect of Dabupi Decoction freeze-dried powder solution on the proliferation activity of gastric cancer cells through cell experiments; the TCMSP and TCMID databases were used to collect the compound components of Dabupi Decoction. Swiss Target Prediction is used to predict potential targets of compounds. DrugBank, GeneCards, TTD, and DisGeNET were used to collect potential targets for gastric cancer. Analyze protein interactions of potential targets through the STRING database. DAVID database was used for KEGG enrichment analysis; Dabupi Decoction was divided into Wenzhong group (dried ginger), Yiqi group (ginseng, licorice, Atractylodes macrocephala), nourishing Yin group (Ophiopogon japonicus, Schisandra) and Jiangni group according to its efficacy characteristics. The inverse group (inula) has 4 functional compatibility groups. Cytoscape was used to construct a network of "medicinal flavor-potential active ingredient-key target" respectively, and the network was used to analyze the scientific connotation of the compatibility of efficacy groups. The Schrödinger software was used to verify the molecular docking of the core components and the core targets. The material basis of the Dabupi Decoction to prevent and treat gastric cancer was discovered through the combination of pattern analysis and combined free energy calculation. The core drug was analyzed from the perspective of dynamics through molecular dynamics simulation. Potential targets and representative potential compounds interact with each other. Cell experiments confirmed that Dabupitang freeze-dried powder solution can down-regulate the mitochondrial membrane potential of AGS gastric cancer cells, block the cell cycle in the G0/G1 phase (P < 0.05), and inhibit its proliferation (P < 0.05). The pathways enriched by the four functional groups contained in Dabupi Decoction are mainly distributed in the body's energy metabolism, inflammation-immune system regulation, and cycle-apoptotic functions. Each module is connected by a common target gene and has its own focus. The results of molecular docking showed that the compounds liquiritigenin, quercetin, kaempferol, isorhamnetin, methylophiopogonanone A, etc. may be the effective multi-target components of Dabupi Decoction. Estrogen receptor 1, androgen receptor, ATP-binding cassette superfamily G member 2, epidermal growth factor receptor, glycogen synthase kinase-3 beta and other targets have good affinity with each potential active compound, which may be a potential target of Dabupi Decoction for preventing and treating gastric cancer. Among them, kaempferol and the drug target EGFR not only have good binding ability, but also have good binding stability. This study is based on computer-aided drug design combined with complex network analysis strategies to initially reveal the material basis and molecular mechanism of Dabupi Decoction in the prevention and treatment of gastric cancer. It also explores the scientific connotation of Dabupi Decoction in the prevention and treatment of gastric cancer with different efficacy groups, and its clinical application provide chemical bioinformatics basis.
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Angelicae Sinensis Radix excels in activating blood, but the scientific mechanism has not been systematically analyzed, thus limiting the development of the medicinal. This study employed the computer-aided drug design methods, such as structural similarity-based target reverse prediction, complex network analysis, molecular docking, binding free energy calculation, cluster analysis, and ADMET(absorption, distribution, metabolism, excretion, toxicity) calculation, and enzyme activity assay in vitro, to explore the components and mechanism of Angelicae Sinensis Radix in activating blood. Target reverse prediction and complex network analysis yielded 40 potential anticoagulant targets of the medicinal. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis indicated that the targets mainly acted on the complement and coagulation cascade signaling pathway to exert the anticoagulant function. Among them, the key enzymes thrombin(THR) and coagulation factor Xa(FXa) in coagulation cascade and thrombosis were the drug targets for thromboembolic diseases. At the same time, molecular docking and cluster analysis showed that the medicinal had high selectivity for FXa. According to binding free energy score, 8 potential active components were selected for enzyme activity assay in vitro. The results demonstrated that 8 components inhibited THR and FXa, and the inhibition was stronger on FXa than on THR. The pharmacophore model of 8 active compounds was constructed, which suggested that the components had the common pharmacophore AAHH. The ADMET calculation result indicated that they had good pharmacokinetic properties and were safe. Based on target reverse prediction, complex network analysis, molecular docking and binding free energy calculation, anticoagulant activity in vitro, spatial binding conformation of molecules and targets, pharmacophore model construction, and ADMET calculation, this study preliminarily clarified the material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood from the perspective of big data, and calculated the pharmacology and toxicology parameters of the active components. Our study, for the first time, revealed that the medicinal had obvious selectivity and pertinence for different coagulation proteins, reflecting the unique effect of different Chinese medicinals and the biological basis. Therefore, this study can provide clues for precision application of Angelicae Sinensis Radix and the development of the blood-activating components with modern technology.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation , Drug Design , Drugs, Chinese Herbal/pharmacology , Molecular Docking SimulationABSTRACT
Objective:The targets and signaling pathways of Xuanfei Huazhuo prescription (XFHZP) for the treatment of coronavirus disease-2019 (COVID-19) were explored, and its possible action mechanisms were described through network pharmacology and basic analysis of modern pharmacology. Method:The compounds and targets in XFHZP were collected through TCMSP and BATMAN-TCM databases. The targets of COVID-19 were studied by GeneCards, NCBI and CTD databases. The PPI network was constructed through STRING database. The networks of "herb-meridian" and "traditional Chinese medicines-compounds-targets-disease" were generated by Cytoscape 3.7.0. Then, Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis and Gene Ontology（GO） analysis were made for shared targets through the Omicshare platform. In addition, the disease targets of multiple organ injury, immune injury and severe acute respiratory syndrome (SARS) were retrieved and then mapped with XFHZP. The ratio of intersection targets to XFHZP's targets was calculated. Result:XFHZP has 10 traditional Chinese medicines in total, including 6 medicines with the meridian tropism to lung, 5 medicines with the meridian tropism to the spleen and 5 medicines with the meridian tropism to the stomach. There were 409 compounds and 2 271 targets. There were 8 same inflammatory factors in targets between XFHZP and COVID-19, and each inflammatory factor corresponded to multiple compounds. XFHZP and COVID-19 had 135 intersection targets, and 36 key targets were screened out. A total of 172 signaling pathways were screened out through KEGG signal pathway enrichment (P<0.05). There were 4 000 biological processes, 254 cell components, and 408 molecular functions (P<0.05) according to GO analysis. XFHZP had many common targets with various organ damage targets and immune damage targets, with the ratio of about 7.6%-97.8%. XFHZP had 173 intersection targets with SARS. Conclusion:XFHZP may treat COVID-19 through anti-inflammatory, organ protecting and immune effects. It will provide a certain theoretical basis for the development of drugs for COVID-19.
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Objective:Structure-based angiotension converting enzyme 2 (ACE2) and interleukin-6R (IL-6R) were taken as the target proteins to in the investigation of the material basis of Xuanfei Huazhuo prescription in the treatment of coronavirus disease-2019 (COVID-19) by molecular docking. Method:The compounds in Xuanfei Huazhuo prescription were retrieved through TCMSP. Structure-based ACE2 and IL-6R were taken as the target proteins to screen out the compounds with a better activity by molecular docking, and analyze structural properties of these compounds. Furthermore, the potential molecular mechanism of Xuanfei Huazhuo prescription in the treatment of COVID-19 was analyzed by target reverse prediction. Result:There were 312 potentially active compounds in Xuanfei Huazhuo prescription, including 75 highly active compounds and 15 highly active compounds for ACE2. There were 100 eligible active compounds and 3 highly active compounds for IL-6R, most of which belong to flavonoids. The herb-component-target network included 10 herbs, 126 compounds and 130 targets. String analysis showed that PIK3R1, SRC, AKT1, AR and EGFR might be the key targets of Xuanfei Huazhuo prescription. Conclusion:Based on the virtual screening of multi-target molecular docking, the anti-virus and anti-inflammatory material basis of Xuanfei Huazhuo prescription was preliminarily obtained. At the same time, based on the reverse prediction and analysis, potential targets and molecular mechanism of the recipe in the treatment of COVID-19 were explored, so as to provide clues for the multi-angle mining of Xuanfei Huazhuo prescription and its relevant prescriptions and the modernization development of monomer components.
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Objective:To evaluate the clinical efficacy of Xuanfei Huazhuo prescription in the treatment of coronavirus disease-2019 (COVID-19). Method:A total of 40 patients with COVID-19 were selected and treated with Xuanfei Huazhuo prescription. The changes of body temperature, clinical symptoms, computed tomography (CT), blood routine and biochemical indexes were observed before and after treatment. Result:The 40 patients included 15 males and 25 females, with a male to female ratio of 1∶1.7. They were aged between 20-94 years old, with the average age of （43.9±16.3） years old. The course of disease was 8-23 days, with the average of （14±4.4） days. Compared with before administration, the patients' clinical symptoms, such as cough, fever, sputum, diarrhea, loss of appetite and fatigue, were all improved (P<0.05). Before treatment the traditional Chinese medicine (TCM) syndromes of patients were mainly cold dampness lung (57.5%) and cold dampness Lung (42.5%), and the tongue coating was mainly white greasy coating (52.9%). After adjuvant treatment with Xuanfei Huazhuo prescription, the fever removal time was (2.48±2.56) days; white blood cell (WBC), lymphocyte percentage (LYM%), neutrophil percentage (NEUT%), absolute value of lymphocytes (LYM #) indexes of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total bilirubin (TBIL), ratio of glutamic oxaloacetic transaminase to glutamic pyruvic transaminase (AST/ALT) and lactate dehydrogenase (LDH) were basically restored to the normal range (P<0.05) compared with before administration. After adjuvant treatment with Xuanfei Huazhuo prescription, the results of three pharyngeal test virus nucleic acid tests were negative, and the lung CT showed that infected lesions were absorbed and all met the discharge criteria. All 40 patients met the discharge criteria and were all cured and discharged, with a cure rate of 100%. There has been no case of recurrence with a positive result of nucleic acid detection so far. The score of symptom and clinical index of patients after administration was （1.62±1.90）, which was significantly lower than that before administration (7.65±4.08, P<0.05). Conclusion:In the adjuvant treatment of COVID-19, Xuanfei Huazhuo prescription can reduce body temperature, promote the absorption of pulmonary inflammation, and improve clinical symptoms, such as fever and cough.
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The pathological anatomical results of coronavirus disease-2019 (COVID-19) patients showed that excessive inflammatory reaction in the lungs is one of the important causes for such complications as acute lung injury or acute respiratory distress syndrome. Therefore, regulation of immune response may be an effective measure for COVID-19. Alveolar macrophages have a high heterogeneity and plasticity. The dynamic changes of subsets balance and function of M1/M2 alveolar macrophages have a significant effect on pulmonary inflammatory response during the early and late stages of infection. This paper reviews the classification and function of macrophages and explores the mechanism of alveolar macrophage in the pathological process of COVID-19 at different stages and the pharmacodynamic mechanism of traditional Chinese medicine. Besides, it provides ideas for the treatment of COVID-19 with traditional Chinese medicine and other drugs' research and development based on the regulation of macrophage polarization.
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Objective: To study the effect of small molecule compounds of Hedysari Radix in ntagonizing tumor necrosis factor receptor type 1 (TNFR1) based on molecular docking. Method: The structure of small molecular compound of Hedysari Radix was downloaded from the chemical composition compound library of traditional Chinese medicine, and then optimized to obtain the composition compound library of Hedysari Radix. The three-dimensional structure of the inflammatory target TNFR1 (PDB ID:1TNR) was identified. After hydrotreating and anhydrating, the binding pocket residues were identified according to the literature. According to the defined target structure and binding pocket, the flexible molecular docking was conducted between the composition compound library and the target, and the score (Glide Score) was obtained. Based on the results of molecular docking, the first nine small molecular compounds of Glide Score were selected as candidate components. On this basis, the drug-likeness was analyzed, which involved small molecular compounds that meet the number of hydrogen-bonded receptors, the number of hydrogen-bonded donors, the formula weight, the number of rotatable key and the numerical range of lipo-hydro partition coefficient. Finally, the binding mode was analyzed according to pharmacokinetic parameters and complex structure of composition-target docking. Result: The residue set in the TNFR1 drug-binding pocket were identified as glutamic acid109 (Glu109), lysine 35(Lys35), alanine62 (Ala62), serine 74 (Ser74), lysine75 (Lys75), cysteine76 (Cys76), argnine 77(Arg77), glutamine82 (Gln82), threonine89 (Thr89), asparticacid91 (Asp91), argnine92 (Arg92), aspartic acid93 (Asp93), threonine 94(Thr94), valine95 (Val95), cysteine 96(Cys96), argnine104 (Arg104), tyrosine106 (Tyr106), asparagine110 (Asn110), leucine111 (Leu111), phenylalanine112(Phe112), glutamic acid 131(Glu131) and lysine132 (Lys132). Totally 43 small molecular compounds of Hedysari Radix were obtained. Five small molecular compounds, namely hedysari radix, quercetin, isoliquiritin, naringenin, calycosin and liquiritigenin, were screened by comprehensive factors, like docking scoring. Conclusion: Quercetin, isoliquiritin, naringenin, calycosin and liquiritigenin are the effective anti-inflammatory substances of Hedysari Radix, with a great possibility of becoming TNFR1 antagonists.
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<p><b>OBJECTIVE</b>To evaluate the relationship between the duration of apnea episodes and the severity of hypoxemia of obstructive sleep apnea-hypopnea syndrome (OSAHS) patients and explore the possible causes of the disassociation between the severity of hypoxemia and AHI in some OSAHS subjects.</p><p><b>METHODS</b>Polysomnography data of eighty-two OSAHS patients was analyzed. Firstly, apnea and hypopnea events were classified into 4 groups respectively according to it's lengths, i.e., longer or equals to 10 s, 15 s, 20 s, 25 s, AHI10, AHI15, AHI20, AHI25 were obtained by calculating apnea hypopnea events per hour with respective lengths. Secondly, total apnea time per hour was calculated in all cases. Thirdly Spearman correlation coefficient and Linear regression analysis were used to measure the associations between numerical parameters referred above and three parameters of hypoxia: the lowest oxygen saturation level (LSaO2), the mean oxygen saturation level during sleep time (MeanSaO2), the percent of the total recorded time spent below 0.90 oxygen saturation level (TS90).</p><p><b>RESULTS</b>The apnea-hypopnea index (AHI10, AHI15, AHI20, AHI25) correlated negatively with the LSaO2 (r was -0.636, -0.634, -0.649, -0.657), P < 0.01. The apnea-hypopnea index (AHI10, AHI15, AHI20, AHI25) correlated negatively with the MeanSaO2 (r was -0.659, -0.647, -0.648, -0.629), P < 0.01. The apnea-hypopnea index (AHI10, AHI15, AHI20, AHI25) correlated positively with the TS90 (r was 0.810, 0.806, 0.806, 0.770), P < 0.01. Further linear regression analysis all showed significant clinical value with r(2) > 0.50. The amount time of apnea events per hour of total sleep time (T) showed high correlations with LSaO2, MeanSaO2, TS90 (r was -0.650, -0.628, 0.776), while P < 0.01.</p><p><b>CONCLUSIONS</b>The duration of apnea episodes has a significant clinical value in accessing the degree of hypoxia of the OSAHS patients. The TS90 combined with the LSaO2 reflects the severity of hypoxia of the OSAHS patients objectively.</p>
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Blood Gas Analysis , Body Mass Index , Hypoxia , Oximetry , Polysomnography , Regression Analysis , Sleep Apnea, Obstructive , Time FactorsABSTRACT
Objective To investigate the trend of developmental expression of GluR2,subtype of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) receptor and synaptophysin(SYP) in the rat cochlear nucleus(CN) in different developmental stages,and explore the association of GluR2 expression with the development of synapse. Methods SD rats of 2,3,4,6,8 and 10 weeks old were selected,the expression of GluR2 and SYP in CN was detected with immunofluorescence histochemical method,and the association of them was explored. Results GluR2 expression was observed in all the neurons of CN in each postnatal groups.The expression was relatively weaker in the second and third week,became denser in the fourth week,reached the peak in the sixth week and then sharply decreased to the weakest in the tenth week.The expression of GluR2 was denser at granular cell layer,while weaker at molecular layer and multipolar cell layer in the dorsal CN.SYP expression was detected in all the neurons of CN in each postnatal groups.The expression was weakest in the second week,significantly denser in the fourth week,reached the peak in the sixth week,was then sharply decreased and stably maintained. Conclusion The expressions of GluR2 and SYP in the postnatal rat CN exhit an equally age-dependent tendency.The expression of GluR2 in the CN may be associated with the the maturation and function development of the CN.The different expression and distribution of GluR2 and SYP in the rat CN of different developmental stages may be involved in the development and plasticity of auditory center.
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<p><b>OBJECTIVE</b>To discuss outcome of thyroid tumor patients treated with surgery.</p><p><b>METHODS</b>Total number of patients was 2228. These patients of thyroid tumors from 1992-2004 (2072 cases of benign thyroid diseases and 156 cases of thyroid carcinoma) were recruited. The clinical and follow-up datum were retrospective analyzed.</p><p><b>RESULTS</b>(1) Benign thyroid tumors with near-total thyroidectomy including 1761 thyroid adenoma, 207 nodular goiter and 104 Hashimoto thyroiditis, the incidence of recurrent laryngeal nerve paralysis was 0.2%, 55 cases (2.6%) received secondary surgery. All the patients have no hypocalcemia or hemorrhage after operation. (2) Eighty-one cases of papillary carcinoma of the thyroid ( > 1 cm) and 60 cases of microcarcinoma. Unilateral thyroidectomy, contralateral near-total thyroidectomy and ipsilateral modified neck dissection were performed in unilateral papillary carcinoma of thyroid. Among the 9 cases of follicular carcinoma of thyroid, 7 were performed of near-total thyroidectomy without neck dissection, others were the same as papillary carcinoma. Bilateral total thyroidectomy and bilateral modified neck dissection were performed in 2 cases of the medullary thyroid cancer and 1 case of the undifferentiated thyroid cancer. By direct method the 5-year survival was 95.5% (64/67), and by Kaplan-Meier method, it was 98.0%. The treatment of microcarcinoma are multiple. There is no relapse or metastases in 60 cases of papillary thyroid microcarcinoma. The 5-year survival was 100.0%, 1 cases occurred recurrent laryngeal nerve paralysis in thyroid cancer. No hypocalcemia or hemorrhage. Eight case relapsed in 156 cases of thyroid carcinoma,3 cases died.</p><p><b>CONCLUSION</b>The correct surgical management for the patients with thyroid tumor should benefit for the prognosis and reduce the complications and the recurrence of the operation.</p>