Computer-aided Drug Design and Experimental Validation Reveal Molecular Mechanism of Saikosaponin D-induced Apoptosis of Bladder Cancer Cells / 中国实验方剂学杂志

ObjectiveTo explore the role of saikosaponin D （SSD） targeting signal transducer and activator of transcription 3 （STAT3） in inducing apoptosis of bladder cancer cells by computer-aided drug design and experimental verification. MethodThe druggability and biotoxicity of SSD were explored by Bayesian classifier modeling. The information about SSD， the active ingredient of Bupleuri Radix， was searched against the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform （TCMSP）. The targets of SSD were predicted by PubChem， TCMSP， a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine （BATMAN-TCM）， Coremine， an Encyclopedia of Traditional Chinese Medicine （ETCM）， and SwissTargetPrediction. GeneCards， Therapeutic Target Database （TTD）， and Online Mendelian Inheritance in Man （OMIM） were employed to predict the potential therapeutic targets of bladder cancer. Then， the common targets shared by SSD and bladder cancer were selected for Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses. Molecular docking was adopted to explore the binding affinity and structural stability of SSD with target proteins. Cytoscape 3.9.1 was used to construct the STAT3-drug regulatory network and STAT3-apoptosis regulatory network. UM-UC-3 cells were treated with 0， 5， 10， 15 μmol·L-1 SSD for 24 h. Then， flow cytometry was used to detect the apoptosis of bladder cancer cells， and Western blot was employed to determine the protein levels of B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， Bcl-2-associated death promoter （Bad）， STAT3， and phosphorylation （p）-STAT3. ResultBayesian classifier modeling and molecular docking showed that SSD had low biotoxicity and bound well to the target protein STAT3 to form a stable protein-ligand complex. There were 282 common targets between bladder cancer and SSD， among which STAT3 was the most central target. The GO enrichment analysis showed that the potential core therapeutic targets involved 3 036 biological processes， 82 cellular components， and 171 molecular functions. The KEGG enrichment analysis showed that the potential core targets were mainly related to the C-type lectin receptor signaling pathway， Toll-like receptor signaling pathway， and cell apoptosis pathway. The STAT3-drug regulatory network and STAT3-apoptosis regulatory network showed that 29 drugs interacted with STAT3， and 27 apoptosis-related genes had a strong correlation with STAT3. Flow cytometry showed that the apoptosis rate increased with the increase in SSD concentration （P<0.05）. Western blotting results showed that SSD down-regulated the protein levels of p-STAT3 and Bcl-2 and up-regulated the protein levels of Bax and Bad in a concentration-dependent manner （P<0.05）. ConclusionSSD has good druggability and low biotoxicity. It may promote the apoptosis of bladder cancer cells by targeting STAT3.

Research on the current status,hotspots,and evolution trends of integrity construction in public hospi-tals:a citespace visualization analysis / 现代医院

Objective To explore the research status,hot topics and trends in the construction of integrity in public hos-pitals in China,provide references for the research on integrity construction in public hospitals and promote their high-quality de-velopment.Methods The relevant literature on the construction of integrity in public hospitals from 2009 to 2022 was collected from the China National Knowledge Infrastructure(CNKI)database.CiteSpace software was used to analyze the selected litera-ture in terms of publication timeline,author co-citation,institution co-citation,keyword co-occurrence,keyword clustering and keyword burst analysis,and visualize the knowledge graph.Results The research on the construction of integrity in public hos-pitals in China showed an upward trend from 2009 to 2022.The hot topics in the research mainly focused on incorruptible medical practices,integrity risks and integrity culture.The keyword burst analysis revealed that discipline inspection and supervision,in-formation platforms and institutional development were the future research directions.Conclusion The research on the construc-tion of integrity in public hospitals in China has a clear policy orientation,and various subfields are being explored.Internal inde-pendent research is predominant,while collaboration among multiple scholars and institutions needs to be strengthened.The con-struction of integrity in public hospitals in China mainly focuses on three areas.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Connectivity between visual brain regions and whole brain among children diagnosed with autism spectrum disorder / 中国学校卫生

Objective@#To explore the functional connectivity between the visual brain regions and whole brain in children with autism spectrum disorder (ASD) at resting state, and to further analyze the correlation with their clinical manifestations.@*Methods@#The functional magnetic resonance imaging (fMRI) data of 34 boys with ASD enrolled from ASD designated rehabilitation institutions and 29 healthy boys enrolled from several kindergartens in Heilongjiang were collected. Based on the resting-state functional connectivity magnetic resonance imaging (rs-fc MRI) analysis, the BA17 of the primary visual brain region and the BA18/19 of the higher visual brain region were taken as the regions of interest (ROI) to calculate the functional connectivity level between the visual brain regions and whole brain, and the differences between the two groups were compared. Multiple developmental scales were used to evaluate the behavior of ASD children, and Pearson correlation analysis was used to explore the relationship between functional connection strength and autistic behavior.@*Results@#The ASD group had decreased positive connectivity between BA17 and the right fusiform gyrus (FFG), and was negatively correlated with social interaction of ADI-R and the total scores of CARS (r=-0.41, -0.48, P<0.05); ASD group had decreased positive connectivity between BA17 and the left FFG, there was a negative correlation with social motivation of SRS (r=-0.43, P<0.05); ASD group had decreased positive connectivity between BA17 and the left posterior cingulate gyrus (PCG). Children with ASD had decreased positive connectivity between BA18/19 and left calcarine fissure and surrounding cortex (CAL), which was positively correlated with attention conversion of AQ, total scores of CARS (r=0.43, 0.40, P<0.05), and the children with ASD had deceased positive connectivity between BA18/19 and right precuneus (PCUN).@*Conclusion@#In resting state, the functional connectivity of primary and higher visual brain regions and whole brain of ASD children is different from that in healthy children, and there is a significant correlation between abnormal level and autistic behaviors.

Current situation of emergency medical service system for patients with acute myocardial infarction in Hebei Province and its influence on treatment and prognosis / 中华急诊医学杂志

Objective:To investigate the current situation of emergency medical service (EMS) system and its effect on treatment of the acute stage and short- and long-term prognosis in patients with acute myocardial infarction in Hebei province.Methods:Totally 2 961 patients with acute myocardial infarction who were admitted to major tertiary and some representative secondary hospitals in Hebei province from January 2016 to December 2016 were collected. According to the pattern of arriving hospital, all the patients were divided into the EMS group and self-transport group. The general conditions, time from onset to treatment, treatment methods, in-hospital mortality rate and 3-year mortality rate were compared between the two groups.Results:Of the included 2 961 patients, 33.13% of them were transported through EMS and 66.87% of them by private transport. Patients with a history of hypertension and ST-segment elevation myocardial infarction were more likely to choose EMS, and the difference was statistically significant ( P<0.05). Moreover, patients in the EMS group were more likely to go to tertiary hospitals for treatment (88.58% vs 85.76%, P=0.033). The time from onset to treatment of the EMS group was significantly shorter than that of the self-transport group (160 min vs 185 min, P<0.01), and the proportion of patients in the EMS group from onset-to-door time in <3 h and 3-6 h was higher than that of the self-transport group (55.76% vs 49.14%, 21.41% vs 19.09%, P<0.01). Compared with the self-transport group, the EMS group has a higher rate of reperfusion therapy (67.48% vs 61.67%, P=0.002). Patients in the EMS group had a higher in-hospital mortality rate in the acute stage (7.03% vs 4.44%, P=0.003), but its 3-year mortality rate was lower than that of the self-transport group (17.31% vs 20.77%, P<0.05). Conclusions:EMS can shorten symptom-onset-to-arrival time, increase the rate of reperfusion therapy and improve long-term prognosis of patients with acute myocardial infarction.

Study on the Effect and Its Mechanism of Dihydroartemisinin on the Metabolism of Amino Acids in Hepatoma Cells / 中国药房

OBJECTIVE：To investigate the effects of dihydroartemisinin （DHA）on the metabolism of amino acid metabolites in human hepatocellular carcinoma cells Huh 7 and BEL- 7402，and to provide theoretic basis for clarifying the mechanism of DHA regulating the metabolism of hepatocellular carcinoma cells. METHODS ：CCK-8 method was taken to detect the effect of different concentrations of DHA （12.5，25，50，100 µmol/L）treating for 24，48，72 h on the two kinds of cells. Two kinds of cells were divided into control group and administration group （DHA，25 µmol/L），and then cultured with drug-free or drug-containing medium for 24 h，operated in parallel for three times. After derivatization of cell samples in each group ，GC-MS method was used to detect the content of amino acid metabolites ，combined with SIMCA-P software analysis and compound library comparison ，the differential metabolites in two kinds of cells were screened out. The pathway enrichment analysis of differential metabolism was conducted with Metaboanalyst 4.0 software. RESULTS ：Compared with control group ，the contents of glutamine ，glutathione， phenylalanine，fumaric acid and taurine were trending down in Huh 7 or BEL- 7402 cells. There were 28 and 29 differential metabolites obtained from the above two kinds of cells ，and 10 of them were common differential metabolites ，including glutamine，glutathione，taurine，fumaric acid ，phenylalanine，etc. The differential metabolites were enriched in 8 and 6 pathways respectively. The common enrichment pathways were amino acid-tRNA biosynthesis ，aspartate-alanine-glutamate metabolism ， nitrogen metabolism ，phenylalanine metabolism and pentose phosphate pathway ，etc. CONCLUSIONS ：DHA can significantly reduce the activities of Huh 7 cells and BEL- 7402 cells，and the contents of glutamine ，glutamic acid ，glutathione and phenylalanine，etc. It may regulate the growth of the two kinds of cells by influencing the mechanism of aspartic acid- alanine-glutamate metabolic pathway ，etc.

Study on the effect of curculigoside on osteoporosis / 中华口腔医学杂志

Objective@#To investigate the regulation of curculigoside on osteogenic differentiation of MG63 and the protective effect on osteoporosis model mice.@*Methods@#The effects of curculigoside on the survival rate of dexamethasone or H2O2 treated MG63 were detected by methyl thiazolyl tetrazolium (MTT). The specimens were divided into six groups: blank control group, blank administration group, model group (dexamethasone or H2O2 treatment group), low dose group (dexamethasone or H2O2+1.0 μmol/L curculigoside), medium dose group (dexamethasone or H2O2+2.5 μmol/L curculigoside) and high dose group (dexamethasone or H2O2+5.0 μmol/L curculigoside), the sample size of each group was 10. Western blotting was used to detect the expression of osteogenic differentiation-related proteins [type Ⅰ collagen, integrin β1, osteoblast-specific transcription factor (Osterix), osteocalcin and osteopontin] in MG63 cells after 1, 7 and 14 days incubated with 0, 1.0, 2.5 and 5.0 μmol/L of curculigoside. The sample size for each group at each time point was six. The experimental mice were divided into 4 groups: blank group, model group (dexamethasone treatment group), curculigoside low-dose group (dexamethasone+5 mg/kg curculigoside) and high-dose group (dexamethasone+45 mg/kg curculigoside), twenty each. After treatment, the tibia of the mice in each group were subjected to sacral HE staining. The number of osteoclasts was counted, and the levels of oxidative related factors in serum were determined by enzyme-linked immunosorbent assay (ELISA).@*Results@#The MTT results showed that compared with the blank control group [(100±3.7)%], the cell survival rate decreased to (44.1±5.7)% after treatment with dexamethasone, and the survival rate increased to (79.7±3.8)% after treatment with 5.0 μmol/L of curculigoside. The cell survival rate decreased to (59.1±4.7)% after H2O2 treatment, and the survival rate increased to (80.8±3.5)% after treatment with 2.5 μmol/L of curculigoside. The results of Western blotting showed that the expression of type Ⅰ collagen and integrin β1 in MG63 cells was significantly increased after 1.0, 2.5 and 5.0 μmol/L of curculigoside for 1, 7 and 14 days compared with 0 μmol/L of curculigo side for the same period. After increasing (P<0.05), the expression of Osterix and osteocalcin was significantly increased after 1 day of incubation (P<0.05). However, compared with 0 μmol/L curculigoside treatment, the expression of osteopontin in MG63 cells was not significantly different after incubation with 1.0, 2.5, 5.0 μmol/L of curculigoside for 7 and 14 days (P>0.05). Compared with the blank group, the number of tibia osteoclasts in the osteoporosis model group increased. In the low-dose and high-dose groups of curculigoside, the tibia cortex was more continuous and the number of osteoclasts decreased. Compared with the blank group, the activity of oxygen in the osteoporosis model group was significantly increased (P<0.05), and superoxide dimutase and catalase were significantly decreased (P<0.05).@*Conclusions@#Curculigoside promotes the differentiation of MG63 cells by increasing the expression of osteoblast differentiation-related proteins, and has a certain therapeutic effect on dexamethasone-induced osteoporosis mice.

Morphological characteristics of expressions of DKK1 in different periods of tooth development in postnatal mice and their significances / 吉林大学学报(医学版)

Objective:To study the expression characteristics of Dickkopf1 (DKK1) in different time and space during tooth development of the postnatal mice, and to provide the theoretical basis for clarifying the mechanism of Wnt signaling pathway in regulating the tooth development.Methods:The postnatal Kunming mice at days 0.5, 6.5, 12.5, 18.5, 24.5, and 30.5 respectively after birth were selected and divided into various groups by time,three in each group.The mice in each group were sacrificed and the paraffin sections of mandibular bone including the first molar were prepared at the thickness of 5 μm, followed by HE staining and immunohistochemical staining in order to detect the expressions of DKK1 in tooth tissue and periodontal tissue.Results:At 0.5 d after birth, the mandibular first molar tooth germ was in the bell stage.At 6.5 d the enamel development of mandibular first molar was almost completed, and the epithelium root sheath extended to the root direction.At 12.5 d the dentin development of crown was completed, with the root formatted about 1/3. At 18.5 d the root had formatted about 2/3.At 24.5 d the root had reached the full length.At 30.5 d the apical foramen was narrow, and the root development was basically completed.There was no DKK1 expression at 0.5 d, but it expressed in the odontoblasts and predentin at 6.5 d. From days 12.5 to 30.5,the expressions of DKK1 were positive in periodontal ligament, alveolar bone, and cellular cementum as odontoblasts, which were gradually increased with the prolongation of time.However, no expression of DKK1 was detected in the pulp.Conclusion:DKK1 shows regular expressions at different tooth developmental stages after birth, suggesting its potential role in the growth of dentin and periodontal tissues.

Controllable Abdominal Breath in treatment of Migraine / 中国心理卫生杂志

Objective:To study the effect of controllable abdominal breath in treatment of migraine.Method:20 patients(10 male,10 female,aged 20-30 years)with migraine according to international diagnostic standard published 1990 were randomly divided into study group and control group.The study group received training of controllable abdominal breath.All subjects were followed for 3 months.Changes of symptoms and hemorhelogy were recorded.Result:Study group improved in both symptom and index of hemorheology after treatment,and the results were better than that of control.Conclusion:Controllable abdominal breath is effective in treatment of migraine.