Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation.

The BCL-XL protein is among the most important members of the anti-apoptotic subfamily of the BCL-2 protein family, and is currently a promising new target for anti-tumor drug research. However, the BCL-XL/2 proteins have similar structures and functions, which could lead to undesirable side effects because of inhibitors that can bind to both BCL-XL and BCL-2. Therefore, it is crucial to expound on the structural basis of the selective mechanism towards BCL-XL/2 inhibition. In the current study, we employed hybrid computational methods including molecular docking and dynamics simulation, MM/GBSA energy calculation, alanine scanning mutagenesis and Hirshfeld surface analysis to comprehensively reveal the selectivity mechanism towards BCL-XL/2 from multiple perspectives, revealing the significant effects of the BCL-XL residues SER106 and LEU108 as well as the BCL-2 residue ASP103 on the inhibitory selectivity. Overall, our findings provide useful references for the rational design of BCL-XL/2 selective inhibitors with better affinity.

Effect of competence health cultivation on the prevention and control of inadvertent perioperative hypothermia.

OBJECTIVE To explore the feasibility of health competence cultivation on the prevention and control of Inadvertent Perioperative Hypothermia (IPH). METHODS Patients with expected spinal surgery were divided into group A and group B by the random number method. Group B followed routine IPH management, and health training measures for performance and ability were implemented in Group A. The scores of the health competence questionnaire, the temperature at different times, IPH complications, and hospitalization for the two groups were observed and compared. RESULTS The main evaluation indexes, such as the health competence questionnaire score, temperature fluctuations, and IPH complications, during the perioperative period in group A were significantly better than those in group B (p < 0.05). The indexes of anesthesia, total hospital expenses, and health service satisfaction in group A were also significantly better than those in group B, which shows the advantages of cultivating health capabilities in both doctors and patients. CONCLUSION Through health competence cultivation and feasible health management measures, the medical staff can improve the quality of IPH prevention and management.

Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors.

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.

Refined pharmacophore features for virtual screening of human thromboxane A2 receptor antagonists.

For a long time, the structural basis of TXA2 receptor is limited due to the lack of crystal structure information, till the release of the crystal structure of TXA2 receptor, which deepens our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor. In this research, we report the successful implementation in the discovery of an optimal pharmacophore model of human TXA2 receptor antagonists through virtual screening. Structure-based pharmacophore models were generated based on two crystal structures of human TXA2 receptor (PDB entry 6IIU and 6IIV). Docking simulation revealed interaction modes of the virtual screening hits against TXA2 receptor, which was validated through molecular dynamics simulation and binding free energy calculation. ADMET properties were also analyzed to evaluate the toxicity and physio-chemical characteristics of the hits. The research would provide valuable insight into the binding mechanisms of TXA2 receptor antagonists and thus be helpful for designing novel antagonists.

Effect of competence health cultivation on the prevention and control of inadvertent perioperative hypothermia

SUMMARY OBJECTIVE To explore the feasibility of health competence cultivation on the prevention and control of Inadvertent Perioperative Hypothermia (IPH). METHODS Patients with expected spinal surgery were divided into group A and group B by the random number method. Group B followed routine IPH management, and health training measures for performance and ability were implemented in Group A. The scores of the health competence questionnaire, the temperature at different times, IPH complications, and hospitalization for the two groups were observed and compared. RESULTS The main evaluation indexes, such as the health competence questionnaire score, temperature fluctuations, and IPH complications, during the perioperative period in group A were significantly better than those in group B (p < 0.05). The indexes of anesthesia, total hospital expenses, and health service satisfaction in group A were also significantly better than those in group B, which shows the advantages of cultivating health capabilities in both doctors and patients. CONCLUSION Through health competence cultivation and feasible health management measures, the medical staff can improve the quality of IPH prevention and management.

RESUMO OBJETIVO Explorar a viabilidade do cultivo da competência em saúde na prevenção e controle da hipotermia perioperativa inadvertida (IPH). MÉTODOS Pacientes com cirurgia espinhal marcada foram divididos em dois grupos, A e B, pelo método de números aleatórios. O grupo B foi conduzido com base na gestão rotineira para prevenção de IPH; já no grupo A, foram implementadas medidas de treinamento em competência de saúde. As pontuações do questionário sobre competência em saúde, a temperatura aferida em diferentes momentos, complicações relacionadas à IPH e hospitalização dos dois grupos foram observadas e comparadas. RESULTADOS Os principais índices de avaliação, como a pontuação do questionário sobre competência em saúde, a variação de temperatura e as complicações relacionadas à IPH durante o período perioperatório foram significativamente melhores no grupo A do que no grupo B (p<0,05). Os índices de anestesia, despesas hospitalares totais e satisfação com o serviço de saúde também foram significativamente melhores no grupo A do que no B, o que demonstra as vantagens do cultivo da competência de saúde tanto em médicos como em pacientes. CONCLUSÃO Por meio do cultivo de competências de saúde e de medidas viáveis de gestão da saúde, a equipe médica pode melhorar a qualidade da prevenção e gestão da IPH.

Computational investigation of TGF-ß receptor inhibitors for treatment of idiopathic pulmonary fibrosis: Field-based QSAR model and molecular dynamics simulation.

The discovery of drugs relevant to transforming growth factor ß (TGF-ß) receptor inhibitors have been considered as a considerable challenge during therapy idiopathic pulmonary fibrosis diseases. For the first time, herein we illustrate a field-based quantitative structure-activity relationship (QSAR) model and molecular dynamics (MD) simulations for novel 7-substituted-pyrazolo [4, 3-b] pyridine derivatives with biological activity for the TGF-ß receptor, with an attempt of elucidating the 3D structural features that are essential for the activity. Results demonstrate that the field-based model (Q2 = 0.548, R2training = 0.840, R2test = 0.750) are acceptable with good predictive capabilities. In addition, MD studies were also carried out on the training set with the aim of exploring their binding modes in the active pocket of TGF-ß receptor, resulting in some of the crucial structural fragments which are responsible for inhibitory activity. Therefore, we summarized the following features required for TGF-ß receptor inhibition: electronegative in region1, bulky groups in region2 and smaller groups in region3. Based on the model and related information, we hope the above information provides an important insight for understanding the interactions of the inhibitors and TGF-ß receptor, which may be useful in discovering novel potent inhibitors.

Design, synthesis and biological evaluation of novel asperphenamate derivatives.

A series of novel asperphenamate derivatives were designed and synthesized, including series I (the A-phenyl group replaced with various aromatic heterocycles) and series II (the acyl group substituted by sulfonyl group). All compounds have been screened for their antiproliferative activity in vitro against MCF-7, HeLa, and BEL-7402 cell lines by the standard MTT method. Structure-activity relationship studies displayed the heterocycle type played an important role in activity. Six-membered ring derivatives displayed more potency than five-membered ring and the sulfonyl group in A-ring region made an important contribution to activity. Among all derivatives, tosyl derivative 8c exhibited the greatest potency in three human cancer cell lines. Especially in MCF-7 cells, the cellular potency of 8c was approximately 3.0-fold more potent than that of cisplatin. Firstly, the mechanism of cell death induced by 8c in MCF-7 cells was investigated. The results showed that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest. Further studies indicated that 8c might induce autophagic cell death in HeLa and BEL-7402 cell lines.

Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups.

The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC50 values in the single-digit µM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines.

[Investigation of relationship between prehospital care for traumatic shock and postoperative acute lung injury/acute respiratory distress syndrome].

OBJECTIVE: To investigate and analyze the correlation and clinical significance of prehospital treatment for traumatic shock and postoperative acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). METHODS: Six hundred cases in the last 10 years were enrolled for double-blind randomized control study. They were divided into 3 groups. Group A consisted of 184 cases who had received combined treatment, group B consisted of 305 cases who had received fluid replacement only and group C consisted of 111 cases with no treatment. The incidence of systemic inflammatory response syndrome (SIRS), ALI and ARDS of each group were analyzed and compared. SIRS was graded at 1 (T0) after admission, 24 (T1), 48 (T2), 96 (T3) and 144 hours (T4) after operation. RESULTS: In 524 cases diagnosis of SIRS was made among 600 patients (87.33%). Among them 73.37% (135/184 cases) were in group A, 91.48% (279/305 cases) belonged to group B and 99.10% (110/111 cases) in group C. The scores of SIRS were notably lower in group A than B and C at each time point (all P<0.01), and they were lower in group B than those in group C (all P<0.01), they recovered at T3 after operation in group A while in group B patients recovered at 144 hours after operation. Eleven patients among 184 (5.98%) were diagnosed to have ALI including 1 case progressed to ARDS and 1 case to MODS and no one died, while in group B 32 cases in 305 (10.49%) had ALI with 7 cases progressed to ARDS and 3 cases to MODS while 3 deaths and in group C 23 among 111 (20.72%) had ALI, and 8 patients progressed to ARDS, 5 cases to MODS and 5 deaths. CONCLUSION: Prehospital treatment is closely related with postoperative ALI, and combined treatment is beneficial in reducing the incidence of postoperative ALI/ARDS.

[Clinical study of the effect of verapamil-procaine compound in prevention and treatment of acute respiratory distress syndrome after high risk operation].

OBJECTIVE: To observe the effect of verapamil-procaine compound (V-P) on prevention and treatment of acute respiratory distress syndrome (ARDS) subsequent to high risk operation. METHODS: Altogether 150 cases of major operations with high risk of ARDS were enrolled for study. They were randomly divided into three groups. V-P group: 5% glucose 500 ml and procaine 1 250 mg and verapamil 10 mg; procaine group: 5% glucose 500 ml and procaine 1 250 mg; control group: only glucose was given. The injection speed of the three groups were the same, and it was kept at 0.5 ml x h(-1) x kg(-1). The dosages of verapamil and procaine in V-P group and procaine group were doubled when the diagnosis of acute lung injury (ALI) or ARDS was confirmed. UT4000F was used in monitoring (non-invasive) blood pressure (BP), electrocardiogram (ECG), pulse oxygen saturation (SpO(2)), respiratory rate, and temperature. Blood routine and arterial blood gases measurements were intermittently performed. Diagnosis of systemic inflammatory response syndrome (SIRS), ALI and ARDS was made respectively according to published diagnostic criteria. SIRS score and acute physiology and chronic health evaluation II (APACHEII) score were performed. RESULTS: Eleven cases in V-P group, 26 in procaine group, and 42 in control group manifested symptoms and signs of SIRS. There were notable differences among groups (all P<0.01). Four patients in V-P group, 7 in procaine group, and 19 in control group were shown to develop ALI. Significant difference was found between control and V-P or procaine group (both P<0.01), but no significant difference was found between procaine group and V-P group. Twelve cases were complicated with ARDS in control group 2 weeks after the operation, and among them 5 died of multiple organ failure. There was significant difference between control group and V-P group or procaine group (both P<0.01). Two patients were complicated with acute renal failure in V-P group, 2 in procaine group, and 5 in control group. CONCLUSION: The V-P can interrupt SIRS to develop ALI, then ARDS and multiple organ dysfunction syndrome(MODS), and thus prevents and cures ARDS.