β-arrestin2 recruitment by β-adrenergic receptor agonists and antagonists / 生理学报

A large number of β-adrenergic receptor (β-AR) agonists and antagonists are widely used in the treatment of cardiovascular diseases and other diseases. Nonetheless, it remains unclear whether these commonly used β-AR drugs can activate downstream β- arrestin-biased signaling pathways. The objective of this study was to investigate β-arrestin2 recruitment effects of β-AR agonists and antagonists that were commonly used in clinical practice. We used TANGO (transcriptional activation following arrestin translocation) assay to detect the β-arrestin2 recruitment by β-AR ligands in HEK293 cell line (HTLA cells) stably transfected with tetracycline transactivator protein (tTA) dependent luciferase reporter and β-arrestin2-TEV fusion gene. Upon activation of β-AR by a β-AR ligand, β-arrestin2 was recruited to the C terminus of the receptor, followed by cleavage of the G protein-coupled receptors (GPCRs) fusion protein at the TEV protease-cleavage site. The cleavage resulted in the release of tTA, which, after being transported to the nucleus, activated transcription of the luciferase reporter gene. The results showed that β-AR non-selective agonists epinephrine, noradrenaline and isoprenaline all promoted β-arrestin2 recruitment at β1-AR and β2-AR. β1-AR selective agonists dobutamine and denopamine both promoted β-arrestin2 recruitment at β1-AR. β2-AR selective agonists procaterol and salbutamol promoted β-arrestin2 recruitment at β2-AR. β-AR non-selective antagonists alprenolol and pindolol promoted β-arrestin2 recruitment at β1-AR. β1-AR selective antagonists celiprolol and bevantolol showed β-arrestin2 recruitment at β1-AR. β2-AR selective antagonists butoxamine showed β-arrestin2 recruitment at β1-AR. These results provide some clues for the potential action of β-AR drugs, and lay a foundation for the screening of β-arrestin-biased β-AR ligands.

A cone-beam computed tomography evaluation of three-dimensional changes of circummaxillary sutures following maxillary protraction with alternate rapid palatal expansions and constrictions / 北京大学学报(医学版)

OBJECTIVE@#To assess three-dimensional (3D) changes of circummaxillary sutures following maxillary protraction with alternate rapid palatal expansions and constrictions (RPE/C) facemask protocol in maxillary retrusive children, and to investigate the relationship between the changes of circum-maxillary sutures and zygomaticomaxillary suture (ZMS) maturation, and to explore the factors of maxilla forward movement with RPE/C and facemask.@*METHODS@#In the study (clinical trial registration No: ChiCTR2000034909), 36 maxillary retrusive patients were recruited and block randomized to either the rapid palatal expansion (RPE) group or the RPE/C group. Patients aged 7 to 13 years, Class Ⅲ malocclusion, anterior crossbite, ANB less than 0°, Wits appraisal less than -2 mm, and A-Np less than 0 mm were included in the study. The RPE group received rapid palatal expansion, whereas the RPE/C group received alternate rapid palatal expansions and constrictions, and both with facemask protraction. Head orientations of cone-beam computed tomography (CBCT) images were implemented by Dolphin 11.7. 3D measurements of circummaxillary sutures on CBCT images were evaluated using Mimics 10.01 before (T0) and after treatment (T1). The changes were analyzed with independent t test, two-way ANOVA, Pearson correlation and regression analysis.@*RESULTS@#Two subjects in the RPE/C group were lost to follow-up. A total of 34 patients reached the completion criteria and were analyzed. Compared with the RPE group, sagittal changes of circummaxillary sutures were significantly increased in the RPE/C group with 1.21 mm advancement of zygomaticotemporal suture, 2.20 mm of ZMS, 1.43 mm of zygoma-ticofrontal suture (P < 0.05, respectively). Except for the zygomaticotemporal suture, the rest forward sagittal changes of other circummaxillary sutures showed no major difference in terms of the ZMS maturation. The Spearman's correlation in RPE/C indicated a strong positive correlation of sagittal changes between ZMS and point A (P < 0.01) with a regression analysis R2=42.5%.@*CONCLUSION@#RPE/C might be more effective on the treatment of maxillary retrusive children. As one of the major mechanical loading sutures during orthopedic therapy, ZMS showed a strong positive correlation with point A on sagittal changes.

Effect of herb-partitioned moxibustion in improving tight junctions of intestinal epithelium in Crohn disease mediated by TNF-α-NF-κB-MLCK pathway / 针灸推拿医学（英文版）

Objective: To explore the effect of herb-partitioned moxibustion (HPM) on tight junctions (TJs) of intestinal epithelial cells in Crohn disease (CD) mediated by tumor necrosis factor-α (TNF-α)-nuclear factor kappa B (NF-κB)-myosin-light- chain kinase (MLCK) pathway. Methods: Forty-eight male Sprague-Dawley rats were randomly divided into a normal control (NC) group, a model control (MC) group, an HPM group and a mesalazine (MESA) group, with 12 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was administered to establish CD models. When the model was confirmed a success, the HPM group rats were treated with HPM at Tianshu (ST 25) and Qihai (CV 6), while the MESA group rats were given MESA solution by lavage. When the intervention finished, the colonic epithelial tissues were separated, purified and cultured in each group to establish the intestinal epithelial barrier model in vitro, and TNF-α was added (100 ng/mL) in the culture medium and maintained for 24 h to establish an increased epithelial permeability model. Transepithelial electrical resistance (TEER) was used to examine the permeability of the barrier; Western blot was used to observe the expressions of the proteins related to TJs of intestinal epithelial cells mediated by TNF-α-NF-κB-MLCK pathway; immunofluorescence staining was used to observe the expressions and distributions of tight junction proteins in the intestinal epithelium. Results: After TNF-α induction, compared with the MC+TNF-α group, the TEER value increased significantly in the HPM+TNF-α and MESA+TNF-α groups (both P<0.001); the expressions of nuclear factor kappa B (NF-κB) p65, MLCK, myosin light chain (MLC), tumor necrosis factor receptor-associated factor 6 (TRAF6) and receptor interaction protein-1 (RIP1) decreased significantly (P<0.01 or P<0.05), and the expression of zinc finger protein A20 (A20) increased significantly (P<0.01); the expressions of occludin, claudin-1, zonula occludens protein 1 (ZO-1) and F-actin also increased significantly (all P<0.01). Compared with the MESA+TNF-α group, the expressions of MLC, occludin, claudin-1, ZO-1 and F-actin increased significantly in the HPM+TNF-α group (P<0.01 or P<0.05). Conclusion: HPM can protect or repair the damage of intestinal epithelial barrier in CD rats, which may be achieved through modulating the abnormal TJs in intestinal epithelium mediated by TNF-α-NF-κB-MLCK pathway.

Efficacy and safety of Nintedanib for idiopathic pulmonary fibrosis: a meta-analysis / 中国实用内科杂志

OBJECTIVE: To systematically review the efficacy and safety of Nintedanib in patient with idiopathic pulmonary fibrosis.METHODS: We search systematically for randomized controlled trials and cohort study of Nintedanib for idiopathic pulmonary fibrosis patients published between January 1999 and May 2018. The literatures that met all eligibility criteria were selected. The extracted data were analyzed with RevMan 5.3. RESULTS: A total of 4 random control trials(RCT) and one cohort study were included. Nintedanib, as compared with placebo, reduced the decline in FVC and the predicted FVC% from baseline by 130 mL/yr or 3.84% of the mean value respectively. It also significantly reduced relative the risk of FVC%pred≥10% or FVE decline≥200 mL(RR 0.78, 95% confidence interval(CI) 0.67 to 0.90, P=0.0006), the hazard ratio(HR) of first acute exacerbation(HR with Nintedanib, 0.53; 95%CI 0.33-0.86;P=0.02), all-cause mortality(HR in the Nintedanib group, 0.70; 95%CI 0.45-1.08; P=0.11) and respiratory mortality(HR in the Nintedanib group, 0.63; 95%CI 0.37-1.10; P=0.11) in IPF patients. The Nintedanib group had a higher rate of gastrointestinal adverse events and a lower rate of cardiovascular events compared to the placebo group(P=0.02). CONCLUSION: Nintedanib delays disease progression in patients with IPF. Nintedanib is generally well tolerated, and the mild gastrointestinal adverse events are more common.

Evaluation of maxillary three-dimensional changes in maxillary protraction with alternating rapid palatal expansion and constriction based on the cone-beam computed tomography / 北京大学学报(医学版)

OBJECTIVE@#To use the cone-beam computed tomography (CBCT) to evaluate the three-dimensional (3D) changes of maxillary landmarks in the maxillary protraction with alternating rapid palatal expansion and constriction and with rapid palatal expansion, and to provide some clinical suggestions for the early treatment of Class III malocclusion.@*METHODS@#A total of 36 maxillary retrusive patients were included and randomized in a 1:1 ratio to either the intervention group (alternating rapid palatal expansion and constriction group, RPE/C) or the control group (rapid palatal expansion group, RPE). Randomization was accomplished with permuted block randomization based on participation sequence. The patients in the RPE/C were treated for 10 weeks (0.5 mm/d) with the repetition of two-week palatal expansion and two-week palatal constriction. The patients in the RPE were taught to complete rapid palatal expansion for 2 weeks (0.5 mm/d ). The patients were instructed to come to the office for the follow-up to ensure the correct procedures. Damaged expanders were repaired (or replaced) and rebanded quickly. Sequential CBCT images including pretreatment (T1), post-expansion (T2) and post-protraction (T3) were required for 3D reconstruction, establishment of landmarks, measurement and analysis by Mimics 10.01.@*RESULTS@#There was significant forward movement of subspinale (A) in the RPE/C after the treatment with (3.06±1.29) mm, compared with RPE (2.16±1.27) mm, P<0.05. There were more symmetrical changes of the landmarks in the RPE/C and there was no statistic significance of the entire treatment time between the two groups. Moreover, the maxillary skeletal landmarks had the following 3D changes of a forward and downward movement during the expansion stages T2-T1, a forward and upward movement during the protraction stages T3-T2 and a forward and downward movement during the total treatments T3-T1 compared with the control group. And the width between the bilateral landmarks increased during the expansion stages T2-T1, narrowed down during the protraction stages T3-T2 and increased during the total treatments T3-T1.@*CONCLUSION@#The maxillary protraction with alternating rapid palatal expansion and constriction provided clinical benefits on maxillary advancement and symmetrical changes in the orthopedic treatment of the patients with maxillary retrognathism and it required further study on the orthodontic analysis and measurements of CBCT.

Key points and difficulties in prevention and treatment of chronic disease-interpretation of guidelines for Prevention and treatment of Chronic diseases in China (2017-2025) / 第二军医大学学报

In January 2017, China issued Guidelines for Prevention and Treatment of Chronic Diseases in China (2017-2025) (hereinafter referred to as the Guidelines). Based on the reality and trends of China’s chronic diseases, the Guidelines clarifies the goals and priorities for prevention and treatment of chronic diseases in the next 8 years and plan the works for prevention and treatment of chronic diseases in the next 5-10 years to reduce the burden caused by diseases, improve the health expectancy of residents and ensure people’s health from start to end. The Guidelines focuses on strengthening the education and prevention of chronic diseases to reduce the burden caused by medical care; the difficulty lies in the establishment of hierarchical medical system and optimization of medical resource distribution.

Effects of IAT and MAT chemotherapeutic regimens in patients with refractory or relapsed acute myeloid leukemia / 中国实验血液学杂志

The aim of this study was to investigate effects of IAT and MAT chemotherapeutic regimens treating patients with refractory and relapsed acute myeloid leukemia (AML). 99 patients with refractory and relapsed AML received IAT regimen or MAT regimen as study objects were retrospectively analyzed (56 patients with refractory AML and 43 patients with relapsed AML). Among of them, 28 patients were treated with IAT regimen, and 71 patients received with MAT regimen. The results showed that in 2 groups mentioned above the OR was 65.7%, CR was 49.5%, PR was 16.2%; in IAT group the OR was 64.3%, CR was 46.4%; in MAT group the OR was 66.2%, CR was 50.7%, no statistical difference was found between these 2 groups; The 2 years overall survival was 25% in IAT group and 15.5% in MAT group. Serious infection in IAT and MAT regime groups was 25% and 9.9%, respectively. It is concluded that both IAT and MAT regimens are effective methods for inducing CR in patients with refractory of relapsed AML. IAT and MAT regimens can be used in treatment of the refractory or relapsed MAL patients who were not respond to other regimen.