Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.     

Propafenone analogue with additional H-bond acceptor group shows increased inhibitory activity on P-glycoprotein

P-glycoprotein (P-gp) is an ATP-dependent efflux pump that has a marked impact on the absorption, distribution, and excretion of therapeutic drugs. As P-gp inhibition can result in drug–drug interactions and altered drug bioavailability, identifying molecular properties that are linked to inhibition is of great interest in drug development. In this study, we combined chemical synthesis, in vitro testing, quantitative structure–activity relationship analysis, and docking studies to investigate the role of hydrogen bond (H-bond) donor/acceptor properties in transporter–ligand interaction. In a previous work, it has been shown that propafenone analogs with a 4-hydroxy-4-piperidine moiety exhibit a generally 10-fold higher P-gp inhibitory activity than expected based on their lipophilicity. Here, we specifically expanded the data set by introducing substituents at position 4 of the 4-phenylpiperidine moiety to assess the importance of H-bond donor/acceptor features in this region. The results suggest that indeed an H-bond acceptor, such as hydroxy and methoxy, increases the affinity by forming a H-bond with Tyr310.     

维格列汀联合门冬胰岛素30注射液对肥胖型2型糖尿病患者胰岛β细胞功能及血清糖化血红蛋白水平的影响

 目的 探讨维格列汀联合门冬胰岛素30注射液对肥胖型2型糖尿病患者胰岛β细胞功能及血清糖化血红蛋白(HbA₁c)水平的影响。方法 选取西安交通大学第一附属医院2017-03至2018-07肥胖型2型糖尿病患者157例,按照随机数字表法分为对照组(n=78)与联合治疗组(n=79),对照组采取门冬胰岛素30注射液治疗,联合治疗组在对照组基础上联合维格列汀治疗,疗程均为12周。观察对比两组疗效及不良反应发生率,并对两组治疗前后空腹血糖(fasting blood glucose,FPG)、餐后2 h血糖(2 h blood glucose,2 h PG)、糖化血红蛋白(HbA₁c)、胰岛β细胞功能指数(HOMA-β)及丝氨酸蛋白酶抑制药(visceral adipose tissue-derived serine protease inhibitor,VASPIN)水平进行比较。结果 联合治疗组HbA₁c达标率和控制理想率均明显高于对照组,差异有统计学意义(P<0.05)。两组治疗后FPG、2 h PG、HbA₁c水平均比治疗前降低,联合治疗组明显低于对照组,差异有统计学意义(P<0.05)。两组治疗后血清HOMA-β、VASPIN水平均较治疗前升高,联合治疗组较对照组明显升高,差异有统计学意义(P<0.05)。两组不良反应发生率差异无统计学意义。结论 维格列汀联合门冬胰岛素30注射液治疗肥胖型2型糖尿病效果确切,能改善患者的血糖和VASPIN水平,保护胰岛β细胞功能,降低低血糖事件的发生率。     

Prediction of successful dose reduction or discontinuation of adalimumab,etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

Background: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients.

Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined.

Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation.

Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.     

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)‐molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI‐MD simulations of the first two compounds (analogs 1 and 2 ) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3 – 5 ) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI‐MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.     

黄芪水提物抑制PI3K/Akt通路预防肺癌发生的作用及机制研究

目的探讨黄芪水提物对肺癌的抑制作用及相关机制。方法采用MTT实验、Ed U实验以及划痕实验检测黄芪水提物对肺癌A549和H1299细胞的活性、增殖能力和迁移能力的影响,采用流式细胞仪考察黄芪水提物对肺癌细胞周期的影响,通过Western blotting实验检测PI3K/Akt通路相关蛋白表达,通过苯并芘诱导的小鼠肺癌模型观察黄芪水提物对体内肺癌的影响。结果 MTT实验结果表明,黄芪水提物作用于A549和H1299细胞48 h后,细胞的生长活性被抑制;Ed U实验结果表明,黄芪水提物能够显著抑制A549和H1299细胞的增殖能力;对细胞周期考察的实验结果表明,黄芪水提物能够将A549和H1299细胞周期阻滞在S期;划痕实验结果表明,黄芪水提物作用于A549和H1299细胞24 h和48 h后,能够显著抑制细胞的迁移能力;Western blotting实验结果表明,黄芪水提物能够下调A549和H1299细胞磷脂酰肌醇3激酶(PI3K)、磷酸化的磷酸肌醇依赖性蛋白激酶1(p-PDK1)和磷酸化的蛋白激酶B(p-Akt)蛋白表达水平;体内实验结果表明,黄芪水提物能够显著抑制小鼠肺部肿瘤数量及大小。结论黄芪水提物能够抑制肺癌,该机制可能与PI3K/Akt信号通路受阻有关。     

泛素蛋白酶体抑制剂在急性髓系白血病中的研究进展

泛素蛋白酶体系统 (UPS)在真核生物蛋白质循环中具有重要生物学作用,出现异常可导致肿瘤的发生。目前包括白血病在内的多种肿瘤患者体内均检测到高水平的泛素蛋白酶体活性。泛素蛋白酶体抑制剂通过影响泛素蛋白酶体系统的E3连接酶、去泛素化酶以及蛋白质降解活性位点能够有效地杀伤肿瘤细胞。临床上已经将相关泛素蛋白酶体抑制剂用于治疗血液系统肿瘤,但在急性髓系白血病中的应用相对较少。本文对影响蛋白质泛素化降解不同阶段的抑制剂在急性髓系白血病中的研究进展进行相关总结,为研发急性髓系白血病有效疗法提供新思路。     

基于刺突蛋白靶点的抗新型冠状病毒药物研究进展

重症急性呼吸综合征冠状病毒2(SARS-CoV-2)引起的新型冠状病毒肺炎(COVID-19)目前仍在不断蔓延,但针对该病毒的特效治疗药物尚在研发当中。本文基于冠状病毒生物学特点和病毒复制过程中的关键蛋白——刺突蛋白,介绍了相关药物作用位点及研究进展,为抗SARS-CoV-2药物的临床应用提供信息依据,为治疗COVID-19药物研发提供思路。     

Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway

Objective Neonatal exposure to propofol has been reported to cause neurotoxicity and neurocognitive decline in adulthood; however, the underlying mechanism has not been established.Methods SD rats were exposed to propofol on postnatal day 7(PND-7). Double-immunofluorescence staining was used to assess neurogenesis in the hippocampal dentate gyrus(DG). The expression of pAkt and p27 were measured by western blotting. The Morris water maze, novel object recognition test,and object location test we...     

隐形矫治器对正畸患者牙周健康牙龈卟啉单胞菌及TSP-1 TIMP-1 MMP-9水平的影响

目的 探讨隐形矫治器对正畸患者牙周健康、牙龈卟啉单胞菌(P.g)和龈沟液血小板反应蛋白-1(TSP-1)、基质金属蛋白酶抑制因子-1(TIMP-1)及MMP-9的影响。方法 采用随机数字表法(序列编码放置在不透光密封信封中)将2020年1~8月于合肥市口腔医院就诊的42例正畸患者分为对照组与观察组,每组21例。对照组采用自锁托槽矫治器治疗,观察组采用隐形矫治器治疗。比较两组患者治疗前及治疗6个月后牙周健康指数,龈下菌斑中P.g检出率和百分含量,龈沟液TSP-1、TIMP-1和MMP-9水平以及并发症发生情况。结果 治疗第6个月,两组患者菌斑指数(PLI)、牙周袋探诊深度(PD)、龈沟出血指数(SBI)、附着丧失(CAL)和牙龈指数(GI)均较治疗前升高,且观察组PLI、PD、SBI、CAL、GI治疗前后差值均低于对照组,差异有统计学意义(t=4.828、2.871、6.624、5.724、5.499;P均<0.05);治疗第6个月,观察组患者P.g百分含量低于对照组,差异有统计学意义(t=3.619,P<0.05);治疗第6个月,观察组患者龈沟液TSP-1、MMP-9水平低于对照组,TIMP-1水平高于对照组,差异均有统计学意义(t=6.994、4.922、7.901;P均<0.05);两组患者并发症总发生率比较,差异无统计学意义(P>0.05)。结论 隐形矫治器有利于口腔卫生维护,减少牙龈卟啉单胞菌,调节龈沟液TSP-1、TIMP-1、MMP-9水平。