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61.
Xia G Liu L Xue M Liu H Yu J Li P Chen Q Xiong B Liu X Shen J 《Molecular and cellular endocrinology》2012,358(1):46-52
Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11β-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11β-HSD1 with an IC(50) of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11β-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11β-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11β-HSD1 inhibitors suitable for in vivo evaluation in rodent models. 相似文献
62.
Park YS Kim JH Chang HI Kim SW Paik HD Kang CW Kim TH Sung HC Yun CW 《Current genetics》2007,52(3-4):187-190
The separation and identification of siderophores produced by microorganisms is a time-consuming and an expensive procedure.
We have developed a new and efficient method to identify siderophores using well-established Saccharomyces cerevisiae deletion mutants. The Δfet3,arn strains fail to sustain growth, even when specific siderophores are supplied, and mutants are siderophore-specific: Δfet3,arn2 for triacetylfusarinine C (TAFC), Δfet3,arn1,sit1 for ferrichrome (FC), and Δfet3,sit1 for ferrioxamine B (FOB). The culture broth of Fusarium graminearum was separated by HPLC, and each peak was subjected to a plate assay using S. cerevisiae mutants. We have found that each peak contained specific siderophores produced by F. graminearum, and these coincided with reference siderophores. This method is quite novel because nobody tried this method to identify
the siderophores. Furthermore, this method will save time and cost in the identification of siderophores produced by microorganisms. 相似文献
63.
Linda D. Simmler Anna Rickli York Schramm Marius C. Hoener Matthias E. Liechti 《Biochemical pharmacology》2014
Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in “Ecstasy” tablets as replacements for 3,4-methylenedioxymethamphetamine (MDMA) or substances sold as “ivory wave.” The pharmacology of these MDMA- and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the pipradrol derivatives desoxypipradrol (2-diphenylmethylpiperidine [2-DPMP]), diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]), and methylphenidate. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine [5-HT]) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporters (NET, DAT, and SERT). We also evaluated the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells and the binding affinity to monoamine transporters and receptors, including trace amine-associated receptor 1 (TAAR1). 5-IAI and MDAI preferentially inhibited the SERT and NET and released 5-HT. 2-AI interacted with the NET. BZP blocked the NET and released DA. m-CPP and TFMPP interacted with the SERT and serotonergic receptors. The pipradrol derivatives were potent and selective catecholamine transporter blockers without substrate releasing properties. BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR1 binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability. 相似文献
64.
《Pharmacological reports : PR》2014,66(1):107-113
BackgroundAberrant epigenetic histone modifications are implicated in cancer pathobiology, therefore histone modifying enzymes are emerging targets for anti-cancer therapy. There is a few evidence for deregulation of the histone modifying enzymes in glioblastomas. Glioma treatment is a clinical challenge due to its resistance to current therapies.MethodsThe effect of selected inhibitors on epigenetic modifications and viability of glioma C6 cells were studied using immunofluorescence and MTT metabolism test.ResultsWe found that VPA and TSA increase histone H4 acetylation in glioma cells, while chaetocin and BIX01294 at low concentrations reduce H3K9me3, and 3DZNep decreases H3K27me3. Long-term treatment with some epigenetic inhibitors affects viability of glioma cells.ConclusionsWe established the concentrations of selected inhibitors which in C6 glioma cells inhibit the enzyme activity, but do not decrease cell viability, hence allow to study the role of histone modifications in C6 glioma biology. 相似文献
65.
Dong Yoon Kang Hyunah Kim SooJeong Ko HyungMin Kim Jiwon Shinn Min-Gyu Kang Sun-ju Byeon Jeong-Hee Choi Soo-Yong Shin Hun-Sung Kim 《Journal of Korean medical science》2022,37(7)
BackgroundThe most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed.MethodsAll patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP.ResultsA total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3–10.0%, P > 0.999).ConclusionOwing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results. 相似文献
66.
磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)/蛋白激酶B(protein kinase B,AKT)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号转导通路在多种肿瘤中异常激活,参与肿瘤细胞增殖、分化和凋亡等生命过程的调控,是抗肿瘤药物研发的重要靶点。对目前已应用于乳腺癌临床或处于临床试验阶段的PI3K/AKT/mTOR信号通路抑制剂进行归纳,并综述该通路抑制剂的联合用药策略,以期为不同亚型乳腺癌提供个体化靶向治疗方案。 相似文献
67.
双重酪氨酸激酶抑制剂Lapatinib治疗乳腺癌研究进展 总被引:1,自引:0,他引:1
Lapatinib是一种新型的双重酪氨酸激酶抑制剂(TKI),能够同时作用于表皮生长因子受体(EGFR)和HER-2两个靶点。Lapatinib的临床前期及临床研究结果表明,其对乳腺癌患者有效,尤其对曲妥珠单抗耐药的局部晚期和转移性乳腺癌患者显示出可喜的疗效。以Lapatinib为代表的TKI有望为乳腺癌的治疗开辟一条崭新的途径。 相似文献
68.
基质金属蛋白酶抑制剂KB-R7785对鼠局灶脑缺血的保护作用 总被引:8,自引:6,他引:8
目的 研究表明,脑缺血后基质金属蛋白酶(MMPs)可以破坏血脑屏障、促进脑水肿的形成及炎性细胞的浸润、加快神经细胞的死亡,从而加重缺血性脑损害。本研究观测MMPs抑制剂、KB-R7785对缺血性脑卒中的保护作用。方法 采用线段血管内栓塞大脑中动脉(MCAO)获得小鼠脑缺血模型。观察不同时间、剂量KB-R7785对24h后脑梗塞灶体积的影响,同时应用酶谱印迹技术检测缺血后脑组织中MMPs活性。结果 酶谱印迹显示MMP-9活性在缺血后6h表达增强,24h后达峰值。MCAO前30 min单次注射KB-R7785(100mg·kg-1)可显著抑制 MMP-9的活性;单次注射或缺血后1及4.5h分次注射KB-R7785(100mg·kg-1)均可明显减小脑梗塞体积(P<0.01)。结论MMP-9可促进脑梗塞形成;MMPs抑制剂、KB-R7785具有改善缺血性脑损伤作用。 相似文献
69.
目的探讨失血性休克大鼠肝脏枯否细胞的功能变化以及联合应用甘氨酸和甲强龙对枯否细胞的影响。方法50只大鼠随机分成假休克组(仅进行手术操作但不放血诱导休克)、休克组、甘氨酸组、甲强龙组和联合治疗组(甘氨酸+甲强龙),每组10只。大鼠经动脉放血,造成失血性休克,随后用自体血和生理盐水回输进行复苏。复苏后2h,行肝脏枯否细胞的分离和培养,细胞培养24h后分别用1、10、100和1000ng/ml的脂多糖(LPS)刺激,测定细胞内Ca^2+和肿瘤坏死因子α(TNF-α)水平。结果枯否细胞内Ca^2+在20min左右开始大幅度增高,大约27min达到高峰,同时细胞内Ca^2+浓度增加呈现LPS剂量依赖性。联合治疗组细胞内Ca^2+浓度和TNF-a含量明显低于休克组以及低于甘氨酸、甲强龙治疗组,差异具有统计学意义(P〈0.005)。结论联合应用甘氨酸和甲强龙比单一制剂更有效抑制失血性休克后枯否细胞内Ca^2+升高、抑制枯否细胞的激活,抑制TNF-α的过度产生和机体炎症反应。 相似文献
70.