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《Drug metabolism and pharmacokinetics》2020,35(1):56-70
Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. 相似文献
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目的 研究凉血通瘀方对高血压大鼠急性脑出血模型脑组织miRNA表达的影响,对差异表达的miRNA靶基因进行分析,探索凉血通瘀方可能的药效机制。方法 将自发性高血压大鼠随机分成对照组(B)和实验组(C)。适应性饲养一周后,C组灌胃凉血通瘀方,B组灌胃等体积生理盐水,连续5天,每天1次。构建脑出血模型后收集脑组织,借助全转录组测序技术获得miRNA表达量,与miRBase数据库比对获取已知miRNA,使用miRDeep2预测新miRNA。差异分析软件为DESeq2,筛选阈值为|log2FC| ≥1 并且P <0.05。对显著差异表达的miRNA进行靶基因预测,对靶基因进行GO功能、KEGG通路富集和PPI网络分析。结果 实验组和对照组对比,共发现21个显著差异表达的miRNA,上调有9个,下调有12个,共预测得到1243个有统计学意义的靶基因。GO富集分析发现,生物过程中突触囊泡分泌的调节、神经递质分泌的调节和神经递质运输的调节占前三位,神经元投射终点、全膜、质膜区域和细胞投射则是主要的细胞成分。分子功能分别为小GTPase绑定、底物特异性跨膜转运蛋白活性和离子跨膜转运体活性。通路分析结果显示,靶基因在癌证通路、pI3K-Akt信号通路、人类乳头瘤病毒感染、神经活性配体-受体相互作用和MAPK通路等分布广泛。采用STRING网站和Cytoscape软件,根据MCC算法筛选出ADRA2C、CASR、CCL28、CCR1、DRD2、GNAT3、GRM2、DYNC1LI1、GABBR1、GNAI1等核心靶基因。结论 凉血通瘀方对脑出血急性期鼠脑组织内miRNA的表达有重要影响;显著差异表达miRNAs可能通过靶向核心基因调控凉血通瘀方干预急性脑出血的病理过程及预后。 相似文献
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Lara Feulner Hamed S. Najafabadi Simon Tanguay Janusz Rak Yasser Riazalhosseini 《Urologic oncology》2019,37(2):166-175
Background
Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.Methods
Using The Cancer Genome Atlas (n?=?436) and Cancer Genomics of the Kidney (n?=?89) datasets, we applied regression analysis to examine associations between patient age and gene expression profiles in ccRCC tumors and normal kidney tissues. Pathway enrichment analysis was performed to identify cellular process that is affected by aging in ccRCC. Moreover, connectivity mapping analysis was used to predict age-dependent response to drug treatments.Results
Our analysis revealed different age-dependent gene expression spectra in ccRCC and normal kidney tissues. These findings were significant and independently reproducible in both datasets examined. Age up-regulated genes, showing higher expression in older patients, were significantly enriched (false discovery rate <0.05) in normal tissues for pathways associated with immune response and extracellular matrix organization, whereas age up-regulated genes in tumors were enriched for metabolism and oxidation pathways. Strikingly, age down-regulated genes in normal cells were also enriched for metabolism and oxidation, while those in tumors were enriched for extracellular matrix organization. Further in silico analysis of potential drug targets predicted preferential efficacy of Phosphoinositide 3-kinase inhibitor or immunotherapy in association with age.Conclusion
We report on previously unrecognized associations between age and molecular underpinnings of RCC, including age-associated expression of genes implicated in RCC development or treatment. 相似文献7.
BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal. 相似文献
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Objestive Systemic inflarmmation may be triggered by injury, hypothermia, ischemia-reperfusion and the contact of the blood with foreign body during cardiopulmonary bypass (CPB). To determine the application values of gene chip technique in the clinical practice and the study of cardiovascular stagery, as well as to provide clues to the study of inflammatory responess during CPB, microarry for gene expression profiles was used to identify the differences in the gene expression of myocardium between pre-and post- CPB. Methods Six adult patients who underwent CPB from March to May in 2003 were involved. Samples of right atrium were col- lected before and at immediate end of CPB. BD AtlasTM cDNA Expression Arrays was used to identify the differences in the gene ex- pression of cytokines. The results were compared with that of semi-quantative RT-PCR. Resellts The mean age of 6 patients (5 males and 1 female) was (32.67± 11.72) years. The baseline heart function was gradeⅡin 3 cases and grade Ⅲ in 3 other cases. The baseline left ventricular ejection fraction(LVEF)was (58.17±7.91)%. The mere duration was (91.67±43.88) minutes for CPB and was (58.67±43.46) minutes for aorta blocking. The minimum nasopharynx/rectal temperture was (29.37±1.90)℃/ (32.15±1.52)℃. Gene expression profiles of cytokines in the myocardium pre- and post-CPB were analysed successfully. The ex- pression of IL-6, IFN-γ,Wnt5a, TNFRSF1B, a member of tumor necrosis factor receptor superfamily, PIGF and MFNG in the myo- cardium were unpregulated after CPB. Conclusion Microarray technique is applicable in the study of cytokines changes dying CPB. cDNA microarray identified pleliminarily the differences in the gene expression between pre- and post-CPB. These genes may be in- valved in inflammation and other psthophysiological responses incuced by CPB. The myocardiym is probably one of the major sources of cytokines during CPB. Further study may be helpful in understanding the llngthe development of inflammation during CPB, and eventually, reducing the post-operative complications. 相似文献