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41.
In vitro improvement of quail primordial germ cell expansion through activation of TGF‐beta signaling pathway 下载免费PDF全文
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Fahui Li Lihui Zhang Jinhong Feng Lei Zhang 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):2017
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapeutic target for the development of cholesterol-lowering drugs. In the discovery of PCSK9/LDLR (low-density lipoprotein receptor) protein-protein interaction (PPI) impairing small molecules, a total of 47 phenylbenzo[d][1,3] dioxole-based compounds were designed and synthesised. The result revealed that the 4-chlorobenzyl substitution in the amino group is important for the PPI disrupting activity. In the hepatocyte-based functional tests, active compounds such as A12, B1, B3, B4 and B14, restored the LDLR levels on the surface of hepatic HepG2 cells and increased extracellular LDL uptake in the presence of PCSK9. It is notable that molecule B14 exhibited good performance in all the evaluations. Collectively, novel structures targeting PCSK9/LDLR PPI have been developed with hypolipidemic potential. Further structural modification of derived active compounds is promising in the discovery of lead compounds with improved activity for the treatment of hyperlipidaemia-related disorders. 相似文献
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近年来相关研究显示,肠道微生态在骨质疏松症的发生发展中起着重要作用。中医脏腑理论密切关注脏腑之间的生理病理关系,以中医经典《内经》“心与小肠相表里”理论为基础,探讨心、小肠、肠道微生态与骨质疏松症之间的关系。研究发现肠道微生态可能是心系疾病导致骨质疏松症的途径之一,这一发现可能为骨质疏松症的研究与防治提供一定的理论依据。 相似文献
45.
González I Rakitina D Semashko M Taliansky M Praveen S Palukaitis P Carr JP Kalinina N Canto T 《RNA (New York, N.Y.)》2012,18(4):771-782
Previously, we found that silencing suppression by the 2b protein and six mutants correlated both with their ability to bind to double-stranded (ds) small RNAs (sRNAs) in vitro and with their nuclear/nucleolar localization. To further discern the contribution to suppression activity of sRNA binding and of nuclear localization, we have characterized the kinetics of in vitro binding to a ds sRNA, a single-stranded (ss) sRNA, and a micro RNA (miRNA) of the native 2b protein and eight mutant variants. We have also added a nuclear export signal (NES) to the 2b protein and assessed how it affected subcellular distribution and suppressor activity. We found that in solution native protein bound ds siRNA, miRNA, and ss sRNA with high affinity, at protein:RNA molar ratios ~2:1. Of the four mutants that retained suppressor activity, three showed sRNA binding profiles similar to those of the native protein, whereas the remaining one bound ss sRNA at a 2:1 molar ratio, but both ds sRNAs with 1.5-2 times slightly lower affinity. Three of the four mutants lacking suppressor activity failed to bind to any sRNA, whereas the remaining one bound them at far higher ratios. NES-tagged 2b protein became cytoplasmic, but suppression activity in patch assays remained unaffected. These results support binding to sRNAs at molar ratios at or near 2:1 as critical to the suppressor activity of the 2b protein. They also show that cytoplasmically localized 2b protein retained suppressor activity, and that a sustained nuclear localization was not required for this function. 相似文献
46.
Zhuang Luo Wei Chen Wenjuan Wu Wei Luo Tingting Zhu Gang Guo Liyan Zhang Chu Wang Min Li Shaoqing Shi 《Journal of cellular biochemistry》2019,120(7):11890-11899
Metformin, a first-line antidiabetic drug, has been reported with anticancer activities in many types of cancer. However, its molecular mechanisms remain largely unknown. As a member of inhibitor of apoptosis proteins, survivin plays an important role in the regulation of cell death. In the present study, we investigated the role of survivin in metformin-induced anticancer activity in non–small cell lung cancer in vitro. Metformin mainly induced apoptotic cell death in A549 and H460 cell lines. It remarkably suppressed the expression of survivin, decreased the stability of this protein, then promoted its proteasomal degradation. Moreover, metformin greatly suppressed protein kinase A (PKA) activity and induced its downstream glycogen synthase kinase 3β (GSK-3β) activation. PKA activators, both 8-Br-cAMP and forskolin, significantly increased the expression of survivin. Consistently both GSK-3β inhibitor LiCl and siRNA restored the expression of survivin in lung cancer cells. Furthermore, metformin induced adenosine 5′-monophosphate-activated protein kinase (AMPK) activation. Suppression of the activity of AMPK with Compound C reversed the degradation of survivin induced by metformin, and meanwhile, restored the activity of PKA and GSK-3β. These results suggest that metformin kills lung cancer cells through AMPK/PKA/GSK-3β-axis–mediated survivin degradation, providing novel insights into the anticancer effects of metformin. 相似文献
47.
黄土丘陵区坡面整地和植被耦合下的土壤水分特征 总被引:7,自引:0,他引:7
水分是干旱半干旱地区植被恢复的主要环境制约因子。在黄土高原小流域,合理整地能够有效截留降雨补给土壤水,进而促进植被恢复。选择地处甘肃定西的半干旱黄土小流域为研究区,基于野外实测数据,分析不同植被和整地方式(柠条水平阶、山杏水平沟、侧柏反坡台,油松反坡台)综合影响下的土壤水分特征。采用最优分割法将不同整地方式土壤水分垂直层次划分为活跃层,次活跃层和相对稳定层。结果表明:生长季不同整地方式土壤水分的变化与降水量的变化密切相关,不同月份以及不同深度各整地方式土壤水分之间差异显著(P0.05)。根据土壤水分垂直变化特征,山杏水平沟水分活跃层与次活跃层为0—80cm,其深度范围均大于其他3种整地方式,而柠条水平阶土壤水分均在30 cm以下较为稳定,其深度范围均小于其他3种整地方式。不同整地方式土壤水分含量具体表现为:山杏水平沟侧柏反坡台柠条水平阶油松反坡台。 相似文献
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Nunzia D'Onofrio Michele Caraglia Anna Grimaldi Raffaele Marfella Luigi Servillo Giuseppe Paolisso Maria Luisa Balestrieri 《生物化学与生物物理学报:癌评论》2014
The vasculature of each organ expresses distinct molecular signatures critically influenced by the pathological status. The heterogeneous profile of the vascular beds has been successfully unveiled by the in vivo phage display, a high-throughput tool for mapping normal, diseased, and tumor vasculature. Specific challenges of this growing field are targeted therapies against cancer and cardiovascular diseases, as well as novel bioimaging diagnostic tools. Tumor vasculature-homing peptides have been extensively evaluated in several preclinical and clinical studies both as targeted-therapy and diagnosis. To date, results from several Phase I and II trials have been reported and many other trials are currently ongoing or recruiting patients. In this review, advances in the identification of novel peptide ligands and their corresponding receptors on tumor endothelium through the in vivo phage display technology are discussed. Emphasis is given to recent findings in the clinical setting of vascular-homing peptides selected by in vivo phage display for the treatment of advanced malignancies and their altered vascular beds. 相似文献
49.
Haijun Bin Indunil Angunawela Beibei Qiu Fallon J. M. Colberts Mengmeng Li Matthew J. Dyson Martijn M. Wienk Harald Ade Yongfang Li Ren A. J. Janssen 《Liver Transplantation》2020,10(34)
Compared to conjugated polymers, small‐molecule organic semiconductors present negligible batch‐to‐batch variations, but presently provide comparatively low power conversion efficiencies (PCEs) in small‐molecular organic solar cells (SM‐OSCs), mainly due to suboptimal nanomorphology. Achieving precise control of the nanomorphology remains challenging. Here, two new small‐molecular donors H13 and H14 , created by fluorine and chlorine substitution of the original donor molecule H11 , are presented that exhibit a similar or higher degree of crystallinity/aggregation and improved open‐circuit voltage with IDIC‐4F as acceptor. Due to kinetic and thermodynamic reasons, H13 ‐based blend films possess relatively unfavorable molecular packing and morphology. In contrast, annealed H14 ‐based blends exhibit favorable characteristics, i.e., the highest degree of aggregation with the smallest paracrystalline π–π distortions and a nanomorphology with relatively pure domains, all of which enable generating and collecting charges more efficiently. As a result, blends with H13 give a similar PCE (10.3%) as those made with H11 (10.4%), while annealed H14 ‐based SM‐OSCs have a significantly higher PCE (12.1%). Presently this represents the highest efficiency for SM‐OSCs using IDIC‐4F as acceptor. The results demonstrate that precise control of phase separation can be achieved by fine‐tuning the molecular structure and film formation conditions, improving PCE and providing guidance for morphology design. 相似文献
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