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Design, Synthesize and Bio-Evaluate 1,2-Dihydroisoquinolin-3(4H)-One Derivates as Acetylcholinesterase and β-Secretase Dual Inhibitors in Treatment with Alzheimer’s Disease
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作者 Youchao Deng Yuren Jiang +1 位作者 Xiongjie Zhao Jinlian Wang 《Journal of Biosciences and Medicines》 2016年第1期112-123,共12页
With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses a... With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients. 展开更多
关键词 β-secretase (BACE 1) Acetylcholinesterase (AChE) inhibitor Alzheimer’s Disease (AD)
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Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis
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作者 Qiang Zou Hao-Wen Wang +2 位作者 Xi-Liang Di Yuan Li Hui Gao 《World Journal of Gastrointestinal Oncology》 SCIE 2024年第4期1547-1563,共17页
BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found t... BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression. 展开更多
关键词 Hepatocellular carcinoma Ultrasound microbubbles Long noncoding RNA HAND2-AS1 miR-873-5p Tissue inhibitor of matrix metalloproteinase-2
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Synthesis of 1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas as TNF-αinhibitors
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作者 Xin Ming Zhou Zhi Bing Zheng +4 位作者 Hong Ying Liu Wu Zhong Jun Hai Xiao Li Li Wang Song Li 《Chinese Chemical Letters》 SCIE CAS CSCD 2007年第8期905-908,共4页
A new series of compounds, 1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas, have been synthesized and their structures were confirmed by FAB-MS and IH NMR. The preliminary pharmacological screening showed that these co... A new series of compounds, 1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas, have been synthesized and their structures were confirmed by FAB-MS and IH NMR. The preliminary pharmacological screening showed that these compounds inhibited TNF-α production in lipopolysaccharide (LPS)-stimulated THP-1 cells. 展开更多
关键词 p38 MAPK inhibitor l-Aryl-3-(3 4-dihydro-2H-chromen-5-yl) ureas Synthesis
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Relation between Baseline Lipid Levels and Effectiveness of HMG-CoA Reductase Inhibitors in Patients with Hyperlipidemia
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作者 伍卫 周淑娴 +3 位作者 韦育林 张燕 王景峰 张旭明 《South China Journal of Cardiology》 CAS 2001年第1期13-16,共4页
Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicente... Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicenter clinical trials with similar designs during 1994 to 1999. 166 patients with mean age 58. 9±9. 2 years were involved in Simvastatin Clinical Trial with simvastatin 10 mg once daily for 8 weeks. 146 patients with mean age 57. 9±8. 7years were involved in Lovastatin Clinical Trial with lovastatin 20 mg once daily for 8 weeks. 105 patients with mean age 57. 8±9. 3 years were involved in Atorvastatin Clinical Trial with atorvastatin 10 mg once daily for 6 weeks. Baseline total cholesterol (TC) was more than 5. 98 mmol. L - 1, and baseline triglyceride (TG) was less than 4. 52 mmo. L - 1. The patients were grouped by baseline lipid levels. Results The higher the baseline TC, low density lipoprotein cholesterol (LDL - C) and TG levels were, the more effective the simvastatin, lovastatin, or atorvastatin was in reducing serum TC, LDL - C, and TG, respectively. A positive linear correlation was found between baseline values and effects of simvastatin, lovastatin, or atorvastatin in reducing serum TC, LDL - C, and TG, respectively. Conclusion The changes of reduction on serum lipid with HMG - CoA reductase inhibitors in patients with hyperlipidemia were influenced by baseline lipid levels. 展开更多
关键词 HMG - CoA reductase inhibitors Baseline lipid levels
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The new K_V3.4 inhibitor BDS-I[1–8] as a potential pharmacological opportunity in Alzheimer’s disease therapy 被引量:2
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作者 Ilaria Piccialli Roselia Ciccone Anna Pannaccione 《Neural Regeneration Research》 SCIE CAS CSCD 2020年第7期1255-1256,共2页
Alzheimer's disease(AD)is the most common neurodegenerative disorder and the first cause of dementia in the elderly,with no treatment able to prevent or to block disease progression.AD is characterized by memory i... Alzheimer's disease(AD)is the most common neurodegenerative disorder and the first cause of dementia in the elderly,with no treatment able to prevent or to block disease progression.AD is characterized by memory impairment and cognitive dysfunction,followed in the late phases of the disease by severe neurodegeneration and neuronal death.The amyloid-β(Aβ)peptide,generated upon the processing of the amyloid precursor protein,is considered the main initiator of AD pathology.Indeed,Aβpeptides,which aggregate and accumulate to form extracellular plaques and intraneuronal deposits. 展开更多
关键词 inhibitor BDS-I[1-8] BDS Alzheimer
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A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells 被引量:7
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作者 Zuo-fu PENG Lin-xiang LAN +4 位作者 Fang ZHAO Jing LI Qiang TAN Han-wei YIN Hui-hui ZENG 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2008年第1期16-21,共6页
Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigat... Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigated on human leu-kemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to inves-tigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors. 展开更多
关键词 Thioredoxin reductase (TrxR) Novel TrxR inhibitor 1 2-[bis(1 2-benzisoselenazolone-3(2H)-ketone)]ethane(BBSKE) APOPTOSIS
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Synthesis and Crystal Structure of a Novel Ethyl 5-(4-(2-Phenylacetamido)phenyl)-1H-pyrazole-3-carboxylate as an Acrosin Inhibitor 被引量:2
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作者 祁晶晶 周有骏 +5 位作者 刘雪飞 丁莉莉 郑灿辉 盛春泉 吕加国 朱驹 《Chinese Journal of Structural Chemistry》 SCIE CAS CSCD 2011年第11期1604-1608,共5页
The title compound (ethyl5-(4-(2-phenylacetamido)phenyl)-lH-pyrazole-3-carboxylate, C20H19N3O3) was synthesized by the reaction of Claisen condensation, cyclization, reduction and acylation. The structure was ch... The title compound (ethyl5-(4-(2-phenylacetamido)phenyl)-lH-pyrazole-3-carboxylate, C20H19N3O3) was synthesized by the reaction of Claisen condensation, cyclization, reduction and acylation. The structure was characterized by X-ray diffraction, MS, NMR and IR. It belongs to the monoclinic system, space group C2/c with a = 22.723(9), b = 9.324(4), c = 18.890(8) A, β = 114.259(6)°, V = 3649(3) A^3, Dc = 1.272 Mg·m^3, Z = 8, Mr = 349.38, p = 0.087 mm^-1, F(000) = 1472, the final R = 0.0615 and wR = 0.1643. The biological test shows that the title compound has a moderate acrosin inhibition activity. 展开更多
关键词 ethyl 5-(4-(2-phenylacetamido)phenyl)-1H-pyrazole-3-carboxylate crystal structure acrosin inhibitor
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A new angiotensin-converting enzyme inhibitor from Peperomia pellucida(L.) Kunth 被引量:1
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作者 Islamudin Ahmad Neneng Siti Silfi Ambarwati +5 位作者 Berna Elya Hanita Omar Kamarza Mulia Arry Yanuar Osamu Negishi Abdul Mun'im 《Asian Pacific Journal of Tropical Biomedicine》 SCIE CAS 2019年第6期257-262,共6页
Objective:To isolate,identify,and evaluate a new angiotensin-converting enzyme inhibitor from Peperomia pellucida(L.)Kunth herbs.Methods:A dried sample of Peperomia pellucida herb was successively macerated with n-hex... Objective:To isolate,identify,and evaluate a new angiotensin-converting enzyme inhibitor from Peperomia pellucida(L.)Kunth herbs.Methods:A dried sample of Peperomia pellucida herb was successively macerated with n-hexane and ethyl acetate.The ethyl acetate extract solution was evaporated to obtain the crude extract.Vacuum liquid column chromatography and thin layer chromatography were performed to obtain two pure compounds.Then,both compounds were elucidated and identified using the spectroscopic method.Angiotensin-converting enzyme inhibitory activity studies of both compounds were determined using angiotensin-converting enzyme kit WST-1 with spectrophotometer microplate reader 96-well at 450 nm wavelength.Results:Two bioactive compounds were successfully isolated from Peperomia pellucida herb,including a new compound of 2,3,5-trimethoxy-9-(12,14,15-trimethoxybenzyl)-1 H-indene and pellucidin A.Both compounds demonstrated angiotensin-converting enzyme inhibitory activity,with IC50 values of 72 μM(27.95 μg/mL)and 1 1μM(4.4 μg/mL),respectively.Conclusions:In the present study,two active angiotensin-converting enzyme inhibitors were successfully isolated and purified from Peperomia pellucida which is used as an antihypertensive in traditional medicine,and support its use as an angiotensin-converting enzyme-inhibiting drug. 展开更多
关键词 2 3 5-trimethoxy-9-(12 14 15-trimethoxybenzyl)-1H-indene Angiotensin-converting ENZYME inhibitor Pellucidin A PEPEROMIA pellucida(L) Kunth
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Effect of protease inhibitor from Agaricus bisporus on glucose uptake and oxidative stress in 3T3-L1 adipocytes
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作者 Reena Vishvakarma Abha Mishra 《Asian Pacific Journal of Tropical Biomedicine》 SCIE CAS 2020年第3期136-146,共11页
Objective:To explore the effect of the protease inhibitor from Agaricus bisporus(J.E.Lange)Imbach(AbPI)on glucose uptake and oxidative stress in 3 T3-L1 adipocytes.Methods:Adipocytes were differentiated and stained wi... Objective:To explore the effect of the protease inhibitor from Agaricus bisporus(J.E.Lange)Imbach(AbPI)on glucose uptake and oxidative stress in 3 T3-L1 adipocytes.Methods:Adipocytes were differentiated and stained with OilRed-O staining to confirm adipogenesis.The toxic/protective effect of AbPI on the adipocytes was determined by MTT assay,intracellular reactive oxygen species generation through flow cytometry,and morphologically through confocal microscopy using propidium iodide,4,6-diamino-2-phenylindol dihydrochloride,and 2’,7’-dichlorofluorescein diacetate dyes.The uptake of fluorescent glucose analog,2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose by adipocytes was also studied through confocal microscopy.Results:MTT assay showed that the cell survival rate was(28.00±3.00)%,(92.33±2.60)%,and(71.34±2.10)%in the presence of 2 mM H2O2,AbPI alone,and AbPI and H2O2 both,respectively,in comparison to the control.Oil-Red-O staining indicated that Ab PI enhanced adipogenesis.AbPI stimulated the glucose uptake by adipocytes similar to the drug rosiglitazone,and showed insulinsensitizing effect in the presence of insulin,but failed to stimulate the uptake in the absence of insulin.Intracellular reactive oxygen species generation was reduced in differentiating adipocytes upon Ab PI treatment.Confocal microscopy showed that the damaged cell population rose to 3.50%,117.84%,and 261.50%in the presence of Ab PI alone,AbPI with H2O2,and H2O2 alone,respectively.Conclusions:The protease inhibitor enhances glucose uptake by adipocytes and exhibits a cytoprotective effect on them. 展开更多
关键词 Protease inhibitor AGARICUS bisporus 2-[N-(7-nitrobenz-2-oxa-1 3-diazol-4-yl)amino]-2-deoxy-d-glucose Oxidative stress Hydrogen PEROXIDE 3T3-L1 ADIPOCYTES
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The New Molecular Entity Evolocumab, One Kind of PCSK9 Inhibitor, Reduce Plasma Small Size LDL-Cholesterol Levels by Using a New Standardized Method of Measuring LDL Size
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作者 Ikuo Inoue Ryo Kubota +5 位作者 Shohan Yanagi Masumi Akita Takanari Nakano Shigehiro Katayama Akira Shimada Mistuhiko Noda 《Open Journal of Molecular and Integrative Physiology》 2017年第1期1-23,共23页
Aims: There has been no evidence on the effects of evolocumab, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, on small size LDL. We observationally investigated the efficacy and side effects of evolocum... Aims: There has been no evidence on the effects of evolocumab, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, on small size LDL. We observationally investigated the efficacy and side effects of evolocumab on the LDL subfraction particle diameter using PAGE system for lipoprotein analysis. Methods: We defined 30 patients with high-risk hyperlipidemia. As for analysis of LDL subfraction profile, we used polyacrylamide gel electrophoresis three methods: 1) 3% nondenatured poly-acrylamide gel electrophoresis method (3%PAGE), 2) 2% - 16% nondenatured poly-acrylamide gradient gel electro-phoresis method (2% - 16% GGE) and 3) 2.7% - 5% GGE. Evolocumab 140 mg/day administered together with statin significantly improved serum total cholesterol (TC), triglyceride (TG), high-dense lipoprotein-cholesterol (HDL-C), and LDL-C after four-week treatment. Results: TC, TG, HDL-C and LDL-C levels were improved by, respectively, 33%, 20%, 10%, and 54%. The mean LDL size significantly increased from 25.6 ± 0.4 nm to 26.4 ± 0.8 nm. The small dense LDL-cholesterol (sdLDL-C), large buoyant LDL-cholesterol (lbLDL-C), and mid-band lipoprotein-cholesterol were reduced, respectively. Therefore, the preliminary study on this paper can be the first step into a new insight on the world of lipid metabolism. Conclusion: Short-term administration of evolocumab addedons to statin therapy, significantly reduced small size LDL levels. 展开更多
关键词 PCSK9 inhibitor Evolocumab LDL Heterogeneicity Small Size LDL 3% PAGE 2% - 16% GGE
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Notch信号通路调控上皮-间质转化影响膀胱癌侵袭性和耐药性 被引量:13
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作者 刘志欢 王义兵 +4 位作者 王共先 黄亮 郎斌 许晓源 傅斌 《基础医学与临床》 CSCD 2015年第2期145-151,共7页
目的体外探讨Notch信号通路对膀胱癌细胞侵袭性与耐药性的影响及分子机制。方法采用Notch信号通路受体完全阻断剂(γ分泌酶抑制剂)处理膀胱癌T24、5637和J82细胞48 h后,倒置显微镜观察膀胱癌细胞增生及形态;用RT-PCR和Western blot在mRN... 目的体外探讨Notch信号通路对膀胱癌细胞侵袭性与耐药性的影响及分子机制。方法采用Notch信号通路受体完全阻断剂(γ分泌酶抑制剂)处理膀胱癌T24、5637和J82细胞48 h后,倒置显微镜观察膀胱癌细胞增生及形态;用RT-PCR和Western blot在mRNA和蛋白水平检测上皮-间质转化(EMT)分子标志物E-cadherin、N-cadherin、vimentin和Alpha-smooth muscle actin的表达;MTT、Transwell检测膀胱癌细胞耐药性及侵袭能力。结果完全阻断Notch信号通路后,镜下显示膀胱癌细胞形态变小,细胞分散;EMT分子标志物E-cadherin mRNA和蛋白水平表达上调(P<0.05),N-cadherin、vimentin、Alpha-smooth muscle actin mRNA和蛋白水平表达下调(P<0.05);膀胱癌细胞T24、5637和J82增殖明显被抑制(P<0.05);膀胱癌细胞T24、5637和J82穿过微孔膜的细胞数明显减少(P<0.05)。结论 Notch信号通路可通过调控EMT的变化而改变膀胱癌的侵袭性与耐药性。 展开更多
关键词 膀胱癌 NOTCH信号通路 上皮-间质转化 γ分泌酶抑制剂
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Notch2/Hes-1信号通路活化参与调控肾缺血-再灌注诱导炎症因子的表达研究 被引量:9
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作者 黄仁发 赖虹伊 +8 位作者 梁群卿 黄国东 向少伟 汪东涛 马晓露 黄海燕 胡维 林心如 周巧玲 《中国现代医学杂志》 CAS 北大核心 2015年第17期5-11,共7页
目的观察肾缺血-再灌注(IR)大鼠肾小管Notch2/Hes-1信号通路的活化,及信号通路关键酶γ-泌肽酶抑制剂DAPT对血清肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)、肾小管上皮细胞单核细胞趋化蛋白-1(MCP-1)表达的影响。方法 45只SD大鼠随机分... 目的观察肾缺血-再灌注(IR)大鼠肾小管Notch2/Hes-1信号通路的活化,及信号通路关键酶γ-泌肽酶抑制剂DAPT对血清肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)、肾小管上皮细胞单核细胞趋化蛋白-1(MCP-1)表达的影响。方法 45只SD大鼠随机分为假手术组(Sham组)、缺血-再灌注组(I/R组)和γ-泌肽酶抑制剂组(DAPT组),每组15只,按先摘除右肾然后夹闭左肾蒂60 min的方法建立肾I/R模型。Sham组和I/R组手术前后灌服生理盐水2 ml/d,DAPT组手术前后灌服DAPT 500μg/(kg·d)。结果HE染色结果显示,Sham组大鼠肾小管间质未见明显病变;I/R组肾小管出现小管扩张、管腔内管型、刷状缘丢失、间质炎症细胞浸润等病变,小管损伤以I/R后24 h最重。I/R组大鼠24、48和72 h的尿素氮(BUN)和血肌酐(Scr)、肾小管间质半定量计分、血清TNF-α和IL-6水平、肾小管Notch2、Hes-1、MCP-1蛋白表达比相同时间Sham组增高(P<0.01);而经DAPT处理后,小管结构较I/R组完整清晰,病理改变明显减轻。DAPT组BUN、Scr、肾小管间质半定量评分、血清TNF-α和IL-6水平、肾小管Notch2、Hes-1、MCP-1蛋白表达比相同时间I/R组大鼠降低(P<0.01)。结论肾I/R可诱导肾小管Notch2/Hes-1信号通路活化,并参与调控炎症因子IL-6、TNF-α、MCP-1表达,γ-泌肽酶抑制剂DAPT可能具有一定的肾保护作用。 展开更多
关键词 肾缺血-再灌注损伤 Notch2/Hes-1信号通路 炎症 γ-泌肽酶抑制剂DAPT
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γ-促分泌酶抑制剂对毛细支气管炎模型大鼠体内Th17细胞分化的影响 被引量:4
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作者 王海英 刘良宵 +1 位作者 吴福玲 高萌 《中国免疫学杂志》 CAS CSCD 北大核心 2016年第12期1765-1768,共4页
目的:研究γ-促分泌酶抑制剂阻断Notch信号对毛细支气管炎(简称毛支)模型大鼠Th17细胞发育和分化的影响,为毛支治疗寻找新的药物提供理论基础。方法:按随机对照原则将SD大鼠分为正常组、毛支组和γ-促分泌酶抑制剂组,滴鼻法成功建立毛... 目的:研究γ-促分泌酶抑制剂阻断Notch信号对毛细支气管炎(简称毛支)模型大鼠Th17细胞发育和分化的影响,为毛支治疗寻找新的药物提供理论基础。方法:按随机对照原则将SD大鼠分为正常组、毛支组和γ-促分泌酶抑制剂组,滴鼻法成功建立毛支模型,而后尾静脉注射γ-促分泌酶抑制剂MW167,通过HE染色观察肺组织病理改变,ELISA检测血浆中白介素17(IL-17)的水平,实时荧光定量PCR检测肺组织和外周血单个核细胞中RORγt mRNA的表达,Western blot检测肺组织中Notch信号、RORγt的蛋白表达。结果:与毛支组相比,MW167组肺组织病理学改变减轻;血浆IL-17水平也较毛支组降低;肺组织及外周血单个核细胞RORγt mRNA在MW167注射组表达均减弱;MW167组肺组织Notch信号和RORγt蛋白的表达也显著降低。结论:静脉注射γ-促分泌酶抑制剂能够通过阻断Notch信号通路抑制Th17细胞的分化,缓解毛支模型大鼠的气道炎症,对毛支有潜在的治疗价值。 展开更多
关键词 毛细支气管炎 NOTCH γ-促分泌酶抑制剂 TH17细胞
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γ-分泌酶抑制剂在哮喘小鼠模型Th17/Treg平衡失调中的作用 被引量:5
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作者 辛娜 李敬梅 +4 位作者 王永锋 王瑶 陈婕 杨超 吴跃刚 《山西医科大学学报》 CAS 2017年第9期918-921,共4页
目的研究γ-分泌酶抑制剂DAPT对哮喘气道炎症、气道高反应和Th17/Treg失衡的干预作用,为其抗哮喘活性制剂的研究与开发提供理论依据。方法 6-8周雌性C57BL/6小鼠45只被随机分为对照组,哮喘组和DAPT组,每组15只苏木精-伊红(HE)染色法观... 目的研究γ-分泌酶抑制剂DAPT对哮喘气道炎症、气道高反应和Th17/Treg失衡的干预作用,为其抗哮喘活性制剂的研究与开发提供理论依据。方法 6-8周雌性C57BL/6小鼠45只被随机分为对照组,哮喘组和DAPT组,每组15只苏木精-伊红(HE)染色法观察气道病理改变,酶联免疫吸附法检测小鼠支气管肺泡灌洗液(BALF)中细胞因子和炎性介质的水平,逆转录聚合酶链反应法(RT-PCR)分析脾脏Foxp3 mRNA的表达。结果 DAPT组较哮喘组气道炎症明显减轻,气道内黏液分泌显著减少。哮喘组IgE、IL-17、IL-10和TGF-β1的含量分别为(695±148)ng/ml,(58±6)pg/ml,(148±12)pg/ml,(18±3)pg/ml;DAPT组IgE、IL-17、IL-10和TGF-β1的含量分别为(486±152)ng/ml,(27±6)pg/ml,(193±17)pg/ml,(33±5)pg/ml。与哮喘组比较,DAPT组气道灌洗液中IL-17、IgE水平显著降低(P<0.01),IL-10、TGF-β1水平显著增加(P<0.01),Foxp3 mRNA的表达也显著增加(P<0.01)。结论γ-分泌酶抑制剂DAPT具有抗哮喘小鼠Th17/Treg失衡的作用。 展开更多
关键词 支气管哮喘 NOTCH信号 γ-分泌酶抑制剂 Th17/Treg失衡 小鼠
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γ-分泌酶抑制剂的药效团模型构建 被引量:6
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作者 鄢浩 姜凤超 《物理化学学报》 SCIE CAS CSCD 北大核心 2006年第3期359-364,共6页
利用Catalyst软件系统,选择具有较高体外抑制活性的苯并二氮类化合物作为训练集,经计算机建模,构象优化,由Catalyst系统构建出药效团模型.并结合γ-分泌酶的作用机制等因素,筛选出一个含有一个芳环中心,一个疏水中心和两个氢键受体的具... 利用Catalyst软件系统,选择具有较高体外抑制活性的苯并二氮类化合物作为训练集,经计算机建模,构象优化,由Catalyst系统构建出药效团模型.并结合γ-分泌酶的作用机制等因素,筛选出一个含有一个芳环中心,一个疏水中心和两个氢键受体的具有较好预测能力(RMS=0.366343,Correl=0.95535,Weight=1.17389,Config=18.8671)的药效团模型.该模型的建立有助于设计及合成新型结构的γ-分泌酶抑制剂. 展开更多
关键词 阿尔茨海默病 计算机辅助药物设计 γ-分泌酶抑制剂 药效团
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γ-分泌酶抑制剂DAPT通过下调NOTCH1信号通路抑制结肠癌HCT116细胞增殖的实验研究 被引量:1
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作者 尹鹏 胡君 +5 位作者 储著凌 霍中华 侯乐伟 吕盛 栾荣刚 胡国强 《西部医学》 2015年第11期1616-1619,共4页
目的探讨γ-分泌酶抑制剂DAPT能否通过下调NOTCH1信号通路抑制结肠癌HCT116细胞增殖,以及对Hes1基因表达的影响。方法使用不同浓度的DAPT(0μM、1μM和10μM)对结肠癌HCT116细胞进行干预。在不同时间点(0h、24h和48h)使用MTT法对HCT116... 目的探讨γ-分泌酶抑制剂DAPT能否通过下调NOTCH1信号通路抑制结肠癌HCT116细胞增殖,以及对Hes1基因表达的影响。方法使用不同浓度的DAPT(0μM、1μM和10μM)对结肠癌HCT116细胞进行干预。在不同时间点(0h、24h和48h)使用MTT法对HCT116细胞活性进行测定。在干预48h后,使用RT-PCR对在不同浓度(0μM、1μM和10μM)DAPT干预后细胞NOTCH1和Hes1mRNA的表达水平进行测定。使用western blot对在不同浓度(0μM、1μM和10μM)DAPT干预后细胞NOTCH1和Hes1蛋白表达水平进行测定。结果使用不同浓度DAPT(0μM、1μM和10μM)对结肠癌HCT116细胞进行干预后,细胞活性呈时间依赖性和浓度依赖性降低,差异均存在显著统计学意义(P均<0.05)。不同浓度DAPT(0μM、1μM和10μM)干预48h后,结肠癌HCT116细胞NOTCH1和Hes1mRNA和蛋白的表达水平呈浓度依赖性的下降,差异均存在显著统计学意义(P均<0.05)。结论本实验表明γ-分泌酶抑制剂DAPT可以通过下调NOTCH1信号通路,抑制结肠癌HCT116细胞增殖。 展开更多
关键词 γ-分泌酶抑制剂 DAPT HCT116细胞 NOTCH1 HES1
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γ-促分泌酶抑制剂对Notch1蛋白表达阳性的原代非小细胞肺癌细胞生长的抑制作用及其机制 被引量:1
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作者 陈楠 张莹 +4 位作者 李高峰 李恒 向旭东 郭刚 马千里 《广西医学》 CAS 2018年第23期2816-2819,共4页
目的探讨γ-促分泌酶抑制剂MW167Ⅱ对Notch1蛋白表达阳性的原代非小细胞肺癌细胞生长的抑制作用及其机制。方法收集11例非小细胞肺癌患者的癌组织标本,应用胶原酶消化法获取细胞后进行细胞培养,采用染色、免疫组化法鉴定为Notch1蛋白表... 目的探讨γ-促分泌酶抑制剂MW167Ⅱ对Notch1蛋白表达阳性的原代非小细胞肺癌细胞生长的抑制作用及其机制。方法收集11例非小细胞肺癌患者的癌组织标本,应用胶原酶消化法获取细胞后进行细胞培养,采用染色、免疫组化法鉴定为Notch1蛋白表达阳性非小细胞肺癌细胞。将细胞分为对照组、实验1组、实验2组、实验3组,分别加入生理盐水、0. 25μmol/L MW167Ⅱ、0. 50μmol/L MW167Ⅱ、0. 75μmol/L MW167Ⅱ,观察各组细胞周期分布情况、细胞存活率及Notch1 mRNA表达情况。结果与对照组比较,各实验组的G0/G1期细胞比例增高、细胞存活率及Notch1 mRNA表达量均降低(均P <0. 05)。G0/G1期的细胞比例与MW167Ⅱ的浓度呈正相关(P <0. 05)。培养24 h及48 h后,实验1组、实验2组、实验3组的细胞存活率及Notch1 mRNA表达量依次降低(均P <0. 05),且各实验组细胞培养48 h后的细胞存活率均低于培养24 h后(均P <0. 05)。结论γ-促分泌酶抑制剂可抑制Notch1蛋白表达阳性的非小细胞肺癌细胞的增殖分化,且呈浓度和时间双重依赖性,这可能与其抑制γ-促分泌酶的活性阻断Notch信号通路有关。 展开更多
关键词 非小细胞肺癌 γ-促分泌酶抑制剂 NOTCH1蛋白 体外实验
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β-分泌酶抑制剂的筛选方法及其天然来源的研究进展 被引量:1
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作者 聂影影 刘亚月 张翼 《天然产物研究与开发》 CAS CSCD 北大核心 2017年第5期873-881,共9页
β-淀粉样蛋白(Aβ)的聚集是目前公认的导致阿尔茨海默病(AD)发病的关键因素,而β-分泌酶(BACE1)是将大脑中的淀粉样β-蛋白前体(APP)转化成Aβ的第一个蛋白酶,也是Aβ产生的限速酶。因此,对BACE1的抑制是有效治疗AD的策略之一。本文阐... β-淀粉样蛋白(Aβ)的聚集是目前公认的导致阿尔茨海默病(AD)发病的关键因素,而β-分泌酶(BACE1)是将大脑中的淀粉样β-蛋白前体(APP)转化成Aβ的第一个蛋白酶,也是Aβ产生的限速酶。因此,对BACE1的抑制是有效治疗AD的策略之一。本文阐述了目前可用于β-分泌酶抑制剂筛选的荧光法、可见光比色法和酵母细胞筛选模型的原理和特点,并对来源于植物、微生物、动物的天然β-分泌酶抑制剂的研究进展进行了综述,为更多活性更强、毒副作用更小的抗AD天然产物先导化合物的发现和结构优化提供了借鉴和启示。 展开更多
关键词 Β-淀粉样蛋白 阿尔茨海默病 Β-分泌酶抑制剂 天然产物
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Ⅲ期结肠癌辅助化疗过程中血清CEA和TIMP-1水平的变化 被引量:2
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作者 闾晨涛 韩潞 +1 位作者 江勇 韩东兴 《浙江医学》 CAS 2014年第14期1217-1219,共3页
目的观察Ⅲ期结直肠癌患者化疗过程中癌胚抗原(CEA)和组织金属蛋白酶抑制剂-1(TIMP-1)水平的变化。方法选择接受结直肠癌根治性切除患者30例,以mFOLFOX6方案进行12周期化疗。化疗前(d0)、第1周期后(d4)、第2周期前后(d14、d18)、第6周... 目的观察Ⅲ期结直肠癌患者化疗过程中癌胚抗原(CEA)和组织金属蛋白酶抑制剂-1(TIMP-1)水平的变化。方法选择接受结直肠癌根治性切除患者30例,以mFOLFOX6方案进行12周期化疗。化疗前(d0)、第1周期后(d4)、第2周期前后(d14、d18)、第6周期前后(d70、d74)分别采集血样,分别测定CEA和TIMP-1水平。结果血清CEA水平6个时间点分别为(1.66±0.35)、(1.16±0.26)、(1.71±0.28)、(1.69±0.51)、(1 63±0.16)、(1.61±0.20)μg/L,化疗中除d4与d0差异有统计学意义,其余各时点CEA水平与化疗前差异均无统计学意义。TIMP-1水平6个时点分别为(150.70±15.32)、(153.53±16.91)、(166.28±12.64)、(190.81±1 1.73)、(140.48±12.30)、(145_20±10 49)μg/L,d4、d14与d0的差异均无统计学意义,d18与d0相比升高,差异有统计学意义。结论辅助化疗过程中,CEA保持稳定,而TIMP-1在化疗开始第2周后有一过性升高。 展开更多
关键词 结直肠癌 组织金属蛋白酶抑制剂-1 癌胚抗原 辅助化疗 Tissue inhibitor of metalloproteinases-1
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Hsa-miR-205-5p对食管鳞癌细胞系耐药的影响 被引量:1
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作者 王芳 肖帅帅 阎婷 《山西医科大学学报》 CAS 2017年第6期525-529,共5页
目的研究hsa-miR-205-5p对食管鳞癌铂类化疗耐药的影响。方法首先用RT-PCR法检测hsa-miR-205-5p在食管鳞癌耐药细胞系EcA109和敏感细胞系KYSE150中的表达。然后在EcA109和KYSE150中分别转染hsa-miR-205-5p mimics,mimics NC和hsa-miR-20... 目的研究hsa-miR-205-5p对食管鳞癌铂类化疗耐药的影响。方法首先用RT-PCR法检测hsa-miR-205-5p在食管鳞癌耐药细胞系EcA109和敏感细胞系KYSE150中的表达。然后在EcA109和KYSE150中分别转染hsa-miR-205-5p mimics,mimics NC和hsa-miR-205-5p inhibitor,inhibitor NC,用MTT和CCK8法检测奥沙利铂浓度为60,120,240,480,960μmol/L对细胞增殖的影响。结果 hsa-miR-205-5p在食管癌耐药细胞系EcA109比在敏感细胞系KYSE150中低表达(P<0.05)。MTT和CCK8实验结果表明,与转染NC组相比,随着奥沙利铂浓度的增加,转染hsa-miR-205-5p mimics组的EcA109细胞抑制率上升(P<0.05),转染hsa-miR-205-5p inhibitor组的KYSE150细胞抑制率下降(P<0.05)。结论转染hsa-miR-205-5p mimics后Ec A109细胞对奥沙利铂敏感性提高,转染hsa-miR-205-5p inhibitor后KYSE150细胞对奥沙利铂耐药性增加。说明hsa-miR-205-5p过表达可抑制食管鳞癌细胞产生耐药性。 展开更多
关键词 hsa-miR-205-5p mimics/inhibitor 食管鳞癌 耐药
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