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VP-16对HL-60细胞凋亡的影响
为探讨HL-60细胞分化与凋亡的关系,我们在诱导HL-60细胞凋亡[1]的基础上,仍以鬼臼乙叉甙(VP-16)为凋亡诱导剂,选择全反式维甲酸(all-trans retinoic acid, ATRA)等作为分化诱导剂,对经不同分化诱导剂诱导分化的HL-60细胞的凋亡情况进行了初步研究.
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全反式维甲酸对子宫颈癌细胞增殖及survivin、半胱氨酸天冬氨酸蛋白酶3表达的影响
在恶性肿瘤发生和发展的过程中,细胞增殖和凋亡调节的失控起着重要作用.全反式维甲酸(all-trans retinoic acid,ATRA)是一种在实验和临床研究中得到广泛证实的细胞诱导分化剂,能够调节肿瘤细胞的生长和分化,诱导多种肿瘤细胞凋亡,具有显著的抗肿瘤作用,但其诱导细胞凋亡的确切机制目前还不十分清楚,其在宫颈癌中的作用也少有报道.
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Glial cell line-derived neurotrophic factor recombinant adenovirus vector-transfected bone marrow mesenchymal stem cells were induced to differentiate into neuron-like cells using inductive medium containing retinoic acid and epidermal growth factor. Cell viability, micro-tubule-associated protein 2-positive cell ratio, and the expression levels of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43 protein in the su-pernatant were signiifcantly higher in glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells compared with empty virus plasmid-transfected bone marrow mes-enchymal stem cells. Furthermore, microtubule-associated protein 2, glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43 mRNA levels in cell pellets were statistically higher in glial cell line-derived neurotrophic factor/bone marrow mesen-chymal stem cells compared with empty virus plasmid-transfected bone marrow mesenchymal stem cells. These results suggest that glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells have a higher rate of induction into neuron-like cells, and this enhanced differentiation into neuron-like cells may be associated with up-regulated expression of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43.
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In the field of developmental neurobiology, accurate and ordered regulation of the cel cycle and apoptosis are crucial factors contributing to the normal formation of the neural tube. Preliminary studies identified several genes involved in the development of neural tube defects. In this study, we established a model of developmental neural tube defects by administration of retinoic acid to pregnant rats. Gene chip hybridization analysis showed that genes related to the cel cycle and apoptosis, signal transduction, transcription and translation regulation, energy and metabolism, heat shock, and matrix and cytoskeletal proteins were al involved in the formation of developmental neural tube defects. Among these, cel cycle-related genes were predominant. Retinoic acid ment caused differential expression of three cel cycle-related genes p57kip2, Cdk5 and Spin, the expression levels of which were downregulated by retinoic acid and upregulated during normal neural tube formation. The results of this study indicate that cel cycle-related genes play an im-portant role in the formation of neural tube defects. P57kip2, Cdk5 and Spin may be critical genes in the pathogenesis of neural tube defects.
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全反式维生素A酸对抑制视网膜母细胞瘤株增殖的实验研究
全反式维生素A酸(all-trans retinoic acid, AT-RA)能抑制肿瘤细胞的增殖而达到治疗肿瘤的目的[1,2].我们采用AT-RA对视网膜母细胞瘤(Retinoblastoma, RB)株进行增殖抑制的实验研究,以期探索肿瘤治疗的新途径.
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眼用维甲酸缓释胶囊的制备和体外药物释放速率的测定
一定浓度的维甲酸可有效抑制细胞增殖,诱导细胞分化和生理凋亡,有望在后发性白内障的预防研究中发挥作用[1,2].我们自1999年7月开始研制一种可长期恒定释放一定药物浓度的新型眼用全反式维甲酸(all-trans retinoic acid, RA)缓释胶囊,现将其制备方法和体外药物释放特点报告如下.
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维甲酸类化合物对非小细胞肺癌作用机制的研究
维甲酸类化合物是维生素A类衍生物,包括维甲酸(retinoic acid,RA)、维胺酸、维胺酯及天然维生素A等,约有4 000多种.其中以RA常用,包括几种异构体:全反式维甲酸(alltran retinoic acid,ATRA)、9顺维甲酸(9-cis retinoic acid,9-cis RA)和13顺维甲酸(13-cis retinoic acid,13-cis RA)等.体内外研究发现,它们对组织细胞的生长、发育及功能维持起重要作用,并能预防恶性肿瘤的发生和诱导多种恶性肿瘤细胞的分化,逆转肿瘤细胞的恶性表型等.因此,近年来倍受重视,为抗肿瘤新药的研究开辟了一条新方向.
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三氧化二砷治疗急性早幼粒细胞白血病过程中外周血白细胞的变化
全反式维甲酸(all-trans retinoic acid,ATRA)和三氧化二砷(As2O3)开辟了急性早幼粒细胞白血病(APL)诱导分化治疗的新篇章,大大提高了APL患者的长期无复发生存率.
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Objective To investigate the role of suppressor gene p16 in the process of differential regulation of retinoic acid (RA) on the A549 lung cancer cells.Methods Tumor suppressor gene p16 was transferred into A549 cells and the cells were treated with all-trans retinoic acid (ATR) at the dosage of 5×10-6 mol/L for 4 d. After that, the proliferation and differentiation of A549 cells were examined by growth curve and cytometry analysis, the change of lung lineage-specific marker MUC1 was tested by immunohistochemical staining. Meanwhile, Western blot was used to observe the change of p16 protein expression in A549 cells treated with ATRA.Results ATRA could obviously inhibit the growth and induce the differentiation of A549 Cells that were transferred with p16 gene. There were more cells arrested in G1/G0 phase and the expression of MUG1 was markedly down-regulated than in control cells. The expression of p16 protein was up-regulated in A549 cells treated with ATRA.Conclusion Suppressor gene p16 could enhance the effects of RA and proliferated suppression and differential induction of A549 cells.
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全反式维甲酸对食管癌细胞增殖及分化相关基因mRNA表达的影响
肿瘤的发生与细胞增殖与分化失调有关,诱导分化治疗是肿瘤治疗的途径之一.维甲酸类化合物是常用的诱导分化剂,对多种恶性肿瘤具有诱导分化、抑制增殖、诱导肿瘤细胞凋亡的作用[1,2].分化相关基因(NDRG1)是1997年发现的一种基因,研究表明,NDRG1在结肠腺癌、乳腺癌和前列腺癌等肿瘤组织中呈低表达[3],上调NDRG1表达可促进结肠上皮细胞的分化,抑制细胞增殖[4];为探讨全反式维甲酸(all-trans retinoic acid,ATRA)对食管癌细胞NDRG1表达及细胞增殖的影响,我们以ATRA作用于食管癌EC9706细胞,观察NDRG1表达、细胞周期及裸鼠移植瘤生长的变化.
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全反式维甲酸和三氧化二砷治疗急性早幼粒细胞白血病APL的进展
一、引言急性早幼粒细胞白血病(Acute Promyelocytic Leukemia,APL)是FAB分型中急性非淋巴细胞白血病(Acute nonlymphocytic Leukemia ,ANLL)的M3亚型,占所有ANLL的10%~15%,具有独特的临床表现,细胞形态学,细胞遗传学和分子生物学特征.近十年的研究表明APL是第一个联合应用全反式维甲酸(all-trans retinoic acid,ATRA),三氧化二砷(Aa2O3)和化疗取得成功的人类恶性肿瘤,开创了诱导分化治疗的新篇章[1-3].本文总结了近年对APL分子发病机理,ARA和A2O3诱导分化/凋亡以及联合化疗的临床应用及其作用机制的研究概况.
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全反式维A酸诱导分化治疗急性早幼粒细胞白血病的机制研究
1985年,我所于体外研究证明,全反式维A酸(ATRA)可以诱导HL-60及新鲜APL细胞向终末成熟细胞分化.1986年我所在国际上首先应用ATRA治疗APL 24例,23例取得完全缓解(CR).该结果发表在Blood(1988,72:567),并在以后的年代里,得到国内外广泛的证实.进一步的临床研究结果指出,APL用ATRA与化疗合理组合治疗,CR率可提高到90%~95%[1].我所已在1999年总结了临床应用的十年经验[2].
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系统性红斑狼疮患者外周血单一核细胞Th17相关转录因子RORγt mRNA的表达
目的 探讨Th17细胞在系统性红斑狼疮(SLE)免疫炎症反应中的作用机制.方法 逆转录PCR(RT-PCR)检测12例活动期SLE患者、9例非活动期SLE患者和12例正常人对照PBMC中维A酸相关孤儿核受体γt (RORγt) mRNA表达水平.活动期SLE患者组、非活动期SLE患者组与正常人对照组PBMC中RORγt mRNA表达水平采用近似F检验(Welch方法)和校正的多重比较方法(Dunnett's T3)进行分析.结果 活动期SLE患者、非活动期SLE患者及正常人对照RORγt mRNA表达水平分别为1.06±0.44,0.65±0.25,0.22±0.08,3组之间差异有统计学意义(F=23.286,P< 0.01).其中活动期SLE患者组显著高于非活动期患者组(F=2.453,P<0.05)及正常人对照组(F=6.504,P<0.05),非活动期SLE患者组显著高于正常人对照组(F=3.343,P<0.05).SLE患者RORγt mRNA表达水平和SLEDAI之间存在显著正相关(rp=0.623,P< 0.01).结论 证实SLE患者存在Th17细胞极化现象,拮抗调控Th17细胞分化的关键转录因子RORγt能减轻SLE的免疫炎症反应而达到治疗SLE的目的.
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口服9-顺式视黄酸(Alitretinoin)治疗骨髓增生异常综合征:实验性研究结果
视黄酸是非特异性分化诱导药物,在体外它对正常细胞及白血病细胞有明显的作用.视黄酸增加细胞因子诱导的粒系-巨噬系及红系祖细胞的集落形成.而且,体外研究显示,视黄酸抑制人白血病细胞克隆生长且诱导其分化.对视黄酸的反应由核受体——视黄酸受体(RAR )和视黄酸X受体(RXR)介导. 骨髓增生异常综合征(MDS)是克隆性疾病,以无效造血及后期常常发展为急性白血病为发病特征.原发性MDS中无效造血机制尚不清楚,但可能涉及到抑制性细胞因子的抑制作用、自发性凋亡增强,以及由于生长因子受体或受体后信号传导通路失常而导致对生长因子反应的缺陷,使所有三系造血的细胞分化受阻.
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全反式维甲酸对转化生长因子β1诱导肾小球系膜细胞环氧化酶2表达及Smad信号通路的影响
转化生长因子β1(TGF-β1)可能是致组织纤维化的核心因子,其经典信号通路为Smad通路.环氧化酶2(COX-2)是一种膜结合蛋白,在炎性反应中起重要作用.局部浸润的炎性细胞、肾小球的巨噬细胞、系膜细胞都是COX-2的来源[1].维甲酸能抑制肾脏纤维化,保护肾功能[2],其主要包括全反式维甲酸(atRA),92顺式维甲酸和132顺式维甲酸.本研究探讨atRA对肾小球系膜细胞TGF-β-Smad信号通路中COX-2表达的影响.
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全反式维甲酸相关多药耐药机制及其逆转的研究进展
全反式维甲酸(All-trans retinoic acid,ATRA)是急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)有效的诱导分化剂,用于APL患者诱导分化治疗,完全缓解(complete recovery,CR)率可达85%~90%,其良好疗效已被国内外学者所公认.ATRA现已列为APL诱导缓解治疗的首选药物,且广泛用于其它恶性肿瘤的诱导分化治疗.ATRA使用后肿瘤细胞迅速出现的耐药现象,严重影响ATRA诱导分化治疗的疗效[1,2].因此,ATRA相关多药耐药已成为临床甚为棘手的问题.尽管一些可能的机制已经提出,但目前ATRA相关多药耐药的机制仍不十分清楚,且逆转其耐药的治疗策略仍未建立.为此,本文就这两方面的研究现状综述如下.
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全反式维甲酸治疗急性早幼粒细胞白血病发生阴囊溃疡1例
全反式维甲酸(all-trans retinoic acid,ATRA)作为治疗急性早幼粒细胞白血病(APL)的首选用药可使85%以上的APL患者获得完全缓解.但是,在治疗过程中会出现许多不良反应,其中阴囊溃疡的发生率较低,现将1例报道如下.
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急性早幼粒细胞白血病发病机制研究及药物治疗进展
急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)约占成人急性髓系白血病(acute myelocytic leukemia,AML)的10%,是临床上第一个应用诱导分化治疗取得显著疗效的人类恶性肿瘤.自从1986年我国首先使用全反式维甲酸(all-trans retinoic acid,ATRA)诱导治疗APL以来,随着对APL发病机制的深入研究,已有许多药物被证明对APL治疗有效,APL的疗效进一步改善.本文就APL发病机制研究现状及药物治疗进展作一综述.
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维甲酸预防和治疗肿瘤的作用机制的研究进展
维甲酸类化合物( retinoids)是一类维生素A衍生物,是一组与维生素A在结构上十分类似的化合物,其分子化学结构由苯环、多烯侧链和极性终末基因3个部分组成.根据结构的不同,将其分为三代:第一代为极性末端被不同基团取代;第二代为环状末端基团的改变;第三代是多烯肽侧链的改变,并由于羧基方向的不同而分为两种异构体,即顺式维甲酸(cis-retinoic acid,cis RA)及全反式维甲酸(all-trans retinoic acid,ATRA),其中全反式构型为稳定和常见.
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The Effect of Opsteoporotic Model Rats Induced by Retinoic Acid
Objective: To study the effect of retinoic acid on inducing osteoporosis in female rat. Methods: 48SD female rats were divided randomly into experiment group and control group. Retinoic acid was administered orally to experiment group with 80mg.kg-1d-1 for 15 days. Then the rats were sacrificed on the 0th, 30th, 60th days after last administration. The serum concentration of Ca, P, BGP, E2, AKP and TRAP were detected. Components of collagen and proteoglycan in the bones and BMD were also assayed .The femoral morphometric change and epiphyseal plate cartilage histological changes were observed. Results: After a 15-day period treatment with retinoic acid, charateristics of experiment group were compared with control, it is shown that the concentration of serum E2 and BGP declined, the activity of AKP and TRAP increased while BMP decreased, the bone mass of both spongy bone and cortical bone reduced, the number of spongy bone osteoclasts and their activity increased, number of epiphyseal plate chondrocyte reduced, cartilage hypertrophic zone displayed dyscalcification, and no difference of other markers was found in the two groups. On the 30th day after the last administration, the experiment group appeared a declined number of cancellous bone osteoclast and level of serum AKP yet they were still higher than control. Number of epiphyseal chondrocyte, serum BGP and tibial BMD, though higher than before, were still lower than control. Other markers were no difference. On the 60th day after treatment, although the femoral cancellous bone mass was still less and cancellous osteoblast was more than control, the cortical bone mass, cancellous osteoclast number and level of serum Ca and P were all remained no different between two groups.Conclusion: Retinoic acid possessed a better short-term effect than long-term effect. Cancellous bone loss lasted much longer than cortical bone and more obviously; the bone matrix in this osteoporosis model was able to repair itself gradually after withdrawal of retinoic acid.