• 【[非洲男性乳腺癌,与瓦加杜古大学教学医院 (布基纳法索) 的5例病例有关]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Sano D,Dao B,Lankoandé J,Touré B,Sakandé B,Traoré SS,Wandaogo A,Dakouré R,Sanou A
    BACKGROUND & AIMS: :A retrospective study of male breast cancer was undertaken at Ouagadougou University Teaching Hospital over a 3 year period (1993-1996). Authors report 5 cases representing 4.16% of all breast cancers. The patients' mean age was 61 years. The average duration of signs and symptoms before the diagnosis was 13 months. Clinically all the 5 cases presented advanced cancers (4 T4N2M0, 1 T4N2M1 according to UICC TNM System) with size ranging from 5.5, to 11.5 cm. Histology found: 2 medullary infiltrating carcinoma, 1 canalar infiltrating carcinoma, 1 colloid mucous carcinoma and 1 lobular infiltrating carcinoma. All patients had mastectomy associated with axillary clearance in 4 cases. Radiotherapy, chemotherapy and hormonotherapy were not associated because unavailable in Burkina Faso. Three patients died: the first, 10 days after surgical treatment and the 2 others respectively after 14 and 17 months. We have lost sight 1 patients. The last one is still alive. Authors find that to get better prognosis, it is important to improve medical and technical means, to increase information and to promote early detection.
    背景与目标: : 在瓦加杜古大学教学医院进行了为期3年 (1993-1996年) 的男性乳腺癌回顾性研究。作者报告了5例代表所有乳腺癌4.16% 的病例。患者的平均年龄为61岁。诊断前症状和体征的平均持续时间为13个月。临床上所有5例均表现为晚期癌症 (根据UICC TNM系统,4个T4N2M0,1个T4N2M1),大小从5.5到11.5厘米。组织学发现: 髓质浸润性癌2例,管内浸润性癌1例,胶体粘液性癌1例,小叶浸润性癌1例。所有患者均行乳房切除术伴腋窝清除4例。放疗,化疗和激素治疗不相关,因为在布基纳法索不可用。3例患者死亡: 手术治疗后第1、10天,另外2例分别在14和17个月后死亡。我们已经看不见1个病人了。最后一个还活着。作者发现,要获得更好的预后,必须改善医疗和技术手段,增加信息并促进早期发现。
  • 【一系列赛庚胺类似物的合成,对5-HT2A,5-HT2B和5-HT2C 5-羟色胺受体的亲和力和结构-活性关系。】 复制标题 收藏 收藏
    DOI:10.1248/cpb.45.842 复制DOI
    作者列表:Honrubia MA,Rodriguez J,Dominguez R,Lozoya E,Manaut F,Seijas JA,Villaverde MC,Calleja JM,Cadavid MI,Maayani S,Sanz F,Loza MI
    BACKGROUND & AIMS: :Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
    背景与目标: : 赛庚啶是一种对2型 (5-HT2) 受体显示高亲和力的药物。我们研究了通过修饰Cyp (二苯并环庚二烯) 的三环体系获得的一系列化合物: 2f (噻吩),2g (xanthene),2h (二氢二苯并环庚二烯),2j (二苯基),2i (芴) 和3b (苯基甲基)。它们在大鼠大脑皮层5-HT2A受体上的活性为 (pKi +/-s.e.M.): 8.80 +/- 0.11 (Cyp),8.60 +/- 0.07 (2f),8.40 +/- 0.02 (2g),8.05 +/- 0.03 (2h),7.87 +/- 0.12 (2j),6.70 +/- 0.02 (2i) 和6.45 +/- 0.02 (3b); 大鼠胃底5-HT2B受体 (pA2 +/-s.e.M.) 为: 9.14 +/- 0.25 (Cyp),8.49 +/- 0.07 (2f),7.58 +/- 0.58 (2g),7.02 +/- 0.14 (2h),6.07 +/- 0.20 (2j) 和不可检测 (2i,3b): 猪脉络丛5-HT2C受体 (pKi +/-s.e.M.) 为: 8.71 +/- 0.08 (Cyp),8.68 +/- 0.01 (2f),8.58 +/- 0.20 (2g),7.95 +/- 0.05 (2h) 、7.57 +/- 0.04 (2j) 、6.98 +/- 0.04 (2i) 和6.63 +/- 0.20 (3b)。坡度与统一没有显着差异。这些化合物在每种类型的受体上都表现出相同的活性顺序,并且最具活性的分子呈现某些空间 (三环系统的蝴蝶构象) 和静电 (中心环顶部的质子亲和力) 模式。结论是,赛庚啶衍生物在5-HT2受体上的活性与这些分子特征有关,这使得与所有三种5-HT2亚型相互作用的共同处置是可行的。
  • 【受体激活剂NFkappaB配体和骨保护素蛋白在人根尖周囊肿和肉芽肿中的表达。】 复制标题 收藏 收藏
    DOI:10.1016/j.tripleo.2005.10.054 复制DOI
    作者列表:Menezes R,Bramante CM,da Silva Paiva KB,Letra A,Carneiro E,Fernando Zambuzzi W,Granjeiro JM
    BACKGROUND & AIMS: OBJECTIVE:The purpose of this study was to determine the expression of receptor activator of NFkappaB ligand (RANKL) and osteoprotegerin (OPG) associated with bone destruction in periapical cysts and granulomas. STUDY DESIGN:Forty human dental chronic periapical lesions were collected after periapical surgery. The lesions collected were fixed in 10% buffered formalin and histologically processed. At least 2 sections of each specimen were stained with hematoxylin and eosin for microscopic diagnosis. After that, 10 human periapical granulomas and 10 cysts were selected for immunohistochemical analysis for RANKL, OPG, and CD68+. RESULTS:Polymorphonuclear neutrophils, macrophages, endothelial cells, and lymphocytes were stained for RANKL and OPG in both lesions. Epithelial cells were also stained for RANKL and OPG in periapical cysts. Quantitative analysis was conducted and the results were expressed as a ratio of the number of immunostained cells over the total number of cells in the field (n = 100). The ratio of RANKL+/total cells was higher than OPG+/total cells in periapical granulomas (0.553 +/- 0.153 and 0.483 +/- 0.189, respectively; P < .0012; paired t test) and in cysts (0.519 +/- 0.09 and 0.339 +/- 0.117, respectively; P < .0001; paired t test). The ratios of OPG+/total cells (P < .0001; paired t test) and RANKL+/total cells (P < .0322; paired t test) were greater in granulomas than in cysts. However, the ratio RANKL+/OPG+ in granulomas (1.336 +/- 0.723) and cysts (1.404 +/- 0.385) was not significantly different. The ratio of CD68+/total cells was significantly higher in granulomas (0.381 +/- 0.040) than in cysts (0.307 +/- 0.068) (P < .0001; unpaired t test with Welch correction). CONCLUSION:Taking into account the limitations of the experimental approach employed, our findings indicate the presence of RANKL and OPG in cysts and granulomas, strongly suggesting the involvement of these gene products in the development of periapical lesions.
    背景与目标:
  • 【大鼠I型清道夫受体 (SRBI) 在卵巢中的克隆,表征和细胞分布。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6646 复制DOI
    作者列表:Mizutani T,Sonoda Y,Minegishi T,Wakabayashi K,Miyamoto K
    BACKGROUND & AIMS: :An immediately inducible gene by gonadotropin was isolated from rat ovaries primed with pregnant mare serum gonadotropin (PMSG) by using a subtraction cloning procedure. Homology analysis revealed that the gene is a rat homologue of scavenger receptor class B-I, which was recently identified as a specific receptor for high density lipoprotein (HDL). The structure of rat SRBI was determined by nucleotide sequence analysis of full-length cDNAs for SRBI. Northern blot analysis revealed that rat SRBI mRNA levels were rapidly and strongly increased within 3 h by the injection of PMSG. In situ hybridization study revealed that SRBI mRNA was strongly induced in theca interna cells of immature rat ovary stimulated with 30 IU of PMSG for 6 h. SRBI mRNA expression was also observed in corpora lutea of the adult rat ovary. These findings indicate that expression of SRBI mRNA is restricted to and induced in the ovarian steroidogenic cell types where cholesterol is used as a substrate for synthesis of steroid hormones. Our data strongly suggest that SRBI may play a significant role in the ovarian steroidogenesis by mediating selective uptake of cholesterol from HDL to ovarian theca interna cells or to corpus luteum.
    背景与目标: : 使用减法克隆程序从用妊娠母马血清促性腺激素 (PMSG) 引发的大鼠卵巢中分离出促性腺激素立即诱导的基因。同源性分析表明,该基因是清道夫受体B-I类的大鼠同源物,最近被鉴定为高密度脂蛋白 (HDL) 的特异性受体。通过SRBI全长cdna的核苷酸序列分析确定大鼠SRBI的结构。Northern印迹分析显示,通过注射PMSG,大鼠SRBI mRNA水平在3小时内迅速且强烈地增加。原位杂交研究表明,用30 IU的PMSG刺激6 h,在未成熟大鼠卵巢的卵泡膜细胞中强烈诱导SRBI mRNA。在成年大鼠卵巢的黄体中也观察到了SRBI mRNA的表达。这些发现表明,SRBI mRNA的表达仅限于并在其中胆固醇用作合成类固醇激素的底物的卵巢类固醇生成细胞类型中诱导。我们的数据强烈表明,SRBI可能通过介导胆固醇从HDL到卵巢卵泡膜细胞或黄体的选择性摄取而在卵巢类固醇生成中起重要作用。
  • 【细菌基因lfpA影响Burkholderia pseudomalei诱导的TRAP阳性多核巨细胞中降钙素受体和破骨细胞相关基因的有效诱导。】 复制标题 收藏 收藏
    DOI:10.1111/j.1462-5822.2006.00807.x 复制DOI
    作者列表:Boddey JA,Day CJ,Flegg CP,Ulrich RL,Stephens SR,Beacham IR,Morrison NA,Peak IR
    BACKGROUND & AIMS: :Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis, a spectrum of potentially fatal diseases endemic in Northern Australia and South-East Asia. We demonstrate that B. pseudomallei rapidly modifies infected macrophage-like cells in a manner analagous to osteoclastogenesis. These alterations include multinucleation and the expression by infected cells of mRNA for factors required for osteoclastogenesis: the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 gamma (MIP-1gamma), 'regulated on activation normal T cell expressed and secreted' (RANTES) and the transcription factor 'nuclear factor of activated T-cells cytoplasmic 1' (NFATc1). An increase in expression of these factors was also observed after infection with Burkholderia thailandensis. Expression of genes for the osteoclast markers calcitonin receptor (CTR), cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) was also increased by B. pseudomallei-infected, but not by B. thailandensis-infected cells. The expression by B. pseudomallei-infected cells of these chemokine and osteoclast marker genes was remarkably similar to cells treated with RANKL, a stimulator of osteoclastogenesis. Analysis of dentine resorption by B. pseudomallei-induced osteoclast-like cells revealed that demineralization may occur but that authentic excavation does not take place under the tested conditions. Furthermore, we identified and characterized lfpA (for lactonase family protein A) in B. pseudomallei, which shares significant sequence similarity with the eukaryotic protein 'regucalcin', also known as 'senescence marker protein-30' (SMP-30). LfpA orthologues are widespread in prokaryotes and are well conserved, but are phylogenetically distinct from eukaryotic regucalcin orthologues. We demonstrate that lfpA mRNA expression is dramatically increased in association with macrophage-like cells. Mutation of lfpA significantly reduced expression of the tested host genes, relative to the response to wild-type B. pseudomallei. We also show that lfpA is required for optimal virulence in vivo.
    背景与目标: : pseudomalei伯克霍尔德菌是一种兼性细胞内病原体,也是类鼻疽病的病原体,类鼻疽是澳大利亚北部和东南亚流行的一系列潜在致命疾病。我们证明假单胞菌以类似于破骨细胞发生的方式快速修饰感染的巨噬细胞样细胞。这些改变包括破骨细胞形成所需的因子的多核和感染细胞的mRNA表达: 趋化因子单核细胞趋化蛋白1 (MCP-1),巨噬细胞炎性蛋白1 γ (MIP-1gamma),“调节活化正常T细胞表达和分泌” (RANTES) 和转录因子 “活化T细胞胞质核因子1” (NFATc1)。感染泰国伯克霍尔德菌后,还观察到这些因子的表达增加。破骨细胞标记物降钙素受体 (CTR),组织蛋白酶K (CTSK) 和耐酒石酸酸性磷酸酶 (TRAP) 的基因表达也被假假性芽孢杆菌感染的细胞增加,但未被泰国芽孢杆菌感染的细胞增加。这些趋化因子和破骨细胞标记基因的假假单胞菌感染细胞的表达与用破骨细胞生成刺激物RANKL处理的细胞非常相似。假单胞菌诱导的破骨细胞样细胞对牙本质的吸收分析表明,可能会发生脱矿质,但在测试条件下不会发生真正的挖掘。此外,我们在假单胞菌中鉴定并鉴定了lfpA (用于内酯酶家族蛋白A),该蛋白与真核蛋白 “regucalin” (也称为 “衰老标记蛋白-30” (SMP-30)) 具有显着的序列相似性。LfpA直系同源物在原核生物中广泛存在,并且保存良好,但在系统发育上与真核生物regucalcin直系同源物不同。我们证明lfpA mRNA表达与巨噬细胞样细胞相关显着增加。相对于对野生型B.Pseudomalei的反应,lfpA的突变显着降低了所测试宿主基因的表达。我们还表明,lfpA是体内最佳毒力所必需的。
  • 【MacMARCKS与代谢型谷氨酸受体7型相互作用,并调节g蛋白介导的钙通道组成型抑制。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.2006.04121.x 复制DOI
    作者列表:Bertaso F,Lill Y,Airas JM,Espeut J,Blahos J,Bockaert J,Fagni L,Betz H,El-Far O
    BACKGROUND & AIMS: :We have previously shown that the interaction of Ca2+/calmodulin with the metabotropic glutamate receptor type 7 (mGluR7) promotes the G-protein-mediated inhibition of voltage-sensitive Ca2+ channels (VSCCs) seen upon agonist activation. Here, we performed a yeast two-hybrid screen of a new-born rat brain cDNA library using the cytoplasmic C-terminal tail of mGluR7 as bait and identified macrophage myristoylated alanine-rich c-kinase substrate (MacMARCKS) as a binding protein. The interaction was confirmed in vitro and in vivo by pull-down assays, immunoprecipitation, and colocalization of mGluR7 and MacMARCKS in transfected HEK293 cells and cultured cerebellar granule cells. Binding of MacMARCKS to mGluR7 was antagonized by Ca2+/calmodulin. In neurons, cotransfection of MacMARCKS with mGluR7, but not mGluR7 mutants unable to bind MacMARCKS, reduced the G-protein-mediated tonic inhibition of VSCCs in the absence of mGluR7 agonist. These results suggest that competitive interactions of Ca2+/calmodulin and MacMARCKS with mGluR7 control the tonic inhibition of VSCCs by G-proteins.
    背景与目标: : 我们以前已经表明,Ca2/钙调蛋白与代谢型谷氨酸受体7 (mGluR7) 的相互作用促进了g蛋白介导的对激动剂激活后看到的电压敏感Ca2通道 (vscc) 的抑制。在这里,我们使用mGluR7的细胞质C末端尾巴作为诱饵进行了新生大鼠脑cDNA文库的酵母双杂交筛选,并确定了巨噬细胞肉豆蔻基化的富含丙氨酸的c激酶底物 (MacMARCKS) 作为结合蛋白。通过下拉测定,免疫沉淀以及mGluR7和MacMARCKS在转染的HEK293细胞和培养的小脑颗粒细胞中的共定位,在体外和体内证实了相互作用。Ca2 +/钙调蛋白拮抗MacMARCKS与mGluR7的结合。在神经元中,在没有mGluR7激动剂的情况下,MacMARCKS与mGluR7共转染,但不能与MacMARCKS结合的mGluR7突变体,降低了g蛋白介导的VSCCs的强直抑制。这些结果表明,Ca2/钙调蛋白和MacMARCKS与mGluR7的竞争性相互作用控制了g蛋白对VSCCs的强直抑制。
  • 【对AUG和替代引发剂密码子的识别在4位的G中增加,但通常不受5位和6位核苷酸的影响。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.9.2482 复制DOI
    作者列表:Kozak M
    BACKGROUND & AIMS: A primer extension (toeprinting) assay was used to monitor selection by ribosomes of the first versus the second AUG codon as a function of introducing mutations on the 3' side (positions +4, +5 and +6) of the first AUG codon. Six different flanking codons starting with G (GCG, GCU, GCC, GCA, GAU and GGA) strongly augmented selection of AUG#1 when compared with matched mRNAs that had A or C instead of G in position +4. Augmentation by G in position +4 failed only when it was combined with U in position +5, as in the sequence augGUA. In contrast with the usual enhancing effect of introducing G in position +4, most mutations in position +5 had no discernible effect, as shown with the series augANA (where N = C, A, G or U) and the series augCNA. AUG codon recognition was also unaffected by mutations in position +6, as shown by testing four mRNAs that had augCCN as the start site. Thus the primary sequence context that augments the recognition of AUG start codons does not appear generally to extend beyond G in position +4. When the toeprinting assay was used with mRNAs that initiate translation at CUG instead of AUG, cugGAU was not recognized better than cugGGU, contradicting the hypothesis that initiation at non-AUG codons might be favored by A instead of G in position +5.

    背景与目标: 引物延伸 (toeprinting) 测定法用于监测第一个AUG密码子与第二个AUG密码子的核糖体选择,这是在第一个AUG密码子的3' 侧 (位置4、5和6) 引入突变的函数。与在4位具有A或C而不是G的匹配mrna相比,以G开头的六个不同的侧翼密码子 (GCG,GCU,GCC,GCA,GAU和GGA) 强烈增强了AUG #1的选择。仅当G在位置4与U在位置5结合时,G的增强才失败,如序列augGUA所示。与通常在4位引入G的增强作用相反,5位的大多数突变没有明显的作用,如augANA系列 (其中N = C,A,G或U) 和augCNA系列所示。AUG密码子识别也不受6位突变的影响,如测试四个以augCCN为起始位点的mrna所示。因此,增强对AUG起始密码子的识别的主要序列上下文通常不会扩展到4位中的G以外。当toeprinting测定法与在CUG而不是AUG启动翻译的mrna一起使用时,cugGAU的识别并不比cugGGU更好,这与以下假设相矛盾: A而不是G在5位可能有利于非AUG密码子启动。
  • 【Interseptin调节表皮生长因子受体内吞作用,泛素化和信号传导。】 复制标题 收藏 收藏
    DOI:10.1124/mol.106.028274 复制DOI
    作者列表:Martin NP,Mohney RP,Dunn S,Das M,Scappini E,O'Bryan JP
    BACKGROUND & AIMS: :Receptor tyrosine kinases (RTKs) are critical for normal cell growth, differentiation, and development, but they contribute to various pathological conditions when disrupted. Activation of RTKs stimulates a plethora of pathways, including the ubiquitylation and endocytosis of the receptor itself. Although endocytosis terminates RTK signaling, it has emerged as a requisite step in RTK activation of signaling pathways. We have discovered that the endocytic scaffolding protein intersectin (ITSN) cooperated with epidermal growth factor receptor (EGFR) in the regulation of cell growth and signaling. However, a biochemical link between ITSN and EGFR was not defined. In this study, we demonstrate that ITSN is a scaffold for the E3 ubiquitin ligase Cbl. ITSN forms a complex with Cbl in vivo mediated by the Src homology (SH) 3 domains binding to the Pro-rich COOH terminus of Cbl. This interaction stimulates the ubiquitylation and degradation of the activated EGFR. Furthermore, silencing ITSN by RNA interference attenuated EGFR internalization as well as activation of the extracellular signal-regulated kinasemitogen-activated protein kinase pathway, thereby demonstrating the importance of ITSN in EGFR function. Given the cooperativity between ITSN and additional RTKs, these results point to an important evolutionarily conserved, regulatory role for ITSN in RTK function that is necessary for both signaling from receptors as well as the ultimate termination of receptor signaling.
    背景与目标: 受体酪氨酸激酶 (rtk) 对于正常的细胞生长,分化和发育至关重要,但是当它们被破坏时,它们会导致各种病理状况。RTKs的激活刺激了多种途径,包括受体本身的泛素化和内吞作用。尽管胞吞作用终止了RTK信号传导,但它已成为RTK激活信号传导途径的必要步骤。我们发现,内吞支架蛋白intersectin (ITSN) 与表皮生长因子受体 (EGFR) 配合调节细胞生长和信号传导。然而,ITSN和EGFR之间的生化联系尚未确定。在这项研究中,我们证明了ITSN是E3泛素连接酶Cbl的支架。ITSN通过与Cbl的富含前COOH末端结合的Src同源 (SH) 3结构域在体内与Cbl形成复合物。这种相互作用刺激活化的EGFR的泛素化和降解。此外,通过RNA干扰沉默ITSN减弱了EGFR的内在化以及细胞外信号调节的激酶原激活蛋白激酶途径的激活,从而证明了ITSN在EGFR功能中的重要性。鉴于ITSN和其他RTK之间的协同作用,这些结果表明ITSN在RTK功能中具有重要的进化保守调节作用,这对于受体的信号传导以及受体信号传导的最终终止都是必需的。
  • 【正常年轻和老年妇女肠道维生素d受体,钙吸收和血清1,25二羟基维生素d之间的关系。】 复制标题 收藏 收藏
    DOI:10.1359/jbmr.1997.12.6.922 复制DOI
    作者列表:Kinyamu HK,Gallagher JC,Prahl JM,DeLuca HF,Petranick KM,Lanspa SJ
    BACKGROUND & AIMS: The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25-35 years were compared with 41 elderly women age 65-83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12-30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

    背景与目标: 随着年龄的增长,肠道钙吸收减少的确切机制尚不清楚。血清1,25-二羟基维生素d (1,25(OH)2D) 随着年龄的增长而降低或肠道维生素d受体 (VDR) 蛋白浓度降低是可能的原因。这项研究的目的是检查年龄对这些因素的影响。将59名年龄在25-35岁之间的年轻女性与41名年龄在65-83岁之间的老年女性进行了比较,这些女性接受了VDR,使用20 mg和100 mg钙载体的钙吸收以及钙促激素的测量。与年轻女性相比,老年女性两种测试对钙的吸收均较低 (p <0.05)。血清1,25(OH)2D和十二指肠VDR蛋白浓度在两个年龄组之间没有显着差异。血清1,25(OH)2D与青年 (r = 0.35,p <0.007) 和老年妇女 (r = 0.58,p <0.0001) 的20 mg钙吸收试验相关,与老年人的100 mg钙吸收相关 (r = 0.32; p <0.05)。VDR与年轻女性或老年女性的钙吸收无关,也与血清1,25(OH)2D和血清25-羟基维生素d无关。总而言之,钙吸收的减少不能用肠道VDR的减少来解释。血清1,25(OH)2D与两种钙吸收测试之间的相关性仅占钙吸收测试中年龄相关变化的12-30%。其他尚未了解的因素是钙吸收随年龄下降的原因。
  • 【人ADP-核糖基化因子5 (ARF5) 基因的定位和表征。】 复制标题 收藏 收藏
    DOI:10.1006/geno.1997.4689 复制DOI
    作者列表:McGuire RE,Daiger SP,Green ED
    BACKGROUND & AIMS: ADP-ribosylation factor 5 (ARF5) is a member of the ARF gene family. The ARF proteins stimulate the in vitro ADP-ribosyltransferase activity of cholera toxin and appear to play a role in vesicular trafficking in vivo. We have mapped ARF5, one of the six known mammalian ARF genes, to a well-defined yeast artificial chromosome contig on human chromosome 7q31.3. In addition, we have isolated and sequenced an approximately 3.2-kb genomic segment that contains the entire ARF5 coding region, revealing the complete intron-exon structure of the gene. With six coding exons and five introns, the genomic structure of ARF5 is unique among the mammalian ARF genes and provides insight about the evolutionary history of this ancient gene family.

    背景与目标: ADP-核糖基化因子5 (ARF5) 是ARF基因家族的成员之一。ARF蛋白刺激霍乱毒素的体外ADP-核糖基转移酶活性,并似乎在体内囊泡运输中起作用。我们已经将ARF5 (六个已知的哺乳动物ARF基因之一) 映射到人类7q31.3染色体上定义明确的酵母人工染色体重叠群。此外,我们已经分离并测序了包含整个ARF5编码区的约3.2 kb基因组片段,揭示了该基因的完整内含子-外显子结构。具有六个编码外显子和五个内含子,ARF5的基因组结构在哺乳动物ARF基因中是独特的,并提供了有关该古老基因家族进化历史的见解。
  • 【表皮生长因子受体靶向分子治疗头颈部鳞状细胞癌。】 复制标题 收藏 收藏
    DOI:10.1517/14728222.10.5.639 复制DOI
    作者列表:Egloff AM,Grandis J
    BACKGROUND & AIMS: :Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.
    背景与目标: : 几种分子靶向疗法已在治疗头颈部鳞状细胞癌 (HNSCC) 的临床试验中进行了测试。其中,针对表皮生长因子受体 (EGFR) 的疗法已被最广泛地研究,并且一些药物已证明可测量的临床有效性。然而,旨在定义可能对EGFR靶向治疗有反应的HNSCC患者亚组的分子研究尚未确定与临床反应相关的分子特征。在这里,作者总结了相关的临床发现,并重点报道了针对HNSCC的EGFR靶向治疗的分子相关研究。作者特别关注评估与临床反应相关的分子标志物,并包括来自其他癌症部位的EGFR靶向临床研究的数据,他们预计头颈癌症研究和治疗社区将对此感兴趣。
  • 【内源性interleukin-1受体拮抗剂具有神经保护作用。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6436 复制DOI
    作者列表:Loddick SA,Wong ML,Bongiorno PB,Gold PW,Licinio J,Rothwell NJ
    BACKGROUND & AIMS: Interleukin-1 (IL-1) has been implicated in chronic and acute cerebral neuropathologies. IL-1 receptor antagonist (IL-1ra), a naturally occurring protein that binds to IL-1 receptors without inducing signal transduction, blocks several actions of IL-1. IL-1ra acts at the local level and it also circulates in the bloodstream. We now report evidence for a biological function of IL-1ra in the brain as an endogenous neuroprotective molecule. Cerebral expression of IL-1ra mRNA is induced rapidly by focal cerebral ischemia in rats, and inhibition of the action of IL-1ra, by passive immuno-neutralization, markedly enhances ischemic damage. To our knowledge this is the first report of an action of endogenous IL-1ra in the brain. Control of IL-1ra expression or action may therefore provide a useful therapeutic strategy to limit acute neurodegeneration.

    背景与目标: Interleukin-1 (IL-1) 与慢性和急性脑神经病变有关。IL-1受体拮抗剂 (IL-1ra) 是一种天然存在的蛋白质,与IL-1受体结合而不诱导信号转导,可阻断IL-1的多种作用。IL-1ra在地方一级起作用,它也在血液中循环。我们现在报告了IL-1ra作为内源性神经保护分子在大脑中的生物学功能的证据。大鼠局灶性脑缺血可迅速诱导IL-1ra mRNA的表达,而通过被动免疫中和抑制IL-1ra的作用可显着增强缺血损伤。据我们所知,这是大脑内源性IL-1ra作用的第一份报告。因此,控制IL-1ra表达或作用可能会提供一种有用的治疗策略,以限制急性神经变性。
  • 【N1-Benzoyl-N2-[1-(1-萘基) 乙基]-trans-1,2-二氨基环己烷: 4-氯苯基甲酰胺 (calhex 231) 作为新的钙感应受体配体的开发,证明了有效的钙分解活性。】 复制标题 收藏 收藏
    DOI:10.1021/jm051233+ 复制DOI
    作者列表:Kessler A,Faure H,Petrel C,Rognan D,Césario M,Ruat M,Dauban P,Dodd RH
    BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.
    背景与目标: : 主要在N1-arylsulfonyl-N2-[1-(1-萘基) 乙基]-trans-1,2-二氨基环己烷的N1位置进行了构效关系 (SAR) 研究,作用于钙感应受体 (CaSR) 的新的钙离子家族。该系列中最具活性的化合物是4-(三氟甲氧基) 苯磺酰基衍生物7e,在表达CaSR的中国仓鼠卵巢 (CHO) 细胞中,对钙诱导的tri化肌醇磷酸 ([3H]IP) 积累的抑制作用显示出5.4/- 0.5微米的IC50。用甲酰胺代替该化合物的磺酰胺键导致6倍活动增加 (7m,IC50 = 0.9 +/- 0.2微米)。在合成的甲酰胺中,最具活性的化合物之一是4-氯苯基甲酰胺 (1S,2S,1'R)-7n (Calhex 231,IC50 = 0.33 +/- 0.02微米)。(1S,2S,1'R)-7n是根据对化合物7d的非对映异构体之一的x射线晶体学研究得出的。(1S,2S,1'R)-异构体可以在CaSR的煅烧结合袋的三维模型的基础上合理化。C-1甲基的去除或2-萘基或联苯部分取代1-萘基导致煅烧活性的明显损失。化合物7e,7m,并且Calhex 231不刺激表达或不表达CaSR的CHO细胞中的 [3H]IP积累。
  • 【粒细胞集落刺激因子优先刺激带有同工型IV受体的7号单体细胞的增殖。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0605245103 复制DOI
    作者列表:Sloand EM,Yong AS,Ramkissoon S,Solomou E,Bruno TC,Kim S,Fuhrer M,Kajigaya S,Barrett AJ,Young NS
    BACKGROUND & AIMS: :Granulocyte colony-stimulating factor (GCSF) administration has been linked to the development of monosomy 7 in severe congenital neutropenia and aplastic anemia. We assessed the effect of pharmacologic doses of GCSF on monosomy 7 cells to determine whether this chromosomal abnormality developed de novo or arose as a result of favored expansion of a preexisting clone. Fluorescence in situ hybridization (FISH) of chromosome 7 was used to identify small populations of aneuploid cells. When bone marrow mononuclear cells from patients with monosomy 7 were cultured with 400 ng/ml GCSF, all samples showed significant increases in the proportion of monosomy 7 cells. In contrast, bone marrow from karyotypically normal aplastic anemia, myelodysplastic syndrome, or healthy individuals did not show an increase in monosomy 7 cells in culture. In bone marrow CD34 cells of patients with myelodysplastic syndrome and monosomy 7, GCSF receptor (GCSFR) protein was increased. Although no mutation was found in genomic GCSFR DNA, CD34 cells showed increased expression of the GCSFR class IV mRNA isoform, which is defective in signaling cellular differentiation. GCSFR signal transduction via the Jak/Stat system was abnormal in monosomy 7 CD34 cells, with increased phosphorylated signal transducer and activation of transcription protein, STAT1-P, and increased STAT5-P relative to STAT3-P. Our results suggest that pharmacologic doses of GCSF increase the proportion of preexisting monosomy 7 cells. The abnormal response of monosomy 7 cells to GCSF would be explained by the expansion of undifferentiated monosomy 7 clones expressing the class IV GCSFR, which is defective in signaling cell maturation.
    背景与目标: : 粒细胞集落刺激因子 (GCSF) 的施用与严重先天性中性粒细胞减少症和再生障碍性贫血中7号单体的发展有关。我们评估了GCSF的药理剂量对7号单体细胞的影响,以确定这种染色体异常是从头出现还是由于预先存在的克隆的有利扩增而出现的。7号染色体的荧光原位杂交 (FISH) 用于鉴定非整倍体细胞的小群体。当用400 ng/ml GCSF培养来自7号单体患者的骨髓单个核细胞时,所有样品均显示7号单体细胞的比例显着增加。相反,来自核型正常再生障碍性贫血,骨髓增生异常综合征或健康个体的骨髓在培养物中未显示出7号单体细胞的增加。在骨髓增生异常综合征和7号单体患者的骨髓CD34细胞中,GCSF受体 (GCSFR) 蛋白升高。尽管在基因组GCSFR DNA中未发现突变,但CD34细胞显示GCSFR IV类mRNA同工型的表达增加,这在信号细胞分化方面存在缺陷。通过Jak/Stat系统的GCSFR信号转导在7号CD34单体细胞中异常,磷酸化信号转导增加,转录蛋白激活,STAT1-P,相对于STAT3-P,STAT5-P增加。我们的结果表明,GCSF的药理剂量增加了先前存在的7号单体细胞的比例。7号单体细胞对GCSF的异常反应可以通过表达IV类GCSFR的未分化的7号单体克隆的扩增来解释,后者在信号细胞成熟方面存在缺陷。
  • 【MEN15596,一种新型的非肽速激肽NK2受体拮抗剂。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.08.021 复制DOI
    作者列表:Cialdai C,Tramontana M,Patacchini R,Lecci A,Catalani C,Catalioto RM,Meini S,Valenti C,Altamura M,Giuliani S,Maggi CA
    BACKGROUND & AIMS: :The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2
    背景与目标: : 描述了MEN15596或 (6-甲基-苯并 [b]thiophene-2-carboxylic [1-(2-苯基-1r-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-氨基甲酰基}-乙基氨基甲酰基)-环戊基]-酰胺) 的药理学特征,一种具有口服活性的新型有效和选择性速激肽NK2受体拮抗剂。在人重组速激肽NK2受体上,MEN15596显示亚纳摩尔亲和力 (pKi 10.1),并有效拮抗 (pKB 9.1) 神经激肽A诱导的细胞内钙释放。MEN15596对速激肽NK2受体的选择性通过在重组速激肽NK1 (pKi 6.1) 和NK3 (pKi 6.4) 受体以及在包括受体、转运蛋白和离子通道在内的许多34个分子靶标上的结合研究来评估。在分离的平滑肌制剂中,MEN15596在速激肽NK2受体上显示出明显的物种选择性,在豚鼠结肠,人和猪膀胱中具有最高的拮抗剂效力 (pKB 9.3,9.2和8.8,分别),而在大鼠和小鼠膀胱中效力降低了三个数量级 (分别为pKB 6.3和5.8)。与结合实验一致,MEN15596在阻断选择性NK1或NK3受体激动剂诱导的豚鼠回肠制剂收缩 (pA2 <或 = 6) 方面表现出较低的效力。在麻醉的豚鼠中,MEN15596以剂量相关且持续的方式抑制由选择性速激肽NK2受体激动剂 [betaAla8] 神经激肽a (4-10) (3 nmol/kg静脉注射) 诱导的结肠收缩 (ED50 0.18 micromol/kg),十二指肠内 (ED50 3.16微摩尔/千克) 或口服给药 (10-30微摩尔/千克),不影响NK1受体选择性激动剂 [Sar9] 物质P砜 (3 nmol/千克) 产生的结肠收缩。此外,MEN15596可有效抑制静脉注射引起的支气管收缩。[Βala8] 神经激肽A(4-10) 的给药。总体而言,结果表明MEN15596是一种有效的选择性速激肽NK2受体拮抗剂,对豚鼠,猪和人受体具有高亲和力和效力,在体内实验中作用时间长,口服生物利用度好。

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