• 【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。
  • 【HIV-1血清阳性北印第安人TIM-1外显子4单倍型和CD4 + T细胞计数状况。】 复制标题 收藏 收藏
    DOI:10.1016/j.humimm.2012.11.013 复制DOI
    作者列表:Sharma G,Ohtani H,Kaur G,Naruse TK,Sharma SK,Vajpayee M,Kimura A,Mehra N
    BACKGROUND & AIMS: :The TIM (T cell/transmembrane, immunoglobulin and mucin) proteins are crucial regulators of Th1/Th2 immune responses and have been implicated in several diseases including HIV-1/AIDS. The TIM1 exon 4 that codes for mucin domain is highly diverse, with sequence variants associated with varying phenotypes. In this study, TIM1 exon 4 was sequenced among 227 HIV-1 seroprevalent and 288 healthy non infected individuals from North Indian population and haplotypes established. A novel but rare haplotype D1(∗) was identified among the healthy and differed from D1 by a synonymous substitution G>T at Thr208Thr. The TIM1 haplotype diversity showed no association with susceptibility to HIV-1 infection. The seroprevalent individuals carrying D3A had relatively higher median CD4+T cell counts (368/μl) than those without (313/μl; p=0.02). A comparison of CD4+T counts between D3-A individuals on ART or ART naïve did not show any significant difference plausibly due to confounding nature of ART and other factors.
    背景与目标: : TIM (T细胞/跨膜,免疫球蛋白和粘蛋白) 蛋白是Th1/Th2免疫反应的关键调节剂,并与包括HIV-1/艾滋病在内的多种疾病有关。编码粘蛋白结构域的TIM1外显子4是高度多样化的,其序列变异与不同的表型相关。在这项研究中,TIM1外显子4在来自北印度人群的227 HIV-1血清阳性和288健康的非感染个体中进行了测序,并建立了单倍型。在健康人群中发现了一种新颖但罕见的单倍型D1(∗),与D1的区别在于Thr208Thr的同义替换G>T。TIM1单倍型多样性与HIV-1感染的易感性无关。携带D3A的血清复价个体的CD4 + T细胞中位数计数 (368/μ l) 相对高于不携带的个体 (313/μ l; p = 0.02)。由于ART的混杂性质和其他因素,对ART或ART天真的D3-A个体之间的CD4 T计数进行比较并未显示出任何显着差异。
  • 【用负载乳酸菌的树状大分子-G(4)-PAMAM-FITC索拉非尼靶向人肝癌细胞。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijpharm.2017.06.049 复制DOI
    作者列表:Iacobazzi RM,Porcelli L,Lopedota AA,Laquintana V,Lopalco A,Cutrignelli A,Altamura E,Di Fonte R,Azzariti A,Franco M,Denora N
    BACKGROUND & AIMS: :Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.
    背景与目标: : 此处报道的是载有索拉非尼的靶向第四代丙酰胺胺树状分子 (G(4)-PAMAM) 的去唾液酸糖蛋白受体 (asgp-r) 的合成和生物学评估。通过将乳糖酸 (La) 与G(4)-PAMAM树状大分子偶联,然后对游离氨基进行乙酰化 (Ac) 以减少非特异性相互作用,从而获得asgp-r靶向的树状大分子细胞膜。此外,通过另外接枝荧光素 (FITC),很容易表征目标树状分子Ac-La-G(4)-PAMAM-FITC的内化途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验允许研究树状大分子影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实,与未表达的HLE细胞相比,Ac-La-G(4)-PAMAM-FITC树状聚合物在分化良好且表达asgp-r的人肝癌细胞系HepG-2更高的结合和摄取能力。载有索拉非尼的Ac-La-G(4)-PAMAM-FITC树枝状大分子稳定,并显示出持续的索拉非尼释放。正如细胞毒性研究所证明的那样,与摩尔当量剂量的游离索拉非尼相比,包含在树枝状聚合物中的索拉非尼保持了其有效性,并且能够在一段时间内产生更长的持久效果。这种新的靶向树枝状聚合物似乎是将索拉非尼递送到表达asgp-r的肝癌细胞的合适载体。
  • 【DPP-4抑制剂利格列汀可抵消正常和糖尿病小鼠大脑中的中风: 与格列美脲的比较。】 复制标题 收藏 收藏
    DOI:10.2337/db12-0988 复制DOI
    作者列表:Darsalia V,Ortsäter H,Olverling A,Darlöf E,Wolbert P,Nyström T,Klein T,Sjöholm Å,Patrone C
    BACKGROUND & AIMS: :Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.
    背景与目标: : 2型糖尿病是中风的重要危险因素。利格列汀是临床抗2型糖尿病的二肽peptidase-4 (DPP-4) 抑制剂。这项研究的目的是确定利格列汀在2型糖尿病小鼠中的潜在抗中风功效。为了了解疗效是否由血糖调节介导,与磺酰脲类格列美脲进行了比较。为了确定利格列汀介导的疗效是否取决于糖尿病背景,在非糖尿病小鼠中进行了实验。通过给小鼠喂食高脂饮食32周而诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。短暂性大脑中动脉闭塞在治疗4周时诱发中风。在整个实验中评估血液DPP-4活性,胰高血糖素样肽-1 (GLP-1) 水平,葡萄糖,体重和食物摄入量。通过确定中风量和纹状体/皮质中存活神经元的立体定量来测量缺血性脑损伤。我们显示了利格列汀在2型糖尿病和正常小鼠中的明显抗中风功效,而格列美脲仅在正常小鼠中被证明对中风有效。这些结果表明利格列汀介导的神经保护作用是不依赖葡萄糖的并且可能涉及GLP-1。这些发现可能为糖尿病患者预防和治疗中风的DPP-4抑制剂的开发提供动力。
  • 【4 '-O-甲基化类黄酮在B16F10黑色素瘤细胞中诱导黑素生成。】 复制标题 收藏 收藏
    DOI:10.1007/s11418-012-0727-y 复制DOI
    作者列表:Horibe I,Satoh Y,Shiota Y,Kumagai A,Horike N,Takemori H,Uesato S,Sugie S,Obata K,Kawahara H,Nagaoka Y
    BACKGROUND & AIMS: :Agents to control melanogenesis are in demand for the development of cosmetics to improve pigmentation disorders of skin and hair. In this study, we examined and evaluated the effects of flavonoids on melanogenesis in the melanogenic cells model, murine B16F10 melanoma cells. In the course of this study, we found that incubation of the cells in a medium containing 10 μM of the 4'-O-methylated flavonoids, diosmetin (4'-O-methylluteolin), acacetin (4'-O-methylapigenin) or kaempferide (4'-O-methylkaempferol), increased the melanin contents of the cells 3- to 7-fold higher than the control cells. The concentration-dependence test revealed that 20 μM acacetin showed the highest effect, up to 33-fold higher than the vehicle. On the other hand, the corresponding 4'-OH-type flavonoids, luteolin, apigenin and kaempferol, had a significantly smaller effect. Furthermore, by evaluating the melanogenic proteins, we found that the cells treated with 4'-O-methylated flavonoids showed higher tyrosinase activity, as well as upregulation of tyrosinase expression, preceded by activation of cAMP response element binding protein (CREB) and extracellular signal-regulated kinases types 1 and 2 (ERK1/2). These results indicate that the 4'-O-methyl group of flavonoids plays an important role in the induction of melanogenesis by activating its major signal transduction pathway through the upregulation of phospho-CREB in murine B16F10 melanoma cells.
    背景与目标: : 控制黑素生成的药物是化妆品开发的需求,以改善皮肤和头发的色素沉着疾病。在这项研究中,我们检查并评估了类黄酮对黑色素生成细胞模型鼠B16F10黑素瘤细胞中黑色素生成的影响。在这项研究的过程中,我们发现细胞在含有10μm的4 '-O-甲基化类黄酮,地奥美汀 (4'-O-methylluteolin),acacetin (4 '-O-methyapigenin) 或kaempferide (4'-O-methylameferol),使细胞的黑色素含量比对照细胞高3至7倍。浓度依赖性测试表明,20μm acacetin的效果最高,比媒介物高33倍。另一方面,相应的4 '-OH型类黄酮木犀草素,芹菜素和山奈酚的作用明显较小。此外,通过评估黑素蛋白,我们发现用4 '-O-甲基化类黄酮处理的细胞显示出更高的酪氨酸酶活性以及酪氨酸酶表达的上调,在激活cAMP反应元件结合蛋白 (CREB) 和细胞外信号调节激酶类型1和2 (ERK1/2) 之前。这些结果表明,类黄酮的4 '-O-甲基通过上调小鼠B16F10黑素瘤细胞的磷酸化CREB激活其主要信号转导途径,在黑素生成的诱导中起重要作用。
  • 【设计和发现新的 (3S,5R)-5-[4-(2-氯苯基)-2,2-二甲基-5-氧代哌嗪-1-基] piperidine-3-carboxamides作为有效的肾素抑制剂。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.09.103 复制DOI
    作者列表:Mori Y,Ogawa Y,Mochizuki A,Nakamura Y,Sugita C,Miyazaki S,Tamaki K,Matsui Y,Takahashi M,Nagayama T,Nagai Y,Inoue S,Nishi T
    BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
    背景与目标: : 利用x射线晶体结构分析,设计了 (3S,5R)-5-[4-(2-氯苯基)-2,2-二甲基-5-氧代哌嗪-1-基] piperidine-3-carboxamides,并鉴定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。
  • 【2-取代-4-(3 ',4',5 '-三甲氧基苯基)-5-芳基噻唑类抗癌剂的合成及生物学评价。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.001 复制DOI
    作者列表:Romagnoli R,Baraldi PG,Salvador MK,Camacho ME,Preti D,Tabrizi MA,Bassetto M,Brancale A,Hamel E,Bortolozzi R,Basso G,Viola G
    BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.
    背景与目标: : 与微管蛋白结合并破坏微管动力学的抗肿瘤剂在过去几年中引起了极大的关注。为了扩展我们对噻唑环作为combretastatin A-4中存在的顺式烯烃的合适模拟物的了解,我们将3,4,5-三甲氧基苯基固定在噻唑核的C4-position。我们发现C2-和C5-positions的取代基对抗增殖活性具有深远的影响。比较噻唑环C5-position具有相同取代基的化合物,C2-position部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2)。相对于C2-amino对应物,N-甲基氨基取代基显着提高了MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基C2-position的空间体积增加导致活性降低1-2对数。2-n-甲基氨基噻唑衍生物3b,3d和3e是作为抗增殖剂的最具活性的化合物,其IC(50) 值从低微摩尔到个位数纳摩尔,此外,它们在多药耐药细胞系中也具有活性过表达P-糖蛋白。抗增殖活性可能是由化合物与微管蛋白聚合的秋水仙碱位点结合并破坏微管动力学引起的。此外,活性最高的化合物3e通过激活caspase-2,-3和-8诱导细胞凋亡,但3e并未引起线粒体去极化。
  • 【N-{4-[5-(4-氟苯基)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-乙酰胺 (CBS-3595),一种对tnf α 相关疾病具有活性的p38α MAPK/PDE-4双重抑制剂.】 复制标题 收藏 收藏
    DOI:10.1021/acs.jmedchem.6b01647 复制DOI
    作者列表:Albrecht W,Unger A,Bauer SM,Laufer SA
    BACKGROUND & AIMS: :The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.
    背景与目标: : p38丝裂原活化蛋白激酶 (MAPK) 抑制剂的抗炎潜力被巧合地扩展为对p38α MAPK和磷酸二酯酶4 (PDE4) 的双重抑制,并且两种炎症相关酶的阻断所产生的潜在益处被彻底研究。在对啮齿动物,狗和猴子施用1之后,在体外实验以及体外和体内临床前研究中相继评估了最有希望的化合物CBS-3595 (1)。所得数据清楚地表明有效抑制了肿瘤坏死因子 α 的释放。为了在向健康的人类志愿者施用1时再次确认动物研究的结果,进行了I期临床试验。除了有关1的药代动力学和药效学特征的进一步信息外,还证明了p38α MAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。
  • 【脂多糖通过诱导肠细胞膜表达以及TLR-4和cd14的定位,在体外和体内引起肠紧密连接通透性的增加。】 复制标题 收藏 收藏
    DOI:10.1016/j.ajpath.2012.10.014 复制DOI
    作者列表:Guo S,Al-Sadi R,Said HM,Ma TY
    BACKGROUND & AIMS: :Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4-dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4-dependent up-regulation of CD14 membrane expression.
    背景与目标: : 细菌来源的脂多糖 (LPS) 在炎症性肠病的炎症过程中起着至关重要的作用。肠紧密连接 (TJ) 屏障缺陷是炎症性肠病和肠道其他炎症状况的重要致病因素。尽管LPS在介导肠道炎症中的重要性,但其对肠上皮屏障的生理作用仍不清楚。这项研究的主要目的是使用体外 (过滤生长的Caco-2单层) 和体内 (小鼠肠灌注) 确定生理相关浓度的LPS (0至1 ng/mL) 对肠屏障功能的影响。) 肠上皮模型系统。LPS在生理相关浓度 (0至1 ng/mL) 下,在基底外侧区室中产生了Caco-2 TJ通透性的时间依赖性增加,而没有诱导细胞死亡。腹膜内注射LPS (0.1 mg/kg) 导致临床上相关的血浆浓度,也引起体内肠通透性的时间依赖性增加。LPS诱导的肠TJ通透性增加是由肠细胞膜TLR-4表达的增加和膜相关蛋白cd14的膜共定位的TLR-4-dependent增加介导的。总之,这些研究首次表明,LPS通过涉及CD14膜表达的TLR-4-dependent上调的细胞内机制引起肠通透性的增加。
  • 【高风险心血管疾病的西班牙受试者的面包消费变化和肥胖的4年变化。】 复制标题 收藏 收藏
    DOI:10.1017/S000711451200476X 复制DOI
    作者列表:
    BACKGROUND & AIMS: :The effects of bread consumption change over time on anthropometric measures have been scarcely studied. We analysed 2213 participants at high risk for CVD from the PREvención con DIeta MEDiterránea (PREDIMED) trial to assess the association between changes in the consumption of bread and weight and waist circumference gain over time. Dietary habits were assessed with validated FFQ at baseline and repeatedly every year during 4 years of follow-up. Using multivariate models to adjust for covariates, long-term weight and waist circumference changes according to quartiles of change in energy-adjusted white and whole-grain bread consumption were calculated. The present results showed that over 4 years, participants in the highest quartile of change in white bread intake gained 0·76 kg more than those in the lowest quartile (P for trend = 0·003) and 1·28 cm more than those in the lowest quartile (P for trend < 0·001). No significant dose-response relationships were observed for change in whole-bread consumption and anthropometric measures. Gaining weight (>2 kg) and gaining waist circumference (>2 cm) during follow-up was not associated with increase in bread consumption, but participants in the highest quartile of changes in white bread intake had a reduction of 33 % in the odds of losing weight (>2 kg) and a reduction of 36 % in the odds of losing waist circumference (>2 cm). The present results suggest that reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat.
    背景与目标: : 面包消费随时间变化对人体测量的影响很少被研究。我们分析了来自prevenci ó n con DIeta meditr á nea (predmed) 试验的2213名CVD高危参与者,以评估随时间推移面包和体重变化与腰围增加之间的关联。在基线时使用经过验证的FFQ评估饮食习惯,并在随访的4年中每年重复进行。使用多变量模型对协变量进行调整,根据能量调整后的白色和全麦面包消费量变化的四分位数,计算了长期体重和腰围的变化。目前的结果表明,在过去的4年里,白面包摄入量变化最高四分位数的参与者比最低四分位数的参与者增加了0·76千克 (趋势P = 0·003),比最低四分位数的参与者增加了1·28厘米 (趋势P <0·001)。对于全面包消费和人体测量的变化,未观察到明显的剂量反应关系。随访期间体重增加 (> 2千克) 和腰围增加 (> 2厘米) 与面包消耗量增加无关,但是,白面包摄入量变化最高四分位数的参与者的减肥几率降低了33% (> 2千克),而腰围下降的几率降低了36% (> 2厘米)。目前的结果表明,在地中海风格的食物模式环境中,减少白面包而不是全麦面包的消费与体重和腹部脂肪的减少有关。
  • 【神经生长因子的鼻内递送可减轻大鼠颅脑损伤后的aquaporins-4-induced水肿。】 复制标题 收藏 收藏
    DOI:10.1016/j.brainres.2012.11.028 复制DOI
    作者列表:Lv Q,Fan X,Xu G,Liu Q,Tian L,Cai X,Sun W,Wang X,Cai Q,Bao Y,Zhou L,Zhang Y,Ge L,Guo R,Liu X
    BACKGROUND & AIMS: :Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.
    背景与目标: : 创伤性脑损伤 (TBI) 仍然是与伤害相关的死亡和残疾的主要原因。脑水肿是TBI的主要并发症之一,可导致颅内压升高和TBI后预后不良。神经生长因子 (NGF) 似乎是治疗脑水肿和TBI的可行策略。不幸的是,由于其血脑屏障 (BBB) 渗透性差,NGF的临床应用受到了极大的限制。我们先前证明鼻内NGF可以绕过BBB并分布在整个大脑中。在这里,我们进一步研究了鼻内NGF是否可以减轻TBI诱导的脑水肿及其推测的机制。TBI是通过改进的重量下降模型产生的。我们发现,经TBI诱导后12小时,24小时和72小时,鼻内施用NGF (5 μ g/d) 可减轻脑水肿,如半球含水量所测定。这种衰减与aquaporin-4含量的显着降低有关,这在脑水肿的形成中起着关键作用。通过rt-pcr和ELISA,我们发现鼻内NGF显着抑制促炎细胞因子 (包括IL-1β 和TNF-α) 的转录和表达。电泳迁移率变化测定 (EMSA) 显示TBI后核因子-κ b的显着激活,但是,在NGF处理的大鼠中,这一激活大大降低。此外,在鼻内补充NGF时,TBI后线粒体介导的凋亡被最小化,如Bcl-2上调和caspase-3下调所表明的。总的来说,我们的发现表明鼻内NGF可能是治疗脑水肿和TBI的有希望的策略。
  • 【OP-1 (rhBMP-7) 替代后外侧腰椎关节固定术的自体髂骨移植的安全性和有效性: 一项初步研究的至少4年随访。】 复制标题 收藏 收藏
    DOI:10.1016/j.spinee.2007.03.012 复制DOI
    作者列表:Vaccaro AR,Whang PG,Patel T,Phillips FM,Anderson DG,Albert TJ,Hilibrand AS,Brower RS,Kurd MF,Appannagari A,Patel M,Fischgrund JS
    BACKGROUND & AIMS: BACKGROUND CONTEXT:Although autogenous bone is still considered to be the gold standard graft material for promoting spinal fusion, other bone graft substitutes have been developed in an attempt to improve arthrodesis rates and avoid the complications associated with the procurement of autograft. The bone morphogenetic proteins (BMPs) represent a family of osteoinductive growth factors that are known to stimulate the osteoblastic differentiation of stem cells. Osteogenic protein-1 (OP-1) Putty is a commercially available BMP preparation that is already approved for use in humans. Previous clinical studies involving patients with degenerative spondylolisthesis have reported that the efficacy and safety of OP-1 Putty is comparable to that of autograft at both 1- and 2-year follow-up. PURPOSE:The purpose of this study was to evaluate the intermediate-term efficacy and safety of OP-1 Putty as an alternative to autogenous bone by comparing the 4-year radiographic, clinical, and safety data of these same patients who underwent decompression and uninstrumented fusion with either OP-1 Putty or iliac crest autograft. STUDY DESIGN/SETTING:A prospective, randomized, controlled, multicenter clinical pilot study. PATIENT SAMPLE:Thirty-six patients undergoing decompressive laminectomy and single-level uninstrumented fusion for degenerative spondylolisthesis and symptomatic spinal stenosis were randomized in a 2:1 fashion to receive either OP-1 Putty (24 patients) or autogenous iliac crest bone graft (12 patients). OUTCOME MEASURES:Patient-reported outcome measures consisting of Oswestry Disability Index and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) scores were used to evaluate clinical efficacy. Perioperative data including operative time, estimated blood loss, and duration of hospital stay were also recorded for each surgery. Postoperatively, a neurological examination and an assessment of donor-site pain (if applicable) were performed at every follow-up visit. Radiographic fusion success was defined as the presence of continuous bridging bone formation between the transverse processes at the level of the spondylolisthesis with minimal motion evident on dynamic lateral x-ray films. The primary efficacy endpoint was the overall success rate, a composite measure derived from both radiographic and clinical parameters. The safety of OP-1 Putty was confirmed by comparing the nature and frequency of all adverse events and complications that were prospectively observed in either of the groups. METHODS:Thirty-six patients with degenerative spondylolisthesis and symptoms of neurogenic claudication underwent decompressive laminectomy and single-level uninstrumented fusion with either OP-1 Putty or autograft. All patients were evaluated at 6 weeks and 3, 6, 9, 12, and 24 months, after which time they were instructed to return on a yearly basis. Multiple neuroradiologists blinded to the assigned treatment reviewed static and dynamic X-ray films with digital calipers to assess fusion status according to the presence of continuous bridging bone across the transverse processes as well as the amount of residual motion evident at the level of interest. Oswestry Disability Index surveys and SF-36 questionnaires were used to assess clinical outcomes. RESULTS:At the 48-month time point, complete radiographic and clinical data were available for 22 of 36 patients (16 OP-1 Putty and 6 autograft) and 25 of 36 patients (18 OP-1 Putty and 7 autograft), respectively. Radiographic evidence of a solid arthrodesis was present in 11 of 16 OP-1 Putty patients (68.8%) and 3 of 6 autograft patients (50%). Clinically successful outcomes defined as at least a 20% improvement in preoperative Oswestry scores were experienced by 14 of 19 OP-1 Putty patients (73.7%) and 4 of 7 autograft patients (57.1%); these clinical findings were corroborated by similar increases in SF-36 scores. The respective overall success rates of the OP-1 Putty and autograft group were 62.5% and 33.3%. In this study, there were no incidents of local or systemic toxicity, ectopic bone production, or other adverse events directly related to the use of OP-1 Putty. CONCLUSION:Despite the challenges associated with obtaining a solid uninstrumented fusion in patients with degenerative spondylolisthesis, the rates of radiographic fusion, clinical improvement, and overall success associated with the use of OP-1 Putty were at least comparable to that of the autograft controls for at least 48 months after surgery. These results appear to validate the short-term results previously reported for OP-1 Putty and suggest that this material may potentially represent a viable bone graft substitute for certain fusion applications.
    背景与目标:
  • 【在人膀胱中表达的CYP2A13代谢激活4-氨基联苯。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22136 复制DOI
    作者列表:Nakajima M,Itoh M,Sakai H,Fukami T,Katoh M,Yamazaki H,Kadlubar FF,Imaoka S,Funae Y,Yokoi T
    BACKGROUND & AIMS: :Cigarette smoking is the predominant risk factor for bladder cancer. Aromatic amines such as 4-aminobiphenyl (ABP) is the major carcinogens found in tobacco smoke. Although it is generally accepted that ABP is metabolically activated via N-hydroxylation by CYP1A2 in human liver, previous studies using Cyp1a2-null mice indicated the involvement of other enzyme(s). Here we found that CYP2A13 can metabolically activate ABP to show genotoxicity by Umu assay. The K(m) and V(max) values for ABP N-hydroxylation by recombinant CYP2A13 in E. coli were 38.5 +/- 0.6 microM and 7.8 +/- 0.0 pmol/min/pmol CYP, respectively. The K(m) and V(max) values by recombinant CYP1A2 were 9.9 +/- 0.9 microM and 39.6 +/- 0.9 pmol/min/pmol CYP, respectively, showing 20-fold higher intrinsic clearance than CYP2A13. In human bladder, CYP2A13 mRNA, but not CYP1A2, is expressed at a relatively high level. Human bladder microsomes showed ABP N-hydroxylase activity (K(m) = 34.9 +/- 4.7 microM and V(max) = 57.5 +/- 1.9 pmol/min/mg protein), although the intrinsic clearance was 5-fold lower than that in human liver microsomes (K(m) = 33.2 +/- 2.0 microM and V(max) = 293.9 +/- 5.8 pmol/min/mg protein). The activity in human bladder microsomes was prominently inhibited by 8-methoxypsoralen, but not by fluvoxamine, anti-CYP1A2 or anti-CYP2A6 antibodies. CYP2S1, which is expressed in human bladder and has relatively high amino acid identities with CYP2As, did not show detectable ABP N-hydroxylase activity. In conclusion, although the enzyme responsible for ABP N-hydroxylation in human bladder microsomes could not be determined, we found that CYP2A13 metabolically activates ABP.
    背景与目标: 吸烟是膀胱癌的主要危险因素。芳香胺 (例如4-氨基联苯 (ABP)) 是烟草烟雾中发现的主要致癌物。尽管人们普遍认为ABP通过CYP1A2在人肝脏中通过N-羟基化代谢激活,但先前使用Cyp1a2-null小鼠的研究表明其他酶的参与。在这里,我们发现CYP2A13可以通过Umu测定代谢激活ABP以显示遗传毒性。重组CYP2A13在大肠杆菌中abpn-羟基化的K(m) 和V(max) 值分别为38.5 +/- 0.6 microM和7.8 +/- 0.0 pmol/min/pmol CYP。重组CYP1A2的K(m) 和V(max) 值分别为9.9 +/- 0.9 microM和39.6 +/- 0.9 pmol/min/pmol CYP,显示出比CYP2A13高20倍的固有清除率。在人膀胱中,CYP2A13 mRNA而不是CYP1A2以相对较高的水平表达。人膀胱微粒体显示ABP N-羟化酶活性 (K(m) = 34.9 +/- 4.7微米和V(max) = 57.5 +/- 1.9 pmol/min/mg蛋白),虽然内在清除率比人肝微粒体低5倍 (K(m) = 33.2 +/- 2.0微米和V(max) = 293.9 +/- 5.8 pmol/min/mg蛋白)。8-甲氧基补骨脂素显着抑制人膀胱微粒体的活性,但氟伏沙明,anti-CYP1A2或anti-CYP2A6抗体不抑制人膀胱微粒体的活性。CYP2S1在人膀胱中表达,与CYP2As具有较高的氨基酸同一性,但未显示可检测到的ABP N-羟化酶活性。总之,尽管无法确定负责人膀胱微粒体中ABP N-羟基化的酶,但我们发现CYP2A13代谢激活ABP。
  • 【在伤口愈合的体外模型中,α6β4整联蛋白的表面重新定位和半桥体的组装。】 复制标题 收藏 收藏
    DOI:10.1083/jcb.115.6.1737 复制DOI
    作者列表:Kurpakus MA,Quaranta V,Jones JC
    BACKGROUND & AIMS: :A transmembrane extracellular matrix receptor of the integrin family, alpha 6 beta 4, is a component of the hemidesmosome, an adhesion complex of importance in epithelial cell-connective tissue attachment (Stepp, M. A., S. Spurr-Michaud, A. Tisdale, J. Elwell, and I. K. Gipson. 1990. Proc. Natl. Acad. Sci. USA. 87:8970-8974; Jones, J. C. R., M. A. Kurpakus, H. M. Cooper, and V. Quaranta. 1991. Cell Regulation. 2:427-438). Cytosolic components of hemidesmosomes include bullous pemphigoid (BP) antigens while extracellular components include a 125-kD component of anchoring filaments (CAF) and collagen type VII-containing anchoring fibrils. We have monitored the incorporation of the alpha 6 beta 4 integrins into forming hemidesmosomes in an in vitro wound-healing explant model. In epithelial cells recently migrated from the edges of unwounded sites over bare connective tissue, alpha 6 beta 4 first appears along the entire cell surface. At this stage, these cells contain little or no cytosolic hemidesmosomal components, at least as detectable by immunofluorescence using BP autoantibodies, whereas they are already positive for laminin and CAF. At a later stage, as cells become positive for cytosolic hemidesmosome components such as BP antigens as well as collagen type VII, alpha 6 beta 4 becomes concentrated along the basal pole of the epithelial cell where it abuts the connective tissue of the explant. Polyclonal antibodies to beta 4 do not interfere with the migration of epithelial cells in the explant. However, they prevent assembly of hemidesmosomal complexes and inhibit expression of collagen type VII in cells that have migrated over wound areas. In addition, they induce disruption of established hemidesmosomes in nonmigrating cells of the unwounded area of the explant. Monoclonal antibodies to alpha 6 have a more dramatic effect, since they completely detach epithelial cells in the unwounded area of the explant. Antibodies to CAF also detach epithelial cells in unwounded areas, apparently by inducing separation between epithelium and connective tissue at the lamina lucida of the basement membrane zone. These results suggest a model whereby polarization of alpha 6 beta 4 to the basal surface of the cells, perhaps induced by a putative anchoring filament-associated ligand, triggers assembly of hemidesmosome plaques.
    背景与目标: : 整联蛋白家族的跨膜细胞外基质受体 α6β4是半染色体的组成部分,半染色体是上皮细胞-结缔组织附着中重要的粘附复合物 (Stepp,m.a.,S. Spurr-Michaud,A. Tisdale,J. Elwell,和I. K. Gipson。1990. Proc. Natl. Acad. Sci.美国。87:8970-8974; Jones,j.c.R.,M.Kurpakus,H. M. Cooper和V. Quaranta。1991.细胞调控。2:427-438)。半桥粒的胞质组分包括大疱性类天疱疮 (BP) 抗原,而细胞外组分包括锚定细丝 (CAF) 的125-kD组分和含VII型胶原的锚定原纤维。我们已经在体外伤口愈合外植体模型中监测了 α6β4整合素在形成半桥体中的掺入。在最近从裸露的结缔组织上未受伤部位的边缘迁移的上皮细胞中,α6β4首先出现在整个细胞表面。在这个阶段,这些细胞含有很少或没有胞质半染色体成分,至少可以通过使用BP自身抗体的免疫荧光检测到,而它们已经对层粘连蛋白和CAF呈阳性。在稍后的阶段,随着细胞对胞质半桥粒成分 (例如BP抗原) 以及VII型胶原呈阳性,α6β4沿着上皮细胞的基极集中,并与外植体的结缔组织邻接。针对 β4的多克隆抗体不会干扰外植体中上皮细胞的迁移。但是,它们阻止了半桥粒复合体的组装,并抑制了在伤口区域迁移的细胞中VII型胶原的表达。此外,它们还会诱导外植体未受伤区域的非迁移细胞中已建立的半桥粒的破坏。针对 α6的单克隆抗体具有更显着的作用,因为它们完全脱离了外植体未受伤区域的上皮细胞。针对CAF的抗体也可以通过诱导基底膜区的上皮和结缔组织之间的分离而分离未受伤区域的上皮细胞。这些结果提出了一个模型,其中 α6β4极化到细胞的基底表面,可能是由假定的锚定细丝相关配体诱导的,触发了半桥粒斑块的组装。
  • 【睡眠质量与肾上腺素和4小时睡眠时间相关的自我评价差异。】 复制标题 收藏 收藏
    DOI:10.1111/j.1440-1819.1996.tb00564.x 复制DOI
    作者列表:Nishihara K,Mori K
    BACKGROUND & AIMS: The present study examined the differences of self-ratings of 4 h sleep in three statesL-WE, where the percentage of waking time and urinary epinephrine are low (< 20% waking time); H-W, where the percentage of waking time and epinephrine levels increase along the basal regression line as determined by a previous study (20-100% waking time and < 7 ng/min); H-E, where epinephrine levels increase more than expected from the basal regression line for the two parameters (> 7 ng/min). Eight healthy male subjects participated twice in a 4 h polysomnograph experiment with four types of sleep onset (total of 64 observations). In group L-WE (52 observations for eight subjects), there were no excessively negative feelings on sleep latency, sleep depth, and feelings of sleep compared with usual sleep according to the questionnaire. Subjective sleep diagrams in group L-WE were similar to polysomnographic findings. Thus, group L-WE was thought objectively and subjectively to have a good sleep state. Groups H-W (eight observations for four subjects) and H-E (four observations for two subjects) had negative feelings regarding sleep depth and feelings of sleep compared with usual sleep. Approximately half the group H-W underrated their sleep compared with objective diagrams, while all cases in group H-E remarkably underrated their sleep in the subjective diagrams. The state of remarkable adrenal medullary secretory activity seen in group H-E and that of the slightly increased activity shown in group H-W were included in poor sleep states objectively and subjectively.

    背景与目标: 本研究检查了三种状态下4 h睡眠自我评分的差异,其中清醒时间和尿肾上腺素的百分比较低 (< 20% 清醒时间); H-w,其中清醒时间和肾上腺素水平的百分比沿基础回归线增加,如先前的研究 (20-100% 清醒时间和 <7 ng/min); H-e,其中肾上腺素水平增加超过两个参数的基础回归线的预期 (> 7 ng/min)。八名健康的男性受试者两次参加了4小时多导睡眠图实验,其中有四种睡眠发作类型 (总共64个观察结果)。根据问卷,在l-we组 (八名受试者的52项观察结果) 中,与通常的睡眠相比,在睡眠潜伏期,睡眠深度和睡眠感觉方面没有过度负面的感觉。L组的主观睡眠图-我们与多导睡眠图的发现相似。因此,客观和主观地认为L-WE组具有良好的睡眠状态。与通常的睡眠相比,h-w组 (四名受试者的八次观察) 和h-e组 (两名受试者的四次观察) 对睡眠深度和睡眠感觉有负面感觉。与客观图相比,大约一半的h-w组低估了他们的睡眠,而h-e组的所有病例在主观图中都明显低估了他们的睡眠。客观和主观地将h-e组中明显的肾上腺髓质分泌活动状态和h-w组中显示的轻度活动状态包括在不良的睡眠状态中。

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