• 【小鼠短暂性大脑中动脉闭塞后新皮层血管周围aquaporin-4的暂时性丧失。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0605796103 复制DOI
    作者列表:Frydenlund DS,Bhardwaj A,Otsuka T,Mylonakou MN,Yasumura T,Davidson KG,Zeynalov E,Skare O,Laake P,Haug FM,Rash JE,Agre P,Ottersen OP,Amiry-Moghaddam M
    BACKGROUND & AIMS: :The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.
    背景与目标: : 血管周围星形胶质细胞膜中的aquaporin-4 (AQP4) 池已被证明与脑水肿的形成和溶解密切相关。脑水肿是中风发病和死亡的主要原因。因此,必须了解缺血性损伤后AQP4的血管周围池是上调还是下调,因为这种变化将决定水肿形成的时间过程。在这里,我们通过定量免疫金细胞化学证明,在大脑中动脉闭塞90分钟后,缺血纹状体和新皮层在再灌注阶段显示出不同的AQP4表达模式。再灌注24小时时,纹状体核心显示血管周围AQP4丢失,没有随后恢复的迹象。皮质中受影响最大的部分也表现出血管周围aqp4的损失。这种损失的幅度与纹状体核心相似,但在再灌注72小时后显示部分恢复。通过冷冻断裂,我们表明血管周围AQP4的丢失与颗粒的正方形晶格的消失有关,这些正方形晶格通常是血管周围星形胶质细胞膜的独特特征。皮质边界区与缺血性病变的中央部分不同,在再灌注24小时时未显示血管周围AQP4的丢失,但略有增加。这些数据表明,在水肿形成和溶解过程中控制大脑和血液之间流体交换的AQP4池的大小在再灌注阶段会发生较大且区域特定的变化。
  • 【使用iodine-123-N-(2-二乙氨基乙基) 4-碘苯甲酰胺SPECT观察眼部黑色素瘤。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Everaert H,Bossuyt A,Flamen P,Mertens J,Franken PR
    BACKGROUND & AIMS: UNLABELLED:Radiolabeled benzamides have recently been introduced for the detection of melanoma. We evaluated the potential clinical applicability of 123I-N-(2-diethylaminoethyl) 4-iodobenzamide ([123I]IDAB) for SPECT imaging of ocular melanoma.

    METHODS:Fourteen patients were studied, 10 with or suspected of malignant ocular melanoma and four with ocular naevi. All patients underwent SPECT imaging of the head and whole-body scintigraphy 4-5 hr after injection of 170 MBq [123I]IDAB.

    RESULTS:A definite tracer hyperfixation was observed in the pathological eye in 9 of 10 (90%) patients with ocular melanoma. The pathological-to-normal eye ratio averaged 1.46 (range 1.07-2.86). The melanoma nature of the scintigraphic lesions was confirmed after enucleation in eight cases and by clinical evolution in two. A false-negative scan was reported in a patient with a small and hypochromic lesion. In patients with ocular naevi, no false-positive scintigrams were documented.

    CONCLUSION:Iodine-123-IDAB scintigraphy may contribute significantly to decide about enucleation in cases where some doubt persists with conventional techniques.

    背景与目标: 未标记 : 最近已引入放射性标记的苯甲酰胺用于检测黑色素瘤。我们评估了123I-N-(2-二乙氨基乙基) 4-碘苯甲酰胺 ([123I]IDAB) 在眼部黑色素瘤SPECT成像中的潜在临床适用性。
    方法 : 研究了14名患者,10例患有或怀疑患有恶性眼部黑色素瘤,4例患有眼部恶性黑色素瘤。注射170 MBq [123I]IDAB后4-5小时,所有患者均接受了头部SPECT成像和全身闪烁显像。
    结果 : 在10例 (90% 例) 眼部黑色素瘤患者中,有9例在病理眼中观察到了明确的示踪剂超固定。病理与正常眼的比率平均为1.46 (范围1.07-2.86)。闪烁显像病变的黑色素瘤性质在8例摘除后得到证实,两例通过临床进化得到证实。在一名患有小的低色度病变的患者中报告了假阴性扫描。在患有眼痣的患者中,没有记录假阳性闪烁图。
    结论 : 在常规技术仍然存在疑问的情况下,Iodine-123-IDAB闪烁显像可能会大大有助于决定摘除。
  • 【膜结合eotaxin-3介导IL-4-stimulated上皮细胞嗜酸性粒细胞经上皮迁移。】 复制标题 收藏 收藏
    DOI:10.1002/eji.200636112 复制DOI
    作者列表:Yuan Q,Campanella GS,Colvin RA,Hamilos DL,Jones KJ,Mathew A,Means TK,Luster AD
    BACKGROUND & AIMS: :Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic-type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2-type cytokine-driven release of eosinophil-active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin-3 produced by IL-4-stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin-3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non-allergic patients. Surprisingly, eotaxin-3 in IL-4-stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin-3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin-3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface-associated eotaxin-3 is the critical IL-4-dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation.
    背景与目标: : 上皮细胞在协调粘膜免疫反应中起重要作用。在过敏型炎症中,上皮细胞控制嗜酸性粒细胞向粘膜的募集。Th2-type细胞因子驱动的嗜酸性粒细胞活性趋化因子从上皮细胞释放引导嗜酸性粒细胞迁移到粘膜上皮中。主要的嗜酸性粒细胞趋化因子受体CCR3调节这一过程; 然而,单个CCR3配体在嗜酸性粒细胞跨上皮迁移中的各自作用尚不清楚。使用体外经上皮趋化系统,我们发现IL-4-stimulated气道上皮细胞和嗜酸性粒细胞上的CCR3产生的eotaxin-3仅介导嗜酸性粒细胞经上皮迁移。与非过敏患者相比,从过敏患者恢复的鼻粘膜上皮中Eotaxin-3蛋白水平也增加。令人惊讶的是,IL-4-stimulated气道上皮细胞中的eotaxin-3主要是细胞表面结合的,细胞表面形式对于嗜酸性粒细胞经上皮迁移至关重要。Eotaxin-3细胞表面缔合部分依赖于糖胺聚糖 (GAG),但完全依赖于蛋白质,这表明eotaxin-3与GAG和细胞表面蛋白均相关。因此,我们提供的证据表明,在过敏性炎症环境中,细胞表面相关eotaxin-3是介导嗜酸性粒细胞跨上皮迁移的关键IL-4-dependent趋化信号。
  • 【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。
  • 【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。
  • 【用负载乳糖酸-G(4)-PAMAM-FITC索拉非尼的树状大分子靶向人肝癌细胞。】 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。

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