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【内源性白介素-1受体拮抗剂具有神经保护作用。】
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DOI：10.1006/bbrc.1997.6436
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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： 白介素-1（IL-1）已牵涉到慢性和急性脑神经病理学。 IL-1受体拮抗剂（IL-1ra）是一种与IL-1受体结合而不诱导信号转导的天然蛋白质，可阻断IL-1的多种作用。 IL-1ra在局部起作用，并且也在血液中循环。我们现在报告IL-1ra在脑中作为内源性神经保护分子的生物学功能的证据。大鼠局灶性脑缺血可快速诱导IL-1ra mRNA的脑表达，并且被动免疫中和抑制IL-1ra的作用可显着增强缺血性损伤。据我们所知，这是大脑中内源性IL-1ra作用的首次报道。因此，控制IL-1ra的表达或作用可能为限制急性神经变性提供了有用的治疗策略。
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【N1-苄基-N2- [1-（1-萘基）乙基]-反式1,2-二氨基环己烷：4-氯苯基羧酰胺（calhex 231）的开发作为一种新型的钙感应受体配体，具有强大的钙分解活性。】
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DOI：10.1021/jm051233+
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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： ：结构活性关系（SAR）研究主要在N1-芳基磺酰基-N2- [1-（1-（萘基）乙基]-反式1,2-二氨基环己烷的N1位置进行的钙敏感受体（CaSR）。该系列中活性最高的化合物是4-（三氟甲氧基）苯磺酰基衍生物7e，在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯（[3H] IP）积累方面，其IC50为5.4 /-0.5 microM。表达CaSR的卵巢（CHO）细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍（7m，IC50 = 0.9 /-0.2 microM）。在合成的羧酰胺中，活性最高的化合物之一是4-氯苯基羧酰胺（1S，2S，1'R）-7n（Calhex 231，IC50 = 0.33 /-0.02 microM）。 （1S，2S，1'R）-7n的绝对构型是通过对化合物7d的一种非对映异构体进行X射线晶体学研究得出的。 （1S，2S，1'R）-异构体的立体化学偏好可以基于CaSR钙解结合口袋的三维模型来合理化。除去C-1'甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e，7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。
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3 Status of TIM-1 exon 4 haplotypes and CD4+T cell counts in HIV-1 seroprevalent North Indians.
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【HIV-1血清流行的北印度人中TIM-1外显子4单倍型和CD4 T细胞计数的状态。】
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DOI：10.1016/j.humimm.2012.11.013
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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 / AIDS在内的多种疾病有关。编码粘蛋白结构域的TIM1外显子4高度多样化，具有与不同表型相关的序列变体。在这项研究中，TIM1外显子4在来自北印度人口的227个HIV-1血清流行和288个健康的未感染个体中进行了测序，并建立了单倍型。在健康人群中鉴定出一种新颖但罕见的单倍型D1（∗），与D1的区别在于在Thr208Thr处的同义替代G> T。 TIM1单倍型多样性表明与HIV-1感染的易感性无关。携带D3A的血清流行个体的CD4 T细胞计数中位数相对较高（不含313 /μl； p = 0.02）。由于ART和其他因素的混杂，D3-A个体或未接受过ART的D3-A个体之间CD4 T计数的比较似乎没有显示任何显着差异。 -
【白介素28A重组腺病毒（Ad-mIFN-λ2）转染的肺腺癌在体内的抑制作用。】
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DOI：10.1089/cbr.2012.1247
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BACKGROUND & AIMS: :Abstract Type III interferon (IFN-λ) is a novel member of the interferon family, which preferentially promotes antiviral responses from epithelial cells and cooperates with type I IFNs in the clearance of viral infections. However, the effect of mIFN-λ2 to the LA795 lung adenocarcinoma cell is largely unknown. In this study, we transfected Ad-mIFN-λ2 vector into LA795 tumor-bearing mice to explore the effect of mIFN-λ2 on the proliferation of LA795 lung adenocarcinoma cell and on the immune response of the mice. Transfected by Ad-mIFN-λ2 vector, a significant decrease in the tumor growth, the subcutaneous tumor necrosis, cystic degeneration, and tumor apoptosis were more evident; at the same time, mIFN-λ2 protein and gene were significantly more expressed. And, flow cytometry analysis suggested that CD3(+)CD4(+), CD3(+)CD8(+), and NK (CD3(-)CD49(+)) cells were all significantly increased after transfected by Ad-mIFN-λ2. The study demonstrated that recombinant Ad-mIFN-λ2 transfection effectively inhibited the growth of LA795 lung adenocarcinoma cell, which may work through inducing apoptosis of tumor cell and regulating cell immune response.背景与目标： 摘要：III型干扰素（IFN-λ）是干扰素家族的一个新成员，它优先促进上皮细胞的抗病毒反应，并与I型干扰素协同作用以清除病毒感染。然而，很大程度上未知mIFN-λ2对LA795肺腺癌细胞的作用。在这项研究中，我们将Ad-mIFN-λ2载体转染到LA795荷瘤小鼠中，以研究mIFN-λ2对LA795肺腺癌细胞增殖和小鼠免疫反应的影响。 Ad-mIFN-λ2载体转染后，肿瘤生长明显减少，皮下肿瘤坏死，囊性变性和肿瘤细胞凋亡更为明显。同时，mIFN-λ2蛋白和基因的表达明显增加。并且，流式细胞仪分析表明，用Ad-mIFN-λ2转染后，CD3（）CD4（），CD3（）CD8（）和NK（CD3（-）CD49（））细胞均显着增加。研究表明重组Ad-mIFN-λ2转染有效抑制了LA795肺腺癌细胞的生长，其作用可能是通过诱导肿瘤细胞凋亡和调节细胞免疫应答来实现的。
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【靶向人类肝癌细胞与乳酸-G（4）-PAMAM-FITC索拉非尼负载树状聚合物。】
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DOI：10.1016/j.ijpharm.2017.06.049
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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去唾液酸糖蛋白受体（ASGP-R）靶向的第四代多巴胺胺树状大分子（G（4）-PAMAM）的合成和生物学评估。 ASGP-R靶向树状聚合物是通过将乳酸基乳酸（La）与G（4）-PAMAM树状聚合物缀合，然后对游离氨基进行乙酰化（Ac），以减少与细胞膜的非特异性相互作用而获得的。此外，通过额外嫁接荧光素（FITC），很容易表征目标树状聚合物Ac-La-G（4）-PAMAM-FITC的内在途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验可以研究树状聚合物影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实，在未分化的HLE细胞中，Ac-La-G（4）-PAMAM-FITC树状大分子在高分化和表达ASGP-R的人肝癌细胞系HepG-2中具有更高的结合和摄取能力。载有索拉非尼的Ac-La-G（4）-PAMAM-FITC树状聚合物稳定并显示索拉非尼持续释放。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，树状大分子中包含的索拉非尼保持了其有效性，并能够在一段时间内产生更长的持久作用。这种新的靶向树状聚合物看来是将索拉非尼递送至表达ASGP-R的肝癌细胞的合适载体。
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【DPP-4抑制剂linagliptin可以抵消正常和糖尿病小鼠大脑的中风：与格列美脲比较。】
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DOI：10.2337/db12-0988
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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。 Linagliptin是临床上用于治疗2型糖尿病的二肽基肽酶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。为了了解功效是否由血糖调节介导，与磺酰脲格列美脲进行了比较。为了确定利格列汀介导的功效是否取决于糖尿病背景，在非糖尿病小鼠中进行了实验。通过给小鼠喂高脂饮食32周来诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。在治疗的第4周，通过短暂性中脑动脉闭塞诱发中风。在整个实验过程中，评估了血液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。通过测定中风量和纹状体/皮层中存活的神经元的立体定量来测量缺血性脑损伤。我们在2型糖尿病和正常小鼠中显示了利格列汀的显着抗中风功效，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，由利格列汀介导的神经保护作用与葡萄糖无关，并且可能涉及GLP-1。这些发现可能为DPP-4抑制剂的开发提供动力，以预防和治疗糖尿病患者的中风。
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【B16F10黑色素瘤细胞中4'-O-甲基化类黄酮诱导黑色素生成。】
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DOI：10.1007/s11418-012-0727-y
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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： ：需要控制黑素生成的试剂来开发化妆品，以改善皮肤和头发的色素沉着障碍。在这项研究中，我们检查和评估了类黄酮对黑色素生成细胞模型鼠B16F10黑色素瘤细胞中黑色素生成的影响。在这项研究过程中，我们发现细胞在含有10μM4'-O-甲基化类黄酮，薯os皂素（4'-O-甲基木犀草素），阿沙西汀（4'-O-甲基芹菜素）或Kaempferide（4'-O-methylkaempferol）使细胞的黑色素含量比对照细胞高3至7倍。浓度依赖性试验表明，20μM醋氨蝶呤显示出最高的作用，比赋形剂高33倍。另一方面，相应的4'-OH型黄酮，木犀草素，芹菜素和山ka酚的作用明显较小。此外，通过评估黑色素生成蛋白，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，然后激活cAMP反应元件结合蛋白（CREB）和细胞外信号调节的1型和2型激酶（ERK1 / 2）。这些结果表明，类黄酮的4'-O-甲基通过激活鼠B16F10黑色素瘤细胞中的磷酸-CREB激活其主要信号转导途径，从而在诱导黑色素生成中起重要作用。
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【设计和发现新的（3S，5R）-5- [4-（2-氯苯基）-2,2-二甲基-5-氧哌嗪-1-基]哌啶-3-羧酰胺作为有效的肾素抑制剂。】
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DOI：10.1016/j.bmcl.2012.09.103
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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-氧哌嗪-1-基]哌啶-3-甲酰胺，并将其鉴定为肾素抑制剂。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。
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【用作抗癌剂的2-取代的4-（3'，4'，5'-三甲氧基苯基）-5-芳基噻唑的合成和生物学评估。】
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DOI：10.1016/j.bmc.2012.10.001
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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： 近年来，与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中存在的顺式烯烃的合适模拟物的认识，我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现，在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物，C2位上的部分影响抗增殖活性，效力顺序为NHCH（3）> Me> N（CH（3））（2） 。相对于C 2-氨基对应物，N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N，N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b，3d和3e是最有效的化合物作为抗增殖剂，其IC（50）值从低微摩尔到一位数纳摩尔，此外，它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。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不会引起线粒体去极化。
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【发现双p38αN- {4- [5-（4-氟苯基）-3-甲基-2-甲基硫烷基-3H-咪唑-4-基]-吡啶-2-基}-乙酰胺（CBS-3595）具有抗TNFα相关疾病活性的MAPK / PDE-4抑制剂。】
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DOI：10.1021/acs.jmedchem.6b01647
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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）抑制剂的抗炎潜能同时扩展到了p38αMAPK和磷酸二酯酶4（PDE4）的双重抑制作用，并且两种炎症相关酶均被阻断产生了潜在的益处调查。给啮齿动物，狗和猴子施用1后，在体外实验以及离体和体内临床前研究中相继评估了最有前途的化合物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。为了确认对健康的人类志愿者给药1时动物研究的结果，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性的进一步信息外，还证明了对p38αMAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。
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【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道紧密连接通透性的增加。】
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DOI：10.1016/j.ajpath.2012.10.014
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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性状的重要致病因素。尽管其在介导肠炎症中的重要性，但是LPS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（滤器生长的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。在生理相关浓度（0到1 ng / mL）下，基底外侧隔室中的LPS导致Caco-2 TJ通透性随时间的增加，而不会引起细胞死亡。腹膜内注射LPS（0.1 mg / kg）会导致临床上相关的血浆浓度，还会引起体内肠道通透性的时间依赖性增加。 LPS诱导的肠道TJ通透性增加是由肠上皮细胞膜TLR-4表达的增加和与膜相关的蛋白质CD14的膜共定位中TLR-4依赖性的增加介导的。总之，这些研究首次显示LPS通过涉及TLR-4依赖性CD14膜表达上调的细胞内机制引起肠道通透性增加。
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【患有高心血管风险的西班牙受试者的面包消耗变化和肥胖4年变化。】
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DOI：10.1017/S000711451200476X
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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： ：很少研究面包消耗量随时间变化对人体测量学的影响。我们从PREVENCIónCON DIetaMEDiterránea（PREDIMED）试验中分析了2213名有CVD高风险的参与者，以评估面包消耗量和体重变化与腰围增加之间的关系。饮食习惯在基线时通过有效的FFQ进行评估，并在随访的4年中每年重复进行。使用多元模型对协变量进行调整，根据能量调整后的白面包和全麦面包消耗量的变化的四分位数，计算了长期体重和腰围的变化。目前的结果表明，在过去4年中，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 kg（趋势P = 0·003），比最低四分位数的参与者增加了1·28 cm。最低四分位数（趋势<0·001的P）。没有观察到明显的剂量反应关系，即全面包消费和人体测量学的变化。随访期间体重增加（> 2 kg）和腰围增加（> 2 cm）与面包消耗量增加无关，但是参加白面包摄入量变化最高四分位数的参与者的机率降低了33％减轻体重（> 2 kg），减少腰围（> 2 cm）的几率降低36％。目前的结果表明，在地中海式饮食模式下减少白面包食用而不是全麦面包食用与体重增加和腹部脂肪减少有关。
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【白细胞介素-1β和白细胞介素-1受体拮抗剂遗传多态性在炎性肠病中的意义。】
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DOI：
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BACKGROUND & AIMS: OBJECTIVE:Genetic susceptibility to inflammatory bowel disease is well recognized. There is also increasing evidence for the activation of the mucosal immune system and the production of inflammatory cytokines, i.e., interleukin (IL)-1ra and IL-1beta in the inflammatory bowel disease. The aim of this study was to analyze the IL-1beta and IL-1ra gene polymorphism and linkage disequilibrium coefficient between the different alleles of these genes in patients with Crohn's disease (CD) or ulcerative colitis (UC), according to the severity of the disease.
METHODS:Two hundred twenty-eight inflammatory bowel disease patients (87 UC and 141 CD) were included in this study and compared with 113 unrelated controls. The IL-1beta and IL-1ra gene polymorphism was studied after specific amplification of variable regions by PCR. A penta-allelic polymorphism, corresponding to a VNTR region located in intron 2 of the IL-1ra gene, was analyzed, whereas bi-allelic RFLPs displayed by two restriction enzymes (TaqI and AvaI) at position -511 of the IL-1beta gene were analyzed.
RESULTS:There was no significant difference of genotype distribution between controls and CD or UC patients. However, surgically treated UC patients were characterized by a higher frequency of genotype IL-1ra 1-2 (39 vs 16%, pc < 0.01) compared with nonoperated UC patients. Moreover, nonoperated UC patients displayed a lower frequency of IL-1ra allele 2 than surgically treated UC patients (14 vs 34%, pc < 0.002) or controls (14 vs 30%, pc < 0.005). Furthermore, simultaneous analysis of the IL-1beta and IL-1ra genes that are located in the same region of chromosome 2 revealed that CD patients carrying the IL-1beta allele 2 were more often noncarriers of IL-1ra allele 2 (p < 0.005). Moreover, UC and CD patients were, characterized by a lower frequency of the association of IL-1ra allele 2 and IL-1beta allele 2 compared with controls (8.3 vs 20.3% and 10.6 vs 20.3%, p < 0.03).
CONCLUSIONS:IL-1ra and IL-1beta gene polymorphism analysis from a clinical standpoint might help in defining UC prognosis. However, functional studies at both the circulating and mucosal level with stratification on allele associations, especially IL-1ra allele 2-IL-1beta allele 2 subgroups must be realized before therapeutic implications.
背景与目标： 目标：人们对炎症性肠病的遗传易感性已广为人知。也有越来越多的证据表明在炎症性肠病中粘膜免疫系统的活化和炎性细胞因子，即白介素（IL）-1ra和IL-1β的产生。这项研究的目的是分析克罗恩病（CD）或溃疡性结肠炎（UC）患者的IL-1beta和IL-1ra基因多态性以及这些基因的不同等位基因之间的连锁不平衡系数。
方法：该研究纳入了28位炎症性肠病患者（87 UC和141 CD），并将其与113位无关的对照组进行了比较。在通过PCR特异性扩增可变区之后，研究了IL-1β和IL-1ra基因多态性。分析了一个五等位基因多态性，对应于位于IL-1ra基因内含子2的VNTR区，而在IL-1beta基因第-511位的两个限制性酶（TaqI和AvaI）显示的双等位基因RFLP
结果：对照组和CD或UC患者之间的基因型分布没有显着差异。然而，与未手术的UC患者相比，接受手术治疗的UC患者的特征在于基因型IL-1ra 1-2的发生频率更高（39％vs 16％，pc <0.01）。此外，未手术的UC患者显示出IL-1ra等位基因2的频率低于手术治疗的UC患者（14 vs 34％，pc <0.002）或对照组（14 vs 30％，pc <0.005）。此外，同时分析位于2号染色体同一区域的IL-1beta和IL-1ra基因发现，携带IL-1beta等位基因2的CD患者更常为IL-1ra等位基因2的非携带者（p <0.005） 。此外，UC和CD患者的特征是与对照组相比，IL-1ra等位基因2和IL-1β等位基因2的关联频率较低（8.3比20.3％和10.6比20.3％，p <0.03）。
结论：从临床角度分析IL-1ra和IL-1beta基因多态性可能有助于确定UC的预后。但是，必须在循环和粘膜水平上对等位基因关联进行分层功能研究，尤其是IL-1ra等位基因2-IL-1beta等位基因2亚组。 -
【鼻内神经生长因子的递送减轻了大鼠脑外伤后水通道蛋白4引起的水肿。】
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DOI：10.1016/j.brainres.2012.11.028
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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： ：脑外伤（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最主要的并发症之一，导致颅内压升高，TBI后预后较差。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，由于其不良的血脑屏障（BBB）通透性，NGF的临床应用受到了极大的限制。我们先前证明了鼻内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诱导的脑水肿及其可能的机制。 TBI是通过修改后的体重减轻模型产生的。我们发现鼻内施用NGF（5μg/ d）可以减轻脑水肿，通过TBI诱导后12h，24h和72h的半球水含量进行分析。这种衰减与aquaporin-4含量的显着下降有关，aquaporin-4的含量在脑水肿的形成中起着关键作用。通过使用RT-PCR和ELISA，我们显示鼻内NGF明显抑制促炎细胞因子包括IL-1β和TNF-α的转录和表达。电泳迁移率迁移分析（EMSA）显示TBI后核因子-κB的显着激活，但是在NGF治疗的大鼠中其活性大大降低。此外，鼻内补充NGF后，TBI后线粒体介导的凋亡得以最小化，如Bcl-2的上调和caspase-3的下调所示。总体而言，我们的研究结果表明，鼻内NGF可能是治疗脑水肿和TBI的一种有前途的策略。
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【OP-1（rhBMP-7）替代auto外侧自体for骨移植治疗后外侧腰椎关节置换术的安全性和有效性：至少4年的随访研究。】
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DOI：10.1016/j.spinee.2007.03.012
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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： 背景技术：尽管自体骨仍被认为是促进脊柱融合的金标准移植材料，但已开发出其他骨移植替代品以试图提高关节固定率并避免与自体移植相关的并发症。骨形态发生蛋白（BMP）代表一类骨诱导生长因子，已知这些因子可刺激干细胞的成骨细胞分化。成骨蛋白1（OP-1）腻子是一种可商购的BMP制剂，已被批准用于人类。先前涉及退行性脊椎滑脱患者的临床研究报告，在1年和2年的随访中，OP-1腻子的功效和安全性与自体移植相当。
目的：本研究的目的是通过比较这些接受减压和非器械治疗的患者的4年放射学，临床和安全性数据，评估OP-1油灰替代自体骨的中期疗效和安全性与OP-1油灰或骨自体融合。
研究设计/设置：一项前瞻性，随机，对照，多中心临床试验研究。
患者样本：36例行减压椎板切除术和单级非器械融合治疗退行性腰椎滑脱和症状性椎管狭窄的患者以2：1方式随机接受OP-1腻子（24例）或自体骨植骨（12例）耐心）。
结局指标：采用Oswestry残疾指数和医学结局研究36项简表健康调查（SF-36）评分组成的患者报告结局指标，用于评估临床疗效。每次手术还记录了围手术期数据，包括手术时间，估计的失血量和住院时间。术后，每次随访均进行神经系统检查和对供体部位疼痛的评估（如果适用）。影像学上的融合成功定义为在横向滑突之间在脊椎滑脱水平处连续桥接骨形成，而在动态侧向X射线胶片上可见的运动极小。主要功效终点是总体成功率，这是一项从放射学和临床参数中得出的综合指标。 OP-1腻子的安全性通过比较两组中预期观察到的所有不良事件和并发症的性质和频率来确定。
方法：36例退行性腰椎滑脱和神经源性lau行症状的患者接受减压椎板切除术和单层非器械融合OP-1腻子或自体移植。在第6周和第3、6、9、12和24个月对所有患者进行评估，然后指示他们每年返回一次。多位神经放射科医生对指定的治疗方法视而不见，并用数字卡尺检查了静态和动态X射线胶片，以根据横断过程中连续桥接骨的存在以及感兴趣水平上明显的残余运动量来评估融合状态。 Oswestry残疾指数调查和SF-36问卷用于评估临床结局。
结果：在48个月的时间点，分别可获得36例患者中的22例（16例OP-1腻子和6例自体移植）和36例患者中的25例（18例OP-1腻子和7例自体移植）的完整影像学和临床资料。 16例OP-1腻子患者中有11例（68.8％）和6例自体移植患者中有3例（50％）出现了牢固的关节固定的影像学证据。 19例OP-1腻子患者中的14例（73.7％）和7例自体移植患者中的4例（57.1％）经历了临床上成功的结果，定义为术前Oswestry评分至少提高了20％。这些临床发现被SF-36分数的类似提高所证实。 OP-1腻子和自体移植组的总体总体成功率分别为62.5％和33.3％。在这项研究中，没有发生局部或全身毒性，异位骨生成或与使用OP-1腻子直接相关的其他不良事件的事件。
结论：尽管在退行性脊椎滑脱患者中获得牢固的非器械融合具有挑战性，但与使用OP-1腻子相关的放射成像融合率，临床改善率和总体成功率至少可与自体植骨对照用于手术后至少48个月。这些结果似乎证实了先前报道的OP-1油灰的短期结果，并表明该材料可能是某些融合应用中可行的骨移植替代品。
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