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Modeling the QSAR of ACE-Inhibitory Peptides with ANN and Its Applied Illustration. ace抑制肽QSAR的神经网络建模及其应用实例。
Pub Date : 2012-01-01 Epub Date: 2011-06-09 DOI: 10.1155/2012/620609
Ronghai He, Haile Ma, Weirui Zhao, Wenjuan Qu, Jiewen Zhao, Lin Luo, Wenxue Zhu

A quantitative structure-activity relationship (QSAR) model of angiotensin-converting enzyme- (ACE-) inhibitory peptides was built with an artificial neural network (ANN) approach based on structural or activity data of 58 dipeptides (including peptide activity, hydrophilic amino acids content, three-dimensional shape, size, and electrical parameters), the overall correlation coefficient of the predicted versus actual data points is R = 0.928, and the model was applied in ACE-inhibitory peptides preparation from defatted wheat germ protein (DWGP). According to the QSAR model, the C-terminal of the peptide was found to have principal importance on ACE-inhibitory activity, that is, if the C-terminal is hydrophobic amino acid, the peptide's ACE-inhibitory activity will be high, and proteins which contain abundant hydrophobic amino acids are suitable to produce ACE-inhibitory peptides. According to the model, DWGP is a good protein material to produce ACE-inhibitory peptides because it contains 42.84% of hydrophobic amino acids, and structural information analysis from the QSAR model showed that proteases of Alcalase and Neutrase were suitable candidates for ACE-inhibitory peptides preparation from DWGP. Considering higher DH and similar ACE-inhibitory activity of hydrolysate compared with Neutrase, Alcalase was finally selected through experimental study.

基于58个二肽的结构或活性数据(包括肽活性、亲水性氨基酸含量、三维形状、大小和电参数),采用人工神经网络(ANN)方法建立了血管紧张素转换酶(ACE)抑制肽的定量构效关系(QSAR)模型,预测值与实际值的总体相关系数为R = 0.928。将该模型应用于脱脂小麦胚芽蛋白(DWGP)制备ace抑制肽。根据QSAR模型,我们发现肽段的c端对ace抑制活性起着至关重要的作用,即如果c端是疏水氨基酸,那么肽段的ace抑制活性就高,含有丰富疏水氨基酸的蛋白质适合产生ace抑制肽。根据该模型,DWGP含有42.84%的疏水氨基酸,是制备ace抑制肽的良好蛋白材料,QSAR模型的结构信息分析表明,Alcalase和Neutrase蛋白酶是DWGP制备ace抑制肽的合适候选酶。考虑到水解产物与Neutrase相比DH更高,ace抑制活性相似,通过实验研究最终选择了Alcalase。
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引用次数: 51
Proline rich motifs as drug targets in immune mediated disorders. 富脯氨酸基团作为免疫介导疾病的药物靶点。
Pub Date : 2012-01-01 Epub Date: 2012-05-16 DOI: 10.1155/2012/634769
Mythily Srinivasan, A Keith Dunker

The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs) are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies.

当前版本的人类免疫组网络包括近 1400 种相互作用,涉及约 600 种蛋白质。在免疫反应的许多方面都可以观察到由富脯氨酸基序(PRM)介导的分子间相互作用。已知富脯氨酸区域优先采用多脯氨酸 II 型螺旋构象,这种扩展结构有利于瞬时分子间相互作用,如信号转导、抗原识别、细胞间通讯和细胞骨架组织。聚脯氨酸 II 型螺旋的侧链和骨架羰基都有参与界面相互作用的倾向,这使其成为一种极佳的识别图案。这种独特化学特征的一个优点是,即使没有高亲和力,相互作用也能起到鉴别作用。事实上,免疫反应是由精心策划的低亲和力短时分子间相互作用介导的。富含脯氨酸的区域主要位于溶剂暴露区,如环状区、内在无序区或构成分子间界面的结构域之间。有人建议将 PRM 的多肽模拟物作为分子间相互作用的潜在拮抗剂。在本文中,我们将讨论人类免疫组中由 PRM 介导的新型相互作用,它们有可能成为免疫调节和药物开发的诱人靶点,用于治疗炎症和自身免疫性病症。
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引用次数: 0
Platelet-rich plasma peptides: key for regeneration. 富血小板血浆肽:再生的关键。
Pub Date : 2012-01-01 Epub Date: 2012-02-22 DOI: 10.1155/2012/532519
Dolores Javier Sánchez-González, Enrique Méndez-Bolaina, Nayeli Isabel Trejo-Bahena

Platelet-derived Growth Factors (GFs) are biologically active peptides that enhance tissue repair mechanisms such as angiogenesis, extracellular matrix remodeling, and cellular effects as stem cells recruitment, chemotaxis, cell proliferation, and differentiation. Platelet-rich plasma (PRP) is used in a variety of clinical applications, based on the premise that higher GF content should promote better healing. Platelet derivatives represent a promising therapeutic modality, offering opportunities for treatment of wounds, ulcers, soft-tissue injuries, and various other applications in cell therapy. PRP can be combined with cell-based therapies such as adipose-derived stem cells, regenerative cell therapy, and transfer factors therapy. This paper describes the biological background of the platelet-derived substances and their potential use in regenerative medicine.

血小板衍生生长因子(GFs)是一种生物活性肽,可增强组织修复机制,如血管生成、细胞外基质重塑和干细胞募集、趋化性、细胞增殖和分化等细胞效应。富血小板血浆(PRP)被用于各种临床应用,其前提是更高的GF含量应该促进更好的愈合。血小板衍生物代表了一种很有前途的治疗方式,为治疗伤口、溃疡、软组织损伤和细胞治疗中的各种其他应用提供了机会。PRP可以结合细胞疗法,如脂肪来源的干细胞、再生细胞疗法和转移因子疗法。本文介绍了血小板源性物质的生物学背景及其在再生医学中的潜在应用。
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引用次数: 191
Diverse Effects of Glutathione and UPF Peptides on Antioxidant Defense System in Human Erythroleukemia Cells K562. 谷胱甘肽和UPF肽对人红白血病细胞K562抗氧化防御系统的不同影响
Pub Date : 2012-01-01 Epub Date: 2012-02-15 DOI: 10.1155/2012/124163
Ceslava Kairane, Riina Mahlapuu, Kersti Ehrlich, Kalle Kilk, Mihkel Zilmer, Ursel Soomets

The main goal of the present paper was to examine the influence of the replacement of γ-Glu moiety to α-Glu in glutathione and in its antioxidative tetrapeptidic analogue UPF1 (Tyr(Me)-γ-Glu-Cys-Gly), resulting in α-GSH and UPF17 (Tyr(Me)-Glu-Cys-Gly), on the antioxidative defense system in K562 cells. UPF1 and GSH increased while UPF17 and α-GSH decreased the activity of CuZnSOD in K562 cells, at peptide concentration of 10 μM by 42% and 38% or 35% and 24%, respectively. After three-hour incubation, UPF1 increased and UPF17 decreased the intracellular level of total GSH. Additionally, it was shown that UPF1 is not degraded by γ-glutamyltranspeptidase, which performs glutathione breakdown. These results indicate that effective antioxidative character of peptides does not depend only on the reactivity of the thiol group, but also of the other functional groups, and on the spatial structure of peptides.

本文的主要目的是研究谷胱甘肽及其抗氧化四肽类似物UPF1 (Tyr(Me)-γ-Glu-Cys-Gly)中γ-Glu部分被α-Glu取代,从而产生α-GSH和UPF17 (Tyr(Me)-Glu-Cys-Gly)对K562细胞抗氧化防御系统的影响。肽浓度为10 μM时,UPF1和GSH使K562细胞CuZnSOD活性升高42%和38%,UPF17和α-GSH使CuZnSOD活性降低35%和24%。3小时后,UPF1升高,UPF17降低细胞内总谷胱甘肽水平。此外,研究表明UPF1不被γ-谷氨酰转肽酶降解,而γ-谷氨酰转肽酶进行谷胱甘肽分解。这些结果表明,肽的有效抗氧化特性不仅取决于巯基的反应性,还取决于其他官能团的反应性和肽的空间结构。
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引用次数: 9
Synthesis of hemopressin peptides by classical solution phase fragment condensation. 经典液相片段缩合法合成加压素多肽。
Pub Date : 2012-01-01 Epub Date: 2012-11-27 DOI: 10.1155/2012/186034
P Anantha Reddy, Sean T Jones, Anita H Lewin, F Ivy Carroll

A fragment condensation solution phase assembly of the naturally occurring CB(1) inverse agonist nonapeptides, Pro-Val-Asn-Phe-Lys-Phe/Leu-Leu-Ser-His-OH (hemopressins), and two other homologues: N-terminal 2-amino acid (dipeptide) extended undecapeptide, Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH, and three-amino acid (tripeptide) extended dodecapeptide, Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH, both CB(1) agonists, is reported.

报道了天然存在的CB(1)反激动剂非肽,pro - val - asn - ph - lys - phe /Leu-Leu-Ser-His-OH(加压素)的片段缩合液相组装,以及其他两个同源物:n端2氨基酸(二肽)延伸的非肽,val - asp - pro - val - asn - ph - lys -Leu-Leu-Ser-His-OH,和三氨基酸(三肽)延伸的十二肽,arg - val - asp - pro - val - asn - ph - lys -Leu-Leu-Ser-His-OH,都是CB(1)激动剂。
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引用次数: 7
Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. 血管紧张素转换酶2 (ACE2)是肾素血管紧张素系统在健康和疾病中的关键调节剂。
Pub Date : 2012-01-01 Epub Date: 2012-03-20 DOI: 10.1155/2012/256294
Chris Tikellis, M C Thomas

Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.

血管紧张素转换酶2 (ACE2)与血管紧张素转换酶(ACE)具有一定的同源性,但不受ACE抑制剂的抑制。ACE2的主要作用是降解Ang II,形成血管紧张素1-7 (angiotensin 1-7, Ang 1-7),与Ang II的作用相反。升高的Ang II水平被认为上调ACE2活性,在ACE2缺乏的小鼠中,Ang II水平大约是野生型小鼠的两倍,而Ang 1-7水平几乎无法检测到。因此,ACE2在RAS中起着至关重要的作用,因为它反对Ang II的作用。因此,在其表达减少的许多疾病中,如高血压、糖尿病和心血管疾病,它都有有益的作用。毫不奇怪,目前ACE2的治疗策略包括在这些疾病中使用ACE2腺病毒、重组ACE2或化合物来增加其表达,从而提供一些器官保护。
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引用次数: 488
A Novel Cellular Model to Study Angiotensin II AT2 Receptor Function in Breast Cancer Cells. 研究乳腺癌细胞中血管紧张素II AT2受体功能的新细胞模型。
Pub Date : 2012-01-01 Epub Date: 2011-12-06 DOI: 10.1155/2012/745027
Sylvie Rodrigues-Ferreira, Marina Morel, Rosana I Reis, Françoise Cormier, Véronique Baud, Claudio M Costa-Neto, Clara Nahmias

Recent studies have highlighted the AT1 receptor as a potential therapeutic target in breast cancer, while the role of the AT2 subtype in this disease has remained largely neglected. The present study describes the generation and characterization of a new cellular model of human invasive breast cancer cells (D3H2LN-AT2) stably expressing high levels of Flag-tagged human AT2 receptor (Flag-hAT2). These cells exhibit high-affinity binding sites for AngII, and total binding can be displaced by the AT2-selective antagonist PD123319 but not by the AT1-selective antagonist losartan. Of interest, high levels of expression of luciferase and green fluorescent protein make these cells suitable for bioluminescence and fluorescence studies in vitro and in vivo. We provide here a novel tool to investigate the AT2 receptor functions in breast cancer cells, independently of AT1 receptor activation.

最近的研究强调了AT1受体作为乳腺癌的潜在治疗靶点,而AT2亚型在该疾病中的作用在很大程度上仍然被忽视。本研究描述了一种新的人类浸润性乳腺癌细胞模型(D3H2LN-AT2)的产生和表征,该模型稳定表达高水平的flag标记的人类AT2受体(Flag-hAT2)。这些细胞表现出对AngII的高亲和力结合位点,并且总结合可以被at2选择性拮抗剂PD123319取代,但不能被at1选择性拮抗剂氯沙坦取代。有趣的是,荧光素酶和绿色荧光蛋白的高水平表达使这些细胞适合于体外和体内的生物发光和荧光研究。我们在这里提供了一种新的工具来研究乳腺癌细胞中AT2受体的功能,独立于AT1受体的激活。
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引用次数: 9
Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi. 人5HT1a受体胞内环2肽是Gi的差异激活因子。
Pub Date : 2012-01-01 Epub Date: 2012-05-09 DOI: 10.1155/2012/490734
Brian Hall, Carley Squires, Keith K Parker

Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor.

已经研究了人类5HT1a受体胞内环2 (ic2)的肽模拟物,通过干扰受体- g蛋白偶联来抑制激动剂结合的能力。这些肽具有较浅的浓度效应关系。此外,研究人员还研究了这些肽触发gi偶联受体信号转导系统的能力。两个信号参数已被量化:细胞内cAMP的浓度和GTP稳定类似物并入G蛋白的变化。在这两种情况下,ic2中环附近的肽模拟物实际上显示出激动剂活性,其效力在靠近tm3和tm4的环末端都下降。先前的结果表明,TM3/ic2界面附近的环区主要负责受体-G蛋白偶联,而当前的结果强调了ic2中间环区在初始偶联后激活G蛋白的能力。我们还研究了受体TM5/ic3环附近有限数量的肽对激动剂抑制和g蛋白激活的影响。这些肽提供了额外的证据,证明人类5HT1a受体TM5/ic3环区参与了偶联和激活作用。总的来说,这些结果为人类5HT1a受体/ g蛋白系统的潜在药理干预和药物开发提供了进一步的信息。最后,这里产生的结构证据提供了可测试的模型,等待结晶和受体的x射线分析。
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引用次数: 5
Identification and Characterization of a Novel Nontranslated Sequence Variant of the Human Intestinal Di-/Tripeptide Transporter, hPEPT1. 人类肠道二肽/三肽转运蛋白hPEPT1一种新的非翻译序列变异的鉴定和表征。
Pub Date : 2012-01-01 Epub Date: 2012-12-30 DOI: 10.1155/2012/743472
Helle Bach Søndergaard, Carsten Uhd Nielsen, Birger Brodin

The human H(+)-coupled di-/tripeptide transporter (hPEPT1) mediates intestinal absorption of dietary di- and tripeptides, as well as several peptidomimetic drug compounds. The aim of the present study was to investigate the possible role of the hPEPT1 variant hPEPT1-RF in hPEPT1 regulation. However, the proposed hPEPT1-RF mRNA sequence could not be detected in Caco-2 cells or in human intestinal samples. Instead, a new sequence variant, hPEPT1-RFI, was found, which is almost identical to the proposed hPEPT1-RF, except for two nucleotide insertions and one deletion that resulted in a changed open reading frame as compared to hPEPT1-RF. In vitro translation analysis showed that hPEPT1-RFI was not translated. In conclusion, the existence of hPEPT1-RF could not be confirmed; furthermore, the identified sequence variant, hPEPT1-RFI, does not appear to be translated and is therefore unlikely to have a regulatory effect on hPEPT1 transport activity.

人类H(+)偶联二肽/三肽转运蛋白(hPEPT1)介导膳食二肽和三肽以及几种拟肽药物化合物的肠道吸收。本研究的目的是探讨hPEPT1变异体hPEPT1- rf在hPEPT1调控中的可能作用。然而,所提出的hPEPT1-RF mRNA序列在Caco-2细胞或人类肠道样本中无法检测到。相反,发现了一个新的序列变体hPEPT1-RFI,它几乎与提出的hPEPT1-RF相同,除了两个核苷酸插入和一个缺失导致与hPEPT1-RF相比开放阅读框发生变化。体外翻译分析显示,hPEPT1-RFI未被翻译。综上所述,无法证实hPEPT1-RF的存在;此外,鉴定的序列变体hPEPT1- rfi似乎没有被翻译,因此不太可能对hPEPT1转运活性有调节作用。
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引用次数: 1
Ghrelin, appetite regulation, and food reward: interaction with chronic stress. 胃饥饿素、食欲调节和食物奖励:与慢性应激的相互作用。
Pub Date : 2011-01-01 Epub Date: 2011-09-21 DOI: 10.1155/2011/898450
Yolanda Diz-Chaves

Obesity has become one of the leading causes of illness and mortality in the developed world. Preclinical and clinical data provide compelling evidence for ghrelin as a relevant regulator of appetite, food intake, and energy homeostasis. In addition, ghrelin has recently emerged as one of the major contributing factors to reward-driven feeding that can override the state of satiation. The corticotropin-releasing-factor system is also directly implicated in the regulation of energy balance and may participate in the pathophysiology of obesity and eating disorders. This paper focuses on the role of ghrelin in the regulation of appetite, on its possible role as a hedonic signal involved in food reward, and on its interaction with the corticotropin-releasing-factor system and chronic stress.

在发达国家,肥胖已成为导致疾病和死亡的主要原因之一。临床前和临床数据提供了令人信服的证据,证明胃饥饿素是食欲、食物摄入和能量稳态的相关调节剂。此外,胃饥饿素最近被认为是奖励驱动进食的主要因素之一,它可以超越饱足状态。促肾上腺皮质激素释放因子系统也直接参与能量平衡的调节,并可能参与肥胖和饮食失调的病理生理。本文重点介绍了胃饥饿素在食欲调节中的作用,它作为一种参与食物奖励的享乐信号的可能作用,以及它与促肾上腺皮质激素释放因子系统和慢性应激的相互作用。
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引用次数: 41
期刊
International Journal of Peptides
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