内质网硒蛋白的研究进展

硒是哺乳动物必需的一种微量营养元素,主要以硒代半胱氨酸的形式存在于各种硒蛋白中,硒的主要生物功能通过硒蛋白实现.在25种哺乳动物硒蛋白中,有7种硒蛋白位于内质网,分别为2型脱碘酶、15-kDa硒蛋白、硒蛋白M、硒蛋白T、硒蛋白K、硒蛋白S和硒蛋白N.除了2型脱碘酶外,对其余内质网硒蛋白知之甚少.最近一些研究显示,一些内质网硒蛋白在氧化还原平衡调节、蛋白质折叠质量控制、错误折叠蛋白从内质网逆向转运至胞质、Ca2+稳态调节、内质网应激调节及炎症调节等过程中发挥作用.本文介绍了每种内质网硒蛋白的结构、功能及其生理和病理作用的一些最新研究进展,并对未来需要研究的内容进行了展望.     

以蛋自质为基础模拟谷胱甘肽过氧化物酶

硒元素作为一种生命体中必须的微量元素,与人类的健康和疾病息息相关.硒元素主要以硒代半胱氨酸的形式存在于至少25种硒蛋白中,执行着多种生物功能.在这20多种硒蛋白中,谷胱甘肽过氧化物酶( GPx)作为一种主要的抗氧化酶,能够有效地利用谷胱甘肽还原氢过氧化物以防止机体的氧化损伤.这里,我们主要介绍以蛋白质为骨架构筑GPx模...     

以蛋白质为基础模拟谷胱甘肽过氧化物酶

硒元素作为一种生命体中必须的微量元素,与人类的健康和疾病息息相关.硒元素主要以硒代半胱氨酸的形式存在于至少25种硒蛋白中,执行着多种生物功能.在这20多种硒蛋白中,谷胱甘肽过氧化物酶(GPx)作为一种主要的抗氧化酶,能够有效地利用谷胱甘肽还原氢过氧化物以防止机体的氧化损伤.这里,我们主要介绍以蛋白质为骨架构筑GPx模拟物的一些策略和方法,以期望于能够更好的理解硒蛋白的生物学性质,甚至开拓更为有效的技术去模拟这种抗氧化酶.     

硒蛋白S的生物学功能

硒蛋白S是一种新发现的内质网和细胞膜驻留硒蛋白。以往的研究结果揭示硒蛋白S可以保护细胞拮抗氧化损伤及内质网应激诱导的细胞凋亡;参与脂蛋白代谢、精子发育过程、炎症反应及将错误折叠蛋白从内质网腔逆向转移到细胞质中然后降解的过程(即内质网相关蛋白降解)。硒蛋白S基因多态性与糖尿病、冠状动脉心脏病或先兆子痫等疾病密切相关。本文结合本课题组的工作对硒蛋白S的最新研究进展,尤其是硒蛋白S功能的研究成果作了较为详细的介绍,并对未来的研究方向作了展望。     

硒蛋白R——一个独特的甲硫氨酸亚砜还原酶

硒蛋白是一类以硒代半胱氨酸为活性中心的蛋白质,利用硒氢基的强还原性,硒蛋白在生物体内发挥重要的抗氧化功能。目前发现,人类基因组中有25种硒蛋白的编码基因,其中硒蛋白R是唯一一个含有硒代半胱氨酸的甲硫氨酸亚砜还原酶,它位于细胞质及细胞核中,由于其空间结构和硒元素的强亲核性,硒蛋白R能特异性还原R型甲硫氨酸亚砜中被氧化的硫元素。硒蛋白R能够与肌动蛋白、瞬时电位通道蛋白及β-淀粉样蛋白等多种蛋白质相互作用,可能在中枢神经系统中具有重要的功能,并与神经退行性疾病的发生发展具有密切关系。     

蛋氨酸亚砜还原酶及其在白内障发生发展中的作用

蛋氨酸(Met)是生物体内很容易被氧化的氨基酸之一,氧化应激条件下,生成S型和R型蛋氨酸亚砜(MetO), 晶状体蛋白中MetO的增加与晶状体老化和白内障形成相关。生物体内存在着两种不同的蛋氨酸亚砜还原酶(Msr),即MsrA和B,分别能特异性地作用于自由或结合在蛋白质中的S-MetO和R-MetO,将MetO修复为Met,从而避免了蛋白质结构和功能的改变。在哺乳动物中,MsrA以单基因形式存在,而MsrB有3种异构体,分别为MsrB1,MsrB2和MsrB3,其中MsrB1是一个硒蛋白,又被称为硒蛋白R(SelR)。本文介绍了Msrs的基因表达、分布和亚细胞定位,比较了MsrA和MsrBs蛋白结构和催化机制的异同,讨论了晶状体蛋白Met残基的氧化与白内障形成和发展的关系。现有的这些研究结果表明Msrs作为一类特异性的抗氧化还原酶,通过对MetO的修复,在抑制晶状体的损伤方面发挥重要作用。此外,MsrB1作为一个硒蛋白受机体硒水平的调节,因此,通过补硒保持晶状体适当的硒浓度以维持MsrB1的活性,对白内障的形成和发展可能具有一定的预防作用。     

硒蛋白M及其与重大疾病的关系

硒蛋白M(SelM)是2002年应用生物信息学方法发现的一种内质网硒蛋白,其二级结构中含有一个氧化还原调节基序CXXU,且该蛋白在脑中大量表达。SelM因具有维持机体氧化还原水平、保护神经细胞和调节钙稳态平衡等重要作用,近年成为研究热点。本文结合本课题组的研究结果,对硒蛋白M的最新研究进展、生物功能、与重大疾病的关系及今后研究方向等方面进行了综述和展望。     

硒蛋白S的结构、功能及与疾病的关系

硒是一种人体必需的微量营养元素,其主要生物功能是通过硒蛋白实现。硒蛋白S （SELENOS）是一种主要存在于内质网膜的硒蛋白,参与了内质网相关蛋白降解过程。SELENOS主要是通过胞质中的卷曲螺旋结构域和C-端含硒代半胱氨酸残基的无规结构区发挥生物功能的。大量体外研究结果显示,SELENOS有调节氧化应激、内质网应激、炎症等功能,进而可能影响心血管疾病、2型糖尿病、阿尔茨海默症等疾病的发生发展。此外,流行病学观察研究发现SELENOS基因的多种单核苷酸多态性与心血管疾病、癌症等疾病密切相关。本文综述了SELENOS结构、功能及与疾病的关系,总结了SELENOS研究中尚待解决的问题,并对其未来的发展方向进行了展望。     

硒蛋白的分子生物学及与疾病的关系*

硒蛋白是微量元素硒在体内存在和发挥生物功能的主要形式。因硒蛋白的活性中心硒代半胱氨酸由传统终止码TGA编码,故从基因组中预测硒蛋白以及用基因工程技术表达硒蛋白均很困难。有关硒抗氧化、对癌症、神经退行性疾病和病毒作用的报导较多,但结论并不一致。本文综述了硒蛋白基因预测、蛋白质表达调控以及硒和硒蛋白对癌症、神经退行性疾病和病毒的作用及机制等方面的近期进展,研究提高硒蛋白生物信息学预测准确率和基因工程表达量的方法,分析了解硒蛋白与疾病发生发展的关系和机制,探索不同硒蛋白作为预防药物开发、作为癌症治疗和药物筛选靶标的可能性。     

硒蛋白与糖尿病——硒的两面性

糖尿病是危害人类健康的全球性重大疾病,胰岛素抵抗是诱发2型糖尿病的重要因素。微量必需元素硒与人体健康密切相关,通过硒蛋白发挥多种重要生物学功能。近年来硒与糖尿病的关系引人关注,早期研究表明硒具有类胰岛素作用,可望用于防治糖尿病,但近来的人群试验和动物研究却表明硒在糖尿病发生发展中的作用具有两面性,长期补充一定剂量的硒反而增加了胰岛素抵抗和2型糖尿病的发病率。而且,硒在糖尿病发生发展中的两面性被证实与几种硒蛋白密切相关,包括谷胱甘肽过氧化物酶1(GPx1)、硒蛋白S(SelS)和硒蛋白P(SelP)等。本文结合本课题组的工作介绍了硒在糖尿病中的两面性以及硒蛋白在糖尿病发生发展中的作用,并对未来的研究方向进行了展望。     

Effect of selenium in organic and inorganic form on liver,kidney, brain and muscle of <Emphasis Type="Italic">Wistar</Emphasis> rats

Selenium is a micronutrient, localized in the active sites of enzymes such as glutathione peroxidase and thioredoxin reductase, and participating together with these enzymes in an antioxidant defence system of organisms against free radicals. Administration of selenium is necessary for maintaining oxidative homeostasis. The present experiment is aimed at investigation of selenium impact on basal metabolic processes and selected antioxidants in a Wistar rat model, fed selenium in organic and inorganic forms. Liver, kidney, brain and muscle were sampled during a month-long feeding with four different doses of selenium (0.075 mg or 1.5 mg of inorganic and/or organic selenium per kg of feed). We found a significant reduction in glutathione level in liver tissue regardless of the form of the administered selenium. On the other hand, selenium caused a decreased glutathione reductase level in the liver and metallothionein level in the liver, kidney and muscle.      

五味子联苯环辛烯类木脂素成分的结构与药理活性关系和药物创新

传统中药五味子具有多种药理活性。20世纪70年代以来,我国临床发现五味子能改善慢性肝炎病人的肝功能异常,在此基础上,我所化学家和药理学家对五味子分离得到的20余种联苯环辛烯类木酯素成分和其药理作用进行了大量研究。五味子的药理活性主要有:保肝,抗氧化,诱导肝药酶,增强解毒功能,促进蛋白质、糖原合成,克服肿瘤耐药性,增强对抗药癌的敏感性以及对中枢神经系统的镇静作用。在这些研究基础上,合成了保肝作用最强的五味子丙素结构类似物,相继研制出两种抗肝炎新药联苯双酯（DDB）和双环醇（bicyclol）。本文对五味子木脂素类成分的结构与药理活性关系以及两种新药的创制做一综述。     

基于金属的神经退行性疾病治疗策略*

本文综述了金属离子在神经退行性疾病中的重要作用以及针对该类疾病金属治疗药物的研究进展。以老年痴呆症和帕金森氏症为代表,结合本课题组的初步研究结果,讨论了金属离子在蛋白质聚集与氧化应激反应中的重要作用,暗示金属螯合策略应成为治疗该类疾病的首选策略,并介绍了数种已用于或即将用于临床实验的金属螯合制剂;还介绍了烷基化神经退行性疾病相关蛋白的金属结合位点,可以显著抑制该蛋白质聚集体的形成和活性氧的产生,这可能是继螯合策略后一种更有发展潜力的神经退行性疾病治疗方法。     

Extract of Triticum aestivum Sprouts Suppresses Acetaminophen-Induced Hepatotoxicity in Mice by Inhibiting Oxidative Stress

Wheat (Triticum aestivum L.) is the oldest known food crop, and many studies have reported that wheat shoots (i.e., wheatgrass) possess anti-cancer, anti-inflammatory, and antioxidant activities. However, the potentially ameliorative effect of wheat shoots on hepatotoxicity caused by high doses of N-acetyl-para-aminophenol (acetaminophen, APAP) has yet to be reported. C57BL/6 mice received daily oral TAE (100 or 200 mg/kg), positive control (silymarin 100 mg/kg), or negative control (saline vehicle) treatments for 7 days prior to intraperitoneal APAP injection. Histological, serum (ELISA), Western blotting, and quantitative PCR analyses of excised liver tissues were then performed. Pre-treatment with TAE (100 or 200 mg/kg) ameliorated APAP-induced pathological damage (i.e., hepatotoxic lesions), reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and also ameliorated APAP-induced increases in oxidative stress, thereby inhibiting oxidative liver damage and reducing the expression of inflammatory cytokines. In addition, TAE pre-treatment inhibited the expression of Cytochrome P4502E1 (CYP2E1), which is a key enzyme in the onset of APAP-induced hepatotoxicity, suppressed the expression of the target proteins regulated by the antioxidant enzyme Nrf2, and suppressed hepatocyte apoptosis. These findings suggest that TAE is an attractive therapeutic candidate that exhibits potential hepatoprotective activity by inhibiting oxidative stress, inflammation, apoptosis, and liver damage.     

超级化学镀铜填充微道沟的研究

超级化学铜填充技术不仅可以应用于半导体超大集成电路铜互连线, 而且可以应用于三维封装. 研究了不同浓
度、不同分子量的PEG 对以甲醛为还原剂的化学镀铜溶液中铜的沉积速率的影响. 随着添加剂PEG 浓度和分子量的
增大, 化学铜的沉积速率明显降低. 电化学研究结果表明PEG 通过抑制甲醛的氧化反应降低化学铜的沉积速率, PEG
分子量越大, 对化学铜的抑制作用越强. 利用PEG-6000 对化学铜的抑制作用和在溶液中低的扩散系数, 采用添加
PEG-6000 的化学镀铜溶液, 成功地实现了宽度在0.2 μm 以下微道沟的超级化学填充. 就PEG 的分子量、微道沟的深
径比等因素对超级化学铜填充的影响也做了研究.     

Potential Benefits of Flavonoids on the Progression of Atherosclerosis by Their Effect on Vascular Smooth Muscle Excitability

Flavonoids are a group of secondary metabolites derived from plant-based foods, and they offer many health benefits in different stages of several diseases. This review will focus on their effects on ion channels expressed in vascular smooth muscle during atherosclerosis. Since ion channels can be regulated by redox potential, it is expected that during the onset of oxidative stress-related diseases, ion channels present changes in their conductive activity, impacting the progression of the disease. A typical oxidative stress-related condition is atherosclerosis, which involves the dysfunction of vascular smooth muscle. We aim to present the state of the art on how redox potential affects vascular smooth muscle ion channel function and summarize if the benefits observed in this disease by using flavonoids involve restoring the ion channel activity.     

SOD模拟及其抗氧化和抗炎症功能的研究进展*

超氧化物歧化酶(superoxide dismutase, 简称SOD) 作为生物体内超氧离子自由基的清除剂, 具备有效抗氧化、抗炎症、抗衰老之功效, 并用于临床, 其化学模拟引起了人们的广泛研究兴趣。本文将简要介绍近年来SOD 人工模拟酶及其生物医学活性研究所取得的重要进展, 特别是Cu,Zn-SOD 模拟物结构与功能的相互关系、Mn-SOD 模拟物的生物活性及其医学应用。     

Influence of ShuJinHuoXue tablets on ischemia reperfusion injury of animals' skeletal muscle

Ischemia-reperfusion (IR) can lead to serious tissue oxidative injury in animals. ShuJinHuoXue tablet (SJHXT) is a Chinese Traditional Medicine which can relax the muscles and stimulate the blood circulation and has been used as a clinical medicine. In the present study, we investigated the effects of SJHXT pretreatment on oxidative injury using an animal model of acute limb IR. Results showed that SJHXT pre-treatment (200, 300 and 400 mg/kg/day) markedly reduced serum endothelin-1 (ET-1), thromboxane B2 (TXB?) levels and thromboxane B2/6-keto- prostaglandin F1α (TXB?/6-Keto-PGF(1α)), wet weight/dried weight (W/D) ratio, myeloperoxidase (MPO), creatine kinase (CK), lactate dehydrogenase (LDH) activities, and increased serum nitric oxide (NO), 6-Keto-PGF(1α) levels and NO/ET-1 ratio in the IR+SJHXT groups. In addition, the SJHXT pre-treatment (200, 300 and 400 mg/kg/day) markedly reduced skeletal muscle Ca2?, malondialdehyde (MDA) levels, increased Na?-K?-ATPase, Ca2?-Mg2?-ATPase, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities. Our results suggest that SJHXT pre-treatment may improve skeletal muscle blood vessel microcirculation, decrease skeletal muscle oxidative injury and enhance antioxidant enzymes activities in IR animals.     

The effect of ferulic acid ethyl ester on leptin-induced proliferation and migration of aortic smooth muscle cells

Leptin is a peptide hormone, which has a central role in the regulation of body weight; it also exerts many potentially atherogenic effects. Ferulic acid ethyl ester (FAEE) has been approved for antioxidant properties. The aim of this study was to investigate whether FAEE can inhibit the atherogenic effects of leptin and the possible molecular mechanism of its action. Both of cell proliferation and migration were measured when the aortic smooth muscle cell (A10 cell) treated with leptin and/or FAEE. Phosphorylated p44/42MAPK, cell cycle-regulatory protein (for example, cyclin D1, p21, p27), β-catenin and matrix metalloproteinase-9 (MMP-9) proteins levels were also measured. Results demonstrated that leptin (10, 100 ng ml⁻¹) significantly increased the proliferation of cells and the phosphorylation of p44/42MAPK in A10 cells. The proliferative effect of leptin was significantly reduced by the pretreatment of U0126 (0.5 μM), a MEK inhibitor, in A10 cells. Meanwhile, leptin significantly increased the protein expression of cyclin D1, p21, β-catenin and decreased the expression of p27 in A10 cells. In addition, leptin (10 ng ml⁻¹) significantly increased the migration of A10 cells and the expression of MMP-9 protein. Above effects of leptin were significantly reduced by the pretreatment of FAEE (1 and 10 μM) in A10 cells. In conclusion, FAEE exerts multiple effects on leptin-induced cell proliferation and migration, including the inhibition of p44/42MAPK phosphorylation, cell cycle-regulatory proteins and MMP-9, thereby suggesting that FAEE may be a possible therapeutic approach to the inhibition of obese vascular disease.