Legumain在恶性肿瘤中的研究现状

Legumain是一种溶酶体半胱氨酸蛋白酶,是半胱氨酸蛋白酶C13家族的新成员.研究表明,Legumain作为一种应激性蛋白,在多种实体瘤、肿瘤相关巨噬细胞(TAMs)、肿瘤新生血管的内皮细胞中高表达,与恶性肿瘤的血管生成、肿瘤侵袭、扩散和转移密切相关,是近年来备受关注的一类靶标蛋白酶.对Legumain的深入研究将有利于阐明恶性实体瘤的发病机制,明确其作为肿瘤基因治疗新靶标的有效性.     

瞬时受体电位通道M2在恶性肿瘤中的作用

瞬时受体电位通道M2(transient receptor potential channel melastatin 2, TRPM2)是人体中一个重要的Ca²⁺通透性非选择性阳离子通道,通常表达于正常细胞胞膜和溶酶体膜上,并在氧化应激中发挥重要的离子调节作用。但近年发现,TRPM2也在多种恶性肿瘤(神经母细胞瘤,舌/喉鳞状细胞癌,肺癌,乳腺癌,胃癌,胰腺癌,膀胱癌,前列腺癌和T细胞白血病)中高表达,能通过调节细胞线粒体功能和自噬促进肿瘤细胞的生物学能量而促进其生存能力,通过调节抗氧化物水平增强细胞对氧化刺激的耐受力而表现出化疗抵抗作用。同时,在肿瘤细胞膜上该通道大量激活又对化疗药物联合使用发挥协同作用。此外,TRPM2能通过激活多种不同的分子的信号通路,促进细胞增殖、侵袭和转移能力。总之,根据肿瘤的不同,TRPM2对肿瘤细胞生物学行为的调控机制也不同,甚至具有复杂的双重作用。所以,对TRPM2的生化及分子机制的研究必将使我们对肿瘤的发生发展的认识更加全面。本文将从TRPM2蛋白质的结构,生理功能及肿瘤机制等不同角度系统阐述TRPM2的研究现状和进展。     

Antioxidant status,lipid peroxidation,mixed function oxidase and UDP-glucuronyl transferase activities in livers from control and DOCA salt-hypertensive male Sprague Dawley rats

The effects of DOCA-salt hypertensive treatment on hepatic glutathione-dependent defense system, antioxidant enzymes, lipid peroxidation, mixed function oxidase and UDP-glucuronyl transferase activities were investigated in male Sprague Dawley rats.Compared with controls, DOCA-salt hypertensive rats had lower body weights (linked to liver hypertrophy). Mixed function oxidase and p-nitrophenol-UGT activities were not affected by the treatment but a significant lower rate of the glucuronoconjugation rate of bilirubin (p < 0.001) was observed in DOCA-salt hypertensive rats. While cytosolic glutathione contents and glutathione reductase activity were not affected, glutathione peroxidase (p < 0.001), glutathione transferase (p < 0.001) and catalase (p < 0.01) activities were decreased and associated with higher malondialdehyde contents (p < 0.001) in treated rats. The imbalance in liver antioxidant status (increasing generation of cellular radical species), associated with increases in lipid peroxidation, suggests that oxidative stress might be directly related to arterial hypertension in DOCA-salt treated male Sprague Dawley rats.     

光动力疗法在腹部恶性肿瘤的应用

近年来光动力治疗已经应用在腹部的恶性肿瘤的治疗上,并且取得了满意的疗效.对于部分腹部恶性肿瘤,相应的研究在实验室里也有报道.通过对光动力治疗的原理、机制、光敏剂,以及腹部恶性肿瘤光动力治疗相关的文献进行了综述,总结了光动力治疗应用在腹部恶性肿瘤的优势和相关问题.     

神经菌毛素1在恶性肿瘤治疗中的相关研究进展

作为一种跨膜糖蛋白,神经菌毛素1(NRP1)在轴突导向、血管生成和肿瘤免疫等多种反应过程中发挥重要作用。NRP1高表达于多种肿瘤细胞表面,尤其是上皮细胞肿瘤。阻断NRP1不仅能直接对肿瘤细胞的迁移及肿瘤的发生发展产生抑制作用,而且能够间接抑制肿瘤局部血管的生成与发展,继而影响肿瘤的生长发展。因此,NRP1有望成为抗肿瘤治疗的新突破点。简要探讨NRP1在肿瘤发生发展中的作用,以及以NRP1为靶点治疗恶性肿瘤的相关研究进展。     

恶性卵巢肿瘤淋巴转移与相关基因表达

恶性卵巢肿瘤严重威胁着妇女健康和生命,其重要原因之一是易发生淋巴转移,给临床诊断和治疗带来困难。近年来国内外对恶性卵巢肿瘤淋巴转移的机制及其与相关基因表达进行了一系列的研究,现就这方面的进展作一综述。     

铁死亡的生化过程及对肿瘤的影响

铁死亡(ferroptosis）是近年提出的一种调节性细胞死亡方式,主要依赖于细胞内铁和脂质活性氧（reactive oxygen species, ROS）积累所引起的细胞死亡。铁死亡的发生与多种生物化学过程密切相关,包括多不饱和脂肪酸、铁和氨基酸代谢,以及谷胱甘肽、磷脂、烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate, NADPH）和辅酶Q10的生物合成。与正常细胞相比,肿瘤细胞内ROS水平通常较高,因而与ROS有关的铁死亡对肿瘤疾病的影响引人注目。在调节肿瘤细胞如卵巢恶性肿瘤、头颈部癌、弥漫性大B细胞淋巴瘤、肝癌,以及横纹肌肉瘤的生长和增殖中,铁死亡发挥了不可忽视的作用。本文主要阐述了各种生物化学过程对铁死亡的影响,以及铁死亡在肿瘤疾病中的研究进展,为肿瘤疾病的治疗提供新思路。     

线粒体核糖体蛋白质与人类恶性肿瘤

线粒体拥有自身独特的核糖体--线粒体核糖体,用于翻译线粒体DNA（mitochondrial DNA, mtDNA）编码的基因。线粒体核糖体由核基因编码的线粒体核糖体蛋白质(mitochondrial ribosomal protein, MRPs)和线粒体自身编码的rRNA组装而成。MRPs表达失调会引发代谢紊乱、呼吸链受损,导致细胞发生功能障碍和异常增殖,甚至发生癌变等恶性转化。大量研究证明,MRPs在不同的肿瘤细胞中表达异常,提示着MRPs在肿瘤发生发展过程中发挥着重要作用。本文就线粒体核糖体蛋白质与人类恶性肿瘤发生的关系作一综述,为进一步阐明其在恶性肿瘤发生过程中的作用机制奠定基础。     

镉诱导的菊芋幼苗膜脂过氧化和抗氧化酶活性及过氧化物酶同工酶的改变

用含有不同浓度(0~400μmol/L)Cd(NO3)2的Hoagland营养液处理砂培的菊芋。处理50d后,测定植物体内镉积累量以及过氧化物酶(POD)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性,并对POD同工酶进行电泳分析。发现在Cd50~100μmol/L浓度内,随着镉浓度的升高,菊芋根和叶中镉的积累量显著增加,而随后积累量的增加有所减少。根和叶中MDA含量显著上升,说明镉引起了膜脂过氧化。0~100μmol/LCd处理,根和叶中POD活性随Cd浓度增加而增强,而在200~400μmol/LCd处理下有所减弱。根和叶SOD活性在50~200μmol/LCd处理下随Cd浓度增加而增强,而在400μmol/LCd处理下SOD活性明显受到抑制。根和叶CAT活性随Cd浓度升高而增强。电泳结果显示,POD同工酶变化明显,镉诱导出一条新酶带LP10。菊芋POD同工酶可以作为镉污染的土壤的生物指示剂。     

Effects of chronic quercetin treatment on hepatic oxidative status of spontaneously hypertensive rats

The effects of chronic administration of an oral daily dose of quercetin (10 mg Kg^–1), the most abundant dietary flavonoid, were investigated on hepatic oxidative status in spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Decreased liver glutathione peroxidase activity, increased liver total glutathione levels and increased both hepatic and plasmatic malondialdehyde concentrations were observed in spontaneously hypertensive rats when compared to Wistar Kyoto rats. In spontaneously hypertensive rats, treatment with quercetin for 5 weeks reduced blood pressure, increased glutathione peroxidase activity and reduced both plasma and hepatic malondialdehyde levels. However, none of these effects were observed in Wistar Kyoto rats. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of genetic hypertension.     

Lipid peroxidation and antioxidant enzyme activities in erythrocytes of type I and II alcoholics

Reduced and oxidized glutathione (GSH and GSSG), protein-bound glutathione, lipid peroxidation and antioxidant enzyme activities were determined in the erythrocyte lysates and membranes of type I and II alcoholics in order to clarify the effect of age-of-onset and the duration of the alcohol consumption on erythrocyte oxidant and antioxidant status. The osmotic fragility and susceptibility of the erythrocytes to haemolysis were also determined. Erythrocyte lipid peroxidation was significantly increased but, GSH and protein-bound GSH, GSH/GSSG ratio and antioxidant enzyme activities were markedly decreased in the erythrocytes of the alcoholic subgroups. Erythrocyte count and haemoglobin content in the blood of alcoholics were found to be decreased in accordance with the finding that erythrocytes were more fragile and less resistant to haemolysis particularly in type II alcoholics. The present study showed that ethanol-induced oxidative stress in erythrocytes can lead to haemolysis and membrane-specific injuries in erythrocytes of the alcoholic subtypes.     

Up-regulation of the leaf mitochondrial and peroxisomal antioxidative systems in response to salt-induced oxidative stress in the wild salt-tolerant tomato species Lycopersicon pennellii

The response of the antioxidative systems of leaf cell mitochondria and peroxisomes of the cultivated tomato Lycopersicon esculentum (Lem) and its wild salt-tolerant related species Lycopersicon pennellii (Lpa) to NaCl 100 mM stress was investigated. Salt-dependent oxidative stress was evident in Lem mitochondria as indicated by their raised levels of lipid peroxidation and H2O2 content whereas their reduced ascorbate and reduced glutathione contents decreased. Concomitantly, SOD activity decreased whereas APX and GPX activities remained at control level. In contrast, the mitochondria of salt-treated Lpa did not exhibit salt-induced oxidative stress. In their case salinity induced an increase in the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and glutathione-dependent peroxidase (GPX). Lpa peroxisomes exhibited increased SOD, APX, MDHAR and catalase activity and their lipid peroxidation and H2O2 levels were not affected by the salt treatment. The activities of all these enzymes remained at control level in peroxisomes of salt-treated Lem plants. The salt-induced increase in the antioxidant enzyme activities in the Lpa plants conferred cross-tolerance towards enhanced mitochondrial and peroxisomal reactive oxygen species production imposed by salicylhydroxamic acid (SHAM) and 3-amino-1,2,4-triazole (3-AT), respectively.     

Does the grasshopper Chorthippus brunneus adapt to metal polluted habitats? A study of glutathione‐dependent enzymes in grasshopper nymphs

Glutathione contents and activity of glutathione-dependent enzymes in the body of insects inhabiting polluted areas depend on toxin kind, concentration and exposure time. Enzymatic response may be modified by gender, age, developmental stage and state of nutrition. Also, chronic exposure to metals in the environment may cause the selection of individuals resistant to some environmental toxins. To assess the degree of adaptation of Chorthippus brunneus to metal-polluted habitats, we measured glutathione contents and the activity of selected glutathione-dependent enzymes in the offspring of aging mothers which differed in time and intensity of exposure to metals in their habitats. We tested whether differences represent temporal shifts in tolerance range or were genetically preserved and inherited by future generations. We investigated insects from three populations. Two live in heavily metal-burdened areas, exposed to metals for 170 (Szopienice) or 50 years (Olkusz) and the third inhabits an unpolluted reference site (Pilica). The most important findings were age-by-site interactions for all biochemical analyses. Nymphs from Szopienice had lower glutathione contents and lower glutathione-dependent enzyme activity in comparison with nymphs from the reference site. This was especially distinct in nymphs hatched from eggs laid by young females. The offspring of aging females from Olkusz, in terms of glutathione contents and glutathione reductase activities, revealed similar patterns to those from the reference site. For the remaining parameters, enzyme activity patterns in nymphs from Olkusz were similar to those of nymphs from Szopienice.     

Role of zinc on lipid peroxidation and antioxidative enzymes in intestines of ethanol-fed rats

This study was undertaken to investigate the effects of zinc on lipid peroxidation and various antioxidative enzymes in the intestines of male Wistar rats fed on ethanol. It was observed that NADPH-dependent lipid peroxidation (LP) was significantly increased upon ethanol treatment for 4 and 8 wk. The concentraton of glutathione as well as the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were also found to be significantly increased upon ethanol feeding at all of the treatment intervals. The glutathione levels were found to be further elevated upon combined zinc and ethanol treatments. Interestingly, the administration of zinc to ethanol-fed rats was able to bring down the elevated levels of LP, catalase, SOD, and GPx, thus indicating the antiperoxidative potential of zinc under such conditions.     

长链脂酰辅酶A合成酶家族与恶性肿瘤

脂肪酸代谢紊乱容易导致癌症的发生。长链脂酰辅酶A合成酶家族(long chain acyl-coenzyme A synthetase family,ACSLs)负责激活长链脂肪酸,在脂肪酸代谢中发挥重要作用。但在癌细胞中,其调控作用经常被解除,细胞内脂肪酸的分布、种类和数量发生改变,进而导致癌症和其他代谢性疾病的发生。ACSLs 在哺乳动物中包括5种亚型,分别为ACSL1、3、4、5和6。ACSL1在甘油三脂的合成和分配中发挥重要作用;ACSL3有助于脂滴的形成,脂滴对维持脂质稳态具有重要作用;ACSL4的表达与类固醇激素相关,在铁死亡途径中发挥重要作用;ACSL5可以催化外源性脂肪酸的代谢,但不能催化从头合成脂肪酸的代谢;ACSL6在脑内的脂肪酸代谢及生殖器官中精子发生和卵巢功能维持等方面发挥重要作用。ACSLs的调控因子包括转录因子、共激活因子、激素受体、蛋白激酶和小的非编码RNA等。它们通过介导脂肪酸代谢,广泛参与线粒体介导的能量代谢,内质网应激和肿瘤炎性微环境等。此外,ACSLs还作为独立预后因素,成为各种癌症临床诊断和治疗的生物标志物和治疗靶点。近年来,越来越多的研究表明,ACSL家族在癌症的发生发展进程中发挥重要作用。本文从ACSL基因家族,ACSLs与恶性肿瘤及基于ACSLs脂代谢的肿瘤治疗方面进行阐述,为后续ACSL基因家族的研究及肿瘤的靶向治疗提供理论依据和候选分子靶标。     

Oxidative stress and antioxidants in tomato (Solanum lycopersicum) plants subjected to boron toxicity

BACKGROUND AND AIMS: Boron (B) toxicity triggers the formation of reactive oxygen species in plant tissues. However, there is still a lack of knowledge as to how B toxicity affects the plant antioxidant defence system. It has been suggested that ascorbate could be important against B stress, although existing information is limited in this respect. The objective of this study was to analyse how ascorbate and some other components of the antioxidant network respond to B toxicity. METHODS: Two tomato (Solanum lycopersicum) cultivars ('Kosaco' and 'Josefina') were subjected to 0.05 (control), 0.5 and 2 mm B. The following were studied in leaves: dry weight; relative leaf growth rate; total and free B; H(2)O(2); malondialdehyde; ascorbate; glutathione; sugars; total non-enzymatic antioxidant activity, and the activity of superoxide dismutase, catalase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase, ascorbate oxidase and l-galactose dehydrogenase. KEY RESULTS: The B-toxicity treatments diminished growth and boosted the amount of B, malondialdehyde and H(2)O(2) in the leaves of the two cultivars, these trends being more pronounced in 'Josefina' than in 'Kosaco'. B toxicity increased ascorbate concentration in both cultivars and increased glutathione only in 'Kosaco'. Activities of antioxidant- and ascorbate-metabolizing enzymes were also induced. CONCLUSIONS: High B concentration in the culture medium provokes oxidative damage in tomato leaves and induces a general increase in antioxidant enzyme activity. In particular, B toxicity increased ascorbate pool size. It also increased the activity of l-galactose dehydrogenase, an enzyme involved in ascorbate biosynthesis, and the activity of enzymes of the Halliwell-Asada cycle. This work therefore provides a starting point towards a better understanding of the role of ascorbate in the plant response against B stress.     

Antioxidant enzyme activities and lipid peroxidation induced by eicosapentaenoic acid (EPA) in PC12 cells

Eicosapentaenoic acid (EPA) is one of the major dietary polyunsaturated fatty acids and induces apoptosis in several cancer cells. In this study, the EPA induced lipid peroxidation and response of antioxidative enzymes have been investigated in rat pheochromocytoma PC12 cells to elucidate the mechanisms of apoptosis induced by the polyunsaturated fatty acid EPA. We have analyzed superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities and glutathione (GSH) contents in PC12 cells after exposure to different concentrations of EPA. Lipid peroxidation was shown to increase in the presence of EPA as an indication of the oxidative damage. Lipid peroxidation was enhanced by EPA in a dose-dependent manner, and the loss of cell viability was partially reversed by vitamin E. In the case of antioxidant enzyme activities, SOD and GPX activities and GSH contents increased significantly at 50 μmol/L EPA and were respectively 2.41-fold (p < 0.01), 3.49-fold (p < 0.05), and 1.43-fold (p < 0.05) higher than controls. The CAT activity at 10 μmol/L had the highest value and was increased by 25.83% (p < 0.05) compared to control. The results suggest that in PC12 cells the mechanism of apoptosis induced by EPA may be partly due to lipid peroxidation.     

Protection by ebselen against cisplatin-induced nephrotoxicity: Antioxidant system

This study was designed to investigate the cisplatin-induced alteration in renal antioxidant system and the nephroprotection with ebselen. Male Wistar rats were injected with (1) vehicle control; (2) cisplatin; (3) ebselen; and (4) cisplatin plus ebselen. Rats were sacrificed three days post-treatment and plasma as well as kidney were isolated and analyzed. Plasma creatinine increased 598% following cisplatin administration alone which decreased by 158% with ebselen pretreatment. Cisplatin-treated rats showed a depletion of renal glutathione (GSH) levels (52% of control), while cisplatin plus ebselen injected rats had GSH values close to the controls. Antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities decreased 38, 75 and 62% of control, respectively, and malondialdehyde (MDA) levels increased 174% of control following cisplatin administration, which were restored to control levels after ebselen treatment. The renal platinum level did not significantly change with ebselen pretreatment. This study suggests that the protection offered by ebselen against cisplatin-induced nephrotoxicity is partly related to the sparing of antioxidant system.     

Age and sex differences in human skeletal muscle: Role of reactive oxygen species

Previous studies, conducted on experimental animals, have indicated that reactive oxygen species (ROS) are involved in the aging process. The objective of this work was to study the relationship between oxidative damage and human skeletal muscle aging, measuring the activity of the main antioxidant enzymes superoxide dismutase (total and MnSOD), glutathione peroxidase (GPx) and catalase in the skeletal muscle of men and women in the age groups: young (17–40 years), adult (41–65 years) and aged (66–91 years). We also measured glutathione and glutathione disulfide (GSH and GSSG) levels and the redox index; lipid peroxidation and protein carbonyl content. Total SOD activity was lower in the 66–91 year-old vs. the 17–40 year-old men; MnSOD activity was significantly greater in 66–91 year-old vs. 17–40 year-old women. GPx activity remained unchanged. The activity of catalase was lower in adults than in young men but higher in the aged. We observed no changes in GSH levels and significantly higher GSSG levels only in aged men vs. adult men, and a significant decrease in aged women vs. aged men. The protein carbonyl content increased significantly in the 41–65 and 66–91 year-old vs. the 17–40 year-old men. Finally, young women have lower lipid peroxidation levels than young men. Significantly higher lipid peroxidation levels were observed in aged men vs. both young and adult men, and the same trend was noticed for women. We conclude that oxidative damage may play a crucial role in the decline of functional activity in human skeletal muscle with normal aging in both sexes; and that men appear to be more subject to oxidative stress than women.     

Acute Hexachlorocyclohexane-Induced Oxidative Stress in Rat Cerebral Hemisphere

Hexachlorocyclohexane (HCH) is reported to induce oxidative stress in liver and testis of rat. With an objective to examine its effect on brain tissue acute toxicity of HCH (10 and 20 mg/kg body wt, i.p.) on the antioxidant defense system of cerebral hemisphere of rat was evaluated. Lipid peroxidation (LPX) was elevated after 24 h in the crude homogenate and sub-cellular fractions (nuclear and mitochondrial) except the microsomal fraction in which LPX was induced after 6 h and remained elevated till 24 h. The pesticide elicited decrease in the activities of cytosolic total, CN^–-sensitive (not at 24 h) and CN-resistant superoxide dismutases; total, Se-dependent and Se-independent glutathione peroxidases; and catalase throughout the measurement period. In contrast, glutathione reductase activity was elevated till 24 h after a fall at 6 h of pesticide exposure. Cerebral contents of glutathione and ascorbic acid were decreased in response to HCH. The results suggest the possible involvement of reactive oxygen species in the mechanism of HCH-induced neurotoxicity in rat.