阿司匹林抗消化道肿瘤作用的研究

动物实验及流行病学研究发现阿司匹林有一定的抗肿瘤作用。其抗肿瘤作用机制主要通过抑制环氧化酶(cyclooxygenase ,COX)和通过不依赖PGs途径即抑制激活蛋白 (activatorprotein 1,AP 1)活性、降低细胞周期素依赖蛋白激酶的表达来诱导细胞凋亡 ,提高谷胱甘肽 S 转移酶 θ(glutathioneS transferasetheta ,GST θ)活性等来发挥抗肿瘤作用     

铁代谢及铁死亡在心肌病中的作用及调控机制研究进展

心肌细胞代谢及死亡方式是心肌病的重要病理生理学基础。许多研究提示,铁代谢紊乱是心肌病发生发展的关键环节之一。铁是人体重要生理功能所必需的矿物质,参与细胞呼吸、脂质代谢以及蛋白质合成;在病理条件下,铁蓄积诱导的毒性作用可破坏心肌细胞稳态和活力,导致细胞死亡,即铁死亡。过量的铁则通过芬顿反应诱导过氧化物生成,造成心肌细胞功能损害。因此,铁死亡在调控心肌病的发生及发展过程中具有重要意义。本文总结了铁代谢及铁死亡在心肌病中的病理生理改变及其调控机制,深刻认识铁代谢及铁死亡的调控靶点将为心肌病防治开辟新途径。     

血红素加氧酶-1在铁代谢中的作用

铁是机体必需的微量元素,有着广泛的生物学作用,包括氧化运输和细胞呼吸作用,缺铁会引起细胞生长停滞或死亡,铁过载会使细胞发生氧化应激进而损伤细胞膜、蛋白质、核酸.血红素加氧酶-1(HO-1)分解血红素产生铁是铁重复利用最主要的来源,在铁代谢中的作用至关重要.     

细胞铁死亡发生与调控机制的研究进展

正细胞死亡无论在生理还是在病理条件下都是无法避免的重要环节。传统意义上细胞死亡主要分为凋亡(apoptosis)和坏死(necrosis)两大主要类型,但近年来却发现在诸多病理生理情况下亦有自噬(autophagy)、胀亡(oncosis)、副凋亡(paraptosis)、焦亡(pyroptosis)等多种方式参与其中。越来越多细胞死亡方式的发现为进一步明确疾病的发生机制以及为     

阿司匹林促进宫颈癌HeLa细胞凋亡

阿司匹林(acetysalicylicacid,ASA)是非类固醇抗炎药(nonsteroidal antiinflammatory drugs,NSAIDs)的代表药物.最近研究证实,阿司匹林具有高效降低直肠结肠肿瘤发病率的作用~([1]);文献报道普通阿司匹林应用在半年以上,可有效降低宫颈癌的发病率~([2]).本研究对阿司匹林抑制宫颈癌HeLa细胞增殖作用及相关机制进行研究,为宫颈癌的预防与治疗提供有益的探索.     

铁代谢及铁蛋白与心血管疾病关系的现状分析

铁是一种双面元素,铁稳态的紊乱对部分组织有害。研究表明心脏是受铁代谢紊乱影响的主要器官之一。铁代谢障碍无论是缺乏还是超载,都与心血管疾病的发生率和死亡率增加有关。铁蛋白是研究铁状态的唯一指标,被认为是诊断铁状态的最佳单一测定。就目前研究结果来看,多种心血管疾病与铁代谢紊乱有关,如冠心病、心力衰竭、心肌病、阿霉素导致的心肌损伤及心肌缺血再灌注。明确铁代谢紊乱引起细胞损伤的机制,并进一步研究铁蛋白与铁代谢紊乱所引起的心血管疾病的相关性,可以为临床上提供便捷、准确的检测方法,并可指导临床治疗。     

阿司匹林对早发子痫前期外泌体诱导滋养细胞功能的作用

目的 构建子痫外泌体细胞模型研究阿司匹林改善滋养细胞功能并预防子痫前期（PE）的作用及分子机制。方法 收集早发型PE病例14例和正常孕妇作为对照8例,提取血浆外泌体。体外培养人滋养细胞HTR-8/SVneo,分别加入不同浓度的PE外泌体造模并给予阿司匹林处理;CCK-8法检测滋养细胞增殖情况;细胞划痕和Transwell小室检测滋养细胞迁移、侵袭变化;RT-qPCR和Western blot检测血管内皮生长因子（VEGF）mRNA和蛋白表达水平情况;ELISA法检测孕妇血浆VEGF水平。结果 PE外泌体可以显著抑制滋养细胞活力,且PE孕妇血浆中VEGF浓度低于NC组。体外PE外泌体滋养细胞模型实验证实,与NC组相比,100μg/mL PE外泌体显著抑制滋养细胞增殖、影响滋养细胞迁移、侵袭能力,抑制内皮细胞HUVEC小管形成功能,降低VEGF的表达（P<0.001）;而给予阿司匹林处理后,滋养细胞增殖、迁移、侵袭能力以及内皮细胞小管形成功能均改善。结论 阿司匹林提高滋养细胞增殖、迁移和侵袭能力,改善PE外泌体诱导后滋养细胞功能损伤,提高VEGF水平。这为阿司匹林用于早发型PE的预防...     

川芎嗪对大鼠脊髓损伤后铁代谢的影响北大核心

背景:铁代谢紊乱是导致脊髓损伤后神经细胞铁死亡的重要病理因素,不利于脊髓损伤修复。川芎嗪作为行气活血中药川芎的有效活性成分单体,被证实对脊髓损伤具有良好的抗炎、抗脂质过氧化反应以及神经保护作用,需进一步明确其促进脊髓损伤修复的作用机制。目的:研究川芎嗪对大鼠脊髓损伤后铁代谢的调节作用,探讨其改善脊髓损伤的相关机制。方法:将36只SD大鼠随机分为假手术组、模型组和川芎嗪组,每组12只;假手术组仅行椎板切除术,术后给予生理盐水腹腔注射;模型组和川芎嗪组制备脊髓损伤模型,术后分别给予生理盐水和川芎嗪腹腔注射,术后4周取材。采用BBB肢体运动功能评分评价大鼠肢体运动功能,尼氏染色观察神经元形态,普鲁士染色观察脊髓组织铁沉积,铁检测试剂盒检测脊髓组织铁含量,免疫组化检测铁蛋白重链1和铁蛋白轻链表达,Western blot检测铁蛋白重链1和铁蛋白轻链的蛋白表达量。结果与结论:(1)模型组和川芎嗪组大鼠各个时间点BBB评分显著低于假手术组(P <0.01),自术后第14天,川芎嗪组大鼠BBB评分显著高于模型组(P <0.01);(2)尼氏染色结果显示,假手术组神经元形态结构正常,模型组可见大量瘀血,神经元形态结构紊乱,川芎嗪组瘀血较少,神经元形态结构较模型组改善;(3)普鲁士染色结果显示,假手术组铁沉积较少,模型组和川芎嗪组铁沉积较多;普鲁士染色阳性平均吸光度值模型组和川芎嗪组显著大于假手术组(P <0.01),川芎嗪组显著小于模型组(P <0.01);(4)铁含量检测结果显示,模型组和川芎嗪组显著多于假手术组(P <0.01),川芎嗪组显著少于模型组(P <0.01);(5)免疫组化染色结果显示,铁蛋白重链1和铁蛋白轻链阳性表达平均吸光度值模型组和川芎嗪组显著小于假手术组(P <0.01),川芎嗪组显著大于模型组(P <0.01);(6)Western blot检测结果显示,铁蛋白重链1蛋白和铁蛋白轻链蛋白的相对表达量模型组和川芎嗪组显著少于假手术组(P <0.01),川芎嗪组显著多于模型组(P <0.01);(7)结果说明,川芎嗪通过调控铁蛋白重链1和铁蛋白轻链的表达而调节脊髓损伤后铁代谢紊乱,从而发挥神经保护作用,促进脊髓损伤大鼠肢体运动功能恢复。     

阿司匹林对胰腺癌细胞周期的影响及其机制

目的： 观察阿司匹林及其催化产物前列腺素E2（PGE2）对胰腺肿瘤细胞周期及细胞周期相关蛋白p21Wafl/cipl、p27Kipl/pic2表达的影响，探讨阿司匹林抗胰腺癌的作用机制。 方法： 以阿司匹林和PGE2处理胰腺癌细胞后，分别采用MTT检测细胞活力、ELISA检测细胞内PGE2浓度、流式细胞仪检测细胞周期变化、Western blotting检测细胞周期相关蛋白p21Wafl/cipl和p27Kipl/pic2的表达水平。 结果： 阿司匹林可抑制胰腺癌细胞生长并呈剂量依赖性减少细胞内PGE2的生成；阿司匹林可诱导细胞周期相关蛋白p21Wafl/cipl和p27Kipl/pic2表达升高并引起细胞阻滞在G0/G1期。但外源性PGE2并不能拮抗阿司匹林对细胞活力、细胞周期及细胞周期相关蛋白的影响。 结论： 阿司匹林抑制胰腺癌细胞的生长可能并非完全通过环氧合酶途径；诱导p21Wafl/cipl和p27Kipl/pic2表达的升高、进而诱导细胞周期的阻滞可能是其作用机制之一。     

PD-1/PD-L1参与NK细胞调控抗肿瘤免疫的作用机制

NK细胞以其特有的免疫应答在抗肿瘤免疫中倍受重视。作为肿瘤免疫治疗的“明星分子”PD-1/PD-L1在NK细胞及其抗肿瘤免疫中的作用尚不明确。该文通过分析PD-1/PD-L1分子在NK细胞中的表达,为PD-1/PD-L1分子在NK细胞抗肿瘤免疫中的作用、机制以及应用价值提供新思路。     

阿司匹林与氟尿嘧啶协同抑制结肠癌细胞生长增殖的机制研究*

 目的：检测阿司匹林与氟尿嘧啶协同抑制结肠癌细胞生长增殖的能力及相关作用机制。方法：将体外培养的结肠癌细胞分为4组：空白对照组、阿司匹林组、氟尿嘧啶组和阿司匹林+氟尿嘧啶组,采用MTT法检测阿司匹林和氟尿嘧啶抑制结肠癌细胞增殖的效果,采用Hoechst 33258染色、caspase活性检测和流式细胞术检测研究药物诱发凋亡的作用及机制,采用real-time PCR和Western blotting方法检测药物对凋亡相关蛋白表达的调控作用。结果：氟尿嘧啶有效抑制HCT116和SW620结肠癌细胞增殖,且低浓度阿司匹林具有协同抑制的效果。氟尿嘧啶诱发HCT116细胞核出现明显的凋亡形态,caspase酶活性增高及sub-G1期比例增加。阿司匹林协同作用明显提高HCT116细胞凋亡的比例和caspase酶活性。此外,低浓度阿司匹林可以显著增强氟尿嘧啶抑制Bcl-2 mRNA及蛋白表达的效果。结论：阿司匹林和氟尿嘧啶具有协同抑制结肠癌细胞生长增殖的效果,且主要通过诱发细胞凋亡发挥作用。     

Effects of epigallocatechin gallate and quercetin on oxidative damage to cellular DNA

Phenolic phytochemicals are thought to promote optimal health, partly via their antioxidant effects in protecting cellular components against free radicals. The aims of this study were to assess the free radical-scavenging activities of several common phenolic phytochemicals, and then, the effects of the most potent phenolic phytochemicals on oxidative damage to DNA in cultured cells. Epigallocatechin gallate (EGCG) scavenged the stable free radical, α,α-diphenyl-β-picrylhydrazyl (DPPH), most effectively, while quercetin was about half as effective. Genistein, daidzein, hesperetin, and naringenin did not scavenge DPPH appreciably. Jurkat T-lymphocytes that were pre-incubated with relatively low concentrations of either EGCG or quercetin were less susceptible to DNA damage induced by either a reactive oxygen species or a reactive nitrogen species, as evaluated by the comet assay. More specifically, control cells had a comet score of only 17±5, indicating minimal DNA damage. Cells challenged with 25 μM hydrogen peroxide (H₂O₂) or 100 μM 3-morpholinosydnonimine (SIN-1, a peroxynitrite generator) had comet scores of 188±6 and 125±12, respectively, indicating extensive DNA damage. The H₂O₂-induced DNA damage was inhibited with 10 μM of either EGCG (comet score: 113±23) or quercetin (comet score: 82±7). Similarly, the SIN-1-mediated DNA damage was inhibited with 10 μM of either EGCG (comet score: 79±13) or quercetin (comet score: 72±17). In contrast, noticeable DNA damage was induced in Jurkat T-lymphocytes by incubating with 10-fold higher concentrations (i.e., 100 μM) of either EGCG (comet score: 56±17) or quercetin (comet score: 64±13) by themselves. Collectively, these data suggest that low concentrations of EGCG and quercetin scavenged free radicals, thereby inhibiting oxidative damage to cellular DNA. But, high concentrations of either EGCG or quercetin alone induced cellular DNA damage.     

Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease

Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.     

Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy

Tissue iron content is strictly regulated to concomitantly satisfy specialized metabolic requirements and avoid toxicity. Ferritin, a multi-subunit iron storage protein, is central to maintenance of iron homeostasis in the brain. Mutations in the ferritin light chain (FTL)-encoding gene underlie the autosomal dominant, neurodegenerative disease, neuroferritinopathy/hereditary ferritinopathy (HF). HF is characterized by progressive accumulation of ferritin and iron. To gain insight into mechanisms by which FTL mutations promote neurodegeneration, a transgenic mouse, expressing human mutant form of FTL, was recently generated. The FTL mouse exhibits buildup of iron in the brain and presents manifestations of oxidative stress reminiscent of the human disease. Here, we asked whether oxidative DNA damage accumulates in the FTL mouse brain. Long-range PCR (L-PCR) amplification-mediated DNA damage detection assays revealed that the integrity of mitochondrial DNA (mtDNA) in the brain was significantly compromised in the 12- but not 6-month-old FTL mice. Furthermore, L-PCR employed in conjunction with DNA modifying enzymes, which target specific DNA adducts, revealed the types of oxidative adducts accumulating in mtDNA in the FTL brain. Consistently with DNA damage predicted to form under conditions of excessive oxidative stress, detected adducts include, oxidized guanines, abasic sites and strand breaks. Elevated mtDNA damage may impair mitochondrial function and brain energetics and in the long term contribute to neuronal loss and exacerbate neurodegeneration in HF.     

Plasma biomarkers of oxidative and AGE-mediated damage of proteins and glycosaminoglycans during healthy ageing: A possible association with ECM metabolism

The aim of this study was to examine whether oxidative and AGE-mediated processes correlates with the metabolic changes of proteoglycans (PGs) and proteins during physiological ageing. The age and gender-associated changes of PGs metabolism were evaluated by plasma chondroitin sulfates (CS), dermatan sulfates (DS) and heparan sulfates and heparin (HS/H). We found a linear age-related decline in CS, DS and HS/H, the first one being the predominant plasma GAG during ageing. The possible deleterious effect of oxidative phenomenon on proteins’ and proteoglycans’ metabolism during ageing process was analyzed by plasma carbonyls (PCO) and thiols (PSH) as well as by total antioxidant capacity (TAS). An age-dependent increase in PCO and decrease in PSH concentrations were found, both strongly correlated with decreasing with age plasma TAS. Intensity of glycation was assessed by circulating N^?-(carboxymethyl)lysine (CML) and endogenous secretory receptor for AGE (esRAGE), both of them founding associated with ageing. Moreover, all markers of oxidative and AGE-mediated damage correlated with CS and DS level and could be contributing factors to age-related changes of these GAG types. Thus, plasma CS and DS could become promising biomarkers of human ageing to date, owning to its close association with oxidative status and glycation processes.     

Preoperative aspirin resistance does not increase myocardial injury during off-pump coronary artery bypass surgery

We performed a prospective cohort trial on 220 patients undergoing elective off-pump coronary artery bypass surgery and taking aspirin to evaluate the effect of aspirin resistance on myocardial injury. The patients were divided into aspirin responders and aspirin non-responders by the value of the aspirin reaction units obtained preoperatively using the VerifyNow™ Aspirin Assay. The serum levels of troponin I were measured before surgery and 1, 6, 24, 48 and 72 hr after surgery. In-hospital major adverse cardiac and cerebrovascular events, graft occlusion, the postoperative blood loss and reexploration for bleeding were recorded. Of the 220 patients, 181 aspirin responders (82.3%) and 39 aspirin non-responders (17.7%) were defined. There were no significant differences in troponin I levels (ng/mL) between aspirin responders and aspirin non-responders: preoperative (0.04 ± 0.08 vs 0.03 ± 0.06; P = 0.56), postoperative 1 hr (0.72 ± 0.87 vs 0.86 ± 1.10; P = 0.54), 6 hr (2.92 ± 8.76 vs 1.50 ± 2.40; P = 0.94), 24 hr (4.16 ± 13.44 vs 1.25 ± 1.95; P = 0.52), 48 hr (2.15 ± 7.06 vs 0.65 ± 0.95; P = 0.64) and 72 hr (1.20 ± 4.63 vs 0.38 ± 0.56; P = 0.47). Moreover, no significant differences were observed with regard to in-hospital outcomes. In conclusion, preoperative aspirin resistance does not increase myocardial injury in patients undergoing off-pump coronary artery bypass surgery. Postoperative dual antiplatelet therapy might have protected aspirin resistant patients.     

Inhibition of polymorphonuclear leucocyte motility by benoxaprofen related to activation of cellular oxidative metabolism

Incubation of human blood polymorphonuclear leucocytes (PMNL) with benoxaprofen at concentrations of greater than 1 X 10(-5)M caused inhibition of random and leucoattractant-induced migration of these cells in vitro. The drug at the same concentrations and in the absence of an added stimulant caused increased PMNL oxidative metabolism measured by chemiluminescence, hexose-monophosphate shunt activity and myeloperoxidase release. Furthermore benoxaprofen also induced PMNL auto-oxidation detected by cellular auto-iodination. Co-incubation of PMNL with the anti-oxidants ascorbate or levamisole prevented benoxaprofen-mediated inhibition of PMNL migration and cellular auto-oxidation. The drug per se was not an oxidising agent and its inhibitory effects on PMNL motility were dependent upon intact cellular oxidative metabolism. The inhibitory effects of benoxaprofen on PMNL migration in vitro are caused by the proxidant activity of the drug.     

Systemic and cellular consequences of macrophage control of iron metabolism

Iron is necessary for both mammalian cells and microorganisms, which fiercely compete for this essential nutrient. Accordingly, macrophages exploit the denial of iron from microbial pathogens as an important strategy to accomplish their key role in innate immunity and host defense. Macrophages employ multiple mechanisms to accumulate iron and thus contain microbial infections, but this may come at a price. In particular, at the systemic level iron sequestration in the reticuloendothelial cells can lead to the development of anemia of chronic disease. At the local level, iron sequestration in macrophages, which is targeted to extracellular invaders, can in turn favor intracellular pathogens. Moreover, iron accumulation can per se promote pro-inflammatory activation of macrophages and consequently contribute to maintain the process of inflammation, without resolution. Finally, the peculiar iron trafficking that characterizes alternatively polarized macrophages can influence neighboring cells in the microenvironment and impact on the resolution phase of inflammation. In this review, we describe the role of macrophages in iron metabolism in the context of host defense and iron balance.