Marignancy of cell-proliferative diseases by unusual production of phospholipid mediators in response to oxidative stress

首先，我们设计了有用的定量方法的初级（氢过氧化物）和二级[血小板活化因子（PAF）样脂质]产品的过氧化磷脂酰胆碱（PC）。利用这些方法，我们发现在人血浆与Cu^+孵育期间产生了三种具有短链酰基的PAF样脂质[含二羧酸酯（DC）的PC >含二羧酸半醛（DCsa）的PC >含单羧酸酯（MC）的PC]。与Fe^<2+>孵育的人血浆中主要的PAF样脂质是MC-PC。还检测到少量DCsa-PC，但未检测到DC-PC。DC-PC和DCsa-PC在低于25 μM的浓度下均能刺激人脐静脉内皮细胞增殖，但在较高浓度下可诱导内皮细胞凋亡。我们发现，从人血浆中部分纯化的溶血磷脂酶D（lysoPLD）和重组lysoPLD/autotaxin可水解PAF样脂质及其脱酰产物（溶血磷脂酰胆碱）。 ...更多信息 具有短链酰基的磷脂酸和溶血磷脂酸对各种动物细胞具有有效的细胞增殖作用。结果显示，子痫前期和早产患者血清中lysoPLD活性高于正常妊娠妇女，卵巢癌、囊腺瘤、皮样囊肿和子宫肌瘤患者腹腔液中lysoPLD活性高于其他妇科疾病患者。我们认为，动物体内氧化应激的增加引起生物膜和脂蛋白中PC的过氧化，随后C-C键断裂，产生PAF样脂质。PAF样脂质及其脱酰产物在各种生物体液中被lysoPLD活性水解为具有生物活性的磷脂酸和溶血磷脂酸。我们的研究结果表明，高lysoPLD活性的生物流体从先兆子痫患者血管内皮损伤和妇科肿瘤患者可能是一个因素，可以影响疾病的恶性程度。

First, we devised useful quantitative methods for primary (hydroperoxides) and secondary [platelet-activating factor (PAF)-like lipid] products of peroxidized phosphatidylcholines (PC). Using these methods, we found that three PAF-like lipids having a short chain acyl group were generated during incubation of human plasma with Cu^+ [dicarboxylate(DC)-containing PC > dicarboxylate semialdehyde(DCsa)-containing PC > monocarboxylate(MC)-containing PC]. The predominant PAF-like lipid in human plasma incubated with Fe^<2+> was MC-PC. A minor amount of DCsa-PC, but not DC-PC, was also detected. Both DC-PC and DCsa-PC stimulated the proliferation of human umbilical vein endothelial cells at concentrations less than 25 μM, but induced the apoptosis of the endothelial cells at higher concentrations.We found that lysophospholipase D (lysoPLD) partially purified from human plasma and recombinant lysoPLD/autotaxin hydrolyzed PAF-like lipids and their deacylated product (lysophosphatidylcholine) in … More to phosphatidic acid having a short chain acyl group and lysophosphatidic acid that possess a potent cell-proliferative effect on various animal cells.We devised a convenient assay for lysoPLD activity on a microplate reader. With use of the assay, we found that lysoPLD activities in sera from patients suffering from preeclamptia and preterm labor were higher than that observed for women under normal pregnancy, We also found that lysoPLD activities in peritoneal fluids from patients with ovarian cancer, cystadenoma, dermoid cyst and myoma uteri were higher than those for patients with other gynecological disease.From these results, we suggested that increased oxidative stress in animal body caused peroxidation of PC in biomembranes and lipoproteins followed by the cleavage of C-C bond(s), generating PAF-like lipid. The PAF-like lipids and their deacylated product were then hydrolyzed by lysoPLD activity in various biological fluids into bioactive phosphatidic acid and lysophosphatidic acid. Our results indicate that high lysoPLD activity in the biological fluids from preeclamptic patients with injured vascular endothelium and patients with gynecological tumor might be a factor that could affect the malignancy of the diseases Less