Identification of inflammation-mediated oxidized cholesterols as novel biomarkers of the metabolic syndrome

代谢综合征是动脉粥样硬化的危险因素。由脂肪细胞产生的脂肪细胞因子可以激活各种炎症细胞以产生活性氧和活性氮，其在宿主防御病原体以及炎症组织中的组织损伤中起重要作用。最近有报道说，人类活化的中性粒细胞在体内产生臭氧样氧化剂，但也有相互矛盾的实验结果。在本研究中，为了确定人类炎症细胞是否在体内产生臭氧样氧化剂，我们使用动脉粥样硬化-A和B研究了以下内容，动脉粥样硬化-A和B是通过与臭氧反应特异性产生的氧化胆固醇：（1）动脉粥样硬化醛-A和B的合成与表征，（2）开发了使用荧光丹酰肼衍生物检测动脉粥样硬化-A和B的高灵敏度和特异性方法，（3）阐明了动脉粥样硬化-A、B及OZO的形成机制 关于我们 通过炎性细胞在体内的ne-like氧化剂，（4）生物活性，特别是诱导凋亡性细胞死亡的能力，和（5）检测组织如糖尿病大鼠肝脏中的动脉粥样硬化-A和B。我们开发的方法比以前报道的方法灵敏约1000倍，可以很容易地检测化合物的fmol水平。使用这种方法，我们已经表明，增加水平的动脉粥样硬化-B形成的人嗜铬细胞样（HL-60）细胞与佛波酯激活，与那些没有激活。由于动脉粥样硬化-B的形成被抑制臭氧介导的氧化的化合物特异性地抑制，我们的数据强烈地表明，由活化的HL-60产生的臭氧参与动脉粥样硬化的形成。实验还表明，动脉粥样硬化具有很强的细胞毒性。由于我们还检测到糖尿病大鼠肝脏中动脉粥样硬化水平升高，因此这些化合物可以作为代谢综合征的新标记物进行测量。少

The metabolic syndrome is a risk factor for atherosclerosis. Adipocytokines produced by fat cells may activate various inflammatory cells to produce reactive oxygen and nitrogen species, which play important roles in host defenses against pathogens as well as in tissue damage in inflamed tissues. It has recently been reported that human activated neutrophils produce an ozone-like oxidant (s) in vivo, but conflicting experimental results have also been reported. In the present study in order to establish whether human inflammatory cells produce the ozone-like oxidant in vivo, we have investigated the followings using atheronal-A and B, which are oxidized-cholesterols specifically produced by the reaction with ozone: (1) synthesis and characterization of atheronal-A and B, (2) development of a highly sensitive and specific method to detect atheronal-A and B using fluorescent dansyl hydrazine derivatives, (3) elucidation of the mechanism for the formation of atheronal-A and B and also ozo … More ne-like oxidant (s) in vivo by inflammatory cells, (4) biological activities, especially ability to induce apoptotic cell death, and(5)detection of atheronal-A and B in tissues such as the liver of diabetes rats. Our developed method is about one thousand times more sensitive than the previously reported methods and can detect fmol levels of the compounds easily. Using this method, we have shown that increased levels of atheronal-B were formed in human neutrophil-like (HL-60) cells activated with phorbolester, compared to those without activation. As the formation of atheronal-B was inhibited specifically by a compound which inhibits ozone-mediated oxidation, our data strongly suggest that ozone produced by the activated HL-60 is involved in the formation of atheronals. It was also shown that atheronals exhibited strong cytotoxicity. As we also detected elevated levels of atheronals in the liver of diabetes rats, the compounds could be measured as a novel marker for the metabolic syndrome. Less