Adjuvant Therapy for Vascular Inflammation in Diabetes

糖尿病血管炎症的辅助治疗

基本信息

批准号：
7107286
负责人：
Sushil K Jain
金额：
$ 17.58万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2008-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Vascular inflammation and its complications are the leading cause of morbidity and mortality in the diabetic population and their prevention and treatment remain a major public health issue. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are markers of vascular inflammation. In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis. Our preliminary studies have demonstrated that the ketone body acetoacetate (AA) can generate superoxide radicals and increase secretion of pro-inflammatory cytokines IL-6 and TNF-alpha in a cell culture model using U937 monocytes, and the oxidative stress, IL-6 and TNF-alpha levels are higher in the blood of hyperketonemic compared with normoketonemic type 1 diabetic patients. Our preliminary studies also show that chromium (Cr3+) and vitamin E (VE) inhibit the secretion of TNF-alpha and IL-6 caused by ketones (AA) and high glucose (HG) in a cell culture model using U937 monocytes and fresh peripheral blood mononuclear cells (PBMC). Based upon these novel findings, this proposal has two hypotheses. First, ketones increase pro-inflammatory cytokine (IL-6, TNF-alpha) secretion and alter gene expression relating to cytokine production and adhesion molecules in isolated human monocytes and aortic endothelial cells (HAEC). Second, combined supplementation with hydrophilic Cr3+ and lipophilic VE can efficiently prevent oxidative stress, TNF-alpha and IL-6 secretion, and the over-expression of genes relating to cytokine and adhesion molecule production in isolated human monocytes and aortic endothelial cells (HAEC) exposed to ketones and HG. To accomplish these objectives, U937, PBMC and HAEC will be cultured with ketones without and with HG. State of the art techniques, such as gene array and multiplex PCR, will be used. Data will be analyzed statistically. The long-term objective is to understand the role of ketosis in vascular inflammation and to discover a relatively low-cost dietary supplement, such as Cr3+ and VE, to be used as an adjuvant therapy for prevention of the vascular inflammation and complications of type 1 diabetes.

描述（由申请人提供）：血管炎症及其并发症是糖尿病人群发病和死亡的主要原因，其预防和治疗仍然是主要的公共卫生问题。促炎细胞因子肿瘤坏死因子-α (TNF-α) 和白介素-6 (IL-6) 是血管炎症的标志物。除了高血糖之外，1 型糖尿病患者还经常出现酮症。我们的初步研究表明，在使用 U937 单核细胞的细胞培养模型中，酮体乙酰乙酸 (AA) 可以产生超氧自由基并增加促炎细胞因子 IL-6 和 TNF-α 的分泌，以及氧化应激、IL-6 和 TNF-α 的分泌。与正常酮血症 1 型糖尿病患者相比，高酮血症患者血液中 TNF-α 水平较高。我们的初步研究还表明，在使用 U937 单核细胞和新鲜外周血的细胞培养模型中，铬 (Cr3+) 和维生素 E (VE) 抑制酮 (AA) 和高葡萄糖 (HG) 引起的 TNF-α 和 IL-6 的分泌。血液单核细胞（PBMC）。基于这些新颖的发现，该提案有两个假设。首先，酮会增加促炎细胞因子（IL-6、TNF-α）的分泌，并改变与分离的人单核细胞和主动脉内皮细胞（HAEC）中细胞因子产生和粘附分子相关的基因表达。其次，联合补充亲水性 Cr3+ 和亲脂性 VE 可以有效防止氧化应激、TNF-α 和 IL-6 分泌，以及分离的人单核细胞和主动脉内皮细胞 (HAEC) 中与细胞因子和粘附分子产生相关的基因的过度表达暴露于酮和汞。为了实现这些目标，U937、PBMC 和 HAEC 将在不含有或含有 HG 的情况下用酮进行培养。将使用最先进的技术，例如基因阵列和多重 PCR。数据将进行统计分析。长期目标是了解酮症在血管炎症中的作用，并发现一种相对低成本的膳食补充剂，例如 Cr3+ 和 VE，作为预防 1 型血管炎症和并发症的辅助治疗糖尿病。