Adjuvant Therapy for Vascular Inflammation in Diabetes

糖尿病血管炎症的辅助治疗

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7107286
• 关键词: antioxidants; aorta; blood glucose; blood vessel disorder; cell adhesion molecules; chemoprevention; chromium; clinical research; dietary supplements; gene expression; human subject; inflammation; insulin dependent diabetes mellitus; interleukin 6; ketones; medical complication; microarray technology; monocyte; nutrition related tag; oxidative stress; secretion; therapy design /development; tocopherols; tumor necrosis factor alpha; vascular endothelium

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率和死亡率的主要原因及其预防和治疗仍然是一个主要的公共卫生问题。促炎性细胞因子肿瘤坏死因子-Alpha（TNF-Alpha）和白介素6（IL-6）是血管炎症的标志。除高血糖外，1型糖尿病患者经常患酮症。 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 患者。我们的初步研究还表明，使用U937单细胞和新鲜的外围血液单核细胞（PBMC），在细胞培养模型中，铬（CR3+）和维生素E（VE）抑制由酮（AA）和高葡萄糖（AA）和高葡萄糖（AA）和高葡萄糖（AA）和高葡萄糖（HG）的分泌。 根据这些新颖的发现，该提案有两个假设。首先，酮增加了促炎性细胞因子（IL-6，TNF-α）分泌，并改变了与分离的人单核细胞和主动脉内皮细胞（HAEC）中与细胞因子产生和粘附分子有关的基因表达。其次，补充亲水性CR3+和亲脂性VE可以有效预防氧化应激，TNF-Alpha和IL-6分泌，以及与细胞因子和粘附分子产生有关的基因的过表达，在分离的人类单细胞单细胞和主动脉内皮细胞（Haec）和Heg中脱离了盐盐和HG。 为了实现这些目标，U937，PBMC和HAEC将使用没有HG的酮进行培养。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，并发现相对较低的饮食补充剂，例如CR3+和VE，用作预防1型糖尿病的血管炎症和并发症的辅助治疗。

项目成果

Can tryptophan oxidation lead to lower tryptophan level in diabetes? A commentary on "Propagation of protein glycation damage involves modification of tryptophan residues via reactive oxygen species: inhibition by pyridoxamine".

色氨酸氧化会导致糖尿病患者色氨酸水平降低吗？

• DOI: 10.1016/j.freeradbiomed.2008.01.005
• 发表时间: 2008
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Jain,SushilK

Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats.

• DOI: 10.1002/mnfr.200900177
• 发表时间: 2010-09
• 期刊: MOLECULAR NUTRITION & FOOD RESEARCH
• 影响因子: 5.2
• 作者: Jain, Sushil K.;Croad, Jennifer L.;Velusamy, Thirunavukkarasu;Rains, Justin L.;Bull, Rebeca
• 通讯作者: Bull, Rebeca

Low Levels of Hydrogen Sulfide in the Blood of Diabetes Patients and Streptozotocin-Treated Rats Causes Vascular Inflammation?

• DOI: 10.1089/ars.2009.2956
• 发表时间: 2010-06-01
• 期刊: ANTIOXIDANTS & REDOX SIGNALING
• 影响因子: 6.6
• 作者: Jain, Sushil K.;Bull, Rebeca;Bocchini, Joseph A., Jr.
• 通讯作者: Bocchini, Joseph A., Jr.

L-cysteine supplementation lowers blood glucose, glycated hemoglobin, CRP, MCP-1, and oxidative stress and inhibits NF-kappaB activation in the livers of Zucker diabetic rats.

• DOI: 10.1016/j.freeradbiomed.2009.03.014
• 发表时间: 2009-06-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Jain, Sushil K.;Velusamy, Thirunavukkarasu;Croad, Jennifer L.;Rains, Justin L.;Bull, Rebeca
• 通讯作者: Bull, Rebeca

Effects of high glucose and ketosis (acetoacetate, ss-hydroxybutyrate) on PAI-1 secretion in human umbilical vascular endothelial cells.

高葡萄糖和酮症（乙酰乙酸、β-羟基丁酸）对人脐血管内皮细胞 PAI-1 分泌的影响。

• DOI: 10.1177/1076029610366434
• 发表时间: 2011
• 期刊: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
• 作者: Velusamy,Thirunavukkarasu;Jain,SushilK
• 通讯作者: Jain,SushilK