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Molecular Mechanisms of Genistein in the Prevention of Inflammatory Cytokine (TNF

金雀异黄素预防炎症细胞因子（TNF）的分子机制

基本信息

批准号：
8333468
负责人：
Zhenquan Jia
金额：
$ 17.6万
依托单位：
UNIVERSITY OF NORTH CAROLINA GREENSBORO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8333468
关键词：
Molecular Mechanisms Genistein Prevention Inflammatory

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this research is to identify bioactive components and develop novel nutraceuticals that may improve vascular function and therefore decrease the morbidity and mortality related to vascular dysfunction and related complications. Vascular inflammation and its subsequent endothelial dysfunction play a fundamental role in the initiation and progression of atherosclerosis. It is believed that tumor necrosis factor (TNF)-alpha is critically involved in the pathogenesis of atherosclerosis. Studies show that genistein may have vascular protective effects. However, the molecular mechanism of genistein action is not well understood. The main objective of this study is to evaluate the cellular mechanism of action of genistein in its protective effect on (TNF)-alpha-induced vascular dysfunction. We have collected preliminary data, which suggest a potential anti-inflammatory action of genistein against vascular dysfunction: 1) genistein, at physiological concentrations, significantly inhibited TNF-alpha-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), 2) genistein significantly suppressed TNF-alpha-induced production of monocyte chemoattractant protein -1 (MCP-1) and interleukin-8 (IL-8), two chemokines that are the key factors in the firm adhesion of monocytes to activated endothelial cells, (3) TNF-alpha significantly increased NF-KB binding activity indicating that activation of the transcription factor NF-kB might be critical for the TNF-alpha-induced inflammatory response. We have recently demonstrated that genistein directly activates the cAMP/protein kinase A (PKA) signaling in endothelial cells, which is not related to any known genistein action such as inhibition of tyrosine kinase or binding to estrogen receptors. Our working hypothesis is that genistein, at physiological concentrations, suppresses TNF-alpha-induced recruit of monocytes to endothelial cells via activation of the cAMP/PKA signaling (involving modulation of plasma membrane associated G-proteins) that subsequently inhibits NF-kB activity and its regulated chemokine and adhesion molecular expression. Accordingly, the specific aims of this application are: 1) to determine whether genistein inhibits TNF-alpha-induced expression of adhesion molecules, markers of vascular inflammation and NF-kB in HUVECs, 2) to determine whether the effects of genistein on TNF- alpha-induced monocyte adhesion to endothelial cells, expression of chemokine, adhesion molecules as well as NF-KB activation is mediated through the cAMP/PKA pathway, and whether stimulation of cAMP/PKA cascade by genistein is mediated through G proteins, 3) to investigate whether dietary intake of genistein protects against TNF-alpha-induced vascular inflammation in mice. Fulfillment of the above aims will establish the cellular and molecular mechanisms of action of genistein in its protective effect against vascular dysfunction. PUBLIC HEALTH RELEVANCE: Atherosclerotic vascular disease is a major cause of morbidity and mortality in the industrial world. Our preliminary data indicate genistein, a soybean compound, is a promising agent to protect against vascular dysfunction caused by the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The elucidation of the molecular mechanism(s) of action of genistein will provide clinically related strategies in protecting against atherosclerotic vascular disease.

描述(申请人提供)：这项研究的长期目标是确定生物活性成分并开发新的营养食品，可以改善血管功能，从而降低与血管功能障碍和相关并发症相关的发病率和死亡率。血管炎症及其继发的内皮功能障碍在动脉粥样硬化的发生和发展中起着重要作用。肿瘤坏死因子-α被认为在动脉粥样硬化的发病机制中起重要作用。研究表明，金雀异黄素可能具有血管保护作用。然而，染料木素作用的分子机制还不是很清楚。本研究的主要目的是探讨金雀异黄素对肿瘤坏死因子α诱导的血管功能障碍的保护作用的细胞机制。我们收集了一些初步数据，表明金雀异黄素对血管功能障碍有潜在的抗炎作用：1)在生理浓度下，金雀异黄素显著抑制肿瘤坏死因子-α诱导的单核细胞与人脐静脉内皮细胞的黏附；2)金雀异黄素显著抑制肿瘤坏死因子-α诱导的单核细胞趋化蛋白-1(MCP-1)和白介素8(IL-8)的产生，这两种趋化因子是单核细胞与活化内皮细胞牢固黏附的关键因素。(3)肿瘤坏死因子-α显著增强核因子-kB的结合活性，提示转录因子核因子-kB的激活可能在肿瘤坏死因子-α诱导的炎症反应中起关键作用。我们最近证实，染料木素直接激活内皮细胞中的cAMP/蛋白激酶A(PKA)信号，这与金雀异黄素的任何已知作用无关，如抑制酪氨酸激酶或与雌激素受体结合。我们的工作假设是，在生理浓度下，金雀异黄素通过激活cAMP/PKA信号(涉及质膜相关G蛋白的调节)从而抑制NF-kB的活性及其调节的趋化因子和黏附分子的表达，从而抑制TNF-α诱导的单核细胞向内皮细胞的募集。因此，本应用的具体目的是：1)确定金雀异黄素是否抑制肿瘤坏死因子-α诱导的人脐静脉内皮细胞黏附分子、血管炎症标志物和核因子-kB的表达，2)确定金雀异黄素对肿瘤坏死因子-α诱导的单核细胞与内皮细胞的黏附、趋化因子、黏附分子以及核因子-kB激活的影响是否通过cAMP/PKA途径介导，以及金雀异黄素刺激cAMP/PKA级联反应是否通过G蛋白介导；3)研究饮食摄入金雀异黄素是否对肿瘤坏死因子-α诱导的小鼠血管炎症具有保护作用。上述目标的实现将建立染料木素对血管功能障碍的保护作用的细胞和分子机制。公共卫生相关性：动脉粥样硬化性血管疾病是工业世界发病率和死亡率的主要原因。我们的初步数据表明，染料木素，一种大豆化合物，是一种很有前途的药物，可以预防促炎性细胞因子肿瘤坏死因子-α引起的血管功能障碍。阐明染料木素的作用分子机制(S)，将为临床防治动脉粥样硬化性血管疾病提供相关策略。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cell-based therapy in lung regenerative medicine.

DOI：
10.1186/2050-490x-2-7
发表时间：
2014-12
期刊：
Regenerative medicine research
影响因子：
2
作者：
Yang J;Jia Z
通讯作者：
Jia Z

Carbon nanodots interference with lactate dehydrogenase assay in human monocyte THP-1 cells.

碳纳米点干扰人单核细胞 THP-1 细胞中的乳酸脱氢酶测定。

DOI：
10.1186/2193-1801-3-615
发表时间：
2014
期刊：
SpringerPlus
影响因子：
0
作者：
Wright PC;Qin H;Choi MM;Chiu NH;Jia Z
通讯作者：
Jia Z

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway.

DOI：
10.1016/j.jnutbio.2014.11.008
发表时间：
2015-03
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Jia Z;Nallasamy P;Liu D;Shah H;Li JZ;Chitrakar R;Si H;McCormick J;Zhu H;Zhen W;Li Y
通讯作者：
Li Y

Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

萝卜硫素通过干扰 NF-κB 通路减少小鼠血管炎症，并防止 TNF-α 诱导的单核细胞粘附到原代内皮细胞。

DOI：
10.1016/j.jnutbio.2014.03.011
发表时间：
2014-08
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Nallasamy P;Si H;Babu PV;Pan D;Fu Y;Brooke EA;Shah H;Zhen W;Zhu H;Liu D;Li Y;Jia Z
通讯作者：
Jia Z

Natural Compound Resveratrol Attenuates TNF-Alpha-Induced Vascular Dysfunction in Mice and Human Endothelial Cells: The Involvement of the NF-κB Signaling Pathway.