Efficacy/mechanisms of curcumin in diabetic nephropathy

姜黄素治疗糖尿病肾病的功效/机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): Diabetic (DM) nephropathy (DN) is the commonest cause of end stage renal disease. Albuminuria (Ualb) exacerbates DN by ill-defined mechanisms. Podocytes (podo) modulate Ualb via actin cytoskeleton (Actskn) chnages mediated by signaling events. We showed that phospho-p38MAPK induces biphosphorylation (p2) of podo heat shock protein 25 (HSP25, rodents; HSP27, humans) in response to acute glycemic stress, in an adaptation to maintain podo Actskn and prevent Ualb. Adaptation fails later. We also showed that the 12/15 lipoxygenase (LO) pathway of arachidonate metabolism mediates glucose, angiotensin II, PDGF, and TGF- beta actions in podo and mesangial cells, all underlying DN. 12/15LO knockout DM mice exhibit inhibition of renal cortical TGF-beta and CTGF mRNAs, TGF-beta expression, Smad 2/3 signaling, and proteinuria. Thus, our data implicate HSP25 and 12/15LO pathways in DN. Evidence relates the pathways: chemical LO inhibition stimulates HSP27, providing a key pathogenetic link between the benefits conferred by each. The biologic actions of the dietary spice curcumin simulate HSP25 and 12/15LO actions. It increases HSP27 and inhibits LO and TGF-beta. In rats with short-term DM, curcumin inhibited proteinuria and improved renal histology. After preliminary experiments to optimize curcumin product, dose, and route of administration, we will test the hypothesis that curcumin will: 1) Ameliorate DN in mice with long-term DM; 2) Preserve Actskn and inhibit extracellular matrix synthesis by enhancing HSP25 and inhibiting 12/15LO and TGF-beta; 3) Exhibit multiple salutary effects, making it comparable or superior to either HSP27 overexpression or 12/15LO inhibition alone as therapy; and 4) Induce interactions linking HSP27 and 12/15LO. Using novel HSP27 gain of function and 12/15LO loss of function mouse mdoels and state of the art molecular techniques, these studies assess efficacy and define underlying mechanisms of curcumin action. HSP27, TGF-beta, and 12/15LO are not now modifiable directly be medications. In Phase 1 trials, humans tolerated curcumin well in doses up to 8 gm/day. A Phase 2 trial for Alzheimer disease is in progress. Efficacy in experimental DN could translate rapidly into a testable therapy for patients.
描述(由申请人提供):糖尿病(DM)肾病(DN)是终末期肾脏疾病最常见的原因。蛋白尿(Ualb)通过不明确的机制加剧DN。足细胞(podo)通过信号事件介导的肌动蛋白细胞骨架(Actskn)变化来调节Ualb。我们发现,phospho-p38MAPK诱导兔热休克蛋白25 (HSP25,啮齿动物;HSP27,人类)在急性血糖应激反应中双磷酸化(p2),以维持兔热休克蛋白活性和预防兔热休克。后来适应失败了。我们还发现花生四烯酸代谢的12/15脂氧合酶(LO)通路介导细胞和系膜细胞中葡萄糖、血管紧张素II、PDGF和TGF- β的作用,这些都与DN有关。12/15LO敲除DM小鼠表现出肾皮质tgf - β和CTGF mrna、tgf - β表达、Smad 2/3信号传导和蛋白尿的抑制。因此,我们的数据暗示了DN中的HSP25和12/15LO通路。相关的证据表明:化学LO抑制刺激HSP27,在两者所带来的益处之间提供了关键的致病联系。膳食香料姜黄素的生物学作用模拟了HSP25和12/15LO的作用。它增加HSP27,抑制LO和tgf - β。在短期糖尿病大鼠中,姜黄素抑制蛋白尿并改善肾脏组织学。通过对姜黄素产品、剂量和给药途径的初步优化实验,我们将验证姜黄素对长期糖尿病小鼠DN的改善作用;2)通过增强HSP25,抑制12/15LO和tgf - β,保存Actskn,抑制细胞外基质合成;3)表现出多种有益作用,使其与HSP27过表达或12/15LO单独抑制治疗相当或优于;4)诱导HSP27与12/15LO的相互作用。利用新的HSP27功能获得和12/15LO功能丧失小鼠模型和最先进的分子技术,这些研究评估了姜黄素的功效并确定了姜黄素作用的潜在机制。HSP27、tgf - β和12/15LO现在不能通过药物直接改变。在一期试验中,人体耐受高达8克/天的姜黄素。阿尔茨海默病的二期试验正在进行中。对实验性DN的疗效可以迅速转化为可测试的治疗方法。

项目成果

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SHARON G ADLER其他文献

SHARON G ADLER的其他文献

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{{ truncateString('SHARON G ADLER', 18)}}的其他基金

SNP HAPLOTYPING TO DETECT DIABETIC NEPHROPATHY RISK
SNP 单倍型检测糖尿病肾病风险
  • 批准号:
    8174481
  • 财政年份:
    2009
  • 资助金额:
    $ 22.02万
  • 项目类别:
THE SAFETY AND EFFICACY OF MINOCYCLINE AS AN ANTI-PROTEINURIC IN DIABETIC NEPHRO
米诺环素作为抗蛋白尿药物治疗糖尿病肾病的安全性和有效性
  • 批准号:
    8174522
  • 财政年份:
    2009
  • 资助金额:
    $ 22.02万
  • 项目类别:
SNP HAPLOTYPING TO DETECT DIABETIC NEPHROPATHY RISK
SNP 单倍型检测糖尿病肾病风险
  • 批准号:
    7952234
  • 财政年份:
    2008
  • 资助金额:
    $ 22.02万
  • 项目类别:
MEXICAN-AMERICAN ADMIXTURE MAPPING DEVELOPMENT AND APPLICATION TO NIDDM
墨西哥-美国混合图谱开发及其在 NIDDM 中的应用
  • 批准号:
    7952240
  • 财政年份:
    2008
  • 资助金额:
    $ 22.02万
  • 项目类别:
SNP HAPLOTYPING TO DETECT DIABETIC NEPHROPATHY RISK
SNP 单倍型检测糖尿病肾病风险
  • 批准号:
    7606193
  • 财政年份:
    2007
  • 资助金额:
    $ 22.02万
  • 项目类别:
IDENTIFICATION OF DIABETIC NEPHROPATHY RISK GENES
糖尿病肾病风险基因的鉴定
  • 批准号:
    7606149
  • 财政年份:
    2007
  • 资助金额:
    $ 22.02万
  • 项目类别:
Efficacy/mechanisms of curcumin in diabetic nephropathy
姜黄素治疗糖尿病肾病的功效/机制
  • 批准号:
    7295707
  • 财政年份:
    2006
  • 资助金额:
    $ 22.02万
  • 项目类别:
Efficacy/mechanisms of curcumin in diabetic nephropathy
姜黄素治疗糖尿病肾病的功效/机制
  • 批准号:
    7496258
  • 财政年份:
    2006
  • 资助金额:
    $ 22.02万
  • 项目类别:
SNP Haplotyping to Detect Diabetic Nephropathy Risk
SNP 单倍型检测糖尿病肾病风险
  • 批准号:
    6989158
  • 财政年份:
    2005
  • 资助金额:
    $ 22.02万
  • 项目类别:
SNP Haplotyping to Detect Diabetic Nephropathy Risk
SNP 单倍型检测糖尿病肾病风险
  • 批准号:
    7112344
  • 财政年份:
    2005
  • 资助金额:
    $ 22.02万
  • 项目类别:

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The Single Cell Landscape of Early Human Diabetic Nephropathy
早期人类糖尿病肾病的单细胞景观
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