Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum.
Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum.
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DOI：
10.1242/dmm.032375
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发表时间：
2018-01-29
影响因子：
4.3
通讯作者：
Williams RSB
中科院分区：
文献类型：
--
作者：
Cocorocchio M;Baldwin AJ;Stewart B;Kim L;Harwood AJ;Thompson CRL;Andrews PLR;Williams RSB
天然化合物往往具有复杂的分子结构和未知的分子靶标。这些特性使它们很难用经典的药理学方法进行分析。姜黄素是姜黄中的主要类姜黄素，是一种复杂的分子，具有广泛的生物活性、细胞机制和潜在的治疗作用，包括阿尔茨海默病和癌症。在这里，我们研究了姜黄素在盘基网柄菌中的生理作用和分子靶标。我们发现，姜黄素对细胞行为产生严重影响，减少细胞生长，减缓多细胞发育。我们使用了一系列结构相关的化合物来展示不同的结构基团在姜黄素对细胞行为、生长和发育的影响中的不同作用，突出了细胞功能中的活性部分，并表明这些细胞效应与众所周知的姜黄素的抗氧化活性无关。然后，研究了姜黄素和一个合成类似物(EF24)作用的分子机制，以鉴定一个缺乏蛋白磷酸酶2A调节亚基(PSRA)的姜黄素抗性突变体和一个缺乏早老素1同源基因(PsenB)的EF24抗性突变体。利用电子对接分析，我们随后表明姜黄素可能通过直接与PSRA的关键调节区结合而发挥功能。这些发现揭示了姜黄素及其相关化合物发挥作用的新的细胞和分子机制。摘要：为了揭示姜黄素和相关化合物的治疗潜力，我们使用了一个易于处理的模型系统来表征它们的细胞和分子效应，并提出了与疾病有关的新靶点。
Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum. We show that curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds. Summary: To unlock the therapeutic potential of curcumin and related compounds, we employ a tractable model system to characterise their cellular and molecular effects and propose novel targets implicated in disease.
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DOI：
10.1016/j.biocel.2008.06.010
发表时间：
2009-01
影响因子：
4
作者：
Aggarwal, Bharat B.;Harikumar, Kuzhuvelil B.
通讯作者：
Harikumar, Kuzhuvelil B.
影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
3.5
作者：
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通讯作者：
Williams, Robin S. B.
影响因子：
2.7
作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
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