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[分享] 药物代谢组学案例分析

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发表于 2017-3-20 11:20 |显示全部帖子
[p=25, null, left]药理研究:奥曲肽的肝脏保护作用

[p=25, null, left]

[p=25, null, left]研究对象:大鼠

[p=25, null, left]分析检测平台:GC-TOF/MS(BIOTREE)

[p=25, null, left]期刊:Liver international

[p=25, null, left]影响因子:4.85

[p=25, null, left]发表时间:2015

[p=25, null, left]

[p=25, null, left]摘要:

[p=25, null, left]Background & Aims: Insufficient liver regeneration and hepatocyte injury caused by excessive portal perfusion are considered to be responsible for post-hepatectomy liver failure (PLF) or small-for-size syndrome in living- donor liver transplantation. Somatostatin can decrease portal vein pressure (PVP) but simultaneously inhibits liver regeneration. This interesting para- dox motivated us to investigate the outcome of PLF in response to somatostatin treatment. Methods: Rats receiving extended partial hepatectomy (90% PH) were treated with octreotide, a somatostatin analogue, or placebo. Animal survival, serum parameters and hepatic histology were evaluated. Metabolomic analysis was performed to investigate the effect of octreotide on hepatocyte metabolism. Results: Despite significantly inhibiting early regeneration, octreotide application noticeably improved the hepatic histology, liver function and survival after PH but did not decrease the PVP level. Metabolomic analysis exhibited that octreotide profoundly and exclusively altered the levels of five metabolites that participate in or closely associate with the methionine cycle, a biochemical reaction that uniquely produces S-adenosylmethionine (SAMe), an active methyl residual donor for methyl- transferase reactions. Among these metabolites, methylthioadenosine (MTA), a derivate of SAMe, increased three-fold and was found independently improve the hepatic histology and reduce inflammatory cytokines in hepatectomized rats. Conclusions: Octreotide exclusively regulates the methionine cycle reaction and augments the MTA level in hepatocytes. MTA prominently protects hepatocytes against shear stress injury and reduces the secondary inflammation, thereby protecting rats from PLF.

[p=25, null, left]

[p=25, null, left]Keywords: hepatectomy liver failure (PLF)、portal vein pressure (PVP)、methylthioadenosine (MTA)

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[p=25, null, left]一、研究背景:

[p=25, null, left]肝脏在部分切除后仍可通过激活成熟肝细胞进行自我修复,这一特点是肝脏切除术及肝脏活体移植(living-donor liver transplantation, LDLT)技术的重要基础。然而在治疗复杂肝脏疾病时,采用肝脏切除术后常发现术后肝功能失常(post-hepatectomy liver failure, PLF),且肝脏移植后常出现小体积综合症(small-for-size syndrome, SFSS),导致术后死亡率升高。

[p=25, null, left]门静脉过度灌注是PLF的重要征兆,同时门静脉血压和剪切力升高也可直接导致SFSS。因此降低门静脉血压可作为预防SFSS和PLF的一种有效策略。奥曲肽是一种生长抑素,具有降低PVP作用,临床常用于治疗肝硬化引起的上消化道出血。虽然有报道称奥曲肽可降低SFSS发生率,但其机制尚不明确。同时,作为生长抑素,该药品是否会因抑制肝脏细胞再生而导致PLF尚不确定。为尝试回答这些问题,本文尝试在大鼠肝切除术模型中研究奥曲肽的作用效果和机制。

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[p=25, null, left]二、方法流程:

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[p=25, null, left]三、研究结果与讨论:

[p=25, null, left]1奥曲肽使用后大鼠的生物学功能变化:

[p=25, null, left]1)奥曲肽抑制肝细胞早期增殖

[p=25, null, left]2)奥曲肽并未降低门静脉血压(PVP)

[p=25, null, left]3)使用奥曲肽后大鼠存活率和肝功能数据显著高于对照

[p=25, null, left]

[p=25, null, left]1奥曲肽使用后大鼠的生物学功能变化

[p=25, null, left]


[p=25, null, left]2奥曲肽引起的肝脏代谢组变化

[p=25, null, left]1)主成分分析(PCA)表明奥曲肽组的代谢物出现整体变化;

[p=25, null, left]2)使用偏最小二乘回归判别分析(PLS-DA)筛选标志性差异物;

[p=25, null, left]3)结合标志型差异物发现奥曲肽作用途径:蛋氨酸循环

[p=25, null, left]4)蛋氨酸循环中的甲硫腺苷(MTA)可能提高术后肝功能并降低系统性炎症发生

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[p=25, null, left]2 多元变量统计分析建立PCA和PLS-DA模型的得分图

[p=25, null, center]

[p=25, null, left]3多元变量统计分析建立PCA和PLS-DA模型的得分图:

[p=25, null, left]1) 表型特点:虽然抑制早期肝脏细胞自修复,但仍可有效提高术后肝功能

[p=25, null, left]2) 奥曲肽的肝脏保护作用与其降低门静脉血压作用无关

[p=25, null, left]3) 通过代谢组学分析,发现奥曲肽作用的关键因素:细胞内MTA水平的升高

[p=25, null, left]4) 机制探索: MTA通过抑制炎症反应促进肝细胞再生

[p=25, null, left]

[p=25, null, left]3 使用MTA后大鼠的生物学功能变化

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[p=25, null, left]四、亮点和展望

[p=25, null, left]l 奥曲肽虽然抑制了早期肝细胞再生,但仍表现出显著的肝脏保护作用

[p=25, null, left]l 该护肝效果与奥曲肽已知的降低门静脉血压作用并无明显关系

[p=25, null, left]l 通过代谢组学研究分析发现奥曲肽引起新的肝脏保护物质—MTA的上升

[p=25, null, left]l 通过给药实验进一步证明MTA在肝脏切除模型中具有明显的护肝作用

[p=25, null, left]l 展望:奥曲肽提高蛋氨酸途径和MTA水平的详细机制还需进一步研究

[p=25, null, left]l 展望:可通过靶标代谢组学方法对MTA及蛋氨酸途径物质进行精确定量研究,并对可能的临床应用进行考察


[p=25, null, left]阅读文献下载地址:

[p=25, null, left]Zhenggui et al., Octreotide prevents liver failure through upregulating 5'-methylthioadenosine in extended hepatectomized rats. Liver International. (2016). 36(2): 212–222

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发表于 2017-3-31 04:44 |显示全部帖子
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发表于 2017-3-31 13:45 |显示全部帖子
ptwdj 发表于 2017-3-31 04:44
找到好贴不容易,我顶你了,谢了

谢谢
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