代謝組學進展醫(yī)學課件

1、The Need for Biomarkers in Diagnosis and Prognosis of Drug-Induced Liver Disease: Does Metabolomics Have Any Role?生物標志物在藥物誘導的肝臟疾病的診斷和預斷中的需要：代謝組學是否有何作用？ 1The Need for Biomarkers in Dia1. IntroductionLiver injury due to both prescription and over-the-counter drugs is a growing public health problem. A

2、lthough drug-induced liver injury (DILI) is a rare cause of acute liver injury in clinical practice, it is the leading cause of acute liver failure (ALF) in the US and most of Europe.處方藥和非處方藥導致的肝損傷是一個日益嚴重的公共衛(wèi)生問題。 盡管藥物誘導的肝損傷（DILI）在臨床實踐中是急性肝損傷的罕見原因，但它是美國和大多數(shù)歐洲的急性肝衰竭（ALF）的主要原因2.1. IntroductionLiver inj

3、ury du1. IntroductionDespite the extensive safety tests performed in the process of getting a drug to market, DILI remains enigmatic and cannot be predicted in preclinical and clinical trials. Even though different genetic variants and biomarkers have been associated with the risk of developing DILI

4、, hepatotoxicity remains a very common side effect.盡管在藥物上市的過程中進行了廣泛的安全性測試，但肝損傷仍然是神秘的，并且不能在臨床前和臨床試驗中預測。 不同的遺傳變異體和生物標志物與肝損傷發(fā)展的風險相關，肝毒性仍然是非常常見的副作用。3.1. IntroductionDespite the ex1. IntroductionIn this review we will focus on the potential role ofmetabolomic study on the diagnosis and prognosis of DILI.

5、在這篇綜述中，我們將重點關注代謝組學在肝損傷的診斷和預斷中的潛在作用。4.1. IntroductionIn this review2. The Main Challenges in DILI: Accuracy of Diagnosis and Prediction of EvolutionCurrently, DILI is diagnosed by exclusion of other liver diseases and is frequently misdiagnosed. An important part in the diagnosis of DILI is to establ

6、ish a temporal association between a drug and the onset of liver damage. However, in many cases, setting a causal link can be a complex task as most of the idiosyncratic drug-induced reactions occur roughly between a range of 1-2 weeks and 2-3 months from the onset of drug administration 目前，肝損傷是通過排除

7、其他肝病進行診斷的，而且經(jīng)常被誤診。 DILI診斷的一個重要部分是建立藥物與肝損傷起始之間的時間關聯(lián)。 然而，在許多情況下，設置因果關聯(lián)可以說是一件復雜的任務，因為大多數(shù)特異性藥物誘導的反應大致在給藥開始的1-2周和2-3個月的范圍內(nèi)才發(fā)生5.2. The Main Challenges in DILI2. The Main Challenges in DILI: Accuracy of Diagnosis and Prediction of EvolutionImportantly, our knowledge is scarce not only in terms of diagnosti

8、c accuracy. The natural history of DILI is still not completely understood重要的是，我們的知識不僅在準確診斷性方面知道的很少。而且 肝損傷的自然史仍然沒有完全理解6.2. The Main Challenges in DILI2. The Main Challenges in DILI: Accuracy of Diagnosis and Prediction of Evolutionmetabolomics is emerging forcefully in order to identify early toxici

9、ty biomarkers from biofluids collected through minimally invasive procedures that are specific indicators of liver damage.代謝組學可以通過作為肝損傷的具體指標的微創(chuàng)手術(shù)收集生物流體來識別早期毒性的生物標志物。7.2. The Main Challenges in DILI3. Metabolomics: Concept and DefinitionMetabolomics offers a view distinct from Genomics and Proteomics

10、. While Genomics and Proteomics tell us what “can happen,” metabolomics tells us what is “really happening” and, therefore, is the science that can better characterize the phenotypes of living organisms.代謝組學提供了不同于基因組學和蛋白質(zhì)組學的一種全新視圖。 基因組學和蛋白質(zhì)組學告訴我們“可能發(fā)生”，但代謝組學告訴我們 “真正發(fā)生發(fā)生了什么”，因此是更好地表征活性生物體表型的科學8.3. Me

11、tabolomics: Concept and D3. Metabolomics: Concept and DefinitionThe main analytical methods used in metabolomic analyses are nuclear magnetic resonance (NMR) and mass spectrometry (MS). 代謝組學分析中使用的主要分析方法是核磁共振（NMR）和質(zhì)譜（MS）。9.3. Metabolomics: Concept and D4. The Potential Role of Metabolic Profiling int

12、he Diagnosis and Prognosis of DILIBiomarkers are analyzed from blood, urine, or other biological samples that may provide insight into the severity, cause,or outcome of an injury to a specific tissue來自于血液，尿液或其他生物樣品中的生物標志物，可以洞察肝損傷的特定組織的的嚴重性，原因或結(jié)果。10.4. The Potential Role of Metab4. The Potential Role

13、 of Metabolic Profiling inthe Diagnosis and Prognosis of DILIWinnike analyzed the metabolomic profiles in urine samples from 58 healthy adults before and after receiving 4g of APAP per day for 7 days (a regimen that produces mild liver injury in about one-third of subjects). Urine metabolomic profil

14、e obtained 2 days prior to treatment were not sufficient to predict the development of mild liver damage,but the profiles obtained after a short period of administration of APAP were able to predict it. Winnike分析了來自每天給予4g APAP持續(xù)7天（在約三分之一的受試者中產(chǎn)生輕度肝損傷的方案）58名健康成人的尿液樣品中的代謝組學概況。 在治療前2天獲得的尿液代謝組學概況不足以預測肝損傷

15、的發(fā)展，但在短時間施用APAP后獲得的概況能夠預測11.4. The Potential Role of Metab4. The Potential Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIHuo and collaborators have published a study in humans,using a metabolomic approach to identify diagnostic biomarkers of DILI They evaluated the liver toxicity

16、of sodium valproate using ultra-performance LC-MS and HNMR-based metabolomics analysis of serum samples from 34 epileptic patients receiving this drugHUO和合作者在人中進行了一項研究，他們使用代謝組學方法來鑒定診斷DILI的生物標志物，使用超高效液相色譜 - 質(zhì)譜和基于HNMR的代謝組學分析評估了接受丙戊酸鈉這種藥物的34例癲癇患者的血清樣品中的肝毒性，12.4. The Potential Role of Metab4. The Potent

17、ial Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIThey found differences in metabolites involved in glycolysis, lipid metabolism,energy metabolism, and amino acids metabolism between patients with normal liver function and those with elevated liver enzymes due to the mentioned dru

18、g. Thus, they could define metabolites associated with valproate sodium-induced hepatotoxicity.This work demonstrates the potentia lof using metabolomics to discover biomarkers of hepatotoxicity.他們發(fā)現(xiàn)正常肝功能的患者和由于使用丙戊酸鈉后肝酶升高的患者中的，糖酵解，脂質(zhì)代謝，能量代謝和氨基酸代謝中的代謝物的差異。 因此，他們可以鎖定丙戊酸鈉誘導肝毒性相關的代謝物。這項工作表明使用代謝組學可以發(fā)現(xiàn)肝毒性的生物標志物13.4. The Potential Role of Metab5. ConclusionsIn this sense, the tremendous growth metabolomics has experienced over the last decade is notable, with remarkable applications in the area of liver toxicity. It is in this field where met