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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇剛毅 | zh_TW |
| dc.contributor.advisor | Kang-Yi Su | en |
| dc.contributor.author | 陸致云 | zh_TW |
| dc.contributor.author | Chih-Yun Lu | en |
| dc.date.accessioned | 2024-08-27T16:12:46Z | - |
| dc.date.available | 2024-08-28 | - |
| dc.date.copyright | 2024-08-27 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-01 | - |
| dc.identifier.citation | Paracetamol (acetaminophen). IARC Monogr Eval Carcinog Risks Hum, 1990. 50: p. 307-32.
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Berg, T. and D.H. Strand, 13C labelled internal standards—A solution to minimize ion suppression effects in liquid chromatography–tandem mass spectrometry analyses of drugs in biological samples? Journal of Chromatography A, 2011. 1218(52): p. 9366-9374. Stokvis, E., H. Rosing, and J.H. Beijnen, Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not? Rapid Communications in Mass Spectrometry: An International Journal Devoted to the Rapid Dissemination of Up‐to‐the‐Minute Research in Mass Spectrometry, 2005. 19(3): p. 401-407. Wei, A.A.J., et al., Strategies for avoiding saturation effects in ESI-MS. International Journal of Mass Spectrometry, 2020. 450: p. 116306. Russomanno, G., et al., A systems approach reveals species differences in hepatic stress response capacity. Toxicol Sci, 2023. 196(1): p. 112-125. Uzi, D., et al., CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol, 2013. 59(3): p. 495-503. Lecoeur, M., et al., Determination of acetaminophen and its main metabolites in urine by capillary electrophoresis hyphenated to mass spectrometry. Talanta, 2019. 205: p. 120108. Yan, M., et al., Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol, 2018. 17: p. 274-283. Wang, X., et al., Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress. Proc Natl Acad Sci U S A, 2006. 103(10): p. 3604-9. Chen, W., et al., The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells. Aging (Albany NY), 2022. 14(20): p. 8486-8497. Moessmer, P., et al., Active unfolding of the glucocorticoid receptor by the Hsp70/Hsp40 chaperone system in single-molecule mechanical experiments. Proc Natl Acad Sci U S A, 2022. 119(15): p. e2119076119. Kennedy, A. and D.M. Cyr, DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation. Autophagy Rep, 2022. 1(1): p. 559-562. Sanchez-Lopez, E., et al., Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells. Cell Death Dis, 2013. 4(11): p. e933. Zhang, X., et al., Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension, 2010. 55(6): p. 1412-7. Hino, C., et al., Cellular protection from H(2)O(2) toxicity by Fv-Hsp70: protection via catalase and gamma-glutamyl-cysteine synthase. Cell Stress Chaperones, 2023. 28(4): p. 429-439. Guo, S., et al., Heat shock protein 70 regulates cellular redox status by modulating glutathione-related enzyme activities. Cell Stress Chaperones, 2007. 12(3): p. 245-54. Jaeschke, H., M.R. McGill, and A. Ramachandran, Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev, 2012. 44(1): p. 88-106. Chen, H.W., et al., Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1. Cancer Res, 2008. 68(18): p. 7428-38. Guan, G., et al., Curcumin attenuates palmitic acid-induced cell apoptosis by inhibiting endoplasmic reticulum stress in H9C2 cardiomyocytes. Hum Exp Toxicol, 2019. 38(6): p. 655-664. Diane, A., et al., Alpha lipoic acid attenuates ER stress and improves glucose uptake through DNAJB3 cochaperone. Sci Rep, 2020. 10(1): p. 20482. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95068 | - |
| dc.description.abstract | 乙醯胺酚(APAP)是一種常見的藥物，適應症為鎮熱、解痛。處方建議劑量的乙醯胺酚會藉由肝臟進行代謝，一般不會有嚴重的副作用。然而當乙醯胺酚服用過量會對肝臟造成損傷，嚴重的話會發展成急性的肝衰竭。過量乙醯胺酚在進入體內後，會被肝臟的phase I酵素CYP2E1氧化代謝成高反應性的中間產物N-乙醯基對苯醌亞胺(NAPQI)，形成許多NAPQI-蛋白加合物(NAPQI-protein adduct)，進而使細胞面臨較大的氧化壓力和內質網壓力，最終導致急性的肝毒性與肝細胞壞死。目前臨床上對於乙醯胺酚造成的急性肝損傷，通常是給予穀胱甘肽(GSH)、N-乙醯半胱氨酸(NAC)等還原性物質，來減緩肝細胞受到的氧化壓力。儘管能夠對已經發生的肝損傷進行補救性治療，然而在臨床上仍無有效降低因為過量乙醯胺酚引起肝臟毒性的方法。過去的研究經常將肝臟損傷與熱休克蛋白一同提及，而HLJ1作為伴侶蛋白(chaperone)的一員，屬於熱休克蛋白40家族。我們實驗室長期研究HLJ1蛋白的生理功能，發現HLJ1基因剔除小鼠會因為內質網壓力導致脂肪代謝異常，並且對致肝癌劑更敏感，表明HLJ1在維持肝臟恆定與對抗環境壓力的生理功能中有重要的作用。然而HLJ1在肝臟中是如何調控乙醯胺酚引起的肝臟損傷，機制仍不清楚。
在本研究中，我們給予小鼠過量的乙醯胺酚刺激，發現相較於野生型小鼠，HLJ1基因剔除小鼠的肝臟損傷更為嚴重。除此之外，我們使用流體動力注射，在小鼠的肝臟成功表現HLJ1蛋白並給予乙醯胺酚刺激，結果發現在外表現HLJ1蛋白後，HLJ1基因剔除小鼠的肝臟損傷有明顯減輕的情形。為了瞭解乙醯胺酚在小鼠體內的代謝情形，我們建立了質譜儀的分析平台來檢測乙醯胺酚相關的代謝物，結果發現在HLJ1基因剔除小鼠的肝臟中產生較多的phase I代謝物，表示NAPQI-蛋白加合物較多。接著利用RT-qPCR分析肝臟中phase I和phase II酵素相關基因的表現量，並測量了肝臟中穀胱甘肽的含量與氧化還原狀態，發現野生型小鼠和HLJ1基因剔除小鼠的酵素基因表現量與穀胱甘肽都沒有顯著差異，顯示代謝產物量的差異不是因為HLJ1調控了代謝酵素基因所導致。為了釐清HLJ1調控肝臟損傷的機制，使用兩個cDNA array的資料庫來比對找出可能與HLJ1有互動的蛋白質，透過PEPPI的蛋白質交互作用預測，鎖定了HSPa1b (HSP70/72)可能會與HLJ1結合，來調控並緩解肝臟損傷。我們進一步使用免疫沉澱法確認了HLJ1和HSP70的結合。透過西方墨點法確認小鼠肝臟中的內質網壓力(ER stress)，發現原本就會因為乙醯胺酚上升的內質網壓力，在HLJ1缺失、無法與HSP70結合的情況下，內質網壓力會升高的更多，進而使肝臟細胞較容易死亡，造成肝臟損傷。 總而言之，HLJ1可以與HSP70結合，協助NAPQI-蛋白加合物的重新摺疊或降解、調控細胞緩解內質網壓力，進而使肝臟緩解過量乙醯胺酚造成的毒性。本研究結果透過了解HLJ1在肝臟損傷中所扮演的角色，希望可以作為未來發展潛在保肝藥物的依據，本研究的最終目標希望可以應用在肝臟保護藥物的開發上，藉由調控HLJ1的表現量或是與HSP70結合的相關機制，來達到保護肝臟的效果。 | zh_TW |
| dc.description.abstract | Acetaminophen (APAP) is a commonly used pain and fever medication that is generally safe when taken at recommended doses. However, excessive intake can lead to severe liver toxicity. Following APAP intake, it is metabolized by the CYP2E1 enzyme into the toxic metabolite NAPQI. Excessive APAP consumption leads to an overproduction of NAPQI, and the NAPQI-protein adducts causing increased ER stress and oxidative stress in hepatocytes and consequently resulting in liver damage. Despite administering reducing agents such as glutathione (GSH) and N-acetylcysteine (NAC) is effective in therapeutic treatment for existing liver injury, there is no clinically available strategy to reduce the hepatotoxicity of overdosing APAP effectively. Previous studies reported the association of heat shock proteins (HSPs) with liver damage, such as hepatic ischemia-reperfusion injury or APAP-induced liver injury. However, the function of HLJ1, a molecular chaperone from the HSP40 family, in regulating APAP-induced acute liver injury remains uncertain.
This study examines the effect of HLJ1 on APAP-induced liver injury using HLJ1 whole-body knockout (Hlj1-/-) mice. Following APAP administration, Hlj1-/- mice exhibited more severe liver damage. Additionally, we successfully re-expressed HLJ1 protein in the liver of mice through hydrodynamic injection, and this effectively mitigates liver damage caused by APAP in Hlj1-/- mice. We established a mass spectrometry platform to examine APAP-related metabolites, and the results revealed that Hlj1-/- mice generated more phase I metabolite of APAP, indicating more NAPQI-protein adducts were generated. We further analyzed APAP-related metabolic enzymes using RT-qPCR and measured liver glutathione levels. However, the results showed no significant differences in the mRNA expression levels of the enzymes and the glutathione redox state, suggesting that the difference in APAP metabolites is not due to HLJ1 regulating metabolic enzymes. To elucidate the mechanism of how HLJ1 regulates liver injury, we compared two cDNA array datasets to identify potential proteins interacting with HLJ1. HSPa1b (HSP70/72) was identified by the PEPPI online server as a potential HLJ1 binding partner. We further confirmed the HLJ1 and HSP70 interaction by immunoprecipitation. Western blot analysis of ER stress markers in mouse livers revealed that APAP-induced ER stress increased even more in the absence of HLJ1, which prevents its binding with HSP70, leading to higher ER stress and greater susceptibility of liver cells to death and damage. In summary, HLJ1 can bind with HSP70 to regulate cellular ER stress response, thereby mitigating APAP-induced liver toxicity. Understanding HLJ1's role in liver injury offers a basis for developing potential liver-protective drugs. The ultimate goal of our study is to develop a liver-protective drug that reduces liver damage by modulating HLJ1 expression or its interaction with HSP70, thereby achieving liver protection. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-27T16:12:46Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-27T16:12:46Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 I
摘要 III Abstract V Chapter 1. Introduction 1 1.1 Acetaminophen (APAP) 1 1.1.1 Clinical uses and Clinical issues of APAP overdose 1 1.1.2 Mechanisms of action of APAP 2 1.1.3 Metabolic pathways and toxicity of APAP 3 1.1.4 APAP-induced liver injury mouse model 5 1.2 Heat shock protein 6 1.2.1 Overview of heat shock protein 6 1.2.2 Heat shock protein 40 and 70 family 7 1.2.3 DNAJB4/HLJ1 8 1.3 Research Motivation and Specific Aims 9 Chapter 2. Materials and Methods 10 2.1 Mouse Experiment 10 2.1.1 HLJ1 knockout mice 10 2.1.2 APAP-induced liver injury model 10 2.1.3 Liver histological analysis 11 2.1.4 Biochemical analysis 11 2.1.5 HLJ1 Re-expression by Hydrodynamic Injection 11 2.2 Microarray Data Analysis 12 2.3 Analysis of APAP Metabolites by Mass Spectrometry 12 2.3.1 Sample Extraction 12 2.3.2 Instrument Parameters 13 2.3.3 Quality control 14 2.4 Quantitative Real-Time PCR 14 2.4.1 RNA Extraction 14 2.4.2 Reverse Transcription and qPCR 15 2.5 Immunoblotting 16 2.5.1 Protein Extraction and Quantification 16 2.5.2 Immunoprecipitation 17 2.5.3 SDS-PAGE 17 2.6 Glutathione Measurement 17 2.7 Immunohistochemistry (IHC) Staining 18 2.8 Cell model of acetaminophen stimulation 19 2.8.1 Cell culture and acetaminophen stimulation 19 2.8.2 Cell viability assay 20 2.9 Statistical Analysis 20 Chapter 3. Results 21 3.1 HLJ1 deficiency aggravates APAP-induced liver injury. 21 3.1.1 HLJ1 expression is important for maintaining liver physiological functions. 21 3.1.2 Hlj1-/- mice exhibit more severe liver damage after APAP administration. 21 3.2 Re-expression of HLJ1 alleviates acetaminophen-induced liver injury in Hlj1-/- mice. 22 3.3 Hlj1-/- mice generated more phase I metabolites after APAP treatment. 23 3.3.1 Mass spectrometry platform establishment for APAP metabolites analysis. 23 3.3.2 Hlj1-/- mice show an increased abundance of phase I metabolites 25 3.4 HLJ1 deficiency did not alter the expression level of APAP-related metabolic enzymes or the liver GSH. 27 3.4.1 Phase I and Phase II enzyme expression levels are unaffected by HLJ1 status 27 3.4.2 Liver glutathione redox status analysis 27 3.5 Identification and analysis of HLJ1 interaction targets, HSP70, in the APAP model 28 3.5.1 Identifying HLJ1 interaction targets in the APAP model via datasets alignment 28 3.5.2 Interaction between HLJ1 and HSP70 29 3.6 HLJ1-HSP70 Interaction alleviates APAP-Induced ER stress and liver damage 29 3.7 The liver injury region in HLJ1-/- mice exhibits more macrophage infiltration. 30 3.8 Cellular models establishment for APAP 31 Chapter 4. Discussion 32 4.1 Discussion of the mass spectrometry analysis platform 32 4.2 Interaction between HLJ1 and HSP70/72 in reducing ER stress 32 4.3 The role of HLJ1 in glutathione biosynthesis and liver repair 33 4.4 Applications and future prospects 35 Chapter 5. Conclusion and Prospective 36 Chapter 6. Figures 37 Figure 1. Experimental design. 37 Figure 2. Significant differences in acute phase response and drug metabolism in Hlj1-/- mouse liver. 38 Figure 3. Histological analysis of liver tissue from wild type (Hlj1+/+) and Hlj1-/- mice exposed to different dosages of acetaminophen. 40 Figure 4. Hlj1-/- mice exhibit more severe APAP-induced liver injury. 42 Figure 5. Serum markers of liver function were higher in Hlj1-/- mice. 43 Figure 6. Protein and mRNA expression level of HLJ1. 44 Figure 7. Confirm the effectiveness of re-expressing HLJ1 by hydrodynamic injection. 45 Figure 8. Re-expression of HLJ1 alleviates APAP-induced liver injury in Hlj1-/- mice. 46 Figure 9. Enzymatic Metabolism Pathways of Acetaminophen (APAP) in Phase I and Phase II Reactions. 47 Figure 10. Chromatographic results of APAP-metabolites from standards by Mass Spectrometry. 51 Figure 11. Representative calibration curve of each APAP metabolite for absolute quantification by mass spectrometry. 54 Figure 12. Chromatographic results of APAP-metabolites from representative real sample by Mass Spectrometry. 55 Figure 13. Total concentration of APAP metabolites at different time points. 56 Figure 14. Hlj1-/- mice generated more phase I metabolite. 57 Figure 15. Gene expression levels of phase I/phase II enzymes related to acetaminophen metabolism. 58 Figure 16. Protein levels of phase I enzymes related to acetaminophen metabolism. 59 Figure 17. Hlj1-/- mice have lower liver glutathione levels 24 hours after APAP treatment. 60 Figure 18. Potential targets interacting with HLJ1 under APAP stimulation were identified through database alignment. 61 Figure 19. The interaction of HLJ1 and HSP70 was predicted by PEPPI. 62 Figure 20. Immunoprecipitation analysis of HLJ1 and HSP70. 63 Figure 21. ER stress marker was evaluated in Hlj1-/- mice after APAP administration. 64 Figure 22. The liver injury region in Hlj1-/- mice exhibits increased macrophage infiltration. 65 Figure 23. In vitro cellular model of acetaminophen stimulation establishment. 66 Figure 24. Graphical abstract. 67 Chapter 7. Tables 68 Table 1. Analyte-specific and internal standard-specific parameters of mass Spectrometry. 68 Table 2. Calibration standard concentrations for mass spectrometry. 71 Table 3. List of standards and internal standards used in Mass Spectrometry. 73 Table 4. List of primers used in qRT-PCR. 74 Table 5. List of antibodies used in western blot and immunoprecipitation. 75 Reference 76 | - |
| dc.language.iso | en | - |
| dc.subject | 乙醯胺酚 | zh_TW |
| dc.subject | 內質網壓力 | zh_TW |
| dc.subject | 熱休克蛋白 | zh_TW |
| dc.subject | 肝損傷 | zh_TW |
| dc.subject | 質譜儀 | zh_TW |
| dc.subject | acetaminophen | en |
| dc.subject | mass spectrometry | en |
| dc.subject | ER stress | en |
| dc.subject | heat shock protein | en |
| dc.subject | liver injury | en |
| dc.title | 探討熱休克蛋白Dnajb4/HLJ1在調節乙醯胺酚引發肝損傷的作用 | zh_TW |
| dc.title | Investigation of heat shock protein, Dnajb4/HLJ1, in modulating acetaminophen-induced liver injury | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 楊雅倩;郭靜穎;林亮音;王志豪 | zh_TW |
| dc.contributor.oralexamcommittee | Ya-Chien Yang;Ching-Ying Kuo;Liang-In Lin;Chih-Hao Wang | en |
| dc.subject.keyword | 乙醯胺酚,肝損傷,熱休克蛋白,內質網壓力,質譜儀, | zh_TW |
| dc.subject.keyword | acetaminophen,liver injury,heat shock protein,ER stress,mass spectrometry, | en |
| dc.relation.page | 82 | - |
| dc.identifier.doi | 10.6342/NTU202402521 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-08-02 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學系 | - |
| dc.date.embargo-lift | 2026-08-01 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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