臺灣博碩士論文加值系統

組織與全身性發炎反應和氧化壓力增加已知是與肥胖有關，高脂飲食所誘導之肥胖會使氧化壓力與氧化態穀胱甘肽含量增加，造成還原態穀胱甘肽、穀胱甘肽過氧化酶、穀胱甘肽還原酶與穀胱甘肽轉移酶之活性降低。但近來實驗與流行病學研究證實，乙醯胺酚 (acetaminophen) 是與氧化壓力升高有關，其亦與肝功能損傷有關。乙醯胺酚是世界上最廣泛使用之止痛藥與退熱劑。然而乙醯胺酚誘導肥胖大鼠之細胞激素與氧化壓力改變目前仍缺乏相關研究報導，因此本研究將探討乙醯胺酚對正常與肥胖大鼠之細胞激素與氧化壓力改變之影響。研究結果得知，肥胖大鼠給予乙醯胺酚後，可較肥胖大鼠減少體重、腎周圍脂肪與副睪脂肪重量。肥胖大鼠給予乙醯胺酚後，會較肥胖大鼠提升血清總膽固醇、低密度脂蛋白膽固醇、天門冬胺酸胺基轉移酶、丙胺酸胺基轉移酶、介白素-6與介白素-1β。此外，肥胖大鼠給予乙醯胺酚後，會較正常大鼠給予乙醯胺酚增加丙胺酸胺基轉移酶與天門冬胺酸胺基轉移酶之含量。在總抗氧化能力與丙二醛含量上，肥胖大鼠給予乙醯胺酚後，顯著較肥胖大鼠降低肝臟之總抗氧化能力，並增加肝臟與血清之丙二醛含量。而在肝臟抗氧化酵素上，肥胖大鼠給予乙醯胺酚後會顯著較肥胖大鼠降低肝臟麩胱甘肽、麩胱甘肽還原酶與過氧化氫酶活性。在肝組織切片上，肥胖大鼠給予乙醯胺酚後，肝門脈與肝小葉區之發炎狀態會較正常大鼠給予乙醯胺酚更為嚴重。在肝臟基因表現上，肥胖大鼠給予乙醯胺酚後，會較肥胖大鼠顯著提升代謝酵素CYP2E1基因與發炎相關基因 (MCP-1、IL-6、Stat1、Stat3、Jak2與SOCS3) 之表現。而肥胖大鼠給予乙醯胺酚後，會較正常大鼠給予乙醯胺酚降低抗氧化基因 (HO-1、catalase、γ-GCS、GPx1、GPx4、SOD1、SOD2與Nrf2) 與增加促氧化基因 (p47phox與Nox1) 表現。綜合以上結果得知，給予乙醯胺酚會更顯著增加高脂飲食所誘導之氧化壓力升高。

Obesity is associated with increased tissue and systemic inflammation and oxidative stress. Obesity induced by high-fat diets enhances oxidative stress and glutathione disulfide content, and reduces the level of glutathione and activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Several experimental and epidemiological studies have demonstrated that acetaminophen has been associated with elevated levels of oxidative stress, which also causes impaired liver functions. Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the world. However, the literature regarding the effect of acetaminophen-induced changes of cytokines and oxidative stress in obese rats remains unclear. Therefore, the aim of this study is to evaluation of the effect of acetaminophen-induced changes of cytokines and oxidative stress in normal and high fat diet (HFD)-induced obese rats. The data indicated that body weight, perirenal adipose tissue, and epididymal adipose tissue in high fat diet-low dose-acetaminophen (HLA) and high fat diet-high dose-acetaminophen (HHA) groups were significantly decreased as compared to the HFD group. Serum parameter levels of total cholesterol, LDL-cholesterol, aspartate aminotransferase, alanine aminotransferase, interleukin-6, and interleukin-1β in HHA group was significantly increased as compared to the HFD group. The serum parameter levels of alanine aminotransferase and aspartate aminotransferase in HHA group was significantly increased as compared to the normal diet-high dose-acetaminophen (NHA) group. In the trolox equivalent antioxidant capacity (TEAC) and malondialdehyde (MDA), hepatic TEAC in HLA and HHA groups were significantly decreased as compared to the HFD group. Moreover, hepatic and serum levels of MDA in HHA group was significantly increased as compared to the HFD group. In the hepatic antioxidant enzymatic activities, the levels of glutathione, glutathione reductase, and catalase in HHA group was significantly decreased as compared to the HFD group. The pathological results show that the scores of portal inflammation and intralobular degeneration and inflammation in HLA and HHA groups were significantly increased as compared to normal diet-low dose-acetaminophen (NLA) and NHA groups. In the molecular mechanism, hepatic gene expressions of CYP2E1, MCP-1, IL-6, Stat1, Stat3, Jak2, and SOCS3 in HHA group were significantly increased as compared to the HFD group. Hepatic antioxidant related genes of HO-1, catalase, γ-GCS, GPx1, GPx4, SOD1, SOD2, and Nrf2 in HHA group was significantly decreased as compared to the NHA group. Hepatic pro-oxidant related genes of p47phox and Nox1 in HHA group was significantly increased as compared to the NHA group. These results demonstrated that the intake of acetaminophen can enhance oxidative stress and cause impaired liver functions in rats fed a high-fat diet.

中文摘要 I
英文摘要 II
縮寫表 X
前言 1
壹、文獻回顧 3
一、肥胖. 3
(一) 肥胖之簡介 3
(二) 肥胖與疾病 4
二、氧化壓力 9
(一) 氧化壓力之簡介 9
(二) 氧化壓力與細胞防禦機制 10
1.活性氧分子之形成與來源 10
2.對抗氧化壓力相關防禦機制 10
3.抗氧化酵素 11
(1) 麩胱甘肽 11
(2) 麩胱甘肽過氧化酶 11
(3) 超氧岐化酶 12
(4) 過氧化氫酶 13
(5) 血基質氧化酶 13
(三) 氧化壓力與肥胖 14
三、乙醯胺酚 19
(一) 乙醯胺酚之簡介 19
(二) 乙醯胺酚代謝 20
(三) 乙醯胺酚相關機制 21
1.NAPQI與細胞內蛋白結合 21
2.粒線體內氧化壓力之形成 23
3.粒線體氧化壓力之增強 23
4.細胞核內DNA之斷裂 24
5.Nrf2之活化 25
貳、研究動機 29
参、材料方法 30
一、實驗架構 30
二、材料. 31
(一) 儀器 31
(二) 藥品 31
三、方法. 34
(一) 動物、飲食與實驗設計 34
(二) 血清生化參數測定 35
(三) 血清細胞激素分析 35
1.介白素-6 (Interleukin-6, IL-6) 之測定 35
2.介白素-1β (Interleukin-1β, IL-1β) 之測定 36
3.單核球趨化蛋白質 (Monocyte chemotactic protein-1, MCP-1) 之測定 36
4.腫瘤壞死因子 (Tumor necrosis factor α, TNF-α) 之測定 36
5.血基質氧化酶-1 (Heme oxygenase-1, HO-1) 之測定 37
6. 8-異前列腺素 (8-isoprostane) 之測定 37
(四) 組織均質液製備 37
(五) 組織蛋白質含量測定 38
(六) 總抗氧化能力 (Trolox equivalent antioxidant capacity, TEAC) 測 38
(七) 脂質過氧化物丙二醛 (Malondialdehyde, MDA) 分析 38
(八) 肝臟抗氧化酵素分析 39
1.麩胱甘肽 (Glutathione, GSH) 與氧化態麩胱甘肽 (Glutathione disulfide, GSSG) 分析 39
2.麩胱甘肽還原酶 (Glutathione reductase, GRd) 活性測定 39
3.過氧化氫酶酵素 (Catalase) 活性測定 39
4.超氧歧化酶 (Superoxide dismutase, SOD) 活性測定 40
(九) 肝臟一氧化氮 (NO) 之測定 40
(十) 肝組織切片 40
(十一) 基因表現分析 41
1.肝臟RNA萃取 41
2. RNA濃度測定 41
3.反轉錄反應 (Reverse transcription) 41
4.即時定量反轉錄聚合酶連鎖反應 (Real-time RT-PCR) 41
(十二) 統計分析 42
肆、結果 46
一、乙醯胺酚對正常與高脂飲食誘導肥胖大鼠之體重、食物攝取量、能量 攝取與飲水量之影響 46
二、乙醯胺酚對正常與肥胖大鼠之臟器與脂肪組織重量之影響 46
三、乙醯胺酚對正常與肥胖大鼠之血清生化參數之影響 47
四、乙醯胺酚對正常與肥胖大鼠血清細胞激素之影響 47
五、乙醯胺酚對正常與肥胖大鼠血清、肝臟、腎臟與脂肪組織之總抗氧化 能力之影響. 48
六、乙醯胺酚對正常與肥胖大鼠之血清、肝臟、腎臟與脂肪組織生成丙二 醛之影響........................................................................................................48
七、乙醯胺酚對正常與肥胖大鼠肝臟抗氧化酵素之影響 49
八、乙醯胺酚對正常與肥胖大鼠之肝臟一氧化氮之影響 49
九、乙醯胺酚對正常與肥胖大鼠肝臟組織切片之影響 50
十、乙醯胺酚對正常與肥胖大鼠肝臟基因表現之影響 50
(一) 發炎相關基因 50
(二) 抗氧化相關基因 51
(三) 氧化壓力相關基因 52
(四) 促氧化相關基因 52
伍、討論 53
陸、總結論 62
柒、實驗圖表 63
捌、參考文獻 77

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