臺灣博碩士論文加值系統

近年來在臨床和流行病學的研究中，許多慢性疾病的成因和肥胖、體脂增加和癌症風險增加有關息息相關。過去研究中指出，龍葵萃取物具有抗發炎、抗氧化、降血脂與保護肝臟等功效。近年來根據醫學研究文獻指出，龍葵萃取物具有抗發炎、抗氧化、降血脂與保護肝臟等功效。因此本實驗以細胞實驗及動物實驗來探討龍葵萃取物對於非酒精性脂肪肝引發肝炎和肝癌之機制。
　　本實驗主要可分三部分進行。第一部分：在肥胖和脂肪肝研究模式中，C57BL/6小鼠餵食高油脂飼料誘導肥胖，並於飼料中添加0.5%、1%與2%龍葵萃取物，發現龍葵萃取物可降低血中三酸甘油脂、血糖及血脂和減少周邊脂肪和內臟脂肪的堆積。在脂肪代謝方面，小鼠肝臟中，龍葵水萃物可藉由提升p-AMPK訊息路徑調控減少FAS、HMG-CoR、SREBPs脂質生成蛋白相關之表現，以及增加脂質代謝酵素CPT-I及PPAR-α之表現以達到減少肝臟脂肪堆積之效果，藉由降低脂質的累積。在細胞實驗方面，藉由誘導pre-3T3-L1成熟後，在加龍葵多酚處理後，在油紅實驗中發現油滴堆積情況會隨著加藥量增加而減少。脂質生合成蛋白FAS、HMG-CoR、SREBPs會有減少的趨勢，脂質代謝酵素CPT-I及PPAR-α則會明顯的提升，減少脂肪堆積之效果。
　　而第二部份，主要針對龍葵對於非酒精性脂肪肝的機制探討。在動物實驗中，可觀察到龍葵可減少肝臟中脂肪泡的堆積，同時也可以降低肝臟中因肥胖所導致發炎的現象，減少TNF-α和IL-6的表現；另外在Hep-G2細胞中，同樣可觀察龍葵多酚可抑制經油酸誘導後在細胞中脂質堆集的情況，相關脂質生合成蛋白FAS、HMG-CoR、SREBPs表現會有明顯下降的情形，同時脂質代謝酵素CPT-I及PPAR-α則會提升，減少細胞內脂質堆積的情況。
　　在第三部分肝癌模式中，C57BL/6小鼠以高油脂飼料誘導肥胖，並以含有0.01%的化學致癌物質diethylnitrosamine (DEN)飲用水連續餵食 12週後，誘導小鼠自發性產生肝癌。正如預期，肥胖確實會增加DEN所誘導肝癌腫瘤的數目，大小以及肝癌發病率。從結果中可以觀察到，SWE可以改善血液中的肝功能指標酵素如ALT，AST與ALK-P。SWE還能夠加強小鼠肝臟中的解毒酵素和抗氧化酶的活性。在免疫組織染上發現，SWE可以抑制KSR2, Rac-1, PKC-α及AFP等相關target蛋白的表現。
　　根據上述的結果說明，龍葵水萃物能有效降低體脂肪形成，而龍葵多酚能有效降低脂肪細胞3T3-L1的成熟和脂質合成以及Hep-G2細胞脂質合成的情況。最後也證實肥胖確實會增強DEN誘發肝癌的發生，而SWE則具有抑制肥胖促進肝癌發生之能力。

In clinical and epidemiological studies, the causes of many chronic diseases are closely related to obesity, increased body fat and increased risk of cancer in recent years. Past research pointed out that Solanum nigrum water extract has anti-inflammatory, anti-oxidation, lipid-lowering and liver protection and other effects. According to medical research literature pointed out that Solanum nigrum water extract has anti-inflammatory, anti-oxidation and the protection of the liver and other effects. Therefore, this experiment to cell experiments and animal experiments to explore the Solanum nigrum water extract for non-alcoholic fatty liver caused by hepatitis and liver cancer mechanism.
The experiment can be divided into three parts. In the first part,C57BL/6 mice fed a high-fat diet induced obesity in the model of obesity and fatty liver, and 0.5%, 1% and 2% Solanum nigrum water extracts were added to the diet. The results showed that Solanum nigrum water extract can reduce blood triglyceride, glucose and lipids, and reduce the accumulation of peripheral fat and visceral fat. In the area of fat metabolism, Solanum nigrum water extract could reduce the expression of FAS, HMG-CoR, and SREBPs related to lipid production by increasing p-AMPK signaling pathways and increase the expression of lipid metabolism enzymes CPT-I and PPAR-α performance in order to achieve the effect of reducing liver fat accumulation. In cell experiments, the accumulation of oil droplets was found to decrease with the increase of dosing amount in the oil red experiment after the induction of pre-3T3-L1 maturation. Lipid protein synthesis FAS, HMG-CoR, SREBPs will reduce the trend of lipid metabolism enzymes CPT-I and PPAR-α will significantly improve the effect of reducing liver fat accumulation.
The second part focuses on the mechanism of Solanum nigrum for non-alcoholic fatty liver. In animal experiments, solanum can be observed to reduce the accumulation of fat in the liver accumulation, but also can reduce the inflammation caused by obesity in the liver phenomenon, reduce the performance of TNF-α and IL-6. In addition, Solanum nigrum polyphenols can also be observed in Hep-G2 cells can inhibit lipid accumulation in cells after oleic acid-induced accumulation, related lipid raw proteins FAS, HMG-CoR, SREBPs performance will have a significant decline in the situation.
In hepatocellular carcinoma model, C57BL/6 mice induced obesity with high fat diet and induced spontaneous hepatic cancer in mice with continuous feeding of diet containing diethylnitrosamine (DEN) containing 0.01% of chemical carcinogens for 12 weeks. As expected, obesity does increase the number, size, and incidence of liver cancer induced by DEN. It can be observed from the results that Solanum nigrum water extract can improve liver function indexes such as ALT, AST and ALK-P in blood. Solanum nigrum water extract also enhances the activity of detoxifying enzymes and antioxidant enzymes in the liver of mice. The results of immunehistochemistry showed that Solanum nigrum water extract could inhibit the expression of KSR2, STK33, caveolin-1, PKC-α, AFP and other related target proteins.
Based on the above results, Solanum nigrum water extract can effectively reduce body fat formation, while Solanum nigrum polyphenols can effectively reduce the maturation and lipid synthesis of 3T3-L1 adipocytes and the lipid synthesis of Hep-G2 cells. Finally, it is confirmed that obesity can indeed enhance the occurrence of liver cancer induced by DEN, whereas SWE has the ability of inhibiting obesity and promoting the occurrence of liver cancer

中文摘要 7
英文摘要 9
一、緒論 12
脂肪肝 16
非酒精性脂肪肝病(non-alcoholic fatty liver disease, NAFLD) 17
非酒精性脂肪肝炎相關蛋白 19
脂蛋白的調節 24
細胞激素 25
龍葵(Solanum nigrum L.)簡介 28
研究動機 31
二、實驗材料與方法 32
一、動物實驗 錯誤! 尚未定義書籤。
二、細胞實驗 錯誤! 尚未定義書籤。
實驗藥品與器材 45
三、研究結果 49
第一部分、龍葵多酚抑制體脂肪形成 49
1. HPLC Assay for SWE. 49
2. 老鼠體重變化與體脂肪含量 49
3. 動物肝臟脂質代謝蛋白表現 50
4.細胞毒性測試 50
5. 油酸試驗 (Oleic acid, OA) 50
6.以西方點墨法分析調控細胞油脂合成蛋白之表現 51
第一部分Summary 錯誤! 尚未定義書籤。
第二部分、龍葵多酚抑制非酒精性脂肪肝引發肝炎之機轉 52
1. 老鼠體重與肝臟重量 52
2. 血液生化值 52
3. 動物組織切片染色 52
4. 肝臟酵素試驗 52
5. 細胞毒殺試驗 53
6. 油酸試驗 (Oleic acid, OA) 53
7. 西方墨點法 (Western blotting) 53
第二部分Summary 錯誤! 尚未定義書籤。
第三部分、龍葵萃取物抑制肥胖促進二乙基亞硝胺致肝癌之作用 55
1. SWE對於小鼠體重及存活率變化之影響 55
2. SWE對肝臟外觀與重量影響 55
3. 肝臟病理切片之結果 56
4. SWE對血液中肝功能指標的影響 56
5. SWE對肝臟組織的影響 56
6. SWE保護肝臟之相關機制變化(西方墨點法) 57
7. SWE對於肝臟酵素之影響 57
第三部分Summary 錯誤! 尚未定義書籤。
四、討論 59
第一部分、龍葵多酚抑制體脂肪形成 59
第二部分、龍葵多酚抑制非酒精性脂肪肝引發肝炎之機轉 60
第三部分、龍葵萃取物抑制肥胖促進二乙基亞硝胺致肝癌之作用 62
五、總結論： 錯誤! 尚未定義書籤。
六、實驗結果圖表 71
第一部分、龍葵多酚抑制體脂肪形成 71
Figure.1. 72
Figure 2. 73
Figure 3. 74
Figure 4. 75
Figure 5. 76
Figure 6. 77
Figure 7. 78
Figure 8. 79
Figure 9. 80
Figure 10. 81
第二部分、龍葵多酚抑制非酒精性脂肪肝引發肝炎之機轉 83
Figure 1. 83
Table 1. SWE reduce serum lipid and hepatic function markers significantly in HFD-induced obesity mice. 84
Figure 2. 85
Figure 3. 87
Figure 4. 88
Figure 5. 89
Figure 6. 90
第三部分、龍葵萃取物抑制肥胖促進二乙基亞硝胺致肝癌之作用 93
Table 1. SWE reduce serum lipids and hepatic functional markers in HFD+DEN-induced mice. 93
Figure 1. 94
Figure. 2 96
Figure 3. 98
Figure 4. 99
Figure 5. 101
七、Summary 104
八、參考文獻 105
九. 已發表之文獻 114

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