臺灣博碩士論文加值系統

本研究室以前的研究結果，炸油餵食鼠尿中 PGE2 的代謝物Bicyclo PGE2 含量較對照組為高。文獻指出前列腺素合成 (PGHS，又稱cycloxygenase, COX)基因之Promoter區具有XRE序列 (Xenobiotics Responsive Element)。一些Xenobiotics :如TCDD會增加MDCK細胞PGHS基因的表現。我們乃成立假說︰『炸油餵食可能促進前列腺素合成基因的表現而增加前列腺素生合成』。為探討此假說，以動物餵食實驗確定體內PGE2合成受飲食炸油影響之組織器官。再選擇生化代謝特性類似之細胞株供為模式，進一步探討炸油對前列腺素合成脢基因表現之影響。
將新鮮黃豆油在205±5℃ 油炸麵片，每天油炸6小時，連續4天共24小時，作為實驗用油。16隻離乳之Long-Evans 雄鼠隨機分成兩組︰炸油組 (HD)餵食含有15%炸油之飼料，新鮮油組(HF)餵食含有15%新鮮黃豆油之飼料作為對照組，餵養13週。收集72小時尿液分析PGE2及PGE2代謝產物(Bicyclo PGE2)尿中排出量，結果如同預期，此兩種測量值均以炸油組顯著高於對照組(p<0.05)。測定組織中PGE2代謝物生成量，結果炸油組大鼠腎臟及貯精囊(seminal vesicle)中PGE2代謝物生成量顯著高於對照組(p＜0.05)。顯示飲食炸油可能影響腎臟中PGE2生成。
為了探討炸油對前列腺素合成脢基因表現之影響，我們乃選用腎臟來源之細胞株MDCK (Madin Darby Canine kidney cell) 為細胞模式，探討飲食炸油影響PGE2生成之機制。30隻成年 Long-Evans 雄鼠，分別餵予LF (含5% 新鮮黃豆油)，HF (含20%新鮮黃豆油)，HD (含20%炸油) 三種試驗飼料 ，餵食4週後收集各組血清，分析其肝微粒体cytochrome P450 含量，確定飲食處理確已造成影響。將三種血清配入培養液，用以培養MDCK細胞，並以已知之PGHS調控因子TPA作為正對照。培養18小時後測定培養液中PGE2含量，並以MTT染色確定細胞存活率。結果顯示經HD鼠血清培養18小時後，培養液中PGE2生成量顯著高於經其他兩組對照組（LF、HF）鼠血清處理者。以相同方法將3種鼠血清培養纖維母細胞株Swiss 3T3，則三種血清間沒有顯著差異，表示炸油對前列腺素合成的影響具有組織特異性，此結果與炸油增加腎臟PGE2含量的結果相符。以含5%各組血清培養液培養4小時後收集細胞，以免疫轉印檢測MDCK細胞中PGHS蛋白質含量，同時亦以北方轉印法檢測MDCK細胞中PGHS mRNA含量；結果顯示經HD鼠血清處理，細胞內PGHS-2蛋白質含量，為經其他兩組對照組血清處理細胞之180%，mRNA量亦較對照組為高（p<0.05）。顯示炸油血清可能藉由增加PGHS基因表現進而促進PGE2生成量。
前列腺素 (PG) 在調節腎絲球血流、renin 分泌、維持鈉離子及水份恆定上，十分重要，而PGE2及PGI2則具舒張血管而降低血壓的作用。為探討炸油飲食是否因促進腎臟PG生成而改變此等生理狀況，SD離乳雄鼠隨機分成四組︰低、高炸油組（LD、HD) 分別餵食含有5%、20%炸油之飼料，低、高新鮮油組(LF、HF) 則分別餵食含有5%、20%新鮮黃豆油之飼料作為對照組。另取兩組雌鼠分別餵食20% 新鮮油 (FHF) 與20% 炸油（FHD）飼料，餵養4週後測定血壓。結果顯示收縮壓、舒張壓及平均血壓以HD組明顯低於其他各組（p< 0.05），雌鼠也是高炸油組較低。收集72小時尿液測定四種前列腺素Bicyclo PGE2、PGE2、6-keto PGF1α及TXB2含量，均為HD組明顯較高，於雌鼠情形亦如此。BicycloPGE2排出量反映全身體內PGE2生合成及代謝的結果，6-keto PGF1α、PGE2和TXB2排出量則反映腎臟中PGI2、PGE2和TXA2生成的情形。本實驗結果顯示高炸油飲食會增加體內及腎臟PGE2合成，低炸油則否。尿中鈉鉀排出量，高低次序為LD>HF>LF>HD，雌鼠也以HD組較低。血清中鈉鉀則不受飲食改變。各組老鼠Creatinine clearance沒有差異，表示腎絲球過濾率 (GFR) 不受飲食炸油的影響。推測高炸油攝取可能增加體內具有血管舒張作用的PG生成而造成血壓下降。血壓下降引發回饋控制作用，增加renin分泌、angiotensin II上升使得腎小管對鈉鉀再吸收作用增加，尿中鈉鉀排出量較低。炸油對腎臟功能的影響仍有待進一步探討。
腎臟是一結構複雜的器官，PGHS分布在腎元的特定位置，且不同的位置所合成的前列腺素其所扮演的角色有所不同。為了暸解炸油對腎元PGHS分布以及表現量的影響，利用免疫組織染色的方式，比較高炸油（HD）與低新鮮油(LF)兩種飼料餵食鼠 (每組五隻）腎臟中PGHS 分佈與免疫染色強度，同時也利用免疫轉印及RT-PCR方法檢測腎組織髓質與皮質PGHS之蛋白質和mRNA含量。由腎臟組織切片免疫染色結果指出PGHS-1主要分布在髓質亨氏管厚壁上行支（medullary thick ascending limb of Henle''s loop ,mTAL）、薄壁亨氏管(thin segment of Henle''s loop)、PGHS-2則主要分布於皮質部遠曲小管(dital convoluted tubule, DCT)，緻密斑（macula densa）此結果與文獻吻合。炸油餵食鼠之DCT處的PGHS-2免疫染色強度似有高於對照組之狀況。MDCK源自於狗腎臟遠曲小管上皮細胞，此結果與炸油餵食鼠血清增加MDCK細胞PGE2合成之實驗結果一致。以RT-PCR檢測PGHS-1與PGHS-2 mRNA含量，結果得知炸油組老鼠腎臟皮質中PGHS-2 mRNA含量較高，蛋白質量結果亦同，但未達統計意義的標準。此結果與組織切片免疫染色結果相符。測定兩組老鼠腎臟髓質(medulla)及皮質(cortex)處bicyclo PGE2、6-keto PGF1α、PGE2及TXB2含量，皮質部和髓質部bicyclo PGE2含量，兩組老鼠間含量相當，TXB2含量亦如此。炸油組皮質和髓質6-keto PGF1α和PGE2含量均高於LF對照組，但經統計分析兩組間之差異在顯著邊緣（p=0.052，p=0.063）。因此推測若樣本數增加，兩組間的差異應可達統計意義。顯示與皮質部PGHS-2表現受炸油飲食所增加結果相符。
綜上所述，炸油餵食使大鼠腎臟及貯精囊中PGE2生成量增加。炸油餵食鼠血清會藉由增加PGHS蛋白質與mRNA表現而增加MDCK細胞PGE2之生成，至於是炸油成份經吸收後或其代謝物的影響，則待進一步探討。高炸油飲食對腎皮質PGHS mRNA 及蛋白質含量有增加之趨勢，影響位置在於位於皮質的遠曲小管。高炸油可能藉由增加體內前列腺素生成量而造成老鼠血壓降低，影響體內血壓調節系統，尿中鈉鉀排出量改變。

Previously, it was shown that urinary bicyclo PGE2, the metabolite of PGE2 increased significantly in rat fed oxidized frying oil (OFO). It has also been demonstrated that an XRE element has been identified in the 5'' noncoding region of the Prostaglandin H synthase (PGHS) gene. Recently it was observed that TCDD stimulates the expression of PGHS-2 mRNA in MDCK cell line. PGHS has been suggested to be important in the extrahepatic metabolism of xenobiotics. The main aim of this study was to examine whether PGE2 production can be changed by dietary OFO and secondary we were also interested in whether modulation of PGE2 production by OFO is mediated by PGHS mRNA expression.
OFO sample was obtained by frying dough sheet in soybean oil in a cast iron wok under 205 ±5℃ for 24 hours. Two groups of male Long-Evans weanling rats were fed the 15% OFO (HD) or the control diet containing 15% fresh soybean oil (HF) for 13 weeks. 3-day urine samples were collected and analyzed for PGE2 and its metabolite, bicyclo PGE2. The urinary PGE2 and bicyclo PGE2 were significantly higher in the HD group. The bicyclo PGE2 were also analyzed in kidney, liver, heart, stomach, lung, brain, spleen, seminal vesicle and testis. OFO treatment enhanced the bicyclo PGE2 levels in kidney and seminal vesicle (p<0.05). These results indicate that dietary oxidized frying oil increase the PGE2 production in kidney and seminal vesicle.
To investigate the mechanism of the stimulation effect of dietary OFO on the PGE2 production, we have examined the effect and molecular mechanisms for PGHS in Madin Darby canine kidney cell (MDCK). The serum samples were collected from 30 adult Long-Evans male rats fed respectively the three test diets, namely, LF (containing 5% fresh soybean oil), HF (containing 20% fresh soybean oil) and HD (containing 20% OFO) diets for four weeks. Serum samples from each group of rats were pooled, filtered and mixed into MEM medium at various concentrations and used for culturing with MDCK cells for 18 hours. Medium was then collected for the analysis of PGE2 by an EIA kit. MDCK cells cultured with medium containing HD serum produced significantly higher PGE2 (p<0.05) than cells cultured with mediums containing LF or HF serum. There is no significant difference in the PGE2 production among Swiss 3T3 cell cultured with medium containing LF、HF or HD serum. The result indicates that the enhancement of PGE2 production by dietary oxidized frying oil is cell-specific. The PGHS-2 mRNA levels in MDCK cells cultured with HD serum for 2 hours was not higher than cells cultured with LF and HF serum, but the PGE2 production was increased (p<0.05). However, the PGHS-2 protein and mRNA levels in MDCK cells cultured with HD serum for 4 hours was significantly higher than LF and HF serum. The results indicated that the dietary oxidized frying oil stimulates PGE2 production by increasing PGHS-2 catalytic activity, protein and mRNA.
PGs were known to act as local mediators that regulate a variety of renal functions. To investigate the effect of OFO on local distribution of PGHS-1 and PGHS-2 in rat kidney, kidneys of rats fed diets containing 20% OFO (HD) or 5% fresh soybean oil (LF) were examined by immunohistochemistry. The PGHS-1 immuno-reactive protein was observed in medullary thick ascending limb of Henle''s loop (mTAL) and thin segment of Henle''s loop. The PGHS-2 immunoreactive protein was localized in distal convoluted tubule (DCT) and macula densa. PGH-2 protein appeared to be prominent in the DCT of the HD group. Protein and mRNA expression of PGHS isoform in renal cortex and medulla were examined by Western bloting and RT-PCR, respectively. Image analysis of the result showd that dietary oxidized frying oil tended to increase PGHS-2 protein and mRNA levels in renal cortex. The levels of bicyclo PGE2, PGE2, 6-keto PGF1α and TXB2 in renal medulla and cortex were also analyzed. In the HD group, levels of 6-keto PGF1α and PGE2 in renal cortex was higher than those in the LF group (p=0.052, p=0.063). The results implied that dietary oxidized frying oil tend to increase renal PGHS-2 protein and mRNA expression in renal cortex.
It has been demonstrated that prostaglandins play an important role in the control of renal hemodynamics, salt and water homeostasis and renin secretion. PGE2 and PGI2 cause a fall in blood pressure due to systemic vasodilation. To investigate whether some of these renal functions can be changed by dietary OFO due to increases in PG productions, four groups of male Sprague-Dawley weanling rats were fed 5% (LD) or 20% (HD) OFO diets or control diets containing 5% (LF) or 20% (HF) fresh soybean oil for 4 weeks. Two groups of female rats were also fed 20% OFO (FHD) or fresh soybean oil (FHD) diets. HD group showed significantly lower blood pressure the remaining 3 groups. 3 days urine samples were collected and analyzed for bicyclo PGE2, PGE2, 6-keto PGF1α and TXB2. The urinary excretion of all of the four PGs were highest in HD group (p<0.05), indicated that dietary OFO may increased the common step of the production of all these PG2. The order of the levels of urinary sodium and potassium excretion was LD>HF>LF>HD. There were no significant differences in serum sodium and potassium concentrations among the 4 groups. Creatinine clearance of the 4 groups of rats was not significant different (p>0.05). It is speculated that the high dietary oxidized frying oil diet may increase systemic vasodilative PGs production and results in lower blood pressure. Low blood pressure may induce renin-angiotensin system and then increase sodium and potassium reabsorbtion in renal tubule.
In conclusion, dietary oxidized frying oil increased the PGE2 production in rat kidney and seminal vesicle. This can be demonstrated in MDCK cells a kidney tubular epithelium derived cell line, in which, PGE2 production, PGHS-2 protein and mRNA expression were significantly enhanced by culturing with medium containing serum from rats fed a high oxidized frying oil containing diet. In rat kidney, PGHS-2 in distal convoluted duct of the effect of dietary oxidized frying oil on the renal PGE2 production. Rats fed a high oxidized frying oil diet showed lower blood pressure.

封面
目錄
中文摘要
英文摘要
縮寫對照表
第一章 緒言
第一節 前言
第二節 文獻回顧
一、 前列腺素的前生合成：
1. 前列腺素的化學結構
2. Eicosanoid
3. 前列腺素的功能
4. Prostanoid Receptor
5. 前列腺素合成□PGHS-1與PGHS-2
6. PGHS Knockout Mice
7. PGHS的調控：
8. Eicosanoid與腎臟功能：
9. 前列腺素與血壓控制
10. PGHS與Xenobiotics
二、 受熱氧化油脂
1. 油脂在油炸時之化學變化
2. 受熱氧化油脂之一般毒性表現
3. 受熱氧化油脂之致癌性
4. 其它生物效應
5. 氧化油脂與Eicosanoids
第三節 實驗假說與設計
第二章 炸油飲食對大鼠體內PGE生成之影響
第一節 前言
第二節 材料與方法
1. 炸油的製備
2. 試驗飼料的製備
3. 動物飼養、體重變化及攝食情形：
4. 尿液收集
5. 動物犧牲及樣品收集：
6. 肝組織均質：
7. 肝微粒體之製備：
8. 肝微粒體中total cytochrome P-450含量測定
9. 尿中PGE代謝產物bicyclo PGE之測定
10. 尿中PGE含量之測定
11. 尿液中肌酸酐(creatinine)含量之測定
12. 血漿中PGE之含量測定
13. 血漿中PGE代謝物bicyclo PGE之含量測定
14. 組織中PGE代謝物bicyclo PGE之含量測定
14. 統計分析
第三節 結果
1. 生長與攝食情形
2. 相對組織重量
3. 肝微粒體中total cytochrome P-450之含量測定
4. 炸油餵食對尿中、血漿中PGE與PGE代謝產物含量之影響
5. 炸油餵食對各組織PGE代謝產物含量之影響
第四節 討論
1. 生長與攝食情形
2. 相對組織重量
3. 肝微粒體中total cytochrome P-450之含量測定
4. 炸油餵食對尿中、血漿中PGE與PGE代謝產物含量之影響
5. 炸油餵食對各組織PGE代謝產物含量之影響
第三章 建立細胞培養系統探討炸油對PGE生合成之影響
第一節 前言
第二節 材料與方法
1. 動物餵養、尿液、血清及其他樣品的收集
2. 細胞培養用血清TG含量測定
3. 細胞培養用血清總脂肪量(Total Lipids)的測定
4. 細胞培養用血清UV233的測定
5. TBARS濃度測定
6. 細胞培養系統的建立
7. 活細胞數目的測定
8. 三種油脂餵食鼠血清處理對MDCK及Swiss3T3細胞PGE生成之影響：
9. Prostaglandin H synthase蛋白質含量
10. PGHS-2 mRNA量之測定
11. 統計分析
第三節 結果
1. 動物攝食與生長狀況
2. 尿中PGE代謝產物bicyclo PGE含量
3. 肝、腎微粒體cytochrome P450含量
4. 血漿中PGE與bicyclo PGE含量及細胞培養液中PGE濃度
5. 細胞培養用鼠冊清三酸甘油脂、總脂肪量、蛋白質含量及過氧化指標
6. TPA對MDCK細胞及Swiss 3T3 PGE生成量之影響
7. 炸油餵食鼠血清對MDCK細胞及Swiss 3T3細胞PGE生成量的影響
8. 三種鼠血清、FBS及TPA對MDCK細胞生長之影響
9. 免疫轉印偵測MDCK細胞中PGHS蛋白質含量
10. 以Northem blot偵測MDCK細胞中PGHS mRNA含量
第四節 討論
1. 炸油餵食鼠血清對PGE合成之影響具有細胞特異性
2. 炸油餵食鼠血清增加MDCK細胞PGE合成之機制
第四章 炸油飲食對腎臟Prostaglandin H synthase基因表現及於腎臟分佈之影響
第一節 前言
第二節 材料與方法
1. 動物分組與飼養
2. 動物犧牲、樣品收集與腎臟組織固定
3. 組織切片製作
4. 腎臟髓質與皮質PGHS-1、PGHS-2蛋白質含量測定
5. 腎臟皮質、髓質總RNA抽取
6. 腎臟髓質與皮質PGHS-1、PGHS-2 mRNA含量測定
7. 腎臟髓質與皮質bicyclo PGE、PGE、6-keto PGFα and TXB含量測定
8. 統計分析
第三節 結果
1. 動物攝食與生長狀況
2. 餵食炸油對大鼠尿液中PGE2代謝物(bicyclo PGE2)排出量之影響
3. 免疫轉印偵測腎臟髓質及皮質處PGHS-2、PGHS-1蛋白質含量
4. 腎臟髓質及皮質部bicyclo PGE、PGHS-1 mRNA含量
5. 腎臟髓質及皮質部bicyclo PGE、PGE、6-keto PGFα and TXB含量測定
6. 飲食炸油對腎臟PGHS蛋白質分佈及含量的影響
第四節 討論
1. 以免疫轉印、RT-PCR、免疫組織切片染色探討飲食炸油對腎臟PGHS表現的影響
2. 飲食炸油對腎臟髓質及皮質部bicyclo PGE、PGE、6-keto PGFα and TXB含量之影響
3. 飲食炸油可能藉由增加腎臟遠曲小管及緻密斑處PGHS-2而影響腎臟renin的生成及納離子再吸收作用等生理功能
第五章 炸油飲食大鼠血壓及尿液鈉鉀排出量之影響
第一節 前言
第二節 材料與方法
1. 實驗大綱：
2. 動物分組與飼養
3. 血壓測定：
4. 尿中PGE含量及PGE代謝產物bicyclo PGE之測定
5. 尿中PGI代謝產物6-keto bicyclo PGFα之測定
6. 尿中TXA代謝產物TXB之測定
7. 尿中nitrate/nitrite含量之測定
8. 血清及尿液中鈉鉀濃度測定：
9. 血清及尿液中creatinine濃度測定：
10. 統計分析
第三節 結果
1. 動物攝食與生長狀況
2. 心跳速率、收縮壓、平均血壓、及舒張壓之影響
3. 飲食炸油對大鼠尿中bicyclo PGE、PGE、6-keto PGFα and TXB排出量之影響
4. 飲食炸油對大鼠尿中鈉、鉀排出量及血中鈉、鉀含量之影響
5. 飲食炸油對大鼠尿液排出量、尿中creatinine排出量、血清creatinine含量及creatinine clearance之影響
6. 飲食炸油對大鼠尿中NO排出量之影響
7. 各組大鼠鈉鉀攝食量與尿中鈉鉀排出量之比較
8. 各組大鼠血壓高低與尿中前列腺素及尿鈉尿鉀排出量之相關性分析
9. 各組大鼠尿鈉尿鉀排出量與尿中前列腺素之相關性分析
第四節 討論
1. 炸油餵食對動物體的影響不因鼠種不同而不同
2. 高炸油飲食降低血壓
3. 高炸油飲食增加大鼠尿中Bicyclo PGE、PGE、6-keto PGFα、TXB排出量
4. 飲食炸油對大鼠腎功能之影響
5. 低炸油組增加尿鈉排出量的原因
6. 飲食炸油增加體內PG的合成造成血壓下降
第六章 總結
第七章 參考文獻
附錄 Prostaglandin H synthase-2 CDNA質體構築
第一節 前言
第二節 材料與方法
1. 總RNA抽取
2. RNA電泳
3. 反轉錄□-聚合□連鎖反應(RT-PCR)
4. 宿主轉型及菌落篩選
5. 限制□圖譜鑑定
6. DNA序列分析
7. 大量質體之純化置備
第三節 結果與討論
1. RT-PCR產物大小之鑑定：
2. 限制□圖譜之判讀：
3. DNA序列

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