臺灣博碩士論文加值系統

藥物性腎損傷是指暴露於具有毒性或者潛在毒性藥物之後，導致腎受到不同程度的損傷，其臨床表現為尿液檢查異常、腎病理結構異常和腎功能異常等。目前，藥物性腎毒性主要類型有急性腎損傷、急性腎衰竭、急性間質性腎病和腎病綜合症等。順鉑，是一種廣泛使用的抗癌藥物，對幾乎所有身體部位的癌症都有效，包括乳腺癌、肺癌、卵巢癌、睾丸癌、頭部癌和頸癌。順鉑在1965年首次被確定為細胞週期的抑制劑，並且其治療功效已被廣泛研究。 儘管其具有化學治療活性，但不同的研究報導了該分子在人體的幾個重要器官中的毒性，包括心臟，肝臟，腦，脾，並且在腎組織中具有最顯著的有害作用。 然而，直到目前為止，順鉑依然是幾種癌症的唯一藥物選擇。
中醫理論認為，順鉑腎毒性屬“藥毒”、“腎虛”，其本質為腎精氣不足。順鉑在腎中高濃度的分佈和長時間的積累，導致腎不同程度的損傷。順鉑腎毒性的病理機制主要分為2方面：一是減少腎小球濾過率，升高血清中肌酸酐（Creatinine；CRE）和尿素氮（Blood urea nitrogen；BUN）含量；二是腎近端小管上皮細胞缺血甚至壞死。組織病理學分析發現，順鉑能夠嚴重損害腎組織結構，出現大面積壞死區域，細胞排列疏鬆，刷狀緣消失，腎小球出現明顯萎縮，腎小管空泡變性等。
發炎反應是順鉑腎毒性中一種重要的分子機制，該機制與順鉑啟動腫瘤壞死因數α（Tumour necrosis factor alpha-α；TNF-α）有關，從而增加白細胞介素6 （Interleukin-6；IL-6）和IL-1 分泌以及細胞間黏附分子1的表達，並且促進中性粒細胞黏附到腎內皮細胞產生大量的自由基，引起腎損傷。
腎臟纖維化是一種病理生理改變，是腎臟的功能由健康到損傷，再到損壞，直至功能喪失的漸進過程。腎臟由於受到創傷、感染、炎症、血循環障礙，以及免疫反應等多種致病因素刺激，其固有細胞受損，發展到後期出現大量膠原沉積和積聚，造成腎實質逐漸硬化，形成瘢痕，直至腎臟完全喪失臟器功能。腎臟內固有細胞纖維化、硬化的過程也就是腎臟纖維化的過程。腎臟纖維化是以細胞外基質（Extracellular matrix；ECM）的異常沉積為特徵的。
本研究探討松露複方茶包以及松露複方口服液對腎臟因藥物性腎損傷所致的纖維化是否有保護作用，實驗使用雄性小鼠，體重25-28g，隨機分組為控制組、順鉑組、順鉑+松露複方茶包萃取物1g/KG組及順鉑+松露複方口服液萃取物1g/KG組，通過順鉑誘導小鼠慢性腎損傷，實驗為期六週，並在第四週開始口服松露複方茶包及松露複方口服液，結果顯示松露複方茶包及口松露複方服液對腎臟具有保護作用，研究結果可作為慢性腎臟衰竭預防及治療的新方向。

Pharmacologic nephrotoxicity is defined as exposure to toxic or potentially toxic drugs that result in varying degrees of kidney damage, with clinical manifestations such as abnormal urinalysis, abnormal renal pathology and abnormal renal function. Currently, the main types of drug nephrotoxicity are acute kidney injury, acute renal failure, acute interstitial nephropathy, and nephrotic syndrome. Cisplatin, a widely used anti-cancer drug, is effective against almost all types of cancer in the body, including breast, lung, ovarian, testicular, head and neck cancers. Cisplatin was first identified as a cell cycle inhibitor in 1965 and its therapeutic efficacy has been extensively studied. Despite its chemotherapeutic activity, various studies have reported the toxicity of the molecule in several important organs of the body, including the heart, liver, brain, spleen, and most notably in kidney tissue. However, until now, cisplatin has been the only drug of choice for several types of cancer.
According to Chinese medical theory, cisplatin nephrotoxicity is a "drug toxicity" and "kidney deficiency", which is essentially a deficiency of kidney essence. The high distribution of cisplatin in the kidney and its accumulation over a long period of time lead to different degrees of kidney damage. The pathological mechanism of cisplatin nephrotoxicity is mainly divided into two aspects: firstly, it reduces glomerular filtration rate and increases creatinine (CRE) and blood urea nitrogen (BUN) levels in serum; secondly, it causes ischemia or even necrosis of the epithelial cells in the proximal tubules of the kidney. Histopathological analysis revealed that cisplatin can severely damage renal tissue structure with large necrotic areas, loosening of cell arrangement, loss of brush border, significant atrophy of glomeruli, and degeneration of tubular vacuoles .
The inflammatory response is an important molecular mechanism in cisplatin nephrotoxicity, which is associated with the activation of tumour necrosis factor alpha-α (TNF-α) in cisplatin, thereby increasing the secretion of interleukin-6 (IL-6) and IL-1 and the expression of intercellular adhesion molecule 1, and promoting Neutrophils adhere to renal endothelial cells and produce large amounts of free radicals, causing renal damage.
Renal fibrosis is a pathophysiological change, a progressive process in which the function of the kidney changes from healthy to damaged, to damaged, to loss of function. The kidney is stimulated by various pathogenic factors, such as trauma, infection, inflammation, blood circulation disorders, and immune response, and its intrinsic cells are damaged. The process of fibrosis and sclerosis of the intrinsic cells in the kidney is also the process of renal fibrosis. Renal fibrosis is characterized by the abnormal accumulation of extracellular matrix (ECM).
In this study, we investigated whether truffle formula tea bags and truffle formula oral solution had a protective effect on kidney fibrosis due to drug-induced renal injury, and used male mice, weighing 25-28 g, randomly divided into control group, cisplatin group, cisplatin + truffle formula tea bag extract 1 g/KG group and cisplatin + truffle formula oral solution extract 1 g/KG group. The experimental period was six weeks, and the oral administration of truffle formula tea bag and truffle formula oral solution was started in the fourth week. The results showed that truffle formula tea bag and truffle formula oral solution had a protective effect on the kidney, and the results of the study can be a new direction for the prevention and treatment of chronic kidney failure.

目錄
摘要 I
Abstract III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
第一章 前 言 1
第一節、慢性腎臟衰竭的成因 1
第二節、慢性腎臟衰竭常見症狀 2
第三節、慢性腎臟衰竭治療方式 3
第四節、腎臟纖維化分期 3
第五節、保健食品定義 5
第六節、松露複方之食品原料 6
第二章 材料與方法 9
第一節、樣品 9
第二節、樣品萃取 9
第三節、動物 9
第四節、試驗方法與步驟 10
第五節、血清尿素氮和肌酸酐含量的分析 11
第六節、組織學檢查 11
第七節、TNF-α, IL-1β and TGF-β 發炎介質測量 12
第八節、血液相關指標檢驗 12
第九節、數據分析與評估 12
第三章 結果與討論 13
第四章 結論 26
參考文獻 27

表目錄

表1. 個別小鼠腎臟之組織病理變化 16
表2. 個別小鼠胰臟之組織病理變化 17
表3. 松露複方茶包和口服液萃取物對順鉑誘導的慢腎毒性的腎臟指數 18

圖目錄

圖1. 松露複方茶包和口服液萃取物對順鉑誘導的慢腎毒性的保護作用試驗 14
圖2. 松露複方茶包和口服液萃取物對順鉑誘導的腎毒性的腎組織切片（400X）的組織病理學切片的顯微鏡觀察 15
圖3. 松露複方茶包和口服液萃取物對順鉑誘導的慢腎毒性的發炎因子之檢測 21
圖4. 松露複方茶包和口服液萃取物對順鉑誘導的慢腎毒性的血液相關指標檢驗 25

齊文隆 (2002). 苦瓜栽培管理. 台東區農業專訊,41,10-13
劉森炎, 黃海長, 李曉玫. 組織型轉谷氨醯胺酶與腎臟纖維化. 生理學科進展. 2005. 35(4),314-318
劉蘭英, 王耀獻, 劉尚建, 孫衛平. 慢性腎衰竭中醫病機淺析. 中國中醫急症. 2010. 19(3), 453-454
Al-Laith, A. A. A. (2010). Antioxidant components and antioxidant/antiradical activities of desert truffle (Tirmania nivea) from various Middle Eastern origins. Journal of Food Composition and Analysis, 23(1), 15–22.
Benaceur, F., Chaibi, R., Berrabah, F., Neifar, A., Leboukh, M., & Benaceur, K. (2020). Purification and characterization of latent polyphenol oxidase from truffles (Terfezia arenaria). International Journal of Biological Macromolecules, 145, 885–893.
Culler´e, L., Ferreira, V., Venturini, M. E., Marco, P., & Blanco, D. (2013). Potential aromatic compounds as markers to differentiate between Tuber melanosporum and Tuber indicum truffles. Food Chemistry, 141(1), 105–110.
Dahham, S. S., Al-Rawi, S. S., Ibrahim, A. H., Abdul Majid, A. S., & Abdul Majid, A. M. S. (2016). Antioxidant, anticancer, apoptosis properties and chemical composition of black truffle terfezia claveryi. Saudi Journal of Biological Sciences, 25(8), 1524–1534.
Friedman, M. (2015). Chemistry, nutrition, and health-promoting properties of Hericium erinaceus (Lion’s Mane) mushroom fruiting bodies and mycelia and their bioactive compounds. Journal of Agricultural and Food Chemistry, 63(32), 7108–7123.
Gao, L., Zhong, X., Jin, J., Li, J., & Meng, XM. (2020). Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression. Signal Transduction and Targeted Therapy 5, 9. https://doi.org/10.1038/s41392-020-0106-1.
Hannan, M. A., Al-Dakan, A. A., Aboul-Enein, H. Y., & Al-Othaimeen, A. A. (1989). Mutagenic and antimutagenic factor(s) extracted from a desert mushroom using different solvents. Mutagenesis, 4(2), 111–114.
Janakat, S. M., Al-Fakhiri, S. M., & Sallal, A.K.J. (2005). Evaluation of antibacterial activity of aqueous and methanolic extracts of the truffle Terfezia claveryi against Pseudomonas aeruginosa. Saudi Medical Journal, 26(6), 952–955.
Luo, Q., Zhang, J., Yan, L., Tang, Y., Ding, X., & Yang, Z. (2011). Composition and antioxidant activity of water-soluble polysaccharides from Tuber indicum. Journal of Medicinal Food, 14(12), 1609–1616.
Meng, X.M., Nikolic-Paterson, D.J., & Lan, H.Y. (2014). Inflammatory processes in renal fibrosis. Nat. Rev. Nephrol. 10, 493–503. https://doi.org/10.1038/nrneph.2014.114.
Patel, S. (2012). Food, health and agricultural importance of truffles: A review of current scientific literature. Current Trends in Biotechnology and Pharmacy, 6(1), 15–27.
Qi, M., ShiChen, C., Lei, C., Lingling, W., Guolin, C., Jinsheng, M., Zhenghua, G., Guiyang, S., & Zhongyang, D. (2021). Effect of surfactants on the production of polysaccharides from Schizophyllum commune through submerged fermentation. International Journal of Biological Macromolecules, 192, 210-218.
Shapiro, K. & Gong, W.C. (2002). Natural Products Used for Diabetes. Journal of the American Pharmaceutical Association, 42, 217-226.
Woo, T.C., Seo, H.L., & Jong, D.K. (2001). Effect of the extracts from Glycyrrhiza uralensis Fisch on the growth characteristics of human cell lines: anti-tumor and immune activation activities. Cytotechnology 37, 55–64.
Liu, Y., Yang, Y., Feng, Z., Jiang, J., & Zhang, P. (2019). Eight new triterpenoid saponins with antioxidant activity from the roots of Glycyrrhiza uralensis Fisch. Fitoterapia, 133, 186-192
Yujie, Y., Ye, L., Runge, C., Jing, Z., Yunpeng, C., & Giancarlo, F. (2021). Prediction of Renal Failure for Chronic Disease Population Based on Electronic Health Record Big Data. Big Data Research. 2021 25
Zhang, H.C., Liu, J.M., Chen, H.M., Gao, C.C., Lu, H.Y., Zhou, H., Li, Y., & Gao, S.L. (2011) Up-regulation of licochalcone A biosynthesis and secretion by Tween 80 in hairy root cultures of Glycyrrhiza uralensis Fisch. Mol. Biotechnol. 47, 50–56.
Zheya, C., Chaomin, Y., Xiuzhi, F., Kun, M., Fen Y., Ranran, Z., Defang, S., Wei, C., & Hong, G. (2020). Characterization of physicochemical and biological properties of Schizophyllum commune polysaccharide extracted with different methods. International Journal of Biological Macromolecules, 156, 1425-1434