慢性腎臟疾病及最終的末期腎臟病在全世界皆造成健康上的威脅。慢性腎臟疾病患者有明顯偏高的慢性發炎和氧化壓力，特別是糖尿病腎病的患者，慢性發炎和氧化壓力在糖尿病腎病的致病原因中扮演關鍵的角色。目前台灣需要血液透析的末期腎病患者人數節節攀升，而糖尿病腎病是末期腎病的最常見原因。糖尿病腎病的致病機轉包括：胰島素阻抗、胰島細胞破壞、腎臟組織纖維化及蛋白尿；這些機轉都與慢性發炎及氧化壓力有關。抗氧化劑被證明對糖尿病腎病有減緩的效果，但卻很少被用於臨床治療糖尿病腎病。原因可能是由於它需要極高的劑量來達到治療效果，且成本及可能的副作用阻礙了抗氧化劑的使用。由培養菌體來萃取抗氧化劑有速度快及價格低的優勢，比較不受限於天氣及場地的限制。從突變紅球菌提取的新精緻萃取物LCG顯示出比番茄紅素 (lycopene)更低的毒性和更有效的抗氧化活性，突變紅球菌提取LCG的量為 wild type紅球菌提取番茄紅素的3.5倍，LCG也已被證明具有抗發炎活性。
通過核磁共振光譜法 (nuclear magnetic resonance Spectroscopy, NMR) 研究，我們知道LCG的主要成分包含了spheroidenone、methoxyneurosporene、ξ-carotene和neurosporene。使用0.2％ LCG處理30天後，對倉鼠皮膚並沒有明顯刺激反應，證明LCG具有良好的生物相容性。氧化壓力及腎臟纖維化是糖尿病腎病重要的致病機轉，而上皮間質細胞轉型 (epithelial to mesenchymal transition, EMT) 是腎臟纖維化重要的指標，LCG在H2O2處理的HK2細胞中減少活性氧化物 (reactive oxygen species, ROS) 和EMT標記。口服LCG (200mg /kg) 顯著降低糖尿病小鼠模型中的24小時蛋白尿，降低血糖，並降低胰島素阻抗。LCG在糖尿病小鼠的腎組織TUNEL檢測中顯示能降低細胞凋亡。減少凋亡可以減少腎單位損失和減少蛋白尿。LCG減少p38的磷酸化，可以解釋抗發炎作用和減少EMT的機轉。LCG比起Lycopene 有更強的活性及較低的毒性，對於需要高的劑量來達到治療效果的抗氧化劑是個值得研究的標的，但仍然需要進一步的研究確認LCG在糖尿病性腎病中的益處。

Chronic kidney disease (CKD) is a major burden worldwide. Oxidative stress and chronic inflammation play pivotal roles in CKD, especially CKD caused by diabetic nephropathy (DN). End-stage renal disease that needs treatment through hemodialysis is most commonly caused via DN. Antioxidants have been shown to be beneficial against DN. However, antioxidants are rarely used in clinical practice, probably due to the extremely high doses needed to achieve therapeutic effects. Therefore, possible side effects and cost limit the use of antioxidants for therapeutic purposes. Recently, a novel compound LCG that displays anti-inflammatory activity was extracted from transformant Rhodobacter sphaeroides. LCG showed less toxicity and more potent anti-oxidative activity than lycopene, an antioxidant widely used as a nutritional supplement. Microbial carotenoids have many advantages over plant carotenoids. Carotenoid extraction from microorganisms is more effective and less expensive process. Fermentation is independent of the weather situation. The mutant strain displayed a 3.5-fold increase in carotenoid content, relative to the wild type.
The components of LCG were discovered via nuclear magnetic resonance (NMR) studies, these include spheroidenone, methoxyneurosporene, ξ-carotene, and neurosporene. Interestingly, no irritation response was seen on hamster skins after 30 days of treatment with 0.2% LCG, demonstrating that LCG has good biocompatibility. LCG reduced reactive oxygen species and epithelial–mesenchymal transition markers in H2O2-treated HK2 cells. Using a diabetic mouse model, orally administered LCG (200mg/kg) significantly reduced proteinuria, lowered blood sugar, and reduced insulin resistance after 24 hours. LycogenTM reduced apoptosis in diabetic mice measured via the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay from biopsies of renal tissue. A reduction in apoptosis can attenuate nephron loss and decrease proteinuria. LCG reduced phosphorylation of p38, which is probably how LCG presents an anti-inflammatory effect and reduces EMT. Due to less toxicity and more potent anti-oxidative activity than lycopene, LCG is a potential target for further investigation to confirm the benefits of high dose antioxidants treatment in DN.

論文審定書　 i
誌謝 　ii
中文摘要　 iii
Abstract 　iv
Table of Contents　 v
List of Figures 　 vi
List of Tables 　viii
List of abbreviations 　ix

Chapter 1. Introduction 　1
Chapter 2. Methods and materials 　19
Chapter 3. Results 　26
Chapter 4.Tables and figures 　35
Chapter 5. Discussion 　 75
Chapter 6. Reference 　83

Autobiography　 95
Published papers 　97

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