臺灣博碩士論文加值系統

糖尿病相關腎臟病 (DKD) 治療已成為現今臨床巨大的挑戰，為推動綜合管理策略。本論文綜合三項研究結果，探討 DKD 及相關併發症的新穎預防標的、治療方針和生物標記。

第一項研究闡明富含載脂蛋白 C3 的脂蛋白 (AC3RL) 作為 DKD 生物標記的潛力。據中國醫藥大學附屬醫院臨床收案觀察數據顯示，DKD 和慢性腎臟病 (CKD) 患者的 AC3RL 水平升高，且與腎小球濾過率 (GFR) 呈負相關。蛋白質印跡分析證實了 AC3RL 與糖尿病腎病變的關聯，此研究強調了其作為生物指標的前景。

第二項研究探討天然抗氧化物－芝麻酚 (Sesamol, SM) 在減輕腎損傷相關動脈粥狀硬化和發炎方面的治療潛力。使用以六分之五腎臟摘除手術 (5/6 Nx) 建立小鼠腎損傷模型，管餵給予口服芝麻酚，研究結果顯示天然抗氧化物－芝麻酚可顯著減少動脈粥狀硬化標記物並抑制氧化壓力引起的內皮細胞凋亡。此外，透過抑制 IKKα-NF-κB 路徑減輕巨噬細胞介導的腎臟炎症，綜合以上研究，提供腎病變相關併發症新穎的穎預防與治療途徑。

第三項研究透過健保資料庫數據調查了己酮可可鹼 (Pentoxifylline, PTX) 對尚未確診心血管疾病 (CVD) 的 DKD 患者心血管保護作用。使用回顧性隊列進行分析，結果表明，PTX 透過劑量依賴性降低動脈粥狀硬化性心血管疾病 (ASCVD) 風險，透過實驗發現其主要透過 Klotho 介導的途徑降低內皮細胞氧化壓力，減少動脈粥狀硬化。

綜合以上研究，進行整合多面向在治療 DKD 及相關併發症的重要性。 AC3RL 將成為 DKD 疾病進程中，具潛力的生物標誌物；天然抗氧化物－芝麻酚和 PTX 為可減輕腎損傷、動脈粥樣硬化和發炎，研究提供潛在的治療途徑。透過研究結果，闡明 DKD 管理的潛在機制並優化預防與治療策略。

Diabetes-related kidney disease (DKD) presents a formidable challenge, driving the need for comprehensive management strategies. This abstract synthesizes findings from three studies investigating novel interventions and biomarkers in DKD and associated complications.

The first study elucidates the potential of apolipoprotein C3-rich lipoprotein (AC3RL) as a biomarker for DKD progression. Observational data from China Medical University Hospital reveal elevated AC3RL levels in DKD and chronic kidney disease (CKD) patients, with a negative correlation to glomerular filtration rate (GFR). Western blot analysis confirms AC3RL's association with diabetic nephropathy, highlighting its promise as a prognostic indicator.

The second study explores sesamol's therapeutic potential in attenuating renal injury-associated atherosclerosis and inflammation in CKD. Using a rodent CKD model, sesamol administration significantly reduces atherosclerotic markers and suppresses oxidative stress-induced damage. Furthermore, sesamol mitigates macrophage-mediated renal inflammation via inhibition of the IKKα-NF-κB pathway, offering a novel therapeutic avenue for CKD-associated complications.

The third study investigates pentoxifylline's (PTX) cardiovascular protection in DKD patients without established cardiovascular disease (CVD). Retrospective cohort analysis demonstrates PTX's dose-dependent reduction in atherosclerotic cardiovascular disease (ASCVD) risk, mediated by endothelial cell protection through Klotho-mediated pathways.

Integration of these findings underscores the importance of multifaceted approaches in managing DKD and associated complications. AC3RL emerges as a promising biomarker for DKD progression, while sesamol and PTX offer potential therapeutic avenues for mitigating renal injury, atherosclerosis, and inflammation in CKD. Further research is warranted to elucidate underlying mechanisms and optimize therapeutic strategies for DKD management.

CONTENT IV
LIST OF FIGURES/TABLES VII
CHAPTER 1. PREFACE 1
CHAPTER 2. RESEARCH MOTIVATION 2
CHAPTER 3. LITERATURE REVIEW 3
III. 1. Chronic kidney disease, CKD 3
III. 2. CKD and low-density lipoprotein (LDL) 7
III. 3. Oxidative stress and atherosclerosis 9
III. 4. Lipoproteins influence lipoprotein lipase and cause hypertriglyceridemia 11
III. 5. Link of hypertriglyceridemia to atherosclerotic cardiovascular disease (ASCVD) and treatment guidelines 13
III. 6. Novel interventions and biomarkers in DKD 14
III. 7. Sesamol 15
III. 8. Pentoxifylline 15
CHAPTER 4. AIMS OF INVESTIGATION 17
CHAPTER 5. RESEARCH DESIGN AND EXPERIMENTAL METHODS 18
V. 1. Research design and acceptance conditions 18
V. 2. Experimental method 23
V. 2.1. Separation of AC3RL 23
V. 2.2. Data and Sample Source 25
V. 2.3. Cell Culture and Viability and Cellular Apoptosis Assay 26
V. 2.4. Western Blot 27
V. 2.5. Animal Model and Experimental Design 28
V. 2.6. Hematoxylin-Eosin Y stain, and TUNEL staining 28
V. 2.7. Biochemical Test 29
V. 2.8. Statistical analysis 29
CHAPTER 6. RESEARCH RESULT 30
VI. 1. Basic information of each group and AC3RL% 30
VI. 2. DKD and CKD patients have higher mean AC3RL% 32
VI. 3. There is a moderate negative correlation between AC3RL% and GFR in the DKD group 33
VI. 4. AC3RL is present in the plasma LDL of patients with diabetic kidney disease 37
VI. 5. The Impact of Sesamol (SM) on the survival and intracellular reactive oxygen species (ROS) generation of Human Aortic Endothelial Cells (HAECs) Exposed to Hydrogen Peroxide (H2O2) 38
VI. 6. The protective effects of SM against hydrogen peroxide-induced apoptosis in human aortic endothelial cells 41
VI. 7. The impact of SM on the protein expression of Phosphorylated-IKKα, p53, and Cleaved Caspase-3 in Hydrogen Peroxide-treated Human Aortic Endothelial Cells 43
VI. 8. The cytoprotective effects of SM against 5/6 nephrectomy-induced endothelial cell apoptosis in ApoE–/– mice 44
VI. 9. ASCVD risks vary among participants based on their respective pentoxifylline-days-supply 61
VI. 10. Pentoxifylline reduces endothelial cell apoptosis dose-dependently 64
VI. 11. Protective effect of Long-term Pentoxifylline exposure against H2O2-induced endothelial cell is facilitated through the Klotho signaling pathway 68
VI. 12. Pentoxifylline Inhibits Atherosclerosis in DKD Mice Model 71
VI. 13. H&E and TUNEL images showed microscopic features of isolated mice aorta 73
CHAPTER 7. DISCUSSION AND RESEARCH LIMITATIONS 75
VII. 1. AC3RL may be associated with glomerulonephritis 75
VII. 2. Patients with high cardiovascular risk (TG/HDL) may have higher AC3RL% 75
VII. 3. Diabetic nephropathy may be related to AC3RL 76
VII. 4. AC3RL may be associated with oxidative stress 76
VII. 5. Sesamol and Pentoxifylline are protective against the formation of reactive oxygen species (ROS) 77
VII. 6. Research limitations 79
CHAPTER 8. CONCLUSIONS 81
LIST OF ABBREVIATIONS 82
REFERENCES 85

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