富含高度糖化終產物之飲食對小鼠良性攝護腺增生之影響

Abstract

良性攝護腺增生 (benign prostatic hyperplasia, BPH)又稱為攝護腺肥大，為伴隨男性老化常見之下泌尿道疾病。不健康的飲食型態所衍生的代謝症候群 (metabolic syndrome)亦可能是BPH的致病因子。食物於高溫烹調或加工過程中容易因梅納反應 (Maillard reaction)衍生出一系列複雜的高度糖化終產物 (advanced glycation end product, AGE)。AGE具有不易被生理代謝，容易累積於體內的特性；AGE與receptor for AGE (RAGE)結合後可活化NF-κB引發生物體氧化壓力與發炎反應。本研究之目的在於探討攝取高AGE飲食，是否與促進BPH有關。實驗使用雄性ICR小鼠48隻，隨機分成6組：(1) 控制組 (control, standard diet)；(2) 高AGE組 (H-AGE diet)；(3) H-AGE + BPH治療藥物組 (finasteride, 5 reductase inhibitor)；(4) H-AGE + 抗發炎藥物組 (celecoxib, COX-2 inhibitor)；(5) H-AGE + AGE抑制劑組 (ALT-711, AGE inhibitor)；(6) H-AGE + 抗氧化劑組 (vitamin E)。實驗期間，每週定期紀錄小鼠體重、攝食和飲水量變化，並以核磁造影技術 (magnet resonance imaging, MRI)追蹤小鼠之攝護腺體積變化。攝護腺組織病理結構以hematoxylin-eosin staining 評估；細胞增生、氧化壓力、發炎反應與AGE-RAGE-NF-κB等指標分子之蛋白質表現利用immunohistochemistry staining分析。收集血清分析睪固酮 (testosterone)、二氫睪固酮 (dihydrotestosterone, DHT)、螢光AGE及malondialdehyde (MDA)濃度。結果顯示，H-AGE組之攝護腺指數顯著高於控制組1.2–1.5倍 (p< 0.05)，組織型態上可見攝護腺上皮層厚度與Ki67表現增加的現象。長期攝取H-AGE diet小鼠，可造成CML、CEL、MG-H1等AGE累積於攝護腺組織中，並伴隨RAGE與NF-κB之蛋白質表現增加。此外，H-AGE組攝護腺組織之IL-1𝞫、TNF-𝞪、cyclooxygenase-2、8-hydroxy-2-deoxyguanosine蛋白質表現皆顯著高於控制組 (p < 0.05)，而介入ALT-711後，可顯著改善H-AGE所造成之BPH與氧化壓力及發炎反應。綜合上述，AGE可能為造成BPH的飲食因子，且其作用機轉可能與長期攝取AGE促進攝護腺組織之氧化壓力及發炎反應有關。Benign prostatic hyperplasia (BPH), also known as prostate enlargement, is a that is a common aging-related urological disorder in males. Unhealthy dietary pattern may also be a risk factor for the development of BPH due to metabolic syndrome. Advanced glycation end products (AGE) are Maillard reaction products formed during high-temperature cooking or food processing. AGE are not readily metabolized and tend to accumulate in the body. The interaction of AGE with the receptor for AGE (RAGE) can trigger the NF-κB pathway to induce oxidative stress and inflammation. This study aimed to investigate whether a high-AGE diet is associated with the development of BPH. Forty-eight male ICR mice were randomly divided into six groups: (1) control group (control, standard diet); (2) high-AGE group (H-AGE diet); (3) H-AGE + BPH medication group (finasteride, 5 reductase inhibitor); (4) H-AGE + anti-inflammatory medication group (celebrex, COX-2 inhibitor); (5) H-AGE + AGE inhibitor group (ALT-711, AGE inhibitor); (6) H-AGE + antioxidant group (vitamin E). The body weight, food intake, and water intake of mice were recorded weekly, and the prostate volume was monitored using magnet resonance imaging (MRI). H&E staining was used to evaluate the histopathological changes; immunohistochemistry staining was used to exam cell proliferation, oxidative stress, inflammation, and the protein expressions of AGE, RAGE, and NF-κB. The levels of testosterone, dihydrotestosterone, fluorescent AGE, and malondialdehyde were measured in serum. The results showed that the H-AGE group had a prostate index that was 1.2–1.5 times greater than the control group (p < 0.05), as well as increased epithelial cell thicknessand Ki67 expression. Long-term intake of the H-AGE diet caused the accumulation of CML, CEL, MG-H1 in prostate tissues, and increased the protein expressions of RAGE and NF-κB. Moreover, the protein expressions of IL-1𝞫, TNF-𝞪, cyclooxygenase-2, and 8-hydroxy-2-deoxyguanosine in the H-AGE group were significantly higher than in the control group (p< 0.05), whereas ALT-711 reduced these protein expressions significantly (p < 0.05). In conclusion, AGE may be a dietary factor contributing to the development of BPH through the induction of oxidative stress and inflammation in the prostate.