雙去甲氧基薑黃素改善小鼠發炎性腸道疾病及 B[a]P/DSS 誘導之結直腸癌

Abstract

類薑黃素 (curcuminoids) 為源自薑黃 (Curcuma longa L.) 之線性二苯基庚烯類化合物，包括薑黃素 (curcumin, CUR)、去甲氧基薑黃素 (demethoxycurcumin) 與去雙甲氧基薑黃素 (bisdemethoxycurcumin, BDMC)。相較於CUR，BDMC 具較佳之抑制 NF-κB 能力與口服生物可利用率。本論文先於 DSS 誘導之發炎性腸病 (inflammatory bowel disease, IBD) 模式，評估 CUR 與 BDMC 的保健潛力，隨後於食物來源致癌物苯駢芘 (Benzo(a)pyrene, B[a]P) 合併 DSS 的結腸炎相關結直腸癌 (colorectal cancer, CRC) 模式中，檢驗 BDMC 的化學預防效果，最後以短期藥理試驗，探討 CUR 和 BDMC 如何影響 B[a]P 代謝為致癌物 Benzo(a)pyrene-7,8-diol 9,10-Epoxide (BPDE)。結果顯示，CUR 與 BDMC 皆可緩解 DSS 腸炎、強化緊密連結蛋白並降低發炎，且重塑腸道菌相並促進丁酸生成菌的豐富度；且證實模式中 BDMC 的吸收優於 CUR。在 B[a]P/DSS 模式下，等劑量 (0.1%) BDMC 的表現優於 CUR：顯著降低疾病活動指數 (disease activity index)、腹瀉與出血、維持屏障功能、減少腸縮短與腸壁增厚，並降低腫瘤負荷；組織學顯示腺瘤及異型增生與發炎浸潤明顯減少。細胞激素方面，BDMC 使 IL-1β 回復至對照水準並選擇性降低 IL-6；訊息傳遞方面，BDMC 維持 APC、抑制 β-catenin 與 p-AKT 並提高 BAX/BCL-2 的蛋白表現。轉錄體分析顯示，BDMC 廣泛下調趨化/細胞激素/補體與基質-血管新生路徑，同時恢復上皮運輸與恆定；菌相與短鏈脂肪酸結果則是支持 BDMC 可營造一個富含短鏈脂肪酸、且發炎程度較低的腸道生態。在預防機制上，短期試驗證實 BDMC 可抑制早期 AHR 活化、並降低攝入 B[a]P 4 小時後的 CYP1A1 活性，並降低體內 B[a]P 暴露與最終致癌物 BPDE 的生成。綜合上述，BDMC 兼具減少 B[a]P 活化與緩解發炎、調節腸道菌相、維持腸道屏障、抑制 Wnt/AKT 並維持 APC 的雙重作用，能有效改善 IBD 並抑制 B[a]P/DSS 促進的 CRC，為極具前景的腸炎及腸癌化學預防植化素。

Curcuminoids—linear diarylheptanoids from turmeric (Curcuma longa L.)—comprise curcumin (CUR), demethoxycurcumin, and bisdemethoxycurcumin (BDMC). Compared with CUR, BDMC shows stronger NF-κB inhibition and higher oral bioavailability. This dissertation first evaluated the health benefits of CUR and BDMC in a dextran sulfate sodium (DSS)–induced inflammatory bowel disease (IBD) model, then tested the chemopreventive efficacy of BDMC in a colitis-associated colorectal cancer (CRC) model initiated by the food-borne carcinogen benzo[a]pyrene (B[a]P) and promoted by DSS, and finally used a short-term pharmacology study to examine how CUR and BDMC influence metabolic activation of B[a]P to the ultimate carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). Both CUR and BDMC alleviated DSS colitis, strengthened tight-junction proteins, reduced inflammation, and remodeled the gut microbiota with enrichment of butyrate-producing taxa; BDMC also displayed superior absorption to CUR in our models. In the B[a]P/DSS CRC model, dietary BDMC at the same dose (0.1%) outperformed CUR by significantly lowering the disease activity index, diarrhea and bleeding, preserving barrier function, limiting colon shortening and wall thickening, and reducing tumor burden; histology showed fewer adenomas, reduced dysplasia, and diminished inflammatory infiltrates. At the cytokine level, BDMC normalized IL-1β and selectively decreased IL-6. At the signaling level, BDMC preserved APC, suppressed β-catenin and phosphorylated AKT, and increased the BAX/BCL-2 ratio. Transcriptomics indicated broad down-regulation of chemotaxis/cytokine/complement and matrix–angiogenic pathways with restoration of epithelial transport and homeostasis; microbiome and short-chain fatty acid (SCFA) profiles supported a SCFA-rich, less inflammatory intestinal ecosystem under BDMC. Mechanistically, the short-term study demonstrated that BDMC dampened early aryl hydrocarbon receptor (AHR) activation, reduced CYP1A1 activity at 4 h after B[a]P gavage, and lowered systemic B[a]P exposure and BPDE formation. Collectively, BDMC exerts dual actions—attenuating upstream B[a]P bioactivation and downstream inflammation, microbiota dysbiosis, and Wnt/AKT signaling while preserving APC and barrier integrity—thereby improving IBD and suppressing B[a]P/DSS-driven CRC, and emerges as a promising phytochemical for chemoprevention of colitis and colorectal cancer.