学者简介以及论文摘要
杨广宇 ：
医学博士、约瑟夫卡兰德拉研究所病理学教授、通过行业验证资格的解剖和临床病理学家 解剖和外科病理学主任、美国西北大学费恩伯格医学院胃肠病理培训计划部主任。
第一批就职哈罗德艾森伯格研究院学者、 分子致癌杂志副主编、国际临床与实验病理杂志编辑委员会成员、美国转化研究杂志编辑委员会成员、世界胃肠病理生理学杂志编辑委员会成员。
Chemoprevention of chronic colitis-induced carcinogenesis by inositol compounds
Chronic inflammation is a well-recognized risk factor of human cancer. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a typical longstanding chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. An increase in colitis-induced aberrant arachidonic acid metabolites and nitro-oxidative stress is the crucial events leading to cancer development. In order to prevent colitis-induced carcinogenesis, we have performed extensive studies to target inositol compounds including hexaphosphate inositol (IP6) and myo-inositol as the novel agents or approach for prevention of colitis-induced carcinogenesis in mice and clinical trial. 1) Using our novel murine colitis-carcinogenesis model, female C57BL/6 mice were subjected to long-term, cyclic dextran sulfate sodium (DSS) treatment and fed a 2-fold iron-enriched diet to induced colitis-carcinogenesis. The inositol compounds were administered via the drinking fluid. In the DSS-plus-2-fold iron positive control group, colorectal adenocarcinoma incidence was 70.6% (24/34 mice) after 15 cycles of DSS treatment (1 DSS cycle=7 day DSS treatment period followed by a 10 day recovery period). Tumor multiplicity was 1.26+/-1.05 and tumor volume was 21.4+/-5.2 mm3. Adding 1% inositol, tumor incidence was statistically significantly reduced (42%, 9 of 21 mice with tumors), as was tumor multiplicity (0.5+/-0.7) and tumor volume (4.2+/-1.9 mm3). Administration of hexaphosphate inositol noticeably reduced tumor incidence (50%, 12 of 24 mice), tumor multiplicity (0.8+/-0.9) and tumor volume (12.3+/-4.1 mm3). Further mechanistic studies showed that the inhibition of colitis-induced carcinogenesis by inositol compounds might relate to their function on the modulation of macrophage-mediated inflammation, nitro-oxidative stress and cell proliferation in colitis-carcinogenesis. 2) The effects of dietary myo-inositol treatment on p-β-cateninS552 and pAkt levels were further examined by histology and western blot in colitis-carcinogenesis mice and showed that myo-inositol treatment significantly reduced inflammation and p-β-cateninS552 labeled intestinal stem cells. 3) In a pilot clinical trial, myo-inositol administration to two patients with a history of low-grade dysplasia (LGD) displayed a significant reduction of numbers of intestinal stem cell activation compared to the placebo control patient. p-β-cateninS552 also labeled significantly higher number of cryptal stem cells in ulcerative colitis patients with a history of LGD compared to those with benign disease. This study indicates that inositol compounds may have the potential to serve as preventive agents for colitis-carcinogenesis. (Supported by NIH grants: R01CA164041; R01CA172431; R01DK107767; and CCFA Award to Dr. Guang-Yu Yang)
肌醇化合物对慢性诱发性结肠癌的预防
慢性炎症是公认的人类恶性肿瘤的风险因素。包括溃疡性结肠炎在内的炎症性肠道疾病以及克罗恩病是典型长期存在于肠道内的慢性活跃炎症的过程。诱发性结肠炎的增加引发的异常花生四烯酸代谢物和硝基氧化应激是导致癌症发展的关键。为了防止诱发性结肠炎癌变，我们在小鼠和临床试验中把包括肌醇六磷酸肌醇（IP6）以及肌-肌醇在内的新药物或预防诱发性结肠炎癌变的有效途径作为目标肌醇化合物进行了广泛的研究。以我们采用的新型鼠科结肠炎癌变为模型，对雌性C57BL/6类小鼠进行长期循环葡聚糖硫酸钠（DSS)）疗法并用2倍的富铁饮食作用于诱发性结肠炎癌变。肌醇化合物通过饮用液体发生作用。在葡聚糖硫酸钠铁阳性对照组(DSS-plus-2-fold)、大肠腺癌的发生率为70.6%（24／34小鼠）15个周期后（1 DSS周期为7天的DSS治疗期，随后是为期10天的恢复期）。肿瘤多样性为1.26+/-1.05和肿瘤体积为21.4+/-5.2立方毫米。添加1%的肌醇，肿瘤发生率统计数据显著降低（42%，9比21的携带肿瘤小鼠），肿瘤多样性（0.5±0.7）和肿瘤体积（4.2+/-1.9立方毫米）。服用六磷酸肌醇明显减少肿瘤发生率（50%，12比24只小鼠），肿瘤多样性（(0.8+/-0.9)和肿瘤体积（12.3+/-4.1立方毫米）。调整巨噬细胞介导炎症的功能, 进一步的机理研究表明，肌醇化合物抑制诱导性结肠炎癌变的发生可能与其调节巨噬细胞介导的炎症、硝基氧化应激和细胞增殖在结肠炎癌变中的作用有关。2）饮食肌醇治疗在磷酸连环蛋白（p-β-cateninS552）上的作用和磷酸化蛋白（pAkt）水平的影响得到结肠炎癌变小鼠组织学和蛋白质印迹（Western blot）的进一步验证，表明肌醇治疗显著降低炎症和带磷酸连环蛋白（p-β-cateninS552）标记的肠道干细胞。 3）在临床试点试验中，较安慰剂控制的病人，带有低度异型增生（LGD）病史的两例接受肌-肌醇治疗的病人，显示肠道干细胞活化数有明显的减少。较良性疾病患者，磷酸连环蛋白（p-β-cateninS552）被冠以隐匿性干细胞数明显高于带有低度异型增生（LGD）溃疡性结肠炎病史的患者。这项研究表明肌醇化合物具有预防结肠炎癌变的潜在可能。（由美国国立卫生研究院资助：R01CA164041; R01CA172431; R01DK107767; 食品添加剂法典委员会 杨广宇博士)
