Nitric oxide as a target for dietary intervention in colitis

描述(申请人提供)：目前对结肠炎的医学干预措施包括应用抗炎和/或免疫抑制药，每种药物都会出现不良副作用。尽管有治疗选择，但对许多患者来说，疾病仍然难以治愈，并伴有间歇性缓解期。显然，需要新的治疗策略来减少结肠炎的影响和后遗症。替代医学的使用在美国很常见，40%的结肠炎患者目前使用膳食补充剂。然而，使用替代药物的科学证据往往缺乏或薄弱，潜在有益的行动机制也没有得到严格的评估。诱导型一氧化氮合酶(INOS)引起的一氧化氮过多被认为是结肠炎的致病因素。在此，我们假设两种抗氧化剂银杏和西洋参通过抑制一氧化氮合酶，抑制随后的一氧化氮生成，从而抑制一氧化氮诱导的DNA损伤，从而抑制结肠炎。尽管已发表的研究表明，银杏和人参都能抑制不同类型细胞中一氧化氮的产生，但它们对人类结直肠细胞的影响尚未被研究过。本项目的目的是确定银杏和人参调节一氧化氮产生和一氧化氮诱导的人结肠癌细胞DNA损伤的作用和机制。我们还将确定银杏或人参是否可以减少结肠炎，并通过使用iNOS-/-和iNOS+/+诱导的结肠炎小鼠来检查这是否是一种一氧化氮介导的事件。除了病理学检查结肠炎的程度外，我们还将通过检查银杏和人参对炎症驱动的DNA损伤的影响来扩大体外研究结果。由于pRb过度磷酸化与癌变有关，在结肠炎中pRb过度磷酸化，我们将研究银杏和人参对pRb过度磷酸化的影响。这些研究应该为银杏和人参通过明确的分子途径改善实验性结肠炎的潜在用途提供强有力的临床前证据。这项应用的总体目标是为公众提供一些保证，即膳食补充剂银杏和人参，有能力缓解结肠炎。

DESCRIPTION (provided by applicant): Current medical interventions for colitis consist of application of anti-inflammatory and/or immunosuppressive agents, each complicated by the development of undesirable side effects. Despite treatment options, for many patients disease remains refractory with episodic periods of remission. Clearly, novel therapeutic strategies are needed to lessen the impact and sequelae of colitis. Use of alternative medicine is common in the United States and 40% of colitis suffers currently use dietary supplements. However, the scientific evidence for the use of alternative medicines is often lacking or weak, and potentially beneficial mechanisms of action have not rigorously been assessed. Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in colitis. Here, we postulate that two antioxidant herbal supplements, Ginkgo biloba and American ginseng (Panax quinquefolis), will inhibit colitis through the inhibition of nitric oxide synthase, inhibiting subsequent nitric oxide production, and thus modulate nitric oxide-induced DNA damage. Although published studies have shown ginkgo and ginseng both inhibit nitric oxide production in various cell types, their effects in human colorectal cells have not been studied. An objective of this project is to determine the effects and mechanisms by which ginkgo and ginseng modulate nitric oxide production and nitric oxide induced DNA damage in human colon cancer cells. We will also determine whether ginkgo or ginseng reduce colitis and examine whether this is a nitric oxide- mediated event by using iNOS-/- and iNOS+/+ mice with induced colitis. In addition to pathology to examine the extent of colitis, we will extend in vitro findings by examining the effects of ginkgo and ginseng on inflammation-driven DNA damage. Because pRb hyperphosphorylation is associated with carcinogenesis and it is hyperphosphorylated in colitis, we will examine the effects of ginkgo and ginseng on pRb hyperphosphorylation. These studies should provide strong pre-clinical evidence for the potential use of ginkgo and ginseng in the amelioration of experimental colitis through defined molecular pathways. The overall goal of this application is to provide the public some assurance that the dietary supplements gingko and ginseng, have the capacity to alleviate colitis.