Nitric oxide as a target for dietary intervention in colitis

一氧化氮作为结肠炎饮食干预的目标

• 批准号: 7091092
• 负责人: MICHAEL WARGOVICH
• 金额: $ 21.3万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091092
• 关键词: alternative medicine; colitis; drug screening /evaluation; enzyme induction /repression; gastrointestinal disorder chemotherapy; ginkgo biloba; human genetic material tag; inflammation; laboratory mouse; medicinal plants; nitric oxide; nitric oxide synthase; phosphorylation; plant extracts; retinoblastoma protein; tissue /cell culture

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.

描述（由申请人提供）：当前用于结肠炎的医疗干预措施包括抗炎和/或免疫抑制剂的应用，每种药物都因不良副作用的发展而复杂。尽管选择了治疗选择，但对于许多患者，疾病仍然具有偶发性缓解时期的难治性。显然，需要新的治疗策略来减轻结肠炎的影响和后遗症。替代药物的使用在美国很常见，目前有40％的结肠炎患有饮食补充剂。但是，使用替代药物的科学证据通常缺乏或弱，并且可能没有严格评估行动的潜在有益机制。已经提出，通过诱导型一氧化氮合酶（INOS）生产一氧化氮的过量生产是结肠炎的致病因素。在这里，我们假设两种抗氧化草药补充剂，Ginkgo Biloba和American Ginseng（Panax Quinquefolis），将通过抑制一氧化氮合酶来抑制结肠炎，抑制随后的一氧化氮产生，从而调节氮氧化物诱导的DNA损伤。尽管已发表的研究表明，银杏和人参均抑制了各种细胞类型的一氧化氮的产生，但尚未研究它们在人类结直肠细胞中的作用。该项目的一个目的是确定银杏和人参调节人类结肠癌细胞中一氧化氮的产生和一氧化氮诱导的DNA损伤的作用和机制。我们还将确定银杏或人参是否会减少结肠炎，并通过使用iNOS - / - 和iNOS+/+小鼠使用诱导结肠炎检查这是否是一氧化氮介导的事件。除了检查结肠炎程度的病理外，我们还将通过检查银杏和人参对炎症驱动的DNA损伤的影响来扩展体外发现。由于PRB高磷酸化与癌变有关，并且在结肠炎中被过度磷酸化，因此我们将检查银杏和人参对PRB过度磷酸化的影响。这些研究应提供有力的临床前证据，以通过定义的分子途径来缓解实验性结肠炎的潜在使用。该应用程序的总体目标是向公众提供一些保证，即饮食补充剂Gingko和Ginseng具有减轻结肠炎的能力。