Full Project I: "Identification of pro-inflammatory molecules involved in Areca nun carcinogenesis"

项目总结/摘要 全世界约有6亿人食用槟榔，使其成为第四大消费群体。 酒精、烟草和咖啡背后的天然产物。槟榔的消费有很大的影响， 为全球和美国太平洋岛屿关岛领土的公共卫生服务，因为这是一种常见的做法 在土著查莫罗人和居住在关岛的密克罗尼西亚社区中，槟榔利用 与口腔癌、口腔癌前病变、口腔粘膜下纤维性变 以及牙周病和炎性疾病。槟榔致癌作用的主要理论 咀嚼是槟榔中发现的一些生物碱在口腔中发生化学转化， 倾向于产生亚硝胺衍生物，这些衍生物被认为是产生亚硝胺的主要原因。 口腔癌活性氧（Reactive oxygen species，ROS）是导致细胞和组织损伤的主要原因 通过几种途径与慢性炎症性疾病相关，包括刺激宿主免疫细胞 释放多种炎症细胞因子。槟榔介导的促炎介质的产生 口腔因此可能促成促进牙病的炎症微环境， 粘膜下纤维化，并最终发展为口腔癌。我们的初步数据表明， 槟榔提取物升高几种炎症免疫细胞的细胞内钙浓度， 这是钙介导的细胞因子产生所必需和充分的。前体的活性组分（一种或多种） 道仍然未知，是Ca 2+的变化的机制。因此，我们提出了一个多方面的建议， 将分析化学和结构化学与细胞测定（生物化学，phar， 宏观、显微荧光和生物物理）以及动物致癌模型，以实现以下目的： 具体目的如下：1）提取、鉴定和表征槟榔的活性化学成分， 介导免疫细胞中的钙信号，并确定它们参与的细胞机制，以及2）评估 非生物碱槟榔成分在引发或加剧肿瘤转化中的作用。这些 研究可以告知暴露的风险，并帮助建立槟榔使用的指导方针， 戒烟的努力，以减少癌症的发病率。

Project Summary/Abstract Around 600 million people worldwide consume Areca (betel) nuts, making it the fourth-most consumed psy- choactive natural product behind alcohol, tobacco, and coffee. Betel nut consumption has significant implica- tions for public health both globally and for the U.S. Pacific Island Territory of Guam as it is a common practice among indigenous Chamorros and segments of the Micronesian communities that reside on Guam. Areca use is associated with a high prevalence of oral carcinoma, oral pre-cancerous lesions, oral submucous fibrosis, as well as periodontal and inflammatory diseases. The leading theory for the carcinogenic effects of Areca nut chewing is that some of the alkaloids found in the Areca nut undergo chemical transformations in the oral cavi- ty to produce nitrosamine derivatives, and these are implied as the principal causative agents for the resultant oral cancers. Reactive oxygen species (ROS) are proposed to be a major cause of the cell and tissue damage associated with chronic inflammatory diseases via several pathways, including stimulation of host immune cells that release a variety of inflammatory cytokines. Areca-mediated production of pro-inflammatory mediators in the oral cavity may therefore contribute to an inflammatory microenvironment that promotes dental disease, submucous fibrosis, and ultimately the development of oral cancers. Our preliminary data demonstrate that Areca nut extracts elevate intracellular calcium concentration in several inflammatory immune cells, a process that is necessary and sufficient for calcium-mediated cytokine production. The active component(s) of the ex- tract remain unknown, as are the mechanisms underlying changes in Ca2+. Therefore, we propose a multidis- ciplinary approach that combines analytical and structural chemistry with cellular assays (biochemical, phar- macological, microfluorimetric and biophysical) as well as animal carcinogenesis models to accomplish the fol- lowing specific aims: 1) extract, identify, and characterize the active chemical components of Areca nuts that mediate calcium signals in immunocytes and determine the cellular mechanisms they engage, and 2) assess the role of non-alkaloid Areca nut components in initiating or exacerbating neoplastic transformations. These studies may inform about risks of exposure and help establish guidelines for Areca use as well as instigate cessation efforts in order to reduce the incidence of cancer.