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

项目摘要/摘要 全球约有6亿人食用槟榔，使其成为全球第四大食用槟榔。 酒精、烟草和咖啡之后的天然活性物质。槟榔的消费具有重要的意义-- 对全球和美国太平洋岛国关岛的公共卫生的呼吁，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的部分人中。槟榔的使用 与口腔癌、口腔癌前病变、口腔粘膜下纤维化的高发病率有关，如 以及牙周病和炎症性疾病。槟榔致癌作用的主导理论 咀嚼是槟榔中发现的一些生物碱在口腔中发生化学转化-- TY产生亚硝胺衍生物，而这些被暗示为产生的主要致病因素 口腔癌。活性氧簇(ROS)被认为是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 释放多种炎性细胞因子。槟榔介导炎性介质的产生 口腔因此可能有助于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 槟榔提取物提高几个炎症免疫细胞的细胞内钙浓度，这是一个过程 这对于钙介导的细胞因子的产生是必要的，也是充分的。前黄连的活性成分(S) 肌束仍然未知，钙离子变化的机制也是未知的。因此，我们提出了一个多元化的- 一种将分析和结构化学与细胞分析相结合的学科方法(生化、药物和生物化学)。 微生物、微量荧光和生物物理学)以及动物致癌模型来完成以下工作： 以下具体目标：1)提取、鉴定和表征槟榔的活性化学成分 调节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启动或加剧肿瘤转化中的作用。这些 研究可能会告知接触的风险，并有助于建立槟榔使用指南以及煽动 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.