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

完整项目 I：“鉴定参与槟榔癌发生的促炎分子”

• 批准号: 9043970
• 负责人: JIAN YANG
• 金额: $ 2.54万
• 依托单位: UNIVERSITY OF GUAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043970
• 关键词: Alcohols; Alkaloids; Analytical Chemistry; Animals; Areca; Asians; Biochemical; Biological Assay; Biological Factors; Calcium; Calcium Signaling; Cancer Center; Cancerous; Cell Culture Techniques; Cell membrane; Cells; Cellular Assay; Chemical Structure; Chemicals; China; Chronic; Coffee; Communities; Conditioned Culture Media; Consumption; Data; Development; Disease; Environment; Fibrosis; Fractionation; Guam; Guidelines; Hawaii; Health; High Pressure Liquid Chromatography; High Prevalence; Immune; In Vitro; Incidence; Indigenous; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Ion Channel; Lesion; Leukotrienes; Link; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mastication; Mediating; Mediator of activation protein; Mesocricetus auratus; Modeling; Molecular; Mouth Carcinoma; Mucous Membrane; Nature; Neoplastic Cell Transformation; Nitrosamines; Nuclear Magnetic Resonance; Nuts; Oncogenic; Oral; Oral Submucous Fibrosis; Oral cavity; Oral mucous membrane structure; Oxidative Stress; Pacific Islands; Pathway interactions; Population; Process; Production; Prostaglandins; Public Health; Reactive Oxygen Species; Relative (related person); Risk; Role; Source; Southeastern Asia; Structural Chemistry; System; T-Lymphocyte; Tissues; Tobacco; Tooth Diseases; Tumor Necrosis Factor-alpha; Universities; abstracting; aqueous; carcinogenesis; carcinogenicity; cell type; cytokine; design; global health; insight; interdisciplinary approach; macrophage; malignant mouth neoplasm; mast cell; monocyte; multidisciplinary; neutrophil; theories; tumor progression

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.

项目概要/摘要 全球约有 6 亿人食用槟榔，使其成为第四大食用槟榔。 酒精、烟草和咖啡背后的选择性天然产物。食用槟榔具有重大意义 全球和美国太平洋岛屿关岛领土的公共卫生问题，因为这是一种常见做法 土著查莫罗人和居住在关岛的密克罗尼西亚社区的一部分。槟榔用途 与口腔癌、口腔癌前病变、口腔粘膜下纤维化的高患病率相关， 以及牙周病和炎症性疾病。槟榔致癌作用的主导理论 咀嚼过程中，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，并且这些被暗示为所产生的主要致病因素 口腔癌。活性氧（ROS）被认为是细胞和组织损伤的主要原因 通过多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 因此，口腔可能会形成炎症微环境，从而促进牙科疾病， 粘膜下纤维化，最终发展为口腔癌。我们的初步数据表明 槟榔提取物提高了几种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且充分的。前的活性成分 Ca2+ 变化的机制仍然未知。因此，我们提出了一种多方位 将分析和结构化学与细胞分析（生物化学、药物分析）相结合的学科方法 宏观学、微荧光学和生物物理学）以及动物致癌模型，以完成以下任务 具体目标：1) 提取、鉴定和表征槟榔中的活性化学成分， 介导免疫细胞中的钙信号并确定它们参与的细胞机制，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 研究可能会告知暴露风险并帮助制定槟榔使用指南以及促进 戒烟努力以减少癌症的发病率。