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: 9344552
• 负责人: JIAN YANG
• 金额: $ 6.15万
• 依托单位: UNIVERSITY OF GUAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9344552
• 关键词: Alcohols; Alkaloids; Analytical Chemistry; Animals; Areca; Asians; Biochemical; Biological Assay; Biophysics; Calcium; Calcium Signaling; Cancer Center; Cell Culture Techniques; Cell membrane; Cells; Cellular Assay; Chemical Structure; Chemicals; China; Chronic; Coffee; Communities; Consumption; Data; Development; Disease; Fibrosis; Fractionation; Guam; Guidelines; Hawaii; High Pressure Liquid Chromatography; High Prevalence; Immune; In Vitro; Incidence; Indigenous; 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; Natural Products; 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; Pharmacology; Population; Premalignant; Process; Production; Prostaglandins; Public Health; Reactive Oxygen Species; Risk; Role; Source; Southeastern Asia; Structural Chemistry; System; T-Lymphocyte; TNF gene; Tissues; Tobacco; Tooth Diseases; Universities; aqueous; carcinogenesis; carcinogenicity; cell type; cytokine; design; global health; inflammatory milieu; insight; interdisciplinary approach; macrophage; malignant mouth neoplasm; mast cell; monocyte; 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.

项目总结/文摘