Epigenetic mechanisms of indole-3-carbinol/diindolylemthane and triterpenoids in prevention of prostate inflammation and related disease

吲哚-3-甲醇/二吲哚柠檬烷和三萜类化合物预防前列腺炎症和相关疾病的表观遗传机制

• 批准号: 9120455
• 负责人: Ah-Ng Tony Kong
• 金额: $ 66.3万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120455
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; 3-nitrotyrosine; Acute Disease; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Arachidonate 15-Lipoxygenase; Autoimmune Diseases; Automobile Driving; Beets; Biological Markers; Blueberries; CCL25 gene; CXCL14 gene; CXCL6 gene; Cardiovascular Diseases; Cell Culture System; Cell Line; Chronic; Chronic Disease; Clinical Trials; Cranberries; DNA Modification Process; Disease; Epigenetic Process; Future; Genes; Goals; Human; IL17C gene; IL18 gene; IL1R1 gene; IL4R gene; In Vitro; Indole-3-Carbinol; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-13; Investigation; Knockout Mice; LNCaP; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medicinal Plants; Methylation; Modification; Mus; Neurologic; Nude Mice; Oxidative Stress; PTEN gene; PTGS2 gene; Pathway interactions; Prevention; Prevention approach; Preventive; Process; Property; Prostate; Prostatic; Prostatic Diseases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Publishing; Regimen; Regulation; Reporting; Technology; Tissues; Toll-Like Receptor 2; VCaP; Xenograft procedure; base; carcinogenesis; cell type; cruciferous vegetable; cyclooxygenase 2; diindolylmethane; disorder prevention; epigenome; epigenomics; fruits and vegetables; histone modification; in vivo; inflammatory marker; mouse model; prevent; prostate cancer cell; prostate cancer cell line; success; transgenic adenocarcinoma of mouse prostate; ursolic acid

Excessive and chronic inflammation can contribute to many acute and chronic diseases including autoimmune disease, neurological, cardiovascular disease, and cancer. Increasing evidence suggests that chronic inflammation is closely associated with epigenetic alterations, mediated by DNA and histone modifications, driving changes in the expression of many inflammatory genes, such as IL1R1, IL-1β, toll-like receptor 2, 15-LOX, COX-2, CXCL14, CCL25, CXCL6, IL13, IL17C and IL4R. Importantly several classes of natural CAM products including indole-3-carbinol and triterpenoids possess antiinflammatory and epigenetic-modifying properties. Our Preliminary Studies show that: (1) the epigenetic CpG methylation status of inflammatory genes were altered in TRAMP prostate tumor as compared to the wild type control using MeDIP-seq technology; (2) in 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced inflammation/high-grade PIN (HGP) in the prostate of CYP1A-humanized mice, inflammatory markers such as 8-oxo-dG, nitrotyrosine, COX-2, p-AKT, and PTEN were increased; (3) inflammatory infiltrates were increased in mouse prostate specific Pten-/- HGP; and (4) Indole-3-carbinol (I3C)/3,3'-diindolylmethane (DIM) from cruciferous vegetables and triterpenoid ursolic acid (UA) from medicinal plants, fruits and vegetables such as blueberries, cranberry, beets, and mushrooms, which possess potent anti-inflammatory activities in different types of cells, were found to trigger epigenetics modifying activities. Despite these promising results, the epigenomic changes and the underlying epigenetics mechanisms of prostate inflammation and related diseases including prostate cancer (PCa) and how CAM products epigenetically modified the inflammatory epigenome leading to inhibition of these aberrant processes remains unknown. Based on our preliminary studies and previous published reports, we hypothesize that chronic inflammatory processes would drive changes of inflammatory epigenome and CAM products would modify these inflammatory epigenomic alterations resulting in suppression of inflammation and its related diseases including cancer in the prostate with three Specific Aims: (1) To investigate the epigenome alterations imparted by I3C and triterpenoid UA in prevention of prostate inflammation and carcinogenesis in Pten-/-, PhiP-hCYP1A and TRAMP mice; (2) To determine the preventive efficacy and epigenetic alterations elicited by I3C and triterpenoid UA in human prostate VCaP xenograft in NCr(-/-) mice; and (3) To elucidate the in vitro epigenetic mechanisms of regulation of the inflammatory/oxidative stress and pro-apoptotic genes obtained from in vivo Aims 1 and 2 by DIM and triterpenoid UA in TRAMP C1, Pten-CaP2, VCaP and LNCaP cell culture system. Better understanding of the epigenetics mechanisms of how CAM products inhibit inflammation and its related disease would open new avenue of approaches for the prevention and treatment of chronic inflammatory diseases including the PCa in human.

过度和慢性炎症可导致许多急性和慢性炎症