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 慢性疾病包括自身免疫性疾病、神经系统疾病、心血管疾病和癌症。 有证据表明，慢性炎症与表观遗传改变密切相关，由 DNA 和组蛋白修饰，驱动许多炎症基因表达的变化，例如 IL1R1、IL-1β、Toll 样受体 2、15-LOX、COX-2、CXCL14、CCL25、CXCL6、IL13、IL17C 和 IL4R。 几类天然 CAM 产品，包括吲哚-3-甲醇和三萜类化合物，具有抗炎作用 我们的初步研究表明：（1）表观遗传 CpG。 与野生型相比，TRAMP 前列腺肿瘤中炎症基因的甲基化状态发生了改变 使用 MeDIP-seq 技术进行控制；(2) 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶 (PhIP) 诱导 CYP1A 人源化小鼠前列腺中的炎症/高级别 PIN (HGP)，炎症标记物，例如 (3)炎症浸润增加 小鼠前列腺特异性 Pten-/- HGP；和 (4) 吲哚-3-甲醇 (I3C)/3,3'-二吲哚基甲烷 (DIM) 十字花科蔬菜和三萜类熊果酸 (UA)，来自药用植物、水果和蔬菜，例如 蓝莓、蔓越莓、甜菜和蘑菇，在不同的部位具有有效的抗炎活性 尽管有这些有希望的结果，但发现不同类型的细胞可以触发表观遗传学修饰活动。 前列腺炎症及相关疾病的表观基因组变化和潜在表观遗传学机制 包括前列腺癌 (PCa) 在内的疾病以及 CAM 产品如何通过表观遗传改变炎症 根据我们的初步研究，导致这些异常过程受到抑制的表观基因组仍然未知。 研究和之前发表的报告，我们勇敢地承认慢性炎症过程会驱动 炎症表观基因组和 CAM 产品的变化会改变这些炎症表观基因组 导致炎症及其相关疾病（包括癌症）抑制的改变 前列腺具有三个具体目标：(1) 研究 I3C 和 三萜 UA 预防 Pten-/-、PhiP-hCYP1A 和 Pten-/- 前列腺炎症和癌变 TRAMP 小鼠；(2) 确定 I3C 和引起的预防功效和表观遗传改变 NCr(-/-) 小鼠人前列腺 VCaP 异种移植物中的三萜类 UA；以及 (3) 阐明体外 炎症/氧化应激和促凋亡基因调节的表观遗传机制 通过 TRAMP C1、Pten-CaP2、VCaP 和 DIM 和三萜 UA 从体内目标 1 和 2 获得 LNCaP 细胞培养系统。更好地了解 CAM 产生的表观遗传学机制。 抑制炎症及其相关疾病将为预防和治疗开辟新途径 治疗人类慢性炎症性疾病，包括 PCa。