Mesothelioma inhibition by secoisolariciresinol diglucoside (SDG)

开环异落叶松树脂醇二葡萄糖苷 (SDG) 抑制间皮瘤

• 批准号: 8598613
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 6.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598613
• 关键词: Acute; Alveolar Macrophages; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Area; Asbestos; Asbestos-Related Malignant Neoplasm; Australia; Botanicals; Breathing; Cells; Cereals; Cessation of life; Chemopreventive Agent; Chronic; Clinical Trials; DNA; DNA Damage; Development; Diet; Disease; Environmental Exposure; Epithelial Cells; Exhibits; Exposure to; Family; Fiber; Fibrosis; Financial compensation; Flax; Foxes; Free Radical Scavengers; Generations; Genes; Human; Individual; Inflammation; Inflammatory; Institutes; Intercept; Intervention; Lead; Lignans; Link; Lung; Lung diseases; Malignant - descriptor; Malignant Neoplasms; Malignant mesothelioma; Malignant neoplasm of lung; Medical Surveillance; Mesothelial Cell; Mesothelioma; Modality; Modeling; Molecular; Mus; Nitrogen; Occupational Exposure; Oxidants; Oxygen; Particulate; Pathogenesis; Peritoneal; Philadelphia; Play; Pneumonia; Preclinical Testing; Preventive; Process; Property; Proteins; Radiation; Radiation Toxicity; Reactive Oxygen Species; Rodent Model; Role; Signal Pathway; Signal Transduction Pathway; Simian virus 40; Testing; Tissues; Toxic effect; Tumor Burden; cancer cell; cancer prevention; cancer risk; carcinogenesis; cell injury; cell transformation; chemokine; cytokine; design; dietary supplements; environmental carcinogenesis; flaxseed lignan; human disease; macromolecule; macrophage; mouse model; novel; oxidation; pollutant; prevent; public health relevance; secoisolariciresinol diglucoside; stressor; tumor

DESCRIPTION (provided by applicant): Despite worldwide banning of asbestos use, domestic and environmental exposure to asbestos unfortunately persists. Exposure to asbestos fibers has been linked to the development of malignant mesothelioma (MM) and lung cancer (LC); however, the pathogenesis of asbestos-related diseases is complicated and still poorly understood. Pulmonary inflammation related to asbestos exposure has been shown in both animal models and humans. Additional studies revealed that asbestos fibers generate reactive oxygen and nitrogen species (ROS/RNS) and cause oxidation and/or nitrosylation of proteins and DNA. In addition to damaging macromolecules, such oxidants play important roles in the initiation of numerous signal transduction pathways that are linked to apoptosis, inflammation, and proliferation. Unfortunately, while asbestos-exposed individuals are offered medical surveillance or financial compensation, but nothing is currently being undertaken to decrease their cancer risk. In fact the long latency of asbestos-related cancers ranging from 10 years for LC and up to 50 years for MM, allows a wide window for chemopreventive strategies to be used whereby one can intervene with natural or synthetic agents to intercept or prevent malignant transformation due to exposure. Remarkably, nothing is currently being done to lower cancer risk to asbestos-exposed individuals and the scarcity of clinical trials in this area underscores the unmet need for intervention. Our group has evaluated wholegrain flaxseed in murine models of oxidative lung damage such as radiation toxicity and attributed its tissue protective properties mainly to the antioxidant, anti-inflammatory and anti-fibrotic effects of its lignan component. The predominant bioactive lignan in flax seed is Secoisolariciresinol Diglucoside (SDG), a biphenolic agent. Importantly, SDG-supplemented diets robustly mitigated radiation toxicity manifested as chronic inflammation, oxidative tissue damage and fibrosis when administered to mice long after the initial radiation insult occurred. We therefore, hypothesize that SDG will similarly abrogate asbestos toxicity by interfering with initiation and propagation of ongoing damaging processes that would ultimately lead to lung fibrosis, chronic inflammation and oxidative tissue damage, conditions found to be linked to MM development. To test this, we designed two Aims whereby the action of SDG in 2 mouse models of asbestos-induced MM will be evaluated. In Specific Aim 1 we will test anti-inflammatory effects of flaxseed and SDG lignan diets in the SV40 TAg and the NF2 +/- mouse model of asbestos-inflammation and in Specific Aim 2 we will test the cancer chemopreventive effects in blunting MM formation and boosting survival. If our intervention proves effective in inhibiting inflammation, delaying the onset of malignancy or decreasing tumor burden in any of the models, we will pursue mechanistic studies to evaluate SDG in asbestos-exposed mesothelial cells and macrophages for inflammasome activation, apoptosis, DNA damage, ROS/RNS generation and signaling pathway activation (Fos and Jun families).

描述（由申请人提供）：尽管全世界禁止使用石棉，但不幸的是，国内和环境暴露于石棉。接触石棉纤维与恶性间皮瘤（MM）和肺癌（LC）的发展有关。然而，与石棉相关疾病的发病机理是复杂的，并且仍然很了解。在动物模型和人类中都显示了与石棉暴露有关的肺部炎症。其他研究表明，石棉纤维产生活性氧和氮种（ROS/RN），并引起蛋白质和DNA的氧化和/或硝基化。除了破坏大分子外，这种氧化剂在启动许多与凋亡，炎症和增殖有关的信号转导途径的启动中起着重要作用。不幸的是，虽然向石棉暴露的人提供医疗监视或经济补偿，但目前没有采取任何措施来降低其癌症风险。实际上，与石棉相关的癌症的较长潜伏期从LC的10年到50年的MM不等，可以使用宽阔的窗口，以便使用化学预防策略的窗口，从而可以介入自然或合成剂拦截或防止因暴露而导致的恶性转化。值得注意的是，目前没有采取任何措施来降低对石棉暴露的个体的癌症风险，并且该领域的临床试验稀缺强调了对干预的未满足需求。我们的小组在氧化性肺损伤的鼠模型中评估了全格兰亚麻籽，例如辐射毒性，并归因于其组织保护特性 主要针对其木质胶成分的抗氧化剂，抗炎和抗纤维化作用。这 亚麻种子中的主要生物活性木质激素是双苯酚剂二糖尿甲醇（SDG）。重要的是，在初始辐射损伤发生后很长一段时间后，当对小鼠施用时，可加强可持续发展可靠的饮食可降低辐射毒性，表现为慢性炎症，氧化组织损伤和纤维化。因此，我们假设可持续发展目标将通过干扰正在进行的损害过程的起始和传播来消除石棉毒性，这些过程最终会导致肺纤维化，慢性炎症和氧化组织损伤，发现与MM发育有关。为了测试这一点，我们设计了两个目标，可以评估可持续发展目标在2个小鼠诱导的MM鼠标模型中的作用。在特定目的1中，我们将测试SV40标签中亚麻籽和可持续发展木质饮食的抗炎作用，以及石棉-Inflammation的NF2 +/-小鼠模型，在特定目标2中，我们将测试癌症化学预防效应在MM形成和增强MM形成和增强生存中的癌症化学预防作用。如果我们的干预措施在抑制炎症，延迟恶性肿瘤或减轻肿瘤负担的任何模型中有效，我们将进行机械研究，以评估石棉暴露的间皮细胞和巨噬细胞中的可持续发展疾病，以及炎性症的炎症，proptistoration，proptoctoration，proptositation，DNA损害，DNA损害，ROS/RNS的产生和信号path和信号激活（FOS）和信号激活（FOS）（FOS）和信号激活（OS）。