Mechanistic Determinants of Dietary Polyphenol Bioactivity in Bone

膳食多酚在骨中生物活性的机制决定因素

基本信息

批准号：
10435568
负责人：
JANET L FUNK
金额：
$ 17.05万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-21 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435568
关键词：
Address Adult Aging American Area Arthritis Back Beta-glucuronidase Biological Availability Blood Circulation Bone Diseases Bone Marrow Cells Botanical dietary supplements Botanicals C3H/HeJ Mouse Cells Chronic Clinical Clinical Research Collaborations Communities Curcumin Data Defect Dependence Diet Dietary Polyphenol Drug Kinetics Enzyme Tests Enzymes FDA approved Genotype Glucuronides Goals Haplotypes Health Benefit Hematopoietic Hepatotoxicity Human Impairment In Vitro Ingestion Intestines Investigation Knockout Mice Laboratories Light Liver Mediating Menopause Metabolic Metabolism Methods Modeling Mus Musculoskeletal Mutation Osteoclasts Osteoporosis Pathology Persons Pharmacology Phenotype Plants Population Postmenopausal Osteoporosis Postmenopause Prevalence Process Quercetin Recombinants Replacement Therapy Reporting Research Rheumatoid Arthritis Rodent Role Sales Serum Site Solid Supplementation Testing Tumeric United States Wild Type Mouse Work bone bone health bone loss bone metabolism bone preservation clinically relevant dietary supplements experimental study extracellular healthspan in vivo inhibitor liver function mannose receptor personalized approach polyphenol preservation prevent protective effect receptor response secondary outcome treatment effect uptake

项目摘要

ABSTRACT An exponential increase in sales of curcumin-containing turmeric dietary supplements (DS), now the top selling botanical DS in the United States, has been associated with a marked increase in turmeric DS usage by Americans for the treatment of chronic musculoskeletal conditions, such as rheumatoid arthritis (30% prevalence). Scientifically, however, it has been difficult to reconcile in vivo evidence of bone protective effects of curcumin in humans and rodents with pharmacokinetic data demonstrating barely detectable circulating levels of aglycone curcumin following curcumin ingestion, due to its rapid conjugation by intestine and liver to form curcumin glucuronide, a major circulating metabolite shown to be largely inactive. Recent work by our laboratory has shed light on this process, demonstrating high activity levels of enzymatic deconjugation of curcumin glucuronide within bone to form bioactive aglycone in concentrations similar to those required in vitro to inhibit bone-resorbing osteoclast formation, a key driver of bone loss in all major bone diseases, including osteoporosis. Because glucuronidation is a common metabolic fate for many bone-protective dietary polyphenols, the primary goal of this project is to determine whether bone-protective polyphenol bioactivity is similarly dependent on ß- glucuronidase (GUSB), the enzyme required for the deconjugation of glucuronides of curcumin and other bone protective dietary polyphenols, such as quercetin, within bone. This question has great clinical relevance since GUSB expression is highly variable in human populations. Experiments will utilize a model of post-menopausal bone loss (ovariectomized [OVX] mice), mice with defects in GUSB activity and/or processing, and supplementation with a FDA-approved GUSB enzyme to assess the GUSB-dependence of bone preservation in OVX mice in response to curcumin or quercetin treatment. An investigation of the relative importance of extracellular (e.g. secreted) vs. intracellular GUSB-mediated deconjugation of dietary polyphenol glucuronides, a key question when assessing relevant enzyme phenotypes and replacement therapies in humans, will also be addressed. Given recent clinical reports of turmeric dietary supplement-associated hepatotoxicity, effects of GUSB phenotypes on liver function in curcumin-treated mice will be a secondary outcome. Our collaborative investigative team is well poised to address these research questions. Proof of concept data obtained here will be impactful, challenging our understanding and supporting new research regarding the role of enzyme phenotypes in maintaining bone health in response to dietary polyphenols, and opening new avenues for personalized approaches to promote the healthspan of our aging US population.

抽象的含姜黄素的姜黄膳食补充剂 (DS) 的销量呈指数级增长，现已成为最畅销的产品在美国，植物 DS 与姜黄 DS 使用量的显着增加有关美国人用于治疗慢性肌肉骨骼疾病，例如类风湿性关节炎（30% 然而，从科学角度来说，很难协调骨保护作用的体内证据。姜黄素在人类和啮齿动物体内的含量，药代动力学数据表明几乎检测不到循环水平摄入姜黄素后，姜黄素的糖苷配基通过肠道和肝脏快速结合形成姜黄素葡萄糖醛酸，一种主要的循环代谢物，我们实验室最近的工作显示基本上不活跃。揭示了这一过程，证明了姜黄素酶促解离的高活性水平骨内的葡萄糖苷酸形成生物活性糖苷配基，其浓度与体外抑制所需的浓度相似骨吸收破骨细胞的形成，是所有主要骨病（包括骨质疏松症）骨质流失的关键驱动因素。由于葡萄糖醛酸化是许多骨骼保护性膳食多酚的常见代谢命运，因此主要该项目的目标是确定骨保护多酚生物活性是否同样依赖于 ß- 葡萄糖醛酸酶（GUSB），姜黄素和其他骨的葡萄糖醛酸苷解结合所需的酶骨骼中的保护性膳食多酚，例如槲皮素，这个问题具有很大的临床意义。 GUSB 表达在人群中变化很大。实验将利用绝经后模型。骨质流失（卵巢切除 [OVX] 小鼠）、GUSB 活性和/或处理缺陷的小鼠，以及补充 FDA 批准的 GUSB 酶以评估骨保存的 GUSB 依赖性 OVX 小鼠对姜黄素或槲皮素治疗的相对重要性的研究。细胞外（例如分泌的）与细胞内 GUSB 介导的膳食多酚葡萄糖醛酸解结合，评估人类相关酶表型和替代疗法时的一个关键问题是鉴于最近姜黄膳食补充剂相关肝毒性的临床报告，姜黄素治疗小鼠肝功能的 GUSB 表型将是我们的合作的次要结果。调查团队已准备好解决这些研究问题，此处获得的概念数据将得到验证。具有影响力，挑战我们的理解并支持有关酶作用的新研究响应膳食多酚维持骨骼健康的表型，并开辟新途径个性化的方法来延长美国老龄化人口的健康寿命。