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

• 批准号: 10303242
• 负责人: JANET L FUNK
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303242
• 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/antagonist; liver function; mannose receptor; personalized approach; polyphenol; preservation; prevent; protective effect; receptor; response; secondary outcome; treatment effect; uptake

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.

摘要 含姜黄素的姜黄膳食补充剂（DS）的销售呈指数级增长，现在是最畅销的 植物DS在美国，已与显着增加姜黄DS的使用， 美国人用于治疗慢性肌肉骨骼疾病，如类风湿性关节炎（30%） 患病率）。然而，从科学角度来看，很难调和体内骨保护作用的证据 姜黄素在人类和啮齿类动物中的药代动力学数据表明几乎检测不到循环水平 姜黄素摄入后的糖苷配基姜黄素，由于其快速结合的肠和肝脏， 姜黄素葡糖苷酸，一种主要的循环代谢物，显示出很大程度上无活性。我们实验室最近的工作 揭示了这一过程，证明了高活性水平的酶解结合姜黄素 葡糖苷酸在骨内形成生物活性糖苷配基，其浓度与体外抑制 骨吸收破骨细胞形成，是所有主要骨疾病（包括骨质疏松症）中骨丢失的关键驱动因素。 由于葡萄糖醛酸化是许多保护骨骼的膳食多酚的常见代谢命运， 该项目的目标是确定骨保护多酚生物活性是否类似地依赖于骨- 葡萄糖醛酸酶（GUSB），姜黄素和其他骨的葡萄糖醛酸解结合所需的酶 保护性的膳食多酚，如槲皮素，在骨内。这个问题有很大的临床意义，因为 GUSB表达在人群中高度可变。实验将利用绝经后的模型， 骨丢失（卵巢切除[OVX]小鼠），GUSB活性和/或加工缺陷的小鼠，和 补充FDA批准的GUSB酶以评估骨保存的GUSB依赖性 在OVX小鼠中响应于姜黄素或槲皮素治疗。研究的相对重要性 胞外（例如分泌的）与胞内GUSB介导的膳食多酚葡糖苷酸解缀合， 在评估人类相关酶表型和替代疗法时，一个关键问题也将是 处理。鉴于姜黄膳食毒性相关肝毒性的最新临床报告， 姜黄素处理小鼠中GUSB表型对肝功能的影响将是次要结果。我们的协作 调查小组已做好准备解决这些研究问题。在此获得的概念验证数据将 具有影响力，挑战我们的理解并支持有关酶作用的新研究 表型在维持骨骼健康响应膳食多酚，并开辟新的途径， 个性化的方法来促进我们美国老龄人口的健康。