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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：
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
项目类别：
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

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.

摘要