MECHANISMS OF CHONDROPROTECTION BY POMEGRANATE FRUIT EXTRACT

石榴果提取物的软骨保护机制

• 批准号: 7315741
• 负责人: Tariq M Haqqi
• 金额: $ 37.54万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315741
• 关键词: Adverse effects; Affect; Age; Animal Model; Anterior Cruciate Ligament; Anthocyanins; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arthritis; Awareness; Binding; Biological Assay; Cartilage; Cartilage Matrix; Cartilage injury; Cells; Cellularity; Chondrocytes; Class; Collagen Gene; Collagen Type II; Condition; Consumption; DNA Binding; Daily; Data; Death Rate; Degenerative polyarthritis; Development; Dinoprostone; Disease; Dose; EMSA; Elderly; Ellagic Acid; Evaluation; Fruit; Functional disorder; Gene Expression; Genes; Genetic Transcription; Glycosaminoglycans; Hand; Health; Hip region structure; Histologic; Human; Immunoprecipitation; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-6; Joints; Knee; Laboratories; MAP2K6 gene; MAP3K7 gene; MAPK14 gene; MAPK8 gene; Matrix Metalloproteinases; Mediator of activation protein; Musculoskeletal Diseases; NF-kappa B; Nitric Oxide; Nitrites; Non-Steroidal Anti-Inflammatory Agents; Oryctolagus cuniculus; Oxidative Stress; PTGS2 gene; Pain; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Play; Pomegranate; Preparation; Prevention; Preventive; Production; Property; Protein Isoforms; Proteins; Publishing; Punica granatum; Quality of life; Reporter; Research; Research Personnel; Risk; Role; Safety; Signal Transduction Pathway; Source; Superoxide Dismutase; Symptoms; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Transfection; United States; Vertebral column; Water; Western Blotting; Work; aging population; articular cartilage; base; cell type; collagenase 3; cytokine; day; delphinidin; dietary supplements; experience; feeding; glutathione peroxidase; in vivo; inhibitor/antagonist; novel; polyphenol; prevent; programs; promoter; repaired; response; transcription factor; type I collagen alpha 1; upstream kinase

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common musculoskeletal disease among the aging population in the United States and throughout the world. OA is characterized by degeneration of articular cartilage of the joints in hands, knees, spine and hips. While conditions predisposing to the development of OA have been identified the actual causes remain unknown. The current treatment options are limited to relief of symptoms using nonsteroidal anti-inflammatory drugs (NSAIDs). Due to complications associated with NSAIDs therapy, the use of herbal extracts for the treatment of OA is on the rise but most of these agents, sold as dietary supplements, have not been evaluated for their efficacy and safety. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit or its extract (PFE) is widely used in several traditional medicinal systems for the treatment of inflammation and pain in arthritis and other diseases. Edible part of pomegranate fruit (PF) is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Published work from this laboratory has shown that PFE exert a potent inhibitory effect on IL-1B-induced activation of p38-MAPK and JNK, NF-kB and expression of matrix metalloproteinases (MMPs) by human cartilage explants and chondrocytes in vitro. However, the mechanism of the inhibition of catabolic response remains elusive. Based on our published and preliminary studies we hypothesize that "pomegranate fruit extract (PFE) inhibit the cartilage degrading effects of IL-1B by regulating the activation of signal transduction pathways and transcription factors which negatively or positively affect the IL-1B-induced transcription of genes associated with the catabolic or anabolic response in human chondrocytes". Proposed studies will determine whether PFE inhibit the MKK3 and MKK6 kinases(Specific Aim 1); inhibit the IL-1B-induced activation of NF-kB by modulating the activation of kinases upstream of IkB (inhibitor of NF-kB) including IKKa and IKKB (Specific Aim 2); whether PFE inhibit the IL-1B-induced oxidative stress and dedifferentiation of human chondrocytes (Specific Aims 3, 4); and determine whether "consumption of PFE will inhibit the cartilage degradation and suppress the progression of experimentally induced OA in rabbits (Specific Aim 5). Our findings may open new avenues regarding the use of PFE or compounds derived from it for the treatment and/or prevention of OA.

描述（由申请人提供）：骨关节炎（OA）是美国及世界各地衰老人群中最常见的肌肉骨骼疾病。 OA的特征是手动，膝盖，脊柱和臀部的关节关节软骨变性。尽管已经确定了OA发展的条件，但实际原因仍然未知。当前的治疗选择仅限于使用非甾体类抗炎药（NSAID）缓解症状。由于与NSAIDS疗法有关的并发症，使用草药提取物用于OA的治疗却有所增加，但这些药物中的大多数作为饮食补充剂出售的大多数尚未根据其功效和安全性进行评估。石榴果实（Punica Granatum L）因其药用特性而被尊敬。石榴果实或其提取物（PFE）被广泛用于几种传统的药物系统中，用于治疗关节炎和其他疾病的炎症和疼痛。石榴果（PF）的可食部分富含花青素，花青素是一组具有抗氧化剂和抗炎活性的多酚化合物。该实验室的发表工作表明，PFE对IL-1B诱导的p38-MAPK和JNK，NF-KB的激活产生了有效的抑制作用，以及人体软骨epplistant和软骨细胞在体外的人体软骨epplistans和基质金属蛋白酶（MMP）的表达。但是，抑制分解代谢反应的机制仍然难以捉摸。基于我们发表的初步研究，我们假设“石榴果实提取物（PFE）通过调节信号转导途径的激活和转录因子的激活来抑制IL-1B的软骨降解效应，从而对IL-1B诱导的基因转录产生负面影响或正面影响的基因转录。拟议的研究将确定PFE是否抑制MKK3和MKK6激酶（特定目标1）；通过调节包括IKKA和IKKB（特定AIM 2）的IKB（NF-KB抑制剂）上游的激活（特定的AIM 2），抑制IL-1B诱导的NF-KB激活NF-KB的激活； PFE是否抑制IL-1B诱导的氧化应激和人体软骨细胞的去分化（特定目的3、4）；并确定“ PFE的消耗是否会抑制软骨降解并抑制兔子中实验诱导的OA的进展（特定目标5）。我们的发现可能会为使用PFE或从中提供用于治疗和/或预防OA的PFE或化合物开放新的途径。