CHONDROPROTECTIVE ACTIVITY OF POMEGRANATE EXTRACT

石榴提取物的软骨保护活性

• 批准号: 7915810
• 负责人: Tariq M Haqqi
• 金额: $ 11.81万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915810
• 关键词: Adverse effects; Adverse event; Affect; Age; Animal Model; Animals; Anterior Cruciate Ligament; Anthocyanins; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Applications Grants; Arthritis; Bioavailable; Biological Availability; Body Weight; Cardiovascular system; Cartilage; Cartilage Matrix; Cartilage injury; Chondrocytes; Chronic; Colitis; Collagen Arthritis; Consumption; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Dinoprostone; Disease; Dose; Drug usage; Ellagi-Tannins; Ellagic Acid; Etiology; Experimental Models; Fruit; Future; Gelatinases; Hand; Health; Hemorrhage; High Pressure Liquid Chromatography; Hip region structure; Histologic; Human; Hydrolyzable Tannins; In Vitro; India; Inflammation; Ingestion; Irrigation; Joints; Knee; Knee Osteoarthritis; Knee joint; Luteolin; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Matrix Metalloproteinases; Methods; Modeling; Molecular; Mus; Musculoskeletal Diseases; Nitric Oxide; Oral; Orthopedics; Oryctolagus cuniculus; PTGS2 gene; Pain; Pharmaceutical Preparations; Plasma; Pomegranate; Preparation; Principal Investigator; Production; Property; Prosthesis; Publishing; Punica granatum; Quality of life; Quercetin; Replacement Arthroplasty; Reporting; Rheumatology; Risk; Signal Transduction Pathway; Source; Supplementation; Symptoms; Synovial Fluid; System; Testing; Therapeutic; Time; United States; Vertebral column; Water; age related; aging population; articular cartilage; base; cartilage matrix protein; collagenase; comparative efficacy; delphinidin; design; drinking water; effective therapy; end stage disease; enzyme activity; feeding; gastrointestinal; in vivo; nephrotoxicity; novel; novel therapeutics; pelargonidin; polyphenol; protein degradation; public health relevance; punicalin; repaired; response; transcription factor; treatment strategy

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 and the current treatment options are limited to relief of symptoms using NSAIDS. However, use of NSAIDS may be complicated by significant side effects that include gastrointestinal bleeding, cardiovascular adverse events and nephrotoxicity. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit (PF) or its extract (PFE) is widely used in Unani and Ayurvedic medicinal systems in India for the treatment of diabetes and Colitis. Edible part of PF is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory properties. We previously reported that PFE exert a potent inhibitory effect on IL-1¿-induced activation of MAPK sub-groups p38-MAPK and JNK, transcription factor NF-?B and the expression of MMPs by human cartilage explants and chondrocytes in vitro. Recently we have shown that (1) oral consumption of PFE inhibited the development of collagen-induced arthritis in mice(CIA); and (2) bioavailable PFE constituents/metabolites inhibited COX-2 activity and IL-1¿-induced production of NO and PGE2 in chondrocytes. Proposed studies capitalizes on these novel findings as here we will extend these studies and will determine the relevance of the in vitro findings to in vivo PFE use in an animal model of OA. We will test the hypothesis that "oral consumption of PFE inhibits cartilage degradation and suppresses the progression of knee OA in rabbits induced by anterior cruciate ligament transection (ACLT)". In aim-1 we will establish the identity and concentration of several of the known PFE-derived anthocyanins and ellagitanins (ET) that become bioavailable in plasma and synovial fluid (SF) in rabbits given different doses of PFE; in aim-2 we will determine and compare the efficacy of plasma and SF containing PFE-derived ET and anthocyanins in inhibiting the IL-1¿-induced catabolic responses in human and rabbit cartilage explants in vitro; in aim-3 we will use the dose determined to be most relevant from above studies for feeding rabbits and evaluate the effect of oral consumption of PFE on articular cartilage degeneration in the ACLT model of OA. Public Health Relevance: Osteoarthritis (OA) is characterized by high high levels of IL-1¿, excessive production of ROS and articular cartilage degeneration in the affected joints. However, its etiology and precise pathogenetic mechanisms remain unclear. Here, we will determine whether consumption of a standardized extract of pomegranate fruit (PFE) can slow or retard the artciular cartilage degeneration in vivo. The broad objectives of the proposed studies are (a) to identify the molecular mechanism in vitro associated with cartilage/chondroprotective activity of PFE; and (b) to test the relevance of in vitro studies to the in vivo situation using a widely used animal model of human OA. Our findings are likely to open the door for the development of novel therapeutic strategies for the treatment of OA.

描述（由申请人提供）：骨关节炎（OA）是美国和全世界老龄人口中最常见的肌肉骨骼疾病，其特征是手、膝盖、脊柱和臀部的关节软骨退化。虽然已经确定了导致 OA 发生的条件，但实际原因仍不清楚，目前的治疗方案仅限于使用 NSAIDS 缓解症状，但使用 NSAIDS 可能会有所帮助。石榴果 (Punica granatum L) 因其药用特性而备受推崇，包括胃肠道出血、心血管不良事件和肾毒性。印度治疗糖尿病和结肠炎的阿育吠陀医学系统是 PF 的食用部分。 富含花青素，这是一组具有抗氧化和抗炎特性的多酚化合物，我们之前报道过 PFE 对 IL-1 具有有效的抑制作用。 - 体外人软骨外植体和软骨细胞诱导的 MAPK 亚组 p38-MAPK 和 JNK、转录因子 NF-κB 的激活以及 MMP 的表达最近我们发现，（1）口服 PFE 抑制了发育。胶原诱导的小鼠关节炎 (CIA)；以及 (2) 生物可利用的 PFE 成分/代谢物抑制 COX-2 活性和 IL-1¿拟议的研究利用了这些新发现，我们将扩展这些研究，并确定体外发现与 OA 动物模型中体内 PFE 使用的相关性。假设“口服 PFE 会抑制软骨退化并抑制由前交叉韧带横断 (ACLT) 引起的兔子膝骨关节炎的进展”，在 Target-1 中，我们将确定这一点和几种已知的 PFE 衍生花青素和鞣花素 (ET) 的浓度，在给予不同剂量的 PFE 的兔子的血浆和滑液 (SF) 中变得可生物利用；在 Objective-2 中，我们将确定并比较含有PFE 衍生的 ET 和花青素抑制 IL-1¿ -在体外人类和兔子软骨外植体中诱导分解代谢反应；在目标 3 中，我们将使用上述研究中确定的最相关剂量来喂养兔子，并评估口服 PFE 对 ACLT 模型中关节软骨退化的影响的 O.A. 公共卫生相关性：骨关节炎 (OA) 的特点是高水平的 IL-1¿然而，其病因和确切的致病机制仍不清楚。在这里，我们将确定食用标准化石榴果提取物（PFE）是否可以减缓或延缓关节软骨退化。拟议研究的主要目标是（a）确定与 PFE 的软骨/软骨保护活性相关的体外分子机制；以及（b）测试其相关性。使用广泛使用的人类 OA 动物模型对体内情况进行体外研究，我们的研究结果可能为开发治疗 OA 的新治疗策略打开大门。