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（由适用提供）：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，并且当前的治疗方案仅限于使用NSAID释放符号。但是，使用NSAID的使用可能会因包括胃肠道出血，心血管不良事件和肾毒性在内的重大副作用而变得复杂。石榴果实（Punica Granatum L）因其医疗特性而被人们尊敬。石榴果（PF）或其提取物（PFE）在印度的Unani和Ayurvedic Medical Systems广泛用于治疗糖尿病和结肠炎。 PF的可食部分是 富含花色苷，一组具有抗氧化剂和抗炎特性的多酚化合物。我们先前报道说，PFE对IL-1？诱导的MAPK亚组P38-MAPK和JNK的激活产生了潜在的抑制作用，转录因子NF-？b以及人类软骨外载体和软骨细胞在体外的表达。最近，我们表明（1）PFE的口服消耗抑制了小鼠胶原蛋白引起的关节炎的发展（CIA）； （2）可生物利用的PFE构成/代谢产物抑制了COX-2活性，而IL-1？诱导的软骨细胞中NO和PGE2的产生。拟议的研究资本利用了这些新发现，因为我们将扩展这些研究，并将确定体外发现与在OA动物模型中使用体内PFE使用的相关性。我们将检验以下假设：“ PFE的口服消耗抑制软骨降解，并抑制由前交叉韧带翻译引起的兔子中的膝关节降解（ACLT）。 （sf）在AIM-2中给出不同剂量的PFE，我们将确定并比较包含PFE衍生的ET和花青素在抑制IL-1缺的效率的效率。 OA ACLT模型中关节软骨变性的PFE。 公共卫生相关性：骨关节炎（OA）的特征是高水平的IL-1，ROS的极端产生和受影响关节的关节软骨变性。但是，其病因和精确的致病机制尚不清楚。在这里，我们将确定消耗石榴果实（PFE）的标准化提取物是否可以减慢或阻碍体内艺术软骨变性。拟议的研究的广泛对象是（a）确定与PFE软骨/软骨保护活性相关的体外分子机制； （b）使用广泛使用的人OA动物模型来测试体外研究与体内情况的相关性。我们的发现很可能为开发新型OA治疗策略的发展打开了大门。