Evaluation of Antioxiodant Drugs for the Treatment of Ochronotic Alkaptonuria in An In Vitro Human Cell Model
Evaluation of Antioxiodant Drugs for the Treatment of Ochronotic Alkaptonuria in An In Vitro Human Cell Model
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DOI：
10.1002/jcp.22199
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发表时间：
2010-10-01
影响因子：
5.6
通讯作者：
Santucci, Annalisa
中科院分区：
文献类型：
--
作者：
Tinti, Laura;Spreafico, Adriano;Santucci, Annalisa
黑酸尿症 (AKU) 是一种罕见的常染色体隐性遗传疾病，与肝脏中尿黑酸 1,2-双加氧酶活性缺乏有关。这导致尿黑酸（HGA）及其聚合形式的氧化衍生物在结缔组织（尤其是关节）中积聚。目前，AKU缺乏合适的治疗方法。因此，我们提出了一种新的 AKU 治疗方法，使用抗氧化剂 N-乙酰半胱氨酸 (NAC) 与抗坏血酸 (ASC) 联合给药，因为 NAC 已被证明可以抵消 ASC 的副作用。我们使用过量 HGA (0.33 mM) 攻击的人关节原代软骨细胞建立了体外细胞模型。我们使用该实验模型对 AKU 的潜在抗氧化疗法进行了临床前测试，评估暴露于 HGA 并单独或联合使用 NAC 和 ASC 治疗的软骨细胞的凋亡、活力、增殖和代谢。 NAC减少了HGA诱导的软骨细胞凋亡，增加了HGA抑制的软骨细胞生长，并部分恢复了HGA抑制的蛋白多糖释放。与单独添加 NAC 和 ASC 相比，联合添加两种抗氧化剂的功效显着提高。我们的新型体外 AKU 模型使我们能够证明 NAC 和 ASC 共同给药的功效，可以抵消 HGA 治疗黄褐斑关节病的负面影响。 J.细胞。生理学。 225: 84-91, 2010。(C) 2010 Wiley-Liss, Inc.
Alkaptonuria (AKU) is a rare autosomal recessive disease, associated with deficiency of homogentisate 1,2-dioxygenase activity in the liver. This leads to an accumulation of homogentisic acid (HGA) and its oxidized derivatives in polymerized form in connective tissues especially in joints. Currently, AKU lacks an appropriate therapy. Hence, we propose a new treatment for AKU using the antioxidant N-acetylcysteine (NAC) administered in combinations with ascorbic acid (ASC) since it has been proven that NAC counteracts the side-effects of ASC. We established an in vitro cell model using human articular primary chondrocytes challenged with an excess of HGA (0.33 mM). We used this experimental model to undertake pre-clinical testing of potential antioxidative therapies for AKU, evaluating apoptosis, viability, proliferation, and metabolism of chondrocytes exposed to HGA and treated with NAC and ASC administered alone or in combination addition of both. NAC decreased apoptosis induced in chondrocytes by HGA, increased chondrocyte growth reduced by HGA, and partially restored proteoglycan release inhibited by HGA. A significantly improvement in efficacy was found with combined addition of the two antioxidants in comparison with NAC and ASC alone. Our novel in vitro AKU model allowed us to demonstrate the efficacy of the co-administration of NAC and ASC to counteract the negative effects of HGA for the treatment of ochronotic arthropathy. J. Cell. Physiol. 225: 84-91, 2010. (C) 2010 Wiley-Liss, Inc.