In Duchenne muscular dystrophy (DMD), the progressive loss of muscle and its ability to function is associated with significant fibrosis, representing the major disease complication in patients. Halofuginone, a halogenated analog of the naturally occurring febrifugine, has been shown to prevent fibrosis in various animal models, including those of muscular dystrophies. Here, two optically active enantiomers of deoxyhalofuginone - a halofuginone analogue in which the hydroxy group in position 3 was removed from the piperidinyl entity - were evaluated with respect to their effect on muscle histopathology in mdx mice. Male mdx mice were treated with either deoxyhalofuginone (as single enantiomers or in racemic form), or halofuginone, for 10 weeks, starting at the age of 4 weeks. Halofuginone caused a significant reduction in total collagen content, degenerative areas, as well as in utrophin and phosphorylated-Smad3 levels in the mdx diaphragms. However, neither the deoxyhalofuginone enantiomers, nor its racemic form had any effect on these parameters. A positive effect of the deoxyhalofuginone (+)-enantiomer was observed on myofiber diameters; however, it was lesser than that of halofuginone. It is concluded that the hydroxy group plays a key role in halofuginone's effects related to fibrosis in DMD, and points towards the transforming growth factor β/Smad3 signaling pathway being involved in this inhibition. Elucidation of the structure-function relationship of halofuginone, in relation to inhibiting fibrosis in muscular dystrophies, is of the utmost importance for creating the next generation of anti-fibrotic therapies that will be more efficacious and less toxic, hence improving life quality of patients.

中文翻译：

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羟氟喹酮依赖性抑制肌纤维化的羟基组要求和md小鼠模型中杜兴氏肌营养不良症的组织病理学改善。

在Duchenne肌营养不良症（DMD）中，肌肉的逐渐丧失及其功能能力与明显的纤维化有关，代表患者的主要疾病并发症。Halofuginone，一种天然存在的非溴双胍的卤代类似物，已被证明可以预防包括肌肉营养不良在内的各种动物模型的纤维化。在此，针对脱氧卤丁酮的两种光学活性对映体-卤丁酮类似物（其中3位上的羟基已从哌啶基实体上除去）进行了评估，它们对mdx小鼠的肌肉组织病理学有影响。从4周龄开始，雄性mdx小鼠用脱氧氟丁酮（单一对映体或消旋体形式）或氟丁酮治疗10周。卤丁酮可导致胶原蛋白总含量显着降低，变性区域，以及mdx隔膜中的卵磷脂和磷酸化Smad3水平。但是，脱氧卤夫酮酮对映异构体及其外消旋形式均未对这些参数产生任何影响。观察到脱氧卤丁酮（+）-对映异构体对肌纤维直径有积极作用。但是，它比卤氟酮低。结论是，羟基在与DMD中的纤维化有关的氟丁酮的作用中起关键作用，并指出该抑制作用涉及转化生长因子β/ Smad3信号传导途径。阐明卤氟酮的结构-功能关系与抑制肌营养不良症的纤维化有关，对于创造下一代更有效，毒性更小的抗纤维化疗法至关重要，