Ghobrial Diana K, El-Nikhely Nefertiti, Sheta Eman, Ragab Hanan M, Rostom Sherif A F, Saeed Hesham, Wahid Ahmed
Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria 21526, Egypt.
Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria 21321, Egypt.
Antioxidants (Basel). 2023 Mar 3;12(3):637. doi: 10.3390/antiox12030637.
Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl-induced liver fibrosis in male Sprague-Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-β) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.
肝纤维化若不治疗可能会危及生命，因为它可能导致严重的、无法治愈的并发症。常见的治疗方法是在干预措施仍适用时逆转纤维化。已表明塞来昔布在诱导的大鼠纤维化肝脏中表现出一些抗纤维化特性。本研究旨在研究与三种新型甲氧基化吡唑并[3,4-d]嘧啶的塞来昔布相比，在雄性Sprague-Dawley大鼠四氯化碳诱导的肝纤维化中可能的抗纤维化特性。三种新合成的化合物被证明是安全的候选物。它们对严重的四氯化碳诱导的纤维化显示出治疗效果，但程度不同。这三种化合物能够通过显示抗氧化特性来部分逆转肝脏结构扭曲并降低纤维化严重程度，即随着谷胱甘肽（GSH）和超氧化物歧化酶（SOD）水平升高降低丙二醛（MDA），重塑细胞外基质蛋白和肝酶平衡，并降低促炎（肿瘤坏死因子-α和白细胞介素-6）和促纤维化（转化生长因子-β）细胞因子水平。结果显示，与塞来昔布和其他两种类似物相比，二甲氧基类似物在所有上述参数中表现出最大活性，这可能归因于衍生物不同的甲氧基化模式。总体而言，二甲氧基衍生物可被认为是一种安全且有前景的抗纤维化候选物。
