Biochemical and Molecular Studies on the Role of Celecoxib and Some Related Bipyrazoles in Mitigating Induced Liver Injury in Experimental Animals.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-05-15 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S512058

Maram Marei, Nefertiti El-Nikhely, Eman Sheta, Hanan Ragab, Ahmed Wahid, Hesham Saeed, Sherif A F Rostom

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引用次数: 0

Abstract

Introduction: Liver fibrosis is a life-threatening disease that greatly impacts the morbidity and mortality of hepatic patients worldwide, resulting mainly as a consequence of hepatitis C, alcoholic and non-alcoholic fatty liver. COX-1 and COX-2 isozymes catalyze the synthesis of prostaglandins (PGs) and thromboxanes (TXs) from arachidonic acid causing inflammation. Owing to the scarcity of approved fibrolytic drugs available for human use, celecoxib (a selective COX-2 inhibitor) has been repurposed as a potential antifibrotic and fibrolytic agent in some chronic liver fibrosis models.

Methods: The present study aims to discover a non-invasive treatment for liver fibrosis through investigating the possible ability of three celecoxib-related bipyrazole compounds HR1-3 to reverse chemically induced liver fibrosis in rats using CCl₄. This fibrolytic effect was verified by histopathological, immunohistochemical, biochemical and biomolecular assays. In addition, in silico computer-aided evaluation of the compounds' binding mode to certain molecular targets was performed, and the in silico physicochemical properties, drug likeness and pharmacokinetic parameters were predicted using web-based applications.

Results: The analogs HR1-3 could serve as novel therapeutic candidates for the mitigation of liver fibrosis that deserves further derivatizations and investigations. In particular, the fluorinated analog HR3 proved to be the most active member in this study when compared to celecoxib due to its distinguished histopathological and immunohistochemical investigation results, beside its antioxidant potential, as well as its reliable effects against some biomarkers, namely, MMP-9, TGF-β1, TIMP-1, IL-6 and TNF-α.

Conclusion: Based on the obtained results, the fluorinated analog HR3 could serve as a novel therapeutic candidate for the amelioration of liver fibrosis that deserves further derivatizations and investigations.

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塞来昔布及相关联吡唑减轻实验性动物肝损伤的生化和分子研究。

肝纤维化是一种危及生命的疾病，极大地影响了全世界肝病患者的发病率和死亡率，主要由丙型肝炎、酒精性和非酒精性脂肪肝引起。COX-1和COX-2同工酶催化花生四烯酸引起炎症合成前列腺素（pg）和血栓烷（TXs）。由于批准的可用于人的纤维溶解药物稀缺，塞来昔布（一种选择性COX-2抑制剂）已被重新用作一些慢性肝纤维化模型中潜在的抗纤维化和纤维溶解药物。方法：本研究旨在通过研究三种塞来昔布相关的联吡唑化合物HR1-3逆转CCl4化学诱导大鼠肝纤维化的可能能力，发现一种无创治疗肝纤维化的方法。通过组织病理学、免疫组织化学、生化和生物分子分析证实了这种纤维溶解作用。此外，通过计算机辅助评估化合物与特定分子靶点的结合模式，并利用基于web的应用程序预测其物理化学性质、药物相似性和药代动力学参数。结果：HR1-3类似物可作为缓解肝纤维化的新候选药物，值得进一步衍生和研究。特别是氟化类似物HR3，由于其独特的组织病理学和免疫组织化学调查结果，以及其抗氧化潜力，以及对一些生物标志物，即MMP-9， TGF-β1, TIMP-1， IL-6和TNF-α的可靠作用，与塞来昔布相比，在本研究中被证明是最活跃的成员。结论：基于所获得的结果，氟化类似物HR3可作为改善肝纤维化的新候选药物，值得进一步衍生和研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.