Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow 226025, India.
Faculty of Mathematical and Statistical Sciences, Shri Ramswaroop Memorial University, Deva Road, Lucknow 225003, India.
Cytokine. 2019 Jun;118:144-159. doi: 10.1016/j.cyto.2018.03.026. Epub 2018 Mar 23.
We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.
我们尝试使用 DMH 诱导的 CRC 大鼠模型进行了一项临床前研究，以评估我们最近合成的 1,3,4-噻二唑类化合物的抗肿瘤潜力。通过 ELISA、qRT-PCR 和 Western blot 分析证实了分子见解。CRC 状况是由 COX-2 和 IL-6 诱导的 JAK2/STAT3 激活引起的，反过来，这是由于 JAK2 和 STAT3 的磷酸化增强。用 1,3,4-噻二唑衍生物（VR24 和 VR27）治疗导致该信号通路的显著阻断。通过使用定量 Western blot 数据进行基于数据的数学建模，进一步证实了 STAT3 群体对 IL-6 和 COX-2 刺激的反应。最后，通过基于 H NMR 的血清代谢组学证实，VR24 和 VR27 恢复了与 DMH 诱导的 CRC 相关的失调代谢物。VR24 和 VR27 的肿瘤保护能力被发现与市场上的化疗药物 5-氟尿嘧啶相当或在某种程度上更好。
