Khedr Eman G, Badr Noha H, El-Feky Ola A
Department of Biochemistry, Faculty of Pharmacy, Tanta University, 31527, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Tanta University, 31527, Egypt.
Arch Biochem Biophys. 2025 Sep;771:110505. doi: 10.1016/j.abb.2025.110505. Epub 2025 Jun 13.
Baricitinib recently gained attention as a selective Janus kinase inhibitor, mediating cytokine signaling pathways and immune-inflammatory cascades. This research designed to explore the potential cardioprotective impact of baricitinib in doxorubicin-induced cardiomyopathy (DIC), tracking its immunomodulatory effect on the JAK/STAT and TLR-4/NF-κB signaling pathways. We also compared its effect with olmesartan, an angiotensin receptor blocker (ARB), which is one of the treatments used for DIC. Five groups were created out of male albino rats: normal control group, doxorubicin group, baricitinib treatment group, olmesartan treatment group, combination treatment group. Doxorubicin, baricitinib and olmesartan were taken with dosages of 4.5 mg/kg day after day IP (Cumulative dose = 22.5 mg/kg), 3 mg/kg/day PO, 10 mg/kg/day PO, respectively for 10 days. The results showed that baricitinib exerted cardioprotective effect on histopathological and biochemical levels compared to doxorubicin group. It also downregulated the activation of the JAK/STAT signaling pathway via significant decreases in p-JAK2 and p-STAT1/3 compared to doxorubicin group. It also downregulated the TLR-4/NF-κB signaling pathway via significant decreases in TLR-4 and NF-κB compared to doxorubicin group. For the first time, we elucidated baricitinib's cardioprotective role against DIC thought modulation of the JAK/STAT and TLR-4/NF-κB immune-inflammatory pathways. Moreover, baricitinib significantly downregulated the two signaling pathways with subsequent downregulation of downstream markers; IL-6, TNF-α, VEGF-α, and NO, which are involved in inflammation and angiogenesis associated with DIC. Olmesartan alone or in combination with baricitinib also exerted cardioprotection by downregulating the two signaling pathways, while baricitinib demonstrated superior anti-inflammatory effects. Thus, baricitinib shows promise in mitigating DIC.
巴瑞替尼作为一种选择性 Janus 激酶抑制剂，介导细胞因子信号通路和免疫炎症级联反应，最近受到了关注。本研究旨在探讨巴瑞替尼在阿霉素诱导的心肌病（DIC）中的潜在心脏保护作用，追踪其对 JAK/STAT 和 TLR-4/NF-κB 信号通路的免疫调节作用。我们还将其与奥美沙坦（一种血管紧张素受体阻滞剂（ARB），用于治疗 DIC 的药物之一）的效果进行了比较。将雄性白化大鼠分为五组：正常对照组、阿霉素组、巴瑞替尼治疗组、奥美沙坦治疗组、联合治疗组。阿霉素、巴瑞替尼和奥美沙坦的给药剂量分别为每天 4.5 mg/kg 腹腔注射（累积剂量 = 22.5 mg/kg）、每天 3 mg/kg 口服、每天 10 mg/kg 口服，持续 10 天。结果表明，与阿霉素组相比，巴瑞替尼在组织病理学和生化水平上发挥了心脏保护作用。与阿霉素组相比，它还通过显著降低 p-JAK2 和 p-STAT1/3 下调了 JAK/STAT 信号通路的激活。与阿霉素组相比，它还通过显著降低 TLR-4 和 NF-κB 下调了 TLR-4/NF-κB 信号通路。我们首次阐明了巴瑞替尼通过调节 JAK/STAT 和 TLR-4/NF-κB 免疫炎症途径对 DIC 的心脏保护作用。此外，巴瑞替尼显著下调了这两条信号通路，随后下调了下游标志物；IL-6、TNF-α、VEGF-α 和 NO，它们参与了与 DIC 相关的炎症和血管生成。单独使用奥美沙坦或与巴瑞替尼联合使用也通过下调这两条信号通路发挥了心脏保护作用，而巴瑞替尼表现出更强的抗炎作用。因此，巴瑞替尼在减轻 DIC 方面显示出前景。
