Unveiling the potential therapeutic role of nifuroxazide and liraglutide combination in mitigating LPS-induced acute lung injury through modulation of AT1R/JAK-2/STAT-3 by ACE2/ Ang1‐7/MasR signaling in male albino rats: in vivo and in silico study

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-07-23 DOI:10.1016/j.intimp.2025.115261

Amira Karam Khalifa , Walla'’a A. Osman , Ahmed Naeem Eesa , Nagwa Mahmoud Ramadan , Abeer Abdelkader , Sara Sayed Kadry Abdallah , Basma Emad Aboulhoda , Fatma Al-Zahraa Nabil Al-Shahed , Mansour A. Alghamdi , Ahmed A. Elrashedy , Mohamed Mahmoud Abdelrahim Elshaer , Sameh Saber , Alaa Karam Mahmoud , Taha Ashraf , Lamiaa Mohammed Matter

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Abstract

The current study investigated the possible therapeutic role of a combination of liraglutide and nifuroxazide in ameliorating the JAK2/STAT3/NFĸB signaling pathway by augmenting the counter-regulatory ACE2/Ang1-7/MAS receptor axis of the renin angiotensin system (RAS). This therapeutic potential was further verified through molecular dynamic simulation studies. Seventy-five male Wistar albino rats were randomly allocated into 5 groups. The groups included normal control, LPS-induced ALI, ALI + NIF treated group, ALI + LIR-treated group, and ALI + LIR + NIF-treated group.The study revealed the promising therapeutic role of the liraglutide and nifuroxazide combination in significantly improving 7-day survival rates, ameliorating metabolic acidosis, and dampening the inflammatory response (IL-6, TNFα, iNOS, MPO, IL-1β) in bronchoalveolar lavage fluid (BALF). This was supported by the effective alleviation of pulmonary leakage, as evidenced by a remarkable decrease in wet lung weight/body weight ratio and wet/dry lung ratio. Additionally, the combination restored the redox balance by enhancing levels of SOD, catalase, and GSH. The combination regimen also improved the inflammatory score in histopathological examination, increased Nrf2 expression, and reduced iNOS immunoreactivity. These effects were attributed to the downregulation of total and phosphorylated protein expression of JAK2/STAT3/NFβB, and the upregulation of mRNA expression of ACE2 receptor, MAS receptors, and pulmonary lung surfactant B. Our study, which combined molecular dynamic simulation and experimental validation, provides a comprehensive perspective on managing septic acute lung injury, positioning the liraglutide and nifuroxazide combination regimen as a promising candidate for the management of septic acute lung injury (S-ALI).

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通过ACE2/ Ang1‐7/MasR信号通路调节AT1R/JAK-2/STAT-3，揭示nifuroxazide和利拉鲁肽联合治疗lps诱导的雄性白化大鼠急性肺损伤的潜在治疗作用：体内和计算机研究

目前的研究探讨了利拉鲁肽和硝氟肼联合使用通过增强肾素血管紧张素系统（RAS）的反调控ACE2/Ang1-7/MAS受体轴来改善JAK2/STAT3/NFĸB信号通路的可能治疗作用。通过分子动力学模拟研究进一步验证了这种治疗潜力。雄性Wistar白化大鼠75只，随机分为5组。各组分为正常对照组、lps诱导的ALI、ALI + NIF治疗组、ALI + LIR治疗组、ALI + LIR + NIF治疗组。该研究显示利拉鲁肽联合硝呋噻特在显著提高7天生存率、改善代谢性酸中毒、抑制支气管肺泡灌洗液（BALF）炎症反应（IL-6、TNFα、iNOS、MPO、IL-1β）方面具有良好的治疗作用。肺漏的有效缓解证实了这一点，湿肺重量/体重比和湿肺/干肺比显著降低。此外，该组合通过提高SOD、过氧化氢酶和谷胱甘肽的水平来恢复氧化还原平衡。联合用药可改善组织病理学检查炎症评分，提高Nrf2表达，降低iNOS免疫反应性。这些影响归因于JAK2/STAT3/NFβB总蛋白和磷酸化蛋白表达下调，ACE2受体、MAS受体和肺表面活性物质b mRNA表达上调。我们的研究结合分子动力学模拟和实验验证，为脓毒性急性肺损伤的治疗提供了一个全面的视角。定位利拉鲁肽和硝呋噻特联合方案作为脓毒性急性肺损伤（S-ALI）治疗的有希望的候选方案。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.