Abdulaal Wesam H, Omar Ulfat M, Zeyadi Mustafa, El-Agamy Dina S, Alhakamy Nabil A, Ibrahim Sabrin R M, Almalki Naif A R, Asfour Hani Z, Al-Rabia Mohammed W, Mohamed Gamal A, Elshal Mahmoud
Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia.
Int Immunopharmacol. 2024 Mar 30;130:111732. doi: 10.1016/j.intimp.2024.111732. Epub 2024 Feb 24.
Fulminant hepatic failure (FHF) is the terminal phase of acute liver injury, which is characterized by massive hepatocyte necrosis and rapid hepatic dysfunction in patients without preexisting liver disease. There are currently no therapeutic options for such a life-threatening hepatic failure except liver transplantation; therefore, the terminal phase of the underlying acute liver injury should be avoided. Tomatidine (TOM), asteroidal alkaloid, may have different biological activities, including antioxidant and anti-inflammatory effects. Herein, the lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced FHF mouse model was established to explore the protective potential of TOM and the underlying mechanisms of action. TOM pretreatment significantly inhibited hepatocyte necrosis and decreased serum aminotransferase activities in LPS/D-GalN-stimulated mice. TOM further increased the level of different antioxidant enzymes while reducing lipid peroxidation biomarkers in the liver. These beneficial effects of TOM were shown to be associated with targeting of NF-κB signaling pathways, where TOM repressed NF-κB activation and decreased LPS/D-GalN-induced TNF-α, IL-6, IL-1β, and iNOS production. Moreover, TOM prevented LPS/D-GalN-induced upregulation of Keap1 expression and downregulation of Nrf2 and HO-1 expression, leading to increased Nrf2-binding activity and HO-1 levels. Besides, TOM pretreatment repressed LPS/D-GalN-induced upregulation of proliferating cell nuclear antigen (PCNA) expression, which spared the hepatocytes from damage and subsequent repair following the LPS/D-GalN challenge. Collectively, our findings revealed that TOM has a protective effect on LPS/D-GalN-induced FHF in mice, showing powerful antioxidant and anti-inflammatory effects, primarily mediated via modulating Keap1/Nrf2/HO-1 and NF-κB/TNF-α/IL-6/IL-1β/iNOS signaling pathways.
暴发性肝衰竭（FHF）是急性肝损伤的终末期，其特征是在无基础肝病的患者中出现大量肝细胞坏死和快速肝功能障碍。除肝移植外，目前对于这种危及生命的肝衰竭尚无治疗选择；因此，应避免潜在急性肝损伤的终末期。番茄碱（TOM），一种甾体生物碱，可能具有不同的生物学活性，包括抗氧化和抗炎作用。在此，建立脂多糖（LPS）/D-半乳糖胺（D-GalN）诱导的FHF小鼠模型，以探讨TOM的保护潜力及其潜在作用机制。TOM预处理显著抑制LPS/D-GalN刺激小鼠的肝细胞坏死并降低血清转氨酶活性。TOM进一步提高了不同抗氧化酶的水平，同时降低了肝脏中的脂质过氧化生物标志物。TOM的这些有益作用与靶向NF-κB信号通路有关，其中TOM抑制NF-κB活化并减少LPS/D-GalN诱导的TNF-α、IL-6、IL-1β和iNOS产生。此外，TOM可防止LPS/D-GalN诱导的Keap1表达上调以及Nrf2和HO-1表达下调，从而导致Nrf2结合活性和HO-1水平升高。此外，TOM预处理抑制了LPS/D-GalN诱导的增殖细胞核抗原（PCNA）表达上调，使肝细胞在LPS/D-GalN攻击后免受损伤和随后的修复。总体而言，我们的研究结果表明，TOM对LPS/D-GalN诱导的小鼠FHF具有保护作用，显示出强大的抗氧化和抗炎作用，主要通过调节Keap1/Nrf2/HO-1和NF-κB/TNF-α/IL-6/IL-1β/iNOS信号通路介导。
