Toxicology and applied pharmacology · 2020
Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury.
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El-Sisi Alaa El-Din El-Sayed, Sokar Samia Salim, Shebl Abdelhadi Mohamed, Mohamed Dina Zakaria, Abu-Risha Sally El-Sayed
Аннотация
BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75μg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner.
METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion.
RESULTS: OCT pretreatment at doses (50 or 75 μg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group.
CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.
METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion.
RESULTS: OCT pretreatment at doses (50 or 75 μg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group.
CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.