ABSTRACT
The liver is vulnerable to various hepatotoxins, including carbon tetrachloride (CCl4), which induces oxidative stress and apoptosis by producing reactive oxygen species (ROS) and activating the mitogen-activated protein kinase (MAPK) pathway. Cereblon (CRBN), a multifunctional protein implicated in various cellular processes, functions in the pathogenesis of various diseases; however, its function in liver injury remains unknown. We established a CRBN-knockout (KO) HepG2 cell line and examined its effect on CCl4-induced hepatocellular damage. CRBN-KO cells exhibited reduced sensitivity to CCl4-induced cytotoxicity, as evidenced by decreased levels of apoptosis markers, such as cleaved caspase-3, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. CRBN deficiency enhanced antioxidant defense, with increased superoxide dismutase activity and glutathione ratios (GSH/GSSG), as well as reduced pro-inflammatory cytokine expression. Mechanistically, the protective effects of CRBN deficiency appeared to involve the attenuation of the MAPK-mediated pathways, particularly through decreased phosphorylation of JNK and ERK. Overall, these results suggest the crucial role of CRBN in mediating the hepatocellular response to oxidative stress and inflammation triggered by CCl4 exposure, offering potential clinical implications for liver injury in a wide range of liver diseases.
Subject(s)
Adaptor Proteins, Signal Transducing , Apoptosis , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury , Oxidative Stress , Humans , Apoptosis/drug effects , Hep G2 Cells , Carbon Tetrachloride/toxicity , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/etiology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Oxidative Stress/drug effects , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/deficiency , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinases/metabolism , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Magnesium sulfate (MgSO4) has been used in the treatment of pre-eclampsia, hypertension and arrhythmia. Magnesium enhances the neuromuscular block of rocuronium. This study has been conducted to evaluate the reversal efficacy of sugammadex from deep rocuronium-induced neuromuscular block (NMB) during consistent pretreatment of MgSO₄ in rabbits. METHODS: Twenty-eight rabbits were randomly assigned to four groups, a control group or study groups (50% MgSO₄ 150–200 mg/kg and 25 mg/kg/h IV), and received rocuronium 0.6 mg/kg. When post-tetanic count 1–2 appeared, sugammadex 2, 4, and 8 mg/kg was administered in the 2-mg group, control and 4-mg group, and 8-mg group, respectively. The recovery course after reversal of sugammadex administration was evaluated in each group. RESULTS: The mean serum concentration of magnesium was maintained at more than 2 mmol/L in the study groups, and the total dose of MgSO₄ was more than 590 mg. The reversal effect of sugammadex on rocuronium-induced NMB in pretreated MgSO₄ was not different from that in the group without MgSO₄. The recovery time to train-of-four ratio 0.9 after sugammadex administration in the 2-mg group was longer than in the other groups (P < 0.001); there were no other significant differences among the groups. CONCLUSIONS: The reversal of sugammadex from a deep rocuronium-induced NMB during large pretreatment of MgSO₄ was not affected. However, we should consider that the reversal effect of sugammadex varied depending on the dose.
Subject(s)
Rabbits , Arrhythmias, Cardiac , Control Groups , Hypertension , Magnesium Sulfate , Magnesium , Neuromuscular Blockade , Pre-EclampsiaABSTRACT
BACKGROUND: Magnesium sulfate (MgSO4) has been used in the treatment of pre-eclampsia, hypertension and arrhythmia. Magnesium enhances the neuromuscular block of rocuronium. This study has been conducted to evaluate the reversal efficacy of sugammadex from deep rocuronium-induced neuromuscular block (NMB) during consistent pretreatment of MgSO₄ in rabbits. METHODS: Twenty-eight rabbits were randomly assigned to four groups, a control group or study groups (50% MgSO₄ 150–200 mg/kg and 25 mg/kg/h IV), and received rocuronium 0.6 mg/kg. When post-tetanic count 1–2 appeared, sugammadex 2, 4, and 8 mg/kg was administered in the 2-mg group, control and 4-mg group, and 8-mg group, respectively. The recovery course after reversal of sugammadex administration was evaluated in each group. RESULTS: The mean serum concentration of magnesium was maintained at more than 2 mmol/L in the study groups, and the total dose of MgSO₄ was more than 590 mg. The reversal effect of sugammadex on rocuronium-induced NMB in pretreated MgSO₄ was not different from that in the group without MgSO₄. The recovery time to train-of-four ratio 0.9 after sugammadex administration in the 2-mg group was longer than in the other groups (P < 0.001); there were no other significant differences among the groups. CONCLUSIONS: The reversal of sugammadex from a deep rocuronium-induced NMB during large pretreatment of MgSO₄ was not affected. However, we should consider that the reversal effect of sugammadex varied depending on the dose.