Insight into the regulation of NLRP3 inflammasome activation by mitochondria in liver injury and the protective role of natural products.

Due to high mortality rates and poor prognosis, liver injury remains one of the leading causes of mortality worldwide. Amounting evidence suggested that the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which promotes pro-interleukin-1ß (pro-IL-1ß) and pro-interleukin-18 (pro-IL-18) cleavage and maturation play a vital role in the occurrence and development of liver injury and liver disease. Mitochondrial dysfunction is a common co-occurring event in liver injury. Abnormal mitochondrial function has also been shown to be closely related to NLRP3 inflammasome activation. Currently, natural products have attracted the attention of researchers as potential therapeutic agents for liver injury and liver disease due to their less toxicity and multi-targeting advantages. A number of natural products have been discovered to prevent and treat liver injury by modulating the activation of NLRP3 inflammasome. In this review, we highlight the mechanisms involved in the regulation of NLRP3 inflammasome activation by mitochondria during liver injury and natural products that target mitochondrial function processes to prevent or treat liver injury. Our paper may shed insight into novel viewpoint and target for prevention and treatment of liver injury based on NLRP3 inflammasome.

Liver metabonomics study on the protective effect of glycyrrhetinic acid against realgar-induced liver injury.

Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radix et Rhizoma. Our previous study has reported that GA has protective effect on realgar-induced hepatotoxicity. However, the details of the hepatoprotective mechanisms of GA on realgar-induced liver injury remain to be elucidated. In the study, mice were divided into control, GA-control, realgar, and co-treated groups. Their liver tissues were used for metabonomics study by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method. The results illustrate that GA significantly ameliorate the liver injury and metabolic perturbations caused by realgar. Some metabolites, such as phenylalanine, pyroglutamic acid (PGA), proline, carnitine, nicotinamide, choline, lysophosphatidylcholine (LPC) 16 : 0 and LPC 18 : 2 were found responsible for the hepatoprotective effect of GA. These metabolites are associated with the methylation metabolism of arsenic, cell membrane structure, energy metabolism and oxidative stress. From the results of this study, we infer that the potential hepatoprotective mechanism of GA on realgar-induced liver injury may be associated with reducing arsenic accumulation and its methylation metabolism in the liver, promoting the conjugation of arsenic and GSH to play detoxification effect, and ameliorating the liver metabolic perturbations caused by realgar.

Effects of Glycyrrhetinic Acid on GSH Synthesis Induced by Realgar in the Mouse Hippocampus: Involvement of System [Formula: see text], System [Formula: see text], MRP-1, and Nrf2.

Realgar, a type of mineral drug-containing arsenic, exhibits neurotoxicity. Brain glutathione (GSH) is crucial to protect the nervous system and to resist arsenic toxicity. Therefore, the main aim of this study was to explore the neurotoxic mechanisms of realgar and the protective effects of glycyrrhetinic acid (GA) by observing the effects of GA on the hippocampal GSH biosynthetic pathway after exposure to realgar. Institute of Cancer Research (ICR) mice were randomly divided into five groups: a control group, a GA control group, a realgar alone group, a low-dose GA intervention group, and a high-dose GA intervention group. Cognitive ability was tested using an object recognition task (ORT). The ultrastructures of the hippocampal neurons and synapses were observed. mRNA and protein levels of EAAT1, EAAT2, EAAT3, xCT, Nrf2, HO-1, γ-GCS (GCLC, GCLM), and MRP-1 were measured, as was the cellular localization of EAAT3, xCT, MRP-1, and Nrf2. The levels of GSH in the hippocampus, the levels of glutamate (Glu) and cysteine (Cys) in the extracellular fluid of hippocampal CA1 region, and the levels of active sulfur in the brain were also investigated. The results indicate that realgar lowered hippocampal GSH levels, resulting in ultrastructural changes in hippocampal neurons and synapses and deficiencies in cognitive ability, ultimately inducing neurotoxicity. GA could trigger the expression of Nrf2, HO-1, EAAT1, EAAT2, EAAT3, xCT, MRP-1, GCLC, and GCLM. Additionally, the expression of γ-GT and the supply levels of Glu and Cys increased, ultimately causing a significant increase in hippocampal GSH to alleviate realgar-induced neurotoxicity. In conclusion, the findings from our study indicate that GA can antagonize decreased brain GSH levels induced by realgar and can lessen the neurotoxicity of realgar.

Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors.

Realgar is a type of mineral drug containing arsenic. The nervous system toxicity of realgar has received extensive attention. However, the underlying mechanisms of realgar-induced neurotoxicity have not been clearly elucidated. To explore the mechanisms that contribute to realgar-induced neurotoxicity, weanling rats were exposed to realgar (0, 0.3, 0.9, 2.7 g/kg) for 6 weeks, and cognitive ability was tested using the Morris water maze (MWM) test and object recognition task (ORT). The levels of arsenic in the blood and hippocampus were monitored. The ultrastructures of hippocampal neurons were observed. The levels of glutamate (Glu) and glutamine (Gln) in the hippocampus and hippocampal CA1 region; the activities of glutamine synthetase (GS) and phosphate-activated glutaminase (PAG); the mRNA and protein expression of glutamate transporter 1 (GLT-1), glutamate/aspartate transporter (GLAST), and N-methyl-D-aspartate (NMDA) receptors; and the level of intracellular Ca(2+) were also investigated. The results indicate that the rats developed deficiencies in cognitive ability after a 6-week exposure to realgar. The arsenic contained in realgar and the arsenic metabolites passed through the blood-brain barrier (BBB) and accumulated in the hippocampus, which resulted in the excessive accumulation of Glu in the extracellular space. The excessive accumulation of Glu in the extracellular space induced excitotoxicity, which was shown by enhanced GS and PAG activities, inhibition of GLT-1 mRNA and protein expression, alterations in NMDA receptor mRNA and protein expression, disturbance of intracellular Ca(2+) homeostasis, and ultrastructural changes in hippocampal neurons. In conclusion, the findings from our study indicate that exposure to realgar induces excitotoxicity and that the mechanism by which this occurs may be associated with disturbances in Glu metabolism and transportation and alterations in NMDA receptor expression.

[Effect of subchronic realgar exposure on Glu and Gln in infant rat brain].

OBJECTIVE: To study the effect of realgar on Glu and Gln on rat brain tissues. METHODS: Forty-eight Wistar rats were divided into 4 groups randomly:control group,low dosage group, moderate dosage group and high dosage group. The treatment groups were treated with realgar by gastric perfusion at a dosage of 0.3 g/kg, 0.9 g/kg, 2.7 g/kg and the control group ones were orally given the same volume of 0.5% sodium carboxymethylcellulose (CMC-Na) for 6 weeks. The contents of inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in brain tissues were measured by hydride generation-atomic absorption (HG-AAS) method. The contents of amino acid neurotransmitters in brain tissues of rats were determined by means of high performance liquid chromatography with precolumn derivatization. RESULTS: The levels of MMA and DMA in brain increased as the dosage of realgar increased, while the second methylation index declined. Compared with control group,the levels of Glu was significantly decreased in realgar treated group (P < 0.05); Gln also tended to decrease and that of low dosage group was obviously decreased compared with controls. CONCLUSION: Realgar exposure can cause accumulation of MMA and DMA,declination of second methylation index and the reduction of Glu and Gln in brain tissue.