• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.40-47
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• 2023

Activation of the NLRP3 inflammasome is a necessary process to induce fibrosis in nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is a kind of NAFLD that encompasses the spectrum of liver disease. It is characterized by inflammation and ballooning of hepatocytes during steatosis. We tested whether inhibiting the NLRP3 inflammasome could prevent the development and pathology of NASH. We identified loganin as an inhibitor of the NLRP3 inflammasome and investigated whether in vivo administration of loganin prevented NASH symptoms using a methionine-choline deficient (MCD) diet model in mice. We found that loganin inhibited the NLRP3 inflammasome activation triggered by ATP or nigericin, as shown by suppression of the production of interleukin (IL)-1β and caspase-1 (p10) in mouse primary macrophages. The speck formation of apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) was blocked by loganin, showing that the assembly of the NLRP3 inflammasome complex was impaired by loganin. Administration of loganin reduced the clinical signs of NASH in mice fed the MCD diet, including hepatic inflammation, fat accumulation, and fibrosis. In addition, loganin reduced the expression of NLRP3 inflammasome components in the liver. Our findings indicate that loganin alleviates the inflammatory symptoms associated with NASH, presumably by inhibiting NLRP3 inflammasome activation. In summary, these findings imply that loganin may be a novel nutritional and therapeutic treatment for NASH-related inflammation.

• BMB Reports
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• v.54 no.5
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• pp.260-265
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• 2021

Dysregulation of inflammation induced by noninfectious stress conditions, such as nutrient deprivation, causes tissue damage and intestinal permeability, resulting in the development of inflammatory bowel diseases. We studied the effect of autophagy on cytokine secretion related to intestinal permeability under nutrient deprivation. Autophagy removes NLRP3 inflammasomes via ubiquitin-mediated degradation under starvation. When autophagy was inhibited, starvation-induced NLRP3 inflammasomes and their product, IL-1β, were significantly enhanced. A prolonged nutrient deprivation resulted in an increased epithelial mesenchymal transition (EMT), leading to intestinal permeability. Under nutrient deprivation, IL-17E/25, which is secreted by IL-1β, demolished the intestinal epithelial barrier. Our results suggest that an upregulation of autophagy maintains the intestinal barrier by suppressing the activation of NLRP3 inflammasomes and the release of their products, including pro-inflammatory cytokines IL-1β and IL-17E/25, under nutrient deprivation.

• BMB Reports
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• v.54 no.11
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• pp.557-562
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• 2021

Microglial activation is closely associated with neuroinflammatory pathologies. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasomes are highly organized intracellular sensors of neuronal alarm signaling. NLRP3 inflammasomes activate nuclear factor kappa-B (NF-κB) and reactive oxygen species (ROS), which induce inflammatory responses. Moreover, NLRP3 dysfunction is a common feature of chronic inflammatory diseases. The present study investigated the effect of a novel thiazol derivative, N-cyclooctyl-5-methylthiazol-2-amine hydrobromide (KHG26700), on inflammatory responses in lipopolysaccharide (LPS)-treated BV-2 microglial cells. KHG26700 significantly attenuated the expression of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in these cells, as well as the LPS-induced increases in NLRP3, NF-κB, and phospho-IkBα levels. KHG26700 also suppressed the LPS-induced increases in protein levels of autophagy protein 5 (ATG5), microtubule-associated protein 1 light chain 3 (LC3), and beclin-1, as well as downregulating the LPS-enhanced levels of ROS, lipid peroxidation, and nitric oxide. These results suggest that the anti-inflammatory effects of KHG26700 may be due, at least in part, to the regulation of the NLRP3-mediated signaling pathway during microglial activation.

• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.437-442
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• 2020

Activation of the NLRP3 inflammasome is critical for host defense as well as the progression of inflammatory diseases through the production of the proinflammatory cytokine IL-1β, which is cleaved by active caspase-1. It has been reported that overactivation of the NLRP3 inflammasome contributes to the development and pathology of acne vulgaris. Therefore, inhibiting activation of the NLRP3 inflammasome may provide a new therapeutic strategy for acne vulgaris. In this study, we investigated whether auranofin, an anti-rheumatoid arthritis agent, inhibited NLRP3 inflammasome activation, thereby effectively treating acne vulgaris. Auranofin suppressed NLRP3 inflammasome activation induced by Propionibacterium acnes, reducing the production of IL-1β in primary mouse macrophages and human sebocytes. In a P. acnes-induced acne mouse model, injection of P. acnes into the ears of mice induced acne symptoms such as redness, swelling, and neutrophil infiltration. Topical application of auranofin (0.5 or 1%) to mouse ears significantly reduced the inflammatory symptoms of acne vulgaris induced by P. acnes injection. Topical application of auranofin led to the downregulation of the NLRP3 inflammasome activated by P. acnes in mouse ear skin. These results show that auranofin inhibits the NLRP3 inflammasome, the activation of which is associated with acne symptoms. The results further suggest that topical application of auranofin could be a new therapeutic strategy for treating acne vulgaris by targeting the NLRP3 inflammasome.

• International Journal of Oral Biology
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• v.42 no.3
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• pp.85-90
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• 2017

Mitochondria participate in various intracellular metabolic pathways such as generating intracellular ATP, synthesizing several essential molecules, regulating calcium homeostasis, and producing the cell's reactive oxygen species (ROS). Emerging studies have demonstrated newly discovered roles of mitochondria, which participate in the regulation of innate immune responses by modulating NLRP3 inflammasomes. Here, we review the recently proposed pathways to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation: 1) mitochondrial ROS, 2) calcium mobilization, 3) nicotinamide adenine dinucleotide ($NAD^+$) reduction, 4) cardiolipin, 5) mitofusin, 6) mitochondrial DNA, 7) mitochondrial antiviral signaling protein. Furthermore, we highlight the significance of mitophagy as a negative regulator of mitochondrial damage and NLRP3 inflammasome activation, as potentially helpful therapeutic approaches which could potentially address uncontrolled inflammation.

• Nutrition Research and Practice
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• v.13 no.5
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• pp.377-383
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• 2019

BACKGROUND/OBJECTIVES: Hyperglycemia-induced hepatic damage has been recognized as one of the major cause of complications in diabetes. Hepatic complications are associated with inflammation and oxidative stress in diabetes. In this study, we investigated the hypothesis that gamma-tocopherol (GT) supplementation ameliorates NLRP3 inflammasome associated hepatic inflammation in diabetes. MATERIALS/METHODS: Diabetes was induced by the intraperitoneal injection of alloxan (150 mg/kg. BW) in ICR mice. All mice were fed with a control diet (AIN-76A). After diabetes was induced (fasting glucose level ${\geq}250mg/dL$), the mice were treated with tocopherol-stripped corn oil or GT-supplemented (35 mg/kg) corn oil, respectively, by gavage for 2 weeks. RESULTS: GT supplementation reduced fasting blood glucose levels in diabetic mice relative to non-treated diabetic mice. Moreover, GT supplementation ameliorated hyperglycemia-induced hepatic damage by regulation of NOD-like receptor protein 3 (NLRP3)-inflammasome associated inflammation represented by NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain, caspase-1, nuclear $factor-{\kappa}B$ pathway as well as oxidative stress demonstrated by nuclear factor erythroid 2-related factor 2, NAD(P)H dehydrogenase quinone 1, catalase and glutathione-dependent peroxidase in diabetic mice. CONCLUSION: The findings suggested that GT supplementation ameliorated hepatic damage by attenuating inflammation and oxidative stress in alloxan-induced diabetic mice. Taken together, GT could be a beneficial nutrient that can ameliorate inflammatory responses associated with NLRP3 inflammasome in hyperglycemia-induced hepatic damage.

• Journal of Ginseng Research
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• v.47 no.1
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• pp.23-32
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• 2023

Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by a severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). SARS-CoV-2 infection may cause clinical manifestations of multiple organ damage, including various neurological syndromes. There are currently two oral antiviral drugs-Paxlovid and molnupiravir-that are recognized to treat COVID-19, but there are still no drugs that can specifically fight the challenges of SARS-CoV-2 variants. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is a multimolecular complex that can sense heterogeneous pathogen-associated molecular patterns associated with neurological disorders. The NLRP3 activation stimulates the production of caspase-1-mediated interleukin (IL)-1β, IL-18, and other cytokines in immune cells. Panax (P.) ginseng is a medicinal plant that has traditionally been widely used to boost immunity and treat various pathological conditions in the nervous system due to its safety and anti-inflammatory/oxidant/viral activities. Several recent reports have indicated that P. ginseng and its active ingredients may regulate NLRP3 inflammasome activation in the nervous system. Therefore, this review article discusses the current knowledge regarding the pathogenesis of neurological disorders related to COVID-19 and NLRP3 inflammasome activation and the possibility of using P. ginseng in a strategy targeting this pathway to treat neurological disorders.

• Journal of Korean Neurosurgical Society
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• v.63 no.6
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• pp.689-697
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• 2020

Objective : Cerebral edema is the predominant mechanism of secondary inflammation after intracerebral hemorrhage (ICH). Pioglitazone, peroxisome proliferator-activated receptor gamma agonist has been shown to play a role in regulation of central nervous system inflammation. Here, we examined the pharmacological effects of pioglitazone in an ICH mouse model and investigated its regulation on NLRP3 inflammasome and glucose metabolism. Methods : The ICH model was established in C57 BL/6 mice by the stereotactical inoculation of blood (30 µL) into the right frontal lobe. The treatment group was administered i.p. pioglitazone (20 mg/kg) for 1, 3, and 6 days. The control group was administered i.p. phosphate-buffered saline for 1, 3, and 6 days. We investigated brain water contents, NLRP3 expression, and changes in the metabolites in the ICH model using liquid chromatography-tandem mass spectrometry. Results : On day 3, brain edema in the mice treated with pioglitazone was decreased more than that in the control group. Expression levels of NLRP3 in the ICH model treated with pioglitazone were decreased more than those of the control mice on days 3 and 7. The pioglitazone group showed higher levels of glycolytic metabolites than those in the ICH mice. Lactate production was increased in the ICH mice treated with pioglitazone. Conclusion : Our results demonstrated less brain swelling following ICH in mice treated with pioglitazone. Pioglitazone decreased NLRP3-related brain edema and increased anaerobic glycolysis, resulting in the production of lactate in the ICH mice model. NLRP3 might be a therapeutic target for ICH recovery.

• Asian-Australasian Journal of Animal Sciences
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• v.26 no.4
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• pp.455-462
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• 2013

NLR family pyrin domain containing 3 (NLRP3) is a key component of the inflammasome, whose assembly is a crucial part of the innate immune response. The aim of the present study was to evaluate the association between exon 3 polymorphisms of NLRP3 and the susceptibility to digestive disorders in rabbits. In total, five coding single-nucleotide polymorphisms (cSNPs) were identified; all of which are synonymous. Among them, c.456 C> and c.594 G> were further genotyped for association analysis based on case-control design (n =162 vs n =102). Meanwhile, growing rabbits were experimentally induced to digestive disorders by feeding a fiber-deficient diet, subsequently they were subjected to mRNA expression analysis. Association analysis revealed that haplotype H1 (the two cSNPs: GT) played a potential protective role against digestive disorders (p<0.001). The expression of NLRP3 in the group $H1HX_1$ ($H1HX_1$ is composed of H1H1, H1H3 and H1H4) was the lowest among four groups which were classified by different types of diplotypes. Those results suggested that the NLRP3 gene was significantly associated with susceptibility to digestive disorders in rabbit.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.6
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• pp.533-543
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• 2021

Myocardial fibrosis (MF) is the result of persistent and repeated aggravation of myocardial ischemia and hypoxia, leading to the gradual development of heart failure of chronic ischemic heart disease. Triptolide (TPL) is identified to be involved in the treatment for MF. This study aims to explore the mechanism of TPL in the treatment of MF. The MF rat model was established, subcutaneously injected with isoproterenol and treated by subcutaneous injection of TPL. The cardiac function of each group was evaluated, including LVEF, LVFS, LVES, and LVED. The expressions of ANP, BNP, inflammatory related factors (IL-1β, IL-18, TNF-α, MCP-1, VCAM1), NLRP3 inflammasome factors (NLRP3, ASC) and fibrosis related factors (TGF-β1, COL1, and COL3) in rats were dete cted. H&E staining and Masson staining were used to observe myocardial cell inflammation and fibrosis of rats. Western blot was used to detect the p-P65 and t-P65 levels in nucleoprotein of rat myocardial tissues. LVED and LVES of MF group were significantly upregulated, LVEF and LVFS were significantly downregulated, while TPL treatment reversed these trends; TPL treatment downregulated the tissue injury and improved the pathological damage of MF rats. TPL treatment downregulated the levels of inflammatory factors and fibrosis factors, and inhibited the activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome or NF-κB pathway reversed the effect of TPL on MF. Collectively, TPL inhibited the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, and improved MF in MF rats.