• BMB Reports
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• v.49 no.10
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• pp.529-535
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• 2016

The NLRP3 inflammasome is activated by a variety of external or host-derived stimuli and its activation initiates an inflammatory response through caspase-1 activation, resulting in inflammatory cytokine IL-1β maturation and secretion. The NLRP3 inflammasome activation is a kind of innate immune response, most likely mediated by myeloid cells acting as a host defense mechanism. However, if this activation is not properly regulated, excessive inflammation induced by overactivated NLRP3 inflammasome can be detrimental to the host, causing tissue damage and organ dysfunction, eventually causing several diseases. Previous studies have suggested that mitochondrial damage may be a cause of NLRP3 inflammasome activation and autophagy, which is a conserved self-degradation process that negatively regulates NLRP3 inflammasome activation. Recently, mitochondria-selective autophagy, termed mitophagy, has emerged as a central player for maintaining mitochondrial homeostasis through the elimination of damaged mitochondria, leading to the prevention of hyperinflammation triggered by NLRP3 inflammasome activation. In this review, we will first focus on the molecular mechanisms of NLRP3 inflammasome activation and NLRP3 inflammasome-related diseases. We will then discuss autophagy, especially mitophagy, as a negative regulator of NLPP3 inflammasome activation by examining recent advances in research.

• Journal of Ginseng Research
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• v.44 no.6
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• pp.808-814
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• 2020

Background: Korean Red Ginseng extract (RGE) has been reported to act as an inflammasome modulator. Ginsenosides, saponin molecules of RGE, selectively inhibit activation of NLRP3 and AIM2 inflammasomes, while non-saponin molecules of RGE upregulate inflammasome components associated with the initiation of NLRP3 inflammasome activation. In this study, we investigated the effect of non-saponin components of RGE on AIM2 inflammasome activation. Methods: The role of non-saponins of RGE on AIM2 inflammasomes was tested in mouse bone marrow-derived macrophages, a human monocyte-like cell line, and a mouse animal model. Cells or mice were transfected with dsDNA or inoculated with Listeria monocytogenes to activate AIM2 inflammasomes. Several indices of inflammasome activation were examined via immunoblot or ELISA analysis. Results: The non-saponin fraction and saponin-eliminating fraction (SEF) of RGE selectively attenuated the activation of AIM2 inflammasomes, but not that of NLRP3 or NLRC4 inflammasomes. Fructose-arginine, an amino-sugar, was shown to be effective against AIM2 inflammasome activation. Conclusion: Non-saponins of RGE, such as fructose-arginine, might be effective in regulating infectious and autoimmune diseases resulting from AIM2 inflammasome activation.

• Journal of Life Science
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• v.33 no.4
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• pp.349-356
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• 2023

Gout, a chronic inflammatory arthritic disease, is characterized by hyperuricemia. Gout can be induced by an inflammatory response to monosodium urate (MSU) crystals mediated by pro-inflammatory cytokine release following activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Many sulfur-containing phytochemical compounds in garlic (Allium sativum L.) are considered active ingredients because of their potential pharmacological benefits for various diseases, but their efficacy in NLRP3 inflammasome activation-mediated gout has not been demonstrated. In this study, we investigated whether diallyl disulfide (DADS) and diallyl trisulfide (DATS), representative garlic-derived sulfur compounds, have an inhibitory effect on MSU-induced NLRP3 inflammasome activation. Our results showed that under non-cytotoxic conditions, DADS and DATS significantly blocked nitric oxide production and interleukin (IL)-1β release in response to MSU in lipopolysaccharide (LPS)-primed RAW 264.7 macrophages. DADS and DATS also attenuated enhanced expression of NLRP3 and its adapter protein, apoptosis-associated speck-like protein, which was associated with downregulation of and caspase-1 p20 and IL-1β expression, suggesting that MSU-induced LRP3 inflammasome activation was counteracted by DADS and DATS. Furthermore, DADS and DATS blocked oxidative stress, an upstream event for NLRP3 inflammasome activation, as evidenced by the fact that they scavenged reactive oxygen species (ROS) production. Taken together, our findings demonstrate that DADS and DATS suppressed NLRP3 inflammasome activation by inhibiting the ROS/NLRP3 pathway and that they have potential as treatments for NLRP3-dependent gouty arthritis.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.331-336
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• 2022

Coronavirus disease 2019 (COVID-19) exhibits various symptoms, ranging from asymptomatic to severe pneumonia or death. The major features of patients in severe COVID-19 are the dysregulation of cytokine secretion, pneumonia, and acute lung injury. Consequently, it leads to acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ failure, and death. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, influences nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3), the sensor of inflammasomes, directly or indirectly, culminating in the assembly of NLRP3 inflammasome and activation of inflammatory caspases, which induce the inflammatory disruption in severe COVID-19. Accordingly, the target therapeutics for inflammasome has attracted attention as a treatment for COVID-19. Korean Red Ginseng (KRG) inhibits several inflammatory responses, including the NLRP3 inflammasome signaling. This review discusses the role of KRG in the treatment and prevention of COVID-19 based on its anti-NLRP3 inflammasome efficacy.

• Journal of Ginseng Research
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• v.46 no.6
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• pp.722-730
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• 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogenic virus that causes coronavirus disease 2019 (COVID-19), with major symptoms including hyper-inflammation and cytokine storm, which consequently impairs the respiratory system and multiple organs, or even cause death. SARS-CoV-2 activates inflammasomes and inflammasome-mediated inflammatory signaling pathways, which are key determinants of hyperinflammation and cytokine storm in COVID-19 patients. Additionally, SARS-CoV-2 inhibits inflammasome activation to evade the host's antiviral immunity. Therefore, regulating inflammasome initiation has received increasing attention as a preventive measure in COVID-19 patients. Ginseng and its major active constituents, ginsenosides and saponins, improve the immune system and exert anti-inflammatory effects by targeting inflammasome stimulation. Therefore, this review discussed the potential preventive and therapeutic roles of ginseng in COVID-19 based on its regulatory role in inflammasome initiation and the host's antiviral immunity.

• Journal of Ginseng Research
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• v.41 no.4
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• pp.513-523
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• 2017

Background: Korean Red Ginseng extracts (RGE) have been suggested as effective immune modulators, and we reported that ginsenosides possess anti-inflammasome properties. However, the properties of nonsaponin components of RGE have not been well studied. Methods: To assess the roles of nonsaponin fractions (NS) in NLRP3 inflammasome activation, we treated murine macrophages with or without first or second inflammasome activation signals with RGE, NS, or saponin fractions (SF). The first signal was nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$)-mediated transcription of pro-interleukin (IL)-$1{\beta}$ and NLRP3 while the second signal triggered assembly of inflammasome components, leading to IL-$1{\beta}$ maturation. In addition, we examined the role of NS in IL-6 production and IL-$1{\beta}$ maturation in mice. Results: NS induced IL-$1{\beta}$ and NLRP3 transcription via toll-like receptor 4 signaling, whereas SF blocked expression. During the second signal, SF attenuated NLRP3 inflammasome activation while NS did not. Further, NS-injected mice presented increased IL-$1{\beta}$ maturation and IL-6 production. Conclusion: SF and NS of RGE play differential roles in the NLRP3 inflammasome activation. Hence, RGE can be suggested as an NLRP3 inflammasome modulator.

• 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.

• Parasites, Hosts and Diseases
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• v.54 no.6
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• pp.711-717
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• 2016

Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of $pro-IL-1{\beta}$. To elucidate the role of inflammasome components in T. gondiiinfected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine $IL-1{\beta}$ secretion. The results revealed a significant upregulation of $IL-1{\beta}$ after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time-dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection.

• Molecules and Cells
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• v.37 no.6
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• pp.441-448
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• 2014

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multiprotein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-$1{\beta}$ and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-${\kappa}B$-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 ($P2X_7R$), which results in $K^+$ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

• 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.