Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF-κB Pathway and NLRP3 Inflammasome

Inflammation is a complex response to diverse pathological conditions, resulting in negative rather than protective effects when uncontrolled. Orientin (Ori), a flavonoid component isolated from natural plants, possesses abundant properties. Thus, we aimed to discover the potential therapeutic effects of orientin on lipopolysaccharide- (LPS-) induced inflammation in RAW 264.7 cells and the underlying mechanisms. In our studies, we evaluated the effects of Ori on proinflammatory mediator production stimulated by LPS, including tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-18, and IL-1β, along with prostaglandin E2 (PGE2) and NO. Our data indicated that orientin dramatically inhibited the levels of these mediators. Consistent with these results, the expression levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were also reduced. Further study demonstrated that such inhibitory effects of Ori were due to suppression of the nuclear factor-kappa B (NF-κB) pathway and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) inflammasome activation, which may contribute to its anti-inflammatory effects. Together, these findings show that Ori may be an effective candidate for ameliorating LPS-induced inflammatory responses.

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Bisphenol A disrupts inflammatory responses via Nod-like receptor protein 3 pathway in macrophages

Applied Biological Chemistry ◽

10.1186/s13765-020-00562-6 ◽

2020 ◽

Vol 63 (1) ◽

Author(s):

Hee-Weon Lee ◽

Sang Keun Ha ◽

Yoonsook Kim

Keyword(s):

Bisphenol A ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Receptor Protein ◽

Prostaglandin E ◽

Inflammasome Activation ◽

No Production ◽

Dental Resins ◽

Nlrp3 Inflammasome Activation ◽

Mitogen Activated Protein

AbstractBisphenol A (BPA) is a harmful endocrine disruptor that is found in polycarbonate plastics such as plastic food containers and in epoxy resins such as dental resins. In the current study, we investigated the effect of BPA on function of inflammatory responses involving activation of Nod-like receptor protein 3 (NLRP3) inflammasome. Treatment with BPA decreased nitric oxide (NO) production and expression levels of inducible NO synthase (iNOS), prostaglandin E2 (PGE2), and cyclooxygenase (Cox)-2 in RAW 264.7 macrophages. BPA also suppressed activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B activity (NF-κB). BPA significantly down-regulated the secretion of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18. The decreased production of IL-1β and IL-18 induced by BPA was associated with inactivation of the activity of the NLRP3 inflammasome. Collectively, these data suggested that BPA could act as a disruptor of the inflammation activity by regulating the NF-κB/MAPK pathways and NLRP3 inflammasome activation.

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Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

Frontiers in Pharmacology ◽

10.3389/fphar.2020.622074 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yufei Luo ◽

Bojun Xiong ◽

Haiping Liu ◽

Zehong Chen ◽

Huihui Huang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Inhibitory Effect ◽

Receptor Protein ◽

Mechanistic Study ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

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Coixol Suppresses NF-κB, MAPK Pathways and NLRP3 Inflammasome Activation in Lipopolysaccharide-Induced RAW 264.7 Cells

Molecules ◽

10.3390/molecules25040894 ◽

2020 ◽

Vol 25 (4) ◽

pp. 894 ◽

Cited By ~ 3

Author(s):

Yusheng Hu ◽

Qilyu Zhou ◽

Tianlong Liu ◽

Zhongjie Liu

Keyword(s):

Nitric Oxide ◽

Nlrp3 Inflammasome ◽

Cell Model ◽

Receptor Protein ◽

Raw 264.7 Cells ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Coixol, a plant polyphenol extracted from coix (Coix lachryma-jobi L.var.ma-yuen Stapf), has not been investigated for its anti-inflammatory effect. In this study, using a lipopolysaccharide (LPS)-induced macrophage cell model, we observed that coixol can effectively reduce the expression of interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthases (iNOS), and cyclooxygenase (COX)-2, but had no effect on the expression of the anti-inflammatory mediator IL-10. Furthermore, we found that coixol inhibits mitogen-activated protein kinases (MAPKs), nuclear transcription factor κ B (NF-κB) pathways, and NOD-like receptor protein (NLRP) 3 inflammasome activation. In conclusion, the present study demonstrates that coixol exerts certain anti-inflammatory effects by inhibiting the expression of pro-inflammatory mediators in vitro. The mechanism of this effect was in part related to its ability to inhibit the activation of NF-κB, MAPKs pathways, and NLRP3 inflammasome.

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NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis

International Journal of Molecular Sciences ◽

10.3390/ijms20143466 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3466 ◽

Cited By ~ 4

Author(s):

Francesca Bonomini ◽

Mariane Dos Santos ◽

Francisco Veríssimo Veronese ◽

Rita Rezzani

Keyword(s):

Oxidative Stress ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Morphological Alteration ◽

Inflammasome Activation ◽

Protective Effects ◽

Nlrp3 Inflammasome Activation

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

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LncRNA Gm14205 induces astrocytic NLRP3 inflammasome activation via inhibiting oxytocin receptor in postpartum depression

Bioscience Reports ◽

10.1042/bsr20200672 ◽

2020 ◽

Vol 40 (8) ◽

Author(s):

Jialei Zhu ◽

Jing Tang

Keyword(s):

Postpartum Depression ◽

Nlrp3 Inflammasome ◽

Oxytocin Receptor ◽

Pathological Process ◽

Receptor Protein ◽

Inflammasome Activation ◽

Protective Effects ◽

Nlrp3 Inflammasome Activation ◽

New Strategy ◽

Non Coding Rnas

Abstract Postpartum depression (PPD) is a kind of mental disorder characterized by persistent low emotions in puerperium. The most significant physiological change in postpartum is lactation which is regulated by oxytocin receptor (OXTR). However, whether OXTR is related to pathological process of PPD and the potential mechanism still remain unclear. In the present study, we prepared hormone-simulated pregnancy (HSP)-induced PPD mouse model and found that the protein level of OXTR in hippocampus of PPD model mice was down-regulated and Nod-like receptor protein 3 (NLRP3) inflammasome was activated. We identified five long non-coding RNAs (lncRNAs) related to PPD by transcriptome sequencing, including three up-regulated and two down-regulated. The five lncRNAs were associated with the signaling pathway of OXTR according to the bioinformatics analysis. Furthermore, we focused on one of the five lncRNAs, Gm14205, and found that it targeted OXTR which inhibited astrocytic NLRP3 inflammasome activation in hippocampal primary astrocytes. These findings illustrate that OXTR has protective effects in PPD by inhibiting NLRP3 inflammasome activation and provides a new strategy for targeting lncRNA Gm14205 in the pathogenesis of PPD.

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Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7385458 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17

Author(s):

Wenli Yu ◽

Jingshu Lyu ◽

Lili Jia ◽

Mingwei Sheng ◽

Hongli Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion ◽

Mitochondrial Protein ◽

Receptor Protein ◽

Inflammasome Activation ◽

Protective Effects ◽

Hepatic Ischemia ◽

Nlrp3 Inflammasome Activation ◽

Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion (HIR) has been proven to trigger oxidative stress and pyroptosis in the hippocampus. Sirtuin 3 (SIRT3) is an essential mitochondrial protein deacetylase regulating oxidative stress and mitophagy. Dexmedetomidine (Dex) has been demonstrated to confer neuroprotection in different brain injury models. However, whether the protective effects of Dex following HIR are orchestrated by activation of SIRT3-mediated mitophagy and inhibition of NOD-like receptor protein 3 (NLRP3) inflammasome activation remains unknown. Herein, two-week-old rats were treated with Dex or a selective SIRT3 inhibitor (3-TYP)/autophagy inhibitor (3-MA) and then subjected to HIR. The results revealed that Dex treatment effectively attenuated neuroinflammation and cognitive deficits via upregulating SIRT3 expression and activity. Furthermore, Dex treatment inhibited the activation of NLRP3 inflammasome, while 3-TYP and 3-MA eliminated the protective effects of Dex, suggesting that SIRT3-mediated mitophagy executes the protective effects of Dex. Moreover, 3-TYP treatment downregulated the expression level of SIRT3 downstream proteins: forkhead-box-protein 3α (FOXO3α), superoxide dismutase 2 (SOD2), peroxiredoxin 3 (PRDX3), and cyclophilin D (CYP-D), which were barely influenced by 3-MA treatment. Notably, both 3-TYP and 3-MA were able to offset the antioxidative and antiapoptosis effects of Dex, indicating that SIRT3-mediated mitophagy may be the last step and the major pathway executing the neuroprotective effects of Dex. In conclusion, Dex inhibits HIR-induced NLRP3 inflammasome activation mainly by triggering SIRT3-mediated mitophagy.

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Loganin Attenuates High Glucose-Induced Schwann Cells Pyroptosis by Inhibiting ROS Generation and NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells9091948 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1948

Author(s):

Yu-Chi Cheng ◽

Li-Wen Chu ◽

Jun-Yih Chen ◽

Su-Ling Hsieh ◽

Yu-Chin Chang ◽

...

Keyword(s):

Schwann Cell ◽

Nlrp3 Inflammasome ◽

High Glucose ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Purinergic Receptor ◽

Receptor Protein ◽

Ros Generation ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

Diabetic peripheral neuropathy (DPN) is caused by hyperglycemia, which induces oxidative stress and inflammatory responses that damage nerve tissue. Excessive generation of reactive oxygen species (ROS) and NOD-like receptor protein 3 (NLRP3) inflammasome activation trigger the inflammation and pyroptosis in diabetes. Schwann cell dysfunction further promotes DPN progression. Loganin has been shown to have antioxidant and anti-inflammatory neuroprotective activities. This study evaluated the neuroprotective effect of loganin on high-glucose (25 mM)-induced rat Schwann cell line RSC96 injury, a recognized in vitro cell model of DPN. RSC96 cells were pretreated with loganin (0.1, 1, 10, 25, 50 μM) before exposure to high glucose. Loganin’s effects were examined by CCK-8 assay, ROS assay, cell death assay, immunofluorescence staining, quantitative RT–PCR and western blot. High-glucose-treated RSC96 cells sustained cell viability loss, ROS generation, NF-κB nuclear translocation, P2 × 7 purinergic receptor and TXNIP (thioredoxin-interacting protein) expression, NLRP3 inflammasome (NLRP3, ASC, caspase-1) activation, IL-1β and IL-18 maturation and gasdermin D cleavage. Those effects were reduced by loganin pretreatment. In conclusion, we found that loganin’s antioxidant effects prevent RSC96 Schwann cell pyroptosis by inhibiting ROS generation and suppressing NLRP3 inflammasome activation.

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H3 Relaxin Alleviates Migration, Apoptosis and Pyroptosis Through P2X7R-Mediated Nucleotide Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation in Retinopathy Induced by Hyperglycemia

Frontiers in Pharmacology ◽

10.3389/fphar.2020.603689 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kelaier Yang ◽

Jiannan Liu ◽

Xiaohui Zhang ◽

Ziqi Ren ◽

Lei Gao ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inhibitory Effect ◽

Receptor Protein ◽

Inflammasome Activation ◽

Sprague Dawley ◽

Nlrp3 Inflammasome Activation ◽

Underlying Mechanisms ◽

And Migration

Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown.Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome.Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.

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SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

Nature Communications ◽

10.1038/s41467-021-25015-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pan Pan ◽

Miaomiao Shen ◽

Zhenyang Yu ◽

Weiwei Ge ◽

Keli Chen ◽

...

Keyword(s):

Lung Injury ◽

Nlrp3 Inflammasome ◽

Cultured Cells ◽

Inflammatory Responses ◽

Specific Inhibitor ◽

Inflammasome Activation ◽

N Protein ◽

Distinct Mechanism ◽

Nlrp3 Inflammasome Activation ◽

Proinflammatory Responses

AbstractExcessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

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