Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

Molagoda, Ilandarage Menu Neelaka; Athapaththu, Athapaththu Mudiyanselage Gihan Kavinda; Choi, Yung Hyun; Park, Cheol; Jin, Cheng-Yung; Kang, Chang‐Hee; Lee, Mi-Hwa; Kim, Gi‐Young

doi:10.3390/antiox10081215

Cited by 20 publications

(12 citation statements)

References 46 publications

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“…Here, we demonstrated that endometriosis in rats caused the activation of NLRP3 and NF-κB pathways as well as the increase in levels of IL-1β and TNF-α, while fisetin inhibited the activation of NLRP3/NF-κB as well as diminished the levels of IL-1β and TNF-α. These results are in agreement with several works that showed that fisetin treatment was able to reduce the NF-κB/NLRP3 pathway as well as reduce the release of proinflammatory cytokines [ 15 , 57 , 58 ].…”

Section: Discussionsupporting

confidence: 93%

Fisetin, a Natural Polyphenol, Ameliorates Endometriosis Modulating Mast Cells Derived NLRP-3 Inflammasome Pathway and Oxidative Stress

Arangia

Marino

Fusco

et al. 2023

IJMS

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A chronic, painful, and inflammatory condition known as endometriosis is defined by the extra-uterine development of endometrial tissue. The aim of this study was to evaluate the beneficial effects of fisetin, a naturally occurring polyphenol that is frequently present in a variety of fruits and vegetables. Uterine fragments were injected intraperitoneally to cause endometriosis, and fisetin was given orally every day. At 14 days of treatment, laparotomy was performed, and the endometrial implants and peritoneal fluids were collected for histological, biochemical, and molecular analyses. Rats subjected to endometriosis presented important macroscopic and microscopic changes, increased mast cell (MC) infiltration, and fibrosis. Fisetin treatment reduced endometriotic implant area, diameter, and volumes, as well as histological alterations, neutrophil infiltration, cytokines release, the number of MCs together with the expression of chymase and tryptase, and diminished α smooth muscle actin (α-sma) and transforming growth factor beta (TGF β) expressions. In addition, fisetin was able to reduce markers of oxidative stress as well as nitrotyrosine and Poly ADP ribose expressions and increase apoptosis in endometrial lesions. In conclusion, fisetin could represent a new therapeutic strategy to control endometriosis perhaps by targeting the MC-derived NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway and oxidative stress.

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Section: Discussionsupporting

confidence: 93%

Fisetin, a Natural Polyphenol, Ameliorates Endometriosis Modulating Mast Cells Derived NLRP-3 Inflammasome Pathway and Oxidative Stress

Arangia

Marino

Fusco

et al. 2023

IJMS

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“…RAW 264.7 macrophages were seeded at a density of 1 × 10 5 cells/ml in 8-well chamber slides. Prior to exposure to LPS (500 ng/mL) for 24 h, DHP (0–25 μM) or MitoTEMPO (10 μM) was treated for 2 h. The cells were then stained with MitoTracker Green (0.5 μM) for 30 min and counterstained with 2 μM MitoSOX Red for 10 min . In parallel, LPS (0.5 mg/mL, 2 nL in each larva) or PBS was microinjected in the yolk of 3 dpf zebrafish larvae ( n = 20), and the larvae were immediately immersed in embryo medium with DHP (25 μM) or MitoTEMPO (10 μM).…”

Section: Materials and Methodsmentioning

confidence: 99%

“…RAW 264.7 macrophages were seeded at a density of 1 × 10 5 cells/mL in six-well plates and treated with 25 μM DHP, 10 μM MitoTEMPO, or 10 μM TLR4-IN-C34 for 2 h, followed by treatment with 500 ng/mL LPS for an additional 2 h. The cells were then washed with ice-cold PBS and stained using the Muse MitoPotential Kit (Luminex) for 20 min . A Muse cell analyzer was used to measure the mitochondrial membrane potential of the cells exhibiting depolarization.…”

Section: Materials and Methodsmentioning

confidence: 99%

2,4′-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation

Kavinda,

Choi,

Kang

et al. 2024

ACS Pharmacol. Transl. Sci.

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The biochemical properties of 2,4′-dihydroxybenzophenone (DHP) have not been extensively studied. Therefore, this study aimed to investigate whether DHP could alleviate inflammatory responses induced by lipopolysaccharide (LPS) and endotoxemia. The results indicated that DHP effectively reduced mortality and morphological abnormalities, restored heart rate, and mitigated macrophage and neutrophil recruitment to inflammatory sites in LPS-microinjected zebrafish larvae. Additionally, the expression of pro-inflammatory mediators, including inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12), was significantly reduced in the presence of DHP. In RAW 264.7 macrophages, DHP inhibited the LPSinduced inflammatory response by downregulating pro-inflammatory mediators and decreasing the expression of myeloid differentiation primary response 88 (MyD88), phosphorylation of IL-1 receptor-associated protein kinase-4 (p-IRAK4), and nuclear factor-κB (NF-κB). Molecular docking analysis demonstrated that DHP occupies the hydrophobic pocket of myeloid differentiation factor 2 (MD2) and blocks the dimerization of Toll-like receptor 4 (TLR4). A molecular dynamics simulation confirmed that DHP stably bound to the hydrophobic pocket of MD2. Furthermore, the DHP treatment inhibited mitochondrial reactive oxygen species (mtROS) production during the LPS-induced inflammatory response in both RAW 264.7 macrophages and zebrafish larvae, which was accompanied by stabilizing mitochondrial membrane potential. In conclusion, our study highlights the therapeutic potential of DHP in alleviating LPS-induced inflammation and endotoxemia. The findings suggest that DHP exerts its anti-inflammatory effects by inhibiting the TLR4/MD2 signaling pathway and reducing the level of mtROS production. These results contribute to a better understanding of the biochemical properties of DHP and support its further exploration as a potential therapeutic agent for inflammatory conditions and endotoxemia.

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“…LPS is usually used to induce inflammation. The LPS+ATP-treated cells showed obvious pyroptosis, which is the classic pyroptosis model [57,58]. Here, PC12 cells were treated with LPS at different times and ATP for 1 hour to generate an inflammation-related pyroptosis model, which was utilized to assess the expression of HSF1 and NLRP3 in the classic pyroptosis model (Figure 5(a)).…”

Section: Hsf1 Negatively Regulated Nlrp3 and Pyroptosis In Pc12 Cellsmentioning

confidence: 99%

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

et al. 2023

Mediators of Inflammation

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Background. Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient’s prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective. NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods. In this study, we used wild-type mice and hsf1-/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results. The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1-/- mouse model compared to hsf1+/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion. These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

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Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

Cited by 20 publications

References 46 publications

Fisetin, a Natural Polyphenol, Ameliorates Endometriosis Modulating Mast Cells Derived NLRP-3 Inflammasome Pathway and Oxidative Stress

Fisetin, a Natural Polyphenol, Ameliorates Endometriosis Modulating Mast Cells Derived NLRP-3 Inflammasome Pathway and Oxidative Stress

2,4′-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

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