Taxifolin alleviates FCA-induced arthritis via regulating the Th1/Th2 balance, and down-regulates NLRP3 inflammasome axis activation in Jurkat T cells

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory joint disease mediated by T cells. In traditional Chinese medicine, Smilacis Glabrae Rhizoma is commonly used to treat deoxidation, dampness and ease joint movement. One of its active components, a flavonoid called taxifolin, has been the focus of several studies in recent years. However, the pharmacological action of taxifolin in the development of RA remains unknown. Here, we investigated the therapeutic effects of taxifolin on Freund's complete adjuvant (FCA)-induced arthritis model, and then verified the underlying immunoregulatory mechanisms of taxifolin on activated Jurkat T cells. Taxifolin ameliorated the physical signs including paw volume (PV), arthritis index (AI) and body weight (BW) and reduced the organ coefficients (spleen and thymus) in FCA-induced rats, as well as the inflammatory responses in the left hind paw and plasma. The results also showed that taxifolin greatly improved the imbalance of T helper (Th)1/Th2 status in the plasma and spleen. Further, the Th1/Th2 imbalance status and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in the activated Jurkat T cells was inhibited significantly by taxifolin. In conclusion, these results suggested that taxifolin potentially targeted the Th1/Th2 status and NLRP3 inflammasome axis in T cells, contributing valuable insights to elucidating the mechanism of action of taxifolin for future studies on RA therapeutics.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/2495496 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Qingfei Xiao ◽

Zhihui Qu ◽

Ying Zhao ◽

Liming Yang ◽

Pujun Gao

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Receptor Protein ◽

Raw 264.7 Cells ◽

Prostaglandin E ◽

Inflammasome Activation ◽

Therapeutic Effects ◽

Protective Effects ◽

Nlrp3 Inflammasome Activation ◽

Underlying Mechanisms

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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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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Therapeutic Effects of Dipterocarpus tuberculatus with High Antioxidative Activity Against UV-Induced Photoaging of NHDF Cells and Nude Mice

Antioxidants ◽

10.3390/antiox10050791 ◽

2021 ◽

Vol 10 (5) ◽

pp. 791

Author(s):

Su Jin Lee ◽

Ji Eun Kim ◽

Yun Ju Choi ◽

Jeong Eun Gong ◽

So Hae Park ◽

...

Keyword(s):

Nude Mice ◽

Dermal Fibroblast ◽

Radical Scavenging Activity ◽

Radical Scavenging ◽

Inflammasome Activation ◽

Therapeutic Effects ◽

Asiatic Acid ◽

Active Components ◽

Normal Human Dermal Fibroblast ◽

Sod Activity

To investigate the therapeutic effects of methanol extracts of Dipterocarpus tuberculatus Roxb. (MED) against UV-induced photoaging, we assessed for alterations in the antioxidant activity, anti-apoptotic effects, ECM modulation, skin appearances, and anti-inflammatory response in normal human dermal fibroblast (NHDF) cells and nude mice orally treated with MED. High levels of tannin content and high free radical scavenging activity to DPPH were determined in MED, while seven active components, namely, gallic acid, bergenin, ellagic acid, ε-viniferin, asiatic acid, oleanolic acid, and 2α-hydroxyursolic acid, were identified using LC–MS analyses. UV-induced alterations in the NO concentration, SOD activity, and Nrf2 expression were remarkably recovered in MED-treated NHDF cells. Moreover, the decreased number of apoptotic cells and G2/M phase arrest were observed in the UV + MED-treated groups. Similar recoveries were detected for β-galactosidase, MMP-2/9 expression, and intracellular elastase activity. Furthermore, MED treatment induced suppression of the COX-2-induced iNOS mediated pathway, expression of inflammatory cytokines, and inflammasome activation in UV-radiated NHDF cells. The anti-photoaging effects observed in NHDF cells were subsequently evaluated and validated in UV + MED-treated nude mice through skin phenotypes and histopathological structure analyses. Taken together, these results indicate that MED exerts therapeutic effects against UV-induced photoaging and has the potential for future development as a treatment for photoaging.

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Methotrexate enhances antigen presentation and maturation of tumour antigen-loaded dendritic cells through NLRP3 inflammasome activation: a strategy for dendritic cell-based cancer vaccine

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920987056 ◽

2021 ◽

Vol 13 ◽

pp. 175883592098705

Author(s):

Gao-Na Shi ◽

Min Hu ◽

Chengjuan Chen ◽

Junmin Fu ◽

Shuai Shao ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Antigen Presentation ◽

Nlrp3 Inflammasome ◽

Tumour Antigen ◽

Inflammasome Activation ◽

Antigen Uptake ◽

Nlrp3 Inflammasome Activation ◽

Dc Maturation

Background: Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in adaptive cell-mediated immunity by priming and activating T cells against specific tumour and pathogenic antigens. Methotrexate (MTX), a folate derivative, functions as an immunoregulatory agent. However, the possible effect of MTX on tumour antigen-loaded DCs has not yet been investigated. Methods: We analysed the effect of MTX on the maturation and function of DCs along with tumour cell lysates (TCLs). Using bone marrow-derived DCs, we investigated the effect of MTX combined TCL-loaded DCs on T cells priming and proliferation. We also tested the anti-tumour immune effect on DCs when treated with MTX and/or TCL in vivo. Results: MTX combined with TCL not only enhanced DC maturation and stimulated cytokine release but also promoted CD8+ T cell activation and proliferation. The latter was associated with increased tumour antigen uptake and cross-presentation to T cells. Mechanistically, DC maturation and antigen presentation were partly modulated by NLRP3 inflammasome activation. Furthermore, immunisation of mice with MTX and TCL-pulsed DCs before a tumour challenge significantly delayed tumour onset and retarded its growth. This protective effect was due to priming of IFN-γ releasing CD8+ T cells and enhanced killing of tumour cells by cytotoxic T lymphocytes isolated from these immunised mice. Conclusion: MTX can function as a potent adjuvant in DC vaccines by increasing antigen presentation and T cell priming. Our findings provide a new strategy for the application of DC-based anti-tumour immunotherapy.

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NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus

Frontiers in Microbiology ◽

10.3389/fmicb.2021.778950 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hong-Su Park ◽

Yao Lu ◽

Kannupriya Pandey ◽

GuanQun Liu ◽

Yan Zhou

Keyword(s):

Influenza A Virus ◽

Nlrp3 Inflammasome ◽

Influenza A ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Inflammasome Activation ◽

Ns1 Protein ◽

Structural Protein ◽

Caspase 1 ◽

C Terminus

Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.

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Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500944 ◽

2021 ◽

Vol 49 (08) ◽

pp. 2001-2015

Author(s):

Guixian Zhang ◽

Liming Tang ◽

Hongbin Liu ◽

Dawei Liu ◽

Manxue Wang ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Target Genes ◽

Inflammatory Responses ◽

Psidium Guajava ◽

Pancreatic Fibrosis ◽

Inflammasome Activation ◽

Caspase 1 ◽

Nlrp3 Inflammasome Activation

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1[Formula: see text] and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1[Formula: see text] and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.

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Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model

Mediators of Inflammation ◽

10.1155/2018/6158671 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Weicheng Zhao ◽

Xiaolei Huang ◽

Xue Han ◽

Dan Hu ◽

Xiaohuai Hu ◽

...

Keyword(s):

Mast Cells ◽

Proinflammatory Cytokines ◽

Nlrp3 Inflammasome ◽

Intestinal Ischemia ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Interleukin 1 ◽

Intestinal Injury ◽

Cromolyn Sodium ◽

Inflammasome Activation

Background. Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. Methods. Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups (n=8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. Results. Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and β-hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. Conclusions. In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction.

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ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia/Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/2183026 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 123

Author(s):

Letteria Minutoli ◽

Domenico Puzzolo ◽

Mariagrazia Rinaldi ◽

Natasha Irrera ◽

Herbert Marini ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Current Knowledge ◽

Ischemia Reperfusion ◽

Ion Homeostasis ◽

Inflammasome Activation ◽

Mortality And Morbidity ◽

Arterial Blood ◽

Nlrp3 Inflammasome Activation

Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated.

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