Vitrification of aortic valve homografts suppresses NLRP3 inflammasome activation and alleviates the inflammatory response after transplantation

Cryobiology ◽  
2018 ◽  
Vol 82 ◽  
pp. 130-136 ◽  
Author(s):  
Yulong Sui ◽  
Bin Wang ◽  
Qing Fan ◽  
Wenjie Zhu ◽  
Jixian Wang ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Cichoric Acid Ameliorates Monosodium Urate-Induced Inflammatory Response by Reducing NLRP3 Inflammasome Activation via Inhibition of NF-kB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qi Wang ◽  
Bingfeng Lin ◽  
Zhifeng Li ◽  
Jie Su ◽  
Yulin Feng
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Cichoric Acid ◽  
Monosodium Urate ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α

Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. Here, we elucidated the role of the natural compound cichoric acid (CA) on the MSU crystal-stimulated inflammatory response. The THP-1-derived macrophages (THP-Ms) were pretreated with CA and then stimulated with MSU suspensions. The protein levels of p65 and IκBα, the activation of the NF-κB signaling pathway by measuring the expression of its downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. CA treatment markedly inhibited the degradation of IκBα and the activation of NF-κB signaling pathway and reduced the levels of its downstream inflammatory genes such as IL-1β, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-M cells. Therefore, we infer that CA effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, thereby reducing the activation of the NF-κB signaling pathway and the NLRP3 inflammasome. These results suggest that CA could be a novel therapeutic strategy in averting acute episodes of gout.

scholarly journals Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxiety in vivo

2021 ◽  
Author(s):  
Simantini Ghosh ◽  
Zaidan Mohammed ◽  
Itender Singh
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Neuroinflammatory Response ◽  
Pharmacological Inhibition ◽  
Nlrp3 Inflammasome Activation ◽  
Human Stress ◽  
Anxious Behavior

AbstractStress related disorders lead to serious psychiatric disabilities and are comorbid with anxiety and depression. Current therapies targeting several neurotransmitter systems are only able to mitigate symptoms partially. It is well recognized that stress and trauma related disorders lead to a prominent inflammatory response in humans, and in several animal models a robust neuroinflammatory response has been observed. However, the therapeutic potential of targeting specific components of the inflammatory response has not been adequately studied in this context. The current study investigated the NLRP3 - Caspase1-IL-1β pathway, which recent research has identified as a major contributor to exacerbated inflammatory response in several peripheral and central nervous system pathological conditions. Using two different models of stress, first - single prolonged restraint stress followed by brief underwater submersion and second - predator odor exposure in mice, we demonstrate heightened anxious behavior in mice one-week after stress. Females in both models display an exacerbated anxiety response than males within the stressed group. Consistent with this data stressed animals demonstrate upregulation of IL-1β, IL-6, Caspase1 activity and NLRP3 inflammasome activation in brain, with female animals showing a stronger neuroinflammatory phenotype. Pharmacological inhibition of NLRP3 inflammasome activation led to a rescue in terms of anxious behavior as well as attenuated neuroinflammatory response, both of which were significantly more prominent in female animals. Further, we observed induction of activated Bruton’s Tyrosine Kinase (BTK), an upstream positive regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with Ibrutinib, a drug that is already FDA approved for use in certain types of lymphomas and leukemias, as well as a second inhibitor of BTK, LFM-A13. In both sets of experiments, we found inhibition of BTK significantly reduced the anxious behavior in stressed mice and attenuated the induction of NLRP3 inflammasome, Caspase 1 and IL1β. Our results suggest that BTK inhibition can be further investigated in context of human stress and trauma related disorders as a therapeutic strategy.

Targeting the NLRP3 Inflammasome in Diabetic Nephropathy

2021 ◽  
Vol 28 ◽  
Author(s):  
Ming Yang ◽  
Xi Wang ◽  
Yachun Han ◽  
Chenrui Li ◽  
Ling Wei ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
End Stage Renal Disease ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Relationship

: Diabetic nephropathy (DN) is one of the most common complications of diabetes and the main cause of end-stage renal disease (ESRD). The inflammatory response plays a key role in the pathological process of DN. As the most deeply studied inflammasome, NLRP3 should not be overlooked in DN. Its abnormal activation accelerates DN progression. In this review, we summarize our understanding of the structural composition and activation factors of the NLRP3 inflammasome. Moreover, the relationship between NLRP3 inflammasome activation, and the potential of the NLRP3 inflammasome as a therapeutic target for DN will also be discussed.

scholarly journals Effects of the TLR4/Myd88/NF-κB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury

2018 ◽  
Vol 47 (4) ◽  
pp. 1497-1508 ◽  
Author(s):  
Qiang Su ◽  
Lang Li ◽  
Yuhan Sun ◽  
Huafeng Yang ◽  
Ziliang Ye ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Function ◽  
Nlrp3 Inflammasome ◽  
Myocardial Injury ◽  
Neonatal Rat ◽  
Myocardial Inflammation ◽  
Inflammasome Activation ◽  
Coronary Microembolization ◽  
Coronary Syndrome ◽  
Nlrp3 Inflammasome Activation

Background/Aims: Coronary microembolization (CME) is a common complication of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI); Myocardial inflammation, caused by CME, is the main cause of cardiac injury. TLR4/MyD88/NF-κB signaling plays an important role in the development of myocardial inflammation, but its effects on CME remain unclear. To assess the cardiac protective effects of TAK-242 (TLR4 specific inhibitor) on CME-induced myocardial injury, and explore the underlying mechanism. Methods: Cardiac function, serum c-troponin I level, microinfarct were examined by cardiac ultrasound, myocardial enzyme assessment, HBFP staining. The levels of TLR4/MyD88/NF-κB signaling and NLRP3 inflammasome pathway were detected by ELISA, qRT-PCR and western blot. Results: The results showed inflammatory responses in the myocardium after CME, with increased expression levels of pro-inflammatory factors TNF-α, IL-1β and IL-18. Meanwhile, TLR4/MyD88/NF-κB signaling and the NLRP3 inflammasome were involved in the inflammatory process. TAK-242 administration before CME effectively inhibited the inflammatory response in the rat myocardium after CME and reduced myocardial injury, mainly by inhibiting TLR4/ MyD88/NF-κB signaling and reducing NLRP3 inflammasome activation. In addition, in vitro assays with neonatal rat cardiomyocytes further confirmed that TLR4/MyD88/NF-κB signaling was significantly activated in the inflammatory response of LPS-induced cardiomyocytes, via activation of the NLRP3 inflammasome. Inhibition of TLR4/MyD88/NF-κB signaling resulted in increased survival of cardiomyocytes mainly by reducing the release of inflammatory cytokines and decreasing NLRP3 inflammasome activation. Conclusions: TLR4/MyD88/NF-κB signaling participates in the inflammatory response of the myocardium after CME, activating the NLRP3 inflammasome, promoting the inflammatory cascade, and aggravating myocardial injury. Blocking TLR4/MyD88/NF-κB signaling may help reduce myocardial injury and improve cardiac function after CME.

scholarly journals TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

2021 ◽  
Vol 11 (7) ◽  
pp. 896
Author(s):  
Yuan Li ◽  
Weihong Long ◽  
Menghan Gao ◽  
Fangtai Jiao ◽  
Zecai Chen ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Proinflammatory Cytokine ◽  
Inflammasome Activation ◽  
Molecular Function ◽  
Nlrp3 Inflammasome Activation ◽  
Bv2 Cells ◽  
Microglial Inflammation

Background: TREM2 expressed on microglia plays an important role in modulating inflammation in neurodegenerative diseases. It remains unknown whether TREM2 modulates hyperglycemia-induced microglial inflammation. Methods: We investigated the molecular function of TREM2 in high glucose-induced microglial inflammation using western blotting, qPCR, ELISA, pulldown, and co-IP methods. Results: Our data showed that in high glucose-induced BV2 cells, TREM2 was increased, and the proinflammatory cytokine IL-1β was increased. TREM2 knockout (KO) attenuated the proinflammatory cytokine IL-1β; conversely, TREM2 overexpression (OE) exacerbated IL-1β expression. Furthermore, we found that high glucose promoted the interaction of TREM2 with NLRP3. TREM2 KO abolished the interaction of TREM2 with NLRP3, while TREM2 OE enhanced the interaction. Moreover, TREM2 KO reduced high glucose-induced NLRP3 inflammasome activation, and TREM2 OE augmented high glucose-induced NLRP3 inflammasome activation, indicating that high glucose enhances the expression of TREM2, which activates the NLRP3 inflammasome. To further clarify whether the NLRP3 signaling pathway mediates the TREM2-regulated inflammatory response, we blocked the NLRP3 inflammasome by knocking out NLRP3 and treating cells with a caspase1 inhibitor, which decreased the levels of the IL-1β proinflammatory cytokine but did not affect the high glucose-induced expression of TREM2. Conclusions: TREM2 modulates high glucose-induced microglial inflammation via the NLRP3 signaling pathway.

scholarly journals Transcription Factor EB Alleviates Endothelial Cell Inflammation Through NLRP3 Inflammasome-Mediated Cell Pyroptosis in Atherosclerosis

2020 ◽  
Author(s):  
Fengxia Guo ◽  
Bing Hu ◽  
Yanhua Sha ◽  
Kangning Zhu ◽  
Gang Li
Keyword(s):  
Transcription Factor ◽  
Endothelial Cell ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Transcription Factor Eb ◽  
Amp Activated Protein Kinase

Abstract BackgroundIncreasing evidence suggests that transcription factor EB (TFEB) inhibits inflammation in endothelial cell (ECs) and reduces development of atherosclerosis. However, little is known about the mechanism of action of TFEB on inflammation in atherosclerosis (AS).MethodsThe levels of TFEB, NLRP3, VCAM-1, ICAM-1, E-selectin, MCP-1, cleaved caspase-1, IL-1β and IL-18 in ECs were examined by immunoblotting, quantitative real time-polymerase chain reaction (qRT-PCR) , Enzyme-linked immunosorbent assay. The LDH activity were examined by LDH assay. TUNEL-positive cell were examined by TUNEL assay. The relationship between TFEB and NLRP3 were examined by immunofluorescence and coimmunoprecipitation. The effects of TFEB on atherosclerotic lesions by hematoxylin and eosin, TUNEL and collagen staining in the aortic valve of ApoE-/- mice fed a high fat diet (HFD).ResultsHere, we report that H2O2-induced cell pyroptosis and inflammatory response were mainly due to nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. The nuclear protein TFEB was significantly increased by H2O2, and knockdown of TFEB aggravated cell pyroptosis and inflammatory response. TFEB directly bound to NLRP3 and blocked NLRP3-mediated cell pyroptosis and inflammatory response. The effect of H2O2 on TFEB might be associated with AMP-activated protein kinase/mechanistic target of rapamycin-dependent signaling pathways.ConclusionsOur findings indicated that a novel TFEB–NLRP3 axis was a critical regulator in EC pyroptosis and inflammation, which could be potential therapeutic targets in AS and related cardiovascular diseases.

scholarly journals Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Dai ◽  
Bin Liu ◽  
Bibo Peng ◽  
Bo Qu ◽  
Jiezhi Lin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Motor Function ◽  
Nlrp3 Inflammasome ◽  
Neuronal Damage ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Cord Injury

Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI.Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage.Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression.Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

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