scholarly journals AVE 0991 Attenuates Pyroptosis and Liver Damage after Heatstroke by Inhibiting the ROS-NLRP3 Inflammatory Signalling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ming Zhang ◽  
Xintao Zhu ◽  
Huasheng Tong ◽  
Anni Lou ◽  
Yue Li ◽  
...  
Keyword(s):  
Heat Stress ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Hepatic Dysfunction ◽  
Signalling Pathway ◽  
Ang Ii ◽  
Caspase 1 ◽  
Angiotensin Peptides ◽  
Potential Biomarker ◽  
Inflammatory Signalling

We previously demonstrated that angiotensin-(1-7) (Ang-(1-7)), an essential endocrine factor, inhibits the NLRP3 inflammasome by regulating reactive oxygen species (ROS) in fibrotic livers. We also demonstrated that the NLRP3 inflammasome contributes to the liver damage induced by pyroptosis after heatstroke. However, the role of Ang-(1-7) in the hepatocytes under heat stress remains uncertain. We aimed to examine the change in angiotensin peptides in the livers affected by heatstroke and the effect on the ROS-NLRP3 inflammatory signalling pathway. In vivo, increased angiotensin II (Ang II) and decreased Ang-(1-7) in the serum of heatstroke patients suffering from hepatic dysfunction were observed. The change in angiotensin peptides was considered a potential biomarker that could be used to predict hepatic dysfunction. Enhanced Ang II and attenuated Ang-(1-7) levels were also observed in the liver tissue of heatstroke rats, which were consistent with their receptors and converting enzymes. Hepatic damage associated with increased ROS and protein expression levels of NOX4, NLRP3, caspase-1, and IL-1β was attenuated by AVE 0991, an analogue of Ang-(1-7). In vitro, pyroptosis, characterized by activated caspase-1 and IL-1β, was observed in hepatocytes under heat stress, which was enhanced by Ang II and attenuated by antioxidants, NOX4 siRNA, and AVE 0991. In summary, AVE 0991 attenuates pyroptosis and liver damage induced by heat stress by inhibiting the ROS-NLRP3 inflammatory signalling pathway.

scholarly journals Blood Levels of NLRP3 Inflammasome Components is Associated with Obsessive Compulsive Disorder

2020 ◽  
Author(s):  
Melike Tetik ◽  
Nese Direk ◽  
Betul Onder ◽  
Cansu Aykac ◽  
Burcu Ekinci ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Obsessive Compulsive Disorder ◽  
Nlrp3 Inflammasome ◽  
Mrna Levels ◽  
Hamilton Depression Scale ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Protein Levels ◽  
Caspase 1 ◽  
Potential Biomarker

ABSTRACTBackgroundInflammation has a well-known role in the pathogenesis of a range of neuropsychiatric disorders such as major depressive disorder and schizophrenia. Previous studies provided evidence regarding its possible involvement in the etiology of obsessive-compulsive disorder (OCD). However, mechanisms explaining the association of inflammation with OCD are lacking. The NLRP3 inflammasome complex initiates and mediates inflammatory response, which explain one of the most important key mechanisms behind inflammatory response. In this study, we aimed to determine a possible association between NLRP3 inflammasome and OCD, and to evaluate its relationship with clinical features.MethodsThis case-control study included 103 participants (51 OCD and 52 healthy controls). OCD patients were diagnosed using DSM-IV criteria. All participants were evaluated by psychiatric inventories, i.e. Yale Brown Obsessive Compulsive Scale, Hamilton Depression Scale, and Hewitt Multidimensional Perfectionism Scale. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples. RNA and protein were extracted from PBMCs and expression of NLRP3 inflammasome components were evaluated by quantitative real-time PCR (qPCR) and Western blotting. Serum IL-1beta and IL-18 cytokine levels were determined by ELISA.ResultsNEK7 and CASP1 mRNA levels were significantly higher in OCD patients, compared to controls. Pro-Caspase-1 protein levels were elevated, as well. Regression analysis showed that NEK7 mRNA and Caspase-1 protein levels can differentiate OCD and healthy control groups.Discussionpro-Caspase-1 mRNA and protein levels in PBMCs, as well as NEK7 mRNA levels are potential biomarker candidates in OCD. Our results may prompt research into possible role of NLRP3 inflammasome in OCD etiology.

scholarly journals Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1β levels

2021 ◽  
Vol 9 (1) ◽  
pp. e001975
Author(s):  
Nicolas Quezada ◽  
Ilse Valencia ◽  
Javiera Torres ◽  
Gregorio Maturana ◽  
Jaime Cerda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Model Assessment ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Liver Histopathology ◽  
Inflammatory Status

IntroductionSystemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1β, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans.Research design and methodsMetabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription–quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1β levels.ResultsBody Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1β nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1β were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1β levels.ConclusionOur results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

scholarly journals Haemophilus ducreyi Infection Induces Activation of the NLRP3 Inflammasome in Nonpolarized but Not in Polarized Human Macrophages

2013 ◽  
Vol 81 (8) ◽  
pp. 2997-3008 ◽  
Author(s):  
Wei Li ◽  
Barry P. Katz ◽  
Margaret E. Bauer ◽  
Stanley M. Spinola
Keyword(s):  
Nlrp3 Inflammasome ◽  
Interleukin 1 ◽  
Study Data ◽  
Human Infection ◽  
Haemophilus Ducreyi ◽  
Inflammasome Activation ◽  
Microbial Infection ◽  
Content Type ◽  
Ulcer Disease ◽  
Caspase 1

ABSTRACTRecognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whetherHaemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). AlthoughH. ducreyiis predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated inH. ducreyi-infected skin. Infection of MDM with live, but not heat-killed,H. ducreyiinduced caspase-1- and caspase-5-dependent processing and secretion of IL-1β. Blockage ofH. ducreyiuptake by cytochalasin D significantly reduced the amount of secreted IL-1β. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1β production. Consistent with NLRP3-dependent inflammasome activation, blocking ATP signaling, K+efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1β secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1β production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1β secretion elicited byH. ducreyi. Our study data indicate thatH. ducreyiinduces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection.

Effect of luteolin on the gene level expression of apoptosis-associated speck-like protein containing a caspase recruitment domain of NLRP3 inflammasome and NF-κB in rats subjected to experimental pancreatitis – influence of HSP70

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sadanandan Rajapriya ◽  
Arumugam Geetha
Keyword(s):  
Body Weight ◽  
Nlrp3 Inflammasome ◽  
Rank Correlation ◽  
Experimental Period ◽  
Serum Levels ◽  
Normal Diet ◽  
Experimental Pancreatitis ◽  
Caspase 1 ◽  
Spearman’S Rank Correlation ◽  
Pyrin Domain

Abstract Objectives Nod-like receptor pyrin domain containing 3 (NLRP3) is one of the well characterized inflammasome that controls the maturation of pro-inflammatory cytokines and thereby the inflammation in pancreas which could be a promising target for anti-inflammatory drugs. The present study is aimed to explore whether luteolin can target the NLRP3 inflammasome and modulate its activity through the signaling protein, HSP70 in the ethanol-cerulein model of experimental pancreatitis. Methods Male albino Wistar rats were divided into four groups. Groups 1 and 2 rats received normal diet. Groups 3 and 4 rats received isocalorically adjusted diet containing ethanol for 5 weeks and cerulein (20 μg/kg body weight i.p., thrice weekly for the last 3 weeks of the experimental period). Additionally, group 2 and 4 rats received 2 mg/kg body weight of luteolin orally from third week. Results Luteolin co-administration decreased the serum levels of HSP70, oxidative stress markers, myeloperoxidase, GSH/GSSG and GST with concomitant downregulation in the mRNA expression of HSP70, caspase-1, ASC-NLRP3 and NF-κB. Spearman’s rank correlation test showed that serum HSP70 has positive correlation with the expression of ASC-NLRP3, caspase-1, NF-κB and 4-hydroxynonenal and negative correlation with GSH:GSSG ratio. Conclusions The modulating effect of luteolin on the expression of HSP70, NF-κB and thereby on ASC-NLRP3 complex may be claimed for its pancreato-protective activity.

Coptisine from Coptis chinensis blocks NLRP3 inflammasome activation by inhibiting caspase-1

2019 ◽  
Vol 147 ◽  
pp. 104348 ◽  
Author(s):  
Jiasi Wu ◽  
Yu Luo ◽  
Qing Jiang ◽  
Sheng Li ◽  
Wenge Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Coptis Chinensis ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

scholarly journals The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengxiao Chen ◽  
Qi Bai ◽  
Yanting Wu ◽  
Qiongzhen Zeng ◽  
Xiaowei Song ◽  
...  
Keyword(s):  
Essential Oil ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Artemisia Argyi ◽  
Nlrp3 Inflammasome Activation ◽  
Long Time

Artemisia argyi H. Lév. and Vaniot is a traditional medical herb that has been used for a long time in China and other Asian counties. Essential oil is the main active fraction of Artemisia argyi H. Lév. and Vaniot, and its anti-inflammatory potential has been observed in vitro and in vivo. Here, we found that the essential oil of Artemisia argyi H. Lév. and Vaniot (EOAA) inhibited monosodium urate (MSU)- and nigericin-induced NLRP3 inflammasome activation. EOAA suppressed caspase-1 and IL-1β processing and pyroptosis. NF-κB p65 phosphorylation and translocation were also inhibited. In addition, EOAA suppressed nigericin-induced NLRP3 inflammasome activation without blocking ASC oligomerization, suggesting that it may inhibit NLRP3 inflammasome activation by preventing caspase-1 processing. Our study thus indicates that EOAA inhibits NLRP3 inflammasome activation and has therapeutic potential against NLRP3-driven diseases.

scholarly journals Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity

2021 ◽  
Vol 5 (5) ◽  
pp. 1523-1534
Author(s):  
Johan Courjon ◽  
Océane Dufies ◽  
Alexandre Robert ◽  
Laurent Bailly ◽  
Cédric Torre ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Molecular Pattern ◽  
Nlrp3 Inflammasome Activation ◽  
Healthy Donors ◽  
Activation Potential ◽  
Key Factor ◽  
Pathogen Associated Molecular Pattern

Abstract Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient’s evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.

scholarly journals Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries

Hypertension ◽  
2021 ◽  
Author(s):  
Kaiming Wang ◽  
Mahmoud Gheblawi ◽  
Anish Nikhanj ◽  
Matt Munan ◽  
Erika MacIntyre ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Tumor Necrosis Factor Receptor ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Blood Collection ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Angiotensin Peptides

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52–74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1–7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

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