scholarly journals Piperlongumine Is an NLRP3 Inhibitor With Anti-inflammatory Activity

2022 ◽  
Vol 12 ◽  
Author(s):  
Jie Shi ◽  
Yang Xia ◽  
Huihong Wang ◽  
Zhongjie Yi ◽  
Ruoruo Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Piper Longum ◽  
Host Immune Responses ◽  
Pyrin Domain ◽  
Natural Inhibitor ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Receptor Family ◽  
Nlrp3 Activity

Piperlongumine (PL) is an alkaloid from Piper longum L. with anti-inflammatory and antitumor properties. Numerous studies have focused on its antitumor effect. However, the underlying mechanisms of its anti-inflammation remain elusive. In this study, we have found that PL is a natural inhibitor of Nod-like receptor family pyrin domain-containing protein-3 (NLRP3) inflammasome, an intracellular multi-protein complex that orchestrates host immune responses to infections or sterile inflammations. PL blocks NLRP3 activity by disrupting the assembly of NLRP3 inflammasome including the association between NLRP3 and NEK7 and subsequent NLRP3 oligomerization. Furthermore, PL suppressed lipopolysaccharide-induced endotoxemia and MSU-induced peritonitis in vivo, which are NLRP3-dependent inflammation. Thus, our study identified PL as an inhibitor of NLRP3 inflammasome and indicated the potential application of PL in NLRP3-relevant diseases.

scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

scholarly journals Toxoplasma gondii GRA9 Regulates the Activation of NLRP3 Inflammasome to Exert Anti-Septic Effects in Mice

2020 ◽  
Vol 21 (22) ◽  
pp. 8437
Author(s):  
Jae-Sung Kim ◽  
Seok-Jun Mun ◽  
Euni Cho ◽  
Donggyu Kim ◽  
Wooic Son ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Nlrp3 Inflammasome ◽  
Dense Granule ◽  
E Coli ◽  
Pyrin Domain ◽  
Essential Components ◽  
Bactericidal Effects ◽  
Anti Inflammatory

Dense granule proteins (GRAs) are essential components in Toxoplasma gondii, which are suggested to be promising serodiagnostic markers in toxoplasmosis. In this study, we investigated the function of GRA9 in host response and the associated regulatory mechanism, which were unknown. We found that GRA9 interacts with NLR family pyrin domain containing 3 (NLRP3) involved in inflammation by forming the NLRP3 inflammasome. The C-terminal of GRA9 (GRA9C) is essential for GRA9–NLRP3 interaction by disrupting the NLRP3 inflammasome through blocking the binding of apoptotic speck-containing (ASC)-NLRP3. Notably, Q200 of GRA9C is essential for the interaction of NLRP3 and blocking the conjugation of ASC. Recombinant GRA9C (rGRA9C) showed an anti-inflammatory effect and the elimination of bacteria by converting M1 to M2 macrophages. In vivo, rGRA9C increased the anti-inflammatory and bactericidal effects and subsequent anti-septic activity in CLP- and E. coli- or P. aeruginosa-induced sepsis model mice by increasing M2 polarization. Taken together, our findings defined a role of T. gondii GRA9 associated with NLRP3 in host macrophages, suggesting its potential as a new candidate therapeutic agent for sepsis.

scholarly journals Pulsed Electromagnetic Field Inhibits Synovitis via Enhancing the Efferocytosis of Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Junjie Ouyang ◽  
Bin Zhang ◽  
Liang Kuang ◽  
Peng Yang ◽  
Xiaolan Du ◽  
...  
Keyword(s):  
Medial Meniscus ◽  
Current Data ◽  
Pulsed Electromagnetic Field ◽  
Western Blot Assay ◽  
Anti Inflammatory ◽  
Pulsed Electromagnetic ◽  
Underlying Mechanisms ◽  
Pemf Treatment ◽  
Inflammatory Effect

Synovitis plays an important role in the pathogenesis of arthritis, which is closely related to the joint swell and pain of patients. The purpose of this study was to investigate the anti-inflammatory effects of pulsed electromagnetic fields (PEMF) on synovitis and its underlying mechanisms. Destabilization of the medial meniscus (DMM) model and air pouch inflammation model were established to induce synovitis in C57BL/6 mice. The mice were then treated by PEMF (pulse waveform, 1.5 mT, 75 Hz, 10% duty cycle). The synovitis scores as well as the levels of IL-1β and TNF-α suggested that PEMF reduced the severity of synovitis in vivo. Moreover, the proportion of neutrophils in the synovial-like layer was decreased, while the proportion of macrophages increased after PEMF treatment. In addition, the phagocytosis of apoptotic neutrophils by macrophages (efferocytosis) was enhanced by PEMF. Furthermore, the data from western blot assay showed that the phosphorylation of P38 was inhibited by PEMF. In conclusion, our current data show that PEMF noninvasively exhibits the anti-inflammatory effect on synovitis via upregulation of the efferocytosis in macrophages, which may be involved in the phosphorylation of P38.

scholarly journals LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients.

2021 ◽  
Author(s):  
Giuseppe Bombaci ◽  
Mayuresh A Sarangdhar ◽  
Nicola Andina ◽  
Aubry Tardivel ◽  
Eric Chi-Wang Yu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Neutrophil Infiltration ◽  
Inflammasome Activation ◽  
Ribonuclease Inhibitor ◽  
Protein Levels ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
Lrr Protein ◽  
Receptor Family

Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated inflammation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and is also detrimental in COVID-19 infection. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which shares homology with LRRs of NOD-like receptor family pyrin domain (PYD)-containing (NLRP) proteins, attenuates inflammasome activation. Mechanistically, RNH1 decreased pro-IL1b expression and induced proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively showed increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Further, RNH1 protein levels were negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.

scholarly journals Administration of Dexmedetomidine inhibited NLRP3 inflammasome and microglial cell activities in hippocampus of traumatic brain injury rats

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Bin Zheng ◽  
Shuncai Zhang ◽  
Yanlu Ying ◽  
Xinying Guo ◽  
Hengchang Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Improvement Effect ◽  
Improved Performance ◽  
Inflammasome Activity ◽  
Adrenergic Receptor Agonist ◽  
Nlrp3 Activity

The abnormally high nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity is a typical characteristic of traumatic brain injury (TBI). Dexmedetomidine (Dex) is a highly selective α-2 adrenergic receptor agonist that inhibits the activation of NLRP3. Thus, it was hypothesized that Dex could attenuate TBI by inhibiting NLRP3 inflammasome activity in hippocampus. Rats were subjected to controlled cortical impact method to induce TBI, and treated with Dex. The effect of Dex treatment on the cognitive function, NLRP3 activity, and microglial activation in rat brain tissues was assessed. The administration of Dex improved performance of TBI rats in Morris water maze (MWM) test, which was associated with the increased neurone viability and suppressed microglia activity. Moreover, the administration of Dex inhibited the neuroinflammation in brain tissue as well as the expressions of NLRP3 and caspase-1. Additionally, Dex and NLRP3 inhibitor, BAY-11-7082 had a synergistic effect in inhibiting NLRP3/caspase-1 axis activity and improving TBI. The findings outlined in the current study indicated that the improvement effect of Dex on TBI was related to its effect on NLRP3 activity.

scholarly journals Growth differentiation factor 11 ameliorates experimental colitis by inhibiting NLRP3 inflammasome activation

2018 ◽  
Vol 315 (6) ◽  
pp. G909-G920 ◽  
Author(s):  
Lanju Wang ◽  
Yaohui Wang ◽  
Zhenfeng Wang ◽  
Yu Qi ◽  
Beibei Zong ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Inflammasome Activation ◽  
Acute Colitis ◽  
Pyrin Domain ◽  
Differentiation Factor ◽  
Nlrp3 Inflammasome Activation ◽  
Receptor Family

Growth differentiation factor 11 (GDF11) has an anti-inflammatory effect in the mouse model of atherosclerosis and Alzheimer's disease, but how GDF11 regulates intestinal inflammation during ulcerative colitis (UC) is poorly defined. The Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome is closely associated with intestinal inflammation because of its ability to increase IL-1β secretion. Our aim is to determine whether GDF11 has an effect on attenuating experimental colitis in mice. In this study, using a dextran sodium sulfate (DSS)-induced acute colitis mouse model, we reported that GDF11 treatment attenuated loss of body weight, the severity of the disease activity index, shortening of the colon, and histological changes in the colon. GDF11 remarkably suppressed IL-1β secretion and NLRP3 inflammasome activation in colon samples and RAW 264.7 cells, such as the levels of NLRP3 and activated caspase-1. Furthermore, we found that GDF11 inhibited NLRP3 inflammasome activation by downregulating the Toll-like receptor 4/NF-κB p65 pathway and reactive oxygen species production via the typical Smad2/3 pathway. Thus, our research shows that GDF11 alleviates DSS-induced colitis by inhibiting NLRP3 inflammasome activation, providing some basis for its potential use in the treatment of UC. NEW & NOTEWORTHY Here, we identify a new role for growth differentiation factor 11 (GDF11), which ameliorates dextran sodium sulfate-induced acute colitis. Meanwhile, we discover a new phenomenon of GDF11 inhibiting IL-1β secretion and Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome activation. These findings reveal that GDF11 is a new potential candidate for the treatment of ulcerative colitis patients with a hyperactive NLRP3 inflammasome.

scholarly journals Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Leng ◽  
Yingjie Zhang ◽  
Xinran Liu ◽  
Zhen Zhang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Inflammasome Activation ◽  
Astragaloside Iv ◽  
Caspase 1 ◽  
Endothelial Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

scholarly journals The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1552
Author(s):  
Maria Sebastian-Valverde ◽  
Giulio M. Pasinetti
Keyword(s):  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Cellular Mechanisms ◽  
Pyrin Domain ◽  
Human Lifespan ◽  
Age Related ◽  
Inflammatory State ◽  
Chronic Activation ◽  
Receptor Family

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

scholarly journals NLRP3 Inflammasome Is Involved in Calcium-Sensing Receptor-Induced Aortic Remodeling in SHRs

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Zhang ◽  
Siting Hong ◽  
Shuhan Qi ◽  
Wenxiu Liu ◽  
Xiaohui Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Activation Mechanism ◽  
Inflammasome Activation ◽  
Calcium Sensing Receptor ◽  
Pyrin Domain ◽  
Calcium Sensing ◽  
Nlrp3 Inflammasome Activation ◽  
Nucleotide Oligomerization ◽  
Aortic Remodeling ◽  
Receptor Family

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.

IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis

2020 ◽  
Vol 27 (1) ◽  
pp. 84-93
Author(s):  
Yuan Li ◽  
Hongxia Chu ◽  
Mingsheng Zhao ◽  
Chaoze Li ◽  
Yetong Guan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transcriptional Profiling ◽  
Inflammasome Activation ◽  
Downstream Effector ◽  
Nlrp3 Inflammasome Activation ◽  
Polymerase Chain ◽  
Underlying Mechanisms ◽  
And Control ◽  
Nlrp3 Expression

Abstract Background Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a–e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis. Methods NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5′-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1β, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo. Results Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-κB activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1β, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation. Conclusion Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document