scholarly journals Shugan Hewei Decoction Alleviates Cecum Mucosal Injury and Improves Depressive- and Anxiety-Like Behaviors in Chronic Stress Model Rats by Regulating Cecal Microbiota and Inhibiting NLRP3 Inflammasome

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Yue ◽  
Yu Chen ◽  
Hao Liu ◽  
Lesi Xu ◽  
Xian Zhou ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Nlrp3 Inflammasome ◽  
Mucosal Injury ◽  
Gastrointestinal Diseases ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Therapeutic Effects ◽  
Weight Growth ◽  
Treatment Of Depression ◽  
Cecal Microbiota

Chronic stress is a significant cause of depression, anxiety, and intestinal mucosal injury. Gut microbiota disturbances are also associated with these disorders. Shugan Hewei Decoction (SHD), which is a traditional Chinese medicine formula developed by our team, has shown superior therapeutic effects in the treatment of depression, anxiety, and functional gastrointestinal diseases caused by chronic stress. In this study, we investigated the modulatory effect of SHD on the cecal microbiota and cecum mucosal NOD-like receptor protein 3 (NLRP3) inflammasome in a chronic unpredictable stress (CUS)/social isolation rat model. After the SHD intervention, the CUS model rats showed improvements in their depressive- and anxiety-like behaviors, as well as sustained body weight growth and improved fecal characteristics. SHD improved the cecal microbiota diversity and changed the abundance of six microbial genera. A Spearman’s correlation analysis showed a strong correlation between the NLRP3 inflammasome and CUS-perturbed cecal biomarker microbiota. SHD regulated the excessive expression of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in the serum and cecum mucosa induced by CUS, as well as the activation of the Toll-like receptor 4/nuclear factor-κB signaling cascades. Our results reveal the pharmacological mechanisms of SHD and provide a validated therapeutic method for the treatment of depression, anxiety, and cecum mucosal injury.

scholarly journals Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 611 ◽  
Author(s):  
Yunchang Zhang ◽  
Xiaoshi Ma ◽  
Da Jiang ◽  
Jingqing Chen ◽  
Hai Jia ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Gm Csf ◽  
Lps Challenge ◽  
Induce Lung Injury ◽  
Underlying Mechanisms ◽  
Factor Α

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor κB (NF-κB), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
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.

scholarly journals Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4996
Author(s):  
Biswadeep Das ◽  
Chayna Sarkar ◽  
Vikram Singh Rawat ◽  
Deepjyoti Kalita ◽  
Sangeeta Deka ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Wide Spectrum ◽  
Biologically Active ◽  
Receptor Protein ◽  
Therapeutic Effects ◽  
Caspase 1 ◽  
Inflammatory Conditions ◽  
Molecular Patterns ◽  
Scientific Documentation

Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β’s actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.

Paeonol reduces IL-β production by inhibiting the activation of nucleotide oligomerization domain-like receptor protein-3 inflammasome and nuclear factor-κB in macrophages

2021 ◽  
pp. 1-9
Author(s):  
Gang Chen ◽  
Tingwang Guo ◽  
Lin Yang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Binding Activity ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Dna Binding Activity ◽  
Nlrp3 Inflammasome Activation ◽  
Nucleotide Oligomerization

Interleukin-1β, a key cytokine in gouty inflammation, is precisely regulated by the NLRP3 inflammasome and NF-κB. Our previous study demonstrated that paeonol suppressed IL-1β production in rats with monosodium urate (MSU)-induced arthritis. Whether NLRP3 inflammasome or NF-κB is responsible for the anti-inflammatory effect of paeonol remains unclear. In this study, J774A.1 cells induced by lipopolysaccharide (LPS) plus MSU, was used to investigate the effect of paeonol on NLRP3 inflammasome activation, and J774A.1 cells induced by LPS alone were used to investigate the effect of paeonol on NF-κB activation. In J774A.1 cells induced by LPS plus MSU, paeonol decreased the levels of IL-1β and caspase-1 and reduced the MSU-induced interaction of pro-caspase-1 and apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), but did not affect the levels of pro-IL-1β and pro-caspase-1. In J774A.1 cells induced by LPS alone, paeonol reduced the levels of IL-1β, NLRP3, p-IKK, p-IκBα, and p-p65, but did not affect ASC levels. Paeonol also promoted the content of IκBα and retained more p65 in the cytoplasm. Furthermore, paeonol reduced the DNA-binding activity of p65 and lowered the levels of p-JNK, p-ERK, and p-p38. These results suggest that paeonol inhibits IL-1β production by inhibiting the activation of NLRP3 inflammasome, NF-κB, and MAPK signaling pathways.

scholarly journals Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1279
Author(s):  
Erika Ramos-Tovar ◽  
Pablo Muriel
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Related Factor ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Ecm Proteins

Activated hepatic stellate cells (HSCs) and myofibroblasts are the main producers of extracellular matrix (ECM) proteins that form the fibrotic tissue that leads to hepatic fibrosis. Reactive oxygen species (ROS) can directly activate HSCs or induce inflammation or programmed cell death, especially pyroptosis, in hepatocytes, which in turn activates HSCs and fibroblasts to produce ECM proteins. Therefore, antioxidants and the nuclear factor E2-related factor-2 signaling pathway play critical roles in modulating the profibrogenic response. The master proinflammatory factors nuclear factor-κB (NF-κB) and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome may coordinate to produce and activate profibrogenic molecules such as interleukins 1β and 18, which effectively activate HSCs, to produce large amounts of fibrotic proteins. Furthermore, the NLRP3 inflammasome activates pro-caspase 1, which is upregulated by NF-κB, to produce caspase 1, which induces pyroptosis via gasdermin and the activation of HSCs. ROS play central roles in the activation of the NF-κB and NLRP3 signaling pathways via IκB (an inhibitor of NF-κB) and thioredoxin-interacting protein, respectively, thereby linking the molecular mechanisms of oxidative stress, inflammation and fibrosis. Elucidating these molecular pathways may pave the way for the development of therapeutic tools to interfere with specific targets.

scholarly journals NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rongchuan Yue ◽  
Zaiyong Zheng ◽  
Yu Luo ◽  
Xiaobo Wang ◽  
Mingming Lv ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Pressure Overload ◽  
Receptor Protein ◽  
Therapeutic Effects ◽  
Aortic Constriction ◽  
Cardioprotective Effects ◽  
Promising Therapeutic Agent

AbstractThe exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1β, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

NLRP3 inflammasome expression in cultured hepatocytes is regulated by nuclear factor-κB (NF-κB)

2015 ◽  
Vol 53 (01) ◽  
Author(s):  
SG Boaru ◽  
E Borkham-Kamphorst ◽  
E Van de Leur ◽  
C Liedtke ◽  
R Weiskirchen
Keyword(s):  
Nlrp3 Inflammasome ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cultured Hepatocytes

scholarly journals Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1231-1231
Author(s):  
Giulio Pasinetti
Keyword(s):  
Mrna Expression ◽  
Chronic Stress ◽  
Nlrp3 Inflammasome ◽  
Signaling Cascades ◽  
Dietary Polyphenols ◽  
Funding Sources ◽  
Glycation End Products ◽  
Molecular Patterns

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

scholarly journals Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jianjun Jiang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
Gengyun Sun ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Mrna Level ◽  
Scavenger Receptor ◽  
Nuclear Factor Κb ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Irreversible Inhibitor ◽  
Nlrp3 Inflammasome Activation

Abstract Background This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms. Methods Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. Western blotting and real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content. Results Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression. Conclusion This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.

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