scholarly journals Pretreatment with a Heat-Killed Probiotic Modulates the NLRP3 Inflammasome and Attenuates Colitis-Associated Colorectal Cancer in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 516 ◽  
Author(s):  
I-Che Chung ◽  
Chun-Nan OuYang ◽  
Sheng-Ning Yuan ◽  
Hsin-Chung Lin ◽  
Kuo-Yang Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
E Coli ◽  
Nlrp3 Inflammasome Activation ◽  
Safe Strategy ◽  
Inflammatory Bowel ◽  
Fecal Content

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically, E. faecalis attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments, E. faecalis can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand, E. faecalis cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic, E. faecalis, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.

scholarly journals Atractylenolide I Inhibits NLRP3 Inflammasome Activation in Colitis-Associated Colorectal Cancer via Suppressing Drp1-Mediated Mitochondrial Fission

2021 ◽  
Vol 12 ◽  
Author(s):  
Yao Qin ◽  
Yanwei Yu ◽  
Chendong Yang ◽  
Zhuien Wang ◽  
Yi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nlrp3 Inflammasome ◽  
Lentiviral Vector ◽  
Mitochondrial Fission ◽  
Inflammasome Activation ◽  
Atractylenolide I ◽  
Nlrp3 Inflammasome Activation

Inflammatory bowel disease (IBD) is an important high-risk factor that promotes the occurrence and development of colon cancer. Research on the mechanism of regulating NLRP3 can provide potential targets for treating NLRP3 inflammasome–related diseases and changing the inflammatory potential of immune cells. In this study, the effects of atractylenolide I on colitis-associated CRC (caCRC) and inflammasome activation were investigated both in vivo and in vitro. Furthermore, the role of atractylenolide I on Drp1-mediated mitochondrial fission was analyzed via Western blotting and transmission electron microscopy (TEM). Moreover, the Drp1 overexpression lentiviral vector was used to study the role of Drp1 on the signaling mechanisms of atractylenolide I. Atractylenolide I treatment significantly reduced the cell viability of human HCT116 and SW480 cells and induced apoptosis, and effectively inhibited colon tumors in the AOM/DSS mouse model. The reduction of NLRP3 inflammasome activation and excessive fission of mitochondria mediated by Drp1 were associated with the administration of atractylenolide I. Upregulation of Drp1 reversed the inhibitory effect of atractylenolide I on the activation of NLRP3 inflammasomes. Overexpressing the Drp1 expression counteracted the restraint of atractylenolide I on the release of IL-1β of LPS/DSS-stimulated BMDMs. Atractylenolide I inhibited NLRP3 and caspase-1 expression in mice BMDMs, with no influence in the Drp1-overexpressed BMDMs. These results demonstrated that atractylenolide I inhibits NLRP3 inflammasome activation in colitis-associated colorectal cancer via suppressing Drp1-mediated mitochondrial fission.

Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

2021 ◽  
Author(s):  
Sahabuddin Ahmed ◽  
Samir Ranjan Panda ◽  
Mohit Kwatra ◽  
Bidya Dhar Sahu ◽  
VGM Naidu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Free Radicals ◽  
Nlrp3 Inflammasome ◽  
Nuclear Translocation ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Abstract Several activators of NLRP3 inflammasome have been described; however, the central mechanisms of NLRP3 inflammasome activation in brain microglia, especially at the activating step through free radical generation, still require further clarification. Hence the present study aimed to investigate the role of free radicals in activating NLRP3 inflammasome driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in vitro and in vivo models of Parkinson’s disease. Initial priming of microglial cells with lipopolysaccharide (LPS) following treatment with hydrogen peroxide (H2O2) induces NF-κB translocation to nucleus with robust generation of free radicals that act as Signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses nuclear translocation of NF-κB and maintains cellular redox homeostasis in microglia that limits NLRP3 inflammasome activation along with processing active caspase-1, IL-1β and IL-18. To further correlates the in vitro study with in vivo MPTP model, treatment with PA also inhibits the nuclear translocation of NF-κB and downregulates the NLRP3 inflammasome activation. PA administration upregulates various antioxidant enzymes levels and restored the level of dopamine and other neurotransmitters in the striatum of the mice brain with improved behavioural activities. Additionally, treatment with Mito-TEMPO (a mitochondrial ROS inhibitor) was also seen to inhibit NLRP3 inflammasome and rescue dopaminergic neuron loss in the mice brain. Therefore, we conclude that NLRP3 inflammasome activation requires a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting NLRP3 inflammasome pathway in Parkinson’s disease.

Kaempferol Alleviates Corneal Transplantation Rejection by Inhibiting NLRP3 Inflammasome Activation and Macrophage M1 Polarization via Promoting Autophagy

2021 ◽  
Author(s):  
Huiwen Tian ◽  
Shumei Lin ◽  
Jing Wu ◽  
Ming Ma ◽  
Jian Yu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Macrophage Polarization ◽  
Corneal Transplantation ◽  
Inflammasome Activation ◽  
M1 Polarization ◽  
Nlrp3 Inflammasome Activation ◽  
M1 Macrophage ◽  
Transplantation Rejection

Abstract Corneal transplantation rejection remains a major threat to the success rate in high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the relationship between kaempferol and corneal transplantation remains largely unexplored. To address this, both in vivo and in vitro, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model in THP-1 derived human macrophages. In the transplantation experiments, we observed an enhancement in the NLRP3 / IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol can reduce the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed the effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of the NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol could be used as a potential therapeutic agent in the treatment of allograft rejection.

ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Shuhang Li ◽  
Linlin Wang ◽  
Zhihao Xu ◽  
Yuanyuan Huang ◽  
Rufeng Xue ◽  
...  
Keyword(s):  
Metabolic Control ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation ◽  
Multiple Molecules ◽  
Excessive Activation

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASCC171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

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 Vaspin Alleviates Osteoarthritis by Inhibiting NLRP3-mediated Inflammation

2021 ◽  
Author(s):  
Xianjie Zhu ◽  
Shiyou Dai ◽  
Baohua Xia ◽  
Jianbao Gong ◽  
Bingzheng Ma
Keyword(s):  
Nlrp3 Inflammasome ◽  
Wistar Rat ◽  
Cartilage Degradation ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Collagen Formation ◽  
Nlrp3 Inflammasome Activation

Abstract Background:Osteoarthritis (OA) is a chronic degenerative joint bone disease characterized by cartilage degradation. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is associated with the inflammatory and metabolic responses to OA. However, the underlying mechanisms of the pathological process of OA are not clear. The aim of the present study was to examine the protective effects of vaspin both in vitro and in vivo.Methods:Monosodium iodoacetate (MIA)-induced Wistar rat model of OA was used to assess the in vivo effects of vaspin administered for 12 weeks. The characteristics of OA were evaluated by haematoxylin and eosin (H&E) and safranin O/fast green staining. The anti-inflammatory effect of vaspin was assessed using immunohistochemical, qRT-PCR, and western blotting analysis. Parallel experiments to detect the molecular mechanism through which vaspin prevents OA were performed using LPS-treated chondrocytes.Results:Our results showed that the degeneration of cartilage and upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-13 were ameliorated by vaspin. Additionally, vaspin suppressed the activation of TXNIP/NLRP3 and secretion of tumor necrosis factor ɑ and interleukin-1β in vivo. It was further confirmed that vaspin could also suppress LPS-induced NLRP3 inflammasome activation and reduce collagen formation in chondrocytes. Moreover, vaspin inhibited NLRP3 inflammasome activation by suppressing the ROS/TXNIP pathway.Conclusions: Vaspin inhibited OA by repressing TXNIP/NLRP3 activation in in vitro and in vivo models of OA, thus providing a novel therapeutic strategy for OA.

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 Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2427
Author(s):  
Ivan Qi Han Ngui ◽  
Agampodi Promoda Perera ◽  
Rajaraman Eri
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Strong Association ◽  
Signalling Pathways ◽  
Inflammasome Activation ◽  
Intestinal Immunity ◽  
Aryl Hydrocarbon

Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some degree of the inflammatory process to maintain a healthy immune system. A pivotal component in the maintenance of such intestinal homeostasis is the innate immunity component, inflammasomes. Inflammasomes are large, cytosolic protein complexes formed following stimulation of microbial and stress signals that lead to the expression of pro-inflammatory cytokines. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been extensively studied in part due to its strong association with colitis and CAC. The aryl hydrocarbon receptor (AhR) has recently been acknowledged for its connection to the immune system aside from its role as an environmental sensor. AhR has been described to play a role in the inhibition of the NLRP3 inflammasome activation pathway. This review will summarise the signalling pathways of both the NLRP3 inflammasome and AhR; as well as new-found links between these two signalling pathways in intestinal immunity and some potential therapeutic agents that have been found to take advantage of this link in the treatment of colitis and CAC.

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