scholarly journals Inhibitory Role of Berberine, an Isoquinoline Alkaloid, on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6238
Author(s):  
Paromita Sarbadhikary ◽  
Blassan P. George ◽  
Heidi Abrahamse
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
In Vivo Studies ◽  
Inflammasome Activation ◽  
Inflammatory Disorders ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.

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 Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Yufei Luo ◽  
Bojun Xiong ◽  
Haiping Liu ◽  
Zehong Chen ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Mechanistic Study ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

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.

scholarly journals Melatonin Alleviates Microglia-Mediated Neuroinflammation By Suppressing NLRP3 Inflammasome-Mediated Pyroptosis Via ROS/mtDNA/STING Pathway After Spinal Cord Injury

2021 ◽  
Author(s):  
Jin Wang ◽  
Haiyuan Yang ◽  
Fan Zhang ◽  
Minghao Shao ◽  
Haocheng Xu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Cord Injury ◽  
Sting Pathway

Abstract BackgroundMicroglia pyroptosis-induced neuroinflammation has been one of the potential treatment targets for spinal cord injury (SCI). And melatonin is reported to have anti-neuroinflammation effect on SCI, but the underlying mechanism is largely unexplored. In addition, the potential regulatory role of stimulator of interferon genes (STING) mediated innate immune response in the SCI-induced neuroinflammation also remains unknown. The aim of this study is to identify the potential molecular mechanism of the anti-neuroinflammation effect of melatonin in SCI mice and to explore whether STING-mediated signal pathway is involved in this pharmacological process. MethodsIn vivo, the C57BL/6 female mice underwent SCI injury or Sham surgery (laminectomy alone). Melatonin and selective STING antagonist C-176 were administered intraperitoneally after injury in the SCI group once a day for 3 or 28 consecutive days for different experiments. The BMS score system was adopted to assess the motor function of mice. In vitro, the Lipopolysaccharide (LPS)/ATP was combinedly used to induce cell pyroptosis in BV2 microglia and the adenovirus was used to overexpress STING. A series of molecular experiments including Western blot (WB), quantitative real-time polymerase chain reaction (RT-qPCR), enzyme linked immunosorbent assay (ELISA) and immunofluorescence (IF) were performed in vivo and in vitro. ResultsOur results showed that melatonin effectively suppressed NLRP3 inflammasome-induced pyroptosis and STING-mediated pathway after SCI. In addition, C-176 also alleviated the NLRP3 inflammasome-mediated pyroptosis and promoted functional recovery in vivo. In vitro, we also found that melatonin abrogated NLRP3 inflammasome activation in LPS/ATP-induced BV2 cells, while overexpression of STING reversed the anti-pyroptotic role of melatonin. Subsequent results together indicated that the role of melatonin on STING-dependent NLRP3 inflammasome activation may be mediated by decreasing ROS production and cytosolic mtDNA release. ConclusionThis study preliminarily demonstrated that melatonin exerts its anti-neuroinflammation role on SCI by alleviating the NLRP3 inflammasome-mediated pyroptosis, which was mediated by blocking the ROS/mtDNA/STING pathway. It provides us a better understanding of the pathological mechanism after SCI and offer experiment evidence to promote the use of melatonin for SCI.

The role of NLRP3 inflammasome activation in the neuroinflammatory responses to Ag2Se quantum dots in microglia

Nanoscale ◽  
2019 ◽  
Vol 11 (43) ◽  
pp. 20820-20836 ◽  
Author(s):  
Tianshu Wu ◽  
Xue Liang ◽  
Keyu He ◽  
Tingting Wei ◽  
Yan Wang ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Inflammasome Activation ◽  
Activated Microglia ◽  
Nlrp3 Inflammasome Activation

Ag2Se QD exposure activated microglia followed by pro-inflammatory cytokine IL-1β release in vivo and in vitro through NLRP3 inflammasome activation.

Microcystin-LR Induces NLRP3 Inflammasome Activation via FOXO1 Phosphorylation, Resulting in Interleukin-1β Secretion and Pyroptosis in Hepatocytes

2020 ◽  
Author(s):  
Yali Zhang ◽  
Peipei Zhu ◽  
Xiaofeng Wu ◽  
Tianli Yuan ◽  
Zhangyao Su ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Interleukin 1Β ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Nlrp3 Inflammasome Activation ◽  
Phosphatase 2A ◽  
Related Proteins

Abstract Microcystin-LR (MC-LR), the most common and toxic microcystin (MC) present in freshwater, poses a substantial threat to human health, especially hepatotoxicity. Recent evidence reveals that the NLRP3 inflammasome plays an important role in liver injury by activating caspase-1 to promote interleukin-1β (IL-1β) secretion. In this study, we investigated the possible role of NLRP3 inflammasome activation in MC-LR-induced mouse liver inflammatory injury. We found that MC-LR administered to mice by oral gavage mainly accumulated in liver and induced the activation of the NLRP3 inflammasome and production of mature IL-1β. Additionally, we observed an increase in the levels of NLRP3 inflammasome-related proteins and the proportion of pyroptosis in MC-LR-treated AML-12 cells. We also found that inhibition of NLRP3 in mice attenuated MC-LR-induced IL-1β production, indicating an essential role for NLRP3 in MC-LR-induced liver inflammatory injury. In addition, we found that inhibition of FOXO1 by AKT-mediated hyperphosphorylation, due to protein phosphatase 2A (PP2A) inhibition, is required for MC-LR-induced expression of NLRP3. Taken together, our in vivo and in vitro findings suggest a model in which the NLRP3 inflammasome activation, a result of AKT-mediated hyperphosphorylation of FOXO1 through inhibition of PP2A, plays a key role in MC-LR–induced liver inflammatory injury via IL-1β secretion and pyroptotic cell death.

scholarly journals Protective Effect of Piplartine against LPS-Induced Sepsis through Attenuating the MAPKs/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation

2021 ◽  
Vol 14 (6) ◽  
pp. 588
Author(s):  
Chi-Han Huang ◽  
Shu-Chi Wang ◽  
I-Chen Chen ◽  
Yi-Ting Chen ◽  
Po-Len Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ex Vivo ◽  
Biological Properties ◽  
Inflammasome Activation ◽  
Activated Macrophages ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Anti Inflammatory

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the anti-inflammatory activities of piplartine in vitro, ex vivo and in vivo using murine J774A.1 macrophage cell line, peritoneal macrophages, bone marrow-derived macrophages and an animal sepsis model. The results demonstrated that piplartine suppresses iNOS and COX-2 expression, reduces PGE2, TNF-α and IL-6 production, decreases the phosphorylation of MAPKs and NF-κB and attenuates NF-κB activity by LPS-activated macrophages. Piplartine also inhibits IL-1β production and suppresses NLRP3 inflammasome activation by LPS/ATP- and LPS/nigericin-activated macrophages. Moreover, piplartine reduces the production of nitric oxide (NO) and TNF-α, IL-6 and IL-1β, decreases LPS-induced tissue damage, attenuates infiltration of inflammatory cells and enhances the survival rate. Collectively, these results demonstrate piplartine exhibits anti-inflammatory activities in LPS-induced inflammation and sepsis and suggest that piplartine might have benefits for sepsis treatment.

scholarly journals Inhibition of NLRP3 Inflammasome Activation and Pyroptosis in Macrophages by Taraxasterol Is Associated With Its Regulation on mTOR Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Fan Yang ◽  
Xun-jia Ye ◽  
Ming-ye Chen ◽  
Hong-chun Li ◽  
Yao-feng Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Clinical Investigation ◽  
Mtor Signaling ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Aseptic Inflammation ◽  
Inflammatory Disorders ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Taraxasterol (TAS) is an active ingredient of Dandelion (Taraxacum mongolicum Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its therapeutic effects on inflammatory disorders is not completely clear. Inflammasome activation is a critical step of innate immune response to infection and aseptic inflammation. Among the various types of inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3 inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin treatment, resulting in reduced mature interleukin-1β (IL-1β) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of nigericin or extracellular ATP. Consistent with reduced cleavage of GSDMD, nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both mTORC1 and mTORC2) and rapamycin (inhibiting mTORC1 only) also inhibited NLRP3 inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1β levels in vivo. Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.

scholarly journals The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3

2021 ◽  
Vol 12 ◽  
Author(s):  
Tiantian Tang ◽  
Ping Li ◽  
Xinhui Zhou ◽  
Rui Wang ◽  
Xiuqin Fan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Inflammasome Activation ◽  
Regulation Mechanism ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1β secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1β induced by lipopolysaccharide in sera, and more IL-1β secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1β production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

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