NLRP3 inflammasome inhibitor cucurbitacin B suppresses gout arthritis in mice

2021 ◽  
Author(s):  
Ying Xue ◽  
Ran Li ◽  
Ping Fang ◽  
Zheng-qin Ye ◽  
Yong Zhao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Mice Model ◽  
In Vivo Models ◽  
Cucurbitacin B ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Gouty arthritis is a common inflammatory disease characterized by monosodium urate (MSU) crystal induced nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation with up-regulated caspase-1 protease and IL-1β in macrophages. Cucurbitacin B (CuB) is a tetracyclic triterpene that possesses a potential anti-inflammatory activity. However, the immunomodulatory and anti-inflammatory effects of CuB on gout have not been well characterized. Therefore, the purpose of the present study was to determine whether CuB exhibits anti-inflammatory effects on gout and to analyze the underlying molecular mechanism. We examined the effects of CuB on various stimuli-activated bone marrow-derived macrophages (BMDMs) and the mice model with MSU-induced acute gouty arthritis. Our results demonstrated that CuB effectively suppressed multiple stimuli-activated IL-1β secretion by interrupting NLRP3 inflammasome complex formation, inhibiting NLRP3 inflammasome activation and suppressing key enzymes of glycolysis in macrophages. Consistent with this, CuB pretreatment also ameliorated MSU-induced arthritis in vivo models of gout arthritis, manifested by reduced foot swelling and inflammatory cell infiltration. Taken together, our data provide the evidence that CuB is a NLRP3 inflammasome inhibitor with therapeutic potential for treating NLRP3 inflammasome-mediated diseases, especially gouty arthritis.

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 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 Anemoside B4 Protects against Acute Lung Injury by Attenuating Inflammation through Blocking NLRP3 Inflammasome Activation and TLR4 Dimerization

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Renyikun Yuan ◽  
Jia He ◽  
Liting Huang ◽  
Li-Jun Du ◽  
Hongwei Gao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Macrophage Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Acute lung injury (ALI) is an acute inflammatory process in the lung parenchyma. Anemoside B4 (B4) was isolated from Pulsatilla, a plant-based drug against inflammation and commonly applied in traditional Chinese medicine. However, the anti-inflammatory effect and the mechanisms of B4 are not clear. In this study, we explored the potential mechanisms and anti-inflammatory activity of B4 both in vitro and in vivo. The results indicated that B4 suppressed the expression of iNOS, COX-2, NLRP3, caspase-1, and IL-1β. The ELISA assay results showed that B4 significantly restrained the release of inflammatory cytokines like TNF-α, IL-6, and IL-1β in macrophage cells. In addition, B4 rescued mitochondrial membrane potential (MMP) loss in (lipopolysaccharide) LPS plus ATP stimulated macrophage cells. Co-IP and molecular docking results illustrated that B4 disrupted the dimerization of TLR4. For in vivo results, B4 exhibited a protective effect on LPS and bleomycin- (BLM-) induced ALI in mice through suppressing the lesions of lung tissues, the release of inflammatory cytokines, and the levels of white blood cells, neutrophils, and lymphoid cells in the blood. Collectively, B4 has a protective effect on ALI via blocking TLR4 dimerization and NLRP3 inflammasome activation, suggesting that B4 is a potential agent for the treatment of ALI.

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 Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxiety in vivo

2021 ◽  
Author(s):  
Simantini Ghosh ◽  
Zaidan Mohammed ◽  
Itender Singh
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Neuroinflammatory Response ◽  
Pharmacological Inhibition ◽  
Nlrp3 Inflammasome Activation ◽  
Human Stress ◽  
Anxious Behavior

AbstractStress related disorders lead to serious psychiatric disabilities and are comorbid with anxiety and depression. Current therapies targeting several neurotransmitter systems are only able to mitigate symptoms partially. It is well recognized that stress and trauma related disorders lead to a prominent inflammatory response in humans, and in several animal models a robust neuroinflammatory response has been observed. However, the therapeutic potential of targeting specific components of the inflammatory response has not been adequately studied in this context. The current study investigated the NLRP3 - Caspase1-IL-1β pathway, which recent research has identified as a major contributor to exacerbated inflammatory response in several peripheral and central nervous system pathological conditions. Using two different models of stress, first - single prolonged restraint stress followed by brief underwater submersion and second - predator odor exposure in mice, we demonstrate heightened anxious behavior in mice one-week after stress. Females in both models display an exacerbated anxiety response than males within the stressed group. Consistent with this data stressed animals demonstrate upregulation of IL-1β, IL-6, Caspase1 activity and NLRP3 inflammasome activation in brain, with female animals showing a stronger neuroinflammatory phenotype. Pharmacological inhibition of NLRP3 inflammasome activation led to a rescue in terms of anxious behavior as well as attenuated neuroinflammatory response, both of which were significantly more prominent in female animals. Further, we observed induction of activated Bruton’s Tyrosine Kinase (BTK), an upstream positive regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with Ibrutinib, a drug that is already FDA approved for use in certain types of lymphomas and leukemias, as well as a second inhibitor of BTK, LFM-A13. In both sets of experiments, we found inhibition of BTK significantly reduced the anxious behavior in stressed mice and attenuated the induction of NLRP3 inflammasome, Caspase 1 and IL1β. Our results suggest that BTK inhibition can be further investigated in context of human stress and trauma related disorders as a therapeutic strategy.

Antrodia Cinnamomea Attenuates Non-Alcoholic Steatohepatitis by Suppressing NLRP3 Inflammasome Activation In Vitro and In Vivo

2020 ◽  
Vol 48 (08) ◽  
pp. 1859-1874
Author(s):  
I-Chuan Yen ◽  
Jung-Chun Lin ◽  
Yu Chen ◽  
Qian-Wen Tu ◽  
Shih-Yu Lee
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Markers ◽  
Inflammasome Activation ◽  
In Vivo Models ◽  
Antrodia Cinnamomea ◽  
Alcoholic Steatohepatitis ◽  
Stress Markers ◽  
Nlrp3 Inflammasome Activation

Blockade of the NOD-like receptor protein 3 (NLRP3) inflammasome has been shown to be effective in halting the progression of non-alcoholic steatohepatitis (NASH). Antrodia cinnamomea is a well-known indigenous medicine used by Taiwanese aboriginal tribes. However, its effect on NASH remains unclear. This study aimed to examine the mechanistic insight of Antrodia cinnamomea extract (ACE) in both in vitro and in vivo models of NASH. Murine RAW264.7 macrophages and human hepatocellular carcinoma HepG2 cells were treated with the indicated concentration of ACE 30 minutes prior to stimulation with lipopolysaccharide (LPS) for 24 h. Levels of inflammatory markers, NLRP3 inflammasome, components, and endoplasmic reticulum (ER) stress markers were analyzed by Western blotting. For the in vivo experiments, male C57BL/6 mice weighing 21–25 g were fed a methionine/choline deficient (MCD) diet along with vehicle or ACE (100 mg/kg) for 10 consecutive days. The serum glutamate pyruvate transaminase (SGPT) levels of the mice were measured. The liver tissues from the mice underwent histological analysis (hematoxylin and eosin staining), and the levels of inflammatory markers, NLRP3 inflammasome components, and autophagy-related proteins were evaluated. ACE significantly inhibited NLRP3 inflammasome activation in vitro and in vivo. In addition, ACE attenuated the severity of MCD-induced steatohepatitis, reduced the levels of oxidative stress markers, and ameliorated inflammatory responses, but restored autophagic flux. Based on these findings, Antrodia cinnamomea could be developed into an anti-non-alcoholic fatty liver disease/NASH agent.

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.

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