Antimalarial Drug Artemisinin Extenuates Amyloidogenesis and Neuroinflammation in APPswe/PS1dE9 Transgenic Mice via Inhibition of Nuclear Factor-κB and NLRP3 Inflammasome Activation

Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-β, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.

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

Lipids in Health and Disease ◽

10.1186/s12944-021-01446-4 ◽

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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BAY 11-7082 inhibits the NF-κB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis

Clinical Science ◽

10.1042/cs20160645 ◽

2017 ◽

Vol 131 (6) ◽

pp. 487-498 ◽

Cited By ~ 29

Author(s):

Natasha Irrera ◽

Mario Vaccaro ◽

Alessandra Bitto ◽

Giovanni Pallio ◽

Gabriele Pizzino ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Nuclear Translocation ◽

Nuclear Factor Κb ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Dermal Thickness ◽

Nlrp3 Inflammasome Activation ◽

Histological Score ◽

Interesting Approach ◽

Factor Α

BAY 11-7082 antagonizes I-κB kinase-β preventing nuclear translocation of nuclear factor-κB (NF-κB); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-κB is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11-7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis-like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i.p.) or its vehicle (100 μl/i.p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-κB and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-κB, NLRP3, tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-κB and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-κB and NLRP3.

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O1-11-03: Anti-malarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice via inhibition of NF-κB and NLRP3 inflammasome activation

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.04.112 ◽

2013 ◽

Vol 9 ◽

pp. P152-P152 ◽

Cited By ~ 1

Author(s):

Jian-Quan Shi ◽

Jun Xu

Keyword(s):

Transgenic Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Albiflorin Attenuates Mood Disorders Under Neuropathic Pain State by Suppressing the Hippocampal NLRP3 Inflammasome Activation During Chronic Constriction Injury

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa076 ◽

2020 ◽

Author(s):

Pei Liu ◽

Jianjun Chen ◽

Shuai Ma ◽

Jianjun Zhang ◽

Jianyu Zhou

Keyword(s):

Neuropathic Pain ◽

Mood Disorders ◽

Nlrp3 Inflammasome ◽

Chronic Constriction Injury ◽

Anxiety And Depression ◽

Inflammasome Activation ◽

Nuclear Factor ◽

Nlrp3 Inflammasome Activation ◽

Pain State ◽

Neuropathic Pain State

Abstract Background Neuropathic pain is a multifaceted and ubiquitous disease across the globe. Mood disorders, such as anxiety and depression, are frequently observed in patients suffering from neuropathic pain. Both neuropathic pain and comorbid mood disorders seriously impact quality of life. Accumulated evidence shows that activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the neuroinflammatory pathogenesis of neuropathic pain, anxiety, and depression. However, the role of the NLRP3 inflammasome in the pathological process of anxiety and depression under the neuropathic pain state has not been fully described. Albiflorin, a monoterpene glycoside, may be a potential regulator of the NLRP3 inflammasome, but it is not clear whether albiflorin relates to NLRP3 inflammasome activation. Methods We used a systematic pharmacological method to confirm whether the activation of the NLRP3 inflammasome in the hippocampus was involved in the development of neuropathic pain associated with mood disorders and whether albiflorin could be an effective treatment for these symptoms. Results The NLRP3 inflammasome contributed to the neuropathic pain and comorbid anxiety and depression-like behaviors induced by chronic constriction injury of the sciatic nerve, and albiflorin may relieve these symptoms via inhibition of the NLRP3 inflammasome activity. Moreover, albiflorin enhanced the translocation of the nuclear factor erythroid 2-related factor 2 into the nucleus and suppressed nuclear factor-kappa B activity in the hippocampus. Conclusions Albiflorin, as a potential therapeutic agent, might greatly improve the overall symptoms of neuropathic pain.

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Saffron extract attenuates neuroinflammation in rmTBI mouse model by suppressing NLRP3 inflammasome activation via SIRT1

PLoS ONE ◽

10.1371/journal.pone.0257211 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257211

Author(s):

Mariam J. Shaheen ◽

Amira M. Bekdash ◽

Hana A. Itani ◽

Jamilah M. Borjac

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Neurodegenerative Diseases ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nuclear Factor ◽

Caspase 1 ◽

Nlrp3 Inflammasome Activation ◽

Saffron Extract

Traumatic brain injury (TBI) remains a major cause of morbidity and disability worldwide and a healthcare burden. TBI is an important risk factor for neurodegenerative diseases hallmarked by exacerbated neuroinflammation. Neuroinflammation in the cerebral cortex plays a critical role in secondary injury progression following TBI. The NOD-like receptors (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a key player in initiating the inflammatory response in various central nervous system disorders entailing TBI. This current study aims to investigate the role of NLRP3 in repetitive mild traumatic brain injury (rmTBI) and identify the potential neuroprotective effect of saffron extract in regulating the NLRP3 inflammasome. 24 hours following the final injury, rmTBI causes an upregulation in mRNA levels of NLRP3, caspase-1, the apoptosis-associated speck-like protein containing a CARD (ASC), nuclear factor kappa B (NF-κB), interleukin-1Beta (IL-1β), interleukin 18 (IL-18), nuclear factor erythroid 2–related factor 2 (NRF2) and heme oxygenase 1 (HMOX1). Protein levels of NLRP3, sirtuin 1 (SIRT1), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), and neuronal nuclei (Neu N) also increased after rmTBI. Administration of saffron alleviated the degree of TBI, as evidenced by reducing the neuronal damage, astrocyte, and microglial activation. Pretreatment with saffron inhibited the activation of NLRP3, caspase-1, and ASC concurrent to reduced production of the inflammatory cytokines IL-1β and IL-18. Additionally, saffron extract enhanced SIRT1 expression, NRF2, and HMOX1 upregulation. These results suggest that NLRP3 inflammasome activation and the subsequent inflammatory response in the mice cortex are involved in the process of rmTBI. Saffron blocked the inflammatory response and relieved TBI by activating detoxifying genes and inhibiting NLRP3 activation. The effect of saffron on the NLRP3 inflammasome may be SIRT1 and NF-κB dependent in the rmTBI model. Thus, brain injury biomarkers will help in identifying a potential therapeutic target in treating TBI-induced neurodegenerative diseases.

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

Biochemistry and Cell Biology ◽

10.1139/bcb-2021-0255 ◽

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.

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

10.21203/rs.3.rs-68400/v3 ◽

2021 ◽

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

Zeitschrift für Gastroenterologie ◽

10.1055/s-0034-1397079 ◽

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

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