CBD Promotes Oral Ulcer Healing via Inhibiting CMPK2-Mediated Inflammasome

Oral ulcer is a common oral inflammatory lesion accompanied by severe pain but with few effective treatments. Cannabidiol (CBD) is recently emerging for its therapeutic potential in a range of diseases, including inflammatory conditions and cancers. Here we show that CBD oral spray on acid- or trauma-induced oral ulcers on mice tongue inhibits inflammation, relieves pain, and accelerates lesion closure. Notably, the enrichment of genes associated with the NOD, LRR, and NLRP3 pyrin domain–containing protein 3 (NLRP3) inflammasome pathway is downregulated after CBD treatment. The expression of cleaved-gasdermin D (GSDMD) and the percentage of pyroptotic cells are reduced as well. In addition, CBD decreases the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), which subsequently inhibits the generation of oxidized mitochondria DNA and suppresses inflammasome activation. These immunomodulating effects of CBD are mostly blocked by peroxisome proliferator activated receptor γ (PPARγ) antagonist and partially antagonized by CB1 receptor antagonist. Our results demonstrate that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which are mediated mostly by PPARγ in the nucleus and partially by CB1 in the plasma membrane.

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Immunometabolic modulation of retinal inflammation by CD36 ligand

Scientific Reports ◽

10.1038/s41598-019-49472-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Katia Mellal ◽

Samy Omri ◽

Mukandila Mulumba ◽

Houda Tahiri ◽

Carl Fortin ◽

...

Keyword(s):

Mononuclear Phagocytes ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Ppar Γ ◽

Injury Characteristic ◽

And Function ◽

Cluster Of Differentiation

Abstract In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.

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Neuronal GPR30 Participates in Genistein-Mediated Neuroprotection in Ischemic Stroke by Inhibiting NLRP3 Inflammasome Activation in Ovariectomized Female Mice

10.21203/rs.3.rs-1177656/v1 ◽

2021 ◽

Author(s):

Shiquan Wang ◽

Zhen Zhang ◽

Jin Wang ◽

Lina Ma ◽

Jianshuai Zhao ◽

...

Keyword(s):

Ischemic Stroke ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion ◽

Underlying Mechanism ◽

Receptor Protein ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Nlrp3 Inflammasome Activation

Abstract Estrogen replacement therapy (ERT) is potentially beneficial for the prevention and treatment of postmenopausal cerebral ischemia but inevitably increases the risk of cerebral hemorrhage and breast cancer when used for a long period of time. Genistein, a natural phytoestrogen, has been reported to contribute to the recovery of postmenopausal ischemic stroke with reduced risks. However, the underlying mechanism of genistein-mediated neuroprotection remains unclear. We reported that genistein exerted significant neuroprotective effects by enhancing the expression of neuronal G protein-coupled receptor 30 (GPR30) in the ischemic penumbra after cerebral reperfusion in ovariectomized (OVX) mice, and this effect was achieved through GPR30-mediated inhibition of nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we found that Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) was the pivotal molecule that participated in GPR30-mediated inhibition of NLRP3 inflammasome activation in OVX mice after ischemia/reperfusion (I/R) injury. Our data suggest that the neuronal GPR30/PGC-1α pathway plays an important role in genistein-mediated neuroprotection against I/R injury in OVX mice.

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NLRP3 inflammasome mediates white adipose tissue browning after burn

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00180.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. E751-E759 ◽

Cited By ~ 6

Author(s):

Roohi Vinaik ◽

Dalia Barayan ◽

Abdikarim Abdullahi ◽

Marc G. Jeschke

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Nlrp3 Inflammasome ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Adaptive Thermogenesis ◽

Pyrin Domain ◽

Adipose Tissue Remodeling ◽

Main Regulator

A hallmark after burn is the stress and inflammatory-induced hypermetabolic response. Recently, we and others found that browning of white adipose tissue (WAT) is a critical component of this complex detrimental response. Although browning and inflammation have been independently delineated to occur after injury, their interaction is currently not well defined. One of the master regulators of inflammation and adipose tissue remodeling after burns is nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome. The aim of this this study was to determine whether NLRP3 modulates and activates WAT browning after burn. To obtain molecular and mechanistic insights, we used an NLRP3 knockout (NLRP3−/−) murine burn model. We demonstrated that genetic deletion of NLRP3 promoted persistent and augmented browning in adipocytes, evidenced by increased gene expression of peroxisome proliferator-activated receptor γ and CIDEA at 3 days (5.74 vs. 0.29, P < 0.05; 26.0 vs. 0.71, P < 0.05) and uncoupling protein 1 ( UCP1) and PGC1α at 7 days (7,406 vs. 3,894, P < 0.05; 20.6 vs. 2.52, P < 0.01) and enhanced UCP1 staining and multilocularity. Additionally, the main regulator of postburn WAT browning, IL-6, was elevated in the plasma acutely after burn in NLRP3−/− compared with wild-type counterparts (478.9 vs. 67.1 pg/mL, P < 0.05 at 3 days). These results suggest that NLRP3 has antibrowning effects and that blocking NLRP3 increases thermogenesis and augments browning via increased levels of IL-6. Our findings provide insights into targeting innate inflammatory systems for regulation of adaptive thermogenesis, a critical response after burns and other hypermetabolic conditions.

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Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice

Mediators of Inflammation ◽

10.1155/2014/930894 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Jian-Dong Ren ◽

Jie Ma ◽

Jun Hou ◽

Wen-Jin Xiao ◽

Wei-Hua Jin ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Animal Experiments ◽

Therapeutic Benefit ◽

Pancreatic Tissue ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation

Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.

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Krill Oil Inhibits NLRP3 Inflammasome Activation in the Prevention of the Pathological Injuries of Diabetic Cardiomyopathy

Nutrients ◽

10.3390/nu14020368 ◽

2022 ◽

Vol 14 (2) ◽

pp. 368

Author(s):

Xuechun Sun ◽

Xiaodan Sun ◽

Huali Meng ◽

Junduo Wu ◽

Xin Guo ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Nlrp3 Inflammasome ◽

Cardiac Fibrosis ◽

Inflammatory Cell ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Krill Oil ◽

Peroxisome Proliferator Activated Receptor

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM), resulting in high mortality. Myocardial fibrosis, cardiomyocyte apoptosis and inflammatory cell infiltration are hallmarks of DCM, leading to cardiac dysfunction. To date, few effective approaches have been developed for the intervention of DCM. In the present study, we investigate the effect of krill oil (KO) on the prevention of DCM using a mouse model of DM induced by streptozotocin and a high-fat diet. The diabetic mice developed pathological features, including cardiac fibrosis, apoptosis and inflammatory cell infiltration, the effects of which were remarkably prevented by KO. Mechanistically, KO reversed the DM-induced cardiac expression of profibrotic and proinflammatory genes and attenuated DM-enhanced cardiac oxidative stress. Notably, KO exhibited a potent inhibitory effect on NLR family pyrin domain containing 3 (NLRP3) inflammasome that plays an important role in DCM. Further investigation showed that KO significantly upregulated the expression of Sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which are negative regulators of NLRP3. The present study reports for the first time the preventive effect of KO on the pathological injuries of DCM, providing SIRT3, PGC-1α and NLRP3 as molecular targets of KO. This work suggests that KO supplementation may be a viable approach in clinical prevention of DCM.

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Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting

Nature Communications ◽

10.1038/s41467-020-19554-7 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Chad N. Brocker ◽

Donghwan Kim ◽

Tisha Melia ◽

Kritika Karri ◽

Thomas J. Velenosi ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Metabolic Stress ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Interacting Protein ◽

Non Coding Rna ◽

Nlrp3 Inflammasome Activation ◽

Long Non Coding Rna

AbstractExploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARα directly upregulates the long non-coding RNA gene Gm15441 through PPARα binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1β (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to PPARα agonism and fasting. These findings provide evidence for a mechanism by which PPARα attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441.

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The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽

10.3390/nu13030734 ◽

2021 ◽

Vol 13 (3) ◽

pp. 734

Author(s):

Pietro Antonuccio ◽

Herbert Ryan Marini ◽

Antonio Micali ◽

Carmelo Romeo ◽

Roberta Granese ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Targets ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Age Related ◽

Extracellular Signal ◽

Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

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Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells

Cells ◽

10.3390/cells10071652 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1652

Author(s):

Chinmaya Panda ◽

Clara Voelz ◽

Pardes Habib ◽

Christian Mevissen ◽

Thomas Pufe ◽

...

Keyword(s):

Tau Protein ◽

Nlrp3 Inflammasome ◽

Time Dependent ◽

Microglial Cells ◽

Inflammasome Activation ◽

Dependent Manner ◽

Progressive Dementia ◽

Microglial Polarization ◽

Protein Levels ◽

Pyrin Domain

Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.

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Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽

10.1155/2018/2010675 ◽

2018 ◽

Vol 2018 ◽

pp. 1-20 ◽

Cited By ~ 18

Author(s):

Manoj Govindarajulu ◽

Priyanka D. Pinky ◽

Jenna Bloemer ◽

Nila Ghanei ◽

Vishnu Suppiramaniam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Effects ◽

Therapeutic Potential ◽

Protein Accumulation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Continuous Increase ◽

Therapeutic Benefits ◽

The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

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The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.712907 ◽

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.

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