IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the β-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.

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“…Air pouch inflammation model was induced as described by Ali et al (2021) . Mice were randomly divided into groups of 5 animals.…”

Section: Methodsmentioning

confidence: 99%

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice

et al. 2023

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“…Sirt1 is a sequential post translational regulator that deacetylates proteins [59]. It promotes the generation of ROS, which causes the aberrant activation of the NLRP3 inflammasome, which will lead to inflammation [60]. NLRP3 recognizes stress and activates caspase-1, which triggers pyroptosis and cytokine release [61].…”

Section: Inflammation In Macrophagesmentioning

confidence: 99%

“…IIIM-983 also shows NLRP3 inflammasome inhibition when cells are primed with LPS. IIIM-941 suppressed monosodium-urate-crystal-induced IL-1β in conditions of localized inflammation without changing the levels of TNFα and IL-6, and also in MSU-induced mouse paw and foot edema as a model of inflammation [60]. Derivatives of stilbenes that were 2,6-dihalogenated with the substitution of pyridine showed over 90% inhibition of inflammatory symptoms [185].…”

Section: Future Perspectivesmentioning

confidence: 99%

Stilbenes, a Versatile Class of Natural Metabolites for Inflammation—An Overview

et al. 2023

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Stilbenes are polyphenolic allelochemicals synthesized by plants, especially grapes, peanuts, rhubarb, berries, etc., to defend themselves under stressful conditions. They are now exploited in medicine for their antioxidant, anti-proliferative and anti-inflammatory properties. Inflammation is the immune system’s response to invading bacteria, toxic chemicals or even nutrient-deprived conditions. It is characterized by the release of cytokines which can wreak havoc on healthy tissues, worsening the disease condition. Stilbenes modulate NF-κB, MAPK and JAK/STAT pathways, and reduce the transcription of inflammatory factors which result in maintenance of homeostatic conditions. Resveratrol, the most studied stilbene, lowers the Michaelis constant of SIRT1, and occupies the substrate binding pocket. Gigantol interferes with the complement system. Besides these, oxyresveratrol, pterostilbene, polydatin, viniferins, etc., are front runners as drug candidates due to their diverse effects from different functional groups that affect bioavailability and molecular interactions. However, they each have different thresholds for toxicity to various cells of the human body, and thus a careful review of their properties must be conducted. In animal models of autoinflammatory diseases, the mode of application of stilbenes is important to their absorption and curative effects, as seen with topical and microemulsion gel methods. This review covers the diversity seen among stilbenes in the plant kingdom and their mechanism of action on the different inflammatory pathways. In detail, macrophages’ contribution to inflamed conditions in the liver, the cardiac, connective and neural tissues, in the nephrons, intestine, lungs and in myriad other body cells is explored, along with detailed explanation on how stilbenes alleviate the symptoms specific to body site. A section on the bioavailability of stilbenes is included for understanding the limitations of the natural compounds as directly used drugs due to their rapid metabolism. Current delivery mechanisms include sulphonamides, or using specially designed synthetic drugs. It is hoped that further research may be fueled by this comprehensive work that makes a compelling argument for the exploitation of these compounds in medicine.

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“…NLRP3 inflammasomes activation regulates tau kinases and phosphatases to promote tau protein phosphorylation and aggregation, and increases the deposition of Aβ by reducing the phagocytic process [ 203 ]. The NLRP3 inflammasomes activation could be inhibited by the activation of autophagy [ 204 ], in return, the autolysosome functions could also be impaired by NLRP3 inflammasomes mediated inflammatory response in the condition of AD [ 205 ]. The PI3K-Akt signaling pathway is an important regulatory pathway in inflammatory stress and autophagy disorders in neurodegenerative diseases.…”

Section: Autophagy May Be a Bridge Between Ad And Energy Crisismentioning

confidence: 99%

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer’s Disease: Current Evidence and Future Avenues

Fan

Wang

2023

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, and autophagy plays important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD, and discussed the interplays existing between energy crisis, autophagy and ferroptosis. In addition, we highlighted the potential network that autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new strategies for treating AD, meanwhile, the energy crisis in the progression of AD should gain more attention.

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IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

Cited by 9 publications

References 42 publications

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice

Stilbenes, a Versatile Class of Natural Metabolites for Inflammation—An Overview

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer’s Disease: Current Evidence and Future Avenues

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