Phytochemical inhibitors of the NLRP3 inflammasome for the treatment of inflammatory diseases

Özenver, Nadire; Efferth, Thomas

doi:10.1016/j.phrs.2021.105710

Cited by 25 publications

(8 citation statements)

References 252 publications

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“…The NLRP3 inflammasome is a complex macromolecule composed of the NLRP3 protein, an apoptosis-associated speck-like protein containing CARD (ASC) and pro-caspase-1. Activated NLRP3 oligomerizes and recruits ASC and pro-caspase-1, which would initiate downstream pyroptosis to release interleukin 1β (IL-1β). − However, IL-1β is not specifically produced by the activation of the NLRP3 inflammasome but also by the activation of other inflammasomes, like AIM2, NLRC4, etc. Since these Tanshinone I-piperidine hybrid compounds could inhibit the secretion of IL-1β effectively, we were wondering whether they could affect NLRP3 inflammasome activation.…”

Section: Resultsmentioning

confidence: 99%

Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor

Sheng

Wang

et al. 2023

J. Med. Chem.

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Natural products provide inspiration and have proven to be the most valuable source for drug discovery. Herein, we report a scaffold hybrid strategy of Tanshinone I for the discovery of NLRP3 inflammasome inhibitors. 36 compounds were designed and synthesized, and the cheminformatic analyses showed that these compounds occupy a unique chemical space. The biological evaluation identified compounds 5j, 12a, and 12d as NLRP3 inflammasome inhibitors with significant potency, selectivity, and drug-likeness. Mechanistic studies revealed that these Tanshinone I derivatives could inhibit the degradation of the protein NLRP3 and block the oligomerization of NLRP3-induced apoptosis-associated speck-like proteins, thus inhibiting NLRP3 inflammasome activation. In addition, the water solubility, in vitro metabolic stability, and oral bioavailability of these compounds were also greatly improved compared to Tanshinone I. Therefore, this protocol provides a new structural evolution of Tanshinone I and a new class of potent NLRP3 inflammasome inhibitors.

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Section: Resultsmentioning

confidence: 99%

Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor

Sheng

Wang

et al. 2023

J. Med. Chem.

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“…In the inflammatory pathway, NLRP3, a component of the inflammasome cytosolic multiprotein complex generated in bone marrow-derived macrophages, stimulated by microbial agents, is also involved. The NLRP3 inflammasome plays a critical role in innate immunity by stimulating active caspase-1 synthesis, which converts IL-1β and IL-18 precursors into their biologically active forms in a sequence of inflammatory responses that leads to pyroptosis 39 . Inhibitory activity of BCP on NLRP3 was observed in a gouty arthritis model in animals 40 and of DHA on the NLRP3 inflammasome induced using silica inhalation.…”

Section: Discussionmentioning

confidence: 99%

β-caryophyllene and docosahexaenoic acid, isolated or associated, have potential antinociceptive and anti-inflammatory effects in vitro and in vivo

Sousa

Oliveira

Selis

et al. 2022

Sci Rep

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Inflammation is a complex biological response involving the immune, autonomic, vascular, and somatosensory systems that occurs through the synthesis of inflammatory mediators and pain induction by the activation of nociceptors. Staphylococcus aureus, the main cause of bacteremia, is one of the most common and potent causes of inflammation in public health, with worse clinical outcomes in hospitals. Antioxidant substances have been evaluated as alternative therapeutic analgesics, antioxidants, anti-inflammatory agents, antitumor agents, and bactericides. Among these, we highlight the essential oils of aromatic plants, such as β-caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The objective of this study was to evaluate the biological activities of BCP–DHA association in in vitro and in vivo experimental models of antinociception and inflammation. To determine the anti-inflammatory effects, monocytes isolated from the peripheral blood of adult male volunteers were infected with methicillin-resistant S. aureus and incubated with treatment for cytokine dosage and gene expression analysis. Antinociceptive effects were observed in the three models when comparing the control (saline) and the BCP-DHA treatment groups. For this purpose, the antinociceptive effects were evaluated in animal models using the following tests: acetic acid-induced abdominal writhing, paw edema induced by formalin intraplantar injection, and von Frey hypernociception. There was a significant reduction in the GM-CSF, TNFα, IL-1, IL-6, and IL-12 levels and an increase in IL-10 levels in the BCP-DHA treatment groups, in addition to negative regulation of the expression of the genes involved in the intracellular inflammatory signaling cascade (IL-2, IL-6, IRF7, NLRP3, and TYK2) in all groups receiving treatment, regardless of the presence of infection. Statistically significant results (p < 0.05) were obtained in the acetic acid-induced abdominal writhing test, evaluation of paw edema, evaluation of paw flinching and licking in the formalin intraplantar injection model, and the von Frey hypernociception test. Therefore, BCP and DHA, either administered individually or combined, demonstrate potent anti-inflammatory and antinociceptive effects.

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“…Our study confirmed the anti-inflammatory effect of Soyeom pharmacopuncture on acute gout, suggested a promising possibility of using Soyeom pharmacopuncture as the first-choice treatment during acute gout flares. NLRP3 inflammasome components are expressed not only in macrophages but also in various cell types of different organs [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Improvement Effect of Soyeom Pharmacopuncture on Gout via NLRP3 Inflammasome Regulation

et al. 2022

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Objectives: Gout is an inflammatory arthritis of the joints and soft tissues occurring due to deposition of monosodium urate (MSU) crystals, which are caused by persistent hyperuricemia. Soyeom pharmacopuncture is one treatment method that has been traditionally used for pain management in Oriental medicine. However, studies on its effect in reducing gout pain have been insufficient. Therefore, we selected Soyeom pharmacopuncture among natural products used in Korea as the new target of our study. Methods: The effects of Soyeom pharmacopuncture were examined in mouse models of acute gout induced by injection of MSU crystals into footpads. IL-1β, IL-6, and TNF-α production were examined by immunoblotting and enzyme-linked immunosorbent assay as hallmarks of NLRP3 inflammasome and cytokine activation. Results: Soyeom pharmacopuncture reduced foot edema in gout-induced mice, as well as IL-1β, nitrite, IL-6, and TNF-α production. Moreover, Soyeom pharmacopuncture also reduced MSU-induced gout inflammatory gene expressions, specifically those in the NF-kB pathway. Conclusion: Pharmacopuncture may serve as a new solution for other inflammatory diseases as well. Through active follow-up studies, we could thoroughly understand the clinical value of Soyeom pharmacopuncture.

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Phytochemical inhibitors of the NLRP3 inflammasome for the treatment of inflammatory diseases

Cited by 25 publications

References 252 publications

Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor

Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor

β-caryophyllene and docosahexaenoic acid, isolated or associated, have potential antinociceptive and anti-inflammatory effects in vitro and in vivo

Improvement Effect of Soyeom Pharmacopuncture on Gout via NLRP3 Inflammasome Regulation

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