Advancements in Predictive Medicine: NLRP3 Inflammasome Inhibitors and AI-Driven Predictive Health Analytics DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(3), P. 331 - 333

Published: Feb. 13, 2024

Recent advancements in predictive medicine are significantly reshaping the field, primarily through developing novel NLRP3 inflammasome inhibitors and applying AI-driven health analytics. offer new therapeutic strategies for treating inflammatory neurodegenerative diseases. Concurrently, AI's role analytics marks a transformative shift disease management personalized healthcare. By analyzing complex biomarker data, AI provides crucial insights into individual trajectories, enabling early interventions customized treatment plans. This convergence of cutting-edge therapies technology heralds era precision healthcare strategies.

Language: Английский

Inflammasome components as new therapeutic targets in inflammatory disease DOI
Rebecca C. Coll, Kate Schroder

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 9, 2024

Language: Английский

Citations

27
Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors DOI
Juraj Velcicky,

Philipp Janser,

Nina Gommermann

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(2), P. 1544 - 1562

Published: Jan. 4, 2024

NLRP3 is a molecular sensor recognizing wide range of danger signals. Its activation leads to the assembly an inflammasome that allows for caspase-1 and subsequent maturation IL-1β IL-18, as well cleavage Gasdermin-d pyroptotic cell death. The has been implicated in plethora diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, cancer. In this publication, we describe discovery novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. hit (1) could be optimized into advanced compound NP3–562 demonstrating excellent potency human whole blood full inhibition release mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure bound NACHT domain revealed unique binding mode compared known sulfonylurea-based inhibitors. addition, shows also good overall development profile.

Language: Английский

Citations

21
Degrading the key component of the inflammasome: Development of an NLRP3 PROTAC DOI

Tim Keuler,

Dominic Ferber,

Jonas Engelhardt

et al.

Chemical Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

The bifunctional compound V2 induced a VHL-dependent NLRP3 degradation. postulated ternary complex formation involves the molecular interaction of (cyan) to binding sites VHL (magenta) and (orange).

Language: Английский

Citations

1
The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review DOI Open Access
Po‐Ku Chen, Kuo‐Tung Tang, Der‐Yuan Chen

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(1), P. 626 - 626

Published: Jan. 3, 2024

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage bone. RA commonly accompanied extra-articular comorbidities. The pathogenesis its comorbidities complex not completely elucidated. assembly NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces maturation interleukin (IL)-1β IL-18 leads to cleavage gasdermin D with promoting pyroptosis. Accumulative evidence indicates pathogenic role NLRP3 signaling in comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, interstitial lung diseases. Although available therapeutic agents are effective for treatment, their high cost increased infection rate causes concern. Recent revealed components as potential targets In this review, we searched MEDLINE database using PubMed interface reviewed English-language literature on from 2000 2023. current reveals that contributes Consequently, pathway represent promising targets, ongoing research might lead development new, treatments

Language: Английский

Citations

8
Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury DOI Creative Commons
Simone Gastaldi, Magalì Giordano, Federica Blua

et al.

Vascular Pharmacology, Journal Year: 2024, Volume and Issue: 156, P. 107397 - 107397

Published: June 17, 2024

Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) caspase-1. However, may paradoxically exhibit cardioprotective properties. This study aimed assess protective effects novel inhibitor, INF195, both in vitro ex vivo. To investigate relationship between myocardial IRI, we synthetized a series inhibitors, investigated their putative binding mode via docking studies. Through studies identified INF195 optimal for inhibition. We measured infarct-size isolated mouse hearts subjected 30-min global ischemia/one-hour reperfusion presence three different doses (5, 10, or 20-μM). analyzed caspase-1 IL-1β concentration cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed Tukey's test. reduces NLRP3-induced pyroptosis human macrophages. Heart pre-treatment with 5 10-μM significantly infarct size levels. Data suggest that intracardiac contributes IRI low exert reducing size. at 20-μM, efficacy declines, leading lack cardioprotection. Research is required determine if high have off-target dual roles, potentially eliminating harmful functions NLRP3. Our findings highlight potential new chemical scaffold, amenable further optimization, provide inhibition cardioprotection setting.

Language: Английский

Citations

6
Association between silicosis and autoimmune disease DOI Creative Commons
Elizabeth Fireman, Einat Fireman Klein

Current Opinion in Allergy and Clinical Immunology, Journal Year: 2024, Volume and Issue: 24(2), P. 45 - 50

Published: Jan. 24, 2024

Purpose of review There is a well established association between silica inhalational exposure and autoimmune disease, particularly in the context intense exposure. We will provide this article an update overview new sources dust exposure, with evidences mechanisms from human animal studies for diseases, their early detection silicosis options treatment. Recent findings New industries such as jewelry polishing, denim jean production, fabrication artificial stone benchtops, glass manufacturing glassware has led to re-emergence around world. Silicosis long term containing crystalline been examined possible risk factor respect several diseases scleroderma, rheumatoid arthritis, lupus erythematosus, some types small vessel vasculitis renal involvement. The may act promote or accelerate disease development, requiring other factors break immune tolerance initiate autoimmunity. Autophagy, apoptosis, pyroptosis-related signaling pathways have also suggested contribute formation those coordination environmental co-exposure that can magnify vulnerability. Summary Better understanding involve -induced diagnosis.

Language: Английский

Citations

5
Discovery of Potent, Specific, and Orally Available NLRP3 Inflammasome Inhibitors Based on Pyridazine Scaffolds for the Treatment of Septic Shock and Peritonitis DOI
Zhiyuan Fu,

Yangqin Duan,

Heying Pei

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 15711 - 15737

Published: Aug. 22, 2024

The NLRP3 inflammasome is a multiprotein complex that component of the innate immune system, involved in production pro-inflammatory cytokines. Its abnormal activation associated with many inflammatory diseases. In this study, we designed and synthesized series inhibitors based on pyridazine scaffolds. Among them, P33 exhibited significant inhibitory effects against nigericin-induced IL-1β release THP-1 cells, BMDMs, PBMCs, IC50 values 2.7, 15.3, 2.9 nM, respectively. Mechanism studies indicated directly binds to protein (KD = 17.5 nM), inhibiting pyroptosis by suppressing ASC oligomerization during assembly. Additionally, displayed excellent pharmacokinetic properties, an oral bioavailability 62%. vivo efficacy revealed significantly ameliorated LPS-induced septic shock MSU crystal-induced peritonitis mice. These results indicate has great potential for further development as candidate treating inflammasome-mediated

Language: Английский

Citations

5
Metabolite-sensing GPCRs in rheumatoid arthritis DOI
Xuezhi Yang,

Wankang Zhang,

Luping Wang

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(2), P. 118 - 133

Published: Jan. 5, 2024

Language: Английский

Citations

4
Hypocrellin A from an ethnic medicinal fungus protects against NLRP3-driven gout in mice by suppressing inflammasome activation DOI
Yan Li, Shuang Qi, Chao Wu

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Language: Английский

Citations

4
TLR/NLRP3 Inflammasome signaling pathways as a main target in frailty, cachexia and sarcopenia DOI
Sanaz Keshavarz Shahbaz,

Aida Mokhlesi,

Roghaye Keshavarz Sadegh

et al.

Tissue and Cell, Journal Year: 2025, Volume and Issue: 93, P. 102723 - 102723

Published: Jan. 9, 2025

Language: Английский

Citations

0