Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

International Journal of Molecular Medicine, Год журнала: 2023, Номер 51(4)

Опубликована: Март 21, 2023

The inflammasome regulates innate immunity by serving as a signaling platform. Nod‑like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor apoptosis‑associated speck‑like (ASC) and pro‑caspase‑1, is far most extensively studied well‑characterized inflammasome. A variety of stimuli can activate NLRP3 When activated, recruits ASC activates resulting in inflammatory cytokine maturation secretion, which associated inflammation pyroptosis. However, aberrant activation has been linked to various diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus bowel disease. Therefore, emerged promising therapeutic target for diseases. In present review, systematic searches were performed using 'NLRP3 inhibitor(s)' 'inflammatory disease(s)' key words. By browsing literature from 2012 2022, 100 articles retrieved, 35 excluded they reviews, editorials, retracted or unavailable online, 65 included. According retrieved literature, current understanding pathway diseases was summarize, inhibitors targeting other components products highlighted. Additionally, review briefly discusses novel efforts clinical research.

Язык: Английский

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The gasdermin family: emerging therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Язык: Английский

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Role of NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases

Inflammation Research, Год журнала: 2023, Номер 72(9), С. 1839 - 1859

Опубликована: Сен. 1, 2023

Язык: Английский

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Biomaterials Elicit Pyroptosis Enhancing Cancer Immunotherapy

Advanced Functional Materials, Год журнала: 2023, Номер 34(7)

Опубликована: Ноя. 5, 2023

Abstract Cancer immunotherapy has the potential to revolutionize treatment of malignant tumors, but its effectiveness is limited by low immune response rate and immune‐related adverse events. Pyroptosis, as an inflammatory programmed cell death type, triggers strong acute antitumor immunity, converting “cold” tumors “hot”. Particularly, biomaterials loading pyroptosis inducers targeting tumor microenvironment engineer pyroptosis, have achieved great progress in recent years. Herein, design strategy, mechanism pathway, role induce cancer are comprehensively reviewed. The present review focuses on application biomaterials‐induced immunotherapy, including nanogel, polymer prodrug, nanovesicle, mesoporous material. Additionally, synthesis a series stimuli‐responsive nanoplatforms, glutathione‐responsive, pH‐responsive, reactive oxygen species‐responsive, enzyme‐mimicking catalytic performance, described. Meanwhile, it augments multiple processes uptake, antigen presentation, T‐cell activation, expansion. Finally, perspectives pyroptosis‐mediated inflammation break through vascular basement membrane barrier achieving efficient volcanic penetration discussed. Artificial intelligence, multi‐omics analysis, anthropogenic animal models organoids presented, aiming provide guidance assistance for constructing effective controllable pyroptosis‐engineered improving immunotherapy.

Язык: Английский

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Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway

Cell Biology and Toxicology, Год журнала: 2023, Номер 39(3), С. 621 - 639

Опубликована: Янв. 14, 2023

Язык: Английский

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Decursinol angelate relieves inflammatory bowel disease by inhibiting the ROS/TXNIP/NLRP3 pathway and pyroptosis

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 7, 2025

Despite evidence of the efficacy decursinol angelate (DA), a prescription medication derived farom traditional Chinese medicine, in alleviating inflammatory bowel disease (IBD), precise mechanisms behind its action remain unclear. Lipopolysaccharides (LPS) and dextran sodium sulfate (DSS) induction were used as vitro vivo models IBD, respectively, to assess role DA IBD. Enzyme-linked immunosorbent assay (ELISA) was performed detect expression levels pro-inflammatory cytokines mouse serum, Western blot TXNIP/NLRP3 pathway tight junction (TJ) proteins colon tissues cells, immunohistochemistry, immunofluorescence qRT-PCR validate related this signaling pathway. Molecular docking technique co-immunoprecipitation (Co-IP) method applied evaluate targeting effect on NLRP3 proteins, MCC950, specific inhibitor NLRP3, positive control for validation. Our research indicates that DA's distinctive molecular mechanism could entail binding protein, thereby suppressing activation diminishing assembly inflammasome, thus functioning an anti-inflammatory agent. may play improving BD by inhibiting ROS/TXNIP/NLRP3 release mediators, repairing intestinal barrier function.

Язык: Английский

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Non-coding RNAs affecting NLRP3 inflammasome pathway in diabetic cardiomyopathy: a comprehensive review of potential therapeutic options

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Фев. 28, 2025

Cardiomyopathies are a heterogeneous group of disorders that can lead to fulminant heart failure and sudden cardiac death. In recent years, the prevalence all types cardiomyopathies has shown an upward trend globally. Up 40% patients with cardiomyopathy-related have diabetes mellitus (DM). With fast global spread DM, DCM is increasing accordingly it remains leading cause morbidity mortality in chronic diabetic patients. NLRP3 inflammasome significantly contributes development pathological progression DCM. Targeting or any mediators along its activation pathway provides new potential therapeutic targets for developing specialized drugs treat this comprehensive review, we sought introduce summarize non-coding RNAs effects targeting signaling We hope general overview aid future research therapies

Язык: Английский

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Pyrroloquinoline quinone ameliorates renal fibrosis in diabetic nephropathy by inhibiting the pyroptosis pathway in C57BL/6 mice and human kidney 2 cells

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 150, С. 112998 - 112998

Опубликована: Апрель 27, 2022

Diabetic nephropathy (DN), which is characterized by renal fibrosis, a major complication of diabetes, disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis an essential signaling pathway DN-related injuries, such as fibrosis. Pyrroloquinoline quinone (PQQ) naturally occurring bioactive compound protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused high glucose concentrations. However, the nature and underlying mechanism effect PQQ on fibrosis remains unclear. In this study, we evaluated whether has potential protective effects against due to DN establishing type 1 diabetes mice via streptozotocin treatment then inhibiting their pyroptosis pathway. We found compared control mice, area injury were significantly increased diabetic was accompanied levels expression collagen Ⅰ transforming growth factor-β1; concentrations inflammatory cytokines, interleukin (IL)-1β, IL-6, tumor necrosis factor-α; activation components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1β, IL-18. All these changes reversed treatment. Analogously, treated cultured HK-2 with concentration (35 mmol/L), exhibit reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-κB), p-IkappaB, NLRP3, IL-18, loss mitochondrial transmembrane potential. blunted effects. conclusion, study demonstrated attenuates alleviating dysfunction, reducing ROS production, NF-κB/pyroptosis under conditions hyperglycemia.

Язык: Английский

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Identification of pyroptosis-related genes and potential drugs in diabetic nephropathy

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Июль 21, 2023

Diabetic nephropathy (DN) is one of the serious microvascular complications diabetes mellitus (DM). A growing body research has demonstrated that inflammatory state plays a critical role in incidence and development DN. Pyroptosis new way programmed cell death, which particularity natural immune inflammation. The inhibition cytokine expression regulation pathways related to pyroptosis may be novel strategy for DN treatment. aim this study identify pyroptosis-related genes potential drugs DN.DN differentially expressed were identified via bioinformatic analysis Gene Expression Omnibus (GEO) dataset GSE96804. Dataset GSE30528 GSE142025 downloaded verify (DEGs). Least absolute shrinkage selection operator (LASSO) regression was used construct gene predictive model. consensus clustering performed subtypes. Subsequently, Set Variation Analysis (GSVA), Ontology (GO) function enrichment Kyoto Encyclopedia Genes Genomes (KEGG) pathway conducted explore differences between clusters. protein-protein interaction (PPI) network select hub DGIdb database utilized screen therapeutic drugs/compounds targeting genes.A total 24 16 model LASSO analysis. According level these genes, cases divided into two subtypes, subtypes are mainly associated with inflammation, activation response metabolism. In addition, we 10 among predicted 65 therapeutics target key genes.We clusters therapeutical agents/compounds DN, might shed light on treatment

Язык: Английский

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Astragaloside IV attenuates renal tubule injury in DKD rats via suppression of CD36-mediated NLRP3 inflammasome activation

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Март 20, 2024

Background: In recent years, diabetic kidney disease (DKD) has emerged as a prominent factor contributing to end-stage renal disease. Tubulointerstitial inflammation and lipid accumulation have been identified key factors in the development of DKD. Earlier research indicated that Astragaloside IV (AS-IV) reduces oxidative stress, controls accumulation, provides protection kidneys. Nevertheless, mechanisms responsible for its protective effects against DKD not yet completely elucidated. Purpose: The primary objective this was examine properties AS-IV investigate underlying mechanism, which involves CD36, reactive oxygen species (ROS), NLR family pyrin domain containing 3 (NLRP3), interleukin-1β (IL-1β). Methods: rat model created by administering streptozotocin along with high-fat diet. Subsequently, rats palmitic acid (PA)-induced HK-2 cells were treated AS-IV. Atorvastatin used positive control. To assess therapeutic on DKD, various tests including blood sugar levels, profile, function, histopathological examinations conducted. levels ROS, NLRP3, Caspase-1, IL-1β detected using western blot analysis, PCR, flow cytometry. Furthermore, adenovirus-mediated CD36 overexpression applied explore through vitro experiments. Results: vivo experiments demonstrated significantly reduced hyperglycemia, dyslipidemia, urinary albumin excretion, serum creatinine rats. Additionally, it improved structural abnormalities suppressed expression IL-1β, TNF-α, MCP-1. showed decreased expression, ROS production while inhibiting NLRP3 activation secretion PA-induced cells. Conclusion: alleviated tubule interstitial epithelial cell apoptosis CD36-mediated inflammasome activation.

Язык: Английский

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