NLRP3 inflammasome: a key player in the pathogenesis of life-style disorders

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(7), P. 1488 - 1500

Published: July 1, 2024

Abstract Proinflammatory cytokines and chemokines play a crucial role in regulating the inflammatory response, which is essential for proper functioning of our immune system. When infections or threats to body’s defense mechanisms are detected, innate system takes lead. However, an excessive response can lead production high concentrations cytotoxic molecules, resulting tissue damage. Inflammasomes significant contributors immunity, one most extensively studied inflammasome complexes NOD-like receptor 3 (NLRP3). NLRP3 has wide range recognition that streamline activation eliminate pathogens. These cytosolic multiprotein composed effector, adaptor, sensor proteins, identifying intracellular bacterial breakdown products initiating cascade. To understand diverse behavior its significance development lifestyle-related diseases, must delve into study apoptosis mediated by release proinflammatory cytokines. In this review, we briefly explore context lifestyle associated disorders such as obesity, hyperlipidemia, diabetes, chronic respiratory disease, oral cardiovascular disease.

Language: Английский

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Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants

Nature Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β IL-18. Gain-of-function variants in gene encoding (also called cryopyrin) lead to constitutive excessive IL-1β production cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening automated analysis 534 from international INFEVERS registry ClinVar database. This resource captures effect on ASC speck formation spontaneously, at low temperature, after stimulation with specific inhibitor MCC950. Most notably, our facilitated updated classification INFEVERS. Structural suggested multiple mechanisms by which CAPS activate NLRP3, enhanced ATP binding, stabilizing active conformation, destabilizing inactive promoting oligomerization pyrin domain. Furthermore, identified pathogenic can hypersensitize response nigericin cold temperature exposure. We also found most CAPS-related be inhibited MCC950; however, changes proline affecting helices near binding site are resistant MCC950, as domain, likely trigger directly domain ASC. Our findings could help stratify population for clinical trials methodologies implemented molecules different mechanism laboratories worldwide interested adding new functionally validated resource. Overall, study provides improved diagnosis patients CAPS, mechanistic insight into stratification future application targeted therapeutics.

Language: Английский

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Inflammasome activation in traumatic brain injury and Alzheimer's disease

Translational research, Journal Year: 2022, Volume and Issue: 254, P. 1 - 12

Published: Sept. 6, 2022

Language: Английский

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Pyroptosis in diabetes and diabetic nephropathy

Clinica Chimica Acta, Journal Year: 2022, Volume and Issue: 531, P. 188 - 196

Published: April 13, 2022

Language: Английский

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Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis

Journal of Inflammation Research, Journal Year: 2023, Volume and Issue: Volume 16, P. 2727 - 2754

Published: June 30, 2023

Bronchial asthma is a complex heterogeneous airway disease, which has emerged as global health issue. A comprehensive understanding of the different molecular mechanisms bronchial may be an efficient means to improve its clinical efficacy in future. Increasing research evidence indicates that some types programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, contributed pathogenesis, become new targets for future treatment. This review briefly discusses mechanism signaling pathway these forms PCD focuses on summarizing their roles pathogenesis treatment strategies offers therapeutics near

Language: Английский

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Metaflammation in glucolipid metabolic disorders: Pathogenesis and treatment

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114545 - 114545

Published: March 20, 2023

The public health issue of glucolipid metabolic disorders (GLMD) has grown significantly, posing a grave threat to human wellness. Its prevalence is rising yearly and tends affect younger people. Metaflammation an important mechanism regulating body metabolism. Through complicated multi-organ crosstalk network involving numerous signaling pathways such as NLRP3/caspase-1/IL-1, NF-B, p38 MAPK, IL-6/STAT3, PI3K/AKT, it influences systemic regulation. Numerous inflammatory mediators are essential for preserving balance, but more research needed determine how they contribute the co-morbidities diseases. Whether controlling response can influence progression GLMD determines therapeutic strategy This review thoroughly examines role metaflammation in combs progress related approaches, including factor-targeting drugs, traditional Chinese medicine (TCM), exercise therapy. Multiple diseases, diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, others, respond therapeutically anti-inflammatory therapy on whole. Moreover, we emphasize value open question anti-inflammatory-based means treating GLMD.

Language: Английский

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NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 999 - 999

Published: March 23, 2023

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant players such as microglia/monocytes typically exhibit strong NLRP3 inflammasome activation. Hence idea suppression might solve neurodegenerative ailments. Here we review recent Literature about this topic. First, update conditions mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, ethnic/pharmacological agents/extracts regulating function. Second, pinpoint NLRP3-activating mechanisms known inhibition effects in (ischemia, stroke, hemorrhage), (Alzheimer’s disease, Parkinson’s Huntington’s MS, ALS), virus-induced (Zika, SARS-CoV-2, others) diseases. The available data show (i) disease-specific divergent activate (mainly animal) brains NLRP3; (ii) no evidence proves modifies (yet ad hoc trials ongoing); (iii) findings exclude concurrently activated other-than-NLRP3 inflammasomes functionally replace inhibited NLRP3. Finally, highlight among causes persistent therapies species difference problem disease models preference symptomatic over etiologic therapeutic approaches. Therefore, posit neural cell-based could drive etiological, pathogenetic, advances, NLRP3’s other inflammasomes’ regulation, while minimizing failure risks candidate drug trials.

Language: Английский

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METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 13, 2024

Abstract Acute lung injury (ALI) as well its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N 6 -methyladenosine (m A) modification was associated with the progression of several diseases. However, role methyltransferase-like 14 (METTL14)-mediated m A methylation in ALI/ARDS remains unclear. Here, we reported increase overall expression levels and METTL14 circulating monocyte-derived macrophages recruited following ALI, which is correlated severity injury. We further demonstrated critical function activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome vitro mouse models ALI/ARDS, validated NLRP3 downstream target by RNA immunoprecipitation (MeRIP) RIP assays. Mechanistically, METTL14-methylated transcripts were subsequently recognized insulin-like growth factor 2 mRNA-binding (IGF2BP2), reader, stabilized mRNA. Furthermore, observed that IGF2BP2 knockdown diminished LPS-induced ALI mice downregulating expression. In summation, our study revealed molecular mechanism underlying pathogenesis involves METTL14-mediated activation dependent manner, thereby demonstrating potential promising biomarkers therapeutic targets for treatment.

Language: Английский

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Role of pyroptosis in diabetic cardiomyopathy: an updated review

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 5, 2024

Diabetic cardiomyopathy (DCM), one of the common complications diabetes, presents as a specific with anomalies in structure and function heart. With increasing prevalence DCM has high morbidity mortality worldwide. Recent studies have found that pyroptosis, programmed cell death accompanied by an inflammatory response, exacerbates growth genesis DCM. These provide theoretical basis for exploring potential treatment Therefore, this review aims to summarise possible mechanisms which pyroptosis promotes development well relevant targeting DCM, focusing on molecular NLRP3 inflammasome-mediated different cellular pathways associated effects occurring cells drugs inflammasome/pyroptosis This might fresh perspective foundation therapeutic agents

Language: Английский

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Role of Peripheral NLRP3 Inflammasome in Cognitive Impairments: Insights of Non-central Factors

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Language: Английский

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