The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 10, 2022

The NLRP3 inflammasome is a multiprotein complex that plays pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs DAMPs, oligomerizes activates caspase-1 which initiates processing release of pro-inflammatory cytokines IL-1β IL-18. most extensively studied to date due its array activators aberrant several diseases. Studies using small molecules biologics targeting pathway have shown positive outcomes treating various disease pathologies blocking chronic inflammation. In this review, we discuss recent advances understanding mechanism, pathology, provide broad review therapeutics discovered target their challenges.

Language: Английский

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The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 9

Published: Jan. 8, 2019

Oxidative stress and inflammation are the most important pathogenic events in development progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is master regulator cellular protection via induction anti-inflammatory, antioxidant, cyto-protective genes expression. Multiple studies have shown that activation or suppression this transcriptional significantly affect Comprehensive understanding roles Nrf2 activation/expression outcomes its activators/inhibitors indispensable for defining mechanisms therapeutic strategies against In current review, we discussed recent advances function principal by regulating diseases, including acute failure, hepatic ischemia-reperfusion injury, alcoholic disease, viral hepatitis, nonalcoholic fatty steatohepatitis, hepatocellular carcinoma.

Language: Английский

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Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis

Arthritis Research & Therapy, Journal Year: 2019, Volume and Issue: 21(1)

Published: Dec. 1, 2019

Abstract Introduction Osteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in elderly. Reactive oxygen species (ROS) play important role OA development; they may activate NLRP3 inflammasome, thereby inducing secretion proinflammatory IL-1β and IL-18, leading to aggravation downstream response. Nrf2 a key transcription factor regulates expression antioxidant enzymes protect against oxidative stress tissue damage. We aimed explore underlying mechanism development by investigating NLRP3, ASC, Nrf2, HO-1 synovia their regulatory networks OA. Methods Human total knee replacement samples were subjected histology micro-CT analysis determine pathological changes cartilage subchondral bone assess inflammation-related markers synovial immunohistochemistry (IHC), qRT-PCR, Western blot. To investigate these animal model, adult Sprague-Dawley rats anterior cruciate ligament transection medial meniscectomy. Articular also determined same methods used for human samples. Finally, SW982 cells stimulated with lipopolysaccharide (LPS) as vitro cell model. The correlation between was confirmed knocking down or Nrf2. Results Cartilage destruction sclerosis found patients model rats. Significantly increased levels from patients. synovium upregulated group compared sham group. Furthermore, HO-1, IL-1β, IL-18 LPS-treated dose-dependent manner. As expected, upregulated, downregulated after silencing. However, did not affect Conclusions ROS-induced be main cause inflammasome activation subsequent release factors during development. Nrf2/HO-1 signaling could pathway which contribute progression Herein, we discovered novel production facilitate prevention treatment

Language: Английский

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Food as medicine: targeting the uraemic phenotype in chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 17(3), P. 153 - 171

Published: Sept. 22, 2020

Language: Английский

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Potential Applications of NRF2 Inhibitors in Cancer Therapy

Oxidative Medicine and Cellular Longevity, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 34

Published: April 11, 2019

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing expression several cytoprotective genes, transcription factor NRF2 can shelter cells and tissues from multiple sources damage including xenobiotic, electrophilic, metabolic, oxidative stress. Importantly, aberrant activation accumulation NRF2, a common event in many tumors, confers selective advantage to cancer is associated malignant progression, therapy resistance, poor prognosis. Hence, last years, has emerged as promising target treatment efforts have been made identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing results past recent studies, this review, we provide an overview concerning pathway, biological impact solid hematologic malignancies, molecular causing hyperactivation cells. Finally, also describe some approaches that successfully employed counteract activity with particular emphasis on development natural compounds adoption drug repurposing strategies.

Language: Английский

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Inflammasomes and Fibrosis

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: June 11, 2021

Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role progression fibrosis as innate immune receptors. There are four main members inflammasomes, such NOD-like receptor protein 1 (NLRP1), 3 (NLRP3), C4 (NLRC4), and absent melanoma 2 (AIM2), among which NLRP3 inflammasome most studied. typically composed NLRP3, ASC pro-caspase-1. activation involves both “classical” “non-classical” pathways former better understood. that backbone activated by endogenous/exogenous stimulation, leading to assembly. After formation “classic” inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, secreted extracellularly. At present, has not formed a unified model for process. This article reviews NLRP1, NLRC4, AIM2 Caspase-1, IL-1β, IL-18 IL-33 fibrogenesis.

Language: Английский

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Nrf2 and oxidative stress in liver ischemia/reperfusion injury

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(18), P. 5463 - 5479

Published: Dec. 30, 2021

In response to stress signal, nuclear factor‐erythroid 2‐related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification. Nrf2 activity is strictly regulated through a variety mechanisms, including regulation Keap1‐Nrf2 stability, transcriptional (NF‐ĸB, ATF3, ATF4), post‐transcriptional (miRNA), evidencing that responses are critical for maintenance homeostasis. Ischemia‐reperfusion (IR) injury major cause graft loss dysfunction clinical transplantation organ resection. During IR process, generation reactive oxygen species (ROS) leads damage from oxidative stress, oxidation biomolecules, mitochondrial dysfunction. Oxidative can trigger apoptotic necrotic cell death. Stress factors also result assembly inflammasome protein complex subsequent activation secretion proinflammatory cytokines. After activation, downstream upregulation act as primary cellular against cytotoxic effects help promote hepatic recovery during IR. The crosstalk between pathways liver potential therapeutic inducers will be discussed present review.

Language: Английский

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Loop Between NLRP3 Inflammasome and Reactive Oxygen Species

Antioxidants and Redox Signaling, Journal Year: 2021, Volume and Issue: 36(10-12), P. 784 - 796

Published: Sept. 20, 2021

Significance: Inflammasomes are cytosolic multiprotein complexes that mediate innate immune pathways. activate inflammatory caspases and regulate cytokines interleukin (IL)-1β IL-18 as well cell death (pyroptosis). Among known inflammasomes, NLRP3 (NLR family pyrin domain containing 3) inflammasome is unique studied owing to the fact it senses a broad range of stimuli implicated in pathogenesis both microbial sterile diseases. Recent Advances: Reactive oxygen species (ROS), especially derived from mitochondria, one critical mediators activation. Furthermore, inflammasome-driven inflammation recruits cells, including macrophages neutrophils, which turn cause ROS production, suggesting feedback loop between inflammasome. Critical Issues: The precise mechanism how affects activation still need be addressed. This review will summarize current knowledge on molecular mechanisms underlying with particular emphasis intricate balance Future Directions: Understanding this relationship rather than traditionally understood linear enable fine-tune under varied pathological settings. Antioxid. Redox Signal. 36, 784-796.

Language: Английский

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“LONG COVID”—A hypothesis for understanding the biological basis and pharmacological treatment strategy

Pharmacology Research & Perspectives, Journal Year: 2022, Volume and Issue: 10(1)

Published: Jan. 13, 2022

Abstract Infection of humans with SARS‐CoV‐2 virus causes a disease known colloquially as “COVID‐19” symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due the binding ACE‐2 protein on endothelial cells lining blood vessels and entering these in order replicate. Viral replication oxidative stress elevated levels reactive oxygen species. Many (~60%) infected people appear have eliminated their body after 28 days resume normal activity. However, significant proportion (~40%) experience variety (loss smell and/or taste, fatigue, cough, aching pain, “brain fog,” insomnia, shortness breath, tachycardia) 12 weeks are diagnosed syndrome named “LONG COVID.” Longitudinal clinical studies group subjects who were been compared non‐infected matched subjects. A cohort can be identified by battery cytokine markers persistent, low level grade inflammation often self‐report two or more troubling symptoms. There no drug that will relieve effectively. It hypothesized drugs activate intracellular transcription factor, nuclear factor erythroid‐derived 2‐like 2 (NRF2) may increase expression enzymes synthesize antioxidant, glutathione quench free radicals causing stress. The hormone melatonin has an activator NRF2 relatively safe chemical for most ingest chronically. Thus, it option consideration re‐purposing COVID” experiencing depression, fog” but not tachycardia. Appropriately designed trials required evaluate melatonin.

Language: Английский

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The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(9), P. 1790 - 1803

Published: March 9, 2022

Language: Английский

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