Mitochondrial‐Targeted Delivery of Polyphenol‐Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(11)

Published: Jan. 17, 2023

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery drugs to mitochondria efficient clearance mtROS remain challenging. In current study, it discovered that polyphenols such as tannic acid (TA) can mediate the targeting polyphenol/antioxidases complexes mitochondria. This affinity does not depend on membrane potential but stems from strong binding TA outer proteins. Taking advantage feasibility self-assembly between proteins, superoxide dismutase, catalase, are assembled into (referred TSC) enzymatic activity maintenance. vitro fluorescence confocal imaging shows TSC only promoted uptake biological enzymes in hepatocytes also highly overlapped with after lysosomal escape. The results an model hepatocyte oxidative stress demonstrate efficiently scavenges excess reverses depolarization, thereby inflammasome-mediated pyroptosis. More interestingly, maintain superior efficacy compared clinical gold standard drug N-acetylcysteine both acetaminophen- D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. conclusion, this study opens new paradigm inhibit pyroptosis treat inflammatory diseases.

Language: Английский

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LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(5)

Published: May 8, 2023

Abstract Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research great importance in combatting resistance. A comprehensive investigation molecular mechanisms underlying has important implications for overcoming An accumulating body evidence shows that lncRNAs can contribute tumorigenesis and By bioinformatics analysis, we found LINC00969 expression was elevated cells with acquired gefitinib regulated vitro vivo. Mechanistically, gain H3K4me1 H3K27Ac led activation expression. interacts EZH2 METTL3, transcriptionally regulates level H3K27me3 NLRP3 promoter region, posttranscriptionally modifies m6A an m6A-YTHDF2-dependent manner, thus epigenetically repressing suppress NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing antipyroptotic phenotype promoting TKI cancer. Our findings provide a new mechanism lncRNA-mediated from perspective via simultaneous regulation histone methylation RNA methylation. The pivotal role gives it potential be novel biomarker therapeutic target EGFR-TKI

Language: Английский

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Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection

Redox Biology, Journal Year: 2023, Volume and Issue: 67, P. 102894 - 102894

Published: Oct. 6, 2023

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury cardioprotection. In first part, continued need for cardioprotection beyond that by rapid reperfusion acute infarction is emphasized. Then, pathomechanisms to myocardium coronary circulation different modes cell death are characterized. Different mechanical pharmacological interventions protect ischemic/reperfused elective percutaneous artery bypass grafting, cardiotoxicity from cancer therapy detailed. second part keeps focus on ROS providing a comprehensive overview molecular cellular mechanisms involved injury. Starting mitochondria as main sources targets myocardium, complex network extracellular processes discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk NAPDH oxidases, exosomes, cytokines growth factors. While mechanistic insights needed improve our current therapeutic approaches, advancements knowledge ROS-mediated indicate facets oxidative stress opposed requirement physiological protective reactions. This inevitable contrast likely underlie unsuccessful clinical trials limits development novel cardioprotective simply based upon removal.

Language: Английский

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Involvement of inflammasomes in tumor microenvironment and tumor therapies

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: March 17, 2023

Abstract Inflammasomes are macromolecular platforms formed in response to damage-associated molecular patterns (DAMPs) and pathogen-associated patterns, whose formation would cause maturation of interleukin-1 (IL-1) family members gasdermin D (GSDMD), leading IL-1 secretion pyroptosis respectively. Several kinds inflammasomes detecting different types dangers have been found. The activation is regulated at both transcription posttranscription levels, which crucial protecting the host from infections sterile insults. Present findings illustrated that involved not only infection but also pathology tumors implying an important link between inflammation tumor development. Generally, participate tumorigenesis, cell death, metastasis, immune evasion, chemotherapy, target therapy, radiotherapy. Inflammasome components upregulated some tumors, can be activated cancer cells other stromal by DAMPs, chemotherapy agents, radiation. In cases, inhibit progression initiating GSDMD-mediated stimulating signal-mediated anti-tumor immunity. However, signal recruits immunosuppressive subsets cases. We discuss conflicting results propose possible explanations. Additionally, we summarize interventions targeting inflammasome pathways preclinical clinical stages. Interventions promising for immunotherapy combination therapy.

Language: Английский

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Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

Advanced Science, Journal Year: 2023, Volume and Issue: 10(26)

Published: July 12, 2023

In recent years, the incidence of gastrointestinal cancers is increasing, particularly in younger population. Effective treatment crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role growth and development organisms. It also critical maintaining tissue organ homeostasis takes part multiple pathological processes. addition to apoptosis, there are other types programmed such as ferroptosis, necroptosis, pyroptosis, which can induce severe inflammatory responses. Notably, besides pyroptosis contribute occurrence cancers. This review aims provide comprehensive summary on biological roles molecular mechanisms well their regulators hope open up new paths tumor targeted therapy near future.

Language: Английский

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Pyroptosis in health and disease: mechanisms, regulation and clinical perspective

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 20, 2024

Language: Английский

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Role of pyroptosis in the pathogenesis of various neurological diseases

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 117, P. 428 - 446

Published: Feb. 7, 2024

Language: Английский

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BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis

Advanced Science, Journal Year: 2024, Volume and Issue: 11(11)

Published: Jan. 4, 2024

Abstract Various forms of programmed cell death (PCD) exhibit distinct characteristics depending on their specific molecular mechanisms, and there are interactions among these different forms. Ferroptosis, which is related to autophagy apoptosis, has an unknown potential interaction with pyroptosis. This study revealed a mutually antagonistic relationship between ferroptosis pyroptosis, 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) playing key role in interaction. It found that HMGCR predominantly localized mitochondria during but shifted the endoplasmic reticulum following treatment pyroptosis inducer. Furthermore, this demonstrated BRCC36 (BRCA1/BRCA2‐containing complex subunit 36) deubiquitinated manner dependent deubiquitinating enzyme (DUB) activity, inhibited promoted Moreover, as oncogene hepatocellular carcinoma (HCC), cancer proliferation, migration, invasion, tumor growth. Thiolutin, inhibitor BRCC36, effectively suppressed HMGCR, leading inhibition HCC Therefore, targeting can offer novel promising therapeutic strategy for treatment. In conclusion, findings provide new theoretical evidence further characterizing heterogeneity targets diagnosis HCC.

Language: Английский

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Endothelial Dysfunction: Redox Imbalance, NLRP3 Inflammasome, and Inflammatory Responses in Cardiovascular Diseases

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 256 - 256

Published: Feb. 23, 2025

Endothelial dysfunction (ED) is characterized by an imbalance between vasodilatory and vasoconstrictive factors, leading to impaired vascular tone, thrombosis, inflammation. These processes are critical in the development of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension ischemia/reperfusion injury (IRI). Reduced nitric oxide (NO) production increased oxidative stress key contributors ED. Aging further exacerbates ED through mitochondrial oxidative/nitrosative stress, heightening CVD risk. Antioxidant systems like superoxide-dismutase (SOD), glutathione-peroxidase (GPx), thioredoxin/thioredoxin-reductase (Trx/TXNRD) pathways protect against stress. However, their reduced activity promotes ED, vulnerability IRI. Metabolic syndrome, comprising insulin resistance, obesity, hypertension, often accompanied Specifically, hyperglycemia worsens endothelial damage promoting Obesity leads chronic inflammation changes perivascular adipose tissue, while associated with increase The NLRP3 inflammasome plays a significant role being triggered factors reactive oxygen nitrogen species, ischemia, high glucose, which contribute inflammation, injury, exacerbation Treatments, N-acetyl-L-cysteine, SGLT2 or inhibitors, show promise improving function. Yet complexity suggests that multi-targeted therapies addressing metabolic disturbances essential for managing CVDs syndrome.

Language: Английский

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Emerging pyroptosis-engineered nanobiotechnologies regulate cancers and inflammatory diseases: A double-edged sword

Matter, Journal Year: 2022, Volume and Issue: 5(11), P. 3740 - 3774

Published: Nov. 1, 2022

Language: Английский

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