Regulation of immunomodulatory networks by Nrf2-activation in immune cells: Redox control and therapeutic potential in inflammatory diseases

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103077 - 103077

Published: Feb. 11, 2024

Inflammatory diseases present a serious health challenge due to their widespread prevalence and the severe impact on patients' lives. In quest alleviate burden of these diseases, nuclear factor erythroid 2-related 2 (Nrf2) has emerged as pivotal player. As transcription intimately involved in cellular defense against metabolic oxidative stress, Nrf2's role modulating inflammatory responses immune cells garnered significant attention. Recent findings suggest that ability alter redox status underlies its regulatory effects responses. Our review delves into preclinical clinical evidence underscores complex influence Nrf2 activators cell phenotypes, particularly milieu. By offering detailed analysis different populations, we cast light potential shaping response towards more regulated state, mitigating adverse inflammation through modeling cells. Furthermore, explore innovative use nanoencapsulation techniques enhance delivery efficacy activators, potentially advancing treatment strategies for ailments. We hope this will stimulate development expansion Nrf2-targeted treatments could substantially improve outcomes patients suffering from broad range diseases.

Language: Английский

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Thirty years of NRF2: advances and therapeutic challenges

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Language: Английский

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Research in the Field of Drug Design and Development

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(9), P. 1283 - 1283

Published: Sept. 11, 2023

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many exciting techniques being developed over the past 5-10 years alone. Drug design discovery, search for safe well-tolerated compounds, as well ineffectiveness of existing therapies, society's insufficient knowledge concerning prophylactics pharmacotherapy most common diseases today, comprise serious challenge. This can influence not only quality human life, but also health whole societies, which became evident during COVID-19 pandemic. In general, process drug development consists three main stages: preclinical using cell-based animal models/tests, clinical trials on humans and, finally, forward moving toward step obtaining regulatory approval, in order market potential drug. this review, we will attempt outline first important consecutive phases development, based experience cooperating complementary centers Visegrád group; i.e., Medical University Lublin, Poland, Masaryk Brno, Czech Republic, Comenius Bratislava, Slovak Republic.

Language: Английский

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Specific targeting of the NRF2/β-TrCP axis promotes beneficial effects in NASH

Redox Biology, Journal Year: 2024, Volume and Issue: 69, P. 103027 - 103027

Published: Jan. 3, 2024

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises function, for which there not specifically approved medicine. Recent research has identified transcription factor NRF2 as potential therapeutic target. However, current activators, designed to inhibit its repressor KEAP1, exhibit unwanted side effects. Alternatively, we previously introduced PHAR, protein-protein interaction inhibitor of NRF2/β-TrCP, induces mild activation and selectively activates in the liver, close normal physiological levels. Herein, assessed effect PHAR protection against NASH progression fibrosis. We conducted experiments demonstrate effectively activated hepatocytes, Kupffer cells, stellate cells. Then, used STAM mouse model NASH, based on partial damage endocrine pancreas insulin secretion impairment, followed by high fat diet. Non-invasive analysis using MRI revealed protects accumulation. Moreover, attenuated key markers progression, including steatosis, hepatocellular ballooning, inflammation, Notably, transcriptomic data indicate led upregulation 3 anti-fibrotic genes (Plg, Serpina1a, Bmp7) downregulation 6 pro-fibrotic (including Acta2 Col3a1), 11 extracellular matrix remodeling, 8 inflammatory genes. Overall, our study suggests via holds promise strategy addressing

Language: Английский

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Health position paper and redox perspectives – Bench to Bedside Transition for Pharmacological Regulation of NRF2 in Noncommunicable Diseases

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103569 - 103569

Published: March 1, 2025

Nuclear factor erythroid 2-related 2 (NRF2) is a redox-activated transcription regulating cellular defense against oxidative stress, thereby playing pivotal role in maintaining homeostasis. Its dysregulation implicated the progression of wide array human diseases, making NRF2 compelling target for therapeutic interventions. However, challenges persist drug discovery and safe targeting NRF2, as unresolved questions remain especially regarding its context-specific diseases off-target effects. This comprehensive review discusses dualistic disease pathophysiology, covering protective and/or destructive roles autoimmune, respiratory, cardiovascular, metabolic well digestive system cancer. Additionally, we also development drugs that either activate or inhibit discuss main barriers translating NRF2-based therapies from bench to bedside, consider ways monitor activation vivo.

Language: Английский

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The Dual‐Target Nanoparticles with ROS Sensitivity Inhibit the Hedgehog Signaling Pathway and Decrease Oxidative Stress in Activated Hepatic Stellate Cells to Alleviate Liver Fibrosis

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown

Published: July 6, 2024

Abstract Liver fibrosis is characterized by excess reactive oxygen species (ROS) production, hepatic stellate cell (HSC) activation, and subsequent extracellular matrix deposition. Since complex pathways regulate HSC the single‐drug therapy efficacy for live often falls short of expectations. To address this issue, an HSC‐targeted multifunctional nanoparticle (NP) delivery system co‐loaded with cyclopamine (Cyc; hedgehog inhibitor) bilirubin (BR; ROS‐scavenger) designed. The NP, termed RHB, constructed via chemically conjugating hydrophobic to hyaluronic acid (HA), followed inserting into a cRGDyK peptide modified‐PEG shell. RHB can effectively target activated HSCs in fibrotic liver recognizing HA integrin αvβ3 CD44 due their high expression on HSCs. During fibrosis, NPs intelligently released Cyc response elevated ROS, inhibiting signaling activation. Meanwhile, exhibited ROS scavenging capability nuclear factor erythroid 2‐related 2 (Nrf2) stimulated HSCs, deactivating HSC. Cyc‐loaded significantly reversed inflammatory phenotypes mice without evident toxicity. In summary, dual‐targeted deactivated multiple signaling, ameliorating showing great promise treatment.

Language: Английский

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Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo

Redox Biology, Journal Year: 2023, Volume and Issue: 64, P. 102783 - 102783

Published: June 16, 2023

Oxidative stress due to abnormal accumulation of reactive oxygen species (ROS) is an initiator a large number human diseases, and thus, the elimination prevention excessive ROS are important aspects preventing development such diseases. Nuclear factor erythroid 2-related 2 (NRF2) essential transcription that defends against oxidative stress, its function negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1). Therefore, activating NRF2 inhibiting KEAP1 viewed as strategy for combating stress-related Here, we generated cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), which named SD2267, induces proteasomal degradation leads activation. As was intended, SD2267 bound KEAP1, recruited CRBN, induced KEAP1. Furthermore, efficacy diminished MG132 (a inhibitor) but not chloroquine (an autophagy inhibitor), suggested degradation-dependent autophagy-independent. Following degradation, nuclear translocation NRF2, led expression target genes attenuated acetaminophen (APAP) in hepatocytes. Based on vivo pharmacokinetic study, injected intraperitoneally at or 3 mg/kg APAP-induced liver injury mouse model. We observed degraded hepatic damage. Summarizing, described synthesis KEAP1-targeting PROTAC (SD2267) mode action vitro vivo. The results obtained suggest could be used treat diseases related stress.

Language: Английский

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Advances in developing noncovalent small molecules targeting Keap1

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103800 - 103800

Published: Oct. 16, 2023

Kelch-like ECH-associated protein 1 (Keap1) is a drug target for diseases involving oxidative stress and inflammation. There are three covalent Keap1-binding drugs on the market, but noncovalent compounds that inhibit interaction between Keap1 nuclear factor erythroid 2-related 2 (Nrf2) represent an attractive alternative. Both compound types prevent degradation of Nrf2, leading to expression antioxidant antiinflammatory proteins. However, their off-target profiles differ as do exact pharmacodynamic effects. Here, we discuss opportunities challenges targeting with versus inhibitors. We then provide comprehensive overview current Keap1-Nrf2 inhibitors, focus pharmacological effects, examine therapeutic potential this class.

Language: Английский

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Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 269, P. 116270 - 116270

Published: Feb. 29, 2024

Language: Английский

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Recent insights of PROTAC developments in inflammation-mediated and autoimmune targets: a critical review

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(8), P. 2585 - 2600

Published: Jan. 1, 2024

A comprehensive outlook of PROTAC breakthroughs in targeting anti-inflammatory and auto-immune diseases as promising therapeutic approaches for various unresolved disorders.

Language: Английский

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