Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway

Redox Biology, Год журнала: 2022, Номер 54, С. 102389 - 102389

Опубликована: Июнь 29, 2022

The KEAP1-NRF2-ARE signaling pathway plays a central role in mediating the adaptive cellular stress response to oxidative and electrophilic chemicals. This canonical has been extensively studied reviewed past two decades, but rarely was it looked at from quantitative perspective. Signal amplification, i.e., ultrasensitivity, is crucially important for robust induction of antioxidant genes appropriate levels that can adequately counteract stresses. In this review article, we examined number well-known molecular events perspective with focus on how signal amplification be achieved. We illustrated, by using series mathematical models, redox-regulated protein sequestration, stabilization, translation, nuclear trafficking, DNA promoter binding, transcriptional – which are embedded network comprising KEAP1, NRF2, sMaf, p62, BACH1 may generate highly ultrasensitive NRF2 activation gene induction. emergence degree ultrasensitivity depend strengths protein-protein protein-DNA interaction abundances. A unique, understanding will help identify sensitive targets prevention therapeutics stress-related diseases develop adverse outcome models facilitate health risk assessment

Язык: Английский

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Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Апрель 4, 2022

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI further develop into serious diseases such as cirrhosis cancer. Therefore, how to effectively prevent treat has become the focus research. Numerous studies have reported Maresin1 (MaR1) anti-inflammatory effect protective functions on organs. In present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) establish an model, explored mechanism cells death caused by D-GalN/LPS, determined MaR1 D-GalN/LPS-induced ALI. vivo experiments, found that ferrostatin-1 significantly alleviated ALI, reduced serum alanine transaminase aspartate levels, improved survival rate mice. Meanwhile, inhibited hepatocyte death, tissue reactive oxygen species (ROS) expression, malondialdehyde (MDA), glutathione (GSH), GSH/oxidized (GSSG), iron content induced D-GalN/LPS addition, ferroptosis-induced through inhibiting release interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6. Subsequently, western blot showed expression nuclear factor E2-related 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). vitro LPS-induced erastin-induced cell viability reduction. increased MDA GSH levels cells. Western level Nrf2/HO-1/GPX4. Next, Nrf2 was knocked down HepG2 cells, results decreased. Finally, flow cytometry revealed ROS production apoptosis. Overall, our study Nrf2/HO-1/GPX4 activation.

Язык: Английский

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Multifunctional nanoparticle-mediated combining therapy for human diseases

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

Опубликована: Янв. 1, 2024

Abstract Combining existing drug therapy is essential in developing new therapeutic agents disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established treating extensive human diseases. Attributed to synergistic effects by targeting various pathways advantages, such as reduced administration dose, decreased toxicity, alleviated resistance, combinatorial treatment now being pursued delivering combat major clinical illnesses, cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders neurodegenerative Combinatorial involves combining or co-delivering two more for a specific disease. Nanoparticle (NP)-mediated delivery systems, i.e., liposomal NPs, polymeric NPs nanocrystals, are great interest wide range due targeted delivery, extended release, higher stability avoid rapid clearance at infected areas. This review summarizes targets diseases, clinically approved combinations the development multifunctional emphasizes strategies based on severe Ultimately, we discuss challenging NP-codelivery translation provide potential approaches address limitations. offers comprehensive overview recent cutting-edge NP-mediated combination

Язык: Английский

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Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

Biomolecules, Год журнала: 2022, Номер 12(9), С. 1227 - 1227

Опубликована: Сен. 2, 2022

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds quality life these patients. Considering DKD main cause end-stage renal disease (ESRD) in developed countries, extensive research currently investigating matrix pathophysiology. Hyperglycemia, inflammation oxidative stress (OS) are mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-β, NF-κB, MCP-1, VCAM-1, ICAM-1) activation diverse pathways PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state impairment antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations filtration unit. Hitherto, wide spectrum pre-clinical clinical studies shows beneficial use NRF2-inducing strategies, NRF2 activators Bardoxolone methyl, Curcumin, Sulforaphane their analogues), other natural properties treatment. However, limitations regarding lack larger trials, solubility or delivery hamper implementation for use. Therefore, review, we will discuss mechanisms, especially NRF2/KEAP1/ARE involvement, while highlighting potential therapeutic approaches that target via OS.

Язык: Английский

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Mitochondria: It is all about energy

Frontiers in Physiology, Год журнала: 2023, Номер 14

Опубликована: Апрель 25, 2023

Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron calcium homeostasis the of hormones neurotransmitters, such as melatonin. They enable influence communication at all physical levels through interaction with other organelles, nucleus, outside environment. The literature suggests crosstalk between mitochondria circadian clocks, gut microbiota, immune system. might even be hub supporting integrating activity across these domains. Hence, they (missing) link Mitochondrial dysfunction related metabolic syndrome, neuronal diseases, cancer, cardiovascular infectious inflammatory disorders. In this regard, diseases Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), pain are discussed. This review focuses on understanding mitochondrial action that allow for maintenance pathways toward dysregulated mechanisms. Although have allowed us adapt changes over course evolution, turn, evolution has shaped mitochondria. Each evolution-based intervention influences its own way. use physiological stress triggers tolerance stressor, achieving adaptability resistance. describes strategies could recover functioning providing comprehensive, root-cause-focused, integrative approach recovering treating people suffering diseases.

Язык: Английский

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Redox signaling at the crossroads of human health and disease

MedComm, Год журнала: 2022, Номер 3(2)

Опубликована: Март 31, 2022

Abstract Redox biology is at the core of life sciences, accompanied by close correlation redox processes with biological activities. homeostasis a prerequisite for human health, in which physiological levels nonradical reactive oxygen species (ROS) function as primary second messengers to modulate signaling orchestrating multiple sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads biomolecule damage and subsequent occurrence various diseases such type 2 diabetes, atherosclerosis, cancer. Herein, starting evolution biology, we reveal roles multifaceted modulators mediate sustain homeostasis. In addition, also emphasize detailed OS mechanisms involved initiation development several important diseases. double‐edged sword disease progression suggest two different therapeutic strategies treat redox‐relevant diseases, targeting sources redox‐related effectors manipulate will largely promote precision medicine. Therefore, comprehensive understanding networks under pathological conditions facilitate medicine benefit patients

Язык: Английский

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The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Antioxidants, Год журнала: 2022, Номер 11(1), С. 157 - 157

Опубликована: Янв. 14, 2022

One of the most important characteristics brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities oxygen, generating significant amounts reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders nervous system, where pathological processes such aberrant protein oxidation can ultimately lead cellular dysfunction death. Epilepsy, characterized by long-term predisposition epileptic seizures, one common neurological OS. Evidence shows that increased neuronal excitability-the hallmark epilepsy-is accompanied neuroinflammation an excessive production ROS; together, these factors likely key features seizure initiation propagation. This review discusses role OS in epilepsy, connection impact on synaptic function. Considering pharmacological treatment options for epilepsy limited heterogeneity disorders, we also introduce latest advances anti-epileptic drugs (AEDs) how they interact We conclude intertwined numerous physiological molecular mechanisms although causal relationship yet be established.

Язык: Английский

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Quercetin: A promising therapy for diabetic encephalopathy through inhibition of hippocampal ferroptosis

Phytomedicine, Год журнала: 2023, Номер 126, С. 154887 - 154887

Опубликована: Май 20, 2023

Язык: Английский

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Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Язык: Английский

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Polyphenols as Antioxidant/Pro-Oxidant Compounds and Donors of Reducing Species: Relationship with Human Antioxidant Metabolism

Processes, Год журнала: 2023, Номер 11(9), С. 2771 - 2771

Опубликована: Сен. 16, 2023

In this review, we have focused mainly on the study of their antioxidant and pro-oxidant capacity, analysis oxidation catechol group to o-quinone. The redox balance established between different oxidase reductase enzymes generates reducing species, H+ e−, allows polyphenolic groups quinones be reversible. This continuous these nucleophilic electrophilic substances activation NRF2/ARE axis, which regulates cellular responses against oxidative stress, as well cell proliferation. Understanding ambivalent character polyphenols, can act simultaneously antioxidants pro-oxidants, will allow design specific therapies that serve science medicine in tasks.

Язык: Английский

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