The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease

Chakkittukandiyil, Amritha; Sajini, Deepak Vasudevan; Karuppaiah, Arjunan; Selvaraj, Divakar

doi:10.1016/j.neuint.2022.105325

Cited by 32 publications

(18 citation statements)

References 157 publications

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“…Other PD genetic risk factors comprise genes involved in the control of mitochondrial redox balance including Parkin, PTEN-induced kinase 1 (PINK1), parkinsonism-associated deglycase (PARK7), and leucine-rich repeat serine/threonine protein kinase 2 (LRRK2) [ 34 ]. Parkin, an E3 ubiquitin ligase, and PINK1, a serine/threonine kinase, form a signal transduction pathway exerting a pivotal role in the removal of damaged mitochondria by the mitophagic process [ 35 ]; PARK7 encodes for DJ-1, a protein that, by binding the mitochondrial complex I, improves its activity [ 36 ].…”

Section: Implication Of Oxidative Stress and Nrf2 Activation In Neuro...mentioning

confidence: 99%

“…Studies in Drosophila showed that Nrf2 activation induces mitophagy and counteracts neuronal degeneration in Parkin/Pink1 knockdown flies [ 44 ]. In addition to direct neuronal toxicity, α-syn oligomers can activate microglial cells promoting neuroinflammation, which, by further increasing ROS production via NADPH oxydase 2 (NOX2) activation, augments oxidative stress [ 34 , 41 ]. In this context, DJ-1, by interacting with the p47phox subunit of NOX2, inhibits its action, reducing ROS production [ 45 ].…”

Section: Implication Of Oxidative Stress and Nrf2 Activation In Neuro...mentioning

confidence: 99%

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Activators of Nrf2 to Counteract Neurodegenerative Diseases

2023

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Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to oxidative damage. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is strictly related to anti-inflammatory and antioxidative cell response; therefore, its activation and the consequent enhancement of the related cellular pathways have been proposed as a potential therapeutic approach. Several Nrf2 activators with different mechanisms and diverse structures have been reported, but those applied for neurodisorders are still limited. However, in the very last few years, interesting progress has been made, particularly in enhancing the blood–brain barrier penetration, to make Nrf2 activators effective drugs, and in designing Nrf2-based multitarget-directed ligands to affect multiple pathways involved in the pathology of neurodegenerative diseases. The present review gives an overview of the most representative findings in this research area.

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Section: Implication Of Oxidative Stress and Nrf2 Activation In Neuro...mentioning

confidence: 99%

Section: Implication Of Oxidative Stress and Nrf2 Activation In Neuro...mentioning

confidence: 99%

Activators of Nrf2 to Counteract Neurodegenerative Diseases

2023

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“…Nrf2 is the key regulator of the endogenous antioxidant response. Increased ROS levels can cause Nrf2 to recognize ARE, which leads to the production of antioxidant genes like HO-1 and cell resistance to oxidative stress [ 15 ]. Oxidative stress results in a variety of diseases, such as diabetic nephropathy and cerebral infarction [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Catalpol on Proliferation, Apoptosis, Migration, and Oxidative Stress of Lung Cancer Cells Based on Nrf2/ARE Signaling

Wang

Fan

et al. 2022

BioMed Research International

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The effects of catalpol on lung cancer cell proliferation, apoptosis, migration, and oxidative stress via the Nrf2/ARE signaling pathway are investigated in this work. Catalpol-12 g/mL group, catalpol-24 g/mL group, catalpol-48 g/mL group, catalpol − 48 g / mL + vector group , catalpol − 48 g / mL + Nrf 2 group , si-NC group, and si-Nrf2 group were used to split lung cancer cells A549 into control groups. Proliferation was detected using the CCK-8 assay; apoptosis was detected using flow cytometry; migration was detected using the transwell chamber; ROS was distinguished using the DCFHDA method; MDA, SOD, and GSH were detected using the microvolume method; and Cleaved Caspase-3, Cleaved Caspase-9, Nrf2, HO-1, MMP-9, and MMP-2 were detected using the Western blot method. Catalpol 12 g/mL and 24 g/mL-48 g/mL treatment decreased the proliferation activity, migration number, and Nrf2, HO-1, MMP-9, and MMP-2 protein levels of lung cancer cells when compared to the control group. SOD and GSH levels of lung cancer cells were decreased, and MDA and ROS levels were increased. Cleaved caspase-3, cleaved caspase-9 protein expression levels, and apoptosis were boosted ( P < 0.05 ). The proliferation activity, migration number, and protein levels of Nrf2, HO-1, MMP-9, and MMP-2 in the catalpol − 48 g / mL + Nrf 2 group were raised compared to the catalpol − 48 g / mL + vector group , whereas there was an apparent drop in the Cleaved Caspase-3, Cleaved Caspase-9, and apoptosis rate. Similarly, SOD and GSH contents increased, whereas MDA and ROS decreased ( P < 0.05 ). The proliferation activity, migration number, and Nrf2, HO-1, MMP-9, and MMP-2 protein levels of lung cancer cells in the si-Nrf2 group were all decreased when compared to the si-NC and control groups. Cleaved Caspase-3 and Cleaved Caspase-9 protein expression, on the other hand, increased as MDA and ROS levels were raised while SOD and GSH levels dropped ( P < 0.05 ). It reveals that catalpol inhibits the Nrf2/ARE signaling pathway, which causes antiproliferation, migration, apoptosis, and oxidative stress in cancer cells of lungs. The rate of apoptosis was also lowered.

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“…Nrf2 is a basic leucine zipper (bZip) transcription factor, whose main function is to mediate the expression of genes related to cellular antioxidant and self-protection mechanisms [ 45 ]. Additionally, it is also involved in the regulation of mitochondrial metabolism, tissue repair, autophagy, ubiquitin-proteasome system (UPS), inflammation, and immune response, etc.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Capability of Narcissoside in 6-OHDA-Exposed Parkinson’s Disease Models through Enhancing the MiR200a/Nrf-2/GSH Axis and Mediating MAPK/Akt Associated Signaling Pathway

Tsai

Liu

et al. 2022

Antioxidants

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We assessed the antioxidant potential of narcissoside from Sambucus nigra flowers (elderflowers) in Parkinson’s disease models in vitro and in vivo. The results showed that narcissoside lessened the 6-hydroxydopamine (6-OHDA)-induced increase in reactive oxygen species (ROS) and apoptosis in SH-SY5Y cells. In the 6-OHDA-exposed Caenorhabditis elegans model, narcissoside reduced degeneration of dopaminergic neurons and ROS generation, and also improved dopamine-related food-sensitive behavior and shortened lifespan. Moreover, NCS increased total glutathione (GSH) by increasing the expression of the catalytic subunit and modifier subunit of γ-glutamylcysteine ligase in cells and nematodes. Treatment with a GSH inhibitor partially abolished the anti-apoptotic ability of narcissoside. Furthermore, narcissoside diminished the 6-OHDA-induced phosphorylation of JNK and p38, while rising activities of ERK and Akt in resisting apoptosis. The antioxidant response element (ARE)-luciferase reporter activity analysis and electromobility gel shift assay showed that narcissoside promotes the transcriptional activity mediated by Nrf2. Finally, we found that narcissoside augmented the expression of miR200a, a translational inhibitor of the Nrf2 repressor protein Keap1. Downregulation of Nrf2 and miR200a by RNAi and anti-miR200a, respectively, reversed the neuroprotective ability of narcissoside. In summary, narcissoside can enhance the miR200a/Nrf2/GSH antioxidant pathway, alleviate 6-OHDA-induced apoptosis, and has the neuroprotective potential.

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The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease

Cited by 32 publications

References 157 publications

Activators of Nrf2 to Counteract Neurodegenerative Diseases

Activators of Nrf2 to Counteract Neurodegenerative Diseases

The Impact of Catalpol on Proliferation, Apoptosis, Migration, and Oxidative Stress of Lung Cancer Cells Based on Nrf2/ARE Signaling

Neuroprotective Capability of Narcissoside in 6-OHDA-Exposed Parkinson’s Disease Models through Enhancing the MiR200a/Nrf-2/GSH Axis and Mediating MAPK/Akt Associated Signaling Pathway

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