Is there a Link Between NRF2 and Depression?

Marlene Santos ^1,3* Debora Fonseca¹, Renato Caldevilla ^1,2, M. Fátima Barroso ^2, and Agostinho Cruz

¹ CISA|ESS, Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Polytechnic Institute of Porto, Rua Dr. António Bernardino de Almeida, 400, 4200-072, Porto, Portugal;
² REQUIMTE–LAQV, School of Engineering, Polytechnic Institute of Porto, R. Dr. António Bernardino de Almeida 431, 4200-072, Porto, Portugal;
³ Molecular Oncology and Viral Pathology Group, Research Center, Portuguese Oncology Institute of Porto – Francisco Gentil, R. Dr. António Bernardino de Almeida 865, 4200-072 Porto, Portugal;

Email: mes@ess.ipp.pt;

Introduction: Depression is a common mental health disorder that affects millions of people worldwide. Recent studies have highlighted the role of oxidative stress and inflammation in the pathogenesis of depression. NRF2 is a transcription factor that plays a crucial role in cellular defense against oxidative stress by binding to antioxidant response elements (AREs) located in the promoter region of various phase II antioxidant enzymes and stress-responsive enzymes. Decreased Keap1-Nrf2 signaling has been implicated in the development of mood disorders, such as Major Depressive Disorder. Therefore, this review aims to evaluate the in vitro and in vivo evidence of the involvement of Nrf2 in depression.
Methods: A review was conducted on the PubMed database for articles published until March 8, 2022 Papers that evaluated NRF2 in animals and/or cell lines with depression and were published in English were included in the review. Studies that addressed other diseases/topics, systematic reviews, and those that did not address NRF2 were excluded. Quality assessment was performed according to Koch et al., 2022.
Results: Out of the 203 possibly relevant abstracts found through the PubMed search, 45 papers were included in the review. The results suggest that Nrf2 levels tend to decrease in animals exposed to oxidative stress or depressive behavior. When animals were treated with antidepressants or anti-inflammatory drugs, Nrf2 levels increased. Additionally, the study found that IL-10 and BDNF were key elements that were positively influenced by Nrf2 levels, protecting against oxidative stress through Keap1/Nrf2.
Discussion and conclusions: The findings suggest that Nrf2 activation may play a crucial role in controlling oxidative stress and inflammation during depression. Furthermore, it provides evidence of the involvement of Nrf2 in depression and highlights its potential as a therapeutic target. However, further studies on clinical samples are necessary to evaluate NRF2’s putative effect in depression and antidepressant response.

Susceptibility of hepatic progenitor cells lo lipotoxicity and hypoxia: potential role of NRF2 in preserving cell fate

Laura Villamayor^1,2, Inés Barahona^1,2, Noelia Arroyo³, Silvia Calero^1,2, Elena del Fresno¹, Pedro M. Rodrigues^4,5,6, Elena Carceller-López¹, Malgorzata Milkiewicz⁷, Piotr Milkiewicz^8,9, Jesús M. Banales^4,5,6, Anabel Rojas^2,3, Águeda González-Rodríguez^1,2 and Ángela M. Valverde^1,2.

1. Institute of Biomedical Research “Alberto Sols” (CSIC-UAM), 28029, Madrid, Spain.
2. Network Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERdem), 28029, Madrid, Spain.
3. Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), University Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
4. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
5. National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.
6. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
7. Department of Medical Biology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland.
8. Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-097, Warsaw, Poland.
9. Translational Medicine Group, Pomeranian Medical University, 70-204, Szczecin, Poland.
10. Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.

Activation of hepatic progenitor cells (oval cells in mice) has been related to hepatocyte injury during chronic liver diseases as a regenerative response to repair liver damage. Therefore, the plasticity of oval cells can be affected under pathological environments including lipotoxicity and hypoxia. In this study we have investigated, on the one hand, the impact of the treatment with palmitic acid (PA), a saturated FA highly lipotoxic and, on the other, the effects of low oxygen saturation, in oval cell fate. PA induced apoptotic cell death in oval cells in parallel to oxidative stress, mitochondrial damage and impaired autophagy. Likewise, nuclear and cytosolic NRF2 levels, expression of NRF2-target genes (Nqo1, Hmox1) and Heme oxygenase (HO-1) and Catalase protein levels, showed that deficiency in Ptpn1, encoding protein tyrosine phosphatase 1 (PTP1B) upregulated NRF2-mediated antioxidant defences and triggered a rapid antioxidant response against lipotoxic stress. Treatment of oval cells with PA plus sulforaphane increased nuclear NRF2, enhanced antioxidant gene expression and reduced DHE staining and lipid peroxidation. As a result, apoptosis was ameliorated. On the other hand, oval cells exposed to 1% O2 showed features of epithelial-to-mesenchymal transition (EMT). At the molecular level, the up-regulation of hypoxia-inducible transcription factor HIF2α concurred with an elevation of nuclear NRF2, Hmox1 mRNA levels and NQO1 protein levels. In addition, we identified for the first time the zinc-finger transcription factor GATA4, a suppressor of hepatic stellate cells activation, in oval cells and, importantly, its expression decreased under hypoxic conditions. In vivo experiments showed oval cell expansion in mice with non-alcoholic fatty liver disease (NAFLD) and mice exposed to intermittent hypoxia. Finally, gene expression levels related to hepatic progenitor cells, obtained from the NCBI Gene Expression Omnibus database, were significantly increased in NAFLD patients with advanced fibrosis compared to those with mild fibrosis. Moreover, the expression levels of GATA4 in liver samples from patients with biliary diseases (primary sclerosing and primary biliary cholangitis) revealed a significant decrease in PSC patients and a decrease trend in PBC patients. In conclusion our results suggest that targeting NRF2 might be a therapeutic strategy to prevent the loss of oval cell fate during chronic liver diseases.

Genetic variability of NRF2 pathway and neurodegeneration

David Vogrinc^*1, Sara Redenšek Trampuž^*1, Katja Goričar¹, Vita Dolžan¹

¹ Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
^* Both authors contributed equally to the work

e-mail: vita.dolzan@mf.uni-lj.si

As oxidative stress contributes to neurodegeneration, transcription factor NRF2, its repressor KEAP1, and NRF2 target genes present an important signaling pathway in neurodegenerative diseases, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). NRF2 activity was shown to be reduced in AD patients. Additionally, it has a neuroprotective role in PD affecting microglial dynamics and astrocyte activation (1). Genetic variability of NFE2L2 and other genes from the signaling pathway has been associated with PD risk and its symptomatology (2,3). Preliminary results from our group suggest both NFE2L2 and KEAP1 genetic variability might be associated with cerebrospinal fluid biomarkers and symptomatology of AD. miRNA landscapes of the NRF2 pathway have also been associated with both AD and PD (4,5). Our pathway enrichment analysis suggested that miRNAs associated with neurodegeneration as a COVID-19 sequela might also regulate NRF2 signaling pathway and may have a valuable potential for neurodegeneration prediction and therapy in COVID-19 patients (6).

Air Pollution Exposure induces NRF2 in Astrocytes

Saveleva L¹, Ivanova M¹, Afonin A¹, Jalava P², Kanninen KM ¹

¹ A.I.Virtanen institute for Molecular Sciences, University of Eastern Finland
² Dept of Environmental and Biological Sciences, University of Eastern Finland

Email: Katja.Kanninen@uef.fi

Outdoor air pollution is the largest environmental risk factor that has been associated with cardiovascular, lung, and lately also neurodegenerative diseases. Prior work has demonstrated that air pollutant exposure can lead to neuroinflammation, oxidative stress and the appearance of protein aggregates in the brain. Evidence suggests that airborne particles can enter the brain directly through olfactory nerve or enter the blood circulation. However, there is an unmet need for understanding how different brain cell types are involved in the adverse effects of air pollutant exposure. In this study, we aimed to decipher how size-segregated particulate matter (PM) that was collected from urban air in Nanjing, China affects the viability and transcriptome of adult astrocytes. We used mouse primary astrocytes harvested from the adult mouse brain of C57BL/6J mice, which at 21 days in culture were exposed for 24 hours to nanosized (less than 0.2 µm) particulate matter (nPM) collected from urban air. Cell viability and mRNAsequencing data obtained demonstrate that nPM trigger activation of antioxidative stress signalling and detoxification systems in adult astrocytes without affecting cell viability, indicating activation of the cellular protection system in response to nPM. Overall, we found a total number of 2217 genes to be differently expressed when nPM-exposed astrocytes were compared to vehicle control. The most activated canonical pathways after exposure were xenobiotic metabolism and the NRF2 oxidative stress response pathways. We suggest that polycyclic aromatic hydrocarbons that are present in airborne particles trigger activation of xenobiotic metabolism and NRF2 signaling, leading to protective activation of antioxidant genes in astrocytes. These results provide new insight into astrocyte responses to air pollutant exposure.  

Repositioning dimethyl fumarate for the treatment of TDP-43-dependent frontotemporal dementia

Lastres-Becker, I.^1,3, Berrojo-Armisen, A.^1*, Martín -Baquero, R.^2,3*, Fernández-Ruiz, J. ^2,3, De Lago, E. ^2,3

¹ Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Arturo Duperier, 4, Department of Biochemistry, School of Medicine, Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid , 28029 Madrid, Spain.
² Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, UCM, Madrid, Spain, Instituto de Salud Carlos III, Spain, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
³Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)

^* have participated equally in the work

Email: ilbecker@iib.uam.es

Frontotemporal dementia (FTD) is an early-onset, progressive neurodegenerative disease characterized by primarily neuronal degeneration in the frontal and temporal lobes followed by hippocampal atrophy. After Alzheimer’s disease (AD), FTD is the second cause of dementia in adult patients and the most frequent in patients under 65 years of age. From a histopathological and molecular point of view, FTD is a proteinopathy involving the dysregulation (e.g. loss of function, aggregation) of two main proteins: i) the cytoskeleton-related protein TAU or (ii) the ribonucleoprotein TDP-43. There is also dysregulation of redox homeostasis and low-grade chronic neuroinflammation. Currently, there is no approved effective treatment for FTD that could slowdown the course of the disease. Recently, we identified the transcription factor NRF2 as a key factor to limit neurodegenerative process in other diseases. NRF2 has pleiotropic effects by acting on various molecular mechanisms involved in the neurodegenerative process. Within the brain, it has been described that pharmacological activation of NRF2 has beneficial effects against protein aggregates, neuroinflammation, and oxidative stress. Studies carried out by our group demonstrated neuroprotective effects of the NRF2 activator dimethyl fumarate (DMF) in a TAU-dependent FTD model, reducing TAU hyperphosphorylation, neurodegeneration, neuroinflammation and oxidative stress, supporting the reposition of this drug for the treatment of FTD. Furthermore, we observed that TAU overexpression delocalizes TDP-43 from the nucleus to the cytoplasm, and DMF treatment is able to relocate it to the nucleus, indicating an interconnection between TAU and TDP-43. However, the possible efficacy of this treatment in TDP-43-FTD is not known yet. Therefore, in this work we have evaluated the possible neuroprotective effects of DMF treatment in a TDP-43-FTD mouse model as CaMKII-TDP-43-transgenic mice. These mice overexpressed TDP-43 only in the forebrain, mimicking the characteristic phenotype of FTD with ubiquitin-positive inclusions (FTD-U).

Repurposing TXA302 as a novel senotherapeutic

Ognian Neytchev¹, Colin Selman² and Paul G. Shiels¹

¹ School of Molecular Biosciences, MVLS, University of Glasgow
²  School of Biodiversity, One Health and Veterinary Medicine MVLS, University of Glasgow

email: paul.shiels@glasgow.ac.uk

Ageing is a risk factor for multiple chronic diseases, which is both malleable and druggable, using established pharmaceuticals or known naturally occurring bioactive substances, that can mitigate the common effects of the dysregulation of the ageing process. In particular, many of these agents exert their health beneficial effects via Nrf2 agonism.  We have therefore investigated repurposing the capacity of the Angiotensin 1-7 analogue TXA302,  a clinical anti-stroke agent, which has been shown to  provide a senotherapeutic  effect,  the mechanistic basis of which remains undetermined.

We now report on the potential of TXA302 to act as a senotherapeutic agent capable of slowing the rate of organismal ageing and improving health span in a murine model of normative ageing. To assess health span, a range of physiological and molecular markers were measured: grip strength, glucose tolerance, inflammation (IL-6), Nrf2 expression, gut microbiome diversity, telomere length, DNA methylation age, and expression of the CDK inhibitors CDKN1A, CDKN2A, and CDKN2B in a cohort of treated mice (n=102) and untreated controls (n=102). TXA302 was well tolerated and improved several parameters subject to age-associated decline, enhancing grip strength and glucose tolerance, while reducing inflammation, cellular senescence, and increasing gut microbial diversity over the life course of the mice, with no adverse effects detected. Notably, we observed no changes in epigenetic age as measured by a DNAm clock, nor in Nrf2 activity. The implications of these findings will be discussed.