Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Cuadrado, Antonio; Manda, Gina; Hassan, Ahmed; Alcaraz, Marı́a José; Barbas, Coral; Daiber, Andreas; Ghezzi, Pietro; León, Rafael; López, Manuela G.; Oliva, Baldo; Pajares, Marta; Rojo, Ana I.; Robledinos-Antón, Natalia; Valverde, Ángela M.; Güney, Emre; Schmidt, Harald

doi:10.1124/pr.117.014753

Cited by 517 publications

(470 citation statements)

References 351 publications

(341 reference statements)

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“…In support of these findings, it has been demonstrated that acute stimuli of HG led to initial increase in Nrf2 along with increase in ROS. However, longer incubation time led to a noticeable decrease in the expression of Nrf2 and its downstream antioxidant targets . To further determine whether the effects of miR‐27a, and miR‐142‐5p on lipid metabolism are mediated through modulation of the Nrf2 signaling pathway, we transfected HepG2 cells by the mimics or inhibitors of miR‐27a or miR‐142‐5p.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

et al. 2019

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Summary The gene Nrf2 (nuclear factor‐erythroid 2‐related factor 2) is the most important regulator of the cellular antioxidant system and its dysregulation has a role in the etiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the association between Nrf2 targeted miRNAs (miR‐27a, miR‐142‐5p, miR‐153, and miR‐128) with lipid accumulation in vitro and in vivo models of NAFLD. We used two in vivo and in vitro models of NAFLD. The expression of the genes and miRNAs was assessed by real‐time PCR and the protein level was evaluated using western blot. To investigate the potential role of miRNAs in NAFLD, the inhibitors or mimics of the miR‐27a and miR‐142‐5p were transfected into HepG2 cells. The mRNA and protein levels of Nrf2 were significantly decreased in the liver of high fat diet‐fed mice as well as in HepG2 cells treated with high glucose (HG). Reduced expression of Nrf2 was associated with increased expression levels of miR‐27a and miR‐142‐5p in both models of NAFLD. HG‐induced triglyceride accumulation was attenuated by inhibition of miR‐27a or miR‐142‐5p in HepG2 cells. Overexpression of miR‐27a or miR‐142‐5p suppressed the expression of Nrf2 and its downstream antioxidant genes and increased production of reactive oxygen species, whereas inhibition of miR‐27a or miR‐142‐5p reversed these effects. In conclusion, the data of this study may suggest that miR‐27a and miR‐142‐5p are increased in NAFLD, where they suppress Nrf2 expression and contribute to the accumulation of lipids in the hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

et al. 2019

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“…Nevertheless, the common symptom of sleep disturbance is already a sufficient reason for looking closely at low-grade neuroinflammation and pertinent changes such as microglia activation, astrocytic and neuronal damage. Moreover, the association of the incidence of depressive disorders with age, which is anyway related to proinflammatory traits by immunosenescence, senescence-associated secretory phenotype, brain insulin resistance and increased levels of amyloid-β peptides and oligomers, 27,32,49,50 leads to the necessity for particular attention in an aging society. On the side of interventions, the correction of circadian malfunction, e.g., by appropriately timed melatonin and bright light appears to be an option that may deserve more consideration.…”

Section: Resultsmentioning

confidence: 99%

“…More importantly, the induction of low-grade inflammation by sleep deprivation has been recognized as a pathological consequence that has the potential for causing various morbidities, especially by inducing low-grade inflammation [22][23][24][25][26] . Low-grade oxidative stress and neuroinflammation typically precede clinical symptoms of neurodegeneration 27 . Details concerning the relationship between oxidative/nitrosative stress, inflammation and neurodegeneration have been outlined and reviewed elsewhere [28][29][30] .…”

Section: Consequences Of Sleep Disturbancesmentioning

confidence: 99%

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

Hardeland¹

2018

J Mental Health & Clin Psychology

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In the traditional view of mood disorders, the circadian system has been insufficiently considered. However, polymorphisms of circadian oscillator genes in bipolar disorder, seasonal affective disorder, and subforms of major depressive disorder as well as demonstrable deviations in overt circadian rhythms indicate a role of the circadian system in these pathologies. Circadian malfunction affects sleep, and sleep deprivation can initiate proinflammatory responses. Being parts of the circadian system, melatonin and sirtuin 1 deserve particular attention. Either of them displays neuroprotective, antiinflammatory, and circadian amplitude-enhancing properties, which are of relevance to neurodegeneration that is observed in a number of depressive patients. Notably, both circulating melatonin levels as well as sirtuin 1 expression decline by age. In the gerontological context, melatonin upregulates sirtuin 1, which mediates some of melatonin's actions. Correction of a deviating circadian system seems to be of value regarding causes that contribute to depressive symptoms.

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“…CTLs were age‐matched and sex‐matched healthy volunteers who were nonblood relatives of patients without histories or clinical evidence of neurological diseases. Because many conditions may affect the Nrf2 pathway, exclusion criteria were adopted to prevent bias and confounding factors. Unified Parkinson's Disease Rating Scale parts 2 to 3, Non Motor Symptoms Scale, adjusted Mini‐Mental State Exam, the levodopa‐equivalent daily dose were collected for PD patients in on state.…”

Section: Methodsmentioning

confidence: 99%

“…In normal conditions, Nrf2 is quiescent into the cytosol. Contrariwise, when cell homeostasis is perturbed by redox imbalance, xenobiotics, or electrophilic compounds, Nrf2 translocates to the nucleus, triggering a gene expression program aimed at counteracting cellular stress at multiple levels . The Nrf2 pathway is critically involved in the pathogenic processes of PD.…”

mentioning

confidence: 99%

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

et al. 2019

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Background Preclinical studies underlined the relevance of Nuclear factor erythroid 2‐related factor 2 (Nrf2) transcription factor pathway in the pathogenesis of Parkinson's disease (PD). Objective The objective of this study was to explore Nrf2 pathway in vivo in PD, looking for novel disease biomarkers and therapeutic targets. Methods The levels of Nrf2, the downstream effectors (NAD(P)H dehydrogenase [quinone] 1 (Nqo1) enzyme, glutathione metabolism enzymes Glutamate–cysteine ligase (GCL) and Glutathione Reductase (GR)), the upstream activators (redox state and mitochondrial dysfunction), and α‐synuclein oligomers were assessed in the blood leukocytes of PD patients comparatively to controls. Biochemical data were correlated to clinical parameters. Results In PD, Nrf2 was highly transcribed and expressed as well as its target effectors. The mitochondrial complex I activity was reduced and the oxidized form of glutathione prevailed, disclosing the presence of pathway's activators. Also, α‐synuclein oligomers levels were increased. Nrf2 transcript and oligomers levels correlated with PD duration. Conclusions Blood leukocytes mirror pathogenic mechanisms of PD, showing the systemic activation of the Nrf2 pathway and its link with synucleinopathy and clinical events. © 2019 International Parkinson and Movement Disorder Society

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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Cited by 517 publications

References 351 publications

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

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