Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain

Piloni, Natacha Estefanía; Vargas, Romina; Fernández, Virgínia; Videla, Luis A.; Puntarulo, Susana

doi:10.1007/s10534-021-00324-x

Cited by 12 publications

(7 citation statements)

References 53 publications

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“…NRF2 activation stimulates mitochondrial antioxidant enzymes GR, GPx, thioredoxin 2, peroxiredoxin 3 (Prdx3), peroxiredoxin 5 (Prdx5), and SOD2, among others, to counteract the increased ROS production in response to oxidizing conditions ( Figure 5 ). Nevertheless, the exact mechanisms are not fully understood [ 99 , 100 , 101 , 102 , 103 ]. NRF2 can influence mitochondrial activity as direct or secondary action and in different ways, namely by rewiring cellular metabolism to account for the needs of metabolic intermediates such as Fructose 6-Phosphate (F6P) and Glyceraldehyde 3-Phosphate (G3P) between glycolysis and PPP [ 104 ].…”

Section: Part 2: Emerging Evidence Of the Interplay Between Nrf2 And ...mentioning

confidence: 99%

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

Panieri

Pinho

Afonso

et al. 2022

Cells

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The NRF2–KEAP1 system is a fundamental component of the cellular response that controls a great variety of transcriptional targets that are mainly involved in the regulation of redox homeostasis and multiple cytoprotective mechanisms that confer adaptation to the stress conditions. The pleiotropic response orchestrated by NRF2 is particularly relevant in the context of oncogenic activation, wherein this transcription factor acts as a key driver of tumor progression and cancer cells’ resistance to treatment. For this reason, NRF2 has emerged as a promising therapeutic target in cancer cells, stimulating extensive research aimed at the identification of natural, as well as chemical, NRF2 inhibitors. Excitingly, the influence of NRF2 on cancer cells’ biology extends far beyond its mere antioxidant function and rather encompasses a functional crosstalk with the mitochondrial network that can influence crucial aspects of mitochondrial homeostasis, including biogenesis, oxidative phosphorylation, metabolic reprogramming, and mitophagy. In the present review, we summarize the current knowledge of the reciprocal interrelation between NRF2 and mitochondria, with a focus on malignant tumors and cancer stem cells.

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Section: Part 2: Emerging Evidence Of the Interplay Between Nrf2 And ...mentioning

confidence: 99%

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

Panieri

Pinho

Afonso

et al. 2022

Cells

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“…But beyond the acute state, the nuclear Keap1/Nrf2 ratio was found to be significantly higher, which could be a negative feedback mechanism restricting Nrf2 translocation and function in the nucleus. 56,57 We observed that NAC and AOP-treated groups showed significant elevations in Nrf2 and HO-1 gene expressions in comparison with the iron-intoxicated group. These results are consistent with previous studies, [58][59][60] respectively.…”

Section: Discussionmentioning

confidence: 85%

“…On the other hand, other studies demonstrated that iron deposition activated Nrf‐2 and enhanced the expression of the neuroprotective HO‐1, and this could be explained by the fact that iron intoxication in these studies occurred in an acute manner and triggered the brain's antioxidant cellular defense system via upregulation of GSH metabolism associated with Nrf2 activation. But beyond the acute state, the nuclear Keap1/Nrf2 ratio was found to be significantly higher, which could be a negative feedback mechanism restricting Nrf2 translocation and function in the nucleus 56,57 …”

Section: Discussionmentioning

confidence: 99%

Acetylated oligopeptide and N‐acetylcysteine protect against iron overload‐induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO‐1 and downregulation of MMP‐9/TIMP‐1 and GFAP

Kamel,

Nassar,

Meligy

et al. 2024

Cell Biochemistry & Function

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Iron accumulation in the brain causes oxidative stress, blood–brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron‐induced hippocampal damage compared to N‐acetyl cysteine (NAC). This 5‐week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme‐linked immunosorbent assay, spectrophotometry, and qRT‐PCR were used to measure MMP‐9, tissue inhibitor metalloproteinase‐1 (TIMP‐1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP‐9, TIMP‐1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO‐1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload‐induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.

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“…Then, EtOH was removed and the compound was purified by column chromatography (DCM/ MeOH = 5:1, v/v) to obtain DSPI-3 (238 mg, 52.89%). 1 General Procedures for Spectral Test. Preparation of Storage Fluid.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…As a new mode of regulating cell death, ferroptosis is the result of iron-dependent lipid peroxide accumulation, which is dissimilar from traditional apoptosis and necrosis. , Studies have shown that the inhibition of the upstream regulator system XC – (amino acid antiporter) or downstream effector GPX4 (glutathione peroxidase 4) of GSH through drugs or small molecule compounds is considered the typical internal and external pathways of ferroptosis. Consumption of GSH triggers oxidative stress and lipid peroxidation, which leads to ferroptosis. − At present, plenty of evidences have testified that ferroptosis is relevant to some diseases such as acute kidney injury, liver injury, traumatic brain injury, and so on.…”

Section: Introductionmentioning

confidence: 99%

Revealing the Effects of Endoplasmic Reticulum Stress on Ferroptosis by Two-Channel Real-Time Imaging of pH and Viscosity

et al. 2022

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Endoplasmic reticulum (ER) is sensitive to changes in the intracellular environment such as pH and viscosity, and slight changes may trigger stress response. Besides, different from apoptosis and necrosis, ferroptosis is the result of lipid peroxidation accumulation. There is evidence that ferroptosis is closely related to endoplasmic reticulum stress (ERS). However, the possible changes in the pH and viscosity of the ER during the ferroptosis process have not yet been studied. Therefore, we used a new type of ER-targeted dual-excitation fluorescent probe (DSPI-3) to investigate the possible changes of pH and viscosity of ER during the ferroptosis. The novel probe DSPI-3 exhibited a highly sensitive and selective response to pH and viscosity. During the bioimaging process, it was found that the ER acidified and viscosity increased during the ferroptosis process induced by erastin, while the cells treated with ferrostatin-1 did not alter significantly. In addition, when dithiothreitol (DTT) and erastin stimulated the cells at the same time, we discovered that ER was acidified considerably at short notice, but the pH was slightly increased in the later stage. Besides, the change of the viscosity enhanced slowly with the passage of time, and there was a noteworthy decline in the later stage, demonstrating that the DTT-induced ERS accelerated the process of ferroptosis. We hope that this unique fluorescent probe can provide an effective method for studying the relationship between ERS and ferroptosis.

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Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain

Cited by 12 publications

References 53 publications

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

Acetylated oligopeptide and N‐acetylcysteine protect against iron overload‐induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO‐1 and downregulation of MMP‐9/TIMP‐1 and GFAP

Revealing the Effects of Endoplasmic Reticulum Stress on Ferroptosis by Two-Channel Real-Time Imaging of pH and Viscosity

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