Intracellular labile iron determines H 2 O 2 -induced apoptotic signaling via sustained activation of ASK1/JNK-p38 axis

Mantzaris, Michalis D.; Bellou, Sofia; Skiada, V.; Kitsati, Natalia; Fotsis, Theodore; Galaris, Dimitrios

doi:10.1016/j.freeradbiomed.2016.07.002

Cited by 56 publications

(44 citation statements)

References 69 publications

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“…The protective effects were well correlated with the inhibition of H 2 O 2 -induced changes on intracellular labile iron homeostasis, indicating that iron is apparently implicated in the promotion of sustained phosphorylation and activation of JNK and p38 MAP kinases. Although, we have recently shown that desferrioxamine, a specific iron chelating drug, exerts similar effects on H 2 O 2 -induced MAP kinase phosporylation pattern [23], according to our knowledge, it is the first time that the patterns of MAPK phosphorylation is linked to intracellular labile iron modulation by the action of specific compounds, which are abundantly present in Mediterranean diet.…”

Section: Discussionmentioning

confidence: 89%

“…This molecular similarity between the two alcohols allowed us to draw conclusions about the role of the ortho-dihydroxy group, which is also encountered abundantly in many other natural components of human diet and especially in the Mediterranean type of diet. In addition, we tested whether the iron binding capacity of the ortho-dihydroxy structure was able to modulate H 2 O 2 -induced redox signaling pathways, since previous work from our research group has shown that intracellular labile iron represented an important mediator in H 2 O 2 -induced apoptotic signaling [23], [31], [32].…”

Section: Discussionmentioning

confidence: 99%

“…Whether iron is also implicated in these processes is less well examined, although our group has recently presented strong supporting evidence for this notion [23], [32]. The main obstacle in explaining the role of iron in H 2 O 2 -mediated signaling is the difficulty to describe the underlying basic chemistry.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent publication we described also the pivotal role played by intracellular labile iron in redox signaling processes [23]. Thus, it was rational to imagine that dietary components able to modulate intracellular labile iron homeostasis should also influence redox induced signal transduction pathways.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation

2016

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Although it is known that Mediterranean diet plays an important role in maintaining human health, the underlying molecular mechanisms remain largely unknown. The aim of this investigation was to elucidate the potential role of ortho-dihydroxy group containing natural compounds in H2O2-induced DNA damage and apoptosis. For this purpose, the main phenolic alcohols of olive oil, namely hydroxytyrosol and tyrosol, were examined for their ability to protect cultured cells under conditions of oxidative stress. A strong correlation was observed between the ability of hydroxytyrosol to mitigate intracellular labile iron level and the protection offered against H2O2-induced DNA damage and apoptosis. On the other hand, tyrosol, which lacks the ortho-dihydroxy group, was ineffective. Moreover, hydroxytyrosol (but not tyrosol), was able to diminish the late sustained phase of H2O2-induced JNK and p38 phosphorylation. The derangement of intracellular iron homeostasis, following exposure of cells to H2O2, played pivotal role both in the induction of DNA damage and the initiation of apoptotic signaling. The presented results suggest that the protective effects exerted by ortho-dihydroxy group containing dietary compounds against oxidative stress-induced cell damage are linked to their ability to influence changes in the intracellular labile iron homeostasis.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation

2016

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“…Thus, whether taraxerolstimulated cytoprotective effect is involved in MAPKdependent Keap/Nrf2/ARE signaling pathway remains elusive. On the other hand, Mantzaris reported that iron determines H2O2-induced apoptotic signaling by sustaining the ASK1/JNK-p38 axis (Mantzaris et al, 2016). Further investigation is needed to identify upstream regulatory proteins such as ASK1 in protective mechanism of taraxerol in H2O2-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Taraxerol protects the human hepatic L02 cells from hydrogen peroxide-induced apoptosis

Yao

Bai

2017

Bangladesh J Pharmacol

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Taraxerol is known to exhibit anti-inflammatory and anti-cancer activity. However, cytoprotective effect of taraxerol on hepatocytes has not been reported. In the present study, we investigated the hepatoprotective effect of taraxerol in the human hepatic L02 cells injured by hydrogen peroxide (H2O2). Taraxerol decreased H2O2-induced cell viability loss and lactate dehydrogenase release. Taraxerol also inhibited H2O2-induced cell apoptosis. Further, taraxerol attenuated H2O2-induced increase in cleaved-caspase-3 and cleaved-PARP. H2O2-activated p38 and JNK were also inhibited by taraxerol. These data suggest that taraxerol could protect the L02 cells against H2O2-induced apoptosis via suppression of p38 and JNK. Taraxerol may be an effective protective agent against oxidative stress-induced liver injury.

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Excess iron accumulation mediated senescence in diabetic kidney injury

Cheng,

Li,

Chen

et al. 2024

J Biochem & Molecular Tox

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Cellular senescence and iron accumulation were separately observed in diabetic nephropathy (DN). Limited evidence supports that iron was significantly accumulated in senescent cells. We aimed to explore whether iron is involved in the pathogenesis role of senescence in DN. Renal cells were treated with high glucose (HG, 35 mM) for 10 or 15 days, and DN mice were induced by high‐fat diet and streptozotocin. Gene ontology enrichment, gene set enrichment analysis analysis, β‐galactosidase staining, 5‐ethynyl‐2‐deoxyuridine staining, and western blot depicted the upregulated senescence pathway in vitro and in vivo of DN. Lactate dehydrogenase (LDH) release was increased by HG and reversed by p16/p21 knockdown, and the supernatant of HG‐treated cells caused increased LDH release from normal cells. Iron metabolism‐related protein expression was disordered after HG exposure concomitant with senescence. Ferric ammonium citrate (50 μM) upregulated gamma‐H2A.X variant histone and increased the senescence markers in HG‐treated cells. The treatment of deferoxamine (0.5 μM) had the opposite effect. Compared to the non‐DN individual, increased ferritin and senescence markers were verified in DN mice and patients, and the co‐localization of ferritin and senescence markers was observed by immunofluorescence. These results suggested that accumulated iron was correlated with aggravated DNA damage and accelerated senescence, and revealed the role of iron in the cellular senescence of diseases.

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Intracellular labile iron determines H 2 O 2 -induced apoptotic signaling via sustained activation of ASK1/JNK-p38 axis

Cited by 56 publications

References 69 publications

Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation

Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation

Taraxerol protects the human hepatic L02 cells from hydrogen peroxide-induced apoptosis

Excess iron accumulation mediated senescence in diabetic kidney injury

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