Brain antioxidant responses to acute iron and copper intoxications in rats

Semprine, Jimena; Ferrarotti, Nidia; Musacco-Sebio, Rosario; Saporito-Magriñá, Christian; Fuda, Julián; Torti, Horacio; Castro-Parodi, Mauricio; Damiano, Alicia E.; Boveris, Alberto; Repetto, Marisa G.

doi:10.1039/c4mt00159a

Cited by 19 publications

(7 citation statements)

References 42 publications

(74 reference statements)

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“…Importantly, these “self”-reacting copper and sulfur “redoxomes” also interact with each other through the prominent chelation of Cu(I) by thiols of either the antioxidant copper chaperone protein Atox1 or GSH [ 63 , 142 , 160 – 162 ]. Supporting this concept, the GSH/GSSG ratio was found to be the most sensitive indicator of copper intoxication (and subsequent oxidative stress) [ 11 ]. Moreover, sulfur-doped copper clusters are relatively stable and abundant [ 163 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the complex equilibrium system GSH-Cu(I) can switch to the oxidized GSSG-Cu(II) one [ 173 ]. Taken together, these observations have been used to classify the speciation of Cu(I) with GSH as a key feature accompanying redox homeostasis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…The antioxidant responses to copper overloads (0–30 mg/kg ) in rat brains showed markedly decreased brain GSH and GSH/GSSG ratio after chronic copper exposure. Copper overloads are characterized by a t 1/2 of 9-10 h for the decrease in GSH and of 4 h for decreases in the GSH/GSSG ratio, the latter being the most sensitive indicator of copper excess [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Copper signalling: causes and consequences

Kardos¹,

Héja²,

Simon³

et al. 2018

Cell Commun Signal

142

137

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Copper-containing enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chemical energy-transfer for aerobic metabolism. The copper-dependence of O2 transport, metabolism and production of signalling molecules are supported by molecular systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metabolism may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders associated with aberrant copper metabolism.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Copper signalling: causes and consequences

Kardos¹,

Héja²,

Simon³

et al. 2018

Cell Commun Signal

142

137

View full text Add to dashboard Cite

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“…Noteworthy, higher uptake of iron causes cellular injury related ROS formation via Fenton's reaction, generating a variety of free radicals capable of causing cellular damage. [ 35 ] Moreover, brain cells overloaded with iron can develop antioxidant defense mechanisms by consuming O 2 • − by SOD or degrading H 2 O 2 by CAT and increasing their activities. [ 36 ]…”

Section: Discussionmentioning

confidence: 99%

New insights into arsenic, lead, and iron neurotoxicity: Activation of MAPK signaling pathway and oxidative stress

Khedr

Talkan²

2022

J Biochem & Molecular Tox

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Toxic metals cause neurodegeneration via formation of toxic complexes with the cellular compounds and production of highly reactive oxygen species. The present study aimed to investigate the role of mitogen‐activated protein kinase (MAPK) signaling pathway in iron, lead, and arsenic induced neurotoxicity. Also, to explore their effect on brain enzymes, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF‐κB) in rat brains. Rats were divided into four groups (n = 8): Control group, lead group (30 mg/kg lead acetate), arsenic group (5 mg/kg sodium arsenite), and iron group (100 mg/kg ferric hydroxide). Treatments were given three times/week orally for 2 months. Brain tissues were assessed for reduced glutathione and malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), alkaline phosphatase (ALP), acid phosphatase (ACP), Na+/K+ activated adenosine 5′‐triphosphatase (Na+/K+‐ATPase) and acetylcholinesterase (AChE) activities, expression of iNOS and NF‐κB, and Western blot analysis of c‐Jun NH(2)‐terminal kinase (JNK) and extracellular signal‐regulated protein kinase (ERK) proteins. Levels of arsenic, iron, and lead were significantly (p = 0.000) increased in blood and brain tissues. Levels of MDA, SOD, CAT, iNOS, and NF‐κB gene expression, phosphorylated JNK and phosphorylated ERK proteins were increased significantly in lead, arsenic, and iron treated rat groups compared to control. ALP, ACP, AChE, and ATPase activities in brain were significantly altered in metal‐treated rat groups compared to control. Iron, lead, and arsenic induced neurotoxicity activated the pro‐inflammatory mediators NF‐κB, iNOS, and MAPK pathway and altered the activity of brain ALP, ACP, Na+/K+‐ATPase, CAT, SOD, and AChE.

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“…Previous studies suggest that the majority of cytoplasmic Cu is bound to glutathione, a highly abundant thiol-containing tripeptide that helps maintain the reducing potential of the cytosol 32,33 . Excess Cu concentrations are known to disrupt glutathione homeostasis by decreasing the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) 34 . Thus, we tested whether glutathione homeostasis might be disrupted by the loss of ATP7A and/or MT in cells grown in basal medium.…”

Section: Characterization Of the Atp7a-/mt-cellsmentioning

confidence: 99%

Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess

Gudekar

Shanbhag

Wang

et al. 2020

Sci Rep

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Copper (Cu) is an essential, yet potentially toxic nutrient, as illustrated by inherited diseases of copper deficiency and excess. Elevated expression of the ATP7A Cu exporter is known to confer copper tolerance, however, the contribution of metal-binding metallothioneins is less clear. In this study, we investigated the relative contributions of ATP7A and the metallothioneins MT-I and MT-II to cell viability under conditions of Cu excess or deficiency. Although the loss of ATP7A increased sensitivity to low Cu concentrations, the absence of MTs did not significantly affect Cu tolerance. However, the absence of all three proteins caused a synthetic lethal phenotype due to extreme Cu sensitivity, indicating that MTs are critical for Cu tolerance only in the absence of ATP7A. A lack of MTs resulted in the trafficking of ATP7A from the trans-Golgi complex in a Cu-dependent manner, suggesting that MTs regulate the delivery of Cu to ATP7A. Under Cu deficiency conditions, the absence of MTs and / or ATP7A enhanced cell proliferation compared to wild type cells, suggesting that these proteins compete with essential Cudependent pathways when Cu is scarce. These studies reveal new roles for ATP7A and metallothioneins under both Cu deficiency and excess. Copper (Cu) is an essential enzymatic cofactor in organisms across all phyla 1,2. The ability of Cu to cycle between Cu 1+ and Cu 2+ allows cuproenzymes to catalyze redox reactions in many different areas of metabolism 3. In eukaryotic cells, Cu is imported to the cytoplasm by members of the SLC31 family of high-affinity Cu permeases 4. This process is thought to be facilitated by Cu binding to glutathione in the cytoplasm 5. Glutathione-bound Cu is exchangeable with metallochaperones 6,7 , which are small cytoplasmic proteins that deliver Cu in a unidirectional manner to specific cuproenzymes or to Cu-transporting P-type ATPases located in the Golgi. This targeted delivery of Cu is thought to be facilitated by an increasing affinity gradient down successive Cu carriers as well as metal-dependent interactions between metallochaperones and target proteins 3,6,8,9. The same redox property that makes Cu indispensable as an enzymatic cofactor is also responsible for its toxicity when cytoplasmic concentrations become elevated. In its free ionic state, Cu can catalyze the formation of hydroxyl radicals, displace other metals from enzymes and interfere with protein folding 10,11. Accordingly, mechanisms of Cu homeostasis have evolved to prevent free Cu ions from accumulating within the cytoplasm. Virtually all organisms are predicted to contain at least one P-type ATPase that exports Cu from the cytoplasm. In bacteria and mammalian cells, mutations that disrupt Cu-ATPases are known to cause hypersensitivity to Cu, whereas overexpression of these transporters results in Cu resistance 11,12. Mammals possess two Cu-transporting ATPases, ATP7A and ATP7B. ATP7A is expressed ubiquitously, whereas ATP7B is restricted to specific tissues with highest levels in hepatocytes 13. At the cel...

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Brain antioxidant responses to acute iron and copper intoxications in rats

Cited by 19 publications

References 42 publications

Copper signalling: causes and consequences

Copper signalling: causes and consequences

New insights into arsenic, lead, and iron neurotoxicity: Activation of MAPK signaling pathway and oxidative stress

Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess

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