Chronic iron overload induces gender-dependent changes in iron homeostasis, lipid peroxidation and clinical course of experimental autoimmune encephalomyelitis

Ćurko-Cofek, Božena; Kezele, Tanja Grubić; Marinić, Jelena; Tota, Marin; Čizmarević, Nada Starčević; Milin, Čedomila; Ristić, Smiljana; Radošević-Stašić, Biserka; Barac-Latas, Vesna

doi:10.1016/j.neuro.2016.08.014

Cited by 16 publications

(17 citation statements)

References 64 publications

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“…During the acute phase of EAE, female IO rats sequestered more iron in the liver and produced more ferritin than male EAE rats. Male rats, however, reacted on IO by higher production of oxidative stress markers, malondialdehyde and 4-hydroxynonenal, in the neural tissues and showed greater signs of plaque formation and gliosis in the spinal cord [16]. The data point to sexual dimorphism in mechanisms that regulate peripheral and brain iron homeostasis and imply that men and women during MS might be differentially vulnerable to exogenous IO.…”

Section: Iron and Multiple Sclerosismentioning

confidence: 82%

“…Increasing experimental and clinical evidence concerning iron metabolism support the idea that healthy aging processes, as well as neurological disorders, differ between women and men, suggesting the existence of different underlying mechanisms involved in the iron homeostasis and the pathogenesis of diseases (Figure 3) [16][17][18][19][20][21][22]161]. Age and sex are important co-factors to consider when establishing the differences between the pathological neurodegeneration from healthy aging.…”

Section: Sex-related Differences In Iron Homeostasis During Healthy Amentioning

confidence: 99%

“…Investigations in animal model of MS, experimental autoimmune encephalomyelitis (EAE), showed worsening of clinical course in iron overloaded animals, which had an iron accumulation in CNS (brain and spinal cord) [16]. Although female IO rats developed symptoms earlier, male IO rats showed more severe clinical course and higher mortality rate, indicating the existence of sex-dependent mechanisms [163].…”

Section: Iron and Multiple Sclerosismentioning

confidence: 99%

“…An increased number of recent experimental and clinical discoveries about the sex-related differences in iron metabolism present in certain neurological disorders [16][17][18][19][20][21][22] is raising attention, and pointing to the need for future research exploring possible underlying mechanisms, which could be responsible for the sex differences in the susceptibility to these diseases.…”

Section: Introductionmentioning

confidence: 99%

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Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

Kezele

Ćurko-Cofek

2020

Nutrients

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Iron is an essential element that participates in numerous cellular processes. Any disruption of iron homeostasis leads to either iron deficiency or iron overload, which can be detrimental for humans’ health, especially in elderly. Each of these changes contributes to the faster development of many neurological disorders or stimulates progression of already present diseases. Age-related cellular and molecular alterations in iron metabolism can also lead to iron dyshomeostasis and deposition. Iron deposits can contribute to the development of inflammation, abnormal protein aggregation, and degeneration in the central nervous system (CNS), leading to the progressive decline in cognitive processes, contributing to pathophysiology of stroke and dysfunctions of body metabolism. Besides, since iron plays an important role in both neuroprotection and neurodegeneration, dietary iron homeostasis should be considered with caution. Recently, there has been increased interest in sex-related differences in iron metabolism and iron homeostasis. These differences have not yet been fully elucidated. In this review we will discuss the latest discoveries in iron metabolism, age-related changes, along with the sex differences in iron content in serum and brain, within the healthy aging population and in neurological disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and stroke.

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Section: Iron and Multiple Sclerosismentioning

confidence: 82%

Section: Sex-related Differences In Iron Homeostasis During Healthy Amentioning

confidence: 99%

Section: Iron and Multiple Sclerosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

Kezele

Ćurko-Cofek

2020

Nutrients

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“…Notably, the activity of the primary sensor of cellular stress, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is also diminished with ageing 37,38 . Dysfunctional mitochondria and toxin scavenging induce lipid peroxidation (LPO) of unsaturated lipids in membranes, against which OLs are particularly vulnerable to [39][40][41][42] . Upon LPO, reactive aldehydes, such as 4-Hydroxynonenal (4-HNE), will be generated and diffuse in the cytosol, unless scavenged by conjugation to glutathione.…”

mentioning

confidence: 99%

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas/Casp8/Bid-axis

Carlström

Zhu

Ewing

et al. 2020

Preprint

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Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in Multiple Sclerosis (MS) are associated with disease progression but the underlying mechanism are elusive. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that its loss prevents differentiation into myelinating OLs. Also, Gsta4 appeared to be a novel target for Clemastine, in clinical trial for MS. Over-expression of Gsta4 reduced the expression of Fas and activity along the 2 mitochondria-associated Casp8/Bid-axis in adult pre-OLs from the corpus callosum, together promoting enhanced pre-OL survival during differentiation. The Gsta4-mediated input on apoptosis during adult OL differentiation was further verified in the LPC and EAE model, where Casp8 were reduced in pre-OLs with high Gsta4 expression in an immune responseindependent fashion. Our results place Gsta4 as a key regulator of intrinsic mechanisms beneficial for OL differentiation and remyelination, and as a possible target for future MS therapies. IntroductionOligodendrocyte precursor cells (OPC) and oligodendrocytes (OL) are abundant throughout the central nervous system (CNS). They serve important roles in preserving the functionality and integrity of neuronal network connections, including providing metabolic support and enabling axonal signal transmission along myelinated fibers 1-4 . OLs are affected directly or indirectly in many CNS diseases, of which Multiple Sclerosis (MS) is one of the most widely studied 5 . Despite findings of proliferating OPCs around lesions 6,7 , OLs fail to remyelinate axons 8-12 which leads to neurodegeneration 9,13-15 .Previous studies have indicated that as many as 50% of pre-OLs undergo programmed cell death during development and 20-30% during post-natal conditions 16,17 . Recent studies have also shown mechanisms of OLs loss during development 18,19 , similar approached in postnatal animals and adult OLs are lacking.3 Remyelination do occur in adulthood 6,20-23 , but the time interval within which the OLs should receive crucial support in order to survive is restricted [24][25][26] .The OPCs capacity to remyelinate is strongly diminished over-time [27][28][29] and differentiating cells are exposed to considerable cellular stress [30][31][32][33] . Interestingly, mitochondrial function and the capacity to scavenge endogenous toxins are also diminished with ageing and diseaseprocesses such as those present in MS [34][35][36] . Notably, the activity of the primary sensor of cellular stress, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is also diminished with ageing 37,38 . Dysfunctional mitochondria and toxin scavenging induce lipid peroxidation (LPO) of unsaturated lipids in membranes, against which OLs are particularly vulnerable to [39][40][41][42] . Upon LPO, reactive aldehydes, such as 4-Hydroxynonenal (4-HNE), will be generated and diffuse in the cytosol, unless scavenged by conjugation to glutathione. If not scavenged, 4-HNE will bind to macro-molecules and...

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Iron

Kezele¹

2018

Trace Elements and Minerals in Health and Longevity

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Chronic iron overload induces gender-dependent changes in iron homeostasis, lipid peroxidation and clinical course of experimental autoimmune encephalomyelitis

Cited by 16 publications

References 64 publications

Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas/Casp8/Bid-axis

Iron

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