Iron

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Petr75
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Iron

Post by Petr75 » Thu Jan 31, 2019 12:09 am

2018 Dec 20
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306469/

Abstract
Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.

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Re: Iron

Post by Petr75 » Thu Jan 31, 2019 12:13 am

2018 Dec 18
Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
UPR Induction Prevents Iron Accumulation and Oligodendrocyte Loss in ex vivo Cultured Hippocampal Slices
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305600/

Abstract
The accumulation of iron within the brain occurs in many chronic disorders including Alzheimer's and Parkinson's disease and multiple sclerosis. Outside the CNS, a link between levels of iron and the unfolded protein response has already been established. To determine if such a relationship operates in within the brain, we used our ex vivo hippocampal slice-based model of iron accumulation. Ferrocene addition caused accumulation of iron within slices and loss of oligodendrocytes, an effect that was partially inhibited when ferrocene and ER stressor tunicamycin (Tm) were added together. An upward trend (not found to be statistically significant) in the expression of UPR transcripts in response to ferrocene was demonstrated using real-time PCR, while a significant upregulation of mRNA for B cell immunoglobulin-binding protein (BiP) and C/EBP homologous binding protein (CHOP) occurred following exposure to Tm. In silico analysis revealed consensus DNA-binding sequences for UPR-associated transcription factors within the promoter regions of eight iron-regulatory genes. In addition, dual-staining for CHOP and oligodendrocyte transcription factor 2 (OLIG2) or Ionized calcium binding adaptor molecule 1 (Iba1) showed nuclear expression of CHOP in some oligodendrocyte-lineage cells in response to Tm or Tm+ferrocene, but CHOP was rarely found in microglia. Co-expression of UPR-associated activated transcription factor 6 (ATF6) was detected in the nuclei of some oligodendrocyte-lineage cells exposed to Tm alone, or to Tm and ferrocene, but rarely in microglia. These data highlight the therapeutic potential of targeting UPR-associated proteins when developing novel treatments for chronic brain disorders that are affected by dysregulated iron.

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Re: Iron

Post by NHE » Tue Feb 19, 2019 1:26 am

The elephant in the room...

We have been discussing the association of iron with MS lesions on this forum for the past 15 years since 2004, nearly since the forum's inception.
In addition, PubMed's first article discussing iron and MS lesions was published 37 years ago in 1982.
  • Iron deposits surrounding multiple sclerosis plaques.
    Arch Pathol Lab Med. 1982 Aug;106(8):397-9.

    Autopsy samples from cerebral areas of five brains from patients with multiple sclerosis (MS) and from six control brains were stained with Perls acid ferrocyanide to detect nonheme iron present as hemosiderin. Positive iron reactions were observed only in MS sections surrounding demyelinated plaques. Myelinated white matter near the lesion contained numerous iron-laden ovoid bodied and axons that stained positively for iron. Positive reactions were also found within blood vessels of gray matter near the lesion. A possible source of the iron was extravasated blood.

The above review paper published in December 2018 continues the discussion. We now know that iron in the brain is toxic. It potentiates a vicious cycle of inflammation, mitochondrial dysfunction and subsequent neurodegeneration leading to yet more iron deposition. Indeed, excessive iron accumulation in the brain is associated with a variety of neurodegenerative diseases, e.g., MS, Traumatic Brain Injury, Parkinson's Disease, Alzheimer's Disease, dementia, etc. With respect to MS, we now have just over 20 different forums dedicated to the various medical treatments available to MS patients. However, none of these treatments address iron's vicious cycle. Iron is the proverbial elephant in the room. This begs the obvious question, how do we get iron out of the brain? ...and do it safely without precipitating anemia or binding up useful metal cations, e.g., zinc, magnesium, calcium, etc. with chelation therapies?

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Re: Iron

Post by jimmylegs » Tue Feb 19, 2019 5:41 am

a related item which first appeared on the forum in early jan 2009:

Zinc Deficiency-induced Iron Accumulation... (2007)
http://www.jbc.org/content/283/8/5168.full
A number of studies indicate that a diet deficient in zinc can result in the accumulation of iron in numerous tissues, including testes, liver, kidney, and spleen, as well as in fetuses of zinc-deficient dams (2-4).

related, but more recent and not previously posted here:

Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions (2017)
https://link.springer.com/article/10.10 ... 017-1696-8

"Metals are essential for the synthesis, stability, and maintenance of myelin [14, 29, 36, 63, 64], and are required for normal CNS functioning [36, 72]. ... This is the first systematic synchrotron X-ray fluorescence study to compare the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing white matter (normal appearing WM) and periplaque white matter (periplaque WM) from a given patient, and to assess the involvement of these metals in MS lesion pathogenesis.
...
We analyzed formalin-fixed paraffin-embedded archival autopsy tissue from 18 MS patients (Suppl. Table 1), with no known iron metabolism abnormalities.
...
The completely demyelinated inactive center (Fig. 2a) was devoid of iron in six smoldering lesions, while four lesions (three with and one without an iron ring, all from patients younger than 50 years of age) contained patchy subregions of iron accumulation and iron loss visible on XFI (Figs. 2b, h, k, 4a, b), and iron histochemistry (Fig. 2f, i). These iron-rich regions located within the inactive demyelinated center co-localized with areas of reactive astrogliosis and glial scaring (Fig. 2e). Iron within these patches was significantly increased when compared to the iron in the rest of the demyelinated center (p = 0.02), and there was a trend of increase relative to the rim iron (p = 0.06), but not compared to the periplaque WM iron (p = 0.55). Zinc was low in the inactive demyelinated center of smoldering lesions (Fig. 2c), except in one case where zinc was increased periventricularly (Fig. 2j).
...
Zinc in MS lesions is generally decreased, paralleling the myelin loss.
...
Whether there is a role for iron chelation in MS remains controversial [12, 61, 69] and is based on the premise that iron accumulates in lesions. We have generally observed the opposite, as chronic MS plaques tended to be deficient in iron.
...
Further studies are needed to determine whether MRI features reportedly associated with iron rims around smoldering and inactive plaques differ. Although our study focused on chronic non-active MS lesions, XFI-pathological correlative studies examining iron and zinc in actively demyelinating lesions are ongoing, to better define their role in early lesion formation. "

:-? will have to have a scout around for those
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!

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Re: Iron

Post by Petr75 » Sun Mar 24, 2019 10:39 am

2019 Feb 11
IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.
PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378854/

Abstract
Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 μg/dL) than CTRL (mean 78.6, SD = 27.55 μg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 μg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.

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