metallothionein and Iron-Overload

Oxidative stress is considered to be the main cause for several chronic diseases including diabetes. Through hyperglycemia, hyperlipidemia, hypertension and possible iron dyshomeostasis, diabetes induces oxidative stress that causes damage to multiple organs, leading to various complications. Therefore, antioxidant therapy may be an interesting approach to prevent diabetes and diabetic complications. Metallothionein as a potent antioxidant was found to significantly protect heart and kidney against diabetes-induced pathophysiological changes. Zinc as an important trace element and a metallothionein inducer was found to have same protective function. Since diabetes would impair defensive system, including growth factor reduction, exogenous supplementation of fibroblast growth factor (FGF) significantly prevented diabetes-induced cardiac oxidative damage and wound healing impairment. These studies suggest that protective agents such as metallothionein, zinc and FGFs play an important role in preventing the development of diabetes and diabetic complications.

Topics: Animals; Antioxidants; Diabetes Complications; Diabetes Mellitus; Disease Models, Animal; Fibroblast Growth Factors; Humans; Iron Overload; Metallothionein; Oxidative Stress; Trace Elements; Zinc

Topics: Adolescent; Animals; Child; Child, Preschool; Cobalt; Copper; Female; Humans; Infant; Intestinal Mucosa; Iron; Iron Deficiencies; Iron Overload; Male; Malnutrition; Menkes Kinky Hair Syndrome; Metallothionein; Nutrition Policy; Nutritional Requirements; Pregnancy; Selenium; Zinc

Multiple sclerosis is a chronic demyelinating disease of the central nervous system characterised by inflammatory and degenerative changes. It is considered that disease arises from the influence of environmental factors on genetically susceptible individuals. Recent researches, using magnetic resonance imaging, connected iron deposits in different brain regions with demyelinating process in multiple sclerosis patients. Although iron is an essential trace element important for many biological functions it could be harmful because iron excess can induce the production of reactive oxygen species, development of oxidative stress and lipid peroxidation which leads to demyelination. In experimental autoimmune encephalomyelitis model, the most common experimental animal model for multiple sclerosis, we recently found that chronic iron overload influences the clinical course of disease in Dark Agouti rats. In female rats iron overload accelerated the onset of disease, while in male rats it accelerated the progression of disease and increased mortality rate. We hypothesize that those differences arise on molecular level in different expression of stress response proteins hepcidin and metallothioneins in male and female iron overloaded rats. They are both upregulated by metal ions in both sexes. Hepcidin is additionally upregulated by estrogen in female rats and therefore causes higher degradation of iron exporter ferroportin and sequestration of iron in the cells, lowering the possibility for the development of oxidative stress. Antioxidative effect of metallothioneins could be increased in female rats because of their ability to reversibly exchange metal ions with the estrogen receptor. In case of iron excess metallothioneins release zinc, which is normally bound to them. Zinc binds to estrogen receptor and leaves metallothioneins binding domains free for iron, causing at least provisional cytoprotective effect. To test this hypothesis, we propose to determine and compare serum levels of hepcidin and estrogen using ELISA essay as well as expression and distribution of acute stress response proteins hepcidin and metallothioneins, iron and estrogen receptor in the brain and spinal cord tissue using immunohistochemistry in control and chronic iron overloaded male and female rats in experimental autoimmune encephalomyelitis model. It would be also possible to perform the same immunohistochemistry in the brain tissue of multiple sclerosis patients post mortem. The re

Topics: Animals; Brain; Encephalomyelitis, Autoimmune, Experimental; Estrogens; Female; Hepcidins; Humans; Iron; Iron Overload; Male; Metallothionein; Models, Biological; Multiple Sclerosis; Oxidative Stress; Rats; Receptors, Estrogen; Sex Characteristics; Zinc

Although iron overload is implicated in hepatocarcinogenesis, the precise mechanism was not known yet. In the present study, we investigated the effect of iron overload upon the induction of hepatocyte proliferation after 70% partial hepatectomy (PH) in rats fed with rat chow with 3% carbonyl iron for 3 months. In normal-diet rats, the increase in Ki-67 labeling index (LI) commenced at 24 h post-PH and the LIs of proliferating cell nuclear antigen (PCNA) incorporated 5-bromo-2'-deoxyuridine (BrdU) and phospho-histone H3 reached maximum values at 36 and 48 h after PH, respectively. In iron-overload rats, the above parameters occurred 12 h earlier compared to that of normal-diet rats, shortening the G0-G1 transition. Interestingly, nuclear staining for metallothionein (MT), which is essential for hepatocyte proliferation, was noted even at 0 h in iron-overload rats, while MT expression occurred at 6 h in the normal rats. Moreover, nuclear factor kappa B (NF-κB) expression, which is an essential early event leading to liver regeneration, was detected in Kupffer cells at 0 h in iron-overload rats. These results may indicate that overloaded iron, maybe through the induction of MT and NF-κB, may keep liver as a state ready to regenerate in response to PH, by bypassing signal transduction cascades involved in the initiation of liver regeneration.

Topics: Animals; Cell Proliferation; Hepatectomy; Hepatocytes; Immunohistochemistry; Iron Compounds; Iron Overload; Iron, Dietary; Ki-67 Antigen; Kupffer Cells; Liver; Liver Regeneration; Male; Metallothionein; NF-kappa B; Proliferating Cell Nuclear Antigen; Rats

The azo-dye p-dimethylaminoazobenzene (p-DAB) is a potential tumor initiator in rodents, but the underlying mechanism is not clear. Following chronic feeding of the carcinogen for 3, 5 and 7 weeks, trace elemental status, free radical generation, oxidative damage, antioxidant profile were measured in male and female swiss albino mice. The feeding resulted in iron accumulation in male mice liver. No increase in iron level was observed in similarly exposed female mice. The results of this study suggest that p-DAB-induced iron accumulation in male mice with concomitant production of oxidative free radicals is an early event in the hepatocarcinogenic initiation. This occurs selectively in male mice and affects either directly or indirectly in development of chemically induced liver neoplasia. Again, that upregulation of metallothionein (MT) expression in association with increased free radical generation was demonstrated in male mice. Alteration of copper (Cu) and zinc (Zn) levels are described in the light of antioxidant profile in liver tissue. The current results thus provide evidence in support of iron accumulations producing oxidative damage, and enhanced metallothionein expression as possible contributors in the mode of action of p-DAB induced hepatocarcinogenesis.

Topics: Animals; Antioxidants; Cell Transformation, Neoplastic; Female; Free Radicals; Iron; Iron Overload; Liver; Liver Neoplasms, Experimental; Male; Metallothionein; Mice; Oxidative Stress; p-Dimethylaminoazobenzene; Reactive Oxygen Species; Sex Factors; Time Factors; Trace Elements; Up-Regulation

Oxidative stress can trigger a cellular stress response characterized by induction of antioxidants, acute phase reactants (APRs) and heat shock proteins (HSPs), which are presumed to play a role in limiting tissue damage. In rodents, hepatic iron overload causes oxidative stress that results in upregulation of antioxidant defenses with minimal progressive liver injury. The aim of this study was to determine whether iron overload modulates expression of other stress-responsive proteins such as APRs and HSPs that may confer protection against iron-induced damage in rodent liver.. Male rats received repeated injections of iron dextran or dextran alone over a 6-month period. Hepatic transcript levels for a panel of APRs and HSPs were quantitated by real-time PCR and protein expression was evaluated by Western blot and immunohistochemistry.. Hepatic iron concentrations were increased >50-fold in the iron-loaded rats compared to controls. Iron loading resulted in striking increases in mRNAs for Hsp32 (heme oxygenase-1; 12-fold increase vs. controls) and metallothionein-1 and -2 (both increased approximately 6-fold). Transcripts for alpha1-acid glycoprotein, the major rat APR, were increased approximately 3-fold, while expression of other classical APRs was unaltered. Surprisingly, although mRNA levels for the HSPs were not altered by iron, the abundance of Hsp25, Hsp70 and Hsp90 proteins was uniformly reduced in the iron-loaded livers, as were levels of NAD(P)H:quinone oxidoreductase 1, an Hsp70 client protein.. Chronic iron administration elicits a unique pattern of stress protein expression. These alterations may modulate hepatic responses to iron overload, as well as other injury processes.

Topics: Acute-Phase Proteins; Animals; Apoferritins; Blood Proteins; Blotting, Western; Chronic Disease; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepatocytes; Immunohistochemistry; Injections, Intraperitoneal; Iron Overload; Iron-Dextran Complex; Iron-Regulatory Proteins; Kupffer Cells; Liver; Male; Metallothionein; NAD(P)H Dehydrogenase (Quinone); Orosomucoid; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction