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1.  Taurine supplementation reduces oxidative stress and protects the liver in an iron-overload murine model 
Molecular Medicine Reports  2014;10(5):2255-2262.
We previously demonstrated that iron overload induces liver damage by causing the formation of reactive oxygen species (ROS). Taurine is a potent free radical scavenger that attenuates the damage caused by excessive oxygen free radicals. Therefore, the aim of the present study was to investigate whether taurine could reduce the hepatotoxicity of iron overload with regard to ROS production. Mice were intraperitoneally injected with iron 5 days/week for 13 weeks to achieve iron overload. It was found that iron overload resulted in liver dysfunction, increased apoptosis and elevated oxidative stress. Taurine supplementation increased liver taurine levels by 40% and led to improved liver function, as well as a reduction in apoptosis, ROS formation and mitochondrial swelling and an attenuation in the loss of the mitochondrial membrane potential. Treatment with taurine mediated a reduction in oxidative stress in iron-overloaded mice, attenuated liver lipid peroxidation, elevated antioxidant enzyme activities and maintained reduced glutathione levels. These results indicate that taurine reduces iron-induced hepatic oxidative stress, preserves liver function and inhibits hepatocyte apoptosis. Therefore, taurine may be a potential therapeutic drug to reduce liver damage caused by iron overload.
doi:10.3892/mmr.2014.2544
PMCID: PMC4199407  PMID: 25201602
taurine; iron overload; liver; oxidative stress; apoptosis
2.  Radiation protection following nuclear power accidents: a survey of putative mechanisms involved in the radioprotective actions of taurine during and after radiation exposure 
Microbial Ecology in Health and Disease  2012;23:10.3402/mehd.v23i0.14787.
There are several animal experiments showing that high doses of ionizing radiation lead to strongly enhanced leakage of taurine from damaged cells into the extracellular fluid, followed by enhanced urinary excretion. This radiation-induced taurine depletion can itself have various harmful effects (as will also be the case when taurine depletion is due to other causes, such as alcohol abuse or cancer therapy with cytotoxic drugs), but taurine supplementation has been shown to have radioprotective effects apparently going beyond what might be expected just as a consequence of correcting the harmful consequences of taurine deficiency per se. The mechanisms accounting for the radioprotective effects of taurine are, however, very incompletely understood. In this article an attempt is made to survey various mechanisms that potentially might be involved as parts of the explanation for the overall beneficial effect of high levels of taurine that has been found in experiments with animals or isolated cells exposed to high doses of ionizing radiation. It is proposed that taurine may have radioprotective effects by a combination of several mechanisms: (1) during the exposure to ionizing radiation by functioning as an antioxidant, but perhaps more because it counteracts the prooxidant catalytic effect of iron rather than functioning as an important scavenger of harmful molecules itself, (2) after the ionizing radiation exposure by helping to reduce the intensity of the post-traumatic inflammatory response, and thus reducing the extent of tissue damage that develops because of severe inflammation rather than as a direct effect of the ionizing radiation per se, (3) by functioning as a growth factor helping to enhance the growth rate of leukocytes and leukocyte progenitor cells and perhaps also of other rapidly proliferating cell types, such as enterocyte progenitor cells, which may be important for immunological recovery and perhaps also for rapid repair of various damaged tissues, especially in the intestines, and (4) by functioning as an antifibrogenic agent. A detailed discussion is given of possible mechanisms involved both in the antioxidant effects of taurine, in its anti-inflammatory effects and in its role as a growth factor for leukocytes and nerve cells, which might be closely related to its role as an osmolyte important for cellular volume regulation because of the close connection between cell volume regulation and the regulation of protein synthesis as well as cellular protein degradation. While taurine supplementation alone would be expected to exert a therapeutic effect far better than negligible in patients that have been exposed to high doses of ionizing radiation, it may on theoretical grounds be expected that much better results may be obtained by using taurine as part of a multifactorial treatment strategy, where it may interact synergistically with several other nutrients, hormones or other drugs for optimizing antioxidant protection and minimizing harmful posttraumatic inflammatory reactions, while using other nutrients to optimize DNA and tissue repair processes, and using a combination of good diet, immunostimulatory hormones and perhaps other nontoxic immunostimulants (such as beta-glucans) for optimizing the recovery of antiviral and antibacterial immune functions. Similar multifactorial treatment strategies may presumably be helpful in several other disease situations (including severe infectious diseases and severe asthma) as well as for treatment of acute intoxications or acute injuries (both mechanical ones and severe burns) where severely enhanced oxidative and/or nitrative stress and/or too much secretion of vasodilatory neuropeptides from C-fibres are important parts of the pathogenetic mechanisms that may lead to the death of the patient. Some case histories (with discussion of some of those mechanisms that may have been responsible for the observed therapeutic outcome) are given for illustration of the likely validity of these concepts and their relevance both for treatment of severe infections and non-infectious inflammatory diseases such as asthma and rheumatoid arthritis.
doi:10.3402/mehd.v23i0.14787
PMCID: PMC3747764  PMID: 23990836
ionizing radiation; radiation illness; therapy; rheumatoid arthritis; asthma; diarrhoea
3.  The C57BL/6 genetic background confers cardioprotection in iron-overloaded mice 
Blood Transfusion  2013;11(1):88-93.
Background
Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart.
Methods
Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods.
Results
As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1±0.1 mm to 3.5±0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group.
Conclusions
These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.
doi:10.2450/2012.0176-11
PMCID: PMC3557493  PMID: 22790263
beta-blockers; iron overload; heart failure; packed red blood cells; transfusion therapy
4.  Interdependence of Cardiac Iron and Calcium in a Murine Model of Iron Overload 
Iron cardiomyopathy in β-thalassemia major patients is associated with vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, while the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone (PTH)) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca2+-channel blocker verapamil. Mn2+ was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ amongst the treatment groups; however, liver iron was increased in vitamin D-depleted animals (p<0.0003). Cardiac iron levels did not correlate with manganese uptake, but were proportional to cardiac calcium levels (r2 = 0.6, p < 0.0001). Verapamil treatment reduced both cardiac (p <0.02) and hepatic (p < 0.003) iron levels significantly by 34% and 28%. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r2 = 0.3, p < 0.008). Vitamin D-depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related.
doi:10.1016/j.trsl.2010.11.002
PMCID: PMC3073567  PMID: 21256461
b-thalassemia; vitamin D; iron overload; hemojuvelin
5.  Rapid monitoring of iron-chelating therapy in thalassemia major by a new cardiovascular MR measure: the reduced transverse relaxation rate 
NMR in biomedicine  2010;24(7):771-777.
In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R2*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R2), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the ‘reduced transverse relaxation rate’ (RR2), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR2 could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR2 (7.8%, p < 0.01) and R2 (5.5%, p < 0.05), but not in R2* (1.7%, p > 0.90). Although the difference between changes in RR2 and R2 was not significant (p > 0.3), RR2 was consistently more sensitive than R2 (and R2*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected. Although further studies are needed, myocardial RR2 may be a promising investigational method for the rapid assessment of the effects of iron-chelating therapy in the heart.
doi:10.1002/nbm.1639
PMCID: PMC3138893  PMID: 21190261
MRI; heart; cardiomyopathy; iron chelation; R2
6.  Iron Overload Favors the Elimination of Leishmania infantum from Mouse Tissues through Interaction with Reactive Oxygen and Nitrogen Species 
Iron plays a central role in host-parasite interactions, since both intervenients need iron for survival and growth, but are sensitive to iron-mediated toxicity. The host's iron overload is often associated with susceptibility to infection. However, it has been previously reported that iron overload prevented the growth of Leishmania major, an agent of cutaneous leishmaniasis, in BALB/c mice. In order to further clarify the impact of iron modulation on the growth of Leishmania in vivo, we studied the effects of iron supplementation or deprivation on the growth of L. infantum, the causative agent of Mediterranean visceral leishmaniasis, in the mouse model. We found that dietary iron deficiency did not affect the protozoan growth, whereas iron overload decreased its replication in the liver and spleen of a susceptible mouse strain. The fact that the iron-induced inhibitory effect could not be seen in mice deficient in NADPH dependent oxidase or nitric oxide synthase 2 suggests that iron eliminates L. infantum in vivo through the interaction with reactive oxygen and nitrogen species. Iron overload did not significantly alter the mouse adaptive immune response against L. infantum. Furthermore, the inhibitory action of iron towards L. infantum was also observed, in a dose dependent manner, in axenic cultures of promastigotes and amastigotes. Importantly, high iron concentrations were needed to achieve such effects. In conclusion, externally added iron synergizes with the host's oxidative mechanisms of defense in eliminating L. infantum from mouse tissues. Additionally, the direct toxicity of iron against Leishmania suggests a potential use of this metal as a therapeutic tool or the further exploration of iron anti-parasitic mechanisms for the design of new drugs.
Author Summary
Leishmania are important vector-borne protozoan pathogens that cause different forms of disease, ranging from cutaneous self-healing lesions to life-threatening visceral infection. L. infantum is the most common species causing visceral leishmaniasis in Europe and the Mediterranean basin. Iron plays a critical role in host-pathogen interactions. Both the microorganism and its host need iron for growth. However, iron may promote the formation of toxic reactive oxygen species, which contribute to pathogen elimination, but also to host tissue pathology. We investigated the effect of manipulating host iron status on the outcome of L. infantum infection, using the mouse as an experimental model. We found that dietary iron deprivation had no effect on L. infantum growth, and iron-dextran injection decreased the multiplication of L. infantum in mouse organs. The fact that this anti-parasitic effect of iron was not observed in mice genetically deficient in superoxide and nitric oxide synthesis pathways indicates that iron is likely to act in synergy with reactive oxygen and nitrogen species produced by the host's macrophages. This work clearly shows that iron supplementation improves the host's capacity to eliminate L. infantum parasites and suggests that iron may be further explored as a therapeutic tool to fight this type of infection.
doi:10.1371/journal.pntd.0002061
PMCID: PMC3573095  PMID: 23459556
7.  Co-Administration of Silymarin and Deferoxamine against Kidney, Liver and Heart Iron Deposition in Male Iron Overload Rat Model 
Background:
Tissue iron deposition may disturb functions of the organs. In many diseases like thalassemia, the patients suffer from iron deposition in kidney and heart tissues. Deferoxamine (DF) is a synthetic iron chelator and silymarin (SM) is an antioxidant and also a candidate for iron chelating. This study was designed to investigate the effect of DF and SM combination against kidney and heart iron deposition in an iron overload rat model.
Methods:
Male Wistar rats were randomly assigned to 5 groups. The iron overloading was performed by iron dextran 100 mg/kg/day every other day during 2 weeks and in the 3rd week, iron dextran was discontinued and the animals were treated daily with combination of SM (200 mg/kg/day, i.p.) and DF (50 mg/kg/day, i.p.) (group 1), SM (group 2), DF (group 3) and saline (group 4). Group 5 received saline during the experiment. Finally, blood samples were obtained and kidney, heart and liver were immediately removed and prepared for histopathological procedures.
Results:
The results indicated no significant difference in kidney function and endothelial function biomarkers between the groups. However, combination of SM and DF did not attenuate the iron deposition in the kidney, liver and heart. DF alone, rather than DF and SM combination, significantly reduced the serum level of malondialdehyde (P < 0.05). Co-administration of SM and DF significantly increased the serum level of ferritin (P < 0.05).
Conclusions:
DF and SM may be potentially considered as iron chelators. However, combination of these two agents did not provide a protective effect against kidney, liver and heart iron deposition.
PMCID: PMC3915463  PMID: 24555000
Deferoxamine; heart; iron deposition; kidney; liver; silymarin
8.  Cardiac Iron Determines Cardiac T2*, T2, and T1 in the Gerbil Model of Iron Cardiomyopathy 
Circulation  2005;112(4):535-543.
Background
Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, which creates a potential mechanism for iron quantification. However, because of the danger and variability of cardiac biopsy, tissue validation of cardiac iron estimates by MRI has not been performed. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver using a gerbil iron-overload model.
Methods and Results
Twelve gerbils underwent iron dextran loading (200 mg · kg−1 · wk−1) from 2 to 14 weeks; 5 age-matched controls were studied as well. Animals had in vivo assessment of cardiac T2* and hepatic T2 and T2* and postmortem assessment of cardiac and hepatic T1 and T2. Relaxation measurements were performed in a clinical 1.5-T magnet and a 60-MHz nuclear magnetic resonance relaxometer. Cardiac and liver iron concentrations rose linearly with administered dose. Cardiac 1/T2*, 1/T2, and 1/T1 rose linearly with cardiac iron concentration. Liver 1/T2*, 1/T2, and 1/T1 also rose linearly, proportional to hepatic iron concentration. Liver and heart calibrations were similar on a dry-weight basis.
Conclusions
MRI measurements of cardiac T2 and T2* can be used to quantify cardiac iron. The similarity of liver and cardiac iron calibration curves in the gerbil suggests that extrapolation of human liver calibration curves to heart may be a rational approximation in humans.
doi:10.1161/CIRCULATIONAHA.104.504415
PMCID: PMC2896311  PMID: 16027257
magnetic resonance imaging; anemia; iron overload; thalassemia; cardiomyopathy
9.  Reducing power and iron chelating property of Terminalia chebula (Retz.) alleviates iron induced liver toxicity in mice 
Background
The 70% methanol extract of Terminalia chebula Retz. fruit (TCME) was investigated for its in vitro iron chelating property and in vivo ameliorating effect on hepatic injury of iron overloaded mice.
Methods
The effect of fruit extract on Fe2+-ferrozine complex formation and Fe2+ mediated pUC-18 DNA breakdown was studied in order to find the in vitro iron chelating activity. Thirty-six Swiss Albino mice were divided into six groups of: blank, patient control and treated with 50, 100, 200 mg/kg b.w. of TCME and desirox (standard iron chelator drug with Deferasirox as parent compound). Evaluations were made for serum markers of hepatic damage, antioxidant enzyme, lipid per oxidation and liver fibrosis levels. The reductive release of ferritin iron by the extract was further studied.
Results
In vitro results showed considerable iron chelation with IC50 of 27.19 ± 2.80 μg/ml, and a significant DNA protection with [P]50 of 1.07 ± 0.03 μg/ml along with about 86% retention of supercoiled DNA. Iron-dextran injection (i.p.) caused significant increase in the levels of the serum enzymes, viz., alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP) and Bilirubin, which were subsequently lowered by oral administration of 200 mg/kg b.w. dose of the fruit extract by 81.5%, 105.88%, 188.08% and 128.31%, respectively. Similarly, treatment with the same dose of the extract was shown to alleviate the reduced levels of liver antioxidant enzyme superoxide dismutase, catalase, glutathione S-transferase and non-enzymatic reduced glutathione, by 49.8%, 53.5%, 35.4% and 11% respectively, in comparison to the iron overloaded mice. At the same time, the fruit extract effectively lowered the iron-overload induced raised levels of lipid per oxidation, protein carbonyl, hydroxyproline and liver iron by 49%, 67%, 67% and 26%, respectively, with oral treatment of 200 mg/kg b.w. dose of TCME. The fruit extract also showed potential activity for reductive release of ferritin iron.
Conclusions
These findings suggest that Terminalia chebula extract may contain active substances capable of lessening iron overload induced toxicity, and hence possibly be useful as iron chelating drug for iron overload diseases.
doi:10.1186/1472-6882-12-144
PMCID: PMC3489879  PMID: 22938047
10.  Comparison of twice-daily vs once-daily deferasirox dosing in a gerbil model of iron cardiomyopathy 
Experimental hematology  2007;35(7):1069-1073.
Objective
Despite the availability of deferoxamine chelation therapy for more than 20 years, iron cardiomyopathy remains the leading cause of death in thalassemia major patients. Effective chelation of cardiac iron is difficult; cardiac iron stores respond more slowly to chelation therapy and require a constant gradient of labile iron species between serum and myocytes. We have previously demonstrated the efficacy of once-daily deferasirox in removing previously stored cardiac iron in the gerbil, but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that daily divided dosing, by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable daily dose.
Methods
Twenty-four 8- to 10-week-old female gerbils underwent iron dextran—loading for 10 weeks, followed by a 1-week iron equilibration period. Animals were divided into three treatment groups of eight animals each and were treated with deferasirox 100 mg/kg/day as a single dose, deferasirox 100 mg/kg/day daily divided dose, or sham chelation for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron and tissue histology.
Results
Hepatic and cardiac iron contents were not statistically different between the daily single-dose and daily divided-dose groups. However, the ratio of cardiac to hepatic iron content was lower in the divided-dose group (0.78% vs 1.11%, p = 0.0007).
Conclusion
Daily divided dosing of deferasirox changes the relative cardiac and liver iron chelation profile compared with daily single dosing, trading improvements in cardiac iron elimination for less-effective hepatic chelation.
doi:10.1016/j.exphem.2007.04.001
PMCID: PMC2892931  PMID: 17588475
11.  Serum taurine and risk of coronary heart disease: a prospective, nested case-control study 
European journal of nutrition  2012;52(1):169-178.
Purpose
Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk.
Methods
We conducted a case-control study nested in the New York University Women’s Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels.
Results
Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber, and iron, and negatively related to dietary intake of saturated fat (all p values ≤ 0.05). There was no statistically significant association between the risk of CHD and serum taurine levels. The adjusted ORs for CHD in increasing taurine tertiles were 1.0 (reference), 0.85 (95% CI, 0.51–1.40), and 0.66 (0.39–1.13; p for trend = 0.14). There was a significant inverse association between serum taurine and CHD risk among women with high total serum cholesterol (>250 mg/dl) (adjusted OR = 0.39 (0.19–0.83) for the third vs. first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk.
Conclusions
The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.
doi:10.1007/s00394-011-0300-6
PMCID: PMC3920833  PMID: 22322924
Taurine; serum; coronary heart disease; NYUWHS; epidemiology
12.  Methamphetamine Decreases Levels of Glutathione Peroxidases 1 and 4 in SH-SY5Y Neuronal Cells: Protective Effects of Selenium 
Neurotoxicology  2013;37:240-246.
Methamphetamine interferes with dopamine reuptake, and the resulting increased dopamine oxidation that creates oxidative stress can lead to degeneration of dopaminergic terminals. Previous studies have shown that the trace element selenium protects against methamphetamine toxicity. However, the specific selenoproteins responsible for protection have not been elucidated. Glutathione peroxidases 1 and 4 (GPx1 and GPx4) incorporate selenium into the amino acid selenocysteine, and their known antioxidant functions make them good candidates for protection from methamphetamine-induced oxidative damage. We differentiated SH-SY5Y neuronal cells in serum-free media with defined supplement containing 0, 10 and 100 nM selenium, and then challenged the cells with a 24-hour exposure to methamphetamine. We found that 100 μM methamphetamine decreased GPx1 and GPx4 protein levels. However, both proteins were upregulated with increasing media selenium concentration. GPx enzymatic activity was also increased by selenium and decreased by methamphetamine and correlated with GPx protein levels. Total glutathione levels were reduced by methamphetamine at lower selenium conditions, while the oxidized fraction of GSH was increased at higher selenium levels. Additionally, we observed an increased generation of reactive oxygen species with methamphetamine exposure in media with 0 nM selenium, which was ameliorated by selenium supplementation. These results show that methamphetamine increases oxidative stress by reducing GPx levels, and this can be reversed with addition of selenium. These findings have important implications for treating patients with acute methamphetamine toxicity.
doi:10.1016/j.neuro.2013.05.009
PMCID: PMC3717519  PMID: 23721877
Methamphetamine; selenium; glutathione peroxidase; glutathione; dopamine; oxidative stress
13.  Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration 
PLoS ONE  2012;7(10):e42017.
Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.
doi:10.1371/journal.pone.0042017
PMCID: PMC3480351  PMID: 23115615
14.  Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications 
Antioxidants & Redox Signaling  2008;10(6):997-1030.
Abstract
Maintenance of proper “labile iron” levels is a critical component in preserving homeostasis. Iron is a vital element that is a constituent of a number of important macromolecules, including those involved in energy production, respiration, DNA synthesis, and metabolism; however, excess “labile iron” is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation–reduction reactions that generate harmful free radicals. Because of this dual nature, elaborate systems tightly control the concentration of available iron. Perturbation of normal physiologic iron concentrations may be both a cause and a consequence of cellular damage and disease states. This review highlights the molecular mechanisms responsible for regulation of iron absorption, transport, and storage through the roles of key regulatory proteins, including ferroportin, hepcidin, ferritin, and frataxin. In addition, we present an overview of the relation between iron regulation and oxidative stress and we discuss the role of functional iron overload in the pathogenesis of hemochromatosis, neurodegeneration, and inflammation. Antioxid. Redox Signal. 10, 997–1030.
Introduction
Iron Transport
Nonintestinal iron transport by transferring
Iron-bound transferrin binds the transferrin receptor for cellular iron uptake
Regulation of transferrin receptor 1 by iron regulatory element–iron regulatory protein system
Transcriptional regulation of transferrin receptor 1
Differential regulation of transferrin receptor 1 and transferrin receptor 2
Transferrin receptor 1 is regulated by hereditary hemochromatosis protein
Transferrin-independent cellular iron uptake
Intestinal iron absorption
Regulation of divalent metal transporter 1
Ferroportin is responsible for cellular iron efflux
Ferroportin associates and cooperates with ceruloplasmin
Ferroportin and hephaestin cooperate in iron efflux from intestinal cells
Hepcidin
Iron Storage and Ferritin
Structure, tissue distribution, and importance of cytoplasmic ferritin
Iron efflux and ferritin degradation
Serum ferritin and ferritin receptor
Mitochondrial ferritin
Nuclear ferritin
Regulation of Ferritin
Iron-mediated ferritin regulation
Ferritin regulation by reactive oxygen species
Ferritin transcriptional regulation by cytokines
Ferritin regulation in erythroleukemic cells
Frataxin and Iron Homeostasis
Frataxin and Friedreich ataxia
Frataxin and mitochondrial iron traffic
Frataxin, heme synthesis, and iron–sulfur cluster biogenesis
Frataxin gene regulation
Treatments
Functional Iron Overload and Human Health
Hereditary hemochromatosis
Mutant iron-responsive element-mediated iron overload
Iron regulation and neurodegeneration
Conclusions and Future Directions
doi:10.1089/ars.2007.1893
PMCID: PMC2932529  PMID: 18327971
15.  Nutritional deficiencies in iron overloaded patients with hemoglobinopathies 
American journal of hematology  2009;84(6):344-348.
One of the hallmarks of both sickle cell disease (SCD) and thalassemia major (TM) is accelerated oxidative damage. Decreased antioxidant levels and increased oxidant stress biomarkers are found in both diseases. Although isolated vitamin deficiencies have been reported in TM and nontransfused SCD patients, a comprehensive evaluation of vitamin and trace mineral levels has never been performed in chronically transfused SCD or TM patients. As vitamins and trace minerals may be consumed as a result of chronic oxidative stress; we hypothesized that levels of these compounds would correlate with surrogates of iron overload, hemolysis, and inflammation in chronically transfused patients. Using a convenience sample of our group of chronically transfused patients we studied 43 patients with SCD (17 male, 26 female) and 24 patients with TM (13 male and 11 female). The age range for our patients varied from 1.5 to 31.4 years. Levels of vitamins A, thiamin, B6, B12, C, D, E as well as selenium, zinc, copper, and ceruloplasmin were measured. We found that 40–75% of the patients were deficient in A, C, D and selenium and 28–38% of the patients had low levels of B vitamins and folate. There was little association with iron overload, hemolysis, or inflammation. Although the precise mechanism of these deficiencies is unclear, they may contribute to the morbidity of chronically transfused hemoglobinopathy patients.
doi:10.1002/ajh.21416
PMCID: PMC2887656  PMID: 19415722
16.  Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats 
Hepatology (Baltimore, Md.)  2009;49(5):1554-1562.
Chronic ethanol feeding decreases expression of adiponectin by adipocytes and circulating adiponectin. Adiponectin treatment during chronic ethanol feeding prevents liver injury in mice. Chronic ethanol feeding also increases oxidative and endoplasmic reticulum (ER) stress in adipose tissue. Here we tested the hypothesis that supplemental taurine, an amino acid that functions as a chemical chaperone/osmolyte and enhances cellular anti-oxidant activity, would prevent ethanol-induced decreases in adiponectin expression and attenuate liver injury. Serum adiponectin concentrations decreased as early as 4–7 days after feeding rats a 36% ethanol diet. This rapid decrease was associated with increased oxidative, but not ER, stress in subcutaneous adipose tissue. Taurine prevented ethanol-induced oxidative stress and increased inflammatory cytokine expression in adipose tissue. Ethanol feeding also rapidly decreased expression of transcription factors regulating adiponectin expression (C/EBPα, PPARγ and PPARα) in subcutaneous adipose tissue. Taurine prevented the ethanol-induced decrease in C/EBPα and PPARα normalizing adiponectin mRNA and serum adiponectin concentrations. In the liver, taurine prevented ethanol-induced oxidative stress and attenuated TNF-α expression and steatosis, at least in part, by increasing expression of genes involved in fatty acid oxidation.
In conclusion
In subcutaneous adipose tissue, taurine decreased ethanol-induced oxidative stress and cytokine expression, as well as normalized expression of adiponectin mRNA. Taurine prevented ethanol-induced decreases in serum adiponectin; normalized adiponectin was associated with a reduction in hepatic oxidative stress, TNF-α expression and steatosis. Taken together, these data demonstrate that taurine has important protective effects against ethanol-induced tissue injury in both adipose and liver.
doi:10.1002/hep.22811
PMCID: PMC2677130  PMID: 19296466
Adiponectin; Ethanol feeding; Taurine
17.  Curcumin reduces the toxic effects of iron loading in rat liver epithelial cells 
Background/aims
Iron overload can cause liver toxicity and increase the risk of liver failure or hepatocellular carcinoma in humans. Curcumin (diferuloylmethane), a component of the food spice turmeric, has antioxidant, iron binding, and hepatoprotective properties. The aim of this study was to quantify its effects on iron overload and resulting downstream toxic effects in cultured T51B rat liver epithelial cells.
Methods
T51B cells were loaded with ferric ammonium citrate (FAC) with or without the iron delivery agent 8-hydroxyquinoline. Cytotoxicity was measured by MTT assay. Iron uptake and iron bioavailability were documented by chemical assay, quench of calcein fluorescence, and ferritin induction. Reactive oxygen species (ROS) were measured by fluorescence assay using 2′,7′-dichlorodihydrofluorescein diacetate. Oxidative stress signaling to jnk, c-jun, and p38 was measured by western blot with phospho-specific antibodies.
Results
Curcumin bound iron, but did not block iron uptake or bioavailability in T51B cells given FAC. However, it reduced cytotoxicity, blocked generation of ROS, and eliminated signaling to cellular stress pathways caused by iron. Inhibition was observed over a wide range of FAC concentrations (50 – 500 μM), with an apparent IC50 in all cases between 5 and 10 μM curcumin. In contrast, desferoxamine blocked both iron uptake and toxic effects of iron at concentrations that depended on the FAC concentration. Effects of curcumin also differed from those of α-tocopherol, which did not bind iron and was less effective at blocking iron-stimulated ROS generation.
Conclusions
Curcumin reduced iron-dependent oxidative stress and iron toxicity in T51B cells without blocking iron uptake.
doi:10.1111/j.1478-3231.2008.01793.x
PMCID: PMC2614453  PMID: 18492020
curcumin; iron; liver disease; oxidative stress; stress activated MAP kinase
18.  Cardiac iron across different transfusion-dependent diseases 
Blood reviews  2008;22(Suppl 2):S14-S21.
Summary
Iron overload occurs in patients who require regular blood transfusions to correct genetic and acquired anaemias, such as β-thalassaemia major, sickle cell disease, and myelodysplastic syndromes. Although iron overload causes damage in many organs, accumulation of cardiac iron is a leading cause of death in transfused patients with β-thalassaemia major. The symptoms of cardiac iron overload will occur long after the first cardiac iron accumulation, at a point when treatment is more complex than primary prevention would have been. Direct measurement of cardiac iron using T2* magnetic resonance imaging, rather than indirect methods such as measuring serum ferritin levels or liver iron concentration have contributed to earlier recognition of myocardial iron loading and prevention of cardiac toxicity. Cardiac siderosis occurs in all transfusional anaemias, but the relative risk depends upon the underlying disease state, transfusional load, and chelation history. All three available iron chelators can be used to remove cardiac iron, but each has unique physical properties that influence their cardiac efficacy. More prospective trials are needed to assess the effects of single-agent or combination iron chelation therapy on the levels of cardiac iron and cardiac function. Ultimately, iron chelation therapies should be tailored to meet individual patient needs and lifestyle demands.
doi:10.1016/S0268-960X(08)70004-3
PMCID: PMC2896332  PMID: 19059052
Cardiac iron; Iron chelation therapy; Myelodysplastic syndrome; Sickle cell disease; β-Thalassaemia major
19.  Ethanol- and/or Taurine-Induced Oxidative Stress in Chick Embryos 
Journal of Amino Acids  2013;2013:240537.
Because taurine alleviates ethanol- (EtOH-) induced lipid peroxidation and liver damage in rats, we asked whether exogenous taurine could alleviate EtOH-induced oxidative stress in chick embryos. Exogenous EtOH (1.5 mmol/Kg egg or 3 mmol/Kg egg), taurine (4 μmol/Kg egg), or EtOH and taurine (1.5 mmol EtOH and 4 μmol taurine/Kg egg or 3 mmol EtOH and 4 μmol taurine/Kg egg) were injected into fertile chicken eggs during the first three days of embryonic development (E0–2). At 11 days of development (midembryogenesis), serum taurine levels and brain caspase-3 activities, homocysteine (HoCys) levels, reduced glutathione (GSH) levels, membrane fatty acid composition, and lipid hydroperoxide (LPO) levels were measured. Early embryonic EtOH exposure caused increased brain apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress, as measured by decreased brain GSH levels; decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Although taurine is reported to be an antioxidant, exogenous taurine was embryopathic and caused increased apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress (decreased brain GSH levels); decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Combined EtOH and taurine treatments also caused increased apoptosis rates and oxidative stress.
doi:10.1155/2013/240537
PMCID: PMC3628655  PMID: 23606945
20.  High Fat Diet Subverts Hepatocellular Iron Uptake Determining Dysmetabolic Iron Overload 
PLoS ONE  2015;10(2):e0116855.
Increased serum ferritin associated with mild hepatic iron accumulation, despite preserved upregulation of the iron hormone hepcidin, is frequently observed in patients with dysmetabolic overload syndrome (DIOS). Genetic factors and Western diet represent predisposing conditions, but the mechanisms favoring iron accumulation in DIOS are still unclear. Aims of this study were to assess the effect a high-fat diet (HFD) on hepatic iron metabolism in an experimental model in rats, to further characterize the effect of free fatty acids on iron metabolism in HepG2 hepatocytes in vitro, and to assess the translational relevance in patients with fatty liver with and without iron accumulation. Despite decreased uptake of dietary iron, rats fed HFD accumulated more hepatic iron than those fed regular diet, which was associated with steatosis development. Hepatic iron accumulation was paralleled by induction of ferritin, in the presence of preserved upregulation of hepcidin, recapitulating the features of DIOS. HFD was associated with increased expression of the major iron uptake protein Transferrin receptor-1 (TfR-1), consistently with upregulation of the intracellular iron sensor Iron regulated protein-1 (IRP1). Supplementation with fatty acids induced TfR-1 and IRP1 in HepG2 hepatocytes, favoring intracellular iron accumulation following exposure to iron salts. IRP1 silencing completely abrogated TfR-1 induction and the facilitation of intracellular iron accumulation induced by fatty acids. Hepatic TfR-1 mRNA levels were upregulated in patients with fatty liver and DIOS, whereas they were not associated with liver fat nor with inflammation. In conclusion, increased exposure to fatty acids subverts hepatic iron metabolism, favoring the induction of an iron uptake program despite hepatocellular iron accumulation.
doi:10.1371/journal.pone.0116855
PMCID: PMC4315491  PMID: 25647178
21.  Effects of Selenium on Colon Carcinogenesis Induced by Azoxymethane and Dextran Sodium Sulfate in Mouse Model with High-Iron Diet 
Laboratory Animal Research  2011;27(1):9-18.
Selenium (Se) is known to prevent several cancers while the relationship between high iron and the risk of colorectal cancer is controversial. To investigate the effects of Se in colon carcinogenesis, we subjected three different levels of Se and high-iron diet to a mouse model of colon cancer in which animals were treated with three azoxymethane (AOM) injections followed by dextran sodium sulfate (DSS) administration. There were five experimental groups including vehicle group [normal-Fe (NFe, 45 ppm)+medium-Se (MSe, 0.1 ppm)], positive control group (AOM/DSS+NFe+MSe), AOM/DSS+high-Fe (HFe, 450 ppm)+low-Se (LSe, 0.02 ppm), AOM/DSS+HFe+MSe, and AOM/DSS+HFe+high-Se (HSe, 0.5 ppm). The animals were fed on the three different Se diets for 24 weeks. The incidence of colon tumor in the high-Se diet group (AOM/DSS+HFe+HSe) showed 19.4% lower than positive control group, 5.9% lower than AOM/DSS+HFe+MSe diet group, and 11.1% lower than AOM/DSS+HFe+LSe group. The tumor multiplicity was significantly higher in the low-Se diet group (AOM/DSS+HFe+LSe) compare to all other AOM/DSS treated groups. In the high-Se diet group, the activity of hepatic GPx was comparable to that of positive control group, and significantly higher than those of low-Se or medium-Se diet groups. Expression level of hepatic GPx-1 showed similar results. Hepatic malondialdehyde (MDA) level (indicator of oxidative stress) in the low-Se diet group showed the highest compared to the other groups, and it was significantly higher than positive control group. In the high-Se diet group the level of MDA in the liver was significantly lower than all other AOM/DSS treated groups. High-Se diet group showed significantly lower proliferative index than low-Se and medium-Se groups. The apoptotic indices in low-Se group and medium-Se group were significantly lower than positive control group. However, apoptotic index of high-Se diet group was significantly higher than all other AOM/DSS treated groups. These findings suggest that dietary Se supplement may have protective effect against colon cancer by decreasing proliferation, increasing apoptosis of tumor cells, and reducing oxidative stress in mice with high iron diet.
doi:10.5625/lar.2011.27.1.9
PMCID: PMC3145991  PMID: 21826154
Azoxymethane (AOM); dextran sodium sulfate (DSS); colon cancer; selenium; iron
22.  Effect of Vitamin E and Selenium Supplement on Paraoxonase-1 Activity, Oxidized Low Density Lipoprotein and Antioxidant Defense in Diabetic Rats  
BioImpacts : BI  2011;1(2):121-128.
Introduction
The aim of the present study was to assess the effects of vitamin E and selenium supplementation on serum paraoxonase (PON1) activity, lipid peroxidation and antioxidant defense in streptozotocin-induced diabetic rats.
Methods
Thirty two female Sprague Dawley rats were divided into 3 groups: the control group (n=8) received a standard diet; streptozotocin (STZ)-induced diabetic rats (n=12), received corn oil and physiological solution; and vitamin E and selenium supplemented diabetic rats (n=12) were treated with oral administration of vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) once a day for 4 weeks.
Results
Significantly lower total antioxidant status (TAS), PON1and erythrocyte SOD activities and a higher fasting plasma glucose level were observed in the diabetic rats compared to the control. A significant increase in SOD and GPX activities in vitamin E and selenium supplemented diabetic group was observed after 5 weeks of the experiment. Compared to the normal rats, malondialdehyde (MDA) and oxidized LDL (Ox-LDL) levels were higher in the diabetic animals; however, these values reduced significantly following vitamin E and selenium supplementation.
Conclusion
Vitamin E and selenium supplementation in diabetic rats has hypolipidemic, hypoglycemic and antioxidative effects and may slow down the progression of diabetic complications through its protective effect on PON1 activity and lipoproteins oxidation.
doi:10.5681/bi.2011.016
PMCID: PMC3648954  PMID: 23678416
Streptozotocin-Induced Diabetes; Oxidative Stress; Vitamin E; Selenium; Paraoxonase 1; Oxidized LDL
23.  Cardiac MRI and Iron Overload Cardiomyopathy in Thalassemia Major: A Case Report 
Introduction:
Heart failure is the leading cause of death in patients with Thalassemia major and primarily results from transfusional iron overload. It is essential to assess myocardial iron load. Previous studies have shown that neither serum ferritin nor liver iron concentration gives a reliable measure of cardiac iron accumulation. Cardiac T2* MRI technique offers noninvasive measurement of myocardial iron load.
Case Report:
A 39-year-old man with a past medical history significant for beta thalassemia major requiring blood transfusions every three-weeks and on iron chelation, presented with a cough, high fevers, and chills. He was subsequently found to have community acquired pneumonia and was treated with ceftriaxone and doxycycline. His hospital course was significant for episodes of atrial fibrillation and non-sustained ventricular tachycardia. An echocardiogram showed normal left ventricular function with an ejection fraction of 70%, which hadn't changed from 2011. Although, the patient didn't have symptoms of heart failure, he likely had ventricular dysfunction that could be masked by the basal high cardiac output which can be seen in patients with chronic anemia and we decided to start the patient on sotalol 80 mg twice a day. The MRI software for multiecho T2* measurement was installed at Queens Medical Center in September 2011 and we were able to obtain images for our patient at that time. His myocardial T2* value was estimated to be 9 milliseconds which suggests an increased risk for the development of future cardiac arrhythmias and heart failure. The repeat cardiac MRI images after discharge showed 8 milliseconds which suggested an interval worsening of the iron deposition within the myocardium.
Discussion:
We were able to keep track of the progression of his iron cardiomyopathy, and start additional treatment. The patient continues to be followed by a hematologist for management of his hemochromatosis and a cardiologist for his infiltrative heart disease both resulting from his need for chronic blood transfusions. In patients with iron overload cardiomyopathy, their systolic function is preserved until a very late stage as iron deposition begins within the epicardium and extends to the myocardium. This case illustrates the importance of assessing cardiac iron content utilizing cardiac MRI as it is less invasive than cardiac biopsy and may show earlier involvement than echocardiogram.
PMCID: PMC4175956
24.  Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil 
Introduction
Deferasirox effectively controls liver iron concentration; however, little is known regarding its ability to remove stored cardiac iron. Deferiprone seems to have increased cardiac efficacy compared with traditional deferoxamine therapy. Therefore, the relative efficacy of deferasirox and deferiprone were compared in removing cardiac iron from iron-loaded gerbils.
Methods
Twenty-nine 8- to 10-week-old female gerbils underwent 10 weekly iron dextran injections of 200 mg/kg/week. Prechelation iron levels were assessed in 5 animals, and the remainder received deferasirox 100 mg/kg/D po QD (n = 8), deferiprone 375 mg/kg/D po divided TID (n = 8), or sham chelation (n = 8), 5 days/week for 12 weeks.
Results
Deferasirox reduced cardiac iron content 20.5%. No changes occurred in cardiac weight, myocyte hypertrophy, fibrosis, or weight-to-dry weight ratio. Deferasirox treatment reduced liver iron content 51%. Deferiprone produced comparable reductions in cardiac iron content (18.6% reduction). Deferiprone-treated hearts had greater mass (16.5% increase) and increased myocyte hypertrophy. Deferiprone decreased liver iron content 24.9% but was associated with an increase in liver weight and water content.
Conclusion
Deferasirox and deferiprone were equally effective in removing stored cardiac iron in a gerbil animal model, but deferasirox removed more hepatic iron for a given cardiac iron burden.
doi:10.1016/j.trsl.2006.05.005
PMCID: PMC2896322  PMID: 17145573
25.  Electrocardiographic consequences of cardiac iron overload in thalassemia major 
American journal of hematology  2011;87(2):139-144.
Background
Iron cardiomyopathy is a leading cause of death in transfusion dependent thalassemia major (TM) patients and MRI (T2*) can recognize preclinical cardiac iron overload, but, is unavailable to many centers.
Design and Methods
We evaluated the ability of 12-lead electrocardiography to predict cardiac iron loading in TM. 12-lead electrocardiogram and cardiac T2* measurements were performed prospectively, with a detectable cardiac iron cutoff of T2*less than 20 ms. Patients with and without cardiac iron were compared using two-sample statistics and against population norms using age and gender-matched Z-scores.
Results
45/78 patients had detectable cardiac iron. Patients having cardiac iron were older and more likely female but had comparable liver iron burdens and serum ferritin. Increased heart rate (HR) and prolonged corrected QT interval (QTc) were present, regardless of cardiac iron status. Repolarization abnormalities were the strongest predictors of cardiac iron, including QT/QTc prolongation, left shift of T-wave axis, and interpretation of ST/T-wave morphology. Recursive partitioning of the data for females using T-axis and HR and for males using QT, HR and T-axis produced algorithms with AUROC’s of 88.3 and 87.1 respectively.
Conclusions
Bradycardia and repolarization abnormalities on 12-lead electrocardiography were the most specific markers for cardiac iron in thalassemia major. Changes in these variables may be helpful to stratify cardiac risk when cardiac MRI is unavailable. However, diagnostic algorithms need to be vetted on larger and more diverse patient populations and longitudinal studies are necessary to determine reversibility of the observed abnormalities.
doi:10.1002/ajh.22205
PMCID: PMC3306475  PMID: 22052662
Electrocardiogram; Thalassemia Major; Cardiac Iron; MRI

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