| Iron is an essential micronutrient for nearly all organisms,while animal production and human health are extensively affected by iron deficiency.Iron supplementation is an effective means of prevention and treating iron deficiency.Nevertheless,iron is crucially involved in the generation of reactive oxygen species,which plays a major role in oxidative damage.1 Effects of excessive iron on growth performance and oxidative stress in pigletsIn pig industry,especially in piglets,commercial starter diets contain amounts of iron in considerable excess of NRC requirement,while whether this high dietary iron affects production efficiency of piglets is not well evaluated.In order to evaluate the effects of excessive iron on growth performance and oxidative stress in weanling pigs,40 piglets were randomly divided into 4 groups.The control group was fed with basal diet(containing 100 mg/kg Fe),one group containing 400 mg Fe/kg,which is amount to commonly used commercial starter diets,two other groups containing 4000 mg Fe/kg and 10000 mg Fe/kg respectively,the feeding experiment was lasted for 28 days.The results showed that even commercial starter diets contain excessive iron,there is no significant effect on average daily gain of piglets.However,supplementation with higher level of iron could significantly induce oxidative stress in intestine and liver of piglets.2 Damage effects of excessive iron on rats and its underlying etiologyThe interactions between redox metabolism and iron supply are well known.However,the detailed histopathological alterations associated with iron-induced oxidative stress and the etiology of side effects or diseases caused by excess iron have not been fully studied.In addition,little is known about the effect of excess iron on intestinal barrier function.In study 1,forty male Sprague-Dawley rats were subjected to oral gavage with 1 ml vehicle or 1 ml liquid iron preparation containing 8 mg,16 mg or 24 mg of iron for 30 d.This study was aimed to determine the effects of excessive iron on oxidative damage.Meanwhile,the cecal microbiota was evaluated by 16S rRNA sequencing.In study 2,twenty rats with the same profile as above were subjected to oral gavage with 1 ml vehicle or 24 mg Fe for 30 d.This study was aimed to determine the effects of excessive iron on intestinal barrier function by in vivo studies and an IV Ussing chamber assay.The results showed that excessive iron induces oxidative stress and histopathological alterations in the intestine and liver,along with swelling mitochondria and cell death.Excessive iron also impairs intestinal barrier function.These effects were accompanied by lower intestinal segment damage and altered gut microbial composition of rats toward a profile with an increased risk of gut disease.3 The mechanisms of excessive iron induced cell deathIn addition to iron supplementation-induced damage,Mutations in the genes encoding iron metabolism regulators may cause iron deposits in the hepatocytes of the liver and induce tissue damage.Whether excessive iron itself induces specific cell death is unclear,and the mechanisms of iron induced cell death are largely elusive.In this study,we mainly selected mouse hepatocytes AML 12 cells and a ferroptosis sensitive cell line HT-1080 cells to study the detailed mechanism of iron-induced cell death.First,we established chronic and acute forms of intracellular iron overload-induced cell death models by using ferric ammonium citrate(FAC)and iron/8-hydroxyquinoline complex(Fe-8HQ),respectively.Then,we applied cell biological means to study the mechanisms iron-induced cell death.The results showed that FAC-induced chronic iron overload causes ferroptosis,and sphingolipid signaling might play a role in ferroptosis.We also identified GSK2334470 as a potent ferroptosis inhibitor.Whereas,Fe-8HQ-induced acute intracellular iron overload,partially activates parthanatos,but causes unregulated necrosis.Unexpectedly,we identified many phenolic compounds as potent inhibitors of Fe-8HQ-induced cell death. |
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