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1.
Nat Commun ; 10(1): 5134, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723130

RESUMO

Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO's own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.


Assuntos
Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Rim/patologia , Nanopartículas/química , Animais , Desferroxamina/farmacocinética , Desferroxamina/uso terapêutico , Desferroxamina/toxicidade , Quelantes de Ferro/química , Quelantes de Ferro/farmacologia , Masculino , Camundongos , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Distribuição Tecidual
2.
Sci Rep ; 7(1): 5756, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720890

RESUMO

Cardiac damage associated with iron overload is the most common cause of morbidity and mortality in patients with hereditary hemochromatosis, but the precise mechanisms leading to disease progression are largely unexplored. Here we investigated the effects of iron overload and age on cardiac hypertrophy using 1-, 5- and 12-month old Hfe-deficient mice, an animal model of hemochromatosis in humans. Cardiac iron levels increased progressively with age, which was exacerbated in Hfe-deficient mice. The heart/body weight ratios were greater in Hfe-deficient mice at 5- and 12-month old, compared with their age-matched wild-type controls. Cardiac hypertrophy in 12-month old Hfe-deficient mice was consistent with decreased alpha myosin and increased beta myosin heavy chains, suggesting an alpha-to-beta conversion with age. This was accompanied by cardiac fibrosis and up-regulation of NFAT-c2, reflecting increased calcineurin/NFAT signaling in myocyte hypertrophy. Moreover, there was an age-dependent increase in the cardiac isoprostane levels in Hfe-deficient mice, indicating elevated oxidative stress. Also, rats fed high-iron diet demonstrated increased heart-to-body weight ratios, alpha myosin heavy chain and cardiac isoprostane levels, suggesting that iron overload promotes oxidative stress and cardiac hypertrophy. Our findings provide a molecular basis for the progression of age-dependent cardiac stress exacerbated by iron overload hemochromatosis.


Assuntos
Cardiomegalia/metabolismo , Modelos Animais de Doenças , Proteína da Hemocromatose/deficiência , Hemocromatose/metabolismo , Sobrecarga de Ferro/metabolismo , Fatores Etários , Animais , Cardiomegalia/genética , Fibrose , Hemocromatose/genética , Proteína da Hemocromatose/genética , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/genética , Isoprostanos/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Sprague-Dawley
3.
Science ; 356(6338): 608-616, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28495746

RESUMO

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.


Assuntos
Ferro/metabolismo , Animais , Células CACO-2 , Absorção Gastrointestinal , Hemoglobinas/metabolismo , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Monoterpenos/metabolismo , Ratos , Saccharomyces cerevisiae/metabolismo , Tropolona/análogos & derivados , Tropolona/metabolismo
4.
J Neurochem ; 138(6): 918-28, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27331785

RESUMO

The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. While iron plays an important role in neural function, the behavioral consequences of DMT1 deficiency are largely unexplored. The goal of this study was to define the neurobehavioral and neurochemical phenotypes of homozygous Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of these phenotypes. The b/b rats (11-12 weeks old) and their healthy littermate heterozygous (+/b) Belgrade rats were subject to elevated plus maze tasks. The b/b rats spent more time in open arms, entered open arms more frequently and traveled more distance in the maze than +/b controls, suggesting increased impulsivity. Impaired emotional behavior was associated with down-regulation of GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA receptor α1 and GABA transporter, indicating altered GABAergic function. Furthermore, metal analysis revealed that b/b rats have decreased total iron, but normal non-heme iron, in the brain. Interestingly, b/b rats exhibited unusually high copper levels in most brain regions, including striatum and hippocampus. Quantitative PCR analysis showed that both copper importer copper transporter 1 and exporter copper-transporting ATPase 1 were up-regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane levels and decreased glutathione/glutathione disulfide ratio in the hippocampus, reflecting elevated oxidative stress. Combined, our results suggest that copper loading in DMT1 deficiency could induce oxidative stress and impair GABA metabolism, which promote impulsivity-like behavior. Iron-copper model: Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status and up-regulate copper absorption, which leads to copper loading in the brain and consequently increases metal-induced oxidative stress. This event disrupts GABAergic neurotransmission and promotes impulsivity-like behavior. Our model provides better understanding of physiological risks associated with imbalanced metal metabolism in mental function and, more specifically, the interactions with GABA and redox control in the treatment of emotional disorders.


Assuntos
Química Encefálica/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/fisiologia , Cobre/metabolismo , Comportamento Impulsivo , Adenosina Trifosfatases/metabolismo , Animais , Ansiedade/genética , Ansiedade/psicologia , Comportamento Animal , Proteínas de Transporte de Cátions/metabolismo , Transportador de Cobre 1 , Regulação para Baixo , Emoções/fisiologia , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Hipocampo/metabolismo , Ferro/metabolismo , Masculino , Metionina/análogos & derivados , Mutação/genética , Ferroproteínas não Heme/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de GABA-A/genética , Ácido gama-Aminobutírico/biossíntese
5.
PLoS One ; 10(3): e0120609, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25746420

RESUMO

While nutritional and neurobehavioral problems are associated with both iron deficiency during growth and overload in the elderly, the effect of iron loading in growing ages on neurobehavioral performance has not been fully explored. To characterize the role of dietary iron loading in memory function in the young, weanling rats were fed iron-loading diet (10,000 mg iron/kg diet) or iron-adequate control diet (50 mg/kg) for one month, during which a battery of behavioral tests were conducted. Iron-loaded rats displayed elevated non-heme iron levels in serum and liver, indicating a condition of systemic iron overload. In the brain, non-heme iron was elevated in the prefrontal cortex of iron-loaded rats compared with controls, whereas there was no difference in iron content in other brain regions between the two diet groups. While iron loading did not alter motor coordination or anxiety-like behavior, iron-loaded rats exhibited a better recognition memory, as represented by an increased novel object recognition index (22% increase from the reference value) than control rats (12% increase; P=0.047). Western blot analysis showed an up-regulation of dopamine receptor 1 in the prefrontal cortex from iron-loaded rats (142% increase; P=0.002). Furthermore, levels of glutamate receptors (both NMDA and AMPA) and nicotinic acetylcholine receptor (nAChR) were significantly elevated in the prefrontal cortex of iron-loaded rats (62% increase in NR1; 70% increase in Glu1A; 115% increase in nAChR). Dietary iron loading also increased the expression of NMDA receptors and nAChR in the hippocampus. These results support the idea that iron is essential for learning and memory and further reveal that iron supplementation during developmental and rapidly growing periods of life improves memory performance. Our investigation also demonstrates that both cholinergic and glutamatergic neurotransmission pathways are regulated by dietary iron and provides a molecular basis for the role of iron loading in improved memory.


Assuntos
Suplementos Nutricionais , Ferro/farmacologia , Memória/efeitos dos fármacos , Reconhecimento Visual de Modelos/efeitos dos fármacos , Animais , Hipocampo/metabolismo , Ferro/farmacocinética , Fígado/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/biossíntese , Receptores de N-Metil-D-Aspartato/biossíntese
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