RESUMO

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Assuntos

Acetilcisteína , Antioxidantes , Ácido Ascórbico , Desferroxamina , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Humanos , Antioxidantes/farmacocinética , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Masculino , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacocinética , Acetilcisteína/efeitos adversos , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/efeitos adversos , Adulto , Estresse Oxidativo/efeitos dos fármacos , Feminino , Desferroxamina/farmacocinética , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Voluntários Saudáveis , Adulto Jovem , Infusões Intravenosas , Pessoa de Meia-Idade , Método Duplo-Cego , Quimioterapia Combinada , Biomarcadores/sangue

RESUMO

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Assuntos

Astrócitos , Diferenciação Celular , Deficiências de Ferro , Oligodendroglia , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Proteínas de Transporte de Cátions/metabolismo , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Ratos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/metabolismo , Desferroxamina/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Ferro/metabolismo

RESUMO

Ilex paraguariensis (Herb mate) is a native plant from South America, widely consumed through the infusion of dried leaves. The presence of antioxidant properties in herb mate may be relevant and contribute to evaluating the effect of its compounds against oxidative stress, which could cause neurodegenerative diseases. Despite having health benefits, there are reports of the presence of heavy metals in extracts obtained from the infusion. One of these metals is iron (Fe), found in large amounts in herb mate. To reverse the cumulative effects of metals and Fe in the body, the use of Deferoxamine (Dfx) is indicated, being a potent chelator of Fe. In this work, we aimed to evaluate the antioxidant potential of the micro-encapsulated extract of I. paraguariensis (MEIP) supplemented with Dfx on zebrafish behavior and biochemical biomarkers. To evaluate the effect per se and the supplementation, four groups were established: the first group was the control (water); the second, fish treated with MEIP; the third group was formed of fish treated with Dfx; while the fourth group was treated with both MEIP and Dfx. When applied alone, Dfx presents an anxiogenic-like pattern on zebrafish (Danio rerio), while the MEIP shows an anxiolytic-like behavior. The antioxidant enzymes are re-modulated close to control when the MEIP + Dfx is applied. The cholinergic system shows an activation of the signaling, as well as the heme radical group formation, which is not affected by the Dfx-chelating effect. Thus, the supplementation of MEIP with Dfx is important to transform this extract into one that is safer and healthier for human consumption.

RESUMO

Abstract Naringin has been shown to exhibit satisfying iron chelation capacity. Considering the side effects of routinely-used iron chelator (desferrioxamine, DFO), we decided to evaluate the iron chelation potency of naringin to discover whether or not it can be a promising natural substitute for treatment of excessive iron-related diseases. 35 mice were classified into five groups of 7 and subjected to iron dextran administration to induce the iron-overload condition. Iron-overloaded mice were then treated with normal saline (as control), naringin or DFO Morphology changes, and iron deposition in liver tissues were studied using H&E and Perl's staining. The results revealed that naringin is more potent than DFO in removing excessive iron ions deposited in liver tissues, indicating that naringin is a promising natural compound for therapy of iron overload disorders

Assuntos

Animais , Masculino , Camundongos , Sobrecarga de Ferro/complicações , Flavanonas/análise , Organização e Administração , Desferroxamina/efeitos adversos

RESUMO

ABSTRACT A 10-year-old Malay girl with underlying HbE/beta-thalassemia, on regular blood transfusion and deferoxamine iron chelation therapy, presented with two-month history of bilateral blurring of vision. On examination, her vision was 6/36 both eyes. Other optic nerve functions were normal. Anterior segment examination of both eyes was unremarkable. Fundus examination of both eyes revealed dull foveal reflex. Optical coherence tomography of both maculae showed increased central subfield thickness. Fundus fluorescence angiography showed patchy hypofluorescence over macular region for both eyes and late staining, indicating retinal pigment epithelium anomalies. A diagnosis of iron-chelation-therapy-related bilateral maculopathy was made. Patient was co-managed with pediatric hematology team to adjust the dose of deferoxamine, and was given three monthly appointments to monitor the progression of maculopathy at the ophthalmology clinic. However patient defaulted ophthalmology follow-up after the first visit.

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RESUMO Uma menina malaia de 10 anos de idade com doença de base- B/beta-talassemia, em transfusão de sangue regular e terapia quelante de ferro deferoxamina, apresentou história de dois meses de visão turva bilateral. Ao exame, sua visão era de 6/36 em ambos os olhos. Outras funções do nervo óptico estavam normais. O exame do segmento anterior de ambos os olhos foi normal. Exame do fundo de ambos os olhos revelou reflexo foveal opaco. A tomografia de coerência óptica de ambas as máculas mostrou aumento da espessura do subcampo central. A angiografia de fluorescência do fundo mostrou hipofluorescência irregular sobre a região macular de ambos os olhos e coloração tardia, indicando anomalias de epitélio pigmentar da retina. Um diagnóstico de maculopatia bilateral relacionada à terapia quelante de ferro foi feito. A paciente foi avaliada em conjunto com a equipe de hematologia pediátrica para ajustar a dose de deferoxamina, e foram oferecidas três consultas mensais na clínica oftalmológica, para monitorar a progressão da maculopatia. No entanto, ela não compareceu para acompanhamento oftalmológico após a primeira visita.

Assuntos

Humanos , Feminino , Criança , Sideróforos/efeitos adversos , Talassemia beta/tratamento farmacológico , Desferroxamina/efeitos adversos , Reação Transfusional , Degeneração Macular/complicações , Transfusão de Sangue , Sideróforos/uso terapêutico , Talassemia beta/diagnóstico , Desferroxamina/uso terapêutico

RESUMO

BACKGROUND: Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. METHODS: Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. RESULTS: Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. CONCLUSIONS: Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

Assuntos

Diabetes Mellitus Tipo 2 , Pé Diabético , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Polineuropatias , Meios de Cultivo Condicionados/farmacologia , Pé Diabético/terapia , Humanos , Camundongos

RESUMO

Iron is an important constituent of our environment, being necessary for both mammalian and pathogenic protozoa survival. Iron-containing proteins exert a wide range of biological processes such as biodegradation and biosynthesis, as well as immune function, fetal development, and physical and mental well-being. This work aimed to investigate the effect of iron deprivation in Toxoplasma gondii infection outcome. C57BL/6 mice were orally infected with T. gondii and treated with an iron chelator, deferoxamine, or supplemented with iron (ferrous sulfate), and the parasitism as well as immunological and histological parameters were analyzed. It was observed that the infection increased iron accumulation in the organs, as well as systemically, and deferoxamine treatment diminished the iron content in serum samples and intestine. The deferoxamine treatment decreased the parasitism and inflammatory alterations in the small intestine and lung. Additionally, they partially preserved the Paneth cells and decreased the intestinal dysbiosis. The ferrous sulfate supplementation, despite not significantly increasing the parasite load in the organs, increased the inflammatory alterations in the liver. Together, our results suggest that iron chelation, which is commonly used to treat iron overload, could be a promising medicine to control T. gondii proliferation, mainly in the small intestine, and consequently inflammation caused by infection.

RESUMO

Acute myocardial infarction is one of the leading causes of death worldwide and thus, an extensively studied disease. Nonetheless, the effects of ischemia/reperfusion injury elicited by oxidative stress on cardiac fibroblast function associated with tissue repair are not completely understood. Ascorbic acid, deferoxamine, and N-acetylcysteine (A/D/N) are antioxidants with known cardioprotective effects, but the potential beneficial effects of combining these antioxidants in the tissue repair properties of cardiac fibroblasts remain unknown. Thus, the aim of this study was to evaluate whether the pharmacological association of these antioxidants, at low concentrations, could confer protection to cardiac fibroblasts against simulated ischemia/reperfusion injury. To test this, neonatal rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion in the presence or absence of A/D/N treatment added at the beginning of simulated reperfusion. Cell viability was assessed using trypan blue staining, and intracellular reactive oxygen species (ROS) production was assessed using a 2',7'-dichlorofluorescin diacetate probe. Cell death was measured by flow cytometry using propidium iodide. Cell signaling mechanisms, differentiation into myofibroblasts and pro-collagen I production were determined by Western blot, whereas migration was evaluated using the wound healing assay. Our results show that A/D/N association using a low concentration of each antioxidant increased cardiac fibroblast viability, but that their separate administration did not provide protection. In addition, A/D/N association attenuated oxidative stress triggered by simulated ischemia/reperfusion, induced phosphorylation of pro-survival extracellular-signal-regulated kinases 1/2 (ERK1/2) and PKB (protein kinase B)/Akt, and decreased phosphorylation of the pro-apoptotic proteins p38- mitogen-activated protein kinase (p38-MAPK) and c-Jun-N-terminal kinase (JNK). Moreover, treatment with A/D/N also reduced reperfusion-induced apoptosis, evidenced by a decrease in the sub-G1 population, lower fragmentation of pro-caspases 9 and 3, as well as increased B-cell lymphomaextra large protein (Bcl-xL)/Bcl-2-associated X protein (Bax) ratio. Furthermore, simulated ischemia/reperfusion abolished serum-induced migration, TGF-ß1 (transforming growth factor beta 1)-mediated cardiac fibroblast-to-cardiac myofibroblast differentiation, and angiotensin II-induced pro-collagen I synthesis, but these effects were prevented by treatment with A/D/N. In conclusion, this is the first study where a pharmacological combination of A/D/N, at low concentrations, protected cardiac fibroblast viability and function after simulated ischemia/reperfusion, and thereby represents a novel therapeutic approach for cardioprotection.

RESUMO

Alterations in iron homeostasis are well described in obese patients. The effects of iron chelators on adipose tissue and other organs affected by obesity have been the interest of experimental studies, both in vivo and in vitro. The aim of this review was to update the available information indicating the potential of iron chelators as adjuvant drugs in the management of obesity and its comorbidities. The pharmacological actions of iron chelators, mainly deferoxamine, deferasirox, and deferiprone, on adipose tissue and liver alterations associated with obesity, were reviewed. Renal and other organ modifications observed in experimental obesity models (endotoxemia, ß-cell function, and systemic inflammation) were included, as well as data from clinical studies that were relevant to this review. The experimental results obtained with iron chelators showed their potential in the control of obesity-induced alterations in the adipose tissue and liver. However, knowledge about the possible systemic effects on endotoxemia and low-grade inflammation in obesity models is still lacking. In endotoxemia in humans, data obtained did not corroborate the anti-inflammatory effect described in experimental models. Clinical and experimental data reveal renal, ß-cell protection and inhibition of advanced glycation end products, which have long-term benefits in obesity. Experimental models of obesity demonstrated the beneficial effects of iron chelators on the adipose tissue, liver, kidneys, and ß-cells. Hence, clinical studies could be designed to evaluate the potential of iron chelators as a therapeutic option in the management of obesity.

Assuntos

Quelantes de Ferro/farmacologia , Obesidade/tratamento farmacológico , Animais , Homeostase/efeitos dos fármacos , Humanos , Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia

RESUMO

Congenital toxoplasmosis is a serious health problem that can lead to miscarriage. HTR-8/SVneo is a first trimester extravillous trophoblast, while BeWo is a choriocarcinoma with properties of villous trophoblast cells. In the placenta, iron is taken up from Fe-transferrin through the transferrin receptor being the ion an important nutrient during pregnancy and also for Toxoplasma gondii proliferation. The aim of this study was to evaluate the role of iron in T. gondii proliferation in BeWo and HTR-8/SVneo cells and in human chorionic villous explants. The cells were infected with T. gondii, iron supplemented or deprived by holo-transferrin or deferoxamine, respectively, and parasite proliferation and genes related to iron balance were analyzed. It was verified that the addition of holo-transferrin increased, and DFO decreased the parasite multiplication in both trophoblastic cells, however, in a more expressive manner in HTR-8/SVneo, indicating that the parasite depends on iron storage in trophoblastic cells for its growth. Also, tachyzoites pretread with DFO proliferate normally in trophoblastic cells demonstrating that DFO itself does not interfere with parasite proliferation. Additionally, T. gondii infection induced enhancement in transferrin receptor mRNA expression levels in trophoblastic cells, and the expression was higher in HTR-8/SVneo compared with BeWo. Finally, DFO-treatment was able to reduce the parasite replication in villous explants. Thus, the iron supplementation can be a double-edged sword; in one hand, it could improve the supplement of an essential ion to embryo/fetus development, and on the other hand, could improve the parasite proliferation enhancing the risk of congenital infection.

Assuntos

Ferro/metabolismo , Complicações Infecciosas na Gravidez/parasitologia , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/metabolismo , Toxoplasmose/metabolismo , Trofoblastos/parasitologia , Linhagem Celular Tumoral , Citoplasma/metabolismo , Feminino , Células HeLa , Humanos , Placenta/química , Placenta/parasitologia , Gravidez , RNA Mensageiro/biossíntese

RESUMO

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.

RESUMO

Trypanosoma cruzi infects and replicates within a wide variety of immune and non-immune cells. Here, we investigated early cellular responses induced in NIH-3T3 fibroblasts upon infection with trypomastigote forms of T. cruzi. We show that fibroblasts were susceptible to T. cruzi infection and started to release trypomastigotes to the culture medium after 4 days of infection. Also, we found that T. cruzi infection reduced the number of fibroblasts in 3-day cell cultures, by altering fibroblast proliferation. Infected fibroblasts displayed distinctive phenotypic alterations, including enlarged and flattened morphology with a nuclei accumulation of senescence-associated heterochromatin foci. In addition, infection induced an overexpression of the enzyme senescence-associated ß-galactosidase (SA-ß-gal), an activation marker of the cellular senescence program, as well as the production of cytokines and chemokines involved with the senescence-associated secretory phenotype (SASP) such as IL-6, TNF-α, IL-1ß, and MCP-1. Infected fibroblasts released increased amounts of stress-associated factors nitric oxide (NO) and reactive oxygen species (ROS), and the treatment with antioxidants deferoxamine (DFO) and N-acetylcysteine reduced ROS generation, secretion of SASP-related cytokine IL-6, SA-ß-gal activity, and parasite load by infected fibroblasts. Taken together, our data suggest that T. cruzi infection triggers a rapid cellular stress response followed by induction of a senescent-like phenotype in NIH-3T3 fibroblasts, enabling them to act as reservoirs of parasites during the early stages of the Chagas disease.

RESUMO

Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in the activity of the enzyme tyrosine aminotransferase, leading to tyrosine accumulation in the body. Although the mechanisms involved are still poorly understood, several studies have showed that higher levels of tyrosine are related to oxidative stress and therefore may affect the cholinergic system. Thus, the aim of this study was to investigate the effects of chronic administration of L-tyrosine on choline acetyltransferase activity (ChAT) and acetylcholinesterase (AChE) in the brain of rats. Moreover, we also examined the effects of one antioxidant treatment (N-acetylcysteine (NAC) + deferoxamine (DFX)) on cholinergic system. Our results showed that the chronic administration of L-tyrosine decreases the ChAT activity in the cerebral cortex, while the AChE activity was increased in the hippocampus, striatum, and cerebral cortex. Moreover, we found that the antioxidant treatment was able to prevent the decrease in the ChAT activity in the cerebral cortex. However, the increase in AChE activity induced by L-tyrosine was partially prevented the in the hippocampus and striatum, but not in the cerebral cortex. Our results also showed no differences in the aversive and spatial memory after chronic administration of L-tyrosine. In conclusion, the results of this study demonstrated an increase in AChE activity in the hippocampus, striatum, and cerebral cortex and an increase of ChAT in the cerebral cortex, without cognitive impairment. Furthermore, the alterations in the cholinergic system were partially prevented by the co-administration of NAC and DFX. Thus, the restored central cholinergic system by antioxidant treatment further supports the view that oxidative stress may be involved in the pathophysiology of tyrosinemia type II.

Assuntos

Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Tirosina/toxicidade , Acetilcisteína/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Desferroxamina/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos Wistar

RESUMO

Abstract Osteoarthritis, also known as degenerative arthritis or degenerative joint disease, is an epidemic disease that affects millions of people worldwide. Despite extensive recent work on the cellular biology of osteoarthritis, the precise mechanisms involved are still poorly understood and there is no effective treatment for this disease. The role of transforming growth factor-beta (TGF-β) in promoting chondrogenesis and inducing the expression of cartilage-specific extracellular matrix molecules to form cartilage is well-established. Historically, TGF-β has been considered to prevent osteoarthritis, but recent work suggests that TGF-β overexpression accelerates the progression of osteoarthritis in vivo. Clinically, it is therefore important to limit TGF-β expression while still providing effective treatment of osteoarthritis. One possible approach to achieve this effect would be to use a combination of TGF-β with other small molecular chemical compounds. Hypoxia promotes chondrogenesis and the usefulness of deferoxamine, a chelating agent that mimics hypoxia, in stimulating chondrogenesis has been investigated in clinical trials. In this study, we investigated the role of deferoxamine in TGF-β-induced chondrogenesis in pre-chondrogenic cells and examined whether deferoxamine synergizes with the TGF-β signaling pathway to promote chondrocyte differentiation.

RESUMO

Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes.

Assuntos

Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Transtorno Depressivo/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Desferroxamina/farmacologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/psicologia , Sequestradores de Radicais Livres/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Wistar , Sideróforos/farmacologia

RESUMO

An in vivo model in rat was developed by intraperitoneally administration of Fe-dextran to study oxidative stress triggered by Fe-overload in rat brain. Total Fe levels, as well as the labile iron pool (LIP) concentration, in brain from rats subjected to Fe-overload were markedly increased over control values, 6h after Fe administration. In this in vivo Fe overload model, the ascorbyl (A)/ascorbate (AH(-)) ratio, taken as oxidative stress index, was assessed. The A/AH(-) ratio in brain was significantly higher in Fe-dextran group, in relation to values in control rats. Brain lipid peroxidation indexes, thiobarbituric acid reactive substances (TBARS) generation rate and lipid radical (LR) content detected by Electron Paramagnetic Resonance (EPR), in Fe-dextran supplemented rats were similar to control values. However, values of nuclear factor-kappaB deoxyribonucleic acid (NFκB DNA) binding activity were significantly increased (30%) after 8h of Fe administration, and catalase (CAT) activity was significantly enhanced (62%) 21h after Fe administration. Significant enhancements in Fe content in cortex (2.4 fold), hippocampus (1.6 fold) and striatum (2.9 fold), were found at 6h after Fe administration. CAT activity was significantly increased after 8h of Fe administration in cortex, hippocampus and striatum (1.4 fold, 86, and 47%, respectively). Fe response in the whole brain seems to lead to enhanced NF-κB DNA binding activity, which may contribute to limit oxygen reactive species-dependent damage by effects on the antioxidant enzyme CAT activity. Moreover, data shown here clearly indicate that even though Fe increased in several isolated brain areas, this parameter was more drastically enhanced in striatum than in cortex and hippocampus. However, comparison among the net increase in LR generation rate, in different brain areas, showed enhancements in cortex lipid peroxidation, without changes in striatum and hippocampus LR generation rate after 6h of Fe overload. This information has potential clinical relevance, as it could be the key to understand specific brain damage occurring in conditions of Fe overload.

Assuntos

Química Encefálica/fisiologia , Sobrecarga de Ferro/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Química Encefálica/efeitos dos fármacos , Catalase/metabolismo , DNA/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres/metabolismo , Ferro/metabolismo , Complexo Ferro-Dextran/farmacologia , Cinética , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo

RESUMO

OBJETIVO: Os antioxidantes são largamente utilizados em modelos animal para prevenir lesão renal após isquemia/reperfusão. Uma questão importante é se os benefícios dos antioxidantes são aditivos ou não. O objetivo deste estudo foi investigar os efeitos protetores da N-acetilcisteína com deferoxamina, em modelo animal, de isquemia renal/traumatismo por reperfusão. MÉTODOS: A isquemia renal bilateral foi mantida por 45 minutos. N-acetilcisteína, deferoxamina ou ambas foram administradas na aorta, acima das artérias renais, antes da isquemia. Cinco ratos de cada grupo foram sacrificados, entre 1, 6 ou 12 horas após reperfusão, para determinar a creatinina no sangue, os parâmetros de danos oxidativos no rim e a atividade da mieloperoxidase. RESULTADOS: A associação de N-acetilcisteína e deferoxamina, mas não o uso isolado de cada uma, evitou o aumento da creatinina após isquemia/reperfusão. Tal evento foi seguido de diminuição consistente da atividade da mieloperoxidase e dos parâmetros de danos oxidativos, tanto no córtex como na medula renais. CONCLUSÃO: O tratamento com N-acetilcisteína e deferoxamina mostrou-se superior ao uso de cada substância isoladamente em modelo animal de isquemia/reperfusão renal.

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OBJECTIVE: Antioxidants are widely used in animal models to prevent renal injury after ischemia/reperfusion, but it is unknown if the benefits of antioxidants are additive. In this study, we aimed to investigate the protective effects of N-acetylcysteine plus deferoxamine in an animal model of kidney ischemia/reperfusion injury. METHODS: Bilateral kidney ischemia was mastintained for 45 minutes. N-acetylcysteine, deferoxamine or both were administered into the aorta above the renal arteries immediately prior to induction of ischemia. Five rats from each group were sacrificed 1, 6 or 12 hours after reperfusion for the determination of blood creatinine, kidney oxidative damage parameters and myeloperoxidase activity. RESULTS: The combination of N-acetylcysteine and deferoxamine, but not their isolated use, prevented the increase in creatinine after ischemia/reperfusion. This prevention was followed by a consistent decrease in myeloperoxidase activity and oxidative damage parameters both in the kidney cortex and medulla. CONCLUSION: Treatment with N-acetylcysteine and deferoxamine was superior to the isolated use of either compound in an animal model of kidney ischemia/reperfusion.

RESUMO

Los pacientes intoxicados representan un reto en el enfoque diagnóstico y terapéutico en los serviciosde urgencias. La intoxicación por hierro es una condición médica relativamente frecuente en los pacientes pediátricos y gestantes, dada la fácil adquisición de este mineral en los suplementosvitamínicos, que son corrientemente formulados en las consultas médicas de promoción y prevención y en los programas de control prenatal. La intoxicación aguda por hierro representa un alto potencialletal y para llegar a dicho estado se requieren dosis extremadamente altas como 200 a 250 mg/kg de hierro elemental, aunque recientemente se describe con valores mayores de 150 mg/kg y otros con 75 mg/kg; sin embargo, se empiezan a observar manifestaciones de toxicidad con ingestas mayores de 15 a 20 mg/kg. En el presente artículo se hace una revisión de la intoxicación aguda por hierro desde su metabolismo básico, pasando por los mecanismos existentes para la regulación de las sobrecargasférricas agudas y tomando conceptos necesarios para la comprensión de los procesos fisiopatológicosde las manifestaciones de toxicidad, según el órgano blanco potencialmente lesionado. Se hace una reseña de las modalidades diagnósticas y terapéuticas establecidas, así como los aportes de algunas investigaciones para la posible identificación de antídotos distintos a la deferoxamina. Por último, sepresenta un algoritmo diagnóstico y terapéutico en base a la revisión hecha.

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Poisoned patients represent a challenge at the diagnostic and therapeutic approach in theemergency department. Iron poisoning is a relativelycommon medical condition in pregnantand pediatric patients due the easy acquisition of the mineral in supplements often prescribedin medical consultations and prenatal care programs. This poisoning has a high lethal potential,however to reach that state are required extremely high doses as 200 to 250 mg/kg of elementaliron, but recently it´s describe doses of 150 mg/kg and some authors reports of 75 mg/Kg,but are beginning to show signs of toxicity with intakes of 15 - 20 mg/kg. In this paper, we madea review of acute iron poisoning, from basic metabolism, through existing mechanisms for theregulation of acute iron overload and taking concepts for understanding the pathophysiologicalprocesses. This review provides an overview of established diagnostic and therapeutic modalities,as well as input from some research forthe possible identification of various antidotes different to deferoxamine. Finally, it presents a diagnostic and therapeutic algorithm based on the review done.

Assuntos

Humanos , Desferroxamina , Sulfato Férrico , Ferro , Intoxicação

RESUMO

One of the most deleterious consequences of iron overload in thalassemia is the presence of non-transferrin bound iron (NTBI), a free radical that acts as a catalyst for free oxygen radicals, in particular for hydroxyl free radicals (OH.). These radicals oxidize both membrane lipids and proteins causing irreversible damage to biologically important molecules and cellular structures. Treatment with iron chelators has been important to improve survival of these individuals. The aim of this work was the study on the effects of deferoxamine (DFO) and deferiprone (DFP) on erythrocytes under the pro-oxidative action of TBHP isolated from normal individuals and patients with β-thalassemia. The in vitro action of deferoxamine and deferiprone on the oxidative metabolism of erythrocytes from β-thalassemic patients treated at the Centro de Hematologia e Hemoterapia do Paraná (HEMEPAR), Brazil, under the pro-oxidative action of TBHP was studied. Methemoglobin concentrations, reduced glutathione (GSH), hemolysis indexes and the enzyme activities of G6-PD and GR were determined. The oxidation indexes were higher in erythrocytes of β-thalassemic individuals than those from normal individuals. Treatment of the normal and β-thalassemic erythrocytes with DFO and/or DFP protected against the formation of GSH promoted by TBHP.

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Uma das maiores consequências da sobrecarga do ferro na β-talassemia é a presença de ferro não ligado à transferrina (NTBI), um radical livre que age como um catalisador do radical livre do oxigênio, particularmente radical hidroxil (OH.). Estes radicais oxidam os lipídeos e as proteínas da membrana causando danos irreversíveis às moléculas biologicamente importantes e às estruturas celulares. O tratamento com quelantes do ferro é importante para a melhoria da sobrevivência destes indivíduos. O objetivo deste trabalho foi o estudo sobre o efeito da desferoxamina (DFO) e da deferiprona (DFP) em eritrócitos isolados de indivíduos normais e de pacientes com β-talassemias, sob a ação pró-oxidativa de TBHP. Neste trabalho foi estudada a ação in vitro da desferoxamina e o deferiprona no metabolismo oxidativo dos eritrócitos de pacientes β-talassêmicos atendidos no Centro de Hematologia e Hemoterapia do Paraná (Hemepar), Brasil, sob a ação pró-oxidativa de TBHP. Concentrações de metahemoglobina glutationa reduzida, índices de hemólises, atividades das enzimas G6PD e GR foram determinadas. Os índices de oxidação analisados foram maiores nos eritrócitos de indivíduos β-talassêmicos do que nos normais. Tratamentos dos eritrócitos normais e β-talassêmicos com DFO e/ou DFP protegem contra a oxidação de GSH promovida por TBHP.

Assuntos

Humanos , Talassemia beta , Desferroxamina , Eritrócitos , Quelantes de Ferro , Distúrbios do Metabolismo do Ferro , Sobrecarga de Ferro

RESUMO

Hepatic ischemics and the effect of the hypothermia, ischemia and protecting drugs of the ischemic lesions and reperfusion have been studied. The use of several types of drugs that reduce the deleterious effects of the binomial ischemia-reperfusion, have been turning focus of several experimental studies seeking possible clinical applications. The objective of the present study is partially to evaluate the effects of the deferoxamine on ischemia and reperfusion on the remaining liver after parenchyma ressection of 70%, being evaluated by mitochondrial function Mice was divided in groups: Group HP (n = 8)-submitted the partial hepatectomy (HP) to 70%; Group HPD (n = 4)-submitted the deferoxamine administration (40 mg/kg) and HP to 70%; Group HPI (n = 7)-hepatectomizeted (HP to 70%) and submitted by ischemia (40 minutes); Group HPID (n = 7)-similar to the previous, however previously receiving deferoxamine; Group C (n = 8)- controls, submitted to the simulate operation for HP to 70%. The statistical analysis among the several groups was made by the tests of Kruskal - Wallis and of Mann - Whitney, with level of significância of 5%. Of that it sorts things out, the state III was similar in all the procedures; the state IV: C HPI, C HPID (p 0,05); RCR: HP C, HPD C, HPI C and HPID C (p 0,05); PM: HPD was larger than the other groups (P 0,05). In the animals hepatectomizated the ischemia induced increase of the state IV, with and without deferoxamine. On the other hand the deferoxamine induced increase of the membrane potential in the animals hepatectomizated (HPD) in relation to the hepatectomizated with and without ischemia. There was decrease of the respiratory control ratio in the animals hepatectomizated with and without ischemia.

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O efeito da hipotermia, precondicionamento isquêmico e drogas protetoras das lesões de isquemia e reperfusão têm sido amplamente estudado. O objetivo do presente estudo é avaliar os efeitos da deferoxamina na isquemia e reperfusão sobre o fígado remanescente após ressecção hepática parcial a 70%, avaliando-se a função mitocondrial hepática. Estudou-se 34 ratos divididos em grupos: Grupo HP (n = 8) - submetidos a hepatectomia parcial (HP) a 70%; Grupo HPD (n = 4) - submetidos a administração de deferoxamina (40 mg/kg) e HP a 70%; Grupo HPI (n = 7) - hepatectomizados (HP a 70%) e submetidos a isquemia (40 minutos); Grupo HPID (n = 7) - semelhante ao anterior, porém recebendo previamente deferoxamina; Grupo C (n = 8) - controle, submetido a operação simulada para HP a 70%. A análise estatística entre os diversos grupos foi feita pelos testes de Kruskal - Wallis e de Mann - Whitney, com nível de significância de 5%. Dessa maneira, o estado III foi semelhante em todos os procedimentos; o estado IV: C HPI, C HPID (p 0,05); a RCR: HP C, HPD C, HPI C e HPID C (p 0,05); o PM: HPD foi maior que os demais grupos (p 0,05). Nos animais hepatectomizados a isquemia i nduziu aumento do estado IV, com e sem deferoxamina Por outro lado a deferoxamina induziu aumento do potencial de membrana nos animais hepatectomizados (HPD) em relação aos hepatectomizados com e sem isquemia. Houve diminuição da razão de controle respiratório nos animais hepatectomizados com e sem isquemia.