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Renal iron overload is a common complication of diabetes that leads to oxidative stress and mitochondrial dysfunction in the kidneys. This study investigated the effects of iron chelation using deferiprone on mitochondrial dysfunction and oxidative stress in the renal cortex of a murine model of type 2 diabetes. Diabetic rats were treated with deferiprone (50 mg/kg BW) for 16 weeks. Our results show that iron chelation with deferiprone significantly increased the nuclear accumulation of Nrf2, a transcription factor that regulates the expression of antioxidant enzymes. This led to enhanced antioxidant capacity, reduced production of reactive oxygen species, and improved mitochondrial bioenergetic function in diabetic rats. However, chronic iron chelation led to altered mitochondrial respiration and increased oxidative stress in non-diabetic rats. In conclusion, our findings suggest that iron chelation with deferiprone protects mitochondrial bioenergetics and mitigates oxidative stress in the renal cortex, involving the NRF2 pathway in type 2 diabetes.
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Deferiprona , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Córtex Renal , Fator 2 Relacionado a NF-E2 , Animais , Masculino , Camundongos , Ratos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Deferiprona/farmacologia , Deferiprona/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Quelantes de Ferro/farmacologia , Córtex Renal/metabolismo , Córtex Renal/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.
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Brazilin is the main compound in Caesalpinia sappan and Haematoxylum braziletto, which is identified as a homoisoflavonoid based on its molecular structure. These plants are traditionally used as an anti-inflammatory to treat fever, hemorrhage, rheumatism, skin problems, diabetes, and cardiovascular diseases. Recently, brazilin has increased its interest in cancer studies. Several findings have shown that brazilin has cytotoxic effects on colorectal cancer, breast cancer, lung cancer, multiple myeloma, osteosarcoma, cervical cancer, bladder carcinoma, also other cancers, along with numerous facts about its possible mechanisms that will be discussed. Besides its flavonoid content, brazilin is able to chelate metal ions. A study has proved that brazilin could be used as an antituberculosis agent based on its ability to chelate iron. This possible iron-chelating of brazilin and all the studies discussed in this review will lead us to the statement that, in the future, brazilin has the potency to be a chemo-preventive and anticancer agent. The article review aimed to determine the brazilin mechanism and pathogenesis of cancer.
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Despite the fact that there are many studies related to the adaptogenic and pro-healthy activities of plant-based compounds, there are some adaptogenic plants whose activities are not fully known, especially those coming from the wild regions of Asia, Africa, and South America. The aim of these studies was to examine the contents of non-nutritional compounds, such as polyphenols, flavonoids, and phenolic acids in ten adaptogenic species (Astragalus membranaceus (AM), Uncaria rhynchophylla (UR), Polygonum multiflorum (PM), Angelica sinensis (AS), Andrographis paniculatea (AP), Tinospora cordifolia (TC), Uncaria tomentosa (UT), Pfaffia paniculate (PP), Sutherlandia frutescens (SF), and Rhaponticum carthamoides (RC)). Considering biological activity, their antioxidant (DPPH, ABTS, FRAP, and ferrous-ion-chelating ability assays), anti-acetylcholinesterase, anti-hyaluronidase, and anti-tyrosinase activities were evaluated. The richest in polyphenols, flavonoids, and phenolic acids was UR (327.78 mg GAE/g, 230.13 mg QE/g, and 81.03 mg CA/g, respectively). The highest inhibitions of acetylcholinesterase, hyaluronidase, and tyrosinase were observed for TC, UR, and PM, respectively. In the case of antioxidant properties, extract from PM appeared to most strongly reduce DPPH, extract from UR inhibited ABTS, and extract from SF showed the best chelating properties. It should be noted that a particularly interesting plant was Ulcaria rhynchophylla. The results mean that there were compounds in UR with broad biological activities, and this species should be explored in more detail. Additionally, our results justify the traditional use of these species in the nutripharmacological or ethnopharmacological care systems of different regions.
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Antioxidantes , Fenóis , Antioxidantes/farmacologia , Polifenóis/farmacologia , África , Ásia , América do Sul , Flavonoides , AcetilcolinesteraseRESUMO
Abstract Introduction Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. Methods We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. Results We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. Conclusions Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
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Humanos , Criança , Talassemia , Sobrecarga de Ferro , Terapia por QuelaçãoRESUMO
Biometals are all metal ions that are essential for all living organisms. About 40% of all enzymes with known structures require biometals to function correctly. The main target of damage by biometals is the central nervous system (CNS). Biometal dysregulation (metal deficiency or overload) is related to pathological processes. Chronic occupational and environmental exposure to biometals, including iron and copper, is related to an increased risk of developing Parkinson's disease (PD). Indeed, biometals have been shown to induce a dopaminergic neuronal loss in the substantia nigra. Although the etiology of PD is still unknown, oxidative stress dysregulation, mitochondrial dysfunction, and inhibition of both the ubiquitin-proteasome system (UPS) and autophagy are related to dopaminergic neuronal death. Herein, we addressed the involvement of redox-active biometals, iron, and copper, as oxidative stress and neuronal death inducers, as well as the current metal chelation-based therapy in PD.
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Doença de Parkinson , Oligoelementos , Humanos , Doença de Parkinson/patologia , Cobre , Metais , Ferro , Estresse Oxidativo , Oxirredução , Neurônios Dopaminérgicos/patologia , Quelantes/farmacologia , Quelantes/uso terapêuticoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. METHODS: We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. RESULTS: We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. CONCLUSIONS: Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
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The effects of bismuth toxicity on the kidney-the main organ responsible for blood filtration-were systematically reviewed. This review was motivated by availability of several sources of bismuth in contact with humans including environmental, medications, dental materials, and cosmetics, potentially leading to kidney filtration of this chemical. No previous studies have systematically reviewed the literature considering this association. A total of 22 studies with a total of 46 individuals met the inclusion criteria, 19 being case reports with only one patient enrolled. The included studies publication dates ranged from 1961 to 2021 and the countries of publication were the United States of America, United Kingdom, Germany, Turkey, Switzerland, and Canada. Bismuth sources affecting the kidneys were uniquely reported as from medical purposes and mostly associated to overdoses with several symptoms, apparently with dose-dependent consequences. Patient history of renal impairment seemed to affect the outcome of the case. Several therapies were conducted following bismuth intoxication, and few studies performed renal biopsies describing its histological findings. It is crucial to reconsider the nephrotoxicity of bismuth compounds, mainly in patients with previous history of renal impairment.
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The iron ion is an essential element for most forms of life, however, it can damage biological systems when found in free form. Chelation therapy is very important, but it is precarious. Caffeic and ferulic acid are antioxidant compounds with many properties described in research such as anti-inflammatory, antiobesogenic, antithrombotic, vasodilator, and anti-tumor. The aim of the study was to evaluate presenting an in silico approach on the toxicity and bioavailability of caffeic and ferulic acid, subsequently, evaluating them in an iron overload model in vivo and providing a pharmacophoric model through molecular docking. The predictive in silico test did not show relevant toxicity of the compounds, therefore, the in vivo test was performed. The rats received dextran iron and the test groups received caffeic and ferulic acid orally for six weeks. Biochemical, hematological parameters, and tissue oxidative stress marker were analyzed. The experimental model showed increased serum iron levels and changes in several serum parameters such as glucose (215.8 ± 20.3 mg/dL), ALT (512.2 ± 128.7 U/L), creatine kinase (186.8 ± 30.1 U/L), and creatine kinase isoform MB (373.3 ± 69.7 U/L). Caffeic acid and, to a lessed degree, ferullic acid, attenuated the effects of iron overload on the rat serum biochemical parameters. Docking showed a pharmacophoric model where carbonic anhydrase interacted with the test molecules and caffeic acid showed less energy expenditure in this interaction. The results illustrate a new therapeutic action of phenolic compounds on iron overload. The possible interference of carbonic anhydrase in iron metabolism needs to be elucidated.
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Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox)2, exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect.
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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
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Animais , Masculino , Camundongos , Sobrecarga de Ferro/complicações , Flavanonas/análise , Organização e Administração , Desferroxamina/efeitos adversosRESUMO
SCOPE: Activation of microglia, the resident immune cells of the central nervous system, has been related to the etiology and progression of neurodegenerative diseases; thus, finding novel approaches to suppress the neuroinflammatory process is of utmost relevance. METHODS AND RESULTS: The anti-inflammatory activity of whey Cu-, Fe-, and Zn-binding peptides and their possible underlying mechanism of action were evaluated in microglia. Whey metal-binding peptides decreased nitric oxide production and tumor necrosis factor α (TNF-α) at mRNA and protein levels by stimulated BV-2 microglia in comparison to the control with no peptide treatment. The hydrophobicity, specific sequences, and possible synergistic effects seem to play a role. Cu-binding peptides (Cu-bp) presented anti-inflammatory activity both in BV-2 and primary microglia cultures. These peptides exert their action by suppressing nuclear factor kappa B (NF-kB) pathway since nuclear translocation of NF-kB p65 is decreased by roughly 30% upon Cu-bp treatment. Specific sequences identified in Cu-bp showed high affinity to bind NF-kB p65 by molecular docking (up to -8.8 kcal mol-1 ), corroborating the immunofluorescence studies. CONCLUSION: Cu-bp represent food-derived peptides that may be useful for neuroprotective purposes. Chelation of copper excess in the CNS and the bioavailability of such peptides, as well as their behavior in in vivo models, deserve further research for future applications.
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Microglia , NF-kappa B , Cobre/metabolismo , Cobre/farmacologia , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The aim of this study was to evaluate curcumin-mediated antimicrobial photodynamic therapy (aPDT) action combined or not with ethylenediaminetetraacetic acid (EDTA) and hydroxyethylidene bisphosphonate (HEBP) on Enterococcus faecalis biofilms. METHODS: Enterococcus faecalis biofilms were grown on dentin bovine discs in brain heart infusion (BHI) medium with 1% glucose, in aerobic conditions at 37°C for 7 days. Then, they were randomly distributed to one of experimental conditions, as follows: control, 75 J.cm-2 LED, 600 µmol.L-1 curcumin, 17% EDTA, 18% HEBP, 600 µmol.L-1 curcumin plus 75 J.cm-2 LED, 600 µmol.L-1 curcumin plus 17% EDTA, 600 µmol.L-1 curcumin plus 18% HEBP, 600 µmol.L-1 curcumin plus 17% EDTA and 75 J.cm-2 LED or 600 µmol.L-1 curcumin plus 18% HEBP and 75 J.cm-2 LED. The viability of microorganisms and the vitality of biofilms were determined by colony forming unit counts and confocal scanning laser microscopy (CSLM), respectively. Statistical analysis was conducted by Kruskal Wallis and Dunn's post-hoc tests (α = 0.05). RESULTS: The results showed that all combinations of aPDT with chelators significantly reduced the viability of microbial cells and the vitality of biofilms in comparison to control, even when considering deeper layers of biofilms. CONCLUSION: The combination of curcumin with EDTA and HEBP similarly improved the effect of aPDT on E. faecalis biofilms.
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Anti-Infecciosos , Curcumina , Fotoquimioterapia , Animais , Anti-Infecciosos/uso terapêutico , Biofilmes , Bovinos , Quelantes/farmacologia , Curcumina/farmacologia , Enterococcus faecalis , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
BACKGROUND: Vertebrate hosts limit the availability of iron to microbial pathogens in order to nutritionally starve the invaders. The impact of iron deficiency induced by the iron chelator deferoxamine mesylate (DFO) was investigated in Atlantic salmon SHK-1 cells infected with the facultative intracellular bacterium Piscirickettsia salmonis. RESULTS: Effects of the DFO treatment and P. salmonis on SHK-1 cells were gaged by assessing cytopathic effects, bacterial load and activity, and gene expression profiles of eight immune biomarkers at 4- and 7-days post infection (dpi) in the control group, groups receiving single treatments (DFO or P. salmonis) and their combination. The chelator appears to be well-tolerated by host cells, while it had a negative impact on the number of bacterial cells and associated cytotoxicity. DFO alone had minor effects on gene expression of SHK-1 cells, including an early activation of IL-1ß at 4 dpi. In contrast to few moderate changes induced by single treatments (either infection or chelator), most genes had highest upregulation in the infected groups receiving DFO. The mildest induction of hepcidin-1 (antimicrobial peptide precursor and regulator of iron homeostasis) was observed in cells exposed to DFO alone, followed by P. salmonis infected cells while the addition of DFO to infected cells further increased the mRNA abundance of this gene. Transcripts encoding TNF-α (immune signaling) and iNOS (immune effector) showed sustained increase at both time points in this group while cathelicidin-1 (immune effector) and IL-8 (immune signaling) were upregulated at 7 dpi. The stimulation of protective gene responses seen in infected cultures supplemented with DFO coincided with the reduction of bacterial load and activity (judged by the expression of P. salmonis 16S rRNA), and damage to cultured host cells. CONCLUSION: The absence of immune gene activation under normal iron conditions suggests modulation of host responses by P. salmonis. The negative effect of iron deficiency on bacteria likely allowed host cells to respond in a more protective manner to the infection, further decreasing its progression. Presented findings encourage in vivo exploration of iron chelators as a promising strategy against piscirickettsiosis.
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Doenças dos Peixes/microbiologia , Deficiências de Ferro , Piscirickettsia/efeitos dos fármacos , Infecções por Piscirickettsiaceae/veterinária , Animais , Carga Bacteriana , Linhagem Celular , Quelantes/farmacologia , Desferroxamina/farmacologia , Regulação da Expressão Gênica , Hepcidinas/genética , Hepcidinas/metabolismo , Piscirickettsia/patogenicidade , Infecções por Piscirickettsiaceae/microbiologia , RNA Mensageiro/metabolismo , Salmo salarRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-ß (Aß) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-ß protein precursor (AßPP) and Aß42 peptide, affecting Aß aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.
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Doença de Alzheimer/tratamento farmacológico , Quelantes/química , Quelantes/uso terapêutico , Polifenóis/química , Polifenóis/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Quelantes/metabolismo , Quelantes/farmacologia , Cobre/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Polifenóis/metabolismo , Polifenóis/farmacologia , Zinco/metabolismoRESUMO
Sickle Cell Disease (SCD) is an inherited disorder of red blood cells that is caused by a single mutation in the ß -globin gene. The disease, which afflicts millions of patients worldwide mainly in low income countries, is characterized by high morbidity, mortality and low life expectancy. The new pharmacological and non-pharmacological strategies for SCD is urgent in order to promote treatments able to reduce patient's suffering and improve their quality of life. Since the FDA approval of HU in 1998, there have been few advances in discovering new drugs; however, in the last three years voxelotor, crizanlizumab, and glutamine have been approved as new therapeutic alternatives. In addition, new promising compounds have been described to treat the main SCD symptoms. Herein, focusing on drug discovery, we discuss new strategies to treat SCD that have been carried out in the last ten years to discover new, safe, and effective treatments. Moreover, non-pharmacological approaches, including red blood cell exchange, gene therapy and hematopoietic stem cell transplantation will be presented.
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Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Eritrócitos , Terapia Genética , Humanos , Qualidade de VidaRESUMO
AIM: To assess the free available chlorine concentration (FAC), organic tissue dissolution and smear layer removal capacity of sodium hypochlorite (NaOCl) alone and when mixtured with etidronate (HEDP) and tetrasodium EDTA (Na4 EDTA), and heated to different temperatures. METHODOLOGY: Mixtures at 1 : 1 ratio of 5% NaOCl with distilled water (considered NaOCl alone), 18% HEDP or 10% Na4 EDTA were heated to 25 °C, 37 °C, 48 °C and 60 °C. The FAC in the mixtures was assessed at 5, 10, 20, 30, 60 and 120 min. Samples of bovine muscle tissue (n = 10) were prepared with similar size and weighed before and after 5, 10 and 15 min of immersion in the mixtures heated to the different temperatures to verify organic matter dissolution. The intergroup results were compared statistically using one-way analysis of variance (anova) and intragroup by two-way analysis of variance (anova), both followed by Tukey's multiple-comparison test (α < 0.01). Bovine dentine blocks (n = 10) were analysed by scanning electron microscopy before and after immersion in the mixtures, and the time taken to remove the smear layer from the surfaces of the samples was determined. The Friedman test was used to compare the scores of the same group (α < 0.01), and the Kruskal-Wallis test with Dunn's post hoc was used to compare the different groups (α < 0.01). Saline solution was used as a control in the experiments of tissue dissolution and smear layer removal, RESULTS: Heating NaOCl alone did not affect its FAC. The higher the temperature of the mixtures with the chelators, the lower the FAC. Organic tissue dissolution was improved by increases in temperature of NaOCl alone and its mixture with HEDP (P < 0.01); however, the mixture with Na4 EDTA had no improvement (P > 0.01). Smear layer removal by NaOCl alone was enhanced by heating resulting in lower scores in some samples and became more rapid in the mixtures with the chelators. The saline solution did not promote tissue dissolution nor smear layer removal (P > 0.01). CONCLUSION: In this laboratory study, heating NaOCl alone or when mixed with HEDP improved its capacity to dissolve organic matter and remove the smear layer. However, the mixture with HEDP required frequent refreshment to retain these effects when heated. Due to the acceleration in the reaction between the irrigants, very rapid reductions in the free available chlorine in the mixtures with Na4 EDTA heated to the different temperatures occurred.
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Ácido Etidrônico , Camada de Esfregaço , Animais , Bovinos , Cavidade Pulpar , Dentina , Ácido Edético/farmacologia , Ácido Etidrônico/farmacologia , Temperatura Alta , Microscopia Eletrônica de Varredura , Irrigantes do Canal Radicular , Preparo de Canal Radicular , Hipoclorito de Sódio/farmacologiaRESUMO
BACKGROUND: Copper (Cu) is a transition metal active in Fenton redox cycling from reduced Cu+ and H2O2, to oxidized Cu2+ and the hydroxyl radical (·OH) highly reactive oxygen species (ROS). At homeostatic Cu levels, ROS promote cell proliferation, migration, angiogenesis, and wound repair. To limit ROS toxicity, cells use Cu-dependent chaperone proteins, Cu-binding ceruloplasmin, and Cu-modulated enzymes like superoxide dismutases (SOD) like SOD1 and SOD3 to scavenge excess superoxide anions which favour Cu+ reduction, and mitochondrial cytochrome c oxidase, important in aerobic energy production. Because Cu helps drive tumor cell proliferation by promoting growth factor-independent receptor tyrosine kinase signaling, and Cu-dependent MEK1 involved in oncogenic BRAF-V600E signaling, further augmenting bioavailable Cu may promote ROS overproduction, cancer progression and eventually tumor cell death. For these reasons, the following clinically approved copper chelators are being repurposed as anti-cancer agents: a) ammonium tetrathiomolybdate (TTM) used to treat Wilson's disease (copper overload) and Menkes disease (copper deficiency); b) Disulfiram (DSF), used against alcoholism, since it inhibits Aldehyde Dehydrogenase (ALDH1) enzyme, important in ethanol detoxification, and a key target against cancer stem cells. Moreover, TTM and DSF are also relevant in cancer clinical trials, because they increase the uptake of both Cu and Platinum (Pt)-containing anti-cancer drugs, since Pt and Cu share the same CTR1 copper transporter. PURPOSE: The majority of reports on Cu chelators dealt separately with either TTM, DSF or others. Here, we compare in parallel, the anti-cancer efficacy of low doses of TTM and DSF, asking whether they can be synergistic or antagonistic. The relevance of their unequal ROS inducing abilities and their different behavior as ionophores is also addressed. SIGNIFICANCE: The potential of Cu chelators as repurposed anti-cancer drugs, should be greater in patients with higher endogenous Cu levels. Since platinum and Cu share uptake receptors, the synergism by drugs containing these metals should not be under-estimated. The potential of disulfiram or its metabolically active Cu-containing form, to inhibit ALDH1-positive tumor cells is therapeutically very important.
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Dissulfiram , Neoplasias , Linhagem Celular Tumoral , Cobre , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Humanos , Peróxido de Hidrogênio , Molibdênio , Neoplasias/tratamento farmacológico , Oxirredução , Espécies Reativas de OxigênioRESUMO
Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer's disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 µM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 µM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe2+ and Zn2+ ions in a 2:1 ligand:metal ratio according to the Job Plot method.
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Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Hidrazonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Quelantes/síntese química , Quelantes/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Peroxidase/antagonistas & inibidores , Peroxidase/metabolismo , Picratos/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: Deferasirox is an oral iron chelator with established dose-dependent efficacy for the treatment of iron overload secondary to transfusion. However, there is few data reporting the use of Desferasirox in adult patients with sickle cell disease (SCD) and transfusional iron overload. METHODS: We conducted a prospective, single center, nonrandomized study from January 2014 to March 2015 in Campinas, Brazil. Seven patients (five women, median age 50 y.o.) who were followed up on regular transfusion program were treated with a single daily dose of deferasirox (median dose 20â mg/kg). They were monitored for clinical symptoms, renal function and hepatotoxicity. RESULTS: One patient discontinued the study due to lack of compliance. Two patients reported mild to moderate adverse events (gastrointestinal disturbances). Five patients had the drug discontinued due to worsening of renal function. One patient had the drug discontinued due to severe hepatotoxicity that evolved to death; no patient finished the study. Discussion and conclusions: Deferasirox does not appear to be well tolerated in SCD patients older than 40 years, in which complications of the underlying disease are already fully installed. The choice of the ideal iron chelator for this population should include an evaluation of comorbidities and organic dysfunctions, as well as the need to find pharmacogenetic safety markers in this group of patients.