Research status of ocular changes in beta-thalassemia major / 国际眼科杂志(Guoji Yanke Zazhi)

Beta-thalassemia major(β-TM)is an inherited disease caused by a defect in the synthesis of globin. The disease requires long-term blood transfusion and iron chelator treatment, which can cause various secondary changes in the body and eye tissues. Compared with normal peers, β-TM patients will show changes in the eye such as steeper corneal curvature, shallower anterior chamber, increased lens thickness, shorter axial length, and reduced tear secretion. At the same time, nutritional deficiencies and the use of iron chelator drugs will increase the risk of complicated cataract and retinal degeneration, thus affecting the quality of life of β-TM patients.This article combines relevant domestic and foreign literatures to explore and review the changes in the eye of β-TM patients, with a view to providing valuable insights for clinical practice.

Research advances in toxicity of uranium in vivo and its new chelators / 中国辐射卫生

Uranium is an important radioactive actinide in nature and an important nuclear material in nuclear industry. After uranium is accidentally released into the environment, it enters the body through the respiratory tract, the digestive tract, and other ways, then enters the circulation system through blood, and is finally mainly deposited in the kidney and bone, causing a certain degree of toxicity. Therefore, efficient low-toxicity chelators are an important way to reduce radionuclide pollution, radiation damage, and chemical toxicity. This article reviews uranium deposition and harm, the detoxification mechanism of uranium chelators, and the research advances in uranium chelators and points out the development trend of uranium chelators.

Ocular Manifestations of ß -Thalassemia Patients with the Use of Oral Iron Chelating Agents

Background: Ocular involvement in β-thalassemia major is very common. Iron chelators like Desferrioxamine and Deferiprone avoid systemic complications but chelate metals in retina. Objectives: 1.To study the relation of oral iron chelator (Deferiprone) on various ocular manifestations in β-thalassemia major patients. 2. To study the relation of serum ferritin with various ocular manifestations. Methods: 100β-thalassemia major patients out of those attending our thalassemia clinic were selected for the study as per our inclusion and exclusion criteria. They were divided into two major groups based on whether they were taking oral iron chelator (Deferiprone) or not. Detailed history, examination and investigations were done and recorded. Results: The study revealed that 52% of the patients had ocular involvement with 86.5% of them taking Deferiprone (p<0.0001), 13% had retinal pigment epithelium (RPE) degeneration with 92.3% of them on Deferiprone (p=0.003) and 18% had RPE mottling with 88.8% of them taking Deferiprone (p=0.001). Other ocular changes like lens opacity, disc hyperemia, best corrected visual acuity (BCVA) and venous tortuosity showed some difference between the two groups but that was insignificant. Further the study also showed that higher serum ferritin levels were significantly associated with ocular changes like decreased BCVA (p<0.001), RPE degeneration (p<0.001), RPE mottling (p<0.001) and venous tortuosity (p<0.025). Conclusion: Ocular changes in β-thalassemia major increases with greater duration of the disease and increased number of blood transfusions due to increased serum ferritin levels. Using iron chelators may reduce iron overload but they causechelator induced ocular involvement.

Phenolic profile and antioxidant activity from peels and seeds of melon (Cucumis melo L. var. reticulatus) and their antiproliferative effect in cancer cells

Melon (Cucumis melo L.) has high economic value and in recent years, its production has increased; however, part of the fruit is wasted. Usually, inedible parts such as peel and seeds are discarded during processing and consumption. Extracts of melon residues were prepared and their phenolic compounds, antioxidants and antiproliferative activities were evaluated. Total phenolic compounds were found in hydroethanolic, hydromethanolic, and aqueous extracts, especially for melon peel (1.016 mg gallic acid equivalent/100 g). Flavonoids total content found for melon peel aqueous extract was 262 µg of catechin equivalent (CA)/100 g. In all extracts of melon peel significant amounts of gallic acid, catechin, and eugenol were found. For total antioxidant capacity, reported as ascorbic acid equivalent, the hydroethanolic and hydromethanolic extracts in peels and hydromethanolic in seeds were 89, 74, and 83 mg/g, respectively. Different extracts of melon showed iron and copper ions chelating activity at different concentrations, especially melon peel aqueous extract, reaching values of 61% for iron and 84% for copper. The hydroethanolic extract of melon peel presented a significant ability for hydroxyl radicals scavenging (68%). To assess the antiproliferative potential in human cancer cell lines, such as kidney carcinoma, colorectal carcinoma, cervical adenocarcinoma and cervical carcinoma, MTT assay was performed. The proliferation was inhibited by 20-85% at extracts concentrations of 0.1-1.0 mg/mL in all cancer cell lines. The results suggest that melon residues extracts display a high antioxidant activity in in vitro assays and have effective biological activity against the growth of human tumor cells.

Current progress of iron metabolism and tumor development / 医学研究生学报

Iron is an essential nutrient that not only participates in cell oxidative phosphorylation, DNA synthesis and replication, but also regulates cancer associated genes through hypoxia-inducible factor (HIF).In the process of cancerization, cells change the way of iron metabolism resulting in a high consumption of iron.In this case, pathways of iron acquisition, efflux, storage and regulation are perturbed.Therefore, iron can significantly contribute to tumor growth, cell survival and metastasis.In this paper, we summarize the iron changes in cancer cells and the relationship between the changes and tumorigenesis.We also briefly state the potential problems of current clinical using iron chelating agents in oncotherapy.Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.

Research progress in heavy metal toxic damage of nervous system / 中国药理学与毒理学杂志

With the development of modern industry,heavy metal pollution in China is becoming increasingly serious.Large-scale water sources and farmland have been severely contaminated.Frequent contact with heavy metal in life or at work has caused a marked increase in heavy metal poisoning in recent years.Nervous system damage caused by heavy metal poisoning is extremely common in clinic,and poses a threat to a patient's life,bringing heavy burden to society and families.Therefore,early prevention and treatment are crucial.This article takes commonpoisoning several common heavy metals as an example and combine the domestic and foreign research to review the damage to the nervous system caused by heavy metal poisoning.We aim to make patients and medical staff more alert to such poisoning and provide the basis for clinical prevention,diagnosis,treatment and research.

Observation on the clinical effectiveness of deferasirox,deferiprone and desferrioxamine in the treatment of iron load in patients with thalassemia major / 中国综合临床

Objective To explore the clinical effectiveness of deferasirox, deferiprone and desferrioxamine in the treatment of iron overload in patients with thalassemia major.Methods Among the severe thalassemia patients with iron overload being diagnosis,treated and followed up in Guigang City People′s Hospital,fifty cases were tested by MRI T2 and were detected with cardiac and liver iron overload,the patients were selected and randomly divided into the deferoxamine treatment(DFO)group(18 case),deferiprone treatment(DFP)group(22 cases)and deferasirox treatment(DFX)group(10 case),The baseline data of the three groups were statistically analyzed.the serum ferritin(SF)value,the cardiac MRI T2 value and the liver MRI T2 value before and after treatment were measured.Results The patients completed the treatment,after 1 years of treatment,the serum SF value,cardiac and liver MRI T2 values of the patients were improved than those before the treatment(P<0.05); the differences in serum SF among the three groups were not statistically significant(F=3.089,P>0.05); the differences in liver MRI T2 value among the three groups were not statistically significant(F=0.131,P>0.05),There were significant differences in heart iron load MRI T2 values among the three groups((34.27 ± 6.30)ms vs.(23 ± 2.79)ms vs.(21.8 ± 2.20)ms,F=39.54,P<0.05) .Conclusion Deferoxamine,deferiprone and deferasirox can effectively alleviate the iron load in patients with thalassemia major.in terms of cardiac iron overload,the curative effects of deferiprone treatment in patients with thalassemia is superior than desferrioxamine and deferasirox treatment,it is worthy of clinical promotion.

Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.

Disruption of iron homeostasis and relevant pharmacotherapies in Alzheimer's disease / 药学学报

Iron is the most abundant metal element to support the body's physiological activities and play crucial roles in the central nervous system. Iron homeostasis is under strict control in normal circumstances, and some diseases will occur once the homeostasis was disrupted. Numerous researches suggest that iron homeostasis disruptes in Alzheimer's disease (AD) and the homeostasis disruption interacts with AD's hallmarks. Dispute still exists on how iron plays a role in AD despite of the great number of researches. This article will focus on iron metabolism, normal function in the brain and recent therapies of AD based on iron chelation.

Improved synthesis of dipyridyl thioselenosemicarbazones / 国际药学研究杂志

Objective To improve the synthesis process of N- allyl- 2-(di(pyridin- 2- yl)methylene)hydrazinecarboselenoamide(4)and2-(di(pyridin-2-yl)methylene)-N,N-dimethylhydrazinecarboselenoamide(8). Methods 4-allyl-3-thiosemicarbazide (1)was the starting material,which reacted with methyl iodide,sodium hydrogen selenide to obtain intermediate 4-allyl-3-selenosemicarbazide(3). Compound(3)reacted with di-2-pyridyl ketone to obtain the target compound 4. 4,4-Dimethyl-3-thiosemicarbazide was the starting materials,which reacted with di-2-pyridyl ketone to obtain intermediate dipyridyl thiosemicarbazone(6). Compound 6 reacted with methyl iodide,sodium hydrogen selenide to obtain the target compound 8. We optimized the reaction conditions of each step. Results We synthesized the target compound 4 and 8 according to the respective synthetic route,the structure of the target compounds and the intermediates were confirmed by 1H NMR and MS. Conclusion The improved processes are easy to operate,cost-saving and suitable for large scale preparation.

Improved synthesis of dipyridyl thioselenosemicarbazones / 国际药学研究杂志

Objective To improve the synthesis process of N-allyl-2-(di(pyridin-2-yl)methylene)hydrazinecarboseleno?amide(4)and 2-(di(pyridin-2-yl)methylene)-N,N-dimethylhydrazinecarboselenoamide(8). Methods 4-allyl-3-thiosemicarbazide (1)was the starting material,which reacted with methyl iodide,sodium hydrogen selenide to obtain intermediate 4-allyl-3-selenosemi?carbazide(3). Compound(3)reacted with di-2-pyridyl ketone to obtain the target compound 4. 4,4-Dimethyl-3-thiosemicarbazide was the starting materials,which reacted with di-2-pyridyl ketone to obtain intermediate dipyridyl thiosemicarbazone(6). Compound 6 re?acted with methyl iodide,sodium hydrogen selenide to obtain the target compound 8. We optimized the reaction conditions of each step. Results We synthesized the target compound 4 and 8 according to the respective synthetic route,the structure of the target com?pounds and the intermediates were confirmed by 1H NMR and MS. Conclusion The improved processes are easy to operate,cost-saving and suitable for large scale preparation.

Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

Objective: To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei ( P. berghei) infected mice. Methods: The CM1 (0-100 mg/kg/day) and GTE (0-100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED

Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

Objective: To evaluate the efficacy of deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) or green tea extract (GTE) in enhancing expression of hepatic hepcidin1 (Hamp1) mRNA and relieving iron overload in β-globin knockout thalassemic mice. Methods: The β-globin knockout thalassemic mice were fed with a ferrocene-supplemented diet for 2 months and oral administration of deionized water, DFP (50 mg/kg), CM1 (50 mg/kg), GTE (50 mg epigallocatechin 3-gallate equivalent/kg), GTE along with DFP (50 mg/kg), and GTE along with CM1 (50 mg/kg) every day for 3 months. Levels of hepatic Hamp1 mRNA, plasma non-transferrin bound iron, plasma alanine aminotransferase activity and tissue iron content were determined. Results: All chelation treatments could reduce plasma non-transferrin bound iron concentrations. Additionally, hepatic Hamp1 mRNA expression was significantly up-regulated in the mice in a GTE + DFP combined treatment, correlating with a decrease in the plasma alanine aminotransferase activity and tissue iron deposition. Conclusions: The GTE + DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent β-thalassemic mice, by chelating toxic iron in plasma and tissues, and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen. There is probably an advantage in giving GTE with DFP when treating patients with iron overload.

Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

Objective:To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei (P. berghei ) infected mice. Methods:The CM1 (0–100 mg/kg/day) and GTE (0–100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine (PYR) (ED50=0.76 mg/kg). GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity. Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron constitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

Progress in treatment of Iead poisoning by antioxidants / 中国药理学与毒理学杂志

Lead poisoning has become a big threat to public health in China. Traditional treatments usually use chelators to accelerate the excretion of lead by forming complex compounds with it. However, chelators exhibit side effects and have little therapeutic effect on lead-induced impairment so that better drugs are needed. As antioxidants are effective for the treatment of lead poisoning, with lasting effect and little side effect, they have been the focus of increasing studies. This review provides a detailed account of updates on the effects of antioxidant drugs in the therapy of lead poisoning, and of the progress in antioxidant activity of puerarin, quercetin, curcumin, allicin and melatonin in treatment of lead poisoning. To some extent, these five types of drugs can reduce lead poisoning by accelerating lead excretion and antioxidant, increase the body′s antioxidant enzyme activity, reduce oxidative stress and repair damage, which promises some clinical value.

Iron-Chelating Property of Phytic Acid in Thalassaemia: An In vitro Study.

Aims: The aim of this study is to report an oral iron chelator phytic acid (PA), on blood samples from different types of thalassaemic patients of various age groups and physical conditions. Study Design: The In vitro iron chelating effect was evaluated by ferritin assay using ELISA. Methodology: Blood from the iron-overloaded 30 Thalassaemic patients of different age groups, body weights and heights were collected and the serum was separated. Patients without any history of blood transfusion and chelation therapy were taken as control group. The ELISA based ferritin assay was performed with standard phytic acid (40% water solution, Fluka), using Desferrioxamine (DFO) as control (0.5g Deferoxamine mesylate USP, Novartis, USA). The serum ferritin levels were recorded in two different conditions (treated with DFO and PA) at different time intervals (10, 30 and 60 min) by measuring absorbance at 450 nm. Results: The Kolmogorov-Smirnov test of patient samples in two different conditions showed that the ferritin concentration, treated by DFO and PA, was significantly decrease in PA treated group compared to DFO, when used in equivalent concentrations, at intervals of 10 min (P=0.760),30 min (P=0.537) and 60 min (P=0.055). Conclusion: The common iron chelators DFO or Deferiprone used as monotherapy may lead to transient and incomplete removal of iron, while PA showed a more complete and sustained removal of ferritin due to specific chemical binding at a wider pH range. However, further trial is required to establish its maintenance dose, comparative efficacy and mechanism of action.

Iron-chelating and anti-lipid peroxidation properties of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in long-term iron loading β-thalassemic mice

Objective: To evaluate the iron-chelating properties and free-radical scavenging activities of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) treatment in chronic iron-loaded β-thalassemic (BKO) mice. Methods: The BKO mice were fed with a ferrocene-rich diet and were orally administered with CM1 [50 mg/(kg.day)] for 6 months. Blood levels of non-transferrin bound iron, labile plasma iron, ferritin (Ft) and malondialdehyde were determined. Results: The BKO mice were fed with an iron diet for 8 months which resulted in iron overload. Interestingly, the mice showed a decrease in the non-transferrin bound iron, labile plasma iron and malondialdehyde levels, but not the Ft levels after continuous CM1 treatment. Conclusions: CM1 could be an effective oral iron chelator that can reduce iron overload and lipid peroxidation in chronic iron overload β-thalassemic mice.

Iron-chelating and anti-lipid peroxidation properties of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in long-term iron loading β-thalassemic mice

<p><b>OBJECTIVE</b>To evaluate the iron-chelating properties and free-radical scavenging activities of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) treatment in chronic iron-loaded β-thalassemic (BKO) mice.</p><p><b>METHODS</b>The BKO mice were fed with a ferrocene-rich diet and were orally administered with CM1 [50 mg/(kg.day)] for 6 months. Blood levels of non-transferrin bound iron, labile plasma iron, ferritin (Ft) and malondialdehyde were determined.</p><p><b>RESULTS</b>The BKO mice were fed with an iron diet for 8 months which resulted in iron overload. Interestingly, the mice showed a decrease in the non-transferrin bound iron, labile plasma iron and malondialdehyde levels, but not the Ft levels after continuous CM1 treatment.</p><p><b>CONCLUSIONS</b>CM1 could be an effective oral iron chelator that can reduce iron overload and lipid peroxidation in chronic iron overload β-thalassemic mice.</p>

Sobrecarga de hierro en enfermedades hematológicas y no hematológicas: una bomba de tiempo / Iron overload in hematological and no hematological disease: a time bomb

La sobrecarga de hierro es una complicación frecuente en un número importante de enfermedades hematológicas que cursan con anemia y requieren transfusiones sanguíneas como parte de su terapia. Entre ellas se destacan la talasemia, la drepanocitosis, los síndromes mielodisplásicos, la anemia de Blackfan-Diamond, la anemia de Fanconi y la deficiencia de piruvato quinasa, La sobrecarga de hieroo tambiún se presenta en otras enfermedades tales como la hemocromatosis hereditaria, la hepatitis viral, el síndrome metabólico y determinados trastornos neurovegetativos. El diagnóstico de sobrecarga suele hacerse mediante la determinación del hierro sérico no unido a la transferrina, la ferritina sérica y un aumento de la concentración hepática de hierro. Las consecuencias más importantes del efecto tóxico de un exceso de hierro son las disfunciones cardíacas y endocrinas, debidas al efecto oxidante del hierro sobre las membranas celulares, con el consiguiente daño celular. Tales alteraciones contribuyen al incremento de la morbilidad y la mortalidad en estos pacientes. El tratamiento consiste básicamente en el usode agentes quelantes de hierro que facilitan la excreción del exceso del metal y reducen su efecto tóxico, Entre tales agentes se cuentan la deferrioxamina (de uso intravenoso). y móa recientemente el deferiprone (ambos de uso orak)

Iron overload is a frequent complication in patients with hematological diseases which develop anemía and require blood transfusion as a therapeutic measure. Thalassemia, drepanocytosis, myelodisplastic syndromes, Blackfan-Diamond anemia, Franconi anemia and pyruvate kinase deficiency are the most common of these diseases. Iron overload is the hallmark of hereditary hemochromatosis, and also complicates diseases such as viral hepatitis, the metabolic syndrome, and certain neurovegetative disfunctions. The diagnosis of iron overload is commonly established through the evaluation of serum iron, transferrin saturation, serum ferritin and liver iron concentration. Cardiac and endocrine dysfunctions are the most important consequences of the toxic efffect of iron accumulation; these are due to the oxidixing effect of iron upon the cellular membranes, followed by cellular damage. Such alterations contribute to the increased morbility and mortality rates in these patients. The treatment of iron overload is based mainly on the use of iron chelators which facilitate the excretion of iron excess and reduce its toxic effect. Deferrioxamine (for intravenous use), and more recently deferiprone and deferasirox (both for oral administration) are the drugs of choice

Promise of Neurorestoration and Mitochondrial Biogenesis in Parkinson's Disease with Multi Target Drugs: An Alternative to Stem Cell Therapy

There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.