Natural Iron Chelators: An Orthomolecular Approach to Treat Iron Overload and Its Related Diseases

Despite its various vital roles in the different body’s metabolisms,iron may have a hazardous impact on health when it exceeds its normal values.Iron overload is triggered by many genetic and behavioral factors.Furthermore,excessive iron levels have also been observed in many pathologies such as Alzheimer’s,Parkinson’s,cardiovascular and some cancerous diseases.This paper describes a set of natural iron chelators as an effective and a safe orthomolecular approach in chelating iron.Orthomolecular medicine is based on providing patients with nutritional supplementation at high doses to treat and prevent diseases.This paper describes the properties of a set of flavonoids and phenolic acids such as curcumin and ferulic acid that can be administered as supplements to patients suffering from iron overload since they are classified as strong chelators.Those natural iron chelators’supplements are mainly extracted from fruits,vegetables,and plants.As chelators,they are able to bind effectively to iron,inhibit the production of reactive oxygen species,and reduce the levels of oxidative stress.They can also play an effective therapeutic role in the treatment of neurodegenerative,cardiovascular,diabetic,and cancerous diseases thanks to their iron chelation,antioxidant,and anti-inflammatory properties.

Baicalin interferes with iron accumulation in C6 glioma cells

Baicalin reacts with ferric ammonium citrate and acts as an-iron chelator. The maximal reaction time for baicalin to interact with irons was approximately 3 hours. C6 glioma cell survival decreased following iron-loading, with a large number of cells accumulating iron. In addition, lipid peroxidation increased. Iron accumulation and lipid peroxidation were the major cause of cellular death. Baicalin and ferric ammonium citrate alleviated iron accumulation in C6 cells and lowered the mortality of nerve cells. In addition, malondialdehyde and lactate dehydrogenase levels reduced. These results indicate that baicalin strongly inhibits lipid peroxidation via chelation, reduces the content of iron in C6 cells, lowers lipid peroxidation, and thus plays a protective role against iron-induced nerve cell death.

Juvenile hemochromatosis:HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage,hypogonadotropic hypogonadism,cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation(g.47G>A),treated with phlebotomies and deferasirox. She presented symptoms such as weakness,skin hyperpigmentation,joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin(SF): 5696 ng/mL,transferrin saturation(TS): 85%]. After sessions of phlebotomies(450 mL every 15 d),the patient presented partial symptomatic improvements and biochemical parameters(SF: 1000 ng/mL,Hb: 11 g/dL). One year later,deferasirox(15 mg/kg per day) was introduced to the treatment,and the patient showed total symptomatic improvement,with significant clearing of the skin,SF: 169 ng/mL,and TS: 50%. Furthermore,after the combined deferasirox-phlebotomy therapy,magnetic resonance imaging measurements revealed normalized level for liver iron(30 μmol/g; reference value < 36 μmol/g). In conclusion,combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Beliefs of Jordanian Children with Thalassemia toward Using Iron Chelation Therapy

Adherence to thalassemia treatment including chelation drugs is influenced by numerous factors. This study aims to explore beliefs about iron chelation therapy and adherence to this medication in Jordanian children with thalassemia major. In this descriptive cross-sectional study, seventy three patients were selected conveniently to complete the study instruments. Participants reported high adherence to their chelation therapy (88.1%). The majority (87.6%) expressed necessity for chelation therapy. However, 42.18% of the participants expressed their concerns about the therapy in which 57.9% of them showed concerns about dependency on medicine and 46.4% of them revealed concerns about the long-term effect of medicine. Overall, about 12.9% of the participants recorded correct and complete answers about thalassemia and its treatment. Knowledge about thalassemia and concerns about chelation were not significantly associated with adherence to the chelation therapy (r = 0.32, p = 0.19;r = 0.29, p = 0.25, respectively). However, there was a significant positive relationship between beliefs about the necessity of the therapy and adherence to it (r = 0.38, p = 0.03). In conclusion, Jordanian children showed proper adherence to their chelation therapy. Health care professionals should discuss patients’ concerns about chelation therapy which might increase patients’ adherence to their therapy.

Influence of Cathode Modification by Chitosan and Fe^(3+)on the Electrochemical Performance of Marine Sediment Microbial Fuel Cell

The electrochemical performances of cathode play a key role in the marine sediment microbial fuel cells(MSMFCs)as a long lasting power source to drive instruments,especially when the dissolved oxygen concentration is very low in seawater.A CTS-Fe^(3+)modified cathode is prepared here by grafting chitosan(CTS)on a carbon fiber surface and then chelating Fe^(3+)through the coordination process.The electrochemical performance in seawater and the output power of the assembled MSMFCs are both studied.The results show that the exchange current densities of CTS and the CTS-Fe^(3+)group are 5.5 and 6.2 times higher than that of the blank group,respectively.The potential of the CTS-Fe^(3+)modified cathode increases by 138 mV.The output power of the fuel cell(613.0 mW m^(-2))assembled with CTS-Fe^(3+)is 54 times larger than that of the blank group(11.4 mW m^(-2))and the current output corresponding with the maximum power output also increases by 56 times.Due to the valence conversion between Fe^(3+)and Fe^(2+)on the modified cathode,the kinetic activity of the dissolved oxygen reduction is accelerated and the depolarization capability of the cathode is enhanced,resulting higher cell power.On the basis of this study,the new cathode materials will be encouraged to design with the complex of iron ion in natural seawater as the catalysis for oxygen reduction to improve the cell power in deep sea.

The soil fungi producing siderophores of Mt.Yangbew,Tawang,La Trinidad,Benguet

Siderophores,being iron-chelators,have received much attention in environmental research,medicine,and biotechnology because of their high affinity and specificity to a wide range of metals.This study aimed to investigate siderophore production of culturable soil fungi from Mt.Yangbew,Tawang,La Trinidad,Benguet and to determine their chemical characteristics.Siderophore production was detected and quantified using Chrome Azurol Sulphonate assay while the siderophore characterization was through FeCl_(3),Csáky’s and Arnow’s tests.It was found that 11 out of 20 pure cultures,which showed positive CAS assay results,produce hydroxamates.ITS primers were used in PCR amplification for the molecular identification of the top-four siderophore-producers.Based on BLASTn analyses of their sequences,the isolates were found to be most homologous to species of Talaromyces,Byssochlamys,Paecilomyces,and Penicillium.The identified species were subjected to phylogenetic analysis using MEGA 7 to the show evolutionary history and relationship among the fungal species.

Perforated duodenal ulcer secondary to deferasirox use in a child successfully managed with laparoscopic drainage:A case report

BACKGROUND A perforated gastroduodenal ulcer is rarely observed in children.Certain medications have been reported to cause ulcerations.Deferasirox,an iron chelating agent,has been previously reported to be associated with the development of gastroduodenal ulcers.CASE SUMMARY We report a case of a 3-year-old boy who was diagnosed with beta thalassemia major and treated with deferasirox.He presented to the emergency department with an acute abdomen.A perforated duodenal ulcer was suspected after X-ray imaging and laparoscopic exploration.It was successfully managed with laparoscopic washout and drainage.CONCLUSION Due to the rarity and severity of this case,it is a reminder that prevention and early recognition of gastrointestinal complications in patients receiving deferasirox are crucial.Minimally invasive laparoscopic surgery is both safe and feasible to treat perforated duodenal ulcers in selected patients.

Iron metabolism in non-alcoholic fatty liver disease: A promising therapeutic target

Non-alcoholic fatty liver disease(NAFLD)has become the most common cause of chronic liver disease worldwide,and is closely associated with the increased risk of the prevalence of obesity and diabetes.NAFLD begins with the presence of>5%excessive lipid accumulation in the liver,and potentially de-velops into non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.Therefore,insight into the pathogenesis of NAFLD is of key importance to its effective treatment.Iron is an essential element in the life of all mammalian organisms.However,the free iron deposition is positively associated with histological severity in NAFLD patients due to the production of reactive oxygen species via the Fenton reaction.Recently,several iron metabolism-targeted therapies,such as phlebotomy,iron chela-tors,nanotherapeutics.and ferroptosis,have shown their potential as a therapeutic option in the treatment of NAFLD and as a clinical strategy to intervene in the progression of NAFLD.Herein,we review the recent overall evidence on iron metabolism and provide the mechanism of hepatic iron overload-induced liver pathologies and the recent advances in iron metabolism-targeted therapeutics in the treatment of NAFLD.

2D-ultrathin MXene/DOXjade platform for iron chelation chemo-photothermal therapy

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation,tumor progression and metastasis.This makes iron metabolism an attractive therapeutic target.Unfortunately,current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities.We report here a dual-therapeutic prodrug,DOXjade,that allows for iron chelation chemo-photothermal cancer therapy.This prodrug takes advantage of the clinically approved iron chelator deferasirox(ExJade®)and the topoisomerase 2 inhibitor,doxorubicin(DOX).Loading DOXjade onto ultrathin 2D Ti_(3)C_(2) MXene nanosheets produces a construct,Ti_(3)C_(2)-PVP@DOXjade,that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites,while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%.Antitumor mechanistic investigations reveal that upon activation,Ti_(3)C_(2)-PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor(TfR).A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo.The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.

Neuroprotective effects of kukoamine A on 6-OHDA-induced Parkinson’s model through apoptosis and iron accumulation inhibition

Objective: Parkinson’s disease(PD) is characterized by the loss of dopaminergic neurons in substantia nigra(SN). Our previous study demonstrated kukoamine A(KuA) to exhibit strong neuroprotective effects through antioxidative stress, and autophagy in MPTP/MPP+-induced PD models in vivo and in vitro. It is necessary to evaluate the efficacy of the anti-PD effects under various models.Methods: In the present study, total chemical synthesis was used to obtain KuA, which performed low content in Lycii Cortex. Then, 6-OHDA-induced PD model of PC12 cells was used to investigate the effects of KuA on PD.Results: Our results demonstrated that KuA ameliorated cell loss and mitochondrial membrane potential(MMP) loss, and inhibited Bax/Bcl-2 ratio increase that were induced by 6-OHDA. Iron accumulation in SN is thought to participate in neuronal death in PD, which subsequently resulted in oxidative stress and overexpression of a-synuclein caused by iron metabolism protein disorder. In our study, KuA could chelate cellular iron content and decrease iron influx. Moreover, KuA could upregulate the expression of ferroportin1 and Hephaestin, downregulate the expression of DMT1, TfR, and Ferritin to maintain cellular iron homeostasis avoiding neuronal death from cellular iron deposition. Moreover, KuA could decrease the expression of a-synuclein in cells. All the results indicated that KuA protected against neurotoxininduced PD due to the apoptosis inhibition and iron homeostasis maintaining.Conclusion: KuA treatment might represent a neuroprotective treatment for PD.

A new iron(Ⅲ) chelator of coprogen-type siderophore from the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059

Mycosphazine A(1), a new iron(Ⅲ) chelator of coprogen-type siderophore, and mycosphamide A(2), a new cyclic amide benzoate, together with six known aryl amides(3-8), were isolated from the fermentation broth of the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059. Alkaline hydrolysis of 1 afforded a new epimer of dimerum acid, mycosphazine B(1 a), and a new bi-fusarinine-type siderophore, mycosphazine C(1 b). The planar structures of the new compounds were elucidated by extensive spectroscopic data analysis. The absolute configurations of amino acid residues in 1 a and 1 b were determined by acid hydrolysis. And the absolute configuration of 2 was established by quantum chemical calculations of the electronic circular dichroism(ECD) spectra. Compound 1 is the first siderophore-Fe(Ⅲ) chelator incorporating both L-ornithine and D-ornithine unites. Compounds 3-8 were reported as natural products for the first time, and the 1 H and 13 C NMR data of 6 and 8 were assigned for the first time. Compounds 1 and 1 a could greatly promote the biofilm formation of bacterium Bacillus amyloliquefaciens with the rate of about 249% and 524% at concentration of 100 μg·mL-1, respectively.

Peroxidase-Like Reactivity at Iron-Chelation Sites in a Mesoporous Synthetic Melanin

High catalytic activity and substrate specificity make enzymes a rich source of inspiration for catalyst development.Co-opting the advantages of natural materials while tuning them to a modified form and purpose,however,is not a straightforward synthetic task.Polymerization of L-3,4-dihydroxyphenylalanine(L-DOPA)results in amorphous polymer nanoparticles that are similar in many ways to natural eumelanin.Herein,the authors introduce mesoporosity and iron ion chelation to synthesize a variant of the L-DOPA polymer with high peroxidase-like activity.Our results indicate catalytic reaction with peroxide under mildly acidic conditions(pH 5.4 and 6)with a greater maximum reaction velocity(Vmax)than horseradish peroxidase(HRP)at optimal pH 3.5–4.5.Comparison between Fe(Ⅲ)and Fe(Ⅱ)loading indicates that either can be used as a starting point to trigger reactivity,though Fe(Ⅱ)loading leads to materials with twice the Vmax of the Fe(Ⅲ)-loaded sample.The lack of catalyst degradation despite the redox changes and presence of radical species is consistent with the robust nature and redox versatility of polydopamine-based materials and demonstrates strong potential as a versatile redox-catalysis platform.

Influence of CaNa_2 EDTA on topical 5-aminolaevulinic acid photodynamic therapy

Background We asssessed whether the CaNa_2 EDTA could improve the accumulation of protoporphyrin Ⅸ (PpⅨ) and photosensitisation in HEp-2 cells as well as the depth of treatment of skin cancers on the topical 5-Aminolaevulinic acid (5-ALA) PDT.Methods HEp-2 cells were incubated with 5-ALA (0-1mmol/L) and CaNa_2EDTA (0-1mmol/L) for 4 hours,intracellular protoporphyrin Ⅸ content was quantified by extraction,and cell viability was assessed by use of the methyl-tetrazolium (MTT) assay four hours after exposure to light. In comparison with the pictures before and after treatment,depth of treatment could be determined using a Acuson Sequioa 512 phase-array system in paired experiments.Results PpⅨ accumulation increased with increasing extracellular concentrations of ALA (0-1mmol/L). Adding 1mmol/L of CaNa_2EDTA increased 30% PpⅨ accumulation over the same period of incubation in the concentration of 1mmol/L ALA. Significant difference was observed between the 5-ALA alone group and 5-ALA combined CaNa_2 EDTA group in the PpⅨ accumulation ( P <0.01). Cell viability after exposure to light decreased with adding CaNa_2 EDTA,a statistical difference in a same fluence above 1.2 J/cm 2 between two groups was demonstrated ( P <0.05,P <0.01 respectively). Depth of treatment of skin cancers were increased in CaNa_2 EDTA-treated group.conclusion CaNa_2 EDTA could improve the PpⅨ accumulation and photosensitisation in HEp-2 cells. Clinically,CaNa_2 EDTA could increase the depth of treatment in the cutaneous cancers.