Advancing glioblastoma treatment through iron metabolism: A focus on TfR1 and Ferroptosis innovations.

Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach.

Iron chelation mitigates mitochondrial dysfunction and oxidative stress by enhancing nrf2-mediated antioxidant responses in the renal cortex of a murine model of type 2 diabetes.

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.

Can iron chelators ameliorate viral infections?

The redox reactivity of iron is a double-edged sword for cell functions, being either essential or harmful depending on metal concentration and location. Deregulation of iron homeostasis is associated with several clinical conditions, including viral infections. Clinical studies as well as in silico, in vitro and in vivo models show direct effects of several viruses on iron levels. There is support for the strategy of iron chelation as an alternative therapy to inhibit infection and/or viral replication, on the rationale that iron is required for the synthesis of some viral proteins and genes. In addition, abnormal iron levels can affect signaling immune response. However, other studies report different effects of viral infections on iron homeostasis, depending on the class and genotype of the virus, therefore making it difficult to predict whether iron chelation would have any benefit. This review brings general aspects of the relationship between iron homeostasis and the nonspecific immune response to viral infections, along with its relevance to the progress or inhibition of the inflammatory process, in order to elucidate situations in which the use of iron chelators could be efficient as antivirals.

In vitro effect of the iron chelator deferiprone on the antimicrobial susceptibility and biofilms of Burkholderia pseudomallei.

This study evaluated the effect of the iron chelator deferiprone (DFP) on antimicrobial susceptibility and biofilm formation and maintenance by Burkholderia pseudomallei. Planktonic susceptibility to DFP alone and in combination with antibiotics was evaluated by broth microdilution and biofilm metabolic activity was determined with resazurin. DFP minimum inhibitory concentration (MIC) range was 4-64 µg/mL and in combination reduced the MIC for amoxicillin/clavulanate and meropenem. DFP reduced the biomass of biofilms by 21 and 12% at MIC and MIC/2, respectively. As for mature biofilms, DFP reduced the biomass by 47%, 59%, 52% and 30% at 512, 256, 128 and 64 µg/mL, respectively, but did not affect B. pseudomallei biofilm viability nor increased biofilm susceptibility to amoxicillin/clavulanate, meropenem and doxycycline. DFP inhibits planktonic growth and potentiates the effect of ß-lactams against B. pseudomallei in the planktonic state and reduces biofilm formation and the biomass of B. pseudomallei biofilms.

Analysis of Renal Cell Carcinoma Cell Response to the Enhancement of 5-aminolevulinic Acid-mediated Protoporphyrin IX Fluorescence by Iron Chelator Deferoxamine†.

As a tumor photodiagnostic agent, 5-aminolevulinic acid (ALA) is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) with fluorescence. ALA-PpIX fluorescence was evaluated in human renal cell carcinoma (RCC) cell lines and non-tumor HK-2 cell lines. We found that extracellular PpIX level was correlated with ABCG2 activity, illustrating its importance as a PpIX efflux transporter. Extracellular PpIX was also related to the Km of ferrochelatase (FECH) that chelates PpIX with ferrous iron to form heme. The Vmax of FECH was higher in all RCC cell lines tested than in the HK-2 cell line. TCGA dataset analysis indicates a positive correlation between FECH expression and RCC patient survival. These findings suggest FECH as an important biomarker in RCC. Effects of iron chelator deferoxamine (DFO) on the enhancement of PpIX fluorescence were assessed. DFO increased intracellular PpIX in both tumor and non-tumor cells, resulting in no gain in tumor/non-tumor fluorescence ratios. DFO appeared to increase ALA-PpIX more at 1-h than at 4-h treatment. There was an inverse correlation between ALA-PpIX fluorescence and the enhancement effect of DFO. These results suggest that enhancement of ALA-PpIX by DFO may be limited by the availability of ferrous iron in mitochondria following ALA administration.

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Intracellular Iron Binding and Antioxidant Activity of Phytochelators.

Phytochelators have been studied as templates for designing new drugs for chelation therapy. This work evaluated key chemical and biological properties of five candidate phytochelators for iron overload diseases: maltol, mimosine, morin, tropolone, and esculetin. Intra- and extracellular iron affinity and antioxidant activity, as well as the ability to scavenge iron from holo-transferrin, were studied in physiologically relevant settings. Tropolone and mimosine (and, to a lesser extent, maltol) presented good binding capacity for iron, removing it from calcein, a high-affinity fluorescent probe. Tropolone and mimosine arrested iron-mediated oxidation of ascorbate with the same efficiency as the standard iron chelator DFO. Also, both were cell permeant and able to access labile pools of iron in HeLa and HepG2 cells. Mimosine was an effective antioxidant in cells stressed by iron and peroxide, being as efficient as the cell-permeant iron chelator deferiprone. These results reinforce the potential of those molecules, especially mimosine, as adjuvants in treatments for iron overload.

Study of anti-diabetic, beta-carotene-bleaching inhibiting and iron chelating properties of Carissa opaca root extracts

Abstract Degenerative diseases diabetes and oxidative stress constitute a major health concern worldwide. Medicinal plants are expected to provide effective and affordable remedies. The present research explored antidiabetic and antioxidant potential of extracts of Carissa opaca roots. Methanolic extract (ME) was prepared through maceration. Its fractions were obtained, sequentially, in hexane, chloroform, ethyl acetate and n-butanol. An aqueous decoction (AD) of the finely ground roots was obtained by boiling in distilled water. The leftover biomass with methanol was boiled in water to obtain biomass aqueous decoction (BAD). The extracts and fractions showed considerable porcine pancreatic α-amylase inhibitory activity with IC50 in the range of 5.38-7.12 mg/mL while acarbose had 0.31 mg/mL. The iron chelating activity in terms of EC50 was 0.2939, 0.3429, 0.1876, and 0.1099 mg/mL for AD, BAD, ME, and EDTA, respectively. The EC50 of beta-carotene bleaching activity for AD, BAD, ME, and standard BHA were 4.10, 4.71, 3.48, and 2.79 mg/mL, respectively. The total phenolic content (TPC) and total flavonoid content (TFC) of AD and BAD were also considerable. In general, ethyl acetate fraction proved to be the most potent. Thus, the C. opaca roots had excellent antioxidant activity while having moderate α-amylase inhibitory potentia

[Deferasirox and Complex Proximal Tubulopathy. Presentation of two clinical cases]. / Deferasirox y Tubulopatía Proximal Compleja. Presentación de dos casos clínicos.

INTRODUCTION: Treatment with iron chelators is essential for patients with iron overload secondary to repeated trans fusions. Deferasirox is the first once-daily oral active iron chelator. As a result, therapeutic adherence has improved, reducing the complications of iron overload, especially heart failure. However, it is not exempt from possible side effects, such as kidney involvement, which is more frequent in children. OBJECTIVE: To report 2 patients with Diamond-Blackfan anemia (DBA) who developed impaired renal function secondary to the administration of Deferasirox. CLINICAL CASES: Case 1. A 15-year-old adolescent diagnosed with DBA undergoing treatment with periodic transfusions and Deferasirox. During an acute gastroenteritis, she developed acute renal failure along with complex proximal tubu- lopathy. Case 2. A 5-year-old boy diagnosed with DBA receiving periodic transfusions and treatment with Deferasirox. He presented polyuria with laboratory abnormalities compatible with acute renal failure and proximal tubular dysfunction. In both cases, they were adequately hydrated and Deferasi rox was temporarily suspended, improving renal function. CONCLUSION: Based on these cases, close monitoring of renal and tubular function, as well as ferritin levels, is recommended in patients recei ving Deferasirox. In the presence of intercurrent processes, adequate hydration should be performed, and an early dose reduction or drug administration interruption should be considered in cases of kidney involvement.

The Labile Iron Pool Reacts Rapidly and Catalytically with Peroxynitrite.

While investigating peroxynitrite-dependent oxidation in murine RAW 264.7 macrophage cells, we observed that removal of the Labile Iron Pool (LIP) by chelation increases the intracellular oxidation of the fluorescent indicator H2DCF, so we concluded that the LIP reacts with peroxynitrite and decreases the yield of peroxynitrite-derived oxidants. This was a paradigm-shifting finding in LIP biochemistry and raised many questions. In this follow-up study, we address fundamental properties of the interaction between the LIP and peroxynitrite by using the same cellular model and fluorescence methodology. We have identified that the reaction between the LIP and peroxynitrite has catalytic characteristics, and we have estimated that the rate constant of the reaction is in the range of 106 to 107 M-1s-1. Together, these observations suggest that the LIP represents a constitutive peroxynitrite reductase system in RAW 264.7 cells.

Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of ß-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms.

FTIR analysis of pyrogallol and phytotoxicity-reductive effect against mercury chloride.

Human activities, especially in industry, have contributed to soil contamination with heavy or toxic metals. The objective of this study was to determine the chelating effect and antioxidant activity of pyrogallol, as well as to evaluate its cytoprotective activity in prokaryotic and eukaryotic models, animal and plant, respectively, against toxic mercury chloride action. Antioxidant activity was determined by DPPH where pyrogallol showed considerable action, chelating even iron ions. For the microbiologic activity assays, microdilution was performed to obtain the minimal inhibitory concentration, minimum bactericidal and minimum fungicide concentration, from which the sub-inhibitory concentrations were determined. The product did not conferred cytoprotection to the tested bacteria and fungi. To evaluate plant cytoprotection, Lactuta sativa seeds were used together with the product at a sub-allelopathic concentration with different HgCl2 concentrations. In this case, the tannin conferred cytoprotection to the plant model, allowing the best growth and development of caulicles and radicles, thus preserving tissues necessary for plant survival. From the results, it is observable that pyrogallol possesses cytoprotective action in the eukaryotic plant model, this action being useful as an alternative which favors the growth of plants in contaminated areas, as the recovering of crop fields or reforestation projects.

Biotechnological Potential of Streptomyces Siderophores as New Antibiotics.

BACKGROUND: Siderophores are small-molecule iron-chelators produced by microorganisms and plants growing mostly under low iron conditions. Siderophores allow iron capture and transport through cell membranes into the cytoplasm, where iron is released for use in biological processes. These bacterial iron uptake systems can be used for antibiotic conjugation or as targets for killing pathogenic bacteria. Siderophores have been explored recently because of their potential applications in environmental and therapeutic research. They are present in Streptomyces, Grampositive bacteria that are an important source for discovering new siderophores. OBJECTIVE: This review summarizes siderophore molecules produced by the genus Streptomyces emphasizing their potential as biotechnological producers and also illustrating genomic tools for discovering siderophores useful for treating bacterial infections. METHODS: The literature search was performed using PUBMED and MEDLINE databases with keywords siderophore, secondary metabolites, Trojan horse strategy, sideromycin and Streptomyces. The literature research focused on bibliographic databases including all siderophores identified in the genus Streptomyces. In addition, reference genomes of Streptomyces from GenBank were used to identify siderophore biosynthetic gene clusters by using the antiSMASH platform. RESULTS: This review has highlighted some of the many siderophore molecules produced by Streptomyces, illustrating the diversity of their chemical structures and a wide spectrum of bioactivities against pathogenic bacteria. Furthermore, the possibility of using siderophores conjugated with antibiotics could be an alternative to overcome bacterial resistance to drugs and could improve their therapeutic efficacy. CONCLUSION: This review confirms the importance of Streptomyces as a rich source of siderophores, and underlines their potential as antibacterial agents.

Elevated Iron Chelating Activity of Ilex paraguariensis Leaf Infusion: in vitro and in vivo Pilot Studies

Abstract This study presents an Ilex paraguariensis leaf infusion with important potential as natural iron-chelating. The impact of infusion time and the water volume to obtain an Ilex paraguariensis leaf infusion with high phenolic content and iron chelating activity, such as the stability of these proprieties in the storage time and temperature (immediately and after 24 h at 8 and 25 (C) were assessed. The acute consumption effect of this infusion to reduce iron absorption in vivo was also evaluated. A preliminary crossover trial with volunteers that ingested a meal containing non-haem iron (11.4 mg) with the treatments: Ilex paraguariensis leaf infusion with the highest phenolic content and iron chelating activity (200 mL) or control (200 mL water). Blood samples were withdrawn before and 1, 2, 3 and 4 h after the meal for serum iron measurement. The highest phenolic content (18.1 mg/mL) and iron chelating activity ((100%) were observed for 10 min infusion time using 30 g leaves/300 mL water. Storage at 8 or 25 (C for 24 h decreased total phenolics and di-caffeoylquinic acids by 23.5% and 25.5%, respectively (p< 0.05), without affecting the iron-chelating activity due to a saturating chelating effect at 3.34 mg/mL phenolic content. Inhibition of the iron absorption in vivo by infusion was 78% considering the iron recovery at peak maximum. The in vitro and preliminary in vivo results showed a functional property of the Ilex paraguariensis leaf infusion that may be useful for adjuvant management of iron overload diseases.

High throughput fluorimetric assessment of iron traffic and chelation in iron-overloaded Caenorhabditis elegans.

The nematode Caenorhabditis elegans (C. elegans) is a convenient tool to evaluate iron metabolism as it shares great orthology with human proteins involved in iron transport, in addition to being transparent and readily available. In this work, we describe how wild-type (N2) C. elegans nematodes in the first larval stage can be loaded with acetomethoxycalcein (CAL-AM) and study it as a whole-organism model for both iron speciation and chelator permeability of the labile iron pool (LIP). This model may be relevant for high throughput assessment of molecules intended for chelation therapy of iron overload diseases.

Inhibition of Fenton reaction is a novel mechanism to explain the therapeutic effect of intra-articular injection of PRP in patients with chronic haemophilic synovitis.

INTRODUCTION AND AIM: Haemarthroses cause major morbidity in haemophilia resulting in chronic haemophilic synovitis (CHS) and arthropathy. Oxidation of haemoglobin-coupled iron released in synovium after haemolysis induces chondrocytes death and cartilage damage, allowing postulate using iron-chelating drugs as potential therapeutic tool for haemophilic joint damage. Considering that albumin, the most abundant plasma protein, is a physiologic iron chelator, we aim to demonstrate that impediment of haemoglobin oxidation is exerted by plasma as a mechanism involved in the therapeutic effect of intra-articular injection of platelet-rich plasma in CHS. METHODS: Oxidation of haemoglobin (Hb) to methaemoglobin (MeHb) through Fenton reaction was induced in vitro by addition of potassium ferricyanide in the presence or absence of peripheral blood-derived platelets-rich or platelets-poor plasma (PRP/PPP) or albumin. The relevance of in vitro findings was analysed in synovial fluid (SF) samples from one patient with CHS obtained before and after 6 months of PRP intra-articular injection. RESULTS: MeHb formation was completely impaired either by of PPP, PRP or albumin indicating that PRP exerts an anti-oxidative effect, probably due by plasma albumin. Analysis of SF samples revealed the presence of MeHb levels and haemosiderin-laden macrophages in SF obtained before PRP treatment. Reduction of synovial MeHb, normalization of cellular composition and improvement of health joint haemophilic score, pain and bleeding episodes were registered after 6 months of PRP intra-articular injection. CONCLUSION: Inhibition of Fenton reaction and the consequent normalization of joint cellular composition is a noncanonical mechanism underlying the therapeutic effect of PRP intra-articular injection in CHS.

Treatment of iron overload syndrome: a general review.

INTRODUCTION: Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS: Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION: Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION: Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

Dietary iron chelate for sows and effects on iron supplementation in piglets.

In order to evaluate iron chelate in diets for sows during gestation and lactation and its effects on iron supplementation for piglets, a total of 50 pregnant sows in the third parity order were distributed according to a randomized block design with two treatments: diet without iron chelate supplementation (n=20); diet supplemented with 0.15% of iron chelate (n=30). The litters of sows were distributed into five different treatments: sows without iron chelate supplementation and piglets receiving intramuscular iron-dextran; sows without iron chelate supplementation and piglets receiving oral iron supplementation; sows supplemented with iron chelate and piglets receiving intramuscular iron-dextran; sows supplemented with iron chelate and piglets receiving oral iron supplementation; sows supplemented with iron chelate and piglets without iron supplementation. No influence of dietary supplementation of iron chelate was verified on the productive parameters of the sows. For the piglets, iron-dextran supplementation promoted higher weaning weight in comparison to non-supplemented piglets, although not differing to those received oral iron supplementation. Thus, iron chelate supplementation did not improve the productive parameters of sows, but it increased iron excretion in the feces, thus requiring iron supplementation for the piglets after birth.