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Thalassemia is an inherited genetic disorder of hemoglobin that affects a large population worldwide, and it is estimated that between 50,000 and 60,000 infants with thalassemia are born each year. The most common treatment for thalassemia is blood transfusion, which leads to iron overload. This in itself is a serious clinical condition, and is commonly managed with iron chelation therapy. However, iron chelators can cause various skin complications, including hyperpigmentation, skin rash, itching, and photosensitivity. These skin side effects can impact patients' quality of life. Therefore, this article provides a comprehensive overview of skin complications caused by iron chelators, along with a proposed comprehensive approach to their management in patients with beta-thalassemia. Key strategies include patient education, regular skin assessment, sun protection measures, symptomatic relief with topical corticosteroids and antihistamines, and consideration of treatment modification if severe complications occur. Collaboration between hematologists and dermatologists, along with psychological support and regular follow-up, is an essential component of this multidisciplinary approach. By implementing these strategies, healthcare providers can optimize skin care for patients with beta-thalassemia treated with iron chelators and improve their quality of life. [ABSTRACT FROM AUTHOR]

Abstract Purpose This study aimed to evaluate the knowledge, attitude, and practice toward iron chelating agents (ICAs) in Iranian thalassemia major patients. Methods A total of 101 patients with thalassemia major were involved in this cross-sectional survey. A deep medication review was done, and participants’ knowledge, attitude, and practice were evaluated by a validated instrument based on a 20-scoring system. Results Statistical analyses showed 52 patients (51.5%) had a poor knowledge level (scores 15). Seventy-seven (76.2%) patients have positive beliefs regarding the dependence of their current health status on taking iron chelators, and 63 (62.4%) believed that they would become very ill without taking medication. The results also showed that the mean practice score in patients who received deferoxamine was 5.81 ± 3.50; in the patients who received deferiprone and those who received deferasirox, the mean scores were 7.36 ± 5.15 and 14.94 ± 4.14. Also, the knowledge and practice level had a direct linear correlation based on the regression analyses (P

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.

Le bilan étiologique d'une hyperferritinémie comprend un examen clinique complet, dont la mesure du tour de taille, et des examens biologiques simples dont le coefficient de saturation de la transferrine. On classe ensuite facilement les hyperferritinémies sans surcharge en fer (inflammation, consommation excessive d'alcool, lyses cellulaires, mutation de la L-ferritine) ou avec surcharge en fer. La surcharge en fer la plus fréquente est l'hépatosidérose dysmétabolique, définie par une augmentation de la ferritine associée à divers critères du syndrome métabolique avec une charge en fer hépatique faible à modérée évaluée par IRM. Les saignées sont souvent mal tolérées et non indiquées. L'hémochromatose génétique de type 1 (mutation homozygote C282Y sur le gène HFE) est responsable d'une diminution de l'hepcidine et d'une augmentation de l'absorption intestinale du fer. Elle représente plus de 95 % des hémochromatoses, mais est d'expression très variable. On doit rechercher une fibrose hépatique par élastométrie lorsque la ferritine dépasse 1000 μg/L. Si les saignées sont débutées précocement, l'espérance de vie est normale. La maladie de la ferroportine, de transmission dominante, est responsable d'une surcharge en fer en général modérée. Les chélateurs du fer sont indiqués dans les surcharges avec anémie (syndromes myélodysplasiques ou thalassémies transfusion-dépendantes). La chélation est débutée lorsque la charge hépatique en fer est supérieure à 120 μmol/g en IRM. Le déférasirox est souvent utilisé en première intention, mais le défériprone peut être intéressant malgré une toxicité hématologique (neutropénie). Le déféroxamine (voie parentérale) est réservé aux surcharges sévères ou en urgence. Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000 μg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120 μmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. β-amyloid plaque (Aβ) deposition and hyperphosphorylated tau, as well as dysregulated energy metabolism in the brain, are key factors in the progression of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, which is closely correlated with the clinical symptoms of AD; therefore, understanding the role of brain iron accumulation in the major pathological aspects of AD is critical for its treatment. This review discusses the main mechanisms and recent advances in the involvement of iron in the above pathological processes, including in iron-induced oxidative stress-dependent and non-dependent directions, summarizes the hypothesis that the iron-induced dysregulation of energy metabolism may be an initiating factor for AD, based on the available evidence, and further discusses the therapeutic perspectives of targeting iron. [ABSTRACT FROM AUTHOR]

Adherence to iron chelation therapy (ICT) remains an issue among thalassemia patients. This study aimed to determine the prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia and the factors associated with it. This was a cross-sectional study conducted between November 2019 and November 2021 at seven tertiary hospitals in Malaysia. Participants registered with Malaysian Thalassemia Registry were recruited by convenience sampling. Adherence was measured via pill count and self-reported adherence. Knowledge about thalassemia and ICT was measured using a questionnaire from Modul Thalassemia by Ministry of Health of Malaysia. A decision tree was used to identify predictors of non-adherence. A total of 135 patients were recruited. The prevalence of non-adherence to ICT in those who took subcutaneous ± oral medications was 47.5% (95% CI: 31.5%, 63.9%) and the prevalence of non-adherence to ICT in those who took oral medications only was 21.1% (95% CI: 13.4%, 30.6%). The median knowledge score was 67.5% (IQR 15%). A decision tree has identified two factors associated with non-adherence. They were ICT's route of administration and knowledge score. Out of 100 patients who were on oral medications only, 79 were expected to adhere. Out of 100 patients who were on subcutaneous ± oral medications and scored less than 56.25% in knowledge questionnaire, 86 were expected to non-adhere. Based on the logistic regression, the odds of non-adherence in patients who took oral medications only was 71% lower than the odds of non-adherence in patients who took subcutaneous ± oral medications (OR = 0.29; 95% CI = 0.13, 0.65; p =.002). The prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia was 20/95 (21.1%) in those who took oral medications only and the prevalence of non-adherence was 19/40 (47.5%) in those who took subcutaneous ± oral medications. The factors associated with non-adherence were ICT's route of administration and knowledge score. [ABSTRACT FROM AUTHOR]

β-thalassemia, a congenital genetic hematological disorder characterized by the decrease or absence of β-globin chains, leads to a decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia also exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications that arise due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, the therapeutic efficacy of different iron chelators in managing iron overload complications is mentioned briefly, along with the guidelines for their usage in India. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia.

Rhabdomyosarcoma (RMS) is an aggressive rare neoplasm that derives from mesenchymal cells, which frequently develops resistance to the current therapies and the formation of metastases. Thus, new therapies are needed. The alteration of iron metabolism in cancer cells was effective in reducing the progression of many tumors but not yet investigated in RMS. Here we investigated the effect of iron modulation in RMS both in vitro and in vivo. We first characterized the most used RMS cell lines representing the most common subtypes, embryonal (ERMS, RD cells) and alveolar (ARMS, RH30 cells), for their iron metabolism, in basal condition and in response to its modulation. Then we investigated the effects of both iron overload and chelation strategies in vitro and in vivo. RMS cell lines expressed iron-related proteins, even if at lower levels compared to hepatic cell lines and they are correctly modulated in response to iron increase and deprivation. Interestingly, the treatment with different doses of ferric ammonium citrate (FAC, as iron source) and with deferiprone (DFP, as iron chelator), significantly affected the cell viability of RD and RH30. Moreover, iron supplementation (in the form of iron dextran) or iron chelation (in the form of DFP) were also effective in vivo in inhibiting the tumor mass growth both derived from RD and RH30 with iron chelation treatment the most effective one. All the data suggest that the iron modulation could be a promising approach to overcome the RMS tumor growth. The mechanism of action seems to involve the apoptotic cell death for both iron supplementation and chelation with the concomitant induction of ferroptosis in the case of iron supplementation. [ABSTRACT FROM AUTHOR]

Background and Aims: One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion‐dependent beta‐thalassemia. Methods: This descriptive cross‐sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta‐thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients. Results: Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5–74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low‐density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high‐density lipoprotein, body mass index, calcium, and EF levels. Conclusion: Improvement in beta‐thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow‐up and early complication detection. [ABSTRACT FROM AUTHOR]

β-thalassemia, a congenital genetic hematological disorder characterized by the decrease or absence of β-globin chains, leads to a decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia also exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications that arise due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, the therapeutic efficacy of different iron chelators in managing iron overload complications is mentioned briefly, along with the guidelines for their usage in India. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia. [ABSTRACT FROM AUTHOR]

Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients' outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion‐dependent beta‐thalassemia. Methods This descriptive cross‐sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta‐thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients. Results Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5–74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low‐density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high‐density lipoprotein, body mass index, calcium, and EF levels. Conclusion Improvement in beta‐thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow‐up and early complication detection.

Abstract Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients’ outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

Introduction and aim. The novel advancements of upcoming iron regulators used to treat diabetic nephropathy have implicated a common manifestation of combination chelation therapy used to eliminate end-stage renal disease associated with inflammation and iron imbalance that is altered by renal iron absorption. However, iron accumulation in the clustered kidneys that filter blood may cause problems that affect diabetic blood sugar regulation. Material and methods. A well-designed method was employed to discover relevant research publications on iron chelators and their potential to treat diabetic nephropathy. "Iron chelators", "diabetic nephropathy", "end-stage renal disease", and "chelation therapy" were searched in Google Scholar, Web of Science, PubMed, and EMBASE. Analysis of literature. Although the specific etiology and development have not been fully explored, emerging evidence on iron pathophysiology helps comprehend the pathogenesis of acute kidney damage and chronic kidney disease, which crucially provides novel iron chelation therapy techniques. Ferroptosis and hepcidin marker proteins increase oxidative/nitrifying stress and kidney injury. Iron chelator medicines including deferoxamine, deferasirox, and deferiprone were tested as prophylactic strategies. Conclusion. This article covers both preclinical and clinical aspects of iron chelators to avoid diabetic nephropathy, including novel iron therapies that must be reviewed when selecting dosing regimens. [ABSTRACT FROM AUTHOR]

Background: Disturbances induced by chelating agents in the essential metal ions, including zinc and copper, can adversely impact the health of patients with transfusion-dependent thalassemia (TDT). Objectives: The aim of this study was to investigate the effect of different iron chelators on the levels of zinc and copper among patients with TDT. Materials and Methods: This case-control study involved 94 patients with TDT and 59 healthy controls, their ages ranged from 5 to 37 years. Patients with TDT were subdivided into two groups: 51 patients were on deferasirox and 43 were on deferoxamine. Blood samples were collected from all participants for complete blood counts and serum ferritin, iron, zinc, and copper levels, which were determined by spectrophotometry. Results: Serum iron, ferritin, and zinc levels were significantly higher among patients with TDT, while the Hb level was significantly lower than that in the healthy population (P < 0.05). Serum copper levels did not differ significantly between the groups. A high frequency of zinc deficiency was reported among patients with TDT on deferasirox (56.9%) and control group (47.5%), compared to 16.3% for patients with TDT on deferoxamine (P < 0.001). For serum copper, most of them had normal levels (81.4%–90.2%). Patients on deferoxamine had significantly higher serum zinc and copper levels than those on deferasirox and control group, although the mean serum values were within the normal range of values for the three groups (P < 0.01). Conclusions: Low serum zinc was reported in a considerable percentage of patients with TDT receiving deferasirox compared to those receiving deferoxamine, while serum copper was within normal range in the majority of patients with TDT.

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 develops 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 chelators, 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.

Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I – Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II – Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response – the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III – Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in 'cytokine storm', ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19. [ABSTRACT FROM AUTHOR]

Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons. Moreover, the role of calcium (Ca2+) signaling in ferroptosis remains elusive. Here, we report that RSL3, a selective inhibitor of GPX4, caused dendritic damage, lipid peroxidation, and induced cell death in rat primary hippocampal neurons. Previous incubation with the ferroptosis inhibitors deferoxamine or ferrostatin-1 reduced these effects. Likewise, preincubation with micromolar concentrations of ryanodine, which prevent Ca2+ release mediated by Ryanodine Receptor (RyR) channels, partially protected against RSL3-induced cell death. Incubation with RSL3 for 24 h suppressed the cytoplasmic Ca2+ concentration increase induced by the RyR agonist caffeine or by the SERCA inhibitor thapsigargin and reduced hippocampal RyR2 protein content. The present results add to the current understanding of ferroptosis-induced neuronal cell death in the hippocampus and provide new information both on the role of RyR-mediated Ca2+ signals on this process and on the effects of GPX4 inhibition on endoplasmic reticulum calcium content. [ABSTRACT FROM AUTHOR]

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades. [ABSTRACT FROM AUTHOR]

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, which inhibit the final step of heme biosynthesis, thereby increasing the protoporphyrin IX concentration. In the presented work, we studied thiosemicarbazone derivative, which is a universal enhancer of the phototoxic effect. We examined several genes that are involved in the transport of the heme substrates and heme itself. The results indicate that despite an elevated level of ABCG2, which is responsible for the PpIX efflux, its concentration in a cell is sufficient to trigger a photodynamic reaction. This effect was not observed for 5-ALA alone. The analyzed cell lines differed in the scale of the effect and a correlation with the PpIX accumulation was observed. Additionally, an increased activation of the iron transporter MFNR1 was also detected, which indicated that the regulation of iron transport is essential in PDT. [ABSTRACT FROM AUTHOR]

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated. [Display omitted] • Mitophagy participate in maintaining mitochondrial and cellular functionality. • Mitophagy dysregulation is deeply associated with serious pathogenesis. • Iron homeostasis and mitophagy regulation are deeply interconnected. • Decrease in free cellular/mitochondrial iron level can induce mitophagy. • Mitophagy normalization is one of the therapeutic effects of iron chelators. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common type of cancer in the world. It is characterized by complex crosstalk between various signaling pathways, as a result of which it is highly challenging to identify optimal therapeutic targets and design treatment strategies. In this study, we tested the effect of 700 compounds on the CRC cell line HT-29 by using the sulforhodamine B assay and screened out 17 compounds that exhibited high toxicity (indicated by an inhibition rate of ≥75 % when applied at a concentration of 10 µM) against the HT-29 cell line. Next, we investigated the mechanisms underlying the effects of these 17 highly toxic compounds. The results of ferroptosis analysis and electron microscopy showed that compounds 575 and 578 were able to significantly reverse RSL3-induced increase in ferroptosis, while compound 580 had a less pronounced ferroptosis-regulating effect. In subsequent experiments, western blotting showed that compounds 575, 578, and 580, which belong to a class of meroterpene-like compounds that affect ferroptosis, do not induce autophagy or apoptosis in the CRC cell line. Instead, Fe2+ chelation experiments showed that these three compounds can serve as iron chelators by chelating Fe2+ at a 1:1 (chelator: Fe2+) ratio. Specifically, the aldehyde and hydroxyl groups of the benzene ring in these compounds may chelate Fe2+, thus reducing Fe2+ levels in cells and inhibiting ferroptosis. These results indicate that these novel meroterpene-like compounds are potential therapeutic small-molecule candidates for targeting ferroptosis in tumors. [Display omitted] • Novel meroterpene-like compounds had no effect on apoptosis autophagy. • Novel meroterpene-like compounds rescue ferroptosis via Fe2+ chelation. • Novel meroterpene-like compounds be a valuable candidate for the anti-cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

Ferritinophagy is one of the most recent molecular mechanisms affecting cardiac function. In addition, it is one of the pathways by which doxorubicin, one of the anticancer drugs commonly used, negatively impacts the cardiac muscle, leading to cardiac function impairment. This side effect limits the use of doxorubicin. Iron chelators play an important role in hindering ferritinophagy. Antioxidants can also impact ferritinophagy by improving oxidative stress. In this study, it was assumed that the antioxidant function of melatonin could promote the action of deferoxamine, an iron chelator, at the level of ferritinophagy. A total of 42 male Wistar rats (150–200 g) were divided into seven groups (n = 6) which consisted of group I: control normal, group II: doxorubicin (Dox), group III: melatonin (Mel), group IV: deferoxamine (Des), group V: Mel + Dox, group VI: Des + Dox, and group VII: Mel + Des + Dox. Groups III, V and VII were orally pretreated with melatonin 20 mg/kg/day for 7 days. Groups IV, VI and VII were treated with deferoxamine at a 250 mg/kg/dose once on D4 before Dox was given. Doxorubicin was given at a 20 mg/kg ip single dose. On the 8th day, the rats were lightly anaesthetized for electrocardiography analysis and echocardiography. Serum samples were collected and then sacrificed for tissue sampling. The following biochemical assessments were carried out: PCR of NCOA4, IREB2, FTH1, SLC7A11, and GPX4; and ELISA for serum cTnI, serum transferrin, tissue GSH, and malondialdehyde. In addition, histopathological assessment of heart injury; immunostaining of caspase-3, Bax, and Bcl2; and physiological function assessment by ECG and ECHO were carried out. Doxorubicin-induced acute significant cardiac injury with increased ferritinophagy and apoptosis responded to single and combined prophylactic treatment, in which the combined treatment showed mostly the best results. In conclusion, using melatonin as an antioxidant with an iron chelator, deferoxamine, could hinder the hazardous cardiotoxic effect of doxorubicin. However, further studies are needed to detect the impact of higher doses of melatonin and deferoxamine with a prolonged treatment period.

Iron overload results in lipid peroxidation (LPO) and the oxidative modification of circulating lipoproteins, which contributes to cardiovascular complications in patients with β-thalassemia. Investigating LPO may provide opportunities for the development of novel therapeutic strategies; however, the chemical pathways underlying iron overload-induced LPO in β-thalassemia lipoproteins remain unclear. In this study, we identified various species of lipid radicals (L • ), the key mediators of LPO, and oxidized cholesteryl esters (oxCE) derived from the in vitro oxidation of major core lipids, cholesteryl linoleate (CE18:2) and cholesteryl arachidonate (CE20:4); the levels of these radical products in low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were measured and compared between β-thalassemia patients and healthy subjects by using a specific fluorescent probe for L • with a liquid chromatography-tandem mass spectrometric method. Our results demonstrated that iron overload substantially decreased the levels of CE18:2 and CE20:4 substrates and α-tocopherol, resulting in higher levels of full-length and short-chain truncated L • and oxCE products. In particular, CE epoxyallyl radicals ( • CE-O) were observed in the lipoproteins of β-thalassemia, revealing the pathological roles of iron overload in the progression of LPO. In addition, we found that intermission for two weeks of iron chelators can increase the production of these oxidized products; therefore, suggesting the beneficial effects of iron chelators in preventing LPO progression. In conclusion, our findings partly revealed the primary chemical pathway by which the LPO of circulating lipoproteins is influenced by iron overload and affected by iron chelation therapy. Moreover, we found that • CE + O shows potential as a sensitive biomarker for monitoring LPO in individuals with β-thalassemia., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Excessive iron accumulation in the brain plays a significant role in neurodegenerative processes, contributing to the pathogenesis of Alzheimer's disease (AD). AD, a prominent neurological disorder affecting the central nervous system, is characterized by the accumulation of beta-amyloid (Aβ) and tau phosphorylation. This accumulation leads to the subsequent development of cognitive impairments, particularly in learning and memory functions. This study investigates the neuroprotective effects of emoxypine succinate in a zebrafish model of iron overload-induced neurodegeneration. Iron was administered to the zebrafish for 28 days to induce neurodegeneration. Following induction, Emoxypine succinate was employed as a treatment intervention for 14 days (concentrations of 4 mg/L, 8 mg/L, and 12 mg/L). Following the end of the treatment, behavioral tests (Y maze test, Novel tank test) were conducted on the zebrafish, and the biochemical (MDA, Catalase, SOD, GSH) and molecular parameters (AchE, Iron levels, IL-1β, TNF-α, CDK-5, GSK-3β, and NLRP3) of the zebrafish brain were also assessed. In the novel tank test, emoxypine succinate-treated groups exhibited significantly increased time in the upper zone (p < 0.001), higher distance travelled (p < 0.001), and shorter latency to the top (p < 0.001) compared to the negative control. Similarly, the Y-maze test revealed improved time in the novel arm (p < 0.001) and total distance travelled (p < 0.001) in treated groups versus the negative control. Assessment of oxidative stress parameters demonstrated significant reductions in oxidative stress in emoxypine succinate-treated groups. Furthermore, AChE activity decreased significantly (p < 0.001), and brain iron levels decreased substantially (p < 0.001) in treated groups, indicating positive therapeutic outcomes. Molecular analysis showed a significant reduction in pro-inflammatory markers like IL-1β, TNF-α, CDK-5, GSK-3β, and NLRP3 (p < 0.001). This comprehensive study highlights the potential efficacy of emoxypine succinate in mitigating neurodegeneration associated with iron dysregulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: When deferasirox is used in iron chelation therapy, maculopapular rash occurs in 10% of patients, but there is no accepted and implemented protocol for the management of these drug reactions in adults., Case Report: A 23-year-old woman diagnosed with thalassemia major is presented. She had taken 1,500 mg oral deferasirox for 1 week. Five hours after the last dose, a pruritic maculopapular rash developed on the body, face, and hands. The rash spread to the whole body within 3 days. The absolute necessity for the patient to take the drug was clarified by the hematology department. The patient's history was evaluated. A delayed-type hypersensitivity reaction due to deferasirox was considered., Management: The slow desensitization protocol described in the literature and applied on a case-by-case basis in pediatric patients was modified to shorten the duration by determining appropriate doses for the current preparation. The desensitization process was started with 1/100,000 of the total dose and the therapeutic dose was reached with a 2- to 2.5-fold increase in dose. No pre-medication was applied. During the procedure, at a low dose of 0.1 mg, local flushing and erythema was observed around the auricle on the face. The reaction did not progress., Conclusion: Slow desensitization protocol for oral deferasirox was successfully applied in an adult patient., Competing Interests: The authors acknowledge that they do not have any conflict of interest regarding the study. Table 1.Deferasirox slow desensitization protocols. Bruner et al. [4] protocolOur protocolTime intervals (days)Dose (mg)Dose (mg)Dose (mL)30.050.05Solution Ba 0.5 mL40.10.1Solution B 1 mL30.20.2Solution B 2 mL40.50.5Solution B 5 mL311Solution Ab 1 mL422Solution A 2 mL345Solution A 5 mL4810Solution A 10 mL31620Solution A 20 mL43240Solution A 40 mL36480Solution A 80 mL4125150Solution A 150 mL32502501 tablet45005002 tablets77507503 tablets71,0001,5006 tablets71,500 aA suspension was made by 1 : 10 dilution of solution A to a final concentration of 0.1 mg/mL (solution B); bA suspension was prepared by dissolving 1 tablet of deferasirox (250 mg) into a volume of 250 mL of water to a final concentration of 1 mg/mL (solution A)., (© Dustri-Verlag Dr. K. Feistle.)

Background: Iron chelators; deferasirox, deferiprone, and deferoxamine; used to treat iron toxicities due to excessive ingestions or blood transfusions, may cause serious adverse reactions., Research Design and Methods: This study investigates pharmacovigilance data to uncover unknown safety information. Disproportionality analysis was conducted using VigiBase, the WHO global database of individual case safety reports, to known safety profile of products and the FDA Adverse Event Reporting System, reviewing over 117.000 iron chelator cases between 2010 and 2020., Results: Commonly reported adverse events for iron chelators are general disorders and administration site conditions and GI-related disorders. Reporting Odds Ratio was calculated for iron chelator associations to headache (common), blurred vision (rare) and sepsis (serious). Strong association between deferoxamine and blurred vision (ROR: 2.47 in VigiBase and 3.04 in FAERS), deferiprone and sepsis (ROR; 5.95 in VigiBase and 1.24 in FAERS) were identified. However, results showed some inconsistent associations, such as headache and deferiprone, blurred vision and deferasirox association as per FAERS data; sepsis and deferasirox and deferoxamine association as per VigiBase data. Forty-five new potential signals with different associative values were suggested., Conclusion: The study identified strong associations between specific iron chelators and adverse events, though some inconsistencies were observed in the data. These findings, including the 45 new potential signals, suggest areas for further review and validation with additional data.

NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa. [ABSTRACT FROM AUTHOR]

Hydroxypyridinones (HOPOs) are excellent class of chelators that have been gaining attention in the field of pharmaceutical drugs by their high chelating efficacy and specificity with different metal ions. Among all the metal ions, they exhibit a high binding affinity towards iron (III) and are clinically used as iron chelators nowadays. The HOPO family has different isomers, out of which 3,4-HOPO possesses applicability for designing drugs. The effect of methyl substitution on different positions of pyridinone ring also plays an essential role in deciding the pM values, thus describing the metal affinity. Several metal ions like Fe, Al, Cu, Zn, and some actinides are found to exhibit good chelation efficacy with HOPOs. In terms of denticity, there are various forms of HOPO. Among these, discussion on bidentate, tetradentate, hexadentate, octadentate, and dendrimers will be done here. This review systematically summarizes the various literature reports on the design and pharmacological activities of the newly developed HOPOs and their derivatives, including antibiotics, anticancer, and antineurodegeneratives. [ABSTRACT FROM AUTHOR]

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment. [ABSTRACT FROM AUTHOR]

Siderophores are structurally unique medicinal natural products and exhibit considerable therapeutic potential. Herein, we report the design and synthesis of azotochelin, a natural siderophore, and an extensive library of azotochelin analogs and their anticancer properties. We modified the carboxylic acid and the aromatic ring of azotochelin using various chemical motifs. We evaluated the cytotoxicity of the compounds against six different cancer cell lines (KB-3-1, SNB-19, MCF-7, K-562, SW-620, and NCI-H460) and a non-cancerous cell line (HEK-293). Among the twenty compounds tested, the IC 50 values of nine compounds (14, 32, 35-40, and 54) were between 0.7 and 2.0 μM against a lung cancer cell line (NCI-H460). Moreover, several compounds showed good cytotoxicity profile (IC 50 <10 μM) against the tested cancer cell lines. The flow cytometry analysis showed that compounds 36 and 38 induced apoptosis in NCI-H460 in a dose-dependent manner. The cell cycle analysis indicated that compounds 36 and 38 significantly arrested the cell cycle at the S phase to block cancer cell proliferation in the NCI-H460 cell line. The study has produced various novel azotochelin analogs that are potentially effective anticancer agents and lead compounds for further synthetic and medicinal chemistry exploration., (© 2024 Wiley-VCH GmbH.)

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, which inhibit the final step of heme biosynthesis, thereby increasing the protoporphyrin IX concentration. In the presented work, we studied thiosemicarbazone derivative, which is a universal enhancer of the phototoxic effect. We examined several genes that are involved in the transport of the heme substrates and heme itself. The results indicate that despite an elevated level of ABCG2, which is responsible for the PpIX efflux, its concentration in a cell is sufficient to trigger a photodynamic reaction. This effect was not observed for 5-ALA alone. The analyzed cell lines differed in the scale of the effect and a correlation with the PpIX accumulation was observed. Additionally, an increased activation of the iron transporter MFNR1 was also detected, which indicated that the regulation of iron transport is essential in PDT.

Ferroptosis is a newly discovered cell death form originates from iron-dependent lipid peroxide accumulation, which differs from traditional apoptosis and necrosis. This is characterized by cytological changes including cell death, shrinkage of cell volume and increased mitochondrial membrane density. Morphologically, mitochondrial membrane condensation, impairment or destruction of the mitochondria crista, and mitochondrial membrane rupture, and smaller mitochondria than normal mitochondria can be seen. Ferroptosis can be induced by class of two small molecule substances known as class 1 and class 2 ferroptosis inducers. In addition to these substances, it can also be induced by drugs such as Sorafenib and artemisine derivative. In cancer cells and some normal cells, such as renal tubule cells, it can be triggered by these drugs and class 1 and 2 ferroptosis inducers. Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, increased endoplasmic reticulum stress, and inhibition of the cystine-glutamate delivery system have been implicated in the induction of ferroptosis. This process is caused by the accumulation of lipid peroxidation products and reactive oxygen species (ROS) derived from iron metabolism. Ferroptosis may be inhibited by iron chelators (eg, Deferoxamine) and lipid peroxidation inhibitors (eg, Ferrostatin). Ferroptosis plays an undeniable role in the proliferation of some tumor cells such as lymphocytoma, pancreatic ductal cell cancer, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Ferroptosis was first described in 2012 as an iron- and lipid peroxidation-dependent form of regulated cell death. Since its initial description, these two characteristics have informed numerous cell culture studies where inhibitors of lipid peroxidation and/or iron chelators have been shown to prevent cell death induced by a wide range of insults. However, it is not clear whether these two characteristics are sufficient to distinguish ferroptosis from other forms of regulated cell death. Thus, the primary goal of this study was to determine whether a unique combination of features could be identified that would provide an approach to more clearly separate ferroptosis from other forms of regulated cell death. To this end, multiple pharmacological inhibitors based on a variety of studies were tested. Many of these inhibitors were previously shown to protect cells from oxytosis, a regulated cell death pathway that mechanistically overlaps with ferroptosis and is induced by some of the same chemicals as ferroptosis. These inhibitors were not only tested against both known ferroptosis and oxytosis inducers but also a number of other insults that have been suggested to induce ferroptosis. The results show that a pharmacological fingerprint for ferroptosis can be established and used to categorize toxic insults into those that overlap with oxytosis/ferroptosis and those that do not. [Display omitted] • Identification of a set of inhibitors that protect from multiple, well characterized inducers of oxytosis/ferroptosis. • Demonstration that most of these inhibitors do not protect from other inducers of oxidative stress-mediated cell death. • Protection from cell death by iron chelators and radical trapping antioxidants is not specific to oxytosis/ferroptosis. • Inhibitor fingerprint is applicable to several distinct cell types and a non-canonical inducer of oxytosis/ferroptosis. [ABSTRACT FROM AUTHOR]

Iron is an essential trace element in the metabolism of almost all living organisms. Iron overload can disrupt bone homeostasis by significant inhibition of osteogenic differentiation and stimulation of osteoclastogenesis, consequently leading to osteoporosis. Iron accumulation is also involved in the osteoporosis induced by multiple factors, such as estrogen deficiency, ionizing radiation, and mechanical unloading. Iron chelators are first developed for treating iron overloaded disorders. However, growing evidence suggests that iron chelators can be potentially used for the treatment of bone loss. In this review, we focus on the therapeutic effects of iron chelators on bone loss. Iron chelators have therapeutic effects not only on iron overload induced osteoporosis, but also on osteoporosis induced by estrogen deficiency, ionizing radiation, and mechanical unloading, and in Alzheimer’s disease-associated osteoporotic deficits. Iron chelators differently affect the cellular behaviors of bone cells. For osteoblast lineage cells (bone mesenchymal stem cells and osteoblasts), iron chelation stimulates osteogenic differentiation. Conversely, iron chelation significantly inhibits osteoclast differentiation. These different responses may be associated with the different needs of iron during differentiation. Fibroblast growth factor 23, angiogenesis, and antioxidant capability are also involved in the osteoprotective effects of iron chelators.

Mucormycosis is an acute fungal infection with 90% of cases in the form of rhino-orbito-cerebellar. It is an aggressive and life-threatening fungal infection causing 50% mortality in people with coronavirus disease 2019 (COVID-19). In COVID-infected patients due to, diabetic ketoacidosis, epithelial damage, ciliary dysfunction, dysfunctional phagocytic mechanism, and immunosuppression, there is impaired chemotaxis and defective intracellular killing leads to fungal spores to invade, germinate and penetrate in surrounding tissues. The use of broad-spectrum antibiotics disrupts the normal microbiomes and increases the probability of growth of Rhizopus spp. Commercially available probiotics such as Lactobacillus, Bifidobacterium, Enterococcus, Streptococcus, and Saccharomyces when administered in adequate quantities form siderophores which induces iron stress in fungus and inhibits spore germination. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to assess ocular changes in β-thalassemia major patients who have received multiple transfusions and different chelating agents. Patients and methods: A cross-sectional study of 90 β-thalassemia major patients from age group 14 to 24 years were selected as case group, and 90 age-matched and sex-matched healthy participants were considered as a control group. Full medical history and thorough physical examinations were done to all patient groups. Ocular examination, including visual acuity, refraction testing, slit-lamp examination, funduscopy, tonometry, perimetry, tear-breakup time test, and color-vision testing, was performed for all the participants. We computed the frequency and duration of blood transfusion, the mean serum ferritin level, pretransfusion hemoglobin concentration, the type, duration, and daily dose of chelation therapy for thalassemia patients based on their records. Results: All thalassemic patients were asymptomatic, but abnormal ocular findings [dry eye (13.3%), cataract (10%), retinal changes (16.7%), color-vision deficiency (3.33%), ocular hypertension (6.67%), and visual acuity (8.88%)] were seen in 58.9% of thalassemic group. The prevalence of ocular abnormalities in the control group was 19.4%, which was significantly lower than that in thalassemia patients (P=0.000). No significant correlation was found between ocular abnormalities and mean serum ferritin level (P=0.627) and mean hemoglobin concentration (P=0.143). A positive correlation between the number of blood transfusions with the presence of ocular abnormalities was found to be statistically significant (P=0.005). Recommendations: As life expectancy for β-thalassemia patients extends, regular ophthalmologic evaluation to detect early changes in their ocular system is recommended. [ABSTRACT FROM AUTHOR]

Deferoxamine mesylate (DFO) is administered as a slow subcutaneous or intravenous infusion due to its poor oral bioavailability and lack of dose proportionality. The aim of the present study was to prepare and optimize polymeric micelles containing DFO, as an oral drug delivery system for increasing permeability and oral bioavailability. Based on a full factorial design with three variables in two levels, eight polymeric micelle formulations were made using film hydration method. Two polymers including 0.1% of carbomer 934 and Poloxamer® P 407 and two blends of surfactant + co-surfactant including 1 and 2 fold of critical micelle concentration of Labrafil® + Labrasol® and Tween 80 + Span 20 were used to prepare polymeric micelles. The effect of variables on particle size (PS), entrapment efficiency (EE), drug release, thermal behavior, in vitro iron bonding and ex vivo rat intestinal permeability were evaluated. The PS of polymeric micelles was less than 83 nm that showed 80% EE with continuous drug release pattern. The change in type of polymer from carbomer to Ploxamer® significantly increased drug release. All polymeric micelles increased the iron-bonding ability of DFO compared to control. This could be due to surfactants that can play an important role in this ability. Polymeric micelles increased drug permeability through intestine more than 2.5 folds compared to control mainly affected by polymer type. Optimized polymeric micelle consists of Tween 80 and Span 20 with 1.35 folds of critical micelle concentration and Poloxamer® demonstrated 97.32% iron bonding and a 3-fold increase in permeation through the rat intestine compared with control.

NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa.

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).