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Considering the dramatic health and economic period that the world experienced during the COVID-19 pandemic, finding new drugs for the treatment of this disease is still a great scientific concern. Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide) is an important selective antiviral against RNA-based viruses, like SARS‐CoV‐2 virus causing COVID-19 disease, and has recently attracted considerable interest. The behavior of Favipiravir in various solvents including water, methanol, ethanol, isopropanol, methyl tert-butyl ether (MTBE), and dimethyl sulfoxide (DMSO) was investigated. A novel iron (III) complex compound derived from FAV as the ligand was synthesized. Subsequently, the newly synthesized complex was subjected to various analytical and spectroscopic techniques, including UV and infrared spectroscopy, mass spectrometry, stoichiometry analysis using the molar ratio method, and thermogravimetric analysis (TG–DTA). It was observed that the keto/enolic equilibrium of favipiravir is influenced by the choice of diluent, with the enol tautomer being the predominant form. Further analysis revealed that the isolated metal complex exhibits a tetrahedral geometry. The complexation reaction is more favorable in a protic medium than in an aprotic one, primarily due to the easier deprotonation in protic environments. Additionally, the molecular structures of the free ligand and its metal complex compound were optimized using density functional theory (DFT) simulations. This study offers valuable insights into the quantum chemical properties related to the structure. The simulation indicates significant chemical stability and a pronounced electrophilic character of the iron complex. Overall, these findings contribute to a deeper understanding of the interaction dynamics and stability of favipiravir's metal complexes. [ABSTRACT FROM AUTHOR]

Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.Abbreviation: ANOVA: analysis of variance; APC: adenomatous polyposis coli; cAMP: cyclic adenosine monophosphate; CDX2: caudal type homeobox 2; CGAS: cyclic GMP-AMP synthase; CRC: colorectal cancer; DNA: deoxyribonucleic acid; DFP: deferiprone; DMEM: Dulbecco’s modified Eagle medium; DSS: dextran sodium sulfate; ERT2-Cre: Cre recombinase fused to a triple mutant form of the human estrogen receptor; EV: empty vector; GLB: glybenclamide/glyburide; H&E: hematoxylin and eosin; ICP-MS: inductively coupled plasma mass spectrometer; IL1B: interleukin 1 beta; kDa: kilodalton; MCU: mitochondrial calcium uniporter; MKI67: marker of proliferation Ki-67; mRNA: messenger ribonucleic acid; MTT: 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide; NLRP3: NLR family pyrin domain containing 3; OE: overexpression; PBS: phosphate-buffered saline; p-CREB: phosphorylated cAMP responsive element binding protein; PINK1: PTEN induced kinase 1; p-PRKAA/AMPK: phosphorylated protein kinase AMP-activated catalytic subunit alpha; qPCR: qualitative polymerase chain reaction; RNA-seq: ribonucleic acid sequencing; ROS: reactive oxygen species; sg: single guide; sh: short hairpin; SLC25A28: solute carrier family 25 member 28; SLC25A37/MFRN: solute carrier family 25 member 37; STING1: stimulator of interferon response cGAMP interactor 1; TP53/p53: tumor protein p53; TUBA: tubulin alpha; µL: microliter; µm: micrometer; µM: micromolar; mm: millimeter. [ABSTRACT FROM AUTHOR]

Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an "iron-phagy" nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment. Our research applied nanotechnology for constructing an autophagy-inhibition prodrug micelle (HTH)-based nano-delivery system (Dp44mT@HTH), for targeted and controlled release of Dp44mT (an iron chelator), in study of the iron chelation antitumor therapy. We advanced this "iron-phagy" strategy to induce irreversible mitochondrial impairments and toxic stacks via disrupting respiratory chain and inhibiting the autophagy-removal of impaired mitochondria, thus leading to tumor cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Patients with β-thalassemia major (TM) require lifelong blood transfusions, leading to iron overload, where active intervention is required. Aims and Objectives: The aim of the study was to evaluate real-world efficacy and safety of deferasirox (DFX) in TM patients at a tertiary care teaching hospital. Materials and Methods: A prospective observational study was conducted at thalassemia ward in a tertiary care teaching hospital in Gujarat for a period of 15 months from April 2021 to July 2022. A total of 100 patients were analyzed during the study period. Patient's demographic profile, laboratory investigation, and treatment details were analyzed using descriptive statistics. Statistical analysis was done through the statistical software GraphPad Prism 9.4.1 (681). Results: A total of 100 patients were included in the study. A serial significant decrease in median serum ferritin levels was observed in >13 years age group after initiation of DFX. A significant increase in the median dose of DFX was observed at 12 months in the age group of 2-≤13 years as compared to baseline (P < 0.05). Adverse reactions observed during the study were increased bilirubin level, increased alanine aminotransferase, and increased serum creatinine, rashes with itching, and arthralgia. Conclusion: A greater reduction in median serum ferritin levels was observed in the adult age group compared to pediatric patients. [ABSTRACT FROM AUTHOR]

A set of sesamol-derived acetamides was designed, synthesized, and evaluated against monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) for targeting neurodegenerative diseases. Most of the tested compounds showed inhibition activity at micromolar to nanomolar ranges. The 3,4-dichoro derivative (compound 19) was the most potent MAO-A inhibitor (IC50 = 0.053 ± 0.001 µM) while the 4-methyl analog (compound 16) emerged as a lead MAO-B inhibitor (IC50 = 0.019 ± 0.001 µM) compared to the reference inhibitors clorgyline (MAO-A IC50 = 0.096 ± 0.003 µM) and selegyline (MAO B IC50 = 0.021 ± 0.002 µM). Further, the 2,4-dichloro analog (compound 20) emerged as a potent dual MAO (MAO-A IC50 = 0.160 ± 0.009 µM, MAO-B IC50 = 0.071 ± 0.002 µM) and ChE (AChE IC50 = 2.611 ± 0.086 µM and BChE IC50 = 4.22 ± 0.162 µM) inhibitor. Moreover, molecular simulation studies revealed that H-bonding and hydrophobic interactions stabilize the virtual lead inhibitor-protein complex. Selected MAO-ChE inhibitors showed significant antioxidant and iron-chelation properties, suggesting their potential in treating neurological disorders characterized by impaired iron homeostasis. In summary, the structural modification attempted in the present study yielded a few nanomolar MAO (MAO-B) inhibitors and, thus, provided new insights into the linker requirements for dual MAO/ChE inhibitory properties. [ABSTRACT FROM AUTHOR]

This study employed a diverse approach to extract antioxidant peptides from red seaweed Palmaria palmata, recognized for its comparatively high protein content. Initially, an aqueous extraction of the entire seaweed was performed, followed by enzymatic hydrolysis of the solid residues prepared from the first step. The effects of three different pH levels (3, 6, and 9) during the aqueous extraction were also examined. Results indicated that the solid fraction from the sequential extraction process contained significantly higher levels of proteins and amino acids than other fractions (p < 0.05). Furthermore, the solid fractions (IC50 ranging from 2.29 to 8.15 mg.mL−1) demonstrated significantly greater free radical scavengers than the liquid fractions (IC50 ranging from 9.03 to 10.41 mg.mL−1 or not obtained at the highest concentration tested) at both stages of extraction (p < 0.05). Among the solid fractions, those produced fractions under alkaline conditions were less effective in radical scavenging than the produced fractions under acidic or neutral conditions. The fractions with most effective metal ion chelating activity were the solid fractions from the enzymatic stage, particularly at pH 3 (IC50 = 0.63 ± 0.04 mg.mL−1) and pH 6 (IC50 = 0.89 ± 0.07 mg.mL−1), which were significantly more effective than those from the initial extraction stage (p < 0.05). Despite no significant difference in the total phenolic content between these solid fractions and their corresponding liquid fractions (3.79 ± 0.05 vs. 3.48 ± 0.02 mg.mL−1 at pH 3 and 2.43 ± 0.22 vs. 2.51 ± 0.00 mg.mL−1 at pH 6) (p > 0.05), the observed antioxidant properties may be attributed to bioactive amino acids such as histidine, glutamic acid, aspartic acid, tyrosine, and methionine, either as free amino acids or within proteins and peptides. [ABSTRACT FROM AUTHOR]

Study Design: Pre‐clinical animal experiment. Objective: In this study, we investigated therapeutic effects of silibinin in a spinal cord injury (SCI) model. In SCI, loss of cells due to secondary damage mechanisms exceeds that caused by primary damage. Ferroptosis, which is iron‐dependent non‐apoptotic cell death, is shown to be influential in the pathogenesis of SCI. Methods: The study was conducted as an in vivo experiment using a total of 78 adult male/female Sprague Dawley rats. Groups were as follows: Sham, SCI, deferoxamine (DFO) treatment, and silibinin treatment. There were subgroups with follow‐up periods of 24 h, 72 h, and 6 weeks in all groups. Malondialdehyde (MDA), glutathione (GSH), and Fe2+ levels were measured by spectrophotometry. Glutathione peroxidase‐4 (GPX4), ferroportin (FPN), transferrin receptor (TfR1), and 4‐hydroxynonenal (4‐HNE)‐modified protein levels were assessed by Western blotting. Functional recovery was assessed using Basso–Beattie–Bresnahan test. Results: Silibinin achieved significant suppression in MDA and 4‐HNE levels compared to the SCI both in 72‐h and 6 weeks group (p < 0.05). GSH, GPX4, and FNP levels were found to be significantly higher in the silibinin 24 h, 72 h, and 6 weeks group compared to corresponding SCI groups (p < 0.05). Significant reduction in iron levels was observed in silibinin treated rats in 72 h and 6 weeks group (p < 0.05). Silibinin substantially suppressed TfR1 levels in 24 h and 72 h groups (p < 0.05). Significant difference among recovery capacities was observed as follows: Silibinin > DFO > SCI (p < 0.05). Conclusion: Impact of silibinin on iron metabolism and lipid peroxidation, both of which are features of ferroptosis, may contribute to therapeutic activity. Within this context, our findings posit silibinin as a potential therapeutic candidate possessing antiferroptotic properties in SCI model. Therapeutic agents capable of effectively and safely mitigating ferroptotic cell death hold the potential to be critical points of future clinical investigations. [ABSTRACT FROM AUTHOR]

As a nutraceutical, bovine lactoferrin (bLf), an iron-binding glycoprotein involved in innate immunity, is gaining elevated attention for its ability to exert pleiotropic functions and to be exceptionally tolerated even at high dosages. Some of bLf's activities, including its anti-inflammatory and antioxidant, are tightly linked to its ability to both chelate iron and enter inside the cell nucleus. Here, we present data about Valpalf®, a new formulation containing bLf, sodium citrate, and sodium bicarbonate at a molar ratio of 10−3. In the present study, Valpalf® exhibits superior iron-binding capacity, resistance to tryptic digestion, and a greater capacity to accumulate into the nucleus over time when compared to the native bLf alone. In agreement, Valpalf® effectively reduces interleukin(IL)-6 levels in lipopolysaccharide-stimulated macrophages and modulates the expression of antioxidant enzymes, such as superoxide dismutase 1 and 2, in phorbol-12-myristate-13-acetate-stimulated monocytes. Of note, this potentiated bioactivity was corroborated in a retrospective study on the treatment of anemia of inflammation in hereditary thrombophilic pregnant and non-pregnant women, demonstrating that Valpalf® improves hematological parameters and reduces serum IL-6 levels to a higher extent than bLf alone. [ABSTRACT FROM AUTHOR]

Ferruginicity is a special condition when soil became rich in iron. This condition is characterized by high pH and reduced bioavailability of plant limiting nutrients. Unfortunately, this type of soil covered 30% of arable lands in Nigeria. This research aimed at using a native plant growth promoting bacteria (Bacillus cereus strain GGBSU-1, Klebsiella variicola strain AUH-KAM-9 and Proteus mirabilis strain TL14-1) with phosphate solubilizing capabilities to remediate iron toxicity and improve soil nutrients, as well as soil micro-biota colonization. Soil physico-chemical properties before rhizo-inoculation (FA), after 16 weeks of rhizoinoculation with the PGPB into the rhizoid of a growing rice seedling (FB) and after 16 weeks of natural attenuation (FC) were analyzed. Phosphate solubilizing capacity of the PGPB was investigated using a developed Pikovskaya’s growth medium. The results showed that FA is rich in iron and deficient in bioavailable phosphorus and nitrogen (200.67 mg/kg, 8.01 mg/kg and 0.20%) respectively, as against the FB soil which showed moderate iron and increased soil nutrients (51.22 mg/kg, 20.21 mg/kg and 0.33%). The presence of acidic exudates, which was indicated by a red litmus paper at the rhizosphere in FB signifies the iron chelation capacity of the PGPBs resulting in iron remediation and soil nutrient improvement. Furthermore, the significant increase in microbial population in the FB soil as against the FA and FC corresponds with the SEM results at the root epidermis. Furthermore, other nitrogen-fixing bacteria such as Bacillus subtilis were observed to be active and motile in the FB. This indicated the effectiveness of PGPB with PSB capacities in iron remediation and soil nutrient enhancement. [ABSTRACT FROM AUTHOR]

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time. [ABSTRACT FROM AUTHOR]

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Summary: Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion‐dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo‐controlled, randomised study to evaluate the iron chelator deferasirox in patients with low‐ or intermediate‐1–risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk. [ABSTRACT FROM AUTHOR]

Neutrophil and (alveolar) macrophage immunity is considered crucial for eliminating Aspergillus fumigatus. Data derived from bronchoalveloar lavage (BAL) characterizing the human immuno-pulmonary response to Aspergillus fumigatus are non-existent. To obtain a comprehensive picture of the immune pathways involved in chronic pulmonary aspergillosis (CPA), we performed proteome analysis on AL of 9 CPA patients and 17 patients with interstitial lung disease (ILD). The dihydrorhodamine (DHR) test was also performed on BAL and blood neutrophils from CPA patients and compared to blood neutrophils from healthy controls (HCs). BAL from CPA patients primarily contained neutrophils, while ILD BAL was also characterized by a large fraction of lymphocytes; these differences likely reflecting the different immunological etiologies underlying the two disorders. BAL and blood neutrophils from CPA patients displayed the same oxidative burst capacity as HC blood neutrophils. Hence, immune evasion by Aspergillus involves other mechanisms than impaired neutrophil oxidative burst capacity per se. CPA BAL was enriched by proteins associated with innate immunity, as well as, more specifically, with neutrophil degranulation, Toll-like receptor 4 signaling, and neutrophil-mediated iron chelation. Our data provide the first comprehensive target organ-derived immune data on the human pulmonary immune response to Aspergillus fumigatus. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a global health crisis. Notably, carbapenem-resistant Enterobacterales (CRE) pose a significant clinical challenge due to the limited effective treatment options. This problem is exacerbated by persisters that develop upon antibiotic exposure. Bacteria persisters can tolerate high antibiotic doses and can cause recalcitrant infections, potentially developing further antibiotic resistance. Iron is a critical micronutrient for survival. We aimed to evaluate the utility of iron chelators, alone and in combination with antibiotics, in managing persisters. We hypothesized that iron chelators eradicate CRE persisters in vitro, when administered in combination with antibiotics. Our screening revealed three clinical isolates with bacteria persisters that resuscitated upon antibiotic removal. These isolates were treated with both meropenem and an iron chelator (deferoxamine mesylate, deferiprone or dexrazoxane) over 24 h. Against our hypothesis, bacteria persisters survived and resuscitated upon withdrawing both the antibiotic and iron chelator. Pursuing our aim, we next hypothesized that iron chelation is feasible as a post-antibiotic treatment in managing and suppressing persisters' resuscitation. We exposed bacteria persisters to an iron chelator without antibiotics. Flow cytometric assessments revealed that iron chelators are inconsistent in suppressing persister resuscitation. Collectively, these results suggest that the iron chelation strategy may not be useful as an antibiotic adjunct to target planktonic bacteria persisters. [ABSTRACT FROM AUTHOR]

Abstract Study Design Pre‐clinical animal experiment. Objective In this study, we investigated therapeutic effects of silibinin in a spinal cord injury (SCI) model. In SCI, loss of cells due to secondary damage mechanisms exceeds that caused by primary damage. Ferroptosis, which is iron‐dependent non‐apoptotic cell death, is shown to be influential in the pathogenesis of SCI. Methods The study was conducted as an in vivo experiment using a total of 78 adult male/female Sprague Dawley rats. Groups were as follows: Sham, SCI, deferoxamine (DFO) treatment, and silibinin treatment. There were subgroups with follow‐up periods of 24 h, 72 h, and 6 weeks in all groups. Malondialdehyde (MDA), glutathione (GSH), and Fe2+ levels were measured by spectrophotometry. Glutathione peroxidase‐4 (GPX4), ferroportin (FPN), transferrin receptor (TfR1), and 4‐hydroxynonenal (4‐HNE)‐modified protein levels were assessed by Western blotting. Functional recovery was assessed using Basso–Beattie–Bresnahan test. Results Silibinin achieved significant suppression in MDA and 4‐HNE levels compared to the SCI both in 72‐h and 6 weeks group (p DFO > SCI (p

Background: β-thalassemia major is microcytic hypochromic anemia disorder inherited from parents, resulting from a mutation in the β-globin locus. As a result, a quantitative defective hemoglobin synthesis and relative excess in α-globin is occurred. As such, frequent blood transfusion is required, that leads to iron overload. Iron overload results in several pathological complications, including cell death, tissue injury, organ dysfunction, and liver fibrosis. The present study examined the effectiveness of nigella Sativa and manuka honey combination or manuka honey alone to the conventional therapy (Deferasirox + blood transfusion) used for preventing and managing iron overload in pediatric β-thalassemia major patients. Methods: One hundred sixty-five patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 500 mg nigella sativa oil combined with manuka honey lozenge (344 mg) daily or manuka honey alone plus the conventional therapy for ten treatment months. Ferritin level, serum iron, transferrin saturation, total iron binding capacity, alanine transaminase, and aspartate transaminase were determined at baseline and month 10. Results: Eventually, serum ferritin and iron were decreased significantly in the nigella sativa + manuka honey group as compared with the control group. Other clinical parameters were significantly impacted. The level of alanine transaminase and aspartate transaminase were significantly decreased in the nigella sativa plus manuka honey group compared with the control group. Conclusion: Results showed that nigella sativa plus manuka honey was more effective than manuka alone or the conventional treatment alone in managing iron overload of β-thalassemia major patients.

The central nervous system is essential for maintaining homeostasis and controlling the body’s physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3–5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.

Thalassemia is a hereditary hemolytic anemia that is prevalent in Southeast Asia. The primary treatment for severe thalassemia involves red cell transfusion, iron chelation, and the treatment of long-term complications, leading to frequent hospital visits and admissions. This study aims to delineate the causes and characteristics of hospital admissions among thalassemia patients under the National Health Coverage (NHC) scheme in Thailand. This cross-sectional analysis (2015–2019), conducted using the National Health Security Office database, identified 336,054 admissions among 41,237 patients, with alpha-thalassemia at 12.5%, beta-thalassemia at 61.5%, other thalassemia at 0.5%, and unclassified thalassemia at 25.5%. The overall admission rate was 3.74 per 100 NHC admissions in the pediatric age group. Infections predominated in younger patients, whereas cardiac complications, diabetes mellitus, and cholecystitis/cholelithiasis were more common in older patients. Hospital admissions for cardiac complications and diabetes mellitus in pediatric patients with thalassemia decreased over the study period. The annual hospital admission cost ranged from 8.19 to 12.01 million US dollars, with one-third attributed to iron chelation. In summary, thalassemia poses a significant healthcare challenge in Thai children, characterized by high admission rates and costs. While infections predominate in younger patients, cardiac complications and diabetes mellitus are more common in older individuals. The diminishing admissions for these complications suggest the successful implementation of iron chelation medications.

Dysregulation of iron homeostasis causes iron-mediated cell death, recently described as ferroptosis. Ferroptosis is reported in many chronic diseases, such as hepatic cancer, renal, and cardiovascular diseases (heart failure, atherosclerosis). However, there is a notable scarcity of research studies in the existing literature that explore treatments capable of preventing ferroptosis. Additionally, as far as the author is aware, there is currently no established model for studying ferroptosis within cardiovascular cells, which would be essential for assessing metal-chelating molecules with the potential ability to inhibit ferroptosis and their application in the treatment of cardiovascular diseases. In this study, a smooth muscle cell-based ferroptosis model is developed upon the inhibition of the system Xc− transporter by erastin associated or not with Fe(III) overload, and its rescue upon the introduction of well-known iron chelators, deferoxamine and deferiprone. We showed that erastin alone decreased the intracellular concentration of glutathione (GSH) without affecting peroxidized lipid concentrations. Erastin with ferric citrate was able to decrease intracellular GSH and induce lipid peroxidation after overnight incubation. Only deferiprone was able to rescue the cells from ferroptosis by decreasing lipid peroxidation via iron ion chelation in a 3:1 molar ratio.

Brazilin is the main compound in Caesalpinia sappan and Haematoxylum braziletto, which is identified as a homoisoflavonoid based on its molecular structure. These plants are traditionally used as an anti-inflammatory to treat fever, hemorrhage, rheumatism, skin problems, diabetes, and cardiovascular diseases. Recently, brazilin has increased its interest in cancer studies. Several findings have shown that brazilin has cytotoxic effects on colorectal cancer, breast cancer, lung cancer, multiple myeloma, osteosarcoma, cervical cancer, bladder carcinoma, also other cancers, along with numerous facts about its possible mechanisms that will be discussed. Besides its flavonoid content, brazilin is able to chelate metal ions. A study has proved that brazilin could be used as an antituberculosis agent based on its ability to chelate iron. This possible ironchelating of brazilin and all the studies discussed in this review will lead us to the statement that, in the future, brazilin has the potency to be a chemo-preventive and anticancer agent. The article review aimed to determine the brazilin mechanism and pathogenesis of cancer. [ABSTRACT FROM AUTHOR]

Thalassemia is a hereditary hemolytic anemia that is prevalent in Southeast Asia. The primary treatment for severe thalassemia involves red cell transfusion, iron chelation, and the treatment of long-term complications, leading to frequent hospital visits and admissions. This study aims to delineate the causes and characteristics of hospital admissions among thalassemia patients under the National Health Coverage (NHC) scheme in Thailand. This cross-sectional analysis (2015–2019), conducted using the National Health Security Office database, identified 336,054 admissions among 41,237 patients, with alpha-thalassemia at 12.5%, beta-thalassemia at 61.5%, other thalassemia at 0.5%, and unclassified thalassemia at 25.5%. The overall admission rate was 3.74 per 100 NHC admissions in the pediatric age group. Infections predominated in younger patients, whereas cardiac complications, diabetes mellitus, and cholecystitis/cholelithiasis were more common in older patients. Hospital admissions for cardiac complications and diabetes mellitus in pediatric patients with thalassemia decreased over the study period. The annual hospital admission cost ranged from 8.19 to 12.01 million US dollars, with one-third attributed to iron chelation. In summary, thalassemia poses a significant healthcare challenge in Thai children, characterized by high admission rates and costs. While infections predominate in younger patients, cardiac complications and diabetes mellitus are more common in older individuals. The diminishing admissions for these complications suggest the successful implementation of iron chelation medications. [ABSTRACT FROM AUTHOR]

Oral consumption of histidyl dipeptides such as l-carnosine has been suggested to promote cardiometabolic health, although therapeutic mechanisms remain incompletely understood. We recently reported that oral consumption of a carnosine analog suppressed markers of fibrosis in liver of obese mice, but whether antifibrotic effects of carnosine extend to the heart is not known, nor are the mechanisms by which carnosine is acting. Here, we investigated whether oral carnosine was able to mitigate the adverse cardiac remodeling associated with diet induced obesity in a mouse model of enhanced lipid peroxidation (i.e., glutathione peroxidase 4 deficient mice, GPx4+/-), a model which mimics many of the pathophysiological aspects of metabolic syndrome and T2 diabetes in humans. Wild-type (WT) and GPx4+/-male mice were randomly fed a standard (CNTL) or high fat high sucrose diet (HFHS) for 16 weeks. Seven weeks after starting the diet, a subset of the HFHS mice received carnosine (80 mM) in their drinking water for duration of the study. Carnosine treatment led to a moderate improvement in glycemic control in WT and GPx4+/-mice on HFHS diet, although insulin sensitivity was not significantly affected. Interestingly, while our transcriptomic analysis revealed that carnosine therapy had only modest impact on global gene expression in the heart, carnosine substantially upregulated cardiac GPx4 expression in both WT and GPx4+/-mice on HFHS diet. Carnosine also significantly reduced protein carbonyls and iron levels in myocardial tissue from both genotypes on HFHS diet. Importantly, we observed a robust antifibrotic effect of carnosine therapy in hearts from mice on HFHS diet, which further in vitro experiments suggest is due to carnosine's ability to suppress collagen-cross-linking. Collectively, this study reveals antifibrotic potential of carnosine in the heart with obesity and illustrates key mechanisms by which it may be acting. [ABSTRACT FROM AUTHOR]

Summary: Haemochromatosis (HC) encompasses a range of genetic disorders. HFE‐HC is by far the most common in adults, while non‐HFE types are rare due to mutations of HJV, HAMP, TFR2 and gain‐of‐function mutations of SLC40A1. HC is often unknown to paediatricians as it is usually asymptomatic in childhood. We report clinical and biochemical data from 24 paediatric cases of HC (10 cases of HFE‐, 5 TFR2‐, 9 HJV‐HC), with a median follow‐up of 9.6 years. Unlike in the adult population, non‐HFE‐HC constitutes 58% (14/24) of the population in our series. Transferrin saturation was significantly higher in TFR2‐ and HJV‐HC compared to HFE‐HC, and serum ferritin and LIC were higher in HJV‐HC compared to TFR2‐ and HFE‐HC. Most HFE‐HC subjects had relatively low ferritin and LIC at the time of diagnosis, so therapy could be postponed for most of them after the age of 18. Our results confirm that HJV‐HC is a severe form already in childhood, emphasizing the importance of early diagnosis and treatment to avoid the development of organ damage and reduce morbidity and mortality. Although phlebotomies were tolerated by most patients, oral iron chelators could be a valid option in early‐onset HC. [ABSTRACT FROM AUTHOR]

Since ancient times, tuberculosis (TB) has been a fatal infectious disease, made even more difficult to treat with the emergence of drug-resistant strains. The present work aimed to evaluate the antituberculosis activity of newly synthesized eugenol derivatives, and their iron chelation ability as well. The mycobacterium H37Rv strain was sensitive to all tested compounds. The compounds 2-methoxy-4-propenyl-1-propynyloxybenzene (1), 3,5-bis(trifluoromethyl) benzyloxy-2-methoxy-4-propenylbenzene (3) and ethyl 2-methoxy-4-propenylphenylcarbonate (5) showed the best growth inhibitory activity at a concentration of 10 µg/mL. Also, a considerable iron chelation activity for 1 and 5 translated by EC50 values of 0.94 and 0.33 µg/mL, respectively. Generally, the synthesized derivatives illustrated an encouraging in silico pharmacokinetic profile. The molecular docking study revealed that compound 3 exhibited the excellent binding affinity within the active sites of MabA and PanK targets, involving hydrogen bond interactions, fluorine interactions and hydrophobic interactions. Our results suggest that compound 3 could potentially act via the inhibition of MabA and PanK proteins. While, derivatives 1 and 5 could have a potential iron chelation mechanism against mycobacterial growth.

Brazilin is the main compound in Caesalpinia sappan and Haematoxylum braziletto, which is identified as a homoisoflavonoid based on its molecular structure. These plants are traditionally used as an anti-inflammatory to treat fever, hemorrhage, rheumatism, skin problems, diabetes, and cardiovascular diseases. Recently, brazilin has increased its interest in cancer studies. Several findings have shown that brazilin has cytotoxic effects on colorectal cancer, breast cancer, lung cancer, multiple myeloma, osteosarcoma, cervical cancer, bladder carcinoma, also other cancers, along with numerous facts about its possible mechanisms that will be discussed. Besides its flavonoid content, brazilin is able to chelate metal ions. A study has proved that brazilin could be used as an antituberculosis agent based on its ability to chelate iron. This possible iron-chelating of brazilin and all the studies discussed in this review will lead us to the statement that, in the future, brazilin has the potency to be a chemo-preventive and anticancer agent. The article review aimed to determine the brazilin mechanism and pathogenesis of cancer.

An iron-containing milk protein named lactoferrin (Lf) has demonstrated antiparasitic and immunomodulatory properties against a variety of human parasites. This protein has shown its capability to bind and transport iron molecules in the vicinity of the host–pathogen environment. The ability of parasites to sequester the iron molecule and to increase their pathogenicity and survival depends on the availability of iron sources. Lf protein has suggested a iron chelating effect on parasites iron and, hence, has shown its antiparasitic effect. Since the parasites have a complex life cycle and have developed drug resistance, vaccines and other treatments are a handful. Therefore, therapeutic research focusing on natural treatment regimens that target the parasite and are non-toxic to host cells is urgently needed. The antiparasitic efficacy of Lf protein has been extensively studied over the past 40 years using both in vitro and in vivo studies. This review article highlighted past important studies on Lf protein that revealed its potential antiparasitic activity against various intracellular and extracellular intestinal or blood-borne human parasites. This review article structures the role of Lf protein in its various forms, such as native, peptide, and nanoformulation, laying the groundwork for its function as an antiparasitic agent and its possible known mechanisms of action.

Oral consumption of histidyl dipeptides such as l-carnosine has been suggested to promote cardiometabolic health, although therapeutic mechanisms remain incompletely understood. We recently reported that oral consumption of a carnosine analog suppressed markers of fibrosis in liver of obese mice, but whether antifibrotic effects of carnosine extend to the heart is not known, nor are the mechanisms by which carnosine is acting. Here, we investigated whether oral carnosine was able to mitigate the adverse cardiac remodeling associated with diet induced obesity in a mouse model of enhanced lipid peroxidation (i.e., glutathione peroxidase 4 deficient mice, GPx4+/−), a model which mimics many of the pathophysiological aspects of metabolic syndrome and T2 diabetes in humans. Wild-type (WT) and GPx4+/−male mice were randomly fed a standard (CNTL) or high fat high sucrose diet (HFHS) for 16 weeks. Seven weeks after starting the diet, a subset of the HFHS mice received carnosine (80 mM) in their drinking water for duration of the study. Carnosine treatment led to a moderate improvement in glycemic control in WT and GPx4+/−mice on HFHS diet, although insulin sensitivity was not significantly affected. Interestingly, while our transcriptomic analysis revealed that carnosine therapy had only modest impact on global gene expression in the heart, carnosine substantially upregulated cardiac GPx4 expression in both WT and GPx4+/−mice on HFHS diet. Carnosine also significantly reduced protein carbonyls and iron levels in myocardial tissue from both genotypes on HFHS diet. Importantly, we observed a robust antifibrotic effect of carnosine therapy in hearts from mice on HFHS diet, which further in vitro experiments suggest is due to carnosine’s ability to suppress collagen-cross-linking. Collectively, this study reveals antifibrotic potential of carnosine in the heart with obesity and illustrates key mechanisms by which it may be acting.

Simple Summary: The lysosomal lipid hydrolase acid ceramidase is upregulated in acute myeloid leukemia and promotes leukemic blast survival, underscoring its potential for therapeutic targeting. B-13 is an established ceramidase inhibitor with demonstrated efficacy in multiple solid cancers. Next-generation lysosome-localizing prodrugs of B-13 have been developed but have not been evaluated in AML. This study characterizes the in vitro anti-leukemic efficacy and cell death mechanisms of the B-13 analog and acid ceramidase inhibitor LCL-805 in acute myeloid leukemia. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide. [ABSTRACT FROM AUTHOR]

(1) Background: The protoporphyrin IX (PpIX)-mediated fluorescence-guided resection and interoperative photodynamic therapy (PDT) of remaining cells may be effective adjuvants to the resection of glioma. Both processes may be enhanced by increasing intracellular PpIX concentrations, which can be achieved through iron chelation. AP2-18 is a novel combinational drug, which ester-links a PpIX precursor (aminolaevulinic acid; ALA) to an iron-chelating agent (CP94). (2) Methods: Human glioma U-87 MG cells were cultured in 96-well plates for 24 h and incubated for 3 or 6 h with various test compound combinations: ALA (±) CP94, methyl aminolevulinate (MAL) (±) CP94 and AP2-18. PpIX fluorescence was measured at 0, 3 or 6 h with a Bio-tek Synergy HT plate reader, as well as immediately after irradiation with a 635 nm red light (Aktilite CL16 LED array), representing the PDT procedure. Cell viability post-irradiation was assessed using the neutral red assay. (3) Results: AP2-18 significantly increased PpIX fluorescence compared to all other test compounds. All treatment protocols effectively achieved PDT-induced cytotoxicity, with no significant difference between test compound combinations. (4) Conclusions: AP2-18 has potential to improve the efficacy of fluorescence-guided resection either with or without the subsequent intraoperative PDT of glioma. Future work should feature a more complex in vitro model of the glioma microenvironment. [ABSTRACT FROM AUTHOR]

The synthesis of Gobichelin‐A, a naturally occurring mixed‐ligand siderophore isolated from Streptomyces sp. NRRL F‐4415, is described. The target molecule was planned to be synthesized by a convergent process involving the combination of two halves, Gob‐A 1st half and Gob‐A 2nd half, at the prefinal stage of the synthetic route. By adopting this method, fully protected Gobichelin‐A was synthesized in excellent yield. [ABSTRACT FROM AUTHOR]

Combination chelation therapies are considered in transfusion‐dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real‐life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron‐dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti‐ferroptotic activity of scutellarein was investigated through CCK8, real‐time quantitative polymerase chain reaction (RT‐qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA‐sequencing (RNA‐seq), electrospray ionization mass spectra (ESI‐MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras‐selective lethal small molecule (RSL)‐3‐induced ferroptosis and mitochondria injury in BEAS‐2B cells, and ameliorated LPS/CS‐induced COPD in mice. Furthermore, scutellarein also repressed RSL‐3‐ or LPS/CS‐induced lipid peroxidation, GPX4 down‐regulation, and overactivation of Nrf2/HO‐1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL‐3‐ or LPS/CS‐induced Fe2+ elevation through directly chelating Fe2+. Moreover, scutellarein bound to the lipid peroxidizing enzyme arachidonate 15‐lipoxygenase (ALOX15), which resulted in an unstable state of the catalysis‐related Fe2+ chelating cluster. Additionally, ALOX15 overexpression partially abolished scutellarein‐mediated anti‐ferroptotic activity. Our findings revealed that scutellarein alleviated COPD by inhibiting ferroptosis via directly chelating Fe2+ and interacting with ALOX15, and also highlighted scutellarein as a candidate for the treatment of COPD and other ferroptosis‐related diseases. [ABSTRACT FROM AUTHOR]

Background: Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The cause of this condition was chronic hypoxia, iron overload, endocrinopathy, inadequate transfusion, and iron chelation. We analyze the relationship between ferritin level and growth status of pediatric TDTs. Methods: This was a cross-sectional study on pediatric TDTs aged 2-18 years old at Dr. Soetomo General Academic Hospital Surabaya, Indonesia conducted in 2020. They required blood transfusion every 2-4 weeks. We evaluated the ratio of upper/lower body segments, weight for age Z-score (WAZ), height for age Z-score (HAZ), and body mass index (BMI) Z-score, based on CDC growth chart as growth status parameters. Serum ferritin was checked every three months to determine iron overload and iron chelation (deferiprone, deferasirox and deferoxamine). We used Spearman correlation and Mann-Whitney U test to analyze between variables (α=0.05). Results: We enrolled 15/29 males with median age 10.5 years. Serum Ferritin had negative correlation with the ratio of upper/lower body segments (rho=-0.552; P=0.002), but not for HAZ (rho=-0.078; P=0.694), WAZ (rho=-0.186; P=0.342), BMI Z-score (rho=-0.089; P=0.653) especially if serum ferritin was above 2500 µ/L. In deferiprone group (n=8), the WAZ (P=0.034) and BMI Z-score (P=0.031) were lower; but the ratio of upper/lower body segments was greater (P=0.039) than the deferasirox group. Conclusion: Growth retardation was more visible in pediatric TDTs with high ferritin and in deferiprone group. The height and the ratio of upper/lower body segments of the body were more affected.

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects.

Antibiotic resistance is a global health crisis. Notably, carbapenem-resistant Enterobacterales (CRE) pose a significant clinical challenge due to the limited effective treatment options. This problem is exacerbated by persisters that develop upon antibiotic exposure. Bacteria persisters can tolerate high antibiotic doses and can cause recalcitrant infections, potentially developing further antibiotic resistance. Iron is a critical micronutrient for survival. We aimed to evaluate the utility of iron chelators, alone and in combination with antibiotics, in managing persisters. We hypothesized that iron chelators eradicate CRE persisters in vitro, when administered in combination with antibiotics. Our screening revealed three clinical isolates with bacteria persisters that resuscitated upon antibiotic removal. These isolates were treated with both meropenem and an iron chelator (deferoxamine mesylate, deferiprone or dexrazoxane) over 24 h. Against our hypothesis, bacteria persisters survived and resuscitated upon withdrawing both the antibiotic and iron chelator. Pursuing our aim, we next hypothesized that iron chelation is feasible as a post-antibiotic treatment in managing and suppressing persisters’ resuscitation. We exposed bacteria persisters to an iron chelator without antibiotics. Flow cytometric assessments revealed that iron chelators are inconsistent in suppressing persister resuscitation. Collectively, these results suggest that the iron chelation strategy may not be useful as an antibiotic adjunct to target planktonic bacteria persisters.

Neutrophil and (alveolar) macrophage immunity is considered crucial for eliminating Aspergillus fumigatus. Data derived from bronchoalveloar lavage (BAL) characterizing the human immuno-pulmonary response to Aspergillus fumigatus are non-existent. To obtain a comprehensive picture of the immune pathways involved in chronic pulmonary aspergillosis (CPA), we performed proteome analysis on AL of 9 CPA patients and 17 patients with interstitial lung disease (ILD). The dihydrorhodamine (DHR) test was also performed on BAL and blood neutrophils from CPA patients and compared to blood neutrophils from healthy controls (HCs). BAL from CPA patients primarily contained neutrophils, while ILD BAL was also characterized by a large fraction of lymphocytes; these differences likely reflecting the different immunological etiologies underlying the two disorders. BAL and blood neutrophils from CPA patients displayed the same oxidative burst capacity as HC blood neutrophils. Hence, immune evasion by Aspergillus involves other mechanisms than impaired neutrophil oxidative burst capacity per se. CPA BAL was enriched by proteins associated with innate immunity, as well as, more specifically, with neutrophil degranulation, Toll-like receptor 4 signaling, and neutrophil-mediated iron chelation. Our data provide the first comprehensive target organ-derived immune data on the human pulmonary immune response to Aspergillus fumigatus.

Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a bona fide biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies. Graphical Abstract Urinalysis to detect portosystemic shunt in mice. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be further subdivided into types 4A (loss-of-function mutations) and 4B (gain-of-function mutations). To date, only a few cases of type 4B cases have been reported, and the treatment has not been clearly mentioned. Here, we report a genotype of hereditary hemochromatosis type 4B involving the heterozygous mutation c.997 T > C (p. Tyr333His) in SLC40A1. The patient was treated with red blood cell apheresis every month for 1 year, followed by oral deferasirox, and the combined therapy was found to be effective. [ABSTRACT FROM AUTHOR]

Bacterial involvement in cancer's development, along with their impact on therapeutic interventions, has been increasingly recognized. This has prompted the development of novel strategies to disrupt essential biological processes in microbial cells. Among these approaches, metal-chelating agents have gained attention for their ability to hinder microbial metal metabolism and impede critical reactions. Nanotechnology has also contributed to the antibacterial field by offering various nanomaterials, including antimicrobial nanoparticles with potential therapeutic and drug-delivery applications. Halloysite nanotubes (HNTs) are naturally occurring tubular clay nanomaterials composed of aluminosilicate kaolin sheets rolled multiple times. The aluminum and siloxane groups on the surface of HNTs enable hydrogen bonding with biomaterials, making them versatile in various domains, such as environmental sciences, wastewater treatment, nanoelectronics, catalytic studies, and cosmetics. This study aimed to create an antibacterial material by combining the unique properties of halloysite nanotubes with the iron-chelating capability of kojic acid. A nucleophilic substitution reaction involving the hydroxyl groups on the nanotubes' surface was employed to functionalize the material using kojic acid. The resulting material was characterized using infrared spectroscopy (IR), thermogravimetric analysis (TGA), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM), and its iron-chelating ability was assessed. Furthermore, the potential for drug loading—specifically, with resveratrol and curcumin—was evaluated through ultraviolet (UV) analysis. The antibacterial assay was evaluated following CLSI guidelines. The results suggested that the HNTs–kojic acid formulation had great antibacterial activity against all tested pathogens. The outcome of this work yielded a novel bio-based material with dual functionality as a drug carrier and an antimicrobial agent. This innovative approach holds promise for addressing challenges related to bacterial infections, antibiotic resistance, and the development of advanced therapeutic interventions. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. WHAT IS KNOWN ALREADY Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN, SIZE, DURATION This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma'). PARTICIPANTS/MATERIALS, SETTING, METHODS This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle–Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. LIMITATIONS, REASONS FOR CAUTION A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTEREST(S) J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818). [ABSTRACT FROM AUTHOR]

Ahmed Saleh Ibrahim,1 Azza Hasan Abd El-Fatah,2 Ayman Fathy Abd El-Halim,3 Farid Fawzy Mohamed2 1Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 2Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 3Department of Hematology, Faculty of Medicine, Zagazig University, Zagazig, EgyptCorrespondence: Ahmed Saleh Ibrahim, Tel +20 109 232 6689, Email abadawi70@yahoo.comBackground: Although beta thalassemia major (BTM) patients are properly treated with blood transfusions in accompany with iron chelation therapy, they suffer from complications, such as diabetes mellitus (DM).Purpose: The purpose was to detect the critical serum ferritin level and other parameters correlated with DM among adult BTM patients. Also, it was to study whether each of these parameters is associated with a certain period of age.Patients and Methods: This study included 200 adult BTM patients. A cross-sectional study was carried out. Patients clinical and laboratory variables, such as ferritin levels, and fasting blood glucose (FBS) were extracted from medical records at Zagazig University Hospital, Egypt. Liver and cardiac iron contents were assessed using MRI T2&ast; methods. Statistical analysis was performed using IBM SPSS V26.0 software package.Results: The overall frequency of DM over the total sample equals 6.5%. There were no impaired fasting glucose (IFG) in the medical records. Statistical significance between serum ferritin and DM was (P = 0.014). The serum ferritin 2500 ng/mL with age group (27–< 32) years-old were risk factors. The distributions of DM according to BMI were (3.5%) of class overweight. Significant association between DM and BMI was (r = 0.357, P < 0.001). Liver MRI T2&ast; has significant correlation with serum ferritin, but cardiac MRI T2&ast; was poorly correlated. Association between liver and cardiac MRI T2&ast; was not found.Conclusion: Age group (27–< 32) years-old and ferritin > 2500 ng/mL should be properly treated immediately. The serum ferritin and BMI of class “overweight” were risk factors for DM. Factors such as diet should be followed. Serum ferritin can be used for estimating liver iron content for economic factors. But cardiac MRI T2&ast; must be performed for evaluating cardiac iron accurately.Keywords: hemoglobin, iron chelation, blood glucose, endocrinopathy

Beta thalassemia is an inherited disorder resulting in abnormal or decreased production of hemoglobin, leading to hemolysis and chronic anemia. The long-term complications can affect multiple organ systems, namely the liver, heart, and endocrine. Myocardial iron overload is a common finding in β-thalassemia. As a result, different cardiovascular complications in the form of cardiomyopathy, pulmonary hypertension, arrhythmias, and vasculopathies can occur, and in extreme cases, sudden cardiac death. Each of these complications pertains to underlying etiologies and risk factors, which highlights the importance of early diagnosis and prevention. In this review, we will discuss different types of cardiovascular complications that can manifest in patients with β-thalassemia, in addition to the current diagnostic modalities, preventive and treatment modalities for these complications.

Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis, progressive cytopenias, and an innate capability of progressing to acute myeloid leukemia. The most common causes of morbidity and mortality are complications related to myelodysplastic syndromes rather than progression to acute myeloid leukemia. Although supportive care measures are applicable to all patients with myelodysplastic syndromes, they are especially essential in patients with lower-risk disease who have a better prognosis compared with their higher-risk counterparts and require longer-term monitoring of disease and treatment-related complications. In this review, we will address the most frequent complications and supportive care interventions used in patients with myelodysplastic syndromes, including transfusion support, management of iron overload, antimicrobial prophylaxis, important considerations in the era of COVID-19 (coronavirus infectious disease 2019), role of routine immunizations, and palliative care in the myelodysplastic syndrome population. [ABSTRACT FROM AUTHOR]

The myelodysplastic syndromes (MDSs) are a heterogeneous group of hematologic neoplasms with varied natural histories and prognoses. Specific to this review, treatment of low-risk MDS most often focuses on improving quality of life by correcting cytopenias, as opposed to urgent disease modification to avoid acute myeloid leukemia. These treatments include transfusion support with iron chelation when necessary, growth factors including novel maturation agents such as luspatercept, lenalidomide for del(5q) disease, and, increasingly, low-dose hypomethylating agents. Recent advances in the understanding of the genetic lesions that drive MDS have prompted a reassessment of how low-risk disease is defined and helped to identify a subset of low-risk MDS patients who may benefit from a more aggressive treatment paradigm, including hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Thalassemia is a monogenic autosomal recessive disorder caused by mutations, which lead to abnormal or reduced production of hemoglobin. Ineffective erythropoiesis, hemolysis, hepcidin suppression, and iron overload are common manifestations that vary according to genotypes and dictate, which diagnosis and therapeutic modalities, including transfusion therapy, iron chelation therapy, HbF induction, gene therapy, and editing, are performed. These conventional therapeutic methods have proven to be effective, yet have several disadvantages, specifically iron toxicity, associated with them; therefore, there are demands for advanced therapeutic methods. Nanotechnology-based applications, such as the use of nanoparticles and nanomedicines for theragnostic purposes have emerged that are simple, convenient, and cost-effective methods. The therapeutic potential of various nanoparticles has been explored by developing artificial hemoglobin, nano-based iron chelating agents, and nanocarriers for globin gene editing by CRISPR/Cas9. Au, Ag, carbon, graphene, silicon, porous nanoparticles, dendrimers, hydrogels, quantum dots, etc., have been used in electrochemical biosensors development for diagnosis of thalassemia, quantification of hemoglobin in these patients, and analysis of conventional iron chelating agents. This review summarizes the potential of nanotechnology in the development of various theragnostic approaches to determine thalassemia-causing gene mutations using various nano-based biosensors along with the employment of efficacious nano-based therapeutic procedures, in contrast to conventional therapies. [ABSTRACT FROM AUTHOR]

Iron levels in mitochondria are critically important for the normal functioning of the organelle. Abnormal levels of iron and the associated formation of toxic oxygen radicals have been linked to a wide range of diseases and consequently it is important to be able to both monitor and control levels of the mitochondrial labile iron pool. To this end a series of iron chelators which are targeted to mitochondria have been designed. This overview describes the synthesis of some of these molecules and their application in monitoring mitochondrial labile iron pools and in selectively removing excess iron from mitochondria. [ABSTRACT FROM AUTHOR]

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria. [ABSTRACT FROM AUTHOR]