Iron Chelator Research Articles

Proteome and Dihydrorhodamine Profiling of Bronchoalveolar Lavage in Patients with Chronic Pulmonary Aspergillosis.

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.

The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

Modeling ferroptosis in human dopaminergic neurons: Pitfalls and opportunities for neurodegeneration research

The activation of ferroptosis is being pursued in cancer research as a strategy to target apoptosis-resistant cells. By contrast, in various diseases that affect the cardiovascular system, kidneys, liver, and central and peripheral nervous systems, attention is directed toward interventions that prevent ferroptotic cell death. Mechanistic insights into both research areas stem largely from studies using cellular in vitro models. However, intervention strategies that show promise in cellular test systems often fail in clinical trials, which raises concerns regarding the predictive validity of the utilized in vitro models.In this study, the human LUHMES cell line, which serves as a model for human dopaminergic neurons, was used to characterize factors influencing the activation of ferroptosis. Erastin and RSL-3 induced cell death that was distinct from apoptosis. Parameters such as the differentiation state of LUHMES cells, cell density, and the number and timing of medium changes were identified as determinants of sensitivity to ferroptosis activation. In differentiated LUHMES cells, interventions at mechanistically divergent sites (iron chelation, coenzyme Q10, peroxidase mimics, or inhibition of 12/15-lipoxygenase) provide almost complete protection from ferroptosis. LUHMES cells allowed the experimental modulation of intracellular iron concentrations and demonstrated a correlation between intracellular iron levels, the rate of lipid peroxidation, as well as the sensitivity of the cells to ferroptotic cell death.These findings underscore the importance of understanding the various factors that influence ferroptosis activation and highlight the need for well-characterized in vitro models to enhance the reliability and predictive value of observations in ferroptosis research, particularly when translating findings into in vivo contexts.

A DFT study of the antioxidant potency of α-tocopherol and its derivatives: PMHC, Trolox, and α-CEHC

In this research, antioxidant potency (in terms of peroxyl radical scavenging and catalytic iron ions sequestration) of α-tocopherol and its analogues, has been theoretically investigated. A DFT based kinetic estimation of HOO• radical scavenging potency of PMHC (lipophilic α-TOH derivative) and Trolox (hydrophilic α-TOH derivative) was performed in eight solvents of different polarity. Calculations employing M06-2X functional, accompanied by 6-311++G(d,p) basis set and SMD solvation model, were found as more accurate in reproducing experimentally determined rate constants than M05-2X functional. Rate constant of Trolox in pentyl ethanoate also was estimated by using Snelgrove−Ingold equation and Abraham’s β2H solvent parameter. Scavenging of CH3OO• and HOO• radicals, which is influenced by location, orientation, and dynamics of α-TOH and its derivatives in the membrane lipid bilayer, was estimated by using M06-2X functional. Position of α-TOH phenolic OH group is opposite to that of its metabolite α-CEHC: α-TOH’s OH group is located at the membrane-water interface, and α-CEHC’s OH group is deeply buried into the bilayer. In the aqueous phase both fHAT and SET were investigated, and inside the bilayer only fHAT was considered as feasible. The spontaneous disproportionation of HOO•/O2•− in aqueous solutions should be taken into account to predict potency of antioxidant in scavenging of HOO• radicals. Iron chelating ability of α-TOH and α-CEHC was also investigated. Obtained results indicate α-CEHC, α-tocopherol final catabolite, as more potent scavenger of CH3OO• and HOO• radicals and iron ions chelator than the parent molecule.

Impact of SCOPE Program on Health-Related Quality of Life and Health Status of Children With Thalassemia: A Quasi-Experimental Study.

Background: Iron chelation, blood transfusions, and complication management are typical hospital requirements for children with beta-thalassemia major. This affects their health-related quality of life (HRQoL). The purpose of this study was to evaluate how the Supportive and Coping strategies, Ongoing Assessment, Prevention of Complications, and Empowerment (SCOPE) Program impacted the HRQoL and overall health of children with thalassemia. Method: The study employed a quasi-experimental pretest-posttest control group with a sequential follow-up design. A nonprobability purposive sampling technique was used to include 80 children with beta-thalassemia major in the sample, ranging in age from 6 to 18. Data were gathered using a Demographic Profile, PedsQLTM Version 4.0, and a Clinical Profile. The children in the intervention group received the SCOPE Program over the course of 6 months. The data collection included a pretest and a posttest with four follow-up evaluations. Results: During the pretest, children with thalassemia had a very low HRQoL. However, the final assessment after the intervention showed a significant difference in the mean scores between the two groups in the areas of physical functioning (p = .001), emotional functioning (p = .0001), social functioning (p = .001), and school functioning (p = .001). Growth indicators also demonstrated a notable improvement in the intervention group of children. Discussion: The SCOPE Program may be a thorough and efficient intervention for enhancing the general health of children with thalassemia. It can be used as a cooperative, well-organized, family-focused care strategy. Further study with a larger sample size is suggested.

Evaluation of the in vitro enzyme inhibition and antioxidant activity of Clinopodium betulifolium (Boiss. & Balansa) Kuntze

Clinopodium betulifolium (Boiss. & Balansa) Kuntze is a perennial herb belonging to the Lamiaceae family. There are few studies on C. betulifolium, except for its essential oil. In this study, Alzheimer's and cosmetic-related enzyme inhibitory activity and antioxidant activity of C. betulifolium species were evaluated. This study extracted C. betulifolium aerial parts by maceration using 70% methanol and water. Antioxidant [DPPH scavenging assay, ABTS cation decolorization, and iron chelating activity] and enzyme inhibition (acetyl-, and butyrylcholine esterase, and tyrosinase) activities of C. betulifolium extracts were evaluated using Elisa microplate reader at 2 mg mL-1 stock concentration. C. betulifolium aqueous extract gave high antioxidant activity (IC50: 34.24 ± 5.01 µg mL-1) in the ABTS method, while its 70% methanol extract (IC50: 100.75 ± 2.62 µg mL-1) was higher than the aqueous extract (IC50: 131.83 ± 4.70 µg mL-1) in the DPPH method. C. betulifolium aqueous and 70% methanol extract have moderate anti-tyrosinase activity. Both 70% methanol and aqueous extracts showed similar and high activity against acetylcholinesterase with the IC50 values of 73.94 ± 2.78 µg mL-1 and 81.71 ± 9.38 µg mL-1, respectively. C. betulifolium 70% methanol extract (IC50: 64.08 ± 1.04 µg mL-1) showed higher inhibitory activity than the aqueous extract (IC50: 146.6 ± 8.27 µg mL-1) against butyrylcholinesterase. These results provide basic information for studies that will yield positive results in the development of pharmaceutical formulations or food supplements to be used to treat Alzheimer's and oxidative stress-related diseases.

Dexrazoxane inhibits the growth of esophageal squamous cell carcinoma by attenuating SDCBP/MDA-9/syntenin-mediated EGFR-PI3K-Akt pathway activation

Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.

Minocycline‐Loaded Cerium Oxide Nanoparticles for the Enhanced Treatment of Intracerebral Hemorrhage

AbstractInflammatory responses and neuronal ferroptosis, which are associated with abnormal accumulation of reactive oxygen species (ROS), exert crucial damaging effects on the brain after intracerebral hemorrhage (ICH). In this study, minocycline (MC)‐loaded cerium oxide nanoparticles (CeO2‐MC) are constructed for combined ICH treatment. Ultra‐small CeO2 (≈5 nm) synthesized via a high‐temperature approach exhibits powerful free‐radical scavenging and iron‐chelating abilities. In vitro experiments demonstrated that CeO2‐MC effectively attenuated the ROS levels in mouse microglial cells and neurons following oxyhemoglobin stimulation. In addition, CeO2‐MC exhibits iron chelation properties and stabilizes the mitochondrial membrane potential, thereby promoting anti‐inflammatory responses and preventing neuronal ferroptosis. In an intracerebral hemorrhage (ICH) mouse model, CeO2‐MC exhibited robust free radical scavenging capabilities and demonstrated the ability to preserve mitochondrial morphology and function, mitigate brain edema, and maintain blood–brain barrier integrity by inhibiting neuroinflammation and ferroptosis. Neurobehavioral tests demonstrated that CeO2‐MC significantly ameliorated spatial learning ability and sensorimotor function after ICH. Consequently, a general strategy using CeO2 nanoparticles to augment the therapeutic efficacy of MC highlights a new perspective for the in‐depth treatment of ICH.

Nano-inducer of ferroptosis for targeted chemotherapy of human triple negative breast carcinoma

Triple negative breast carcinoma (TNBC) accounts for 15–20 % of all incident breast cancers (BC) and is known to be highly invasive, has fewer treatment options, and tends to have a worse prognosis. However, due to its biological heterogeneity and diverse clinical and epidemiological behaviors, TNBC lacks a tumor-specific targeted therapy. In the present work we have developed a TNBC-specific targeted nano-delivery agent comprising of a cRGD labeled magneto-liposome (T-LMD) co-encapsulated with oleic acid coated iron oxide nanoparticles (MN-OA) and doxorubicin (Dox) in the liposome bilayer and core, respectively. T-LMD was found to show enhanced uptake and induction of ferroptotic cell death in MDA-MB-231, a TNBC model cell line. Additionally, T-LMD induced ferroptosis was found to be accompanied by release of HMGB1, an immunogenic cell death marker, suggesting its immunogenicity for augmenting the activation of anti-tumor immunity in TNBC. The strategic placement of IONPs in the liposome bilayer of T-LMD facilitates the sensitization of MDA-MB-231 cells to undergo ferroptosis; predominantly via the activation of the iron/lipid metabolism pathway, as validated by use of small molecule ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine). Activation of ferroptotic cell death was also corroborated by ferroptosis specific-ultrastructural alterations in the shape/size of cellular mitochondria and cell ballooning as observed by transmission electron microscopy and bright field imaging, respectively. Thus, our ferroptosis nano-inducer (T-LMD) can efficiently kill TNBC cells via enhanced LPO and ROS generation leading to membrane damage and consequent release of LDH and HMGB1, induce mitochondrial alterations and enhanced DNA double strand breaks. Altogether, our results suggest significant implications of T-LMD for treatment of TNBC.

Role of magnetic resonance imaging (MRI) in liver iron quantification in thalassemic (thalassemia major) patients

BackgroundIron overload is a major problem in beta thalassemia patients due to repeated blood transfusions. The liver is the first organ to be loaded with iron. An accurate assessment of iron overload is necessary for managing iron chelation therapy in such patients. Iron quantification by MRI scores over liver biopsy due to its non-invasive nature.MethodsFifty-one patients with thalassemia major were subjected to 3.0-T MRI. Multiecho T2* sequence was used to cover the entire liver. Region of interest (ROI) was placed in three areas with maximum signal change, and an average T2* value was obtained. Similarly, a single ROI was placed at the mid-interventricular septum in the heart, and T2* value was obtained. T2* values so obtained were converted to iron concentration with the help of a T2* iron concentration calculator. The liver iron values were correlated with serum ferritin value.ResultsThere was a significant negative correlation between liver iron concentration (LIC) and T2* value of the liver (r = − 0.895, p < 0.01) and between cardiac iron concentration (CIC) and T2* value of the heart (r = − 0.959, p < 0.01). There was a slight positive correlation between LIC and serum ferritin (r = 0.642, p < 0.01) and no correlation between CIC and serum ferritin (r = − 0.137, p = 0.354).ConclusionsMRI is a useful tool to titrate the doses of chelating agents as it is accurate and non-invasive, does not involve radiation hazards and hence can be repeated as and when needed. Simultaneous assessment of cardiac iron overload is an added advantage of MRI.

Purification and Characterization of Desferrioxamine B of Pseudomonas fluorescens and Its Application to Improve Oil Content, Nutrient Uptake, and Plant Growth in Peanuts

Microorganisms produce siderophores, which are low-molecular-weight iron chelators when iron availability is limited. The present analyzed the role of LNPF1 as multifarious PGPR for improving growth parameters and nutrient content in peanut and soil nutrients. Such multifarious PGPR strains can be used as effective bioinoculants for peanut farming. In this work, rhizosphere bacteria from Zea mays and Arachis hypogaea plants in the Salem area of Tamil Nadu, India, were isolated and tested for biochemical attributes and characteristics that stimulate plant growth, such as the production of hydrogen cyanide, ammonia (6 µg/mL), indole acetic acid (76.35 µg/mL), and solubilizing phosphate (520 µg/mL). The 16S rRNA gene sequences identified the isolate LNPF1 as Pseudomonas fluorescens with a similarity percentage of 99% with Pseudomonas sp. Isolate LNPF1 was evaluated for the production of siderophore. Siderophore-rich supernatant using a Sep Pack C18 column and Amberlite-400 Resin Column (λmax 264) produced 298 mg/L and 50 mg/L of siderophore, respectively. The characterization of purified siderophore by TLC, HPLC, FTIR, and 2D-NMR analysis identified the compound as desferrioxamine, a hydroxamate siderophore. A pot culture experiment determined the potential of LNPF1 to improve iron and oil content and photosynthetic pigments in Arachis hypogaea L. and improve soil nutrient content. Inoculation of A. hypogea seeds with LNPF1 improved plant growth parameters such as leaf length (60%), shoot length (22%), root length (54.68%), fresh weight (47.28%), dry weight (37%), and number of nuts (66.66) compared to the control (untreated seeds). This inoculation also improved leaf iron content (43.42), short iron content (38.38%), seed iron (46.72%), seed oil (31.68%), carotenoid (64.40%), and total chlorophyll content (98.%) compared to control (untreated seeds). Bacterized seeds showed a substantial increase in nodulation (61.65%) and weight of individual nodules (95.97) vis-à-vis control. The results of the present study indicated that P. fluorescens might be utilized as a potential bioinoculant to improve growth, iron content, oil content, number of nuts and nodules of Arachishypogaea L., and enrich soil nutrients.

Photodynamic anticancer activity evaluation of novel 5-aminolevulinic acid and 3-hydroxypyridinone conjugates

5-Aminolevulinic acid (ALA) and its derivatives, serving as the endogenous precursor of the photosensitizer (PS) protoporphyrin IX (PpIX), successfully applied in tumor imaging and photodynamic therapy (PDT). ALA and its derivatives have been used to treat actinic keratosis (AK), basal cell carcinoma (BCC), and improve the detection of superficial bladder cancer. However, the high hydrophilicity of ALA and the conversion of PpIX to heme have limited the accumulation of PpIX, hindering the efficiency and potential application of ALA-PDT. This study aims to evaluate the PDT activity of three rationally designed series of ALA-HPO prodrugs, which were based on enhancing the lipophilicity of the prodrugs and reducing the labile iron pool (LIP) through HPO iron chelators to promote PpIX accumulation. Twenty-four ALA-HPO conjugates, incorporating amide, amino acid, and ester linkages, were synthesized. Most of the conjugates, exhibited no dark-toxicity to cells, according to bioactivity evaluation. Ester conjugates 19a-g showed promoted phototoxicity when tested on tumor cell lines, and this increased phototoxicity was strongly correlated with elevated PpIX levels. Among them, conjugate 19c emerged as the most promising (HeLa, IC50 = 24.25 ± 1.43 μM; MCF-7, IC50 = 43.30 ± 1.76 μM; A375, IC50 = 28.03 ± 1.00 μM), displaying superior photodynamic anticancer activity to ALA (IC50 > 100 μM). At a concentration of 80 μM, the fluorescence intensity of PpIX induced by compound 19c in HeLa, MCF-7, and A375 cells was 18.9, 5.3, and 2.8 times higher, respectively, than that induced by ALA. In conclusion, cellular phototoxicity showed a strong correlation with intracellular PpIX fluorescence levels, indicating the potential application of ALA-HPO conjugates in ALA-PDT.

A Study of Hepcidin Gene Polymorphism in Beta Thalassemia Major Egyptian Patients Refractory to Iron Chelation

A Study of Hepcidin Gene Polymorphism in Beta Thalassemia Major Egyptian Patients Refractory to Iron Chelation

Bile Acid-Targeted Hyaluronic Acid Nanoparticles for Enhanced Oral Absorption of Deferoxamine.

Patients with β-thalassemia and sickle cell disease often rely on blood transfusions which can lead to hemochromatosis and chronic oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat hemochromatosis but is suboptimal to patients due to its poor pharmacokinetics which requires long-term infusion regimens. Although the oral route is preferable, DFO has limited oral bioavailability. Studies have shown that hyaluronic acid (HA) and bile acid (BA) can enhance the oral absorption of poorly absorbed drugs. To improve upon the oral delivery of DFO, we report on the synthesis and characterization of HA (MW 15 kD) conjugated to two types of BA, deoxycholic acid (DOCA) and taurocholic acid (TCA), and DFO. The resulting seven polymeric conjugates all formed self-assembled nanoparticles. The degree of BA and DFO conjugation to the HA polymer was confirmed at each step through nuclear magnetic resonance, Fourier transform infrared spectroscopy, and UV-Vis spectroscopy. The best formulations for further in vitro testing were determined based on physicochemical characterizations and included HA-DFO, TCA9-HA-DFO, and DOCA9-HA-DFO. Results from in vitro assays revealed that TCA9-HA-DFO enhanced the permeation of DFO the most and was also less cytotoxic to cells compared to the free drug DFO. In addition, ferritin reduction studies indicated that the conjugation of DFO to TCA9-HA did not compromise its chelation efficiency at equivalent free DFO concentrations. This research provides supportive data for the idea that TCA conjugated to HA may enhance the oral absorption of DFO, improve its cytocompatibility, and maintain its iron chelation efficiency.

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases.

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.

Pharmacogenomics of Drugs Used in β-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications.

In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of β-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.

Preventive effects of lactoferrin on acute alcohol-induced liver injury via iron chelation and regulation of iron metabolism

Lactoferrin is widely found in milk and has the ability to bind iron. Previous studies have reported that lactoferrin was effective in the prevention and treatment of acute alcohol-induced liver injury (AALI). Ferroptosis is a recently discovered cell death and is involved in the development of AALI. However, the potential role of lactoferrin in acute alcohol-induced ferroptosis is still unclear. In this study, we observed that lactoferrin (10, 20 and 40 μg/mL) significantly mitigated alcohol (300 mM)-induced injury in vitro. Additionally, lactoferrin (100 and 200 mg/kg bw) significantly alleviated alcohol (4.8 g/kg bw)-induced injury in vivo. Our results showed that lactoferrin inhibited alcohol-induced upregulation of the ferroptosis marker protein ACSL4 and downregulation of GPX4. Meanwhile, lactoferrin treatment successfully reversed the elevated Malondialdehyde (MDA) levels and the reduced Glutathione (GSH) levels caused by alcohol treatment. These results can indicate that lactoferrin significantly decreased ferroptosis in vivo and in vitro. Lactoferrin has the potential to chelate iron, and our results showed that lactoferrin (20 μg/mL) significantly reduced iron ions and the expression of Ferritin Heavy Chain (FTH) under FeCl3 (100 μM) treatment. It was demonstrated that lactoferrin had a significant iron-chelating effect and reduced iron overload caused by FeCl3 in AML12 cells. Next, we examined iron content and the expression of iron metabolism marker proteins Transferrin Receptor (TFR), Divalent metal transporter 1 (DMT1), FTH, and Ferroportin (FPN). Our results showed that lactoferrin alleviated iron overload induced by acute alcohol. The expression of TFR and DMT1 was downregulated and FPN and FTH were upregulated after lactoferrin treatment in vivo and in vitro. Above all, the study suggested that lactoferrin can alleviate AALI by mitigating acute alcohol-induced ferroptosis. Lactoferrin may offer new strategies for the prevention or treatment of AALI.

Regulation of translation in response to iron deficiency in human cells

Protein synthesis is a highly energy-consuming process that is downregulated in response to many environmental stresses or adverse conditions. Studies in the yeast Saccharomyces cerevisiae have shown that bulk translation is inhibited during adaptation to iron deficiency, which is consistent with its requirement for ribosome biogenesis and recycling. Although iron deficiency anemia is the most common human nutritional disorder, how iron modulates translation in mammals is poorly understood. Studies during erythropoiesis have shown that iron bioavailability is coordinated with globin synthesis via bulk translation regulation. However, little is known about the control of translation during iron limitation in other tissues. Here, we investigated how iron depletion affects protein synthesis in human osteosarcoma U-2 OS cells. By adding an extracellular iron chelator, we observed that iron deficiency limits cell proliferation, induces autophagy, and decreases the global rate of protein synthesis. Analysis of specific molecular markers indicates that the inhibition of bulk translation upon iron limitation occurs through the eukaryotic initiation factor eIF2α and mechanistic target of rapamycin (mTOR) pathways. In contrast to other environmental and nutritional stresses, iron depletion does not trigger the assembly of messenger ribonucleoprotein stress granules, which typically form upon polysome disassembly.

Unveiling Extramedullary Hematopoiesis: A Case Report Highlighting the Causes, Symptoms, and Management Strategies

Extramedullary hematopoiesis (EMH) serves as a compensatory mechanism in chronic hemolytic anemias, such as thalassemia, and can result in spinal cord compression. This case report highlights a 36-year-old woman with transfusion-dependent β-thalassemia (TDT) who presented with lower extremity motor deficiency, pelvic paresthesia, and bladder dysfunction. The patient had a history of lower back pain, bilateral lower limb weakness, and demonstrated poor compliance with iron chelation therapy. MRI findings indicated spinal cord compression attributable to extramedullary hematopoiesis. Due to the infeasibility of surgical intervention, the patient underwent hypertransfusion and iron chelation therapy. While neurological symptoms improved, urinary retention persisted. The patient continues to receive iron chelation treatment and undergo transfusions. Managing extramedullary hematopoiesis in thalassemia necessitates an individualized treatment approach.

Iron regulatory protein from the hard tick Haemaphysalis longicornis: characterization, function and assessment as a protective antigen.

Ticks are blood-feeding ectoparasites with different host specificities and are capable of pathogen transmission. Iron regulatory proteins (IRPs) play crucial roles in iron homeostasis in vertebrates. However, their functions in ticks remain poorly understood. The aim of the present study was to investigate the characteristics, functions, molecular mechanisms, and the vaccine efficacy of IRP in the hard tick Haemaphysalis longicornis. The full-length complementary DNA of IRP from Haemaphysalis longicornis (HlIRP) was 2973 bp, including a 2772 bp open reading frame. It is expressed throughout three developmental stages (larvae, nymphs, and adult females) and in various tissues (salivary glands, ovaries, midgut, and Malpighian tubules). Recombinant Haemaphysalis longicornis IRP (rHlIRP) was obtained via a prokaryotic expression system and exhibited aconitase, iron chelation, radical-scavenging, and hemolytic activities in vitro. RNA interference-mediated IRP knockdown reduced tick engorgement weight, ovary weight, egg mass weight, egg hatching rate, and ovary vitellin content, as well as prolonging the egg incubation period. Proteomics revealed that IRP may affect tick reproduction and development through proteasome pathway-associated, ribosomal, reproduction-related, and iron metabolism-related proteins. A trial on rabbits against adult Haemaphysalis longicornis infestation demonstrated that rHlIRP vaccine could significantly decrease engorged weight (by 10%), egg mass weight (by 16%) and eggs hatching rate (by 22%) of ticks. The overall immunization efficacy using rHlIRP against adult females was 41%. IRP could limit reproduction and development in Haemaphysalis longicornis, and HlIRP was confirmed as a candidate vaccine antigen to impair tick iron metabolism and protect the host against tick infestation. © 2024 Society of Chemical Industry.