Enhancing microbial superoxide generation and conversion to hydroxyl radicals for enhanced bioremediation using iron-binding ligands.

Harnessing bacteria for superoxide production in bioremediation holds immense promise, yet its practical application is hindered by slow production rates and the relatively weak redox potential of superoxide. This study delves into a cost-effective approach to amplify superoxide production using an Arthrobacter strain, a prevalent soil bacterial genus. Our research reveals that introducing a carbon source along with specific iron-binding ligands, including deferoxamine (DFO), diethylenetriamine pentaacetate (DTPA), citrate, and oxalate, robustly augments microbial superoxide generation. Moreover, our findings suggest that these iron-binding ligands play a pivotal role in converting superoxide into hydroxyl radicals by modulating the electron transfer rate between Fe(III)/Fe(II) and superoxide. Remarkably, among the tested ligands, only DTPA emerges as a potent promoter of this conversion process when complexed with Fe(III). We identify an optimal Fe(III) to DTPA ratio of approximately 1:1 for enhancing hydroxyl radical production within the Arthrobacter culture. This research underscores the efficacy of simultaneously introducing carbon sources and DTPA in facilitating superoxide production and its subsequent conversion to hydroxyl radicals, significantly elevating bioremediation performance. Furthermore, our study reveals that DTPA augments superoxide production in cultures of diverse soils, with various soil microorganisms beyond Arthrobacter identified as contributors to superoxide generation. This emphasizes the universal applicability of DTPA across multiple bacterial genera. In conclusion, our study introduces a promising methodology for enhancing microbial superoxide production and its conversion into hydroxyl radicals. These findings hold substantial implications for the deployment of microbial reactive oxygen species in bioremediation, offering innovative solutions for addressing environmental contamination challenges.

In situ implantable DNA hydrogel for diagnosis and therapy of postoperative rehemorrhage following intracerebral hemorrhage surgery.

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

The production of siderophore analogues using precursor-directed biosynthesis.

Siderophores are low-molecular-weight organic bacterial and fungal secondary metabolites that form high affinity complexes with Fe(III). These Fe(III)-siderophore complexes are part of the siderophore-mediated Fe(III) uptake mechanism, which is the most widespread strategy used by microbes to access sufficient iron for growth. Microbial competition for limited iron is met by biosynthetic gene clusters that encode for the biosynthesis of siderophores with variable molecular scaffolds and iron binding motifs. Some classes of siderophores have well understood biosynthetic pathways, which opens opportunities to further expand structural and property diversity using precursor-directed biosynthesis (PDB). PDB involves augmenting culture medium with non-native substrates to compete against native substrates during metabolite assembly. This chapter provides background information and technical details of conducting a PDB experiment towards producing a range of different analogues of the archetypal hydroxamic acid siderophore desferrioxamine B. This includes processes to semi-purify the culture supernatant and the use of liquid chromatography-tandem mass spectrometry for downstream analysis of analogues and groups of constitutional isomers.

High ferritin is associated with liver and bone marrow iron accumulation: Effects of 1-year deferoxamine treatment in hemodialysis-associated iron overload.

BACKGROUND: Iron (Fe) supplementation is a critical component of anemia therapy for patients with chronic kidney disease (CKD). However, serum Fe, ferritin, and transferrin saturation, used to guide Fe replacement, are far from optimal, as they can be influenced by malnutrition and inflammation. Currently, there is a trend of increasing Fe supplementation to target high ferritin levels, although the long-term risk has been overlooked. METHODS: We prospectively enrolled 28 patients with CKD on hemodialysis with high serum ferritin (> 1000 ng/ml) and tested the effects of 1-year deferoxamine treatment, accompanied by withdrawal of Fe administration, on laboratory parameters (Fe status, inflammatory and CKD-MBD markers), heart, liver, and iliac crest Fe deposition (quantitative magnetic resonance imaging [MRI]), and bone biopsy (histomorphometry and counting of the number of Fe positive cells in the bone marrow). RESULTS: MRI parameters showed that none of the patients had heart iron overload, but they all presented iron overload in the liver and bone marrow, which was confirmed by bone histology. After therapy, ferritin levels decreased, although neither hemoglobin levels nor erythropoietin dose was changed. A significant decrease in hepcidin and FGF-23 levels was observed. Fe accumulation was improved in the liver and bone marrow, reaching normal values only in the bone marrow. No significant changes in turnover, mineralization or volume were observed. CONCLUSIONS: Our data suggest that treatment with deferoxamine was safe and could improve Fe accumulation, as measured by MRI and histomorphometry. Whether MRI is considered a standard tool for investigating bone marrow Fe accumulation requires further investigation. Registry and the registration number of clinical trial: ReBEC (Registro Brasileiro de Ensaios Clinicos) under the identification RBR-3rnskcj available at: https://ensaiosclinicos.gov.br/pesquisador.

[Effect of accordion technique and deferoxamine on promoting bone regeneration in distraction osteogenesis].

Objective: To compare the effects of hypoxia-inducible drugs using deferoxamine (DFO) and accordion technique (AT) on activating the hypoxia-inducible factor 1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to promote bone regeneration and remodelling during consolidation phase of distraction osteogenesis (DO). Methods: Forty-five specific-pathogen-free adult male Sprague-Dawley (SD) rats were randomly divided into the control group, DFO group, and AT group, with 15 rats in each group. All rats underwent osteotomy to establish a right femur DO model. Then, continuous distraction was started for 10 days after 5 days of latency in each group. During the consolidation phase after distraction, no intervention was performed in the control group; DFO was locally perfused into the distraction area in the DFO group starting at the 3rd week of consolidation phase; cyclic stress stimulation was given in the AT group starting at the 3rd week of consolidation phase. The general condition of rats in each group was observed. X-ray films were conducted at the end of the distraction phase and at the 2nd, 4th, and 6th weeks of the consolidation phase to observe the calcification in the distraction area. At the 4th and 6th weeks of the consolidation phase, peripheral blood was taken for ELISA detection (HIF-1α, VEGF, CD31, and Osterix), femoral specimens were harvested for gross observation, histological staining (HE staining), and immunohistochemical staining [HIF-1α, VEGF, osteopontin (OPN), osteocalcin (OCN)]. At the 6th week of the consolidation phase, Micro-CT was used to observe the new bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular separation (Tb.Sp), trabecular number (Tb.N), and trabecular thickness (Tb.Th) in the distraction area, and biomechanical test (ultimate load, elastic modulus, energy to failure, and stiffness) to detect bone regeneration in the distraction area. Results: The rats in all groups survived until the termination of the experiment. ELISA showed that the contents of HIF-1α, VEGF, CD31, and Osterix in the serum of the AT group were significantly higher than those of the DFO group and control group at the 4th and 6th weeks of the consolidation phase ( P<0.05). General observation, X-ray films, Micro-CT, and biomechanical test showed that bone formation in the femoral distraction area was significantly better in the DFO group and AT group than in the control group, and complete recanalization of the medullary cavity was achieved in the AT group, and BMD, BV/TV, Tb.Sp, Tb.N, and Tb.Th, as well as ultimate load, elastic modulus, energy to failure, and stiffness in the distraction area, were better in the AT group than in the DFO group and control group, and the differences were significant ( P<0.05). HE staining showed that trabecular bone formation and maturation in the distraction area were better in the AT group than in the DFO group and control group. Immunohistochemical staining showed that at the 4th week of consolidation phase, the expression levels of HIF-1α, VEGF, OCN, and OPN in the distraction area of the AT group were significantly higher than those of the DFO group and control group ( P<0.05); however, at 6th week of consolidation phase, the above indicators were lower in the AT group than in the DFO group and control group, but there was no significant difference between groups ( P>0.05). Conclusion: Both continuous local perfusion of DFO in the distraction area and AT during the consolidation phase can activate the HIF-1α/VEGF signaling pathway. However, AT is more effective than local perfusion of DFO in promoting the process of angiogenesis, osteogenesis, and bone remodelling.

Deferoxamine preconditioning of canine stem cell derived extracellular vesicles alleviates inflammation in an EAE mouse model through STAT3 regulation.

Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs), specifically those preconditioned with deferoxamine (DFO) in canine adipose tissue-derived MSCs (cAT-MSCs), were explored for treating autoimmune diseases. This study assessed the effects of DFO-preconditioned EVs (EVDFO) in an experimental autoimmune encephalomyelitis (EAE) mouse model. cAT-MSCs were treated with DFO for 48 h, after which EVs were isolated. EAE mice received intranasal EV or EVDFO treatments and were euthanized following histopathologic analysis; RNA and protein expression levels were measured. Histologically, EV and EVDFO groups showed a significant reduction in inflammatory cell infiltration and demyelination. Immunofluorescence revealed increased CD206 and Foxp3 expression, indicating elevated M2 macrophages and regulatory T (Treg) cells, particularly in the EVDFO group. Treg cells also notably increased in the spleen of EVDFO -treated mice. STAT3 and pSTAT3 proteins were upregulated in the EAE groups compared to the naïve group. However, following EV treatment, STAT3 expression decreased compared to the EAE group, whereas pSTAT3 expression was similar in both the EV and EAE groups. In conclusion, EVDFO treatment resulted in reduced STAT3 expression, suggesting its role in T cell regulation and the potential of EVDFO in modulating the STAT3 pathway for reducing inflammation more effectively than non-preconditioned EVs.

Efficacy and safety of deferoxamine in moderately ill COVID-19 patients: An open label, randomized controlled trial.

BACKGROUND: Deferoxamine is a potent iron chelator that could remove iron from the virus, and severe acute respiratory syndrome coronavirus 2 requires iron to replication. Also, deferoxamine has antioxidant and cytokine-modulating effects. Therefore, we evaluated the efficacy and safety of deferoxamine in patients with moderate coronavirus disease 2019 (COVID-19). METHODS: In this randomized controlled trial, patients with moderate COVID-19 were randomly assigned in a 1:1 ratio to the deferoxamine group (received a solution of 500 mg deferoxamine divided into 4 doses a day through a nebulizer for 7 days) and the control group. The main outcomes were viral clearance, oxygen saturation (SPO2), body temperature, and respiratory rate (RR). Intensive care unit admission, hospital length of stay, and hospital mortality were also assessed. RESULTS: A total of 62 patients, with 30 in the deferoxamine group and 32 in the control group, were randomly assigned. There was no statistically significant improvement in viral clearance after the intervention ended in the deferoxamine group (36.7%) compared to the control group (34.4%). The results showed there was no significant difference between the analyzed groups in terms of SPO2, body temperature, RR, and the number of patients with a worse prognosis (SPO2 < 96%, temperature ≥ 37.5 °C, or RR ≥ 16/min) at the end of the study. There were no significant differences seen between the groups in terms of intensive care unit admission, hospital length of stay, hospital mortality, and the occurrence of adverse medication events during the follow-up period. CONCLUSION: Deferoxamine had no significant impact on improving moderately ill patients with COVID-19. However, it was well-tolerated in the patients, and this intervention demonstrated a safe profile of adverse events.

Black Phosphorus Nanosheets-Based Hydrogel for Efficient Bacterial Inhibition and Accelerating Wound Healing.

With the swift evolution of multidrug-resistant bacteria resulting from the intense and inappropriate use of antibiotics, there is a pressing need for innovative solutions. In this study, a thermosensitive hydrogel was developed for efficient bacterial inhibition and promotion of wound healing. The antibacterial chitosan (CS) thermosensitive hydrogel, cross-linked with two-dimensional photothermal nanomaterial black phosphorus (BP) nanosheets through electrostatic interactions, effectively encapsulates and sustains the release of angiogenic drug deferoxamine mesylate (DFO). This facilitates the acceleration of re-epithelialization and neovascularization by enhancing cell migration and proliferation. Following near-infrared (NIR) treatment, this hydrogel demonstrates rapid eradication of the most common multidrug-resistant bacteria encountered in clinical settings, achieved through physical disruption of bacterial membranes and photothermal therapies. Noteworthy is the significant upregulation of IL-19 expression via STAT3 signaling pathways by the BP/CS-DFO hydrogel in a full-thickness wound model. This results in the polarization of the anti-inflammatory M2 macrophage phenotype, altering the microenvironment to a pro-healing state and enhancing extracellular matrix deposition and blood vessel formation. In conclusion, the BP/CS-DFO hydrogel shows immense promise as a potential clinical candidate for wound healing and antimicrobial therapy. Its innovative design and multifunctional capabilities position it as a valuable asset in combating antibiotic resistance and enhancing efficiency in wound healing.

Anemia From Inflammation After Intracerebral Hemorrhage and Relationships With Outcome.

BACKGROUND: Baseline anemia is associated with poor intracerebral hemorrhage (ICH) outcomes. However, underlying drivers for anemia and whether anemia development after ICH impacts clinical outcomes are unknown. We hypothesized that inflammation drives anemia development after ICH and assessed their relationship to outcomes. METHODS AND RESULTS: Patients with serial hemoglobin and iron biomarker concentrations from the HIDEF (High-Dose Deferoxamine in Intracerebral Hemorrhage) trial were analyzed. Adjusted linear mixed models assessed laboratory changes over time. Of 42 patients, significant decrements in hemoglobin occurred with anemia increasing from 19% to 45% by day 5. Anemia of inflammation iron biomarker criteria was met in 88%. A separate cohort of 521 patients with ICH with more granular serial hemoglobin and long-term neurological outcome data was also investigated. Separate regression models assessed whether (1) systemic inflammatory response syndrome (SIRS) scores related to hemoglobin changes over time and (2) hemoglobin changes related to poor 90-day outcome. In this cohort, anemia prevalence increased from 30% to 71% within 2 days of admission yet persisted beyond this time. Elevated systemic inflammatory response syndrome was associated with greater hemoglobin decrements over time (adjusted parameter estimate: -0.27 [95% CI, -0.37 to -0.17]) and greater hemoglobin decrements were associated with poor outcomes (adjusted odds ratio per 1 g/dL increase, 0.76 [95% CI, 0.62-0.93]) independent to inflammation and ICH severity. CONCLUSIONS: We identified novel findings that acute anemia development after ICH is common, rapid, and related to inflammation. Because anemia development is associated with poor outcomes, further work is required to clarify if anemia, or its underlying drivers, are modifiable treatment targets that can improve ICH outcomes. REGISTRATION: https://www.clinicaltrials.gov Unique identifier: NCT01662895.

Deferoxamine alleviates chondrocyte senescence and osteoarthritis progression by maintaining iron homeostasis.

BACKGROUND: Osteoarthritis (OA) is a prevalent age-related disease characterized by the gradual deterioration of cartilage. The involvement of chondrocyte senescence is crucial in the pathogenesis of OA. Desferoxamine (DFO) is an iron chelator with therapeutic potential in various diseases. However, the relationship of chondrocyte senescence and iron homeostasis is largely unknown. METHODS: Chondrocyte senescence was induced using tert-butyl hydroperoxide (TBHP), and the impact of DFO on chondrocyte senescence and iron metabolism was assessed through techniques such as western blotting, qRT-PCR, and ß-Galactosidase staining. To assess the impact of DFO on chondrocyte senescence and the progression of osteoarthritis (OA), the surgical destabilization of the medial meniscus model was established. RESULTS: In chondrocytes, TBHP administration resulted in elevated expression of P16, P21, and P53, as well as alterations in SA-ß-gal staining. Nevertheless, DFO effectively mitigated chondrocyte senescence induced by TBHP, and reversed the decrease in collagen II expression and increase in MMP13 expression caused by TBHP. Mechanismly, TBHP induced NCOA4 expression and iron release in chondrocytes. Excessive iron could induce chondrocyte senescence, whereas, DFO could inhibit NCOA4 expression and restore ferritin level, and chelate excessive iron. Importantly, intra-articular injection of DFO enhanced collagen II expression and reduced expression of P16, P21, and MMP13 of cartilage in OA mice, and delayed cartilage degeneration. CONCLUSIONS: Overall, this study provides evidence that DFO has the potential to alleviate chondrocyte senescence induced by TBHP and slow down the progression of osteoarthritis (OA) by effectively chelating excessive iron. These findings suggest that iron chelation could be a promising therapeutic strategy for treating OA.

Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

SiO 2 Induces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model.

Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.

Enterovirus-A71 preferentially infects and replicates in human motor neurons, inducing neurodegeneration by ferroptosis.

Enterovirus A71 (EV-A71) causes Hand, Foot, and Mouth Disease and has been clinically associated with neurological complications. However, there is a lack of relevant models to elucidate the neuropathology of EV-A71 and its mechanism, as the current models mainly utilize animal models or immortalized cell lines. In this study, we established a human motor neuron model for EV-A71 infection. Single cell transcriptomics of a mixed neuronal population reveal higher viral RNA load in motor neurons, suggesting higher infectivity and replication of EV-A71 in motor neurons. The elevated RNA load in motor neurons correlates with the downregulation of ferritin-encoding genes. Subsequent analysis confirms that neurons infected with EV-A71 undergo ferroptosis, as evidenced by increased levels of labile Fe2+ and peroxidated lipids. Notably, the Fe2+ chelator Deferoxamine improves mitochondrial function and promotes survival of motor neurons by 40% after EV-A71 infection. These findings deepen understanding of the molecular pathogenesis of EV-A71 infection, providing insights which suggest that improving mitochondrial respiration and inhibition of ferroptosis can mitigate the impact of EV-A71 infection in the central nervous system.

Awareness and practical evaluation of correct use of iron chelators; a study to track the ambiguities of thalassemia patients on their medications in Iran.

PURPOSE: This study aimed to evaluate the knowledge, attitude, and practice toward iron chelating agents (ICAs) in Iranian thalassemia major patients. METHODS: A total of 101 patients with thalassemia major were involved in this cross-sectional survey. A deep medication review was done, and participants' knowledge, attitude, and practice were evaluated by a validated instrument based on a 20-scoring system. RESULTS: Statistical analyses showed 52 patients (51.5%) had a poor knowledge level (scores < 10) about their medications, 37 (36.6%) had a moderate level (scores 10-15), and 12 (11.9%) had a satisfactory level (scores > 15). Seventy-seven (76.2%) patients have positive beliefs regarding the dependence of their current health status on taking iron chelators, and 63 (62.4%) believed that they would become very ill without taking medication. The results also showed that the mean practice score in patients who received deferoxamine was 5.81 ± 3.50; in the patients who received deferiprone and those who received deferasirox, the mean scores were 7.36 ± 5.15 and 14.94 ± 4.14. Also, the knowledge and practice level had a direct linear correlation based on the regression analyses (P < 0.001). CONCLUSION: In conclusion, results of the present research suggests that the patients' knowledge about the administration, adverse events, and necessity of ICAs was not satisfactory. Improving the knowledge of thalassemia patients toward their medicines through educational interventions is highly recommended to improve their practice level.

Koji Mold-derived Lipids Disrupt the Intracellular Redox State by Decreasing the GPx4 and Intracellular Glutathione Levels, Promoting Membrane Lipid Peroxidation, and Inducing Ferroptosis in HL-60 Cells.

In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent cytotoxicity against a human leukemia cell line. Fractionation of the KML via silica gel chromatography revealed the presence of active components in fraction (Fr.) 6. Cytotoxic effects of Fr. 6 were inhibited by the ferroptosis inhibitors, ferrostatin-1 and SRS11-92, and the iron chelator, deferoxamine. Interestingly, ferroptosis inhibitors failed to prevent the KML-induced cell death. Fr. 6 decreased the expression of glutathione peroxidase 4 (GPx4) and increased the level of peroxidized plasma membrane lipids. Furthermore, Fr. 6 decreased the intracellular glutathione levels. Overall, our results suggest that Fr. 6 included in KML induces ferroptosis in HL-60 cells.

Near-Infrared Responsive Nanocomposite Hydrogel Dressing with Anti-Inflammation and Pro-Angiogenesis for Wound Healing.

Anti-inflammatory and angiogenesis are two important factors in wound healing. Wound dressings with anti-inflammation and vascularization are essential to address complex interventions, expensive treatments, and uncontrolled release mechanisms. Based on the above considerations, we designed a near-infrared (NIR)-responsive hydrogel dressing, which is composed of mPDA-DFO@LA nanoparticles (mPDA: dopamine hydrochloride nanoparticles, DFO: deferoxamine, LA: lauric acid), valsartan (abbreviated as Va), and dopamine-hyaluronic acid hydrogel. The hydrogel dressing demonstrated injectability, bioadhesive, and photothermal properties. The results indicated the obtained dressing by releasing Va can appropriately regulate macrophage phenotype transformation from M1 to M2, resulting in an anti-inflammatory environment. In addition, DFO encapsulated by LA can be sustainably released into the wound site by NIR irradiation, which further prevents excessive neovascularization. Notably, the results in vivo indicated the mPDA-DFO@LA/Va hydrogel dressing significantly enhanced wound recovery, achieving a healing rate of up to 96% after 11 days of treatment. Therefore, this NIR-responsive hydrogel dressing with anti-inflammation, vascularization, and on-demand programmed drug release will be a promising wound dressing for wound infection.

Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice.

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

Iron deposition participates in LPS-induced cognitive impairment by promoting neuroinflammation and ferroptosis in mice.

Neuroinflammation is a common pathological feature and onset in multiple cognitive disorders, including postoperative cognitive dysfunction (POCD). Iron deposition was proved to participate in this process. But how iron mediates inflammation-induced cognitive deficits remains unknown. This study aimed to investigate the mechanism of iron through the neuroprotective effect of the iron chelator deferoxamine (DFO) in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Adult C57BL/6 mice were pretreated with 0.5 µg of DFO three days before intracerebroventricular microinjection of 2 µg of LPS. The mice showed memory deficits by showing decreased percentage of distance and the time within the platform-site quadrant, fewer platform-site crossings, and shortened swimming distance around the platform in the Morris water maze test, which were significantly mitigated by DFO pretreatment. Mechanistically, DFO prevented LPS-induced iron accumulation and modulated the imbalance of proteins expression related to iron metabolism, including elevated transferrin (TF) levels and reduced ferritin (Fth) caused by LPS. DFO attenuated the LPS-induced lipid peroxidation and oxidative stress, which is evidenced by the decrease of malondialdehyde (MDA) and lipid peroxidation (LPO) levels and the increase of superoxide dismutase (SOD) activity and glutathione (GSH) concentration. Moreover, DFO ameliorated ferroptosis-like mitochondrial damages in the hippocampus and also alleviated the expression of ferroptosis-related proteins in the hippocampus. Additionally, DFO attenuated microglial activation, alleviated LPS-induced inflammation, and reduced elevated levels of IL-6 and TNF-α in the hippocampus. Taken together, our findings suggested that DFO exerts neuroprotective effects by alleviating excessive iron participation in lipid peroxidation, reducing the occurrence of ferroptosis, inhibiting the vicious cycle between oxidative stress and inflammation, and ultimately ameliorating LPS-induced cognitive dysfunction, providing novel insights into the immunopathogenesis of inflammation-related cognitive dysfunction and future potential prevention options targeting iron.

Tumor Cell Membrane-Encapsulated MLA Solid Lipid Nanoparticles for Targeted Diagnosis and Radiosensitization Therapy of Cutaneous Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is a common nonmelanoma skin cancer. Radiotherapy plays an integral role in treating SCC due to its characteristics, such as diminished intercellular adhesion, heightened cell migration and invasion capabilities, and immune evasion. These problems lead to inaccurate tumor boundary positioning and radiotherapy tolerance in SCC treatment. Thus, accurate localization and enhanced radiotherapy sensitivity are imperative for effective SCC treatment. To address the existing limitations in SCC therapy, we developed monoglyceride solid lipid nanoparticles (MG SLNs) and enveloped them with the A431 cell membrane (A431 CM) to create A431@MG. The characterization results showed that A431@MG was spherical. Furthermore, A431@MG had specific targeting for A431 cells. In A431 tumor-bearing mice, A431@MG demonstrated prolonged accumulation within tumors, ensuring precise boundary localization of SCC. We further advanced the approach by preparing MG SLNs encapsulating 5-aminolevulinic acid methyl ester (MLA) and desferrioxamine (DFO) with an A431 CM coating to yield A431@MG-MLA/DFO. Several studies have revealed that DFO effectively reduced iron content, impeding protoporphyrin IX (PpIX) biotransformation and promoting PpIX accumulation. Simultaneously, MLA was metabolized into PpIX upon cellular entry. During radiotherapy, the heightened PpIX levels enhanced reactive oxygen species (ROS) generation, inducing DNA and mitochondrial damage and leading to cell apoptosis. In A431 tumor-bearing mice, the A431@MG-MLA/DFO group exhibited notable radiotherapy sensitization, displaying superior tumor growth inhibition. Combining A431@MG-MLA/DFO with radiotherapy significantly improved anticancer efficacy, highlighting its potential to serve as an integrated diagnostic and therapeutic strategy for SCC.

Biomimetic Analogues of the Desferrioxamine E Siderophore for PET Imaging of Invasive Aspergillosis: Targeting Properties and Species Specificity.

The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [68Ga]Ga(III)-FOXE analogues were internalized in A. fumigatus cells via Sit1. Uptake of [68Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus aureus. However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by A. fumigatus compared to that by S. aureus, whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both in vitro and in vivo, including PET imaging in infection models. Overall, this study provided valuable structural insights into the specificity of siderophore uptake and, for the first time, opened up ways for selective targeting and imaging of microbial pathogens by siderophore derivatization.