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Annals of Surgery Open : Perspectives... Mar 2024In this study, we present the first-in-human use of topical deferoxamine (DFO) in the treatment of a beta-thalassemia wound. We elected to use DFO on a patient that...
In this study, we present the first-in-human use of topical deferoxamine (DFO) in the treatment of a beta-thalassemia wound. We elected to use DFO on a patient that suffered from a chronic nonhealing wound in the setting of beta-thalassemia. Despite approximately 55 weeks of marginal improvement in healing, this patient's wound healed completely after 21 weeks of treatment with DFO. We believe that DFO has the potential to accelerate healing in beta-thalassemia wounds through iron chelation.
PubMed: 38883943
DOI: 10.1097/AS9.0000000000000372 -
Pharmacological Research Jun 2024Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in... (Review)
Review
Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in various fundamental biological processes. For example, diabetic cardiomyopathy is associated with elevated levels of Cu in the serum and tissues. Therefore, targeting Cu may be a novel treatment strategy for diabetic complications. This review provides an overview of physiological Cu metabolism and homeostasis, followed by a discussion of Cu metabolism disorders observed during the occurrence and progression of diabetic complications. Finally, we discuss the recent therapeutic advances in the use of Cu coordination complexes as treatments for diabetic complications and their potential mechanisms of action. This review contributes to a complete understanding of the role of Cu in diabetic complications and demonstrates the broad application prospects of Cu-coordinated compounds as potential therapeutic agents.
PubMed: 38876443
DOI: 10.1016/j.phrs.2024.107264 -
BMC Research Notes Jun 2024This study aimed to evaluate the knowledge, attitude, and practice toward iron chelating agents (ICAs) in Iranian thalassemia major patients.
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.
Topics: Humans; Iron Chelating Agents; Iran; Male; Female; Adult; Cross-Sectional Studies; Health Knowledge, Attitudes, Practice; Young Adult; Adolescent; beta-Thalassemia; Thalassemia; Deferiprone; Deferasirox; Deferoxamine; Triazoles; Middle Aged; Pyridones
PubMed: 38872196
DOI: 10.1186/s13104-024-06819-3 -
Experimental Neurology Jun 2024Neuroinflammation is a common pathological feature and onset in multiple cognitive disorders, including postoperative cognitive dysfunction (POCD). Iron deposition was...
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.
PubMed: 38866103
DOI: 10.1016/j.expneurol.2024.114862 -
Research Square May 2024Radiation-induced fibrosis (RIF) is a debilitating sequelae of radiation therapy that has been shown to improve with topical treatment with the iron chelator...
BACKGROUND
Radiation-induced fibrosis (RIF) is a debilitating sequelae of radiation therapy that has been shown to improve with topical treatment with the iron chelator deferoxamine (DFO). We investigated whether DFO exerts this effect through attenuation of ferroptosis, a recently described iron-dependent pathway of cell death.
METHODS
Adult C57BL/6J mice were treated with topical DFO or ferrostastin-1 (Fer-1) and irradiated with 30 Grays of ionizing radiation to the dorsal skin to promote development of chronic RIF. Immunofluorescent staining with 4-hydroxynonenal (4-HNE) antibody was carried out directly following irradiation to assess ferroptosis activity. Perfusion testing with laser Doppler was performed throughout the healing interval. Eight weeks following radiation, dorsal skin was harvested and analyzed histologically and biomechanically.
RESULTS
Immunohistochemical staining demonstrated lower presence of 4-HNE in non-irradiated skin, DFO-treated skin, and Fer-1-treated skin compared to irradiated, untreated skin. DFO resulted in histological measurements (dermal thickness and collagen content) that resembled normal skin, while Fer-1 treatment yielded less significant improvements. These results were mirrored by analysis of extracellular matrix ultrastructure and biomechanical testing, which recapitulated the ability of topical DFO treatment to alleviate RIF across these parameters while Fer-1 resulted in less notable improvement. Finally, perfusion levels in DFO treated irradiated skin were similar to measurements in normal skin, while Fer-1 treatment did not impact this feature.
CONCLUSIONS
Ferroptosis contributes to the development of RIF and attenuation of this process leads to reduced skin injury. DFO further improves RIF through additional enhancement of perfusion not seen with Fer-1.
PubMed: 38853919
DOI: 10.21203/rs.3.rs-4314380/v1 -
BioRxiv : the Preprint Server For... May 2024Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG...
OBJECTIVES
Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated.
METHODS
Differential expression of human B7-H3 (hB7-H3) was transduced into GD2 B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2/hB7-H3 B78 cells relative to GD2/hB7-H3 B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t = 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2/hB7-H3 and GD2/hB7-H3 B78 tumor models.
RESULTS
Flow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2/hB7-H3 B78 cells with high avidity but not GD2/hB7-H3 B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2/hB7-H3 and GD2/hB7-H3 B78 murine tumor showed similar biodistribution in normal tissues for [Zr]Zr-Df-INV34-6, [Zr]Zr-Df-bsAb CTRL, and [Zr]Zr-Df-DINU. Importantly, [Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2/hB7-H3 B78 over GD2/hB7-H3 B78 tumors, and substantially higher to GD2/hB7-H3 B78 than the non-targeted [Zr]Zr-Df-bsAb CTRL control. [Zr]Zr-Df-DINU displayed similar uptake in both GD2 tumor models, with uptake comparable to [Zr]Zr-Df-INV34-6 in the GD2/hB7-H3 B78 model.
CONCLUSION
The GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.
PubMed: 38853889
DOI: 10.1101/2024.05.23.595624 -
Ecotoxicology and Environmental Safety Jul 2024Diquat dibromide (DQ) is a globally used herbicide in agriculture, and its overuse poses an important public health issue, including male reproductive toxicity in...
Diquat dibromide (DQ) is a globally used herbicide in agriculture, and its overuse poses an important public health issue, including male reproductive toxicity in mammals. However, the effects and molecular mechanisms of DQ on testes are limited. In vivo experiments, mice were intraperitoneally injected with 8 or 10 mg/kg/ day of DQ for 28 days. It has been found that heme oxygenase-1 (HO-1) mediates DQ-induced ferroptosis in mouse spermatogonia, thereby damaging testicular development and spermatogenesis. Histopathologically, we found that DQ exposure caused seminiferous tubule disorders, reduced germ cells, and increased sperm malformation, in mice. Reactive oxygen species (ROS) staining of frozen section and transmission electron microscopy (TEM) displayed DQ promoted ROS generation and mitochondrial morphology alterations in mouse testes, suggesting that DQ treatment induced testicular oxidative stress. Subsequent RNA-sequencing further showed that DQ treatment might trigger ferroptosis pathway, attributed to disturbed glutathione metabolism and iron homeostasis in spermatogonia cells in vitro. Consistently, results of western blotting, measurements of MDA and ferrous iron, and ROS staining confirmed that DQ increased oxidative stress and lipid peroxidation, and accelerated ferrous iron accumulation both in vitro and in vivo. Moreover, inhibition of ferroptosis by deferoxamine (DFO) markedly ameliorated DQ-induced cell death and dysfunction. By RNA-sequencing, we found that the expression of HO-1 was significantly upregulated in DQ-treated spermatogonia, while ZnPP (a specific inhibitor of HO-1) blocked spermatogonia ferroptosis by balancing intracellular iron homeostasis. In mice, administration of the ferroptosis inhibitor ferrostatin-1 effectively restored the increase of HO-1 levels in the spermatogonia, prevented spermatogonia death, and alleviated the spermatogenesis disorders induced by DQ. Overall, these findings suggest that HO-1 mediates DQ-induced spermatogonia ferroptosis in mouse testes, and targeting HO-1 may be an effective protective strategy against male reproductive disorders induced by pesticides in agriculture.
Topics: Animals; Male; Ferroptosis; Mice; Spermatogonia; Heme Oxygenase-1; Testis; Diquat; Herbicides; Reactive Oxygen Species; Oxidative Stress; Spermatogenesis; Membrane Proteins
PubMed: 38850704
DOI: 10.1016/j.ecoenv.2024.116562 -
Acta Medica Portuguesa Jun 2024Acute iron poisoning is an exceedingly rare occurrence, mainly when resulting from intentional ingestion in adults. It can lead to multi-organ toxicity and, in severe...
Acute iron poisoning is an exceedingly rare occurrence, mainly when resulting from intentional ingestion in adults. It can lead to multi-organ toxicity and, in severe cases, may evolve into acute liver failure and cardiovascular collapse, which are the main causes of death. The clinical outcome is largely dependent on the amount of elemental iron ingested and the readiness of treatment, which includes support, early intestinal decontamination and deferoxamine. Despite timely intervention, acute liver failure can be life-threatening, with liver transplantation being the only potentially life-saving measure. In this case report, we describe a case of severe acute iron poisoning due to intentional ingestion that led to fulminant liver failure, which was successfully managed with liver transplantation.
Topics: Humans; Liver Failure, Acute; Male; Iron; Acute Disease; Adult
PubMed: 38848701
DOI: 10.20344/amp.21071 -
Heritage Science 2024An innovative green organogel was designed to simultaneously tackle inorganic compounds (i.e., iron corrosion) and organic substances (i.e., acrylic coatings) as...
UNLABELLED
An innovative green organogel was designed to simultaneously tackle inorganic compounds (i.e., iron corrosion) and organic substances (i.e., acrylic coatings) as undesired materials possibly present on the surface of altered indoor metal artworks. Poly-3-hydroxybutyrate (PHB), ethyl lactate (EL), and deferoxamine B (DFO) were employed in the formulation as thickening agent, organic solvent, and complexing agent, respectively, aiming to propose a sustainable and less harmful chemical cleaning method for metal care. The components were selected because they are bio-sourced, renewable, biodegradable, and non- or low-toxic materials. A multi-modal protocol of analysis was carried out to characterise the newly designed PHB-EL-DFO organogel. The cleaning performance of the novel formulation was assessed on mild steel mock-ups presenting both corrosion and organic coating to be removed. The conducted multi-analytical approach verified that the PHB-EL-DFO gel was able to tackle the two undesired materials simultaneously in an adjustable and easy-to-use way thanks to a modular application.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1186/s40494-024-01288-0.
PubMed: 38845742
DOI: 10.1186/s40494-024-01288-0 -
Talanta Jun 2024Aerosol pollutants significantly cause health concerns. Herein, we established an original real-time aerosol exposure system that used a self-designed bionic-lung...
In vitro assessment of ferroptosis of cells exposed to cigarette smoke aerosol using a self-designed on-chip evaluation system based on gas-liquid dual-dimensional exposure.
Aerosol pollutants significantly cause health concerns. Herein, we established an original real-time aerosol exposure system that used a self-designed bionic-lung microfluidic chip. The chip features a 4 × 4 intersecting array within gas and liquid layers, creating 16 distinct microenvironments. A membrane situated between the layers offers attachment for cells and establishes a gas-liquid interface. This design provides a reliable screening capacity for investigating the biological effects of aerosol exposure in vitro by manipulating the gas and/or liquid conditions. Using this system, we validated that cigarette smoke (CS) aerosol triggered a concentration- and time-dependent reduction in cell viability and intracellular glutathione levels, accompanied by an increase in intracellular reactive oxygen species and Fe. Furthermore, CS aerosol significantly downregulated the expression of GPX4, SLC7A11, and FTL mRNA while inducing a notable increase in that of ACSL4 mRNA. Additionally, CS aerosol markedly stimulated the release of proinflammatory cytokines. Crucially, the ferroptosis inhibitor deferoxamine mesylate reversed these biological indicators. These results demonstrate that our novel bionic-lung chip presents a suitably achievable approach to investigate the biological effects induced by aerosol exposure.
PubMed: 38838566
DOI: 10.1016/j.talanta.2024.126352