-
Brain Research Bulletin Feb 2024Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of...
Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of iron metabolism in neuronal survival, yet its effect on vasculature remains unclear. This study aims to explore the impact of endothelial ferroptosis on cerebrovascular function in TBI. A Controlled Cortical Impact (CCI) model was established in mice, resulting in a significant increase in iron-related proteins such as TfR1, FPN1, and FTH, as well as oxidative stress biomarker 4HNE. This was accompanied by a decline in expression of the ferroptosis inhibitor GPX4. Moreover, Perls' staining and nonhemin iron content assay showed iron overload in brain microvascular endothelial cells (BMECs) and the ipsilateral cortex. Immunofluorescence staining revealed more FTH-positive cerebral endothelial cells, consistent with impaired perfusion vessel density and cerebral blood flow. As a specific iron chelator, deferoxamine (DFO) treatment inhibited such ferroptotic proteins expression and the accumulation of lipid-reactive oxygen species following CCI, enhancing glutathione peroxidase (GPx) activity. DFO treatment significantly reduced iron deposition in BMECs and brain tissue, and increased density of the cerebral capillaries as well. Consequently, DFO treatment led to improvements in cerebral blood flow (as measured by laser speckle imaging) and behavioral performance (as measured by the neurological severity scores, rotarod test, and Morris water maze test). Taken together, our results indicated that TBI induces remarkable iron disorder and endothelial ferroptosis, and DFO treatment may help maintain iron homeostasis and protect vascular function. This may provide a novel therapeutic strategy to prevent cerebrovascular dysfunction following TBI.
Topics: Humans; Mice; Animals; Deferoxamine; Endothelial Cells; Ferroptosis; Brain Injuries, Traumatic; Iron
PubMed: 38218407
DOI: 10.1016/j.brainresbull.2024.110878 -
Stroke Dec 2021Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia resulting in high acute mortality and severe chronic neurological deficits. Spasms...
BACKGROUND AND PURPOSE
Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia resulting in high acute mortality and severe chronic neurological deficits. Spasms of the pial and intraparenchymal microcirculation (microvasospasms) contribute to acute cerebral ischemia after SAH; however, the underlying mechanisms remain unknown. We hypothesize that free iron (Fe) released from hemolytic red blood cells into the subarachnoid space may be involved in microvasospasms formation.
METHODS
Male C57BL/6 mice (n=8/group) received 200 mg/kg of the iron scavenger deferoxamine or vehicle intravenously and were then subjected to SAH by filament perforation. Microvasospasms of pial and intraparenchymal vessels were imaged three hours after SAH by in vivo 2-photon microscopy.
RESULTS
Microvasospasms occurred in all investigated vessel categories down to the capillary level. Deferoxamine significantly reduced the number of microvasospasms after experimental SAH. The effect was almost exclusively observed in larger pial arterioles (>30 µm) covered with blood.
CONCLUSIONS
These results provide proof-of-principle evidence that Fe is involved in the formation of arteriolar microvasospasms after SAH and that arteriolar and capillary microvasospasms are triggered by different mechanisms. Deciphering the mechanisms of Fe-induced microvasospasms may result in novel therapeutic strategies for SAH patients.
Topics: Animals; Arterioles; Brain Ischemia; Capillaries; Deferoxamine; Iron; Male; Mice, Inbred C57BL; Siderophores; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Mice
PubMed: 34749506
DOI: 10.1161/STROKEAHA.120.033472 -
The Journal of Surgical Research Feb 2020Deferoxamine (DFX) has been reported to have neuroprotective effect. This study aimed to investigate the neuroprotective effect of DFX and its effect on...
BACKGROUND
Deferoxamine (DFX) has been reported to have neuroprotective effect. This study aimed to investigate the neuroprotective effect of DFX and its effect on hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in rats after traumatic brain injury (TBI).
MATERIALS AND METHODS
Rats were randomly divided into sham operation, TBI + DFX, and TBI + vehicle groups. The rats in the TBI + DFX group were intraperitoneally injected with DFX 2 and 6 h after injury, thereafter once every 12 h. The rats in the TBI + vehicle group were intraperitoneally injected with saline at the same time points. At 6, 12, 24, and 48 h after TBI, 6 rats in each group were euthanized, and the brains were harvested. The expression of HIF-1α and VEGF in the pericontusional area was detected using real-time polymerase chain reaction and Western blot analysis. TBI-induced apoptosis was investigated using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Three days after TBI, the density of microvessels was examined via immunohistochemical staining.
RESULTS
DFX treatment upregulated the expression of HIF-1α and VEGF after TBI. DFX treatment reduced apoptosis and improved the neurobehavioral score after TBI. The density of microvessels was higher in the TBI + DFX group than that in the TBI + vehicle group 3 d after TBI.
CONCLUSIONS
DFX can stimulate angiogenesis, inhibit apoptosis, and play a protective role after TBI. The protective effect of DFX may, at least in part, be through upregulating the expression of HIF-1α and its downstream target gene VEGF.
Topics: Animals; Apoptosis; Behavior, Animal; Brain; Brain Injuries, Traumatic; Deferoxamine; Disease Models, Animal; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Neovascularization, Physiologic; Neurons; Neuroprotective Agents; Rats; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A
PubMed: 31630885
DOI: 10.1016/j.jss.2019.09.023 -
Molecular Pharmaceutics Feb 2023Hereditary hemochromatosis (HH) is a non-transfusional genetic iron overload (IO) disease wherein patients are not able to regulate dietary iron absorption, which...
Hereditary hemochromatosis (HH) is a non-transfusional genetic iron overload (IO) disease wherein patients are not able to regulate dietary iron absorption, which ultimately leads to excess cellular iron accumulation. Preventative measures for HH mainly include phlebotomy and asking patients to minimize dietary iron intake. To investigate alternative iron reduction strategies, we report on prophylactic non-absorbable polymer-deferoxamine (DFO) conjugates capable of chelating and reducing excessive gut uptake of dietary iron. Three different sizes of the conjugates (56 nm, 256 nm, and 7.4 μm) were prepared, and their physicochemical properties, transit times in the gut under fed/fasted conditions, acute safety, and efficacy at reducing iron absorption in a dietary iron-overload mouse model were investigated. The conjugates were synthesized through reverse phase water-in-oil (w/o) emulsions, followed by conjugation of DFO to the resulting polymer scaffolds. studies using Caco-2 transwell assays showed that the conjugates could not permeate across the monolayer, were poorly endocytosed, and did not induce cellular toxicity. mouse studies via oral gavage demonstrated that polymer-DFO conjugates remained in the gastrointestinal (GI) tract for up to 12 h and significantly prevented escalation of serum ferritin levels and excess liver iron accumulation. images of the duodenum suggest that nanometer-sized conjugates (56 and 246 nm) perform better at chelating dietary iron based on longer retention times (i.e., entrapment in the villi of the duodenum) and an overall slower transit from the GI tract compared to larger micron-sized (7.4 μm) conjugates. Overall, nanometer-sized polymer-DFO conjugates were orally non-absorbable, appeared safe, and were more efficacious at reducing dietary iron absorption when taken with non-heme containing food.
Topics: Humans; Mice; Animals; Deferoxamine; Iron, Dietary; Polymers; Caco-2 Cells; Iron Chelating Agents; Iron; Iron Overload
PubMed: 36622899
DOI: 10.1021/acs.molpharmaceut.2c00938 -
Journal of Controlled Release :... Apr 2023Intra-articular (IA) administration of drugs for the treatment of diseases such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis is a common strategy;...
Intra-articular (IA) administration of drugs for the treatment of diseases such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis is a common strategy; however, the rapid clearance from the synovial fluid restricts their effectivity due to the limited retention time. Drug Delivery Systems (DDS) are currently being developed to increase their joint retention time. This study compares the biodistribution and retention time of a senolytic peptide (PEP), with potential application in osteoarthritis disease, and this senolytic peptide encapsulated in a DDS based on a lipid nanoemulsion (PEPNE) by using positron emission tomography (PET) imaging. To this aim, the PEP was conjugated with a chelating agent (DFO) and radiolabeled with zirconium-89 (Zr). Then, [Zr]-PEP was encapsulated in a novel nanoemulsion formulation, composed by vitamin E, sphingomyelin, and a lipid-PEG. Afterward, healthy rats were administered with either the [Zr]-PEP or the [Zr]-PEP-NE via IA injection and underwent PET scans at 0.5-, 24-, 48-, 72-, 168-, 240- and 336 h post-injection. To assess the biodistribution of both radiotracers, several volume-of-interest were manually drawn in different organs of the rat body and the %ID/organ was calculated. The [Zr]-PEP was successfully encapsulated in the NE and their physicochemical properties were minimally affected by the radiolabeling buffer. Adequate stability of both [Zr]-PEP and [Zr]-PEP-NE was found in synovial fluid over 72 h. Quantitative data from PET images revealed a significantly higher [Zr]-PEP-NE retention in the injected knee than with [Zr]-PEP in all follow-up PET scans. The [Zr]-PEP %ID/organ values in the liver and kidney were significantly higher than those from [Zr]-PEP-NE, which might indicate a faster elimination of the [Zr]-PEP. Therefore, the study highlights the higher retention time on the target site of the [Zr]-PEP-NE which may improve the therapeutic effects of the peptide. Thereby, the novel nanoemulsion formulation seems to be a successful DDS for IA injection. In addition, these results represent the first study that evaluates the distribution of a PET-guided DDS after its IA administration.
Topics: Rats; Animals; Tissue Distribution; Senotherapeutics; Deferoxamine; Positron-Emission Tomography; Peptides; Lipids; Cell Line, Tumor
PubMed: 36931471
DOI: 10.1016/j.jconrel.2023.03.025 -
Biomaterials Jan 20193D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal...
3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality.
Topics: Animals; Biocompatible Materials; Bone Regeneration; Cells, Cultured; Deferoxamine; Delayed-Action Preparations; Human Umbilical Vein Endothelial Cells; Humans; Male; Mesenchymal Stem Cells; Neovascularization, Physiologic; Osteogenesis; Printing, Three-Dimensional; Rats, Sprague-Dawley; Tissue Scaffolds
PubMed: 30415019
DOI: 10.1016/j.biomaterials.2018.10.033 -
Plastic and Reconstructive Surgery Mar 2017A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization... (Comparative Study)
Comparative Study
BACKGROUND
A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization and activity of the transcription factor hypoxia-inducible factor (HIF)-1α is impaired in diabetes, leading to deficits in new blood vessel formation in response to injury. In this article, the authors compare the effectiveness of two promising small-molecule therapeutics, the hydroxylase inhibitor dimethyloxalylglycine and the iron chelator deferoxamine, for attenuating diabetes-associated deficits in cutaneous wound healing by enhancing HIF-1α activation.
METHODS
HIF-1α stabilization, phosphorylation, and transactivation were measured in murine fibroblasts cultured under normoxic or hypoxic and low-glucose or high-glucose conditions following treatment with deferoxamine or dimethyloxalylglycine. In addition, diabetic wound healing and neovascularization were evaluated in db/db mice treated with topical solutions of either deferoxamine or dimethyloxalylglycine, and the efficacy of these molecules was also compared in aged mice.
RESULTS
The authors show that deferoxamine stabilizes HIF-1α expression and improves HIF-1α transactivity in hypoxic and hyperglycemic states in vitro, whereas the effects of dimethyloxalylglycine are significantly blunted under hyperglycemic hypoxic conditions. In vivo, both dimethyloxalylglycine and deferoxamine enhance wound healing and vascularity in aged mice, but only deferoxamine universally augmented wound healing and neovascularization in the setting of both advanced age and diabetes.
CONCLUSION
This first direct comparison of deferoxamine and dimethyloxalylglycine in the treatment of impaired wound healing suggests significant therapeutic potential for topical deferoxamine treatment in ischemic and diabetic disease.
Topics: Age Factors; Amino Acids, Dicarboxylic; Animals; Deferoxamine; Diabetes Mellitus; Hyperglycemia; Iron Chelating Agents; Mice; Mixed Function Oxygenases; Wound Healing
PubMed: 28234841
DOI: 10.1097/PRS.0000000000003072 -
Dalton Transactions (Cambridge, England... Jun 2021The synergistic combination of the anticancer drug carboplatin and the iron chelator deferoxamine (DFO) served as a foundation for the development of novel...
The synergistic combination of the anticancer drug carboplatin and the iron chelator deferoxamine (DFO) served as a foundation for the development of novel multifunctional prodrugs. Hence, five platinum(iv) complexes, featuring the equatorial coordination sphere of carboplatin, and one or two DFO units incorporated at axial positions, were synthesized and characterized using ESI-HRMS, multinuclear (H, C, N, Pt) NMR spectroscopy and elemental analysis. Analytical studies demonstrated that the chelating properties of the DFO moiety were not compromised after coupling to the platinum(iv) core. The cytotoxic activity of the compounds was evaluated in monolayer (2D) and spheroid (3D) cancer cell models, derived from ovarian teratocarcinoma (CH1/PA-1), colon carcinoma (SW480) and non-small cell lung cancer (A549). The platinum(iv)-DFO prodrugs demonstrated moderate in vitro cytotoxicity (a consequence of their slow activation kinetics) but with less pronounced differences between intrinsically chemoresistant and chemosensitive cell lines as well as between 2D and 3D models than the clinically used platinum(ii) drug carboplatin.
Topics: Antineoplastic Agents; Carboplatin; Cell Proliferation; Cell Survival; Deferoxamine; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Organoplatinum Compounds; Prodrugs; Tumor Cells, Cultured
PubMed: 34031671
DOI: 10.1039/d1dt00214g -
Journal of Wound Care Jun 2018Angiogenesis, formation of new vessels from pre-existing vessels, is an essential part of wound healing. We aimed to compare amniotic membrane extract with deferoxamine...
OBJECTIVE
Angiogenesis, formation of new vessels from pre-existing vessels, is an essential part of wound healing. We aimed to compare amniotic membrane extract with deferoxamine in angiogenesis and to assess any synergistic effect.
METHOD
We examined four groups of rats (five per group): control, deferoxamine, amniotic membrane extract, and deferocxamine and amniotic membrane extract in combination. A distal-based skin flap was created. Deferoxamine (100mg/kg), amniotic membrane extract (0.1mg/ml), and the combination of both were injected subcutaneously every other day in 10 separate points (0.1 ml at each point) in the skin flap. On day 11, the animals were euthanised for histopathological evaluation.
RESULTS
Results indicated that the amniotic membrane extract raised the angiogenic markers, particularly new vessel numbers (p<0.008) and CD31+ compared with controls (p <0.003), and deferoxamine increased new vessel numbers and Von Willebrand factor (vWF) significantly compared with controls (p<0.008). There was an increase in angiogenic factors in the combined group, however, this was not statistically significant difference was observed. There was no difference between amniotic membrane extract and deferoxamine.
CONCLUSION
Amniotic membrane extract or deferoxamine could be used interchangeably in angiogenesis within wound healing due to their high safety and availability.
Topics: Amnion; Angiogenesis Inducing Agents; Animals; Deferoxamine; Disease Models, Animal; Drug Synergism; In Vitro Techniques; Male; Rats; Rats, Wistar; Skin Ulcer; Surgical Flaps; Wound Healing
PubMed: 29883292
DOI: 10.12968/jowc.2018.27.Sup6.S26 -
Shock (Augusta, Ga.) Mar 2022Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation...
Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 ± 0.060 vs. 0.021 ± 0.016, 1 ± 0.145 vs. 3.338 ± 0.221, 52.010 ± 3.587 ug/g vs. 70.500 ± 3.158 ug/g, all P < 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 ± 0.043, 2.848 ± 0.169, all P < 0.05), (72.43 ± 4.920 ug/g, P > 0.05)], or Deferoxamine (0.203 ± 0.025, 2.683 ± 0.273, 55.95 ± 2.497 ug/g, all P < 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.
Topics: Animals; Cardiopulmonary Resuscitation; Cyclohexylamines; Deferoxamine; Disease Models, Animal; Ferroptosis; Heart Arrest; Male; Myocardial Reperfusion Injury; Phenylenediamines; Rats; Rats, Sprague-Dawley; Siderophores
PubMed: 34618729
DOI: 10.1097/SHK.0000000000001869