Ischemic stroke is characterized by brain tissue iron accumulation. Alpha-synuclein (α-Syn) is a neuronal protein, its overexpression in ischemic stroke triggers apoptosis. Lymphocyte activation gene-3 (LAG-3), a receptor for α-Syn, enhances its neurotoxic effects. It is split from the cell membrane forming soluble LAG-3 (sLAG-3) in the bloodstream. The expression of LAG-3 in the brain, its relation to iron and α-Syn, as well as the association between serum sLAG-3 levels, iron, α-Syn, and stroke severity remains poorly understood. A case-control study was generated involving 24 patients with acute ischemic stroke and 24 healthy controls. In addition, an experimental study was designed involving 24 Wistar-albino rats. We randomly assigned rats to three groups: sham-operated, brain ischemia, and deferoxamine-treated ischemic rats. Ischemia decreased serum levels of iron, while increased serum levels of α-Syn and sLAG-3. Significant diagnostic performance of serum α-Syn and sLAG-3 was determined using the ROC curve (AUC=0.962, 83.33% sensitivity, and 95.83% specificity for α-Syn; AUC=0.755 with 62.50% sensitivity and 87.50% specificity for LAG-3). In rats, ischemia elevated brain tissue iron, α-Syn, and LAG-3 which were reduced following deferoxamine treatment. In conclusion, brain ischemia is associated with iron accumulation that promotes α-Syn expression and aggregation, potentially through increasing LAG-3 expression which improved after deferoxamine injection. In addition, this study illuminates the future beneficial targeting of LAG-3 in brain ischemia.

BackgroundPatellar dislocation (PD) is closely associated with femoral trochlear dysplasia, yet the underlying molecular mechanisms remain unclear. This study aims to investigate the role of HIF-1α/VEGF-mediated angiogenesis-osteogenesis coupling in trochlear dysplasia following PD and to evaluate the therapeutic potential of the iron chelator deferoxamine (DFO) through HIF-1α stabilization.Materials and methodsThe PD model was established in 4-week-old male C57BL/6 N mice, which were then randomly divided into three groups: Sham, PD, and DFO. The DFO group received intra-articular injections of DFO (100 mg/kg, 20 µl) every five days postoperatively. Distal femurs were collected 30 days after surgery. RT-qPCR and Western blot were used to detect the expression of HIF-1α, VEGF, and RUNX2, ALP, and OPN osteogenic markers. The trochlear morphology assessment including sulcus angle and trochlear depth, along with bone microarchitecture parameters such as BV/TV, BMD, Tb.N, Tb.Th, and Tb.Sp, were quantified using micro-CT. Cartilage degeneration was evaluated with HE, Alcian blue, and Safranin O/fast green staining. Immunohistochemistry (IHC) was used to detect the expression of COL2A1 in tissue sections. Statistical analyses were performed using SPSS 21.0, with significance set at P < 0.05.ResultsCompared with the Sham group, the PD group showed significantly decreased mRNA and protein expression of HIF-1α and VEGF, accompanied by reduced expression of osteogenic-specific genes (RUNX2, ALP, OPN). DFO treatment reversed these changes. Micro-CT revealed significantly increased sulcus angle and decreased trochlear depth in the PD group, with partial restoration of trochlear morphology in the DFO group. Regarding bone microstructure, the PD group exhibited decreased BV/TV, BMD, Tb.N and Tb.Th, along with increased Tb.Sp, while DFO treatment improved these bone parameters. Histological and IHC analyses demonstrated reduced cartilage thickness, diminished chondrocyte populations, disrupted structural organization and decreased COL2A1 expression in the PD group, but DFO treatment alleviated cartilage degeneration.ConclusionHIF-1α/VEGF-mediated angiogenesis-osteogenesis coupling plays an important role in trochlear dysplasia following PD. Intra-articular injections of DFO improve trochlear morphology, bone microstructure, and reduce cartilage degeneration by stabilizing HIF-1α to upregulate VEGF and osteogenic markers (RUNX2, ALP, OPN).

Abstract Purpose To assess the efficacy of iron chelation therapy in improving cardiac function in iron overload cardiomyopathy (IOC) rats by using Cardiac magnetic resonance feature-tracking (CMR-FT). Methods The IOC rat model was induced by intraperitoneal injection of iron dextran over 2 months. Subsequently, 7 rats with IOC were assigned as IOC group to receive continued intraperitoneal injections of saline for an additional 2 months, while another group of 5 rats received intraperitoneal injections of deferoxamine (DFO) for the same duration, forming the IOC+DFO group. Meanwhile, a control group consisting of 7 healthy rats received intraperitoneal injections of saline for the entire duration of 4 months. All rats underwent a 7T CMR scan to assess cardiac function, myocardial iron overload, and myocardial fibrosis via cine, T2 mapping, and late gadolinium enhancement (LGE) scanning, respectively. The cardiac function analysis included left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (GLS) using cine images. Following CMR scans, all rats underwent open-chest blood collection to detect serum iron levels, and cardiac gross specimens were then subjected to pathological staining, including hematoxylin and eosin (HE) for cardiomyocytes injury, Prussian blue for iron deposition , and Masson staining for myocardial fibrosis. Furthermore, the ultrastructure of cardiomyocyte was examined using transmission electron microscopy (TEM). Results The T2 value, measured in the septum wall at the mid-layer of the LV, and LVEF, and GLS exhibited a significant decrease in the IOC or IOC+DFO group, compared to the control group, while there were no significant difference observed between the IOC and IOC+DFO group (Fig. 1A, B, C). Myocardial fibrosis was not detected in the LGE images in both IOC and IOC+DFO group. Compared to the control group (37.5±12.5μmol/L) , serum iron levels were significantly elevated in the IOC group (368.6±181.0μmol/L) and in chelation treatment group (106.1±32.2μmol/L). Histological examination with HE staining revealed a normal arrangement of myocardial cells in all rats, without cellular degeneration or necrosis. Prussian blue staining highlighted the presence of iron particles within the myocardial interstitium in the IOC and IOC+DFO groups. Masson staining demonstrated intact myocardial muscle bundles without any evidence of myocardial fibrosis. Transmission electron microscopy (TEM) revealed myocardial mitochondria injury, characterized by ruptured outer membranes, reduced cristae, and vacuolization. Conclusions Following iron chelation therapy, the excessive iron burden in the bloodstream was alleviated. However, myocardial iron overload persisted in IOC rats, with no significant improvement in cardiac function observed. This persistence may be attributed to mitochondrial injury. The findings underscore the importance of monitoring cardiac dysfunction in patients with iron overload.CMR parameters analysis in IOC rats

As one of the most common iron-chelating agents, deferoxamine (DFO) rapidly chelates iron in the body. Moreover, it does not compete for the iron characteristic of hemoglobin in the blood cells, which is common in the clinical treatment of iron poisoning. Iron is a trace element necessary to maintain organism normal life activities. Iron deficiency can lead to anemia, whereas iron overload can cause elevated levels of cellular oxidative stress and cell damage. As a consequence, detection of the iron content in tissues and blood is of great significance. The traditional techniques for detecting the iron content include inductively coupled plasma-mass spectrometry and atomic absorption spectrometry, which cannot be used for imaging purposes. Laser ablation-ICP-MS and synchrotron radiation micro-X-ray fluorescence can map the concentration and distribution of iron in tissues. However, these methods can only be used to measure the total iron levels in blood or tissues. In recent years, due to the deepening understanding of iron metabolism, diseases related to iron overload have attracted increasing attention. Therefore, we took advantage of the properties of DFO in terms of chelating iron and investigated different sampling times following DFO injection in the tail vein of mice. We used mass spectrometry imaging (MSI) technology to detect the DFO and ferrioxamine content in the blood and different tissues to indirectly characterize the non-heme iron content.

Topical patch delivery of deferoxamine (DFO) has been studied as a treatment for this fibrotic transformation in irradiated tissue. Efficacy of a novel cream formulation of DFO was studied as a RIF therapeutic in unwounded and excisionally wounded irradiated skin. C57BL/6J mice underwent 30 Gy of radiation to the dorsum followed by 4 weeks of recovery. In a first experiment, mice were separated into six conditions: DFO 50 mg cream (D50), DFO 100 mg cream (D100), soluble DFO injections (DI), DFO 1 mg patch (DP), control cream (Vehicle), and irradiated untreated skin (IR). In a second experiment, excisional wounds were created on the irradiated dorsum of mice and then divided into four treatment groups: DFO 100 mg Cream (W-D100), DFO 1 mg patch (W-DP), control cream (W-Vehicle), and irradiated untreated wounds (W-IR). Laser Doppler perfusion scans, biomechanical testing, and histological analysis were performed. In irradiated skin, D100 improved perfusion compared to D50 or DP. Both D100 and DP enhanced dermal characteristics, including thickness, collagen density and 8-isoprostane staining compared to untreated irradiated skin. D100 outperformed DP in CD31 staining, indicating higher vascular density. Extracellular matrix features of D100 and DP resembled normal skin more closely than DI or control. In radiated excisional wounds, D100 facilitated faster wound healing and increased perfusion compared to DP. The 100 mg DFO cream formulation rescued RIF of unwounded irradiated skin and improved excisional wound healing in murine skin relative to patch delivery of DFO.

Introduction: Ocular siderosis is a vision-threatening condition resulting from intraocular iron toxicity. This case re-establishes a role for subconjunctival deferoxamine, a chelating agent uncommonly used in ophthalmology, as an adjunctive treatment for ocular siderosis. Case Report: A 37-year-old healthy male presented two months after an injury at work with intermittent pain and blurry vision in the right eye. Presenting visual acuity (VA) was 20/100 in the right eye. With delayed presentation, the patient already had ocular siderosis with corneal rust deposits and retinal damage. The patient underwent pars plana vitrectomy (PPV) with surgical view impaired by corneal deposits and intraocular metallic intraocular foreign body (IOFB) that disintegrated upon attempted removal. At six months postoperatively, VA was 20/70 in the right eye, and examination revealed worsened diffuse, pigmented subepithelial deposits in the central cornea, iris atrophy, cotton wool spots, optic nerve pallor, and a residual IOFB in the anterior vitreous, consistent with worsened ocular siderosis. Superficial keratectomy was performed in combination with repeat PPV to improve surgical visualization and aid in IOFB removal. An amniotic membrane was placed and a subconjunctival injection of deferoxamine was administered. The cornea was well-healed with significantly improved siderosis and no epithelial defects on 2-week postoperative follow-up. Visual acuity was 20/60 at last follow-up two months postoperatively after second surgery. Conclusion: In treating ocular siderosis, subconjunctival injection of deferoxamine can be a useful addition to surgical IOFB removal to prevent the accumulation of iron deposits in the anterior segment of the eye.

Patients with β-thalassemia major depend on lifelong transfusion, resulting in tissue iron overload. This longitudinal retrospective observational study aims to assess myocardial and liver iron overload using magnetic resonance imaging (MRI) and investigate the lag between myocardial and liver iron unloading in β-thalassemia patients undergoing chelation therapy. Beta-thalassemia major patients with at least two MRI studies between 2016 and 2020 were enrolled. Myocardial and liver iron overload were defined as T2 ∗ less than 20 and 2.1, respectively. Outcomes included mortality, myocardial and liver T2 ∗ changes, and systolic dysfunction assessed by cardiac MRI. Fifty-five patients with a mean age of 24.62 ± 7.94 years, a mean follow-up duration of 24.3 ± 12.9 months, and a mean ferritin level of 1475.75 ± 771.12 ng/mL were enrolled. All of the abovementioned patients only took deferoxamine as the iron-chelating medication. Mortality occurred in three patients (5.5%) during follow-up. Liver T2 ∗ significantly increased (p value <0.05), while myocardial T2 ∗ showed a nonsignificant increase. Iron unloading of the myocardium was not significantly different from that of the liver and did not result in a significant lag (56% vs. 44%; p value = 0.419). Baseline myocardial T2 ∗ correlated with extramedullary hematopoiesis, weekly number of deferoxamine injections (p value <0.01), timing between the transfusions, and serum ferritin (p value <0.05). Liver T2 ∗ reduced during deferoxamine chelation therapy, while myocardial T2 ∗ remained unchanged. No significant lag was observed between myocardial and liver iron unloading. Further studies are required to elucidate these findings.

Diabetic nephropathy (DN) is one of the most devastating diabetic microvascular complications. It has previously been observed that iron metabolism levels are abnormal in diabetic patients. However, the mechanism by which iron metabolism levels affect DN is poorly understood. This study was designed to evaluate the role of iron-chelator deferoxamine (DFO) in the improvement of DN. Here, we established a DN rat model induced by diets high in carbohydrates and fat and streptozotocin (STZ) injection. Our data demonstrated that DFO treatment for three weeks greatly attenuated renal dysfunction as evidenced by decreased levels of urinary albumin, blood urea nitrogen, and serum creatinine, which were elevated in DN rats. Histopathological observations showed that DFO treatment improved the renal structures of DN rats and preserved podocyte integrity by preventing the decrease of transcripts of nephrin and podocin. In addition, DFO treatment reduced the overexpression of fibronectin 1, collagen I, IL-1β, NF-κB, and MCP-1 in DN rats, as well as inflammatory cell infiltrates and collagenous fibrosis. Taken together, our findings unveiled that iron chelation via DFO injection had a protective impact on DN by alleviating inflammation and fibrosis, and that it could be a potential therapeutic strategy for DN.

Background/aimsNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Iron overload has been implicated in chronic non-communicable liver diseases, but its relationship with NAFLD remains unclear. This study aimed to investigate the underlying roles of iron overload in the development of NAFLD.MethodsMale Sprague Dawley rats were fed with a high-fat diet (HFD) and/or iron for 8, 12, and 20 weeks. Some rats fed with HFD plus iron also received intraperitoneal injection of deferoxamine (DFO) for 8 weeks. Liver steatosis, lipid metabolism and injury were evaluated.ResultsA NAFLD model, including typical liver steatosis, was established by feeding rats with a HFD, while iron overload alone is not enough to induce severe NAFL. Compared with rats fed a HFD, excess iron further increased lipid accumulation, serum levels of lipids, enzymes of liver function, and expression levels of CD36 and FAS in rat liver. In addition, iron overload decreased the activities of antioxidative enzymes in liver compared with HFD rats. The levels of CPT1 and the ratios of p-ACC/ACC were also decreased by iron overload. DFO effectively reversed the abnormal lipid metabolism and liver damage induced by a high-fat, high-iron diet.ConclusionA HFD plus iron overload might synergistically aggravate lipid metabolism disorders, liver injury, and oxidative damage, compared with a HFD alone. DFO might help to alleviate lipid metabolism dysfunction and improve the pathogenesis of NAFLD.

High altitude environments present many constraints for mammals, the most well‐known being the lack of oxygen or hypoxia. Nevertheless, several ecological reports show that mice (Mus musculus) unlike rats (Rattus norvegicus) are present above 4000m1 although they are not native to this environment. The associated general hypothesis is that mice are pre‐adapted to high altitude environments. There are also differences in mitochondrial2, ventilatory and metabolic3 responses to hypoxia between these two species. One of the mechanisms involved in many of these responses is the hypoxia‐inducible factor HIF, which helps maintain the cell's oxygen homeostasis. What precisely are the different roles of HIF in mitochondrial, ventilatory, and metabolic responses to hypoxia in rats and mice, two species more or less adapted to high‐altitude environments? Does the pharmacological stabilization of HIF in normoxia mimic the responses observed in hypoxia? Conversely, does blocking HIF in hypoxia suppress these same responses? We measured the ventilatory and metabolic responses (whole body plethysmography) of rats (SD) and mice (FVB) under the following conditions: (i) 6h normoxia (21% O2); (ii) 6h hypoxia (10% O2); (iii) 6h normoxia with injection of deferoxamine, a HIF stabilizer (200mg/kg) and (iv) 6h hypoxia with injection of 2‐methoxyestradiol, a HIF blocker (5mg/kg). In addition, we evaluated mitochondrial respiration in homogenates of liver and cerebral cortex, two organs sensitive to hypoxia. Our preliminary results show that hypoxia increases ventilation and reduces metabolism and complex I efficiency in the cerebral cortex. Furthermore, pharmacological stabilization of HIF has no effect on the ventilatory response, but seems to mimic some mitochondrial and metabolic responses to hypoxia, whereas blocking HIF has no effect on these same responses. If in mice blocking HIF in hypoxia reduces the amplitude of the observed responses, our data will demonstrate fundamental differences in the mechanisms of responses to hypoxia between these two species that would strongly support our general hypothesis.

Objective: Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to OA progression. Because iron deposition is a major pathological event in ferroptosis, deferoxamine (DFO), an effective iron chelator, has been used to inhibit ferroptosis in various degenerative disease models. Nevertheless, its OA treatment efficacy remains unknown. We aimed to determine whether DFO alleviates chondrocyte ferroptosis and its effect on OA and to explore its possible mechanism.Methods: Interleukin-1β (IL-1β) was used to simulate inflammation, and chondrocyte ferroptosis was induced by erastin, a classic ferroptosis inducer. A surgical destabilized medial meniscus mouse model was also applied to simulate OA in vivo, and erastin was injected into the articular cavity to induce mouse knee chondrocyte ferroptosis. We determined the effects of DFO on ferroptosis and injury-related events: chondrocyte inflammation, extracellular matrix degradation, oxidative stress, and articular cartilage degradation.Results: IL-1β increased the levels of ROS, lipid ROS, and the lipid peroxidation end product malondialdehyde (MDA) and altered ferroptosis-related protein expression in chondrocytes. Moreover, ferrostatin-1 (Fer-1), a classic ferroptosis inhibitor, rescued the IL-1β–induced decrease in collagen type II (collagen II) expression and increase in matrix metalloproteinase 13 (MMP13) expression. Erastin promoted MMP13 expression in chondrocytes but inhibited collagen II expression. DFO alleviated IL-1β– and erastin-induced cytotoxicity in chondrocytes, abrogated ROS and lipid ROS accumulation and the increase in MDA, improved OA-like changes in chondrocytes, and promoted nuclear factor E2–related factor 2 (Nrf2) antioxidant system activation. Finally, intra-articular injection of DFO enhanced collagen II expression in OA model mice, inhibited erastin-induced articular chondrocyte death, and delayed articular cartilage degradation and OA progression.Conclusion: Our research confirms that ferroptosis occurs in chondrocytes under inflammatory conditions, and inhibition of chondrocyte ferroptosis can alleviate chondrocyte destruction. Erastin-induced chondrocyte ferroptosis can stimulate increased MMP13 expression and decreased collagen II expression in chondrocytes. DFO can suppress chondrocyte ferroptosis and promote activation of the Nrf2 antioxidant system, which is essential for protecting chondrocytes. In addition, ferroptosis inhibition by DFO injection into the articular cavity may be a new OA treatment.

Background: Avascular necrosis of the lunate or Kienböck‎ disease is a rare disorder with unknown etiology and challenging treatment. Objectives: In this study, we evaluated the effects of local deferoxamine injection as an angiogenic molecule and core decompression to treat Kienböck‎ disease. Methods: In a pilot clinical trial, 8 patients with stage I to IIIA of Kienböck‎ disease were treated with core decompression and local deferoxamine injection (0.5 mL 500 mg/mL). The outcome measures included wrist range of motions, pinch and grip strength, patient-rated ‎wrist/hand evaluation (PRWE), a short form of disabilities of the arm, shoulder, and hand (Quick-DASH), and visual analog scale (VAS) for pain. The assessment of lunate revascularization was also done by T1- and T2-weighted magnetic resonance imaging. All measurements were done before the intervention and 3, 6, and 12 months after the intervention. Results: Wrist flexion, extension, ulnar and ‎radial deviation, and pinch and grip strength were continuously improved over the postoperative periods. These improvements were statistically significant. The mean final pinch and grip strength averaged 87.4% and 72.8% of the non-involved hand, respectively. PRWE, Quick-DASH, and VAS scores were also continuously and significantly improved over the study period. The lunate vascularization revealed a continuous improvement in 6(75%) patients. Conclusion: Local deferoxamine injection in addition to core decompression could improve the radiologic and clinical outcomes of patients suffering from Kienböck‎ disease.

BackgroundPoor osseointegration is the key reason for implant failure after arthroplasty,whether under osteoporotic or normal bone conditions. To date, osseointegration remains a major challenge. Recent studies have shown that deferoxamine (DFO) can accelerate osteogenesis by activating the hypoxia signaling pathway. The purpose of this study was to test the following hypothesis: after knee replacement, intra-articular injection of DFO will promote osteogenesis and osseointegration with a 3D printed titanium prosthesis in the bones of osteoporotic rats.Materials and methodsNinety female Sprague–Dawley rats were used for the experiment. Ten rats were used to confirm the successful establishment of the osteoporosis model: five rats in the sham operation group and five rats in the ovariectomy group. After ovariectomy and knee arthroplasty were performed, the remaining 80 rats were randomly divided into DFO and control groups (n = 40 per group). The two groups were treated by intraarticular injection of DFO and saline respectively. After 2 weeks, polymerase chain reaction (PCR) and immunohistochemistry were used to evaluate the levels of HIF-1a, VEGF, and CD31. HIF-1a and VEGF have been shown to promote angiogenesis and bone regeneration, and CD31 is an important marker of angiogenesis. After 12 weeks, the specimens were examined by micro-computed tomography (micro-CT), biomechanics, and histopathology to evaluate osteogenesis and osseointegration.ResultsThe results of PCR showed that the mRNA levels of VEGF and CD31 in the DFO group were significantly higher than those in the control group. The immunohistochemistry results indicated that positive cell expression of HIF-1a, VEGF, and CD31 in the DFO group was also higher. Compared with the control group, the micro-CT parameters of BMD, BV/TV, TB. N, and TB. Th were significantly higher. The maximal pull-out force and the bone-to-implant contact value were also higher.ConclusionsThe local administration of DFO, which is used to activate the HIF-1a signaling pathway, can promote osteogenesis and osseointegration with a prosthesis in osteoporotic bone.

ABSTRACT Objectives: Intracerebral hemorrhage (ICH) is a devastating type of strokes that carries high mortality rates, but effective therapeutic options are still lacking. Here, the adult rat model of ICH was used to investigate the efficacy of a combinational therapy of deferoxamine (DFX) and minocycline. Methods: The ICH was induced by stereotaxic infusion of collagenase into striatum of adult rats. After the induction of ICH, rats were treated with intraperitoneal injection of deferoxamine (50 mg/kg), minocycline (45 mg/kg), or both agents, at 2 hours after ICH and then every 12 hours for up to 3 days. The vehicle group were treated with phosphate-buffered saline (PBS) only. Rats were killed at 1, 2, and 3 day(s) for examination of iron deposition, neuronal death, neurological deficits, the area of brain damage, activation of microglia/macrophages. Results: Our data revealed that the systemic administration of DFX and/or minocycline decreased iron accumulation. And immunofluorescence staining results indicated that drug-treated group significantly decreased the neuronal degeneration, the number of activated microglia/macrophages and the amount of cell death after ICH. In addition, neurological deficits caused by ICH were improved in the presence of DFX and/or minocycline compare with vehicle group. Furthermore, the combination treatment showed better effects in neuroprotection and anti-inflammation when compared to the monotherapy groups. Conclusions: The combination therapy significantly reduces the number of neuronal deaths, suppresses of the activation of microglia/macrophages, decreases iron accumulation in the area around the hematoma, lessening the brain damage area, and improving neurological deficits in ICH.

Cisplatin is a major classical anticancer agents. However, cisplatin induced nephrotoxicity remains a major dose limiting side effect. Several studies has highlighted the role of catalytic iron content in several diseases including cispatin nephrotoxicity opening the doors for adding iron chelators as an adjunct therapy to cisplatin therapy. Since deferoxamine is the major approved chelation therapy in iron overload disorders, the current study was directed to exploring the possible nehroprotective outcomes of deferoxamine in an acute animal model of cisplatin induced renal injury. Male Spargue-Dawley rats were injected i.p. daily for 6 consecutive days with 3 different dose levels of deferoxamine as follows: 100, 200 and 300 mg/kg. On day 3, cisplatin was injected i.p. as a single dose of 7.5 mg/kg and animals were sacrificed on day 7. Measurement of serum creatinine and blood urea nitrogen (BUN) showed that iron chelation by deferoxamine failed to improve kidney function as demonstrated by the consistent high creatinine and BUN levels in all the treated groups. Calculation of kidney indices further confirmed the previous measurements. Histopathological examination of the renal tissues of animals showed the development of tubular degeneration in all treated groups indicating the absence of significant nephroprotection. In conclusion, our results show that the daily i.p. injection of deferoxamine is not protective against cisplatin induced acute renal injury. However, the well-established body of evidence supporting the potential contribution of catalytic iron in cisplatin induced nephrotoxicity establishes the demand for investigating the potential nephroprotective effects of other established iron chelation therapies.

The effect of deferoxamine injection on composite graft survival in rabbits

Background The incidence of osteoporotic fractures is increasing. In this study, we explored the activities of Wnt/β-catenin signaling in bone tissues with iron accumulation. Methods We established rat bipedal walking models (RBWM), and a portion of our RBWM rats were intraperitoneally injected with ferric ammonium citrate, normal saline, and deferoxamine. Bone mineral density was measured with a small animal in vivo imaging system. The protein levels of ferritin, TRAP-5B, RANKL, and OPG in serum were measured by the enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to quantify the RNA and protein expression levels of certain regulators involved in Wnt/β-catenin signaling in bone tissues. Results In the present study, we established a rat bipedal walking model containing 32 bipedal rats, which were randomly classified into four groups, termed as NS, FAC, FAC+NS, and FAC+DFO. Those three experimental groups with FAC injection had significantly lower bone mineral density (BMD) than the control group NS (P < 0.05). The disruption of bone homeostasis and downregulation of Wnt/β-catenin signaling were also observed in the three groups with FAC injection. Moreover, after the injection of deferoxamine, those aberrations in samples with FAC injection seemed repaired as test results returning or getting close to normal ranges. Conclusion The osteoporosis could be caused by iron overload, which reduced the bone mineral density by disrupting the homeostasis of bone formation and absorption and attenuating the Wnt/β-catenin signaling in bone tissues. The deferoxamine had the potential to improve the bone health by reducing the accumulation of iron and increasing the bone mass, which might be a promising therapeutic solution for osteoporosis.

The iron chelator deferoxamine is a hypoxia biomimicry and has received interest as a potential therapeutic in tissue engineering and regenerative medicine. Recently, local injection of this iron chelator deferoxamine has proven to increase bone healing through the activation of the hypoxia-inducible factor-1 signaling pathway that augments angiogenesis and osteogenesis. Repeated injections of deferoxamine are required to achieve local therapeutic levels at fracture site. To achieve local therapeutic levels at fracture site without the use of multiples injections and associated pain and infection issues, we designed and prepared polymeric microspheres made of polycaprolactone and poly(ethylene oxide), in which deferoxamine was encapsulated, via a melting process. The application of this process has enabled to obtain spheres of different poly(ethylene oxide) concentrations for optimizing the drug release rate. The effective local release carrier offers a predetermined rate that can mimic the effect of repeated deferoxamine injections over a 14-day period to selectively stimulate bone repair and thus improve the biological performance to the point where ideally synthetics begin to challenge autograft dominance as the bone replacement of choice.

Purpose: To develop a chromatographic method for the determination of deferoxamine (DFX) and Dpenicillamine (D-PEN) by improving ultra violet (UV)-absorption via complex formation with Fe 2+ and Cu 2+ metal ions. Methods: Chromatographic analysis was performed by Waters RP-HPLC system using a Symmetry® C (18) column with a mobile phase comprising 0.1 % formic acid and methanol (95:5 v/v). For complexation process, drug and metal ion solution were mixed in a ratio of 1:5 and the resulting complex directly analyzed. Validation and system suitability parameters (including chromatographic parameters) were determined. Results: DFX-Fe 2+ and D-PEN-Cu 2+ complexes showed good UV absorption at 260 nm and were easily determined by the newly developed HPLC method. The developed method showed linearity over the concentration range of 8 - 96 μgmL -1 (R 2 > 0.999 for DFX and > 0.99 for D-PEN). Precision and accuracy were also within acceptable limits (100.0 ± 2.0 %). Conclusion: The developed method is robust and validated, and satisfies all the system suitability requirements as per ICH guidelines. DFX injection and D-PEN capsule dosage forms can be successfully analysed with the proposed method. The method is simple, fast and cost-effective for the analysis of D-PEN and DFX individually, or simultaneously in bulk drugs as well as in capsule and parenteral formulations, using UV-detector. Keywords: Deferoxamine, D-penicillamine, Chelate formation, Metal ions, HPLC, Dosage forms

Objective The aim of our study is to compare the role of the new natural alternative (Quercetin) with the current iron-chelation therapy (Deferoxamine (DFO)) in the effect of iron overload on small intestinal tissues and to investigate the possible underlying molecular mechanisms of such toxicity. Methods Forty-two adult male albino rats were divided into six groups: control groups, DFO, Quercetin, iron overload, iron overload+DFO, and iron overload+Quercetin groups. Animals received daily intraperitoneal injection of Deferoxamine (125 mg /kg), Quercetin (10 mg/kg), and ferric dextran (200 mg/kg) for 2 weeks. Results Iron overloaded group showed significant increase in serum iron, total iron binding capacity (TIBC), transferrin saturation percentage (TS %) hepcidin (HEPC), serum ferritin, nontransferrin bound iron (NTBI), and small intestinal tissues iron levels. Iron overload significantly increased the serum oxidative stress indicator (MDA) and reduced serum total antioxidant capacity (TAC). On the other hand, iron overload increased IL6 and reduced IL10 in small intestinal tissues reflecting inflammatory condition and increased caspase 3 reactivity indicating apoptosis and increased iNOs expressing cell indicting oxidative stress especially in ileum. In addition, it induced small intestinal tissues pathological alterations. The treatment with Quercetin showed nonsignificant differences as compared to treatment with DFO that chelated the serum and tissue iron and improved the oxidative stress and reduced tissue IL6 and increased IL10 and decreased caspase 3 and iNOs expressing cells in small intestinal tissues. Moreover, it ameliorated the iron overload induced pathological alterations. Conclusion Our study showed the potential role of Quercetin as iron chelator like DFO in case of iron overload induced small intestinal toxicity in adult rats because of its serum and tissue iron chelation, improvement of serum, and small intestinal oxidative stress, ameliorating iron induced intestinal inflammation, apoptosis, and histopathological alterations.