Rational synthesis of FeNiCo-LDH nanozyme for colorimetric detection of deferoxamine mesylate.

The accurate surveillance and sensitive detection of deferoxamine mesylate (DFO) is of great significance to ensure the safety of thalassemia major patients. Herein, we report a new nanozyme-based colorimetric sensor platform for DFO detection. First, a metal-organic framework (ZIF-67) was used as a precursor for the synthesis of FeNiCo-LDH (Layered Double Hydroxide, LDH) via an ion exchange reaction stirring at room temperature. The results of electron microscopy and nitrogen adsorption-desorption showed that FeNiCo-LDH exhibited a 3D hollow and mesopores structure, which supplied more exposed active sites and faster transfer of mass. The as-prepared FeNiCo-LDH showed superior peroxidase-like activity with a low Km and high υmax. It can catalyze the decomposition of H2O2 to generate reactive oxygen species (ROS) and further react with 3,3',5,5'-tetramethylbenzidine (TMB) to form blue oxidized TMB (oxTMB), which has a characteristic absorption at 652 nm. Once DFO was introduced, it can complex with FeNiCo-LDH and inhibit the peroxidase-like activity of FeNiCo-LDH, making the color of oxTMB lighter. The quantitative range of DFO was 0.8-28 µM with a detection limit of 0.71 µM. This established method was applied to the detection of DFO content in urine samples of thalassemia patients, and the spiked recoveries were falling between 97.7% and 109.6%, with a relative standard deviation was less than 5%, providing a promising tool for the clinical medication of thalassemia patients.

Mitochondrial Metabolism and EV Cargo of Endothelial Cells Is Affected in Presence of EVs Derived from MSCs on Which HIF Is Activated.

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have attracted growing interest as a possible novel therapeutic agent for the management of different cardiovascular diseases (CVDs). Hypoxia significantly enhances the secretion of angiogenic mediators from MSCs as well as sEVs. The iron-chelating deferoxamine mesylate (DFO) is a stabilizer of hypoxia-inducible factor 1 and consequently used as a substitute for environmental hypoxia. The improved regenerative potential of DFO-treated MSCs has been attributed to the increased release of angiogenic factors, but whether this effect is also mediated by the secreted sEVs has not yet been investigated. In this study, we treated adipose-derived stem cells (ASCs) with a nontoxic dose of DFO to harvest sEVs (DFO-sEVs). Human umbilical vein endothelial cells (HUVECs) treated with DFO-sEVs underwent mRNA sequencing and miRNA profiling of sEV cargo (HUVEC-sEVs). The transcriptomes revealed the upregulation of mitochondrial genes linked to oxidative phosphorylation. Functional enrichment analysis on miRNAs of HUVEC-sEVs showed a connection with the signaling pathways of cell proliferation and angiogenesis. In conclusion, mesenchymal cells treated with DFO release sEVs that induce in the recipient endothelial cells molecular pathways and biological processes strongly linked to proliferation and angiogenesis.

Deferoxamine mesylate enhances mandibular advancement-induced condylar osteogenesis by promoting H-type angiogenesis.

BACKGROUND: The effect of functional orthopaedic treatment for mandibular deficiency relies on mandibular advancement (MA)-induced condylar new bone formation. However, this is not easy to achieve, especially in non-growing patients. Therefore, how to obtain reliable MA-induced condylar osteogenesis is a subject much worthy of study. OBJECTIVE: To investigate whether deferoxamine mesylate (DFM) enhances MA-induced condylar osteogenesis in middle-aged mice. METHODS: Forty 30-week-old male C57BL/6J mice were randomly divided into 4 groups: the control (Ctrl), DFM, MA + Ctrl and MA + DFM groups. After a 4-week experimental period, femurs, tibias and condyles were collected for morphological, micro-computed tomography and histological evaluation. RESULTS: For long bones, DFM reversed osteoporosis in middle-aged mice by promoting H-type angiogenesis. For mandibular condyles, MA promoted condylar osteogenesis in middle-aged mice, thereby allowing the mandible to achieve a stable protruding position. In addition, DFM enhanced the volume and quality of MA-induced condylar new bone formation. Furthermore, histological analysis revealed that DFM enhanced MA-induced condylar subchondral ossification. Mechanistically, it was confirmed that DFM increased the number of H-type vessels and their coupled Osterix+ osteoprogenitors by upregulating the hypoxia-inducible factor (HIF)-1α signalling pathway, thereby enhancing MA-induced condylar osteogenesis. CONCLUSION: Applying DFM to enhance MA-induced condylar osteogenesis through H-type angiogenesis is expected to be an effective strategy to achieve favourable functional orthopaedic treatment effectiveness in non-growing patients.

A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4.

CONTEXT: A novobiocin derivative, XN4, has been shown to promote cell apoptosis in chronic myeloid leukaemia. OBJECTIVE: This study explores the mechanism by which XN4 promotes ferroptosis of gastric cancer (GC) cells. MATERIALS AND METHODS: Human GC SGC-7901 and BGC-823 cells were treated with different XN4 concentrations (0, 0.1, 0.5, 1.0, 5.0, and 10.0 µmol/L) to evaluate effects of XN4. Additionally, cells were pre-treated for 24 h with si-NOX4, for 1 h with the iron chelator deferoxamine mesylate (DFO) or for 1 h with the lipid peroxidation inhibitor liproxstatin-1 before being treated with XN4 to analyse the mechanism of XN4. RESULTS: XN4 increased cell death (IC50 values of XN4 on SGC-7901 and BGC-823 cells: 1.592 ± 0.14 µmol/L and 2.022 ± 0.19 µmol/L) and Fe2+ levels in SGC-7901 and BGC-823 cells. These effects of 2.0 µmol/L XN4 were abolished by 100 µmol/L DFO treatment. XN4 enhanced transferrin and transferrin receptor expression to induce Fe2+ accumulation. XN4 decreased mitochondrial membrane potentials in GC cells, similar to erastin. Additionally, XN4 increased MDA, hydrogen peroxide, and ROS levels, but diminished total glutathione levels. Liproxstatin-1 (200 nmol/L) nullified the effects of XN4 (2.0 µmol/L) on MDA levels and cell death. Moreover, GPX4 levels decreased, but NOX4 and ferroptosis-related protein PTGS2 levels increased in GC cells following XN4 treatment, which was nullified by NOX4 knockdown. DISCUSSION AND CONCLUSIONS: The pro-ferroptotic role of XN4 in GC might enable it to become a promising drug for GC treatment in the future despite the need for extensive research.

Localized disruption of redox homeostasis boosting ferroptosis of tumor by hydrogel delivery system.

Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant tumor cells. Nevertheless, the accumulation of toxic lipid peroxides (LPOs) at the tumor site is limited by the level of lipid oxidation. Herein, by leveraging versatile sodium alginate (ALG) hydrogel, a localized ferroptosis trigger consisting of gambogic acid (GA), 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 â€‹nm laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in tumor cells. Meanwhile, GA could inhibit heat shock protein 90 (HSP90) to reduce the heat resistance of tumor cells, and forcefully consume glutathione (GSH) to weaken the antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased reactive oxygen species (ROS) facilitated reduced expression of glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective tumor suppression effect by depleting and generating fatal active compounds at tumor sites, which would pave a new route for the controllable, accurate, and coordinated tumor treatments.

Preparation and characterization of topical solid lipid nanoparticles containing Deferoxamine / Preparación y caracterización de nanopartículas lipídicas sólidas tópicas que contienen deferoxamina

Introducción: El mesilato de deferoxamina aumenta la transactivación alfa inducible por hipoxia del factor 1 al prevenir el estrés por oxígeno reactivo catalizado por hierro, por lo que puede usarse para mejorar la cicatrización de la úlcera diabética. Este estudio se llevó a cabo para desarrollar y estudiar las propiedades fisicoquímicas de nanopartículas lipídicas sólidas cargadas con deferoxamina tópica. Método: Se prepararon nanopartículas de lípidos sólidos utilizando la técnica de homogeneización en frío y un diseño factorial completo para evaluar el efecto del tipo de tensioactivo y la cantidad de lípidos. Se llevó a cabo la caracterización in vitro de las formulaciones, incluido el tamaño y la distribución de las partículas, el comportamiento térmico mediante calorimetría de barrido diferencial, la eficiencia de atrapamiento y el perfil de liberación. Resultados: Los resultados mostraron un rango aceptable de tamaño de partícula (2,88-174 nm), una distribución de tamaño estrecha y un promedio del 60% para la eficacia de atrapamiento del fármaco, lo que es significativo para un fármaco hidrófilo. Los resultados del estudio de liberación mostraron una liberación de ráfaga inicial seguida de una manera lenta y prolongada. Los resultados de la calorimetría diferencial de barrido también confirmaron los resultados obtenidos de las evaluaciones de carga y liberación. La mejor formulación que tenía un alto nivel de carga de fármaco y la menor tasa de liberación de fármaco contenía compritol y ácido oleico en una cantidad del 8% de la fórmula total, así como tween 80 y lecitina como una mezcla de tensioactivos. Conclusiones: El estudio demostró que el mesilato de deferoxamina podría cargarse en nanopartículas de lípidos sólidos para administrar por vía tópica. (AU)

Introduction: Deferoxamine mesylate increases hypoxia inducible factor-1 alpha transactivation by preventing iron-catalyzed reactive oxygen stress, so it can be used to improve diabetic ulcer healing. This study was undertaken to develop and study physicochemical properties of topical deferoxamine-loaded solid lipid nanoparticles. Method: Solid lipid nanoparticles were prepared using cold homogenization technique and full factorial design to evaluate the effect of surfactant type and amount of lipid. In-vitro characterization of formulations including particle size and distribution, thermal behavior using Differential Scanning Calorimetry, entrapment efficiency, and release profile were carried out. Results: The results showed an acceptable range of particle size (2.88–174 nm), a narrow size distribution, and an average of 60% for drug entrapment efficiency which is significant for a hydrophilic drug. The results from release study showed an initial burst release followed by a slow and prolonged manner. Differential Scanning Calorimetry results also confirmed the results obtained from loading and release evaluations. The best formulation which had a high level of drug loading and the lowest drug release rate contained compritol and oleic acid in the amount of 8% of the total formula, as well as tween 80 and lecithin as a mixture of surfactants. Conclusions: The study demonstrated deferoxamine could be loaded in solid lipid nanoparticles to deliver topi-cally. (AU)

Formulation and In-Vitro Characterization of Chitosan-Nanoparticles Loaded with the Iron Chelator Deferoxamine Mesylate (DFO).

The objective of this study was to develop chitosan (CS) nanoparticles (NPs) loaded with deferoxamine mesylate (DFO) for slow release of this iron-chelating drug. Drug nanoencapsulation was performed via ionic gelation of chitosan using sodium tripolyphosphate (TPP) as cross-linker. Nanoparticles with a size ranging between 150 and 400 nm were prepared for neat CS/TPP with a 2/1 molar ratio while their yield was directly dependent on the applied stirring rate during the preparation process. DFO at different content (20, 45 and 75 wt %) was encapsulated into these nanoparticles. We found that drug loading correlates with increasing DFO content while the entrapment efficiency has an opposite behavior due to the high solubility of DFO. Hydrogen-bonding between amino and hydroxyl groups of DFO with reactive groups of CS were detected using FT-IR spectroscopy while X-ray diffraction revealed that DFO was entrapped in amorphous form in the CS nanoparticles. DFO release is directly dependent on the content of loaded drug, while model analysis revealed that the release mechanism of DFO for the CS/TPP nanoparticles is by diffusion. Treatment of murine RAW 264.7 macrophages with nanoencapsulated DFO promoted an increased expression of transferrin receptor 1 (TfR1) mRNA, a typical homeostatic response to iron deficiency. These data provide preliminary evidence for release of pharmacologically active DFO from the chitosan nanoparticles.

[Mechanism of participation of osteocytes in the formation of osteoclasts under hypoxia].

OBJECTIVE: To investigate the mechanism of the participation of osteocytes in the formation of osteoclasts under hypoxia. METHODS: The hypoxia culture system of osteocyte-like cell line MLO-Y4 was established by deferoxamine mesylate (DFO) in vitro. The proliferation of MLO-Y4 cells was examined by CCK-8 cell proliferation/toxicity assay. RAW264.7 cells were induced to osteoclasts by the conditioned medium containing the cultured MLO-Y4. Tartrate-resistant acid phosphatase (TRAP) staining was performed on day 7. Quantitative real-time fluorescence polymerase chain reaction, immunofluorescence, and Western blot were used to detect the expression levels of hypoxia-inducible factor (HIF)-1α and receptor activator of nuclear factor-κB ligand (RANKL) in MLO-Y4 under hypoxia. The effects of siHIF-1α on the expression levels of HIF-1α and RANKL in MLO-Y4 under the same conditions were detected. RESULTS: DFO (100 µmol·L⁻¹) promoted the proliferation of MLO-Y4 at 24 h, which decreased with time (P<0.01). After the addition of soluble sRANKL, the formation of osteoclasts was significantly increased in the DFO group (P<0.001). The expression of RANKL mRNA in MLO-Y4 under 100 µmol·L⁻¹ DFO increased first and then decreased with the duration of hypoxia. This expression reached a peak at 24 h (P<0.01). Hypoxia up-regulated the expression of HIF-1α and RANKL protein (P<0.01). Under hypoxia, siHIF-1α downregulated the expression of HIF-1α and RANKL (P<0.01). siHIF-1α also decreased the number of osteoclasts (P<0.01). CONCLUSIONS: Under hypoxia, MLO-Y4 could facilitate the formation of RANKL through upre-gulating the expression of HIF-1α protein, thereby accelerate the differentiation of RAW264.7 cells into osteoclasts.

Preparation and optimization of polymeric micelles as an oral drug delivery system for deferoxamine mesylate: in vitro and ex vivo studies.

Deferoxamine mesylate (DFO) is administered as a slow subcutaneous or intravenous infusion due to its poor oral bioavailability and lack of dose proportionality. The aim of the present study was to prepare and optimize polymeric micelles containing DFO, as an oral drug delivery system for increasing permeability and oral bioavailability. Based on a full factorial design with three variables in two levels, eight polymeric micelle formulations were made using film hydration method. Two polymers including 0.1% of carbomer 934 and Poloxamer® P 407 and two blends of surfactant + co-surfactant including 1 and 2 fold of critical micelle concentration of Labrafil® + Labrasol® and Tween 80 + Span 20 were used to prepare polymeric micelles. The effect of variables on particle size (PS), entrapment efficiency (EE), drug release, thermal behavior, in vitro iron bonding and ex vivo rat intestinal permeability were evaluated. The PS of polymeric micelles was less than 83 nm that showed 80% EE with continuous drug release pattern. The change in type of polymer from carbomer to Ploxamer® significantly increased drug release. All polymeric micelles increased the iron-bonding ability of DFO compared to control. This could be due to surfactants that can play an important role in this ability. Polymeric micelles increased drug permeability through intestine more than 2.5 folds compared to control mainly affected by polymer type. Optimized polymeric micelle consists of Tween 80 and Span 20 with 1.35 folds of critical micelle concentration and Poloxamer® demonstrated 97.32% iron bonding and a 3-fold increase in permeation through the rat intestine compared with control.

Thermo-sensitive keratin hydrogel against iron-induced brain injury after experimental intracerebral hemorrhage.

In situ keratin hydrogel offer a promising strategy to relieve the brain injury after intracerebral hemorrhage (ICH) by delivering the iron chelator directly to the stroke site. However, the injectable property of traditional keratin hydrogel is unsatisfactory, which can't provide adaptable filling of lesion defects with irregular shapes. Herein, the thermo sensitive keratin-g-PNIPAM polymers with different graft ratios were synthesized, and deferoxamine mesylate (DFO) loaded thermo sensitive keratin hydrogels (TKGs) were prepared using the oxidative crosslinking method. The lower critical solution temperature of TKGs can be tailored from 28.5 to 31.8 °C by varying the graft ratios of keratin to NIPAM, and TKG can fill up the complex shapes of lesion cavities easily due to the characteristic of sol-gel transition. In addition, TKGs exhibit stronger adsorption and clearance capacities for the Fe2+ than keratin gel. Meanwhile, in situ injection of TKG with different DFO loadings (0.1, 1.0, and 10 mg/mL) into the hematoma region after ICH surgery showed a stronger effect on the reduction of ICH-induced iron deposits, brain non-heme iron content, brain edema and ROS level compared to the DFO treatment by intraperitoneal administration. Thus, the developed TKG can be potentially exploited for iron-induced brain injury after ICH.

Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response.

The use of intracortical microelectrode arrays has gained significant attention in being able to help restore function in paralysis patients and study the brain in various neurological disorders. Electrode implantation in the cortex causes vasculature or blood-brain barrier (BBB) disruption and thus elicits a foreign body response (FBR) that results in chronic inflammation and may lead to poor electrode performance. In this study, a comprehensive insight into the acute molecular mechanisms occurring at the Utah electrode array-tissue interface is provided to understand the oxidative stress, neuroinflammation, and neurovascular unit (astrocytes, pericytes, and endothelial cells) disruption that occurs following microelectrode implantation. Quantitative real time polymerase chain reaction (qRT-PCR) was used to quantify the gene expression at acute time-points of 48-hr, 72-hr, and 7-days for factors mediating oxidative stress, inflammation, and BBB disruption in rats implanted with a non-functional 4 × 4 Utah array in the somatosensory cortex. During vascular disruption, free iron released into the brain parenchyma can exacerbate the FBR, leading to oxidative stress and thus further contributing to BBB degradation. To reduce the free iron released into the brain tissue, the effects of an iron chelator, deferoxamine mesylate (DFX), was also evaluated.

Mechanism of participation of osteocytes in the formation of osteoclasts under hypoxia / 华西口腔医学杂志

OBJECTIVE@#To investigate the mechanism of the participation of osteocytes in the formation of osteoclasts under hypoxia.@*METHODS@#The hypoxia culture system of osteocyte-like cell line MLO-Y4 was established by deferoxamine mesylate (DFO) in vitro. The proliferation of MLO-Y4 cells was examined by CCK-8 cell proliferation/toxicity assay. RAW264.7 cells were induced to osteoclasts by the conditioned medium containing the cultured MLO-Y4. Tartrate-resistant acid phosphatase (TRAP) staining was performed on day 7. Quantitative real-time fluorescence polymerase chain reaction, immunofluorescence, and Western blot were used to detect the expression levels of hypoxia-inducible factor (HIF)-1α and receptor activator of nuclear factor-κB ligand (RANKL) in MLO-Y4 under hypoxia. The effects of siHIF-1α on the expression levels of HIF-1α and RANKL in MLO-Y4 under the same conditions were detected.@*RESULTS@#DFO (100 μmol·L⁻¹) promoted the proliferation of MLO-Y4 at 24 h, which decreased with time (P<0.01). After the addition of soluble sRANKL, the formation of osteoclasts was significantly increased in the DFO group (P<0.001). The expression of RANKL mRNA in MLO-Y4 under 100 μmol·L⁻¹ DFO increased first and then decreased with the duration of hypoxia. This expression reached a peak at 24 h (P<0.01). Hypoxia up-regulated the expression of HIF-1α and RANKL protein (P<0.01). Under hypoxia, siHIF-1α downregulated the expression of HIF-1α and RANKL (P<0.01). siHIF-1α also decreased the number of osteoclasts (P<0.01).@*CONCLUSIONS@#Under hypoxia, MLO-Y4 could facilitate the formation of RANKL through upre-gulating the expression of HIF-1α protein, thereby accelerate the differentiation of RAW264.7 cells into osteoclasts.

Augmented migration of mesenchymal stem cells correlates with the subsidiary CXCR4 variant.

Use of mesenchymal stem cells (MSCs) has been introduced as a promising tool, for structural and functional recovery of damaged tissues/organs. Studies have indicated that interactions between chemokine receptors and their ligands have a critical role in homing of MSCs to the site of injury. Although CXCR4 variants have been characterized, the exact role of each transcript in homing has remained unclear. In this study, cells were pretreated with various hypoxia-mimicking compounds (valproic acid, cobalt-chloride, and deferoxamine mesylate). Results indicated that both variants of CXCR4 were overexpressed after 24 hours of treatments and their expression could cooperatively induce and promote the cell migration. Moreover, deferoxamine mesylate was more effective in overexpression of variant A (lo), which resulted in higher level of CXCR4 protein and the highest rate of migration of the cells. In conclusion, our findings may have important potential implications in clinical applications, reinforcing the concept that manipulating the expression of specific CXCR4 variants may increase migration of MSCs.

Effects of Deferoxamine Mesylate on Hematoma and Perihematoma Edema after Traumatic Intracerebral Hemorrhage.

Deferoxamine mesylate can cross the blood-brain barrier and reduce iron accumulation in nervous tissue; moreover, it has a variety of neuroprotective functions in addition to complexing with iron ions. Such iron chelators are expected to become a new treatment option for intracerebral hemorrhage. This study evaluated the effects of deferoxamine mesylate on hematoma and edema absorption after traumatic intracerebral hemorrhage (TICH), and it provides clinical evidence for TICH treatment with deferoxamine mesylate. Patients with isolated TICH, confirmed by head computed tomography, were enrolled prospectively from January 2013 to December 2016. Patients were divided non-randomly into an experimental or control group as decided by the attending neurosurgeon. Patients in the experimental group received intravenous deferoxamine mesylate (20 mg/kg daily) from the day of admission for 5 consecutive days. We evaluated the impact of deferoxamine mesylate on the change in edema volume and the absorption of hematoma volume using a propensity score-matched analysis. In total, 190 patients were included. After matching, 94 patients were included in the final analysis (47 per group); no variable differed significantly between the two groups. The hematoma volume on the 7th day in the control group was higher than that at the same time-point in the experimental group (9.4 ± 7.2 vs. 5.2 ± 4.8 mL; p = 0.001). There was no difference in hematoma volume on Day 1 (12.6 ± 7.8 vs. 12.8 ± 6.4 mL; p = 0.896), Day 3 (12.4 ± 7.4 vs. 11.4 ± 4.9 mL; p = 0.442), and Day 14 (3.2 ± 3.0 vs. 2.5 ± 2.6 mL; p = 0.215) between the groups. The absorption of hematoma volume between the 1st and 3rd days and the 1st and 7th days in the experimental group was higher than that during the same periods in the control group. The edema volumes on the 3rd, 7th, and 14th days in the control group were higher than those at the same time-points in the experimental group. There was no difference in edema volume on the 1st day. The changes in edema volume between the 1st and 3rd days, the 1st and 7th days, and the 1st and 14th days in the control group were higher than those during the same periods in the experimental group. Deferoxamine mesylate may accelerate hematoma absorption and inhibit edema after TICH; however, further investigation is required to reach definitive conclusions.

Composite chitosan/alginate hydrogel for controlled release of deferoxamine: A system to potentially treat iron dysregulation diseases.

Recently, the potential application of deferoxamine (DFO) in several iron dysregulation diseases has been highlighted. However, DFO presents significant limitations in clinical use due to its poor absorption in the gut and very short plasma half-life. To overcome these problems, the feasibility of chitosan/alginate hydrogels as prolonged delivery systems of DFO was investigated. Hydrogel alone or co-formulated with poly(D,L-lactide-co-glycolide) microspheres were prepared and studied in vitro. The influence of the preparation methods on the performance of composite hydrogels on controlled DFO release was explored. Spray-dried microspheres based on poly(D,L-lactide-co-glycolide) were able to encapsulate DFO, a highly water soluble drug. Nevertheless, only the composite hydrogels managed to provide sustained drug release. The inclusion of microspheres into pre-formed chitosan/alginate hydrogel provided the most efficient delivery system; the drug released from microspheres is strongly entrapped in the hydrogel network and slowly released by diffusion.

Effect of the deferoxamine mesylate on the prognosis of patients with intracerebral hemorrhage / 中国综合临床

Objective To study the effect of the deferoxamine mesylate on the prognosis of patients with intracerebral hemorrhage(ICH) after one year. Methods From February 2013 to May 2014,spontaneous ICH patients diagnosed by computed tomography ( CT ) within 18 hours of onset in Mancheng District Hospital of Baoding were evaluated. Patients were randomly divided into experimental group and control group. The treatment of the two groups was similar except that the experimental group received deferoxamine mesylate. Patients were e?valuated by CT and neurology scale( NIHSS scale,GCS scale) at the time of admission and followed up for the first year by the RANKIN( mRS) scale. All clinical data of the two groups were compared. Results Forty?two patients were included in the study, including 21 cases in the experimental group and 21 cases in the control group,there was no significant difference in baseline data between the two groups at admission. There were 6 pa?tients with mRS ≥3 in the experimental group, and 6 patients with mRS ≥3 in the control group after one year. There was no statistically significant difference in the distribution of mRS score between the two groups after one year admission( P=1. 000) . Conclusion There may be no helpful on the prognosis of patients with intrace?rebral hemorrhage by intravenous infusion of deferoxamine mesylate,the further study is needed.

Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy.

Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-ß1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.

Solid microparticles based on chitosan or methyl-ß-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate.

We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-ß-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 µm (DCH) to 3.47 ± 0.05 µm (MCD); the aerodynamic diameters were about 1.1 µm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron-like), but like DCH, it did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial-like). Nasal administration to rats of 200 µg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 µg/mL (DCH) to 14.37 ± 1.69 µg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-ß-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure.

Suppression of immunoglobulin production in human peripheral blood mononuclear cells by monocytes via secretion of heavy-chain ferritin.

In vitro antigen stimulation of peripheral blood mononuclear cells (PBMCs) does not induce immunoglobulin (Ig) production. However, pretreatment of PBMCs with l-leucyl-l-leucine methyl ester (LLME) prior to in vitro stimulation removes the suppression of Ig production. In the present study, we attempted to identify the target cells of LLME and determine the mechanisms by which Ig production in PBMCs is suppressed. We found that CD14(+) monocytes are involved in the suppression of Ig production in PBMCs. Furthermore, we confirmed that heavy-chain ferritin derived from CD14(+) monocytes suppresses Ig production in PBMCs, possibly through iron sequestration.