Drug Deferoxamine Research Articles

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

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

A temperature and pH dual-responsive injectable self-healing hydrogel prepared by chitosan oligosaccharide and aldehyde hyaluronic acid for promoting diabetic foot ulcer healing

Chronic wound, such as skin defect after burn, pressure ulcer, and diabetic foot ulcer is very difficult to cure. Its pathological process is often accompanied with local temperature rise, pH decrease, and other phenomena. Owing to their outstanding hydrophilic, biocompatibility, and responsive properties, hydrogels could accelerate the healing process. In this study, we chose chitosan oligosaccharide (COS) grafted with Pluronic F127 (F127-COS). Aldehyde hyaluronic acid (A-HA) oxidized by NaIO4. And added boric acid (BA) to prepare a thermosensitive and pH-responsive injectable self-healing F127-COS/A-HA/COS/BA (FCAB) hydrogel, loaded with drug deferoxamine (DFO) in order to have an accurate release and promote angiogenesis of diabetic foot ulcer. In vitro experiments had verified that the FCAB hydrogel system loaded with DFO (FCAB/D) could promote migration and angiogenesis of HUVEC. A diabetes rat back wound model further confirmed its role in promoting angiogenesis in wound repair process. The results showed that the FCAB/D hydrogel exhibited unique physicochemical properties, excellent biocompatibility, and significantly enhanced therapeutic effects for diabetic foot ulcer.

Double hits with bioactive nanozyme based on cobalt-doped nanoglass for acute and diabetic wound therapies through anti-inflammatory and pro-angiogenic functions

Regeneration of pathological wounds, such as diabetic ulcers, poses a significant challenge in clinical settings, despite the widespread use of drugs. To overcome clinical side effects and complications, drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events. This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass (namely, CoNZ), which exhibits high enzymatic/catalytic activity while releasing therapeutic ions. Cobalt oxide “Co3O4” tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS. Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process, promoting neovascularization, matrix deposition, and epithelial lining while reducing pro-inflammatory signs. Notably, CoNZ was highly effective in treating pathological wounds (streptozotocin-induced diabetic wounds). Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events. In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ. CoNZ-promoted angiogenesis was attributed to the release of cobalt ions, as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1α. Finally, we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine. Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound, indicating the potential of CoNZ as a novel drug-free therapeutic approach.

3D hypoxia-mimicking and anti-synechia hydrogel enabling promoted neovascularization for renal injury repair and regeneration.

In-situ renal tissue engineering is promising yet challenging for renal injury repair and regeneration due to the highly vascularized structure of renal tissue and complex high-oxidative stress and ischemic microenvironment. Herein, a novel biocompatible 3D porous hydrogel (DFO-gel) with sustained release capacity of hypoxia mimicking micromolecule drug deferoxamine (DFO) was developed for in-situ renal injury repair. In vitro and in vivo experimental results demonstrated that the developed DFO-gels can exert the synchronous benefit of scavenging excess reactive oxygen species (ROS) regulating inflammatory microenvironment and promoting angiogenesis for effective renal injury repair by up-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). The in-situ neogenesis of neonatal glomerular- and tubular-like structures in the implanted areas in the partially nephrectomized rats also suggested the potential for promoting renal injury repair and regeneration. This multifunctional hydrogel can not only exhibit the sustained release and promoted bio-uptake capacity for DFO, but also improve the renal injured microenvironment by alleviating oxidative and inflammatory stress, accelerating neovascularization, and promoting efficient anti-synechia. We believe this work offers a promising strategy for renal injury repair and regeneration.

Neuroprotective carbazole alkaloids from Streptomyces sp. HS-NF-1322 by inhibition of ferroptosis

Three rare new carbazole alkaloids, antiostatin A7 (1), ( ± )-morindolestatin B (2) and morindolestatin C (3), were obtained from a fermentation broth of the soil-derived Streptomyces sp. HS-NF-1322 strain. Their structures were assigned by various spectroscopic techniques including HR-ESI-MS and 2D NMR. These new isolates, together with ( ± )-morindolestatin (4), were assayed for their neuroprotective effects on erastin-induced ferroptosis on the PC12 and HT-22 cell lines. All of these alkaloids significantly improved cell viability, and reduced ROS production of these neuronal cells. Notably, compound 1 dramatically protected PC12 cells from ferroptosis with a higher viability than the positive drug deferoxamine at 10 μM.

Coaxially Fabricated Dual‐Drug Loading Electrospinning Fibrous Mat with Programmed Releasing Behavior to Boost Vascularized Bone Regeneration (Adv. Healthcare Mater. 16/2022)

Controlled Drug Release In article 2200571, Min Zhu, Xudong Wang, Kaili Lin and co-workers fabricate a novel dual-drug loading coaxially electrospinning fibrous mat with programmed release behavior. The early and rapid release of angiogenesis-promoting drug deferoxamine promotes the angiogenesis of vascular endothelial cells and the sustained release of osteogenesis-inducing drug dexamethasone enhances osteogenesis of bone mesenchymal stem cells, and synergistically boosts vascularized bone regeneration.

Dual-crosslinked mussel-inspired smart hydrogels with enhanced antibacterial and angiogenic properties for chronic infected diabetic wound treatment via pH-responsive quick cargo release

The healing of chronic diabetic wounds remains a key challenge due to its susceptibility to bacterial infection, the inflammatory wound microenvironment, and difficulty in angiogenesis. Herein, a pH-responsive, mussel-inspired, double-crosslinking injectable, and adhesive smart hydrogel formula was exploited to overcome these obstacles simultaneously. The multifunctional double-crosslinking hydrogel was developed through the formation of catechol-catechol adducts and a Schiff-based reaction between amino groups (−NH2) in chitosan quaternary ammonium salt (HTCC) and aldehyde groups (–CHO) in oxidized dextran-dopamine (OD-DA). The double-crosslinking mechanism gave the hydrogels great mechanical properties. Most importantly, via the effective encapsulation of silver nanoparticles (AgNPs) and pro-angiogenic drug deferoxamine (DFO), the hydrogel was given with antibacterial and angiogenic features respectively. At the infected diabetic wound area, the double Schiff base bonds (DA and OD; HTCC and OD-DA) in the hydrogels could quickly achieve pH-response and accomplish a sustained and controlled release of drugs to accelerate wound healing. Through the combination of AgNPs and HTCC, the hydrogel exhibited antimicrobial capacities to gram-positive bacteria (S. aureus) and gram-negative bacteria (E. coli), it did not cause toxic side effects and avoided drug resistance. The DFO released at the infected diabetic wound area promoted angiogenesis by enhancing the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). We elucidated the mechanisms by which the designed hydrogels accelerated the healing of bacterial infected diabetic wounds in vitro and in vivo, and our hydrogels represented a general strategy for the healing of a wide range of tissue injuries.

Unexpected activation of N-alkyl hydroxamic acids to produce reactive N-centered free radicals and DNA damage by carcinogenic chlorinated quinones under normal physiological conditions

We found recently that benzohydroxamic acid (BHA) could detoxify the chlorinated quinoid carcinogens via an unusual Lossen rearrangement reaction. However, it is not clear what would happen when the nitrogen hydrogen of BHA was substituted with methyl and other alkyl groups. Here we show that N-methyl benzohydroxamic acid (N-MeBHA, a simple model compound for the classic iron-chelator deferoxamine, which is a typical N-alkyl trihydroxamic acid) could react with 2,5-dichloro-1,4-benzoquinone (DCBQ) to form a relatively stable initial carbon-oxygen bonding conjugation intermediate CBQ-O-N-MeBHA. However, the major final product was identified, unexpectedly, as a carbon-nitrogen bonding conjugate CBQ(OH)–N(CH3)-COAr, which is the rearranged isomer of CBQ-O-N-MeBHA. Interestingly, a new 18-line nitrogen-centered radical and a carbon-centered quinone ketoxy radical were observed by the ESR spin-trapping method, which was further confirmed by HPLC-MS and 15N-isotope labeling methods. We further found that both new DNA adducts and DNA strand breaks could be produced by the reactive nitrogen-centered radical. Taken together, we propose that the reaction between DCBQ and N-MeBHA was not via the Lossen rearrangement, but rather through a novel radical homolysis and recoupling pathway. Analogous results were observed for other chlorinated quinones and N-alkyl hydroxamic acids including the widely-used trihydroxamate iron-chelating drug deferoxamine. This represents the first report of unexpected radical pathway for the reaction between chlorinated quinones and N-alkyl hydroxamic acids under normal physiological conditions, which may have broad biological and environmental significance for future study of carcinogenic chloroquinones and hydroxamic acid drugs.

Multifunctional Polymeric Micelles for Combining Chelation and Detection of Iron in Living Cells.

Multifunctional self-assembled micelles composed of Pluronics F127 polymer chains are developed and investigated for chelation and selective detection of iron(III) in vitro and in iron-overloaded cells. Tetraphenylethene (TPE) is encapsulated into the micelle core and the iron chelate drug deferoxamine (DFO) is conjugated to micelles to generate a fluorescence quenching detection system termed DFO-TFM for short, where T stands for TPE, F for F127, and M for micelle. The key to the successful formation of this fluorescence quenching system is due to the near-ideal overlap between the absorption spectrum of the DFO:iron(III) complex and fluorescence spectrum of TPE. DFO-TFM can retain the iron-chelation properties of DFO and exhibits negligible cytotoxicity compared to free DFO. Furthermore, this fluorescence "turn-off" system can be utilized to detect the presence of iron and to monitor the chelation process in an iron overload cell model. This study serves as an effective proof-of-concept model for designing future in vivo systems capable of combining the features of iron chelation with iron detection and efforts toward the development of such detection systems are currently underway.

Melanin nanoparticles as an endogenous agent for efficient iron overload therapy.

Improving iron-chelating drugs for the safe and efficient therapy of iron overload disease is greatly challenging and highly desired. Endogenous iron chelators are perfect candidates because of their intrinsic biodegradability and biocompatibility, which avoid the severe side effects of the exogenous drugs currently present in clinical applications. Herein, for the first time, we have reported simply using melanin nanoparticles as an efficient natural nano-drug for iron overload therapy in living mice. Its native biocompatibility, biodegradability, high iron-capturing volume and long circulation time endow it with a lower required dosage quantity and frequency, but it accomplishes better therapeutic effects than the traditional drug deferoxamine (DFO).

The Effects of Medicago Sativa and Allium Porrum on Iron Overload in Rats.

Purpose:Iron overload may occur due to regular blood transfusions and high intestinal iron absorption. Currently, there is no effective drug without side effects for the treatment of iron excess in thalassemia and other iron storage diseases, except chelation therapy, which is the only safe method for iron excretion. Thus, scientists are more focused on medicinal plants rich in phytochemical compounds for the removal of iron in thalassemia. Therefore this study was managed to discover the therapeutic potential of hydro- alcoholic extract of Allium porrum and Medicago sativa for iron chelating potential.Methods:Aerial parts of Allium porrum and Medicago sativa werecollected in Yasuj Iran. Rats were divided into seven groups each containing six. Extracts were administrated in four groups (two groups for each extract) by single doses of each plant with 200 and 400 mg / kg body weight by (i.p.) route every other day for28 days. Group 1 as negative control received saline (0.5 ml/kg) by (i.p.) route. Positive control received iron dextran 200 mg/kg body weight. Experimental groups 1 and 2 for each plant extract were fed with 200 and 400 mg/kg, hydro-alcoholic extract respectively via (i.p.) route, 1 h after the injection of iron dextran. Standard group was treated with deferoxamine (DF) 50 mg/kg by (i.p.) route1 h after the injection of iron dextran. Serum iron (SI) and serum total iron binding capacity (TIBC) were determined. The serum ferritin was then measured using enzyme immunoassay ELISA kit for rat. For Analysis of data ANOVA test was used.Results:Hydro-alcoholic extract of Medicago sativa and Allium porrum at 400 mg/kg showed significant (p<0.05) iron chelating activity compared to control. The plant extracts with dose 200 mg/kg also reduced the iron and ferritin content but the effect was lower level compared to higher doses. The plant extract effects were similar to that of standard drug deferoxamine. Iron and ferritin levels were significantly reduced in experimental groups when compared to positive group especially in Medicago sativap<0.05. There was no difference between standard drugs and last concentration of plant extracts.Conclusion:protective effect of M. sativa and A. Porrum against iron overload in rat model was reported. Significant decrease in serum ferritin and iron concentration was reported in iron overload rats which induced by iron dextran.

Validation of Cardio Protective Activity of Standardized Extracts of Unani Medicinal Plants Listed in Ibn-e-Sina's Treatise

Ibn-e-Sina (Persian physician) recommended 63 drugs in his treatise “Advia Qalbiya” for cardioprotection, which are the major components of several cardioprotective formulations used in the Unani system of medicine. The hydroalcoholic extracts of the three most commonly used drugs: Amomum subulatum (Amomum), Coriandrum sativum (Coriander), Nardostachys jatamanshi (Jatamanshi) were selected for cardioprotective activity. In vitro antioxidant activity of extracts were carried out using DPPH, superoxide, nitric oxide free radical scavenging methods as well as reducing power method. The extracts of drugs were previously standardized for total phenolic content and HPTLC fingerprints as well as quantification of their respective marker compounds. Validated analytical methods were used for assay of drugs such as Amomum (alpinatin by HTPLC and HPLC, Cineol by GCMS), Coriander (linalool by GCMS), Jatamanshi (Jatamansone by GCMS). The in vivo cardioprotective activity was carried out against doxorubicine induced toxicity in Wistar rat model for 21 days. Oral administration of Amomum and Coriander extracts (200 mg/kg/day) followed by administration of doxorubicine (2.5 mg/kg twice a week, i.p.) showed significant (p < 0.01) reversal of biochemical parameters such as serum CK-MB, LDH, HMG-CoA, TNF-alpha, IL-6 as well as heart tissue TNF-alpha, caspase-3 and TBARS level as compared to doxorubicine treated group. However, Amomum showed better protection and comparable to standard drug deferoxamine, which were further supported by similar results of DNA fragmentation and histological studies. Acknowledgements: Thanks go to DST (Department of Science and Technology), and CCRUM (AYUSH) Ministry of Health, Government of India.

Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants

A bisabolane sesquiterpene endoperoxide compound, 3,6-epidioxy-1,10-bisaboladiene (EDBD), was isolated from edible wild plants grown in the northern area of Japan, Cacalia delphiniifolia and Cacalia hastata, using a mutant yeast (cdc2-1 rad9Δ). It showed cytotoxicity at IC50=3.4μM and induced apoptosis against the human promyelocytic leukemia cell line HL60 through a new stable rearrangement product (1) when in the presence of FeSO4. This conversion mechanism is different from another sesquiterpene endoperoxide lactone compound, dihydroartemisinin (DHA), which is an anti-malarial drug. The cytotoxicity of EDBD decreased in the presence of the ferrous ion chelating drug deferoxamine mesylate (DFOM), and this suggested that the structural change of the drug caused by Fe2+ may be responsible for its biological activities. EDBD induced apoptosis via phosphorylation of p38 mitogen-activated protein kinase (MAPK) in HL60 cells, and was detected by Western blot. EDBD resulted in an immediate increase in DCF fluorescence intensity in HL60 cells using DCFH-DA (2′,7′-dichlorofluorescin diacetate) assay. The in vitro reaction of EDBD with FeSO4 also increased DCF fluorescence intensity in a dose dependent manner. These results showed that the biological activity of EDBD involves an unstable carbon-centered radical intermediate. Furthermore, there was no similarity between the JFCR39 fingerprints of EDBD and DHA (correlation coefficient on COMPARE Analysis γ=0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo.

Up-Regulation of the Fibroblast Growth Factor 8 Subfamily in Human Hepatocellular Carcinoma for Cell Survival and Neoangiogenesis Δσ

Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several non-liver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy.

Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells.

BackgroundMetal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC), including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19).MethodsCell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS)ResultsHNTMB displayed high cytotoxicity (IC50 200-400 nM) compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM) or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM). In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM). In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS) while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels.ConclusionsThe present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other solid tumors.

Clinically achievable plasma deferoxamine concentrations are therapeutic in a rat model of Pneumocystis carinii pneumonia.

The iron-chelating drug deferoxamine (DFO) has been shown to be active in animal models of Pneumocystis carinii pneumonia (PCP), with effective daily intraperitoneal bolus dosages being 400 and 1,000 mg of DFO mesylate kg of body weight-1 in mouse and rat models, respectively. Continuous infusion produced a moderately improved response in a rat model. The data reported here demonstrate that the response achieved by continuous infusion of 195 and 335 mg of DFO mesylate kg-1 day-1 in the rat model is associated with mean concentrations in plasma of 1.3 and 2.5 micrograms of DFO ml-1 and mean concentrations in lung tissue of 4.9 and 6.0 micrograms of DFO g of lung tissue-1, respectively. Since current clinical use of DFO mesylate for the treatment of iron overload produces higher concentrations in the plasma of patients, DFO may prove to be a useful anti-PCP treatment. The 2.4- to 3.8-fold higher DFO concentration observed in lung tissue compared with that observed in plasma may be important in the response of PCP to DFO.

Iron-chelating therapy.

Because of the catalytic action of iron in one-electron redox reactions, it has a key role in the formation of harmful oxygen derivatives and production of peroxidative damage to vital cellular structures. The clinical manifestations of iron overload may be prevented and even reversed by the effective administration of the iron-chelating drug deferoxamine (DF). Recent experimental evidence suggests that DF may also be useful in modifying disease conditions unrelated to iron overload by preventing the formation of free radicals, the powerful final effectors of tissue damage resulting from the respiratory burst of granulocytes and macrophages participating in the inflammatory response. Although much experimental work is still needed, this novel approach in iron-chelating therapy may have far-reaching implications in the management of autoimmune disease, adult respiratory distress syndrome, and organ transplantation. The poor intestinal absorption of DF, its almost prohibitive price, and short duration of action underline the need for new, orally effective iron chelators. A number of very promising orally effective drugs have been identified in recent years, such as the polyanionic amines, aryl hydrazones, and hydroxypyridones. Further development for clinical use of this new generation of iron-chelating drugs is a major challenge for future research.