-
Frontiers in Pharmacology 2023Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and...
Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-β/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both and . Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.
PubMed: 37007035
DOI: 10.3389/fphar.2023.1135366 -
Biomolecules Aug 2023Diabetic nephropathy (DN) is one of the most devastating diabetic microvascular complications. It has previously been observed that iron metabolism levels are abnormal...
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.
Topics: Animals; Rats; Diabetic Nephropathies; Deferoxamine; Inflammation; Fibrosis; Iron Chelating Agents; Iron; Diabetes Mellitus
PubMed: 37627331
DOI: 10.3390/biom13081266 -
Drug Design, Development and Therapy 2016The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many... (Review)
Review
Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.
The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Syndrome; Thalassemia; Triazoles
PubMed: 26893541
DOI: 10.2147/DDDT.S79458 -
Aging Apr 2023The mechanism underlying xerostomia after menopause has not yet been fully elucidated. This study aimed to investigate the mechanism of xerostomia and the effect of the...
The mechanism underlying xerostomia after menopause has not yet been fully elucidated. This study aimed to investigate the mechanism of xerostomia and the effect of the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (FER) on salivary gland dysfunction in a postmenopausal animal model. Twenty-four female Sprague-Dawley rats were randomly divided into four groups: a SHAM group ( = 6, sham-operated rats), an OVX group ( = 6, ovariectomized rats), an FER group ( = 6, ovariectomized rats injected intraperitoneally with FER), and a DFO group ( = 6, ovariectomized rats injected intraperitoneally with DFO). GPX4 activity, iron accumulation, lipid peroxidation, inflammation, fibrosis, and salivary gland function were analyzed. Recovery of GPX4 activity and a decrease in iron accumulation and cytosolic MDA + HAE were observed in the DFO group. In addition, collagen I, collagen III, TGF-β, IL-6, TNF-α, and TGF-β levels were decreased in the DFO group compared to the OVX group. Recovery of GPX4 activity and the morphology of mitochondria, and reduction of cytosolic MDA + HAE were also observed in the FER group. In addition, decreased expression of inflammatory cytokines and fibrosis markers and increased expression of AQP5 were observed in both the DFO and FER groups. Postmenopausal salivary gland dysfunction is associated with ferroptosis, and DFO and FER may reverse the postmenopausal salivary gland dysfunction after menopause. DFO and FER are hence considered promising treatments for postmenopausal xerostomia.
Topics: Rats; Female; Animals; Deferoxamine; Rats, Sprague-Dawley; Fibrosis; Iron; Salivary Glands; Xerostomia; Transforming Growth Factor beta
PubMed: 37036468
DOI: 10.18632/aging.204641 -
Frontiers in Bioscience (Elite Edition) Jul 2022Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of... (Review)
Review
Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.
Topics: Benzoates; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Pyridones; Risk Assessment; Thalassemia; Triazoles
PubMed: 36137990
DOI: 10.31083/j.fbe1403018 -
The International Journal of... Jun 2023Iron chelators, such as deferoxamine, exert an anticancer effect by altering the activity of biomolecules critical for regulation of the cell cycle, cell metabolism, and...
Iron chelators, such as deferoxamine, exert an anticancer effect by altering the activity of biomolecules critical for regulation of the cell cycle, cell metabolism, and apoptotic processes. Thus, iron chelators are sometimes used in combination with radio- and/or chemotherapy in the treatment of cancer. The possibility that deferoxamine could induce a program of senescence similar to radio- and/or chemotherapy, fostering adaptation in the treatment of cancer cells, is not fully understood. Using established biochemical techniques, biomarkers linked to lipid composition, and coherent anti-Stokes Raman scattering microscopy, we demonstrated that hepatocellular carcinoma-derived HepG2 cells survive after deferoxamine treatment, acquiring phenotypic traits and representative hallmarks of senescent cells. The results support the view that deferoxamine acts in HepG2 cells to produce oxidative stress-induced senescence by triggering sequential mitochondrial and lysosomal dysfunction accompanied by autophagy blockade. We also focused on the lipidome of senescent cells after deferoxamine treatment. Using mass spectrometry, we found that the deferoxamine-induced senescent cells presented marked remodeling of the phosphoinositol, sulfatide, and cardiolipin profiles, which all play a central role in cell signaling cascades, intracellular membrane trafficking, and mitochondria functions. Detection of alterations in glycosphingolipid sulfate species suggested modifications in ceramide generation, and turnover is frequently described in cancer cell survival and resistance to chemotherapy. Blockade of ceramide generation may explain autophagic default, resistance to apoptosis, and the onset of senescence.
Topics: Humans; Deferoxamine; Sulfoglycosphingolipids; Hep G2 Cells; Iron Chelating Agents; Mitochondria; Cellular Senescence
PubMed: 37086817
DOI: 10.1016/j.biocel.2023.106419 -
The Science of the Total Environment Dec 2023Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their...
Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their pathophysiology and toxicology, yet many of their fundamental properties - for example, their in vivo pharmacokinetics - remain poorly understood. In this investigation, we have harnessed positron emission tomography (PET) to track the in vivo fate of micro- and nanoplastics administered to mice intratracheally and intravenously. To this end, 1 μm and 20 nm diameter amine-functionalized polystyrene particles were modified with an isothiocyanate-bearing variant of desferrioxamine (DFO) and radiolabeled with the positron-emitting radiometal [Zr]Zr. Both radioplastics - [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 - were produced in ∼95% radiochemical yield and found to be >85% stable to demetallation over one week at 37 °C in human serum and simulated lung fluid. The incubation of [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 with MH-S cells revealed that the majority of the former were phagocytosed by alveolar macrophages within 4 h, while the latter largely evaded consumption. Finally, the in vivo behavior of the radioplastics was interrogated in mice upon intravenous and intratracheal administration. PET imaging and biodistribution experiments revealed that the intravenously injected plastics accumulated primarily in the liver and spleen, yielding hepatic radioactivity concentrations of 101 ± 48 %ID/g and 92 ± 22 %ID/g at 168 h post-injection for [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 respectively. In contrast, the mice that received the radioplastics via intratracheal installation displayed the highest uptake in the lungs at the end of one week: 4 ± 2 %ID/g for [Zr]Zr-DFO-PS1000 and 32 ± 6 %ID/g for [Zr]Zr-DFO-PS20. Ultimately, this work illustrates the critical role that the route of exposure plays in the bioaccumulation of plastic particles, reveals that size dramatically influences the pulmonary retention of inhaled particles, and underscores the value of PET imaging as a tool for studying the pharmacokinetics of environmental pollutants.
Topics: Humans; Animals; Mice; Radioisotopes; Microplastics; Tissue Distribution; Plastics; Deferoxamine; Positron-Emission Tomography; Zirconium; Environmental Pollutants; Cell Line, Tumor
PubMed: 37586535
DOI: 10.1016/j.scitotenv.2023.166320 -
Advances in Clinical and Experimental... 2017Endometriosis is one of the most common chronic gynecological diseases.
BACKGROUND
Endometriosis is one of the most common chronic gynecological diseases.
OBJECTIVES
The aim of the study was to examine the effects of curcumin and/or deferoxamine on cell proliferation in a rat model of endometriosis.
MATERIAL AND METHODS
Thirty female 12-week-old albino Wistar rats, weighing 200-250 g, were used in this study. All the rats underwent ovariectomy and 0.1-mg β-estradiol 17-valerate pellets were placed intraperitoneally. An experimental model of endometriosis was created in all the animals. To create the experimental model, an approximately 1-cm long section of the uterus was taken, primarily from the right horn of the uterus. Autologous fragments were then placed between the peritoneum and muscle. The animals were divided into 3 groups: Group A, treated only with the vehicle used for curcumin and deferoxamine; group B, treated with curcumin (100 mg/kg body weight); and group C, treated with deferoxamine + curcumin (100 mg/kg body weight). After biopsy samples were obtained, the sections were stained with hematoxylin and eosin. Immunostaining for cytokeratin-7 and proliferating cell nuclear antigen (PCNA) was performed. Blood iron levels were measured using a Perkin Elmer AAnalyst 800 Atomic Absorption Spectrophotometer.
RESULTS
The endometrial implant size increased in Group A, but treatment with curcumin (p = 0.01) and deferoxamine + curcumin (p = 0.007) reduced the implant size. In ectopic endometrial epithelial cells, there were significant decreases in PCNA immunoreactivity between groups A and B (p = 0.044) and between groups A and C (p = 0.033).
CONCLUSIONS
Treatment with curcumin alone and/or in combination with deferoxamine contributed to a reduction in implant size and cell proliferation in a rat endometriosis model. Iron-chelating agents may act in the same manner when used in women with endometriosis; however, further studies from different perspectives are still needed.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Curcumin; Deferoxamine; Disease Models, Animal; Drug Synergism; Endometriosis; Female; Humans; Immunohistochemistry; Iron; Keratin-7; Ovariectomy; Proliferating Cell Nuclear Antigen; Rats, Wistar; Siderophores
PubMed: 28791836
DOI: 10.17219/acem/31186 -
Antioxidant preconditioning attenuates liver ischemia/reperfusion injury after hepatectomy in swine.Journal of B.U.ON. : Official Journal... 2021The purpose of this study was to evaluate whether antioxidant preconditioning with Deferoxamine can attenuate liver ischemia reperfusion injury associated with extended...
PURPOSE
The purpose of this study was to evaluate whether antioxidant preconditioning with Deferoxamine can attenuate liver ischemia reperfusion injury associated with extended hepatectomy in swine.
METHODS
Eighteen swine were randomly assigned to two groups: Deferoxamine (DFO) and Surgery Only (SO). The animals in both groups were subjected to laparotomy, prolonged temporary occlusion of the right and middle hepatic pedicles and subsequent left hepatectomy. The DFO group received IV deferoxamine prior to induction of liver ischemia. Monitoring was performed for 6 h and samples (Protein carbonyls, Thiobarbituric acid reactive substances, Histology, ALT, AST, Lactic acid and WBC) were drawn at 0, 60 and 360 min.
RESULTS
Protein carbonyls and Thiobarbituric acid reactive substances had significantly lower concentration and higher reduction rates in serum and liver tissue of the DFO group. The histological examination of liver tissue showed less inflammation and necrosis in the DFO group. Hepatic enzymes and lactic acid measurements showed higher reduction rate in the DFO group by the end of the experiment.
CONCLUSIONS
This experimental study documents an early protective effect of deferoxamine administration in major hepatectomies against liver ischemia/reperfusion injury.
Topics: Animals; Antioxidants; Deferoxamine; Hepatectomy; Male; Postoperative Complications; Premedication; Random Allocation; Reperfusion Injury; Swine
PubMed: 34268984
DOI: No ID Found -
Revista Brasileira de Terapia Intensiva Mar 2020To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained...
OBJECTIVE
To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained hypotension.
METHODS
Rats were subjected to sepsis induced by cecal ligation and puncture. Animals were divided into two groups: those with high and low plasma levels of interleukin-6. Following stratification, N-acetylcysteine plus deferoxamine or saline was administered to animals starting 3 and 12 hours after surgery. N-Acetylcysteine plus deferoxamine or placebo was administered within 12 hours of meeting the inclusion criteria in hypotensive patients.
RESULTS
N-Acetylcysteine plus deferoxamine increased survival in the cecal ligation and puncture model when administered 3 and 12 hours after sepsis induction. When dividing animals that received antioxidants using plasma interleukin-6 levels, the protective effect was observed only in those animals with high IL-6 levels. The antioxidant effect of N-acetylcysteine + deferoxamine was similar in the two groups, but a significant decrease in plasma interleukin-6 levels was observed in the high-interleukin-6-level group. Compared with patients treated with antioxidants in the low-interleukin-6 subgroup, those in the high-interleukin-6 subgroup had a lower incidence of acute kidney injury but were not different in terms of acute kidney injury severity or intensive care unit mortality.
CONCLUSION
Targeting antioxidant therapy to a high inflammatory phenotype would select a responsive population.
Topics: Acetylcysteine; Adult; Aged; Animals; Antioxidants; Deferoxamine; Humans; Male; Middle Aged; Prognosis; Rats; Rats, Wistar; Retrospective Studies; Sepsis; Treatment Outcome
PubMed: 32401970
DOI: 10.5935/0103-507x.20200016