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Stem Cell Reviews and Reports Aug 2023Mesenchymal stem cells (MSCs) are located in various tissues of the body. These cells exhibit regenerative and reparative properties, which makes them highly valuable... (Review)
Review
Mesenchymal stem cells (MSCs) are located in various tissues of the body. These cells exhibit regenerative and reparative properties, which makes them highly valuable for cell-based therapy. Despite this, majority of MSC-related studies remain to be translated for regular clinical use. This is partly because there are methodical challenges in pre-administration MSC labelling, post-administration detection and tracking of cells, and in retention of maximal therapeutic potential in-vivo. This calls for exploration of alternative or adjunctive approaches that would enable better detection of transplanted MSCs via non-invasive methods and enhance MSC therapeutic potential in-vivo. Interestingly, these attributes have been demonstrated by some iron-related genes and proteins.Accordingly, this unique forward-looking article integrates the apparently distinct fields of iron metabolism and MSC biology, and reviews the utility of iron-related genes and iron-related proteins in facilitating MSC detection and therapy, respectively. Effects of genetic overexpression of the iron-related proteins ferritin, transferrin receptor-1 and MagA in MSCs and their utilisation as reporter genes for improving MSC detection in-vivo are critically evaluated. In addition, the beneficial effects of the iron chelator deferoxamine and the iron-related proteins haem oxygenase-1, lipocalin-2, lactoferrin, bone morphogenetic protein-2 and hepcidin in enhancing MSC therapeutics are highlighted with the consequent intracellular alterations in MSCs. This review aims to inform both regenerative and translational medicine. It can aid in formulating better methodical approaches that will improve, complement, or provide alternatives to the current pre-transplantation MSC labelling procedures, and enhance MSC detection or augment the post-transplantation MSC therapeutic potential.
Topics: Iron; Mesenchymal Stem Cells
PubMed: 37269528
DOI: 10.1007/s12015-023-10569-3 -
Cardiovascular Research Feb 2024Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a serious life-threatening complication, the mechanisms of which have not been fully established, and...
AIMS
Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a serious life-threatening complication, the mechanisms of which have not been fully established, and therefore no effective treatment is currently available. The purpose of the study was to identify new molecular signatures of the cardiomyopathy development in DMD.
METHODS AND RESULTS
For modelling of DMD-associated cardiomyopathy, we prepared three pairs of isogenic control and dystrophin-deficient human induced pluripotent stem cell (hiPSC) lines. Two isogenic hiPSC lines were obtained by CRISPR/Cas9-mediated deletion of DMD exon 50 in unaffected cells generated from healthy donor and then differentiated into cardiomyocytes (hiPSC-CM). The latter were subjected to global transcriptomic and proteomic analyses followed by more in-depth investigation of selected pathway and pharmacological modulation of observed defects. Proteomic analysis indicated a decrease in the level of mitoNEET protein in dystrophin-deficient hiPSC-CM, suggesting alteration in iron metabolism. Further experiments demonstrated increased labile iron pool both in the cytoplasm and mitochondria, a decrease in ferroportin level and an increase in both ferritin and transferrin receptor in DMD hiPSC-CM. Importantly, CRISPR/Cas9-mediated correction of the mutation in the patient-derived hiPSC reversed the observed changes in iron metabolism and restored normal iron levels in cardiomyocytes. Moreover, treatment of DMD hiPSC-CM with deferoxamine (DFO, iron chelator) or pioglitazone (mitoNEET stabilizing compound) decreased the level of reactive oxygen species in DMD hiPSC-CM.
CONCLUSION
To our knowledge, this study demonstrated for the first time impaired iron metabolism in human DMD cardiomyocytes, and potential reversal of this effect by correction of DMD mutation or pharmacological treatment. This implies that iron overload-regulating compounds may serve as novel therapeutic agents in DMD-associated cardiomyopathy.
Topics: Humans; Cardiomyopathies; CRISPR-Cas Systems; Dystrophin; Gene Editing; Homeostasis; Induced Pluripotent Stem Cells; Iron; Muscular Dystrophy, Duchenne; Myocytes, Cardiac; Proteomics
PubMed: 38078368
DOI: 10.1093/cvr/cvad182 -
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 -
Molecular Neurobiology Feb 2024Ferroptosis is a distinct peroxidation-driven form of cell death tightly involved in subarachnoid hemorrhage (SAH). This study delved into the mechanism of deferoxamine...
Ferroptosis is a distinct peroxidation-driven form of cell death tightly involved in subarachnoid hemorrhage (SAH). This study delved into the mechanism of deferoxamine (DFO, an iron chelator) in SAH-induced ferroptosis and inflammation. SAH mouse models were established by endovascular perforation method and injected intraperitoneally with DFO, or intraventricularly injected with the Nrf2 pathway inhibitor ML385 before SAH, followed by detection of neurological function, blood-brain barrier (BBB) permeability, and brain water content. Apoptotic level of hippocampal neurons, symbolic changes of ferroptosis, and levels of pro-inflammatory cytokines were assessed using TUNEL staining, Western blotting, colorimetry, and ELISA. The localization and expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) were detected. HT22 cells were exposed to Hemin as in vitro SAH models and treated with FIN56 to induce ferroptosis, followed by evaluation of the effects of DFO on FIN56-treated HT22 cells. The regulation of Nrf2 in thioredoxin reductase 1 (TXNRD1) was analyzed by co-immunoprecipitation and Western blotting. Moreover, HT22 cells were treated with DFO and ML385 to identify the role of DFO in the Nrf2/TXNRD1 axis. DFO extenuated brain injury, and ferroptosis and inflammation in hippocampal neurons of SAH mice. Nrf2 localized at the CA1 region of hippocampal neurons, and DFO stimulated nuclear translocation of Nrf2 protein in hippocampal neurons of SAH mice. Additionally, DFO inhibited ferroptosis and inflammatory responses in FIN56-induced HT22 cells. Nrf2 positively regulated TXNRD1 protein expression. Indeed, DFO alleviated FIN56-induced ferroptosis and inflammation via activation of the Nrf2/TXNRD1 axis. DFO alleviated neurological deficits, BBB disruption, brain edema, and brain injury in mice after SAH by inhibiting hippocampal neuron ferroptosis via the Nrf2/TXNRD1 axis. DFO ameliorates SAH-induced ferroptosis and inflammatory responses in hippocampal neurons by activating the Nrf2/TXNRD1 axis.
Topics: Rats; Mice; Animals; Rats, Sprague-Dawley; NF-E2-Related Factor 2; Deferoxamine; Thioredoxin Reductase 1; Subarachnoid Hemorrhage; Ferroptosis; Brain Injuries; Hippocampus; Neurons; Inflammation
PubMed: 37676391
DOI: 10.1007/s12035-023-03525-2 -
Molecular Pharmaceutics Sep 2023One of the most aggressive forms of breast cancer involves the overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in ∼25% of all...
One of the most aggressive forms of breast cancer involves the overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in ∼25% of all breast cancers and is associated with increased proliferation, increased rates of metastasis, and poor prognosis. Treatment for HER2-positive breast cancer has vastly improved since the development of the monoclonal antibody trastuzumab (Herceptin) as well as other biological constructs. However, patients still commonly develop resistance, illustrating the need for newer therapies. Nanobodies have become an important focus for potential development as HER2-targeting imaging agents and therapeutics. Nanobodies have many favorable characteristics, including high stability in heat and nonphysiological pH, while maintaining their low-nanomolar affinity for their designed targets. Specifically, the 2Rs15d nanobody has been developed for targeting HER2 and has been evaluated as a diagnostic imaging agent for single-photon emission computed tomography (SPECT) and positron emission tomography (PET). While a construct of 2Rs15d with the positron emitter Ga is currently in phase I clinical trials, the only PET images acquired in preclinical or clinical research have been within 3 h postinjection. We evaluated our in-house produced 2Rs15d nanobody, conjugated with the chelator deferoxamine (DFO), and radiolabeled with Zr for PET imaging up to 72 h postinjection. [Zr]Zr-DFO-2Rs15d demonstrated high stability in both phosphate-buffered saline (PBS) and human serum. Cell binding studies showed high binding and specificity for HER2, as well as prominent internalization. Our in vivo PET imaging confirmed high-quality visualization of HER2-positive tumors up to 72 h postinjection, whereas HER2-negative tumors were not visualized. Subsequent biodistribution studies quantitatively supported the significant HER2-positive tumor uptake compared to the negative control. Our studies fill an important gap in understanding the imaging and binding properties of the 2Rs15d nanobody at extended time points. As many therapeutic radioisotopes have single or multiday half-lives, this information will directly benefit the potential of the radiotherapy development of 2Rs15d for HER2-positive breast cancer patients.
Topics: Humans; Female; Breast Neoplasms; Single-Domain Antibodies; Tissue Distribution; Trastuzumab; Positron-Emission Tomography; Receptor, ErbB-2; Antineoplastic Agents; Cell Line, Tumor; Zirconium
PubMed: 37552575
DOI: 10.1021/acs.molpharmaceut.3c00360 -
Thrombosis and Haemostasis Dec 2023Although thrombosis events are the leading complication of uremia, their mechanism is largely unknown. The interaction between endothelial cells (ECs) and red blood...
BACKGROUND
Although thrombosis events are the leading complication of uremia, their mechanism is largely unknown. The interaction between endothelial cells (ECs) and red blood cells (RBCs) in uremic solutes and its prothrombotic role need to be investigated.
METHODS AND RESULTS
Here, we established an in vitro co-incubation model of uremic RBC and EC as well as a uremic rat model induced by adenine. Using flow cytometry, confocal microscopy, and electron microscopy, we found increased erythrophagocytosis by EC accompanied by increased reactive oxygen species, lipid peroxidation, and impairment of mitochondria, indicating that ECs undergo ferroptosis. Further investigations showed increased proteins' expression of heme oxygenase-1 and ferritin and labile iron pool accumulation in EC, which could be suppressed by deferoxamine (DFO). The ferroptosis-negative regulators glutathione peroxidase 4 and SLC7A11 were decreased in our erythrophagocytosis model and could be enhanced by ferrostatin-1 or DFO. In vivo, we observed that vascular EC phagocytosed RBC and underwent ferroptosis in the kidney of the uremic rat, which could be inhibited by blocking the phagocytic pathway or inhibiting ferroptosis. Next, we found that the high tendency of thrombus formation was accompanied by erythrophagocytosis-induced ferroptosis in vitro and in vivo. Importantly, we further revealed that upregulated TMEM16F expression mediated phosphatidylserine externalization on ferroptotic EC, which contributed to a uremia-associated hypercoagulable state.
CONCLUSION
Our results indicate that erythrophagocytosis-triggered ferroptosis followed by phosphatidylserine exposure of EC may play a key role in uremic thrombotic complications, which may be a promising target to prevent thrombogenesis of uremia.
Topics: Rats; Animals; Ferroptosis; Endothelial Cells; Phosphatidylserines; Erythrocytes; Thrombosis; Uremia
PubMed: 37364609
DOI: 10.1055/a-2117-7890 -
Tissue Engineering. Part B, Reviews Aug 2023Deferoxamine (DFO) is an iron chelator with FDA approval for the clinical treatment of iron excess. As a well-established stabilizer of hypoxia-inducible factor-1α... (Review)
Review
Deferoxamine (DFO) is an iron chelator with FDA approval for the clinical treatment of iron excess. As a well-established stabilizer of hypoxia-inducible factor-1α (HIF-1α), DFO can efficiently upregulate HIF-1α and relevant downstream angiogenic factors, leading to accelerated vascularization. Moreover, as increasing studies have focused on DFO as a hypoxia-mimetic agent in recent years, it has been shown that DFO exhibited multiple functions, including stem cell regulation, immunoregulation, provascularization, and pro-osteogenesis. On the contrary, DFO can bind excess iron ions in wounds of chronic inflammation, while serving as an antioxidant with the characteristic of removing reactive oxygen species. Collectively, these characteristics make DFO a potent modulator in tissue engineering for increasing tissue integration of biomaterials and facilitating wound healing. This review outlines the activity of DFO as a representative hypoxia-mimetic agent in cells as well as the evolution of its application in tissue engineering. It can be concluded that DFO is a medication with tremendous promise and application value in future trends, which can optimize biomaterials and existing tissue engineering techniques for tissue regeneration.
Topics: Humans; Deferoxamine; Tissue Engineering; Hypoxia-Inducible Factor 1, alpha Subunit; Biocompatible Materials; Hypoxia; Iron
PubMed: 36475887
DOI: 10.1089/ten.TEB.2022.0168 -
Pharmaceuticals (Basel, Switzerland) Jul 2023The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more... (Review)
Review
The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases.
The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.
PubMed: 37513928
DOI: 10.3390/ph16071016 -
Cureus Oct 2023Systemic iron chelation therapy has long been used for iron overload, providing a role in returning iron levels to proper homeostatic concentrations. Recently, topical... (Review)
Review
Systemic iron chelation therapy has long been used for iron overload, providing a role in returning iron levels to proper homeostatic concentrations. Recently, topical iron chelation therapy has emerged as a potential strategy for treating skin damage. This narrative review explores the current status and future prospects of topical iron chelation therapy for treating ultraviolet (UV) and non-UV skin damage, as well as its potential application in wound healing. The review was conducted through a literature search across PubMed, Web of Science, and EMBASE databases, spanning publications from 1990 to 2023. The selection of articles was focused on primary research studies, either experimental or clinical, that explored the implications and formulations of topical iron chelators used alone or in conjunction with another therapeutic agent. The search strategy employed a combination of terms, including "topical iron chelation", "topical deferoxamine", "UV", "wound healing", "skin inflammation", "radiation-induced fibrosis", and "skin cancer". Relevant studies, including methods, intervention strategies, measured outcomes, and findings, are summarized. The review also considered the potential challenges in translating research findings into clinical practice. Results indicate that topical iron chelators, such as deferoxamine, are effective in mitigating UV-induced skin damage, reducing tumorigenesis, and decreasing oxidative damage. In addition, the use of these agents in radiation-induced fibrosis has been shown to significantly increase skin elasticity and reduce dermal fibrosis. Several studies also highlight the use of topical iron chelators in difficult-to-treat chronic wounds, such as diabetic neuropathic ulcers and sickle cell ulcers. In conclusion, topical iron chelation therapy represents a novel and promising approach for skin protection and wound healing. Its potential makes it a promising area of future research.
PubMed: 38022031
DOI: 10.7759/cureus.47720 -
International Journal of Medical... 2023Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective...
Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective inhibitors of nuclear export in MM reveals the broad therapeutic prospects of nuclear localization intervention. Sterol regulatory element binding protein 2 (SREBP2) is a lipid regulatory molecule that has been implicated in the effect of drug therapy for MM. SREBP2 has been reported to be regulated by the antimalarial drug artesunate (ART) through alteration of its nuclear localization and has been shown to inhibit ferroptosis in other tumours. However, the mechanism through which this might occur has not been clarified in MM. Our study aimed to explore whether ART can induce ferroptosis in MM through nuclear localization of SREBP2. To evaluate whether ferroptosis is induced by treatment with ART in myeloma, we used two types of myeloma cell lines. We first used a series of molecular approaches and other techniques to investigate the impact of ART on cell growth, production of reactive oxygen species (ROS), Fe levels, lipid peroxidation and expression of genes related to ferroptosis. Then, we further explored the mechanism through which ferroptosis may occur in these cells and the relationship between ferroptosis and the nuclear localization of SREBP2. Upregulation of ROS, Fe, and lipid peroxidation as well as inhibition of cell growth were observed in myeloma cells after treatment with ART. Expression of acyl CoA synthase long chain family member 4 (ACSL4) was increased, while glutathione peroxidase 4 (GPX4) expression was reduced in cells treated with ART. ART-induced cell death could be reversed by ferropstatin-1 (Fer-1) and deferoxamine mesylate (DFO). Nuclear localization of SREBP2 in myeloma cells was inhibited, accompanied by downregulation of isopentenyl pyrophosphate (IPP) and GPX4, after treatment with ART. In conclusion, our study demonstrated that the antimalarial drug ART can inhibit nuclear localization of SREBP2, downregulate IPP and GPX4, and eventually trigger ferroptosis in myeloma cells. Through this study, we hope to establish a correlation between nuclear localization pathways and mediation of ferroptosis in myeloma cells and provide an innovative direction for exploration-related therapy.
Topics: Humans; Antimalarials; Artesunate; Ferroptosis; Multiple Myeloma; Phospholipid Hydroperoxide Glutathione Peroxidase; Reactive Oxygen Species; Sterol Regulatory Element Binding Protein 2
PubMed: 37859702
DOI: 10.7150/ijms.86409