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Cell Death Discovery Jan 2024N-methyl-D-aspartate receptors (NMDARs) are ligand-gated, voltage-dependent channels of the ionotropic glutamate receptor family. The present study explored whether...
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated, voltage-dependent channels of the ionotropic glutamate receptor family. The present study explored whether NMDAR activation induced ferroptosis in vascular endothelial cells and its complicated mechanisms in vivo and in vitro. Various detection approaches were used to determine the ferroptosis-related cellular iron content, lipid reactive oxygen species (LOS), siRNA molecules, RNA-sequence, MDA, GSH, and western blotting. The AMPK activator Acadesine (AICAR), HMGB1 inhibitor glycyrrhizin (GLY), PP2A inhibitor LB-100, and NMDAR inhibitor MK801 were used to investigate the involved in vivo and in vitro pathways. The activation of NMDAR with L-glutamic acid (GLU) or NMDA significantly promoted cellular ferroptosis, iron content, MDA, and the PTGS2 expression, while decreasing GPX4 expression and GSH concentration in human umbilical vein endothelial cells (HUVECs), which was reversed by ferroptosis inhibitors Ferrostatin-1(Fer-1), Liproxstatin-1 (Lip-1), or Deferoxamine (DFO). RNA-seq revealed that ferroptosis and SLC7A11 participate in NMDA or GLU-mediated NMDAR activation. The PP2A-AMPK-HMGB1 pathway was majorly associated with NMDAR activation-induced ferroptosis, validated using the PP2A inhibitor LB-100, AMPK activator AICAR, or HMGB1 siRNA. The role of NMDAR in ferroptosis was validated in HUVECs induced with the ferroptosis activator errasin or RSL3 and counteracted by the NMDAR inhibitor MK-801. The in vivo results showed that NMDA- or GLU-induced ferroptosis and LOS production was reversed by MK-801, LB-100, AICAR, MK-801, and GLY, confirming that the PP2A-AMPK-HMGB1 pathway is involved in NMDAR activation-induced vascular endothelium ferroptosis. In conclusion, the present study demonstrated a novel role of NMDAR in endothelial cell injury by regulating ferroptosis via the PP2A-AMPK-HMGB1 pathway.
PubMed: 38233385
DOI: 10.1038/s41420-023-01794-3 -
Brain Research Bulletin Feb 2024Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of...
Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of iron metabolism in neuronal survival, yet its effect on vasculature remains unclear. This study aims to explore the impact of endothelial ferroptosis on cerebrovascular function in TBI. A Controlled Cortical Impact (CCI) model was established in mice, resulting in a significant increase in iron-related proteins such as TfR1, FPN1, and FTH, as well as oxidative stress biomarker 4HNE. This was accompanied by a decline in expression of the ferroptosis inhibitor GPX4. Moreover, Perls' staining and nonhemin iron content assay showed iron overload in brain microvascular endothelial cells (BMECs) and the ipsilateral cortex. Immunofluorescence staining revealed more FTH-positive cerebral endothelial cells, consistent with impaired perfusion vessel density and cerebral blood flow. As a specific iron chelator, deferoxamine (DFO) treatment inhibited such ferroptotic proteins expression and the accumulation of lipid-reactive oxygen species following CCI, enhancing glutathione peroxidase (GPx) activity. DFO treatment significantly reduced iron deposition in BMECs and brain tissue, and increased density of the cerebral capillaries as well. Consequently, DFO treatment led to improvements in cerebral blood flow (as measured by laser speckle imaging) and behavioral performance (as measured by the neurological severity scores, rotarod test, and Morris water maze test). Taken together, our results indicated that TBI induces remarkable iron disorder and endothelial ferroptosis, and DFO treatment may help maintain iron homeostasis and protect vascular function. This may provide a novel therapeutic strategy to prevent cerebrovascular dysfunction following TBI.
Topics: Humans; Mice; Animals; Deferoxamine; Endothelial Cells; Ferroptosis; Brain Injuries, Traumatic; Iron
PubMed: 38218407
DOI: 10.1016/j.brainresbull.2024.110878 -
Journal of Cancer 2024Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast China, and its metastasis remains an unresolved clinical problem. Ferroptosis,...
Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast China, and its metastasis remains an unresolved clinical problem. Ferroptosis, a type of nonapoptotic cell death, is a critical pathway in tumor metastasis. Berberine (BBR), a plant alkaloid, has been explored as a potential anti-NPC metastatic agent; however, the underlying mechanisms are unknown. Here, we showed that BBR exerted its anti-metastasis role by inhibiting system Xc/GSH/GPX4 axis-driven ferroptosis. The present study demonstrated for the first time that BBR induced ferroptosis in NPC cells by increasing reactive oxygen species, lipid peroxidation and cellular Fe and that the ferroptosis inhibitors Ferrostatin-1 and Deferoxamine mesylate rescued BBR-induced NPC cell death. Moreover, the ferroptotic characteristics of BBR-treated NPC cells were observed using transmission electron microscopy. Mechanistically, system Xc (SLC7A11 and SLC3A2) and GSH levels were found to be suppressed after treatment with BBR. We demonstrated that the system Xc/GSH/GPX4 axis was a critical mediator of BBR-induced ferroptosis. Furthermore, GPX4, a key inhibitor of lipid peroxidation, was greatly suppressed by BBR at both protein and mRNA levels. Molecular docking results showed a strong interaction between GPX4 and BBR. Notably, GPX4 overexpression reversed the effect of BBR-induced ferroptosis in NPC cells. Finally, BBR-mediated inhibition of NPC metastasis was validated using a mouse model. Taken together, our data suggest that BBR induced ferroptosis of NPC cells via suppressing the system Xc/GSH/GPX4 axis, provides new insights into the mechanism of BBR anti-NPC metastasis.
PubMed: 38213727
DOI: 10.7150/jca.90574 -
Photodiagnosis and Photodynamic Therapy Feb 2024We present a case of bilateral maculopathy associated with deferoxamine mesylate (DFO) treatment.
BACKGROUND
We present a case of bilateral maculopathy associated with deferoxamine mesylate (DFO) treatment.
METHODS
A 53-year-old man with myelodysplastic syndrome (MDS) received DFO therapy due to elevated ferritin levels. He was then referred to ophthalmology clinic due to blurred vision. He was diagnosed as bilateral neurosensory retinal detachment of the macula. During follow up, best corrected visual acuity (BCVA), optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and fundus autofluorescence (FAF) were evaluated.
RESULTS
At first visit, OCT showed bilateral foveal neurosensory detachment. Hyperfluorescence of the macula and the peripapillary region were found on FFA. After discontinuation of DFO, BCVA improved from 20/120 to 20/60 with resolution of the foveal detachments on OCT scan. Four weeks later, FAF showed bilateral mottled hyperautofluorescence and hypoautofluorescence at the macula and the peripapillary region.
CONCLUSION
Deferoxamine can cause acute retinal toxicity. Haematologists should be alert to visual complaints associated with DFO therapy, as early diagnosis and discontinuation of the medication allows recovery of visual function with residual fundus findings.
Topics: Male; Humans; Middle Aged; Deferoxamine; Tomography, Optical Coherence; Photochemotherapy; Photosensitizing Agents; Retinal Diseases; Macular Degeneration
PubMed: 38163453
DOI: 10.1016/j.pdpdt.2023.103961 -
GeroScience Apr 2024Aging has a significant impact on the immune system, leading to a gradual decline in immune function and changes in the body's ability to respond to bacterial...
Aging has a significant impact on the immune system, leading to a gradual decline in immune function and changes in the body's ability to respond to bacterial infections. Non-tuberculous mycobacteria (NTM), also known as atypical mycobacteria or environmental mycobacteria, are commonly found in soil, water, and various environmental sources. While many NTM species are considered opportunistic pathogens, some can cause significant infections, particularly in individuals with compromised immune systems, such as older individuals. When mycobacteria enter the body, macrophages are among the first immune cells to encounter them and attempt to engulf mycobacteria through a process called phagocytosis. Some NTM species, including Mycobacterium avium (M. avium) can survive and replicate within macrophages. However, little is known about the interaction between NTM and macrophages in older individuals. In this study, we investigated the response of bone marrow-derived macrophage (BMMs) isolated from young (5 months) and old (25 months) mice to M. avium serotype 4, one of the main NTM species in patients with pulmonary NTM diseases. Our results demonstrated that BMMs from old mice have an increased level of intracellular iron and are more susceptible to M. avium serotype 4 infection compared to BMMs from young mice. The whole-cell proteomic analysis indicated a dysregulated expression of iron homeostasis-associated proteins in old BMMs regardless of mycobacterial infection. Deferoxamine, an iron chelator, significantly rescued mycobacterial killing and phagolysosome maturation in BMMs from old mice. Therefore, our data for the first time indicate that an intracellular iron accumulation improves NTM survival within macrophages from old mice and suggest a potential application of iron-chelating drugs as a host-directed therapy for pulmonary NTM infection in older individuals.
Topics: Humans; Animals; Mice; Aged; Proteomics; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Macrophages; Phagocytosis
PubMed: 38159133
DOI: 10.1007/s11357-023-01048-1 -
Journal of Cancer Research and... Dec 2023Ferroptosis is a novel subtype of programmed cell death caused by iron-dependent lipid peroxidation and excessive reactive oxygen species (ROS) production....
BACKGROUND
Ferroptosis is a novel subtype of programmed cell death caused by iron-dependent lipid peroxidation and excessive reactive oxygen species (ROS) production. Small-molecule ferroptotic drugs have the probability of selectively targeting the specific features of aggressive tumor cells. In particular, pseudolaric acid B (PAB) triggered ferroptosisin breast cancer cells. The aim of this study is to explore the antitumor effect of PAB on A549 cells and provide a theoretical basis for the further development and clinical application of PAB.
METHODS
First, relevant databases were used to predict of target genes related to PAB, Then, EdU proliferation assay, colony formation and wound-healing assays were applied to calculate A549 cells proliferative abilities. Measurement of ferrous iron, lipid peroxidation, ROS, malondialdehyde (MDA) and glutathione (GSH) were utilized to explore the relevant mechanism.
RESULTS
We showed that PAB decreased the viability of lung adenocarcinoma cells in vitro, which was accompanied by abnormally elevated levels of intracellular ferrous iron and overproduction of lipid reactive oxidate species (L-ROS). In turn, deferoxamine (DFO) significantly rescued PAB-induced lipid peroxidation. PAB also improved the intracellular labile iron pool by promoting ferritin autophagy via the upregulation of the nuclear receptor coactivator 4 (NCOA4). Moreover, silencing of NCOA4 alleviated PAB-inducedferroptotic death and reduced the levels of intracellular ferrous iron.
CONCLUSIONS
In summary, PAB-triggered ferroptosis in lung adenocarcinoma cells by enhancing ferritinophagy. thus, PAB is a potential therapeutic agent for lung adenocarcinoma.
Topics: Humans; Ferroptosis; Reactive Oxygen Species; Iron; Autophagy; Transcription Factors; Adenocarcinoma of Lung; Nuclear Receptor Coactivators
PubMed: 38156933
DOI: 10.4103/jcrt.jcrt_806_23 -
Ecotoxicology and Environmental Safety Jan 2024Silica nanoparticles (SiNPs) have been widely used in electronics, chemistry, and biomedicine. Human exposure to SiNPs and possible health effects have attracted much...
Silica nanoparticles (SiNPs) have been widely used in electronics, chemistry, and biomedicine. Human exposure to SiNPs and possible health effects have attracted much attention. The potential cardiovascular toxicity of SiNPs and their related mechanisms are still unclear. Therefore, in this study, we investigated the toxic effects of SiNPs on human umbilical vein endothelial cells (HUVECs). We found that SiNPs could induce HUVECs ferroptosis. The results showed that the level of intracellular divalent iron and lipid peroxidation increased, and mitochondrial cristae decreased. In addition, the pretreatment of the iron chelator deferoxamine mesylate (DFO) could alleviate the ferroptosis of cells. Interestingly, pretreatment of 3-methyladenine (3-MA), an autophagy/PI3K inhibitor could partially inhibit autophagy and reduce ferroptosis, which indicated that autophagy played an important role in cell ferroptosis. Additionally, after knocking down nuclear receptor coactivator 4 (NCOA4), Ferritin Heavy Chain 1 (FTH1) expression was up-regulated, and the levels of divalent iron and lipid peroxidation decreased, which suggested that NCOA4 mediated the ferroptosis of HUVECs induced by SiNPs. In conclusion, this study shows that SiNPs can induce cardiovascular toxicity in which there is ferroptosis. NCOA4-mediated ferritinophagy and resultant ferroptosis by SiNPs may play an important role. This study provides a new theoretical strategy for the treatment and prevention of cardiovascular diseases in the future.
Topics: Humans; Human Umbilical Vein Endothelial Cells; Silicon Dioxide; Phosphatidylinositol 3-Kinases; Ferroptosis; Iron; Transcription Factors; Nanoparticles; Autophagy; Nuclear Receptor Coactivators
PubMed: 38150751
DOI: 10.1016/j.ecoenv.2023.115889 -
International Journal of Molecular... Dec 2023Zr-iPET has been widely used for preclinical and clinical immunotherapy studies to predict patient stratification or evaluate therapeutic efficacy. In this study, we...
Zr-iPET has been widely used for preclinical and clinical immunotherapy studies to predict patient stratification or evaluate therapeutic efficacy. In this study, we prepared and evaluated Zr-DFO-anti-PD-L1-mAb tracers with varying chelator-to-antibody ratios (CARs), including Zr-DFO-anti-PD-L1-mAb_3X (), Zr-DFO-anti-PD-L1-mAb_10X (), and Zr-DFO-anti-PD-L1-mAb_20X (). The DFO-anti-PD-L1-mAb conjugates with varying CARs were prepared using a random conjugation method and then subjected to quality control. The conjugates were radiolabeled with Zr and evaluated in a PD-L1-expressing CT26 tumor-bearing mouse model. Next, iPET imaging, biodistribution, pharmacokinetics, and ex vivo pathological and immunohistochemical examinations were conducted. LC-MS analysis revealed that DFO-anti-PD-L1-mAb conjugates were prepared with CARs ranging from 0.4 to 2.0. Radiochemical purity for all tracer groups was >99% after purification. The specific activity levels of , , and were 2.2 ± 0.6, 8.2 ± 0.6, and 10.5 ± 1.6 μCi/μg, respectively. Zr-iPET imaging showed evident tumor uptake in all tracer groups and reached the maximum uptake value at 24 h postinjection (p.i.). Biodistribution data at 168 h p.i. revealed that the tumor-to-liver, tumor-to-muscle, and tumor-to-blood uptake ratios for , , and were 0.46 ± 0.14, 0.58 ± 0.33, and 1.54 ± 0.51; 4.7 ± 1.3, 7.1 ± 3.9, and 14.7 ± 1.1; and 13.1 ± 5.8, 19.4 ± 13.8, and 41.3 ± 10.6, respectively. Significant differences were observed between and in the aforementioned uptake ratios at 168 h p.i. The mean residence time and elimination half-life for , , and were 25.4 ± 4.9, 24.2 ± 6.1, and 25.8 ± 3.3 h and 11.8 ± 0.5, 11.1 ± 0.7, and 11.7 ± 0.6 h, respectively. No statistical differences were found between-tracer in the aforementioned pharmacokinetic parameters. In conclusion, Zr-DFO-anti-PD-L1-mAb tracers with a CAR of 1.4-2.0 may be better at imaging PD-L1 expression in tumors than are traditional low-CAR Zr-iPET tracers.
Topics: Humans; Mice; Animals; Chelating Agents; Radioisotopes; Positron-Emission Tomography; Antibodies, Monoclonal; Tissue Distribution; B7-H1 Antigen; Deferoxamine; Neoplasms; Zirconium; Cell Line, Tumor
PubMed: 38138961
DOI: 10.3390/ijms242417132 -
Journal of Clinical Medicine Dec 2023Severe hemolytic disease of the fetus and newborn (HDFN) requiring intrauterine transfusions (IUTs) may cause iron accumulation, resulting in liver damage, which may...
Liver Dysfunction with Severe Cholestasis and Coagulation Disorders in the Course of Hemolytic Disease of the Newborn Requiring Chelation Therapy-A Case Report and Review of the Literature.
Severe hemolytic disease of the fetus and newborn (HDFN) requiring intrauterine transfusions (IUTs) may cause iron accumulation, resulting in liver damage, which may lead to cholestasis and coagulation disorders. In this article, we reported a case of a female neonate who underwent chelation therapy with a positive outcome, and we reviewed the English and Polish literature on chelation therapy in HDFN available in PubMed. The patient with maximum ferritin concentration above 33,511.2 ng/mL developed liver dysfunction with coagulation disorders requiring multiple transfusions of fresh frozen plasma (FFP), Octaplex and cryoprecipitate, and hypoalbuminemia treated with numerous albumin infusions. Furthermore, severe cholestasis was observed with direct bilirubin levels up to 33.14 mg/dL. Additionally, the child developed transient myelosuppression with neutropenia, thrombocytopenia, and low reticulocyte count due to several blood transfusions. The differential diagnosis tests were conducted to rule out any causes of hepatic failure other than hemolytic disease of the newborn. This case proves that adequate treatment of severe HDFN with anemia requiring IUT and hepatic failure can lead to positive outcomes with no long-term consequences.
PubMed: 38137714
DOI: 10.3390/jcm12247645 -
PloS One 2023Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often...
BACKGROUND
Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models.
METHODS
Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin.
RESULTS
TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice.
CONCLUSIONS
TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; Chelating Agents; Gene Expression; Molecular Targeted Therapy; Receptors, Transferrin; Transferrin
PubMed: 38117806
DOI: 10.1371/journal.pone.0293700