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Environmental Research Jul 2024This experiment prepared magnetic composite siderophores (DMPs) with strong magnetism, excellent adsorption capacity, and high specific surface area. Exploring the...
This experiment prepared magnetic composite siderophores (DMPs) with strong magnetism, excellent adsorption capacity, and high specific surface area. Exploring the synergistic effect of magnetic nanoparticles and siderophores on Microcystis aeruginosa growth under iron-deficient condition, by utilizing the characteristics of the three-layer core-shell structure of DMPs. This study elucidated the potential mechanism by which DMPs promote the cyanobacterial growth through physiological indicators and transcriptome analysis. On the experiment's final day, cell density in DMPs treatment group at 2, 4, and 8 mg/L were 1.10, 1.14 and 1.16 times higher than those in the control group (Ct), respectively. Similarly, chlorophyll and photosynthetic efficiency results showed improved algae growth with increasing DMPs dosage. The microcystin content in DMPs experimental groups at low, medium, and high concentration were 0.91, 0.86, and 0.83 times that of Ct, indicating alleviation of iron deficiency stress. Additionally, based on extracellular polymers, intracellular and extracellular siderophores, and visualization techniques, DMPs nanoparticles captured free iron sources in the environment, promoting algae growth by entering algal cells and facilitating the uptake and utilization of free iron ions from the solution. During the experiment, the iron uptake and transport genes (feoA and feoB) were significantly upregulated, whereas the algal siderophore synthesis gene (pchF) and the TonB-dependent transport system gene (TonB_C) were significantly downregulated, suggesting heightened activity in intracellular iron uptake and transport. This indicates an abundance of intracellular iron, eliminating the need for secrete siderophores to overcome iron deficiency. Microcystis aeruginosa increased iron bioavailability by using iron transported through DMPs in the environment while internalizing these DMPs. This study explored the mechanism of this synergistic effect to boost algal growth, and provided new ideas for elucidating the mechanism of cyanobacterial bloom outbreaks as well as the innovative application of biotechnology.
Topics: Microcystis; Deferoxamine; Siderophores; Magnetite Nanoparticles; Iron
PubMed: 38719066
DOI: 10.1016/j.envres.2024.119062 -
Neurochemical Research Jul 2024Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy...
Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (P < 0.05). This activation contributed to oxidative stress (P < 0.05), enhanced autophagy (P < 0.05) and cell death (P < 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (P < 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (P < 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (P < 0.05), oxidative stress (P < 0.05), and cell damage (P < 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (P < 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (P < 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (P < 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.
Topics: Nuclear Receptor Coactivators; Animals; Reperfusion Injury; Ferritins; Mice; Autophagy; Cell Line; Oxidative Stress; Brain Ischemia
PubMed: 38713437
DOI: 10.1007/s11064-024-04146-4 -
Journal of Translational Medicine May 2024Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the...
BACKGROUND
Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1 lymphocytes. Due to solid tumor heterogeneity of PD-1 populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1 tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging.
METHODS
We designed a 13 kDa β-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1.
RESULTS
Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1 populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with Galium isotope. Radiochemical purity of Ga-MBA proteins reached values 94.7-99.3% and in vitro stability in human serum after 120 min was in the range 94.6-98.2%. The distribution of Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1 populations in solid tumors.
CONCLUSIONS
Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging.
Topics: Humans; Programmed Cell Death 1 Receptor; Animals; Positron-Emission Tomography; HEK293 Cells; Protein Engineering; Mice; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Lung Neoplasms; Amino Acid Sequence
PubMed: 38711085
DOI: 10.1186/s12967-024-05210-x -
ACS Applied Materials & Interfaces May 2024Vascularization and inflammation management are essential for successful bone regeneration during the healing process of large bone defects assisted by artificial...
Vascularization and inflammation management are essential for successful bone regeneration during the healing process of large bone defects assisted by artificial implants/fillers. Therefore, this study is devoted to the optimization of the osteogenic microenvironment for accelerated bone healing through rapid neovascularization and appropriate inflammation inhibition that were achieved by applying a tantalum oxide (TaO)-based nanoplatform carrying functional substances at the bone defect. Specifically, TaO mesoporous nanospheres were first constructed and then modified by functionalized metal ions (Mg) with the following deferoxamine (DFO) loading to obtain the final product simplified as DFO-Mg-TaO. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that the product was homogeneously dispersed hollow nanospheres with large specific surface areas and mesoporous shells suitable for loading Mg and DFO. The biological assessments indicated that DFO-Mg-TaO could enhance the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The DFO released from DFO-Mg-TaO promoted angiogenetic activity by upregulating the expressions of hypoxia-inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, DFO-Mg-TaO also displayed anti-inflammatory activity by reducing the expressions of pro-inflammatory factors, benefiting from the release of bioactive Mg. experiments demonstrated that DFO-Mg-TaO integrated with vascular regenerative, anti-inflammatory, and osteogenic activities significantly accelerated the reconstruction of bone defects. Our findings suggest that the optimized DFO-Mg-TaO nanospheres are promising as multifunctional fillers to speed up the bone healing process.
Topics: Deferoxamine; Bone Regeneration; Tantalum; Animals; Oxides; Magnesium; Mesenchymal Stem Cells; Osteogenesis; Neovascularization, Physiologic; Rats; Mice; Rats, Sprague-Dawley; Cell Proliferation; Angiogenesis
PubMed: 38709640
DOI: 10.1021/acsami.4c04316 -
Frontiers in Bioengineering and... 2024Repair of large bone defects remains challenge for orthopedic clinical treatment. Porous titanium alloys have been widely fabricated by the additive manufacturing, which...
Repair of large bone defects remains challenge for orthopedic clinical treatment. Porous titanium alloys have been widely fabricated by the additive manufacturing, which possess the elastic modulus close to that of human cortical bone, good osteoconductivity and osteointegration. However, insufficient bone regeneration and vascularization inside the porous titanium scaffolds severely limit their capability for repair of large-size bone defects. Therefore, it is crucially important to improve the osteogenic function and vascularization of the titanium scaffolds. Herein, methacrylated gelatin (GelMA) were incorporated with the porous Ti-24Nb-4Zr-8Sn (Ti2448) scaffolds prepared by the electron beam melting (EBM) method (Ti2448-GelMA). Besides, the deferoxamine (DFO) as an angiogenic agent was doped into the Ti2448-GelMA scaffold (Ti2448-GelMA/DFO), in order to promote vascularization. The results indicate that GelMA can fully infiltrate into the pores of Ti2448 scaffolds with porous cross-linked network (average pore size: 120.2 ± 25.1 μm). Ti2448-GelMA scaffolds facilitated the differentiation of MC3T3-E1 cells by promoting the ALP expression and mineralization, with the amount of calcium contents ∼2.5 times at day 14, compared with the Ti2448 scaffolds. Impressively, the number of vascular meshes for the Ti2448-GelMA/DFO group (∼7.2/mm) was significantly higher than the control group (∼5.3/mm) after cultivation for 9 h, demonstrating the excellent angiogenesis ability. The Ti2448-GelMA/DFO scaffolds also exhibited sustained release of DFO, with a cumulative release of 82.3% after 28 days. Therefore, Ti2448-GelMA/DFO scaffolds likely provide a new strategy to improve the osteogenesis and angiogenesis for repair of large bone defects.
PubMed: 38707506
DOI: 10.3389/fbioe.2024.1372636 -
ACS Biomaterials Science & Engineering Jun 2024Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective...
Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective wound healing without scar formation. This study focuses on the fabrication of electrospun ROS-responsive selenium-containing polyurethane nanofibers incorporating deferoxamine mesylate (Def), indomethacin (Indo), and gold nanorods (AuNRs) as proangiogenesis, anti-inflammatory, and antibacterial agents for synchronized delivery to a full-thickness wound . The structure of the fabricated nanofibers was analyzed by various techniques. Toxicity was checked by CCK-8 and hemolytic assays. The efficiency of wound healing was verified by a transwell assay and cell scratch assay. The wound healing efficiency of the nanofibers was assayed in full-thickness wounds in a rat model. The multifunctional nanofibers had a porous structure, enhanced antioxidation, antibacterial activity, and promoted wound healing. They eradicated TNF-α and IL-6, increased IL-10 expression, and revealed the angiogenic potential by increased expression of HIF-1α, VEGF, and CD31.
Topics: Wound Healing; Polyurethanes; Animals; Nanofibers; Selenium; Reactive Oxygen Species; Gold; Rats; Nanotubes; Anti-Bacterial Agents; Deferoxamine; Rats, Sprague-Dawley; Humans; Indomethacin; Male; Neovascularization, Physiologic; Anti-Inflammatory Agents
PubMed: 38701357
DOI: 10.1021/acsbiomaterials.4c00363 -
Biomedical Materials (Bristol, England) May 2024To effectively address underlying issues and enhance the healing process of hard-to-treat soft tissue defects, innovative therapeutic approaches are required. One...
To effectively address underlying issues and enhance the healing process of hard-to-treat soft tissue defects, innovative therapeutic approaches are required. One promising strategy involves the incorporation of bioactive substances into biodegradable scaffolds to facilitate synergistic tissue regeneration, particularly in vascular regeneration. In this study, we introduce a composite hydrogel design that mimics the extracellular matrix by covalently combining gelatin and hyaluronic acid (HA), with the encapsulation of deferoxamine nanoparticles (DFO NPs) for potential tissue regeneration applications. Crosslinked hydrogels were fabricated by controlling the ratio of HA in the gelatin-based hydrogels, resulting in improved mechanical properties, enhanced degradation ability, and optimised porosity, compared with hydrogel formed by gelatin alone. The DFO NPs, synthesized using a double emulsion method with poly (D,L-lactide-co-glycolide acid), exhibited a sustained release of DFO over 12 d. Encapsulating the DFO NPs in the hydrogel enabled controlled release over 15 d. The DFO NPs, composite hydrogel, and the DFO NPs loaded hydrogel exhibited excellent cytocompatibility and promoted cell proliferation. Subcutaneous implantation of the composite hydrogel and the DFO NPs loaded hydrogel demonstrated biodegradability, tissue integration, and no obvious adverse effects, evidenced by histological analysis. Furthermore, the DFO NPs loaded composite hydrogel exhibited accelerated wound closure and promoted neovascularisation and granular formation when tested in an excisional skin wound model in mice. These findings highlight the potential of our composite hydrogel system for promoting the faster healing of diabetes-induced skin wounds and oral lesions through its ability to modulate tissue regeneration processes.
Topics: Gelatin; Deferoxamine; Animals; Hydrogels; Hyaluronic Acid; Nanoparticles; Mice; Biomimetic Materials; Cell Proliferation; Wound Healing; Tissue Engineering; Tissue Scaffolds; Biocompatible Materials; Humans; Porosity; Regeneration; Biomimetics
PubMed: 38697149
DOI: 10.1088/1748-605X/ad46ba -
Lipids in Health and Disease Apr 2024Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid...
Lipid peroxidation-induced ferroptosis as a therapeutic target for mitigating neuronal injury and inflammation in sepsis-associated encephalopathy: insights into the hippocampal PEBP-1/15-LOX/GPX4 pathway.
BACKGROUND
Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE.
METHODS
Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment.
RESULTS
The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway.
CONCLUSION
These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders.
Topics: Ferroptosis; Animals; Hippocampus; Humans; Sepsis-Associated Encephalopathy; Phospholipid Hydroperoxide Glutathione Peroxidase; Lipid Peroxidation; Mice; Male; Female; Phosphatidylethanolamine Binding Protein; Neurons; Coenzyme A Ligases; Inflammation; Amino Acid Transport System y+; S100 Calcium Binding Protein beta Subunit; Disease Models, Animal; Child, Preschool; Leukocytes, Mononuclear; Signal Transduction; Child; Glial Fibrillary Acidic Protein; Malondialdehyde; Sepsis; Infant
PubMed: 38685023
DOI: 10.1186/s12944-024-02116-x -
Biomaterials Advances Jul 2024Triple negative breast carcinoma (TNBC) accounts for 15-20 % of all incident breast cancers (BC) and is known to be highly invasive, has fewer treatment options, and...
Triple negative breast carcinoma (TNBC) accounts for 15-20 % of all incident breast cancers (BC) and is known to be highly invasive, has fewer treatment options, and tends to have a worse prognosis. However, due to its biological heterogeneity and diverse clinical and epidemiological behaviors, TNBC lacks a tumor-specific targeted therapy. In the present work we have developed a TNBC-specific targeted nano-delivery agent comprising of a cRGD labeled magneto-liposome (T-LMD) co-encapsulated with oleic acid coated iron oxide nanoparticles (MN-OA) and doxorubicin (Dox) in the liposome bilayer and core, respectively. T-LMD was found to show enhanced uptake and induction of ferroptotic cell death in MDA-MB-231, a TNBC model cell line. Additionally, T-LMD induced ferroptosis was found to be accompanied by release of HMGB1, an immunogenic cell death marker, suggesting its immunogenicity for augmenting the activation of anti-tumor immunity in TNBC. The strategic placement of IONPs in the liposome bilayer of T-LMD facilitates the sensitization of MDA-MB-231 cells to undergo ferroptosis; predominantly via the activation of the iron/lipid metabolism pathway, as validated by use of small molecule ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine). Activation of ferroptotic cell death was also corroborated by ferroptosis specific-ultrastructural alterations in the shape/size of cellular mitochondria and cell ballooning as observed by transmission electron microscopy and bright field imaging, respectively. Thus, our ferroptosis nano-inducer (T-LMD) can efficiently kill TNBC cells via enhanced LPO and ROS generation leading to membrane damage and consequent release of LDH and HMGB1, induce mitochondrial alterations and enhanced DNA double strand breaks. Altogether, our results suggest significant implications of T-LMD for treatment of TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Ferroptosis; Cell Line, Tumor; Doxorubicin; Liposomes; Female; Antineoplastic Agents; HMGB1 Protein; Magnetic Iron Oxide Nanoparticles
PubMed: 38677038
DOI: 10.1016/j.bioadv.2024.213868 -
Advanced Science (Weinheim,... Jul 2024Myocardial infarction (MI), a consequence of coronary artery occlusion, triggers the degradation of ferritin, resulting in elevated levels of free iron in the heart and...
Myocardial infarction (MI), a consequence of coronary artery occlusion, triggers the degradation of ferritin, resulting in elevated levels of free iron in the heart and thereby inducing ferroptosis. Targeting myocardial ferroptosis through the chelation of excess iron has therapeutic potential for MI treatment. However, iron chelation in post ischemic injury areas using conventional iron-specific chelators is hindered by ineffective myocardial intracellular chelation, rapid clearance, and high systemic toxicity. A chitosan-desferrioxamine nanosponge (CDNS) is designed by co-crosslinking chitosan and deferoxamine through noncovalent gelation to address these challenges. This architecture facilitates direct iron chelation regardless of deferoxamine (DFO) release due to its sponge-like porous hydrogel structure. Upon cellular internalization, CDNS can effectively chelate cellular iron and facilitate the efflux of captured iron, thereby inhibiting ferroptosis and associated oxidative stress and lipid peroxidation. In MI mouse models, myocardial injection of CDNS promotes sustainable retention and the suppression of ferroptosis in the infarcted heart. This intervention improves cardiac function and alleviates adverse cardiac remodeling post-MI, leading to decreased oxidative stress and the promotion of angiogenesis due to ferroptosis inhibition by CDNS in the infarcted heart. This study reveals a nanosponge-based nanomedicine targeting myocardial ferroptosis with efficient iron chelation and efflux, offering a promising MI treatment.
Topics: Ferroptosis; Animals; Myocardial Infarction; Mice; Iron Chelating Agents; Disease Models, Animal; Deferoxamine; Chitosan; Iron; Nanoparticles; Male; Oxidative Stress; Mice, Inbred C57BL
PubMed: 38671590
DOI: 10.1002/advs.202305895