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Cells Feb 2024Hydrogen sulfide (HS) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study...
Hydrogen sulfide (HS) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of HS on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of HS at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that HS inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent HS generation. These results indicate that HS would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.
Topics: Rats; Animals; Rotenone; Ferroptosis; Mitochondria; Cell Line, Tumor; Iron
PubMed: 38474335
DOI: 10.3390/cells13050371 -
Cells Feb 2024Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that has limited treatment options. Current standard therapies, including surgery followed by...
Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that has limited treatment options. Current standard therapies, including surgery followed by radiotherapy and chemotherapy, are not very effective due to the rapid progression and recurrence of the tumor. Therefore, there is an urgent need for more effective treatments, such as combination therapy and localized drug delivery systems that can reduce systemic side effects. Recently, a handheld printer was developed that can deliver drugs directly to the tumor site. In this study, the feasibility of using this technology for localized co-delivery of temozolomide (TMZ) and deferiprone (DFP) to treat glioblastoma is showcased. A flexible drug-loaded mesh (GlioMesh) loaded with poly (lactic-co-glycolic acid) (PLGA) microparticles is printed, which shows the sustained release of both drugs for up to a month. The effectiveness of the printed drug-eluting mesh in terms of tumor toxicity and invasion inhibition is evaluated using a 3D micro-physiological system on a plate and the formation of GBM tumoroids within the microenvironment. The proposed in vitro model can identify the effective combination doses of TMZ and DFP in a sustained drug delivery platform. Additionally, our approach shows promise in GB therapy by enabling localized delivery of multiple drugs, preventing off-target cytotoxic effects.
Topics: Humans; Glioblastoma; Hydrogels; Drug Liberation; Temozolomide; Printing, Three-Dimensional; Tumor Microenvironment
PubMed: 38391976
DOI: 10.3390/cells13040363 -
Neurotherapeutics : the Journal of the... Oct 2023
PubMed: 37817049
DOI: 10.1007/s13311-023-01448-3 -
International Wound Journal Feb 2024There is an increasing use of non-medicated wound dressing with claims of irreversible bacterial binding. Most of the data are from in vitro models which lack clinical...
There is an increasing use of non-medicated wound dressing with claims of irreversible bacterial binding. Most of the data are from in vitro models which lack clinical relevance. This study employed a range of in vitro experiments to address this gap and we complemented our experimental designs with in vivo observations using dressings obtained from patients with diabetes-related foot ulcers. A hydrophobic wound dressing was compared with a control silicone dressing in vitro. Test dressings were placed on top of a Pseudomonas aeruginosa challenge suspension with increasing concentrations of suspension inoculum in addition to supplementation with phosphate buffered saline (PBS) or increased protein content (IPC). Next, we used the challenge suspensions obtained at the end of the first experiment, where bacterial loads from the suspensions were enumerated following test dressing exposure. Further, the time-dependent bacterial attachment was investigated over 1 and 24 h. Lastly, test dressings were exposed to a challenge suspension with IPC, with or without the addition of the bacteriostatic agent Deferiprone to assess the impacts of limiting bacterial growth in the experimental design. Lastly, two different wound dressings with claims of bacterial binding were obtained from patients with chronic diabetes-related foot ulcers after 72 h of application and observed using scanning electron microscope (SEM). Bacteria were enumerated from each dressing after a 1-h exposure time. There was no statistical difference in bacterial attachment between both test dressings when using different suspension inoculum concentrations or test mediums. Bacterial attachment to the two test dressings was significantly lower (p < 0.0001) when IPC was used instead of PBS. In the challenge suspension with PBS, only the hydrophobic dressing achieved a statistically significant reduction in bacterial loads (0.5 ± 0.05 log colony forming units; p = 0.001). In the presence of IPC, there was no significant reduction in bacterial loads for either test dressing. When bacterial growth was arrested, attachment to the test dressings did not increase over time, suggesting that the number of bacteria on the test dressings increases over time due to bacterial growth. SEM identified widespread adsorption of host fouling across the test dressings which occurred prior to microbial binding. Therein, microbial attachment occurred predominantly to host fouling and not directly to the dressings. Bacterial binding is not unique to dialkylcarbamoyl chloride (DACC) dressings and under clinically relevant in vitro conditions and in vivo observations, we demonstrate (in addition to previously published work) that the bacterial binding capabilities are not effective at reducing the number of bacteria in laboratory models or human wounds.
Topics: Humans; Diabetic Foot; Anti-Infective Agents; Bandages; Foot Ulcer; Bacteria
PubMed: 37770025
DOI: 10.1111/iwj.14416 -
Blood Advances Jun 2023
Randomized Controlled Trial
Kwiatkowski JL, Hamdy M, El-Beshlawy A, et al. Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study. Blood Adv. 2022;6(4):1243-1254.
Topics: Humans; Anemia; Deferiprone; Deferoxamine; Iron Chelating Agents; Iron Overload
PubMed: 37368454
DOI: 10.1182/bloodadvances.2023009896 -
Journal of Fungi (Basel, Switzerland) Mar 2024Pathogens have to cope with oxidative, iron- and carbon(glucose)-limitation stresses in the human body. To understand how combined iron-carbon limitation alters...
Pathogens have to cope with oxidative, iron- and carbon(glucose)-limitation stresses in the human body. To understand how combined iron-carbon limitation alters oxidative stress responses, was cultured in glucose-peptone or peptone containing media supplemented or not with deferiprone as an iron chelator. Changes in the transcriptome in these cultures were recorded after HO treatment. Responses to oxidative stress were highly dependent on the availability of glucose and iron. Out of the 16 stress responsive antioxidative enzyme genes, only the catalase-peroxidase gene was upregulated in more than two culturing conditions. The transcriptional responses observed in iron metabolism also varied substantially in these cultures. Only extracellular siderophore production appeared important regardless of culturing conditions in oxidative stress protection, while the enhanced synthesis of Fe-S cluster proteins seemed to be crucial for oxidative stress treated iron-limited and fast growing (glucose rich) cultures. Although pathogens and host cells live together in the same place, their culturing conditions (e.g., iron availability or occurrence of oxidative stress) can be different. Therefore, inhibition of a universally important biochemical process, like Fe-S cluster assembly, may selectively inhibit the pathogen growth in vivo and represent a potential target for antifungal therapy.
PubMed: 38535229
DOI: 10.3390/jof10030221 -
Corrigendum: Infratentorial superficial siderosis: report of six cases and review of the literature.Frontiers in Neuroscience 2024[This corrects the article DOI: 10.3389/fnins.2024.1373358.].
[This corrects the article DOI: 10.3389/fnins.2024.1373358.].
PubMed: 38516312
DOI: 10.3389/fnins.2024.1388356 -
Neural Regeneration Research Dec 2024JOURNAL/nrgr/04.03/01300535-202412000-00027/figure1/v/2024-04-08T165401Z/r/image-tiff Thalamic hemorrhage can lead to the development of central post-stroke pain....
JOURNAL/nrgr/04.03/01300535-202412000-00027/figure1/v/2024-04-08T165401Z/r/image-tiff Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.
PubMed: 38595289
DOI: 10.4103/NRR.NRR-D-23-01498 -
Blood Transfusion = Trasfusione Del... Jan 2024In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on...
Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.
BACKGROUND
In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months.
MATERIALS AND METHODS
We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique.
RESULTS
At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups.
DISCUSSION
In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.
Topics: Humans; Child, Preschool; Iron; Deferasirox; Deferiprone; Deferoxamine; Iron Chelating Agents; Pyridones; beta-Thalassemia; Benzoates; Triazoles; Drug Therapy, Combination; Thalassemia; Iron Overload; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pancreas
PubMed: 37146300
DOI: 10.2450/BloodTransfus.485