Potent Iron Chelator Research Articles

Streptomyces sp. from desert soil as a biofactory for antioxidants with radical scavenging and iron chelating potential

Iron homeostasis is vital for normal physiology, but in the majority of circumstances, like iron overload, this equilibrium is upset leading to free iron in the plasma. This condition with excess iron is known as hemochromatosis, which has been linked to many side effects, including cancer and liver cirrhosis. The current research aimed to investigate active molecules from Streptomyces sp. isolated from the extreme environment of Bahawalpur deserts. The strain was characterized using 16 S rRNA sequencing. Chemical analysis of the ethyl acetate cure extract revealed the presence of phenols, flavonoids, alkaloids, and tannins. Multiple ultraviolet (UV) active metabolites that were essential for the stated pharmacological activities were also demonstrated by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Additionally, Gas chromatography/mass spectrometry (GC-MS) analysis revealed the primary constituents of the extract to compose of phenol and ester compounds. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to assess the extract’s antioxidant capacity, and the results showed a good half-maximal inhibitory concentration (IC50) value of 0.034 µg/mL in comparison to the positive control ascorbic acid’s 0.12 µg/mL. In addition, iron chelation activity of extract showed significant chelation potential at 250 and 125 µg/mL, while 62.5 µg/mL showed only mild chelation of the ferrous ion using ethylene diamine tetra acetic acid (EDTA) as a positive control. Likewise, the extract’s cytotoxicity was analyzed through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using varying concentrations of the extract and showed 51% cytotoxicity at 350 µg/mL and 65% inhibition of cell growth at 700 µg/mL, respectively. The bioactive compounds from Streptomyces sp. demonstrated strong antioxidant and iron chelating potentials and can prolong the cell survival in extreme environment.

Efficacy and safety of deferoxamine in moderately ill COVID-19 patients: An open label, randomized controlled trial.

Deferoxamine is a potent iron chelator that could remove iron from the virus, and severe acute respiratory syndrome coronavirus 2 requires iron to replication. Also, deferoxamine has antioxidant and cytokine-modulating effects. Therefore, we evaluated the efficacy and safety of deferoxamine in patients with moderate coronavirus disease 2019 (COVID-19). In this randomized controlled trial, patients with moderate COVID-19 were randomly assigned in a 1:1 ratio to the deferoxamine group (received a solution of 500 mg deferoxamine divided into 4 doses a day through a nebulizer for 7 days) and the control group. The main outcomes were viral clearance, oxygen saturation (SPO2), body temperature, and respiratory rate (RR). Intensive care unit admission, hospital length of stay, and hospital mortality were also assessed. A total of 62 patients, with 30 in the deferoxamine group and 32 in the control group, were randomly assigned. There was no statistically significant improvement in viral clearance after the intervention ended in the deferoxamine group (36.7%) compared to the control group (34.4%). The results showed there was no significant difference between the analyzed groups in terms of SPO2, body temperature, RR, and the number of patients with a worse prognosis (SPO2 < 96%, temperature ≥ 37.5 °C, or RR ≥ 16/min) at the end of the study. There were no significant differences seen between the groups in terms of intensive care unit admission, hospital length of stay, hospital mortality, and the occurrence of adverse medication events during the follow-up period. Deferoxamine had no significant impact on improving moderately ill patients with COVID-19. However, it was well-tolerated in the patients, and this intervention demonstrated a safe profile of adverse events.

3-(4-methoxyphenyl) acrylic acid halts redox imbalance and modulate purinergic enzyme activity in iron-induced testicular injury

Abstract Various derivatives of cinnamic acid have been reported to possess significant activities such as antioxidant and hepatoprotective, and neuroprotective activities. Interestingly, testicular toxicity has been linked to several causes, with oxidative damage being one of the pathophysiological mechanisms. 3-(4-methoxyphenyl) acrylic acid (1), a derivative of cinnamic acid, was synthesized and then investigated for its effects on iron-induced testicular injury and oxidative stress via ex vivo and in silico studies, respectively. Evaluations were done on KAD-1’s FRAP, DPPH free radical scavenging activity, and iron chelating potential. Through the ex vivo incubation of tissue supernatant and 0.1 mM FeSO4 for 30 min at 37 °C with different concentration of 1, oxidative testicular damage treatments were induced. The scavenging property of 1 increases significantly (p &lt; 0.05) as the concentration increases when compared with the standard quercetin. The MDA, CAT, ATPase, and ENTPDase activities were reduced when testicular damage was induced (p &lt; 0.05). The group treated with 30 mg/mL had the highest level of MDA. A significant rise in GSH level and activity of SOD were observed. The result obtained indicated that 1 has the potential to prevent oxidative testicular toxicity, as evidenced by its capacity to control nucleotide hydrolysis and reduce oxidative stress. Overall, the results of this experimental study point to some possible uses of 3-(4-methoxyphenyl) acrylic acid (1) in the prevention of oxidative testicular dysfunction. Therefore, 3-(4-methoxyphenyl) acrylic acid (1) would be a good product in developing a medication to alleviate male infertility.

Deferiprone-resveratrol hybrid attenuates iron accumulation, oxidative stress, and antioxidant defenses in iron-loaded human Huh7 hepatic cells.

Chronic liver diseases are complications of thalassemia with iron overload. Iron chelators are required to remove excessive iron, and antioxidants are supplemented to diminish harmful reactive oxygen species (ROS), purposing to ameliorate oxidative liver damage and dysfunctions. The deferiprone-resveratrol hybrid (DFP-RVT) is a synthetic iron chelator possessing anti-β-amyloid peptide aggregation, anti-malarial activity, and hepatoprotection in plasmodium-infected mice. The study focuses on investigating the antioxidant, cytotoxicity, iron-chelating, anti-lipid peroxidation, and antioxidant defense properties of DFP-RVT in iron-loaded human hepatocellular carcinoma (Huh7) cells. In the findings, DFP-RVT dose dependently bound Fe(II) and Fe(III) and exerted stronger ABTS•- and DPPH•-scavenging (IC50 = 8.0 and 164μM, respectively) and anti-RBC hemolytic activities (IC50 = 640μM) than DFP but weaker than RVT (p < 0.01). DFP-RVT was neither toxic to Huh7 cells nor PBMCs. In addition, DFP-RVT diminished the level of redox-active iron (p < 0.01) and decreased the non-heme iron content (p < 0.01) in iron-loaded Huh7 cells effectively when compared without treatment in the order of DFP-RVT > RVT ∼ DFP treatments (50µM each). Moreover, the compound decreased levels of hepatic ROS in a dose-dependent manner and the level of malondialdehyde, which was stronger than DFP but weaker than RVT. Furthermore, DFP-RVT restored the decrease in the GSH content and GPX and SOD activities (p < 0.01) in iron-loaded Huh7 cells in the dose-dependent manner, consistently in the order of RVT > DFP-RVT > DFP. Thus, the DFP-RVT hybrid possesses potent iron chelation, antioxidation, anti-lipid peroxidation, and antioxidant defense against oxidative liver damage under iron overload.

Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Synergistic effect of spermidine and ciprofloxacin against Alzheimer's disease in male rat via ferroptosis modulation

Alzheimer's disease (AD) is a prevalent form of neurodegenerative disease with a complex pathophysiology that remains not fully understood, and the exact mechanism of neurodegeneration is uncertain. Ferroptosis has been linked to the progression of degenerative diseases observed in AD models. The present study is designed to investigate the protective effects of spermidine, a potent antioxidant and iron chelator, and its synergistic interactions with ciprofloxacin, another iron chelator, in modulating ferroptosis and mitigating AD progression in rats. This study investigated AD-related biomarkers like neurotoxic amyloid beta (Aβ), arginase I, and serotonin. Spermidine demonstrated an anti-ferroptotic effect in the AD model, evident from the modulation of ferroptosis parameters such as hippocampus iron levels, reduced protein expression of transferrin receptor 1 (TFR1), and arachidonate 15-lipoxygenase (ALOX15). Additionally, the administration of spermidine led to a significant increase in protein expression of phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) and upregulation of Cystine/glutamate transporter (SLC7A11) gene expression. Moreover, spermidine notably decreased p53 protein levels, acrolein, and gene expression of spermidine/spermine N1-acetyltransferase 1 (SAT1). Overall, our findings suggest that spermidine and/or ciprofloxacin may offer potential benefits against AD by modulating ferroptosis. Furthermore, spermidine enhanced the antioxidant efficacy of ciprofloxacin and reduced its toxic effects.

Therapeutic potential of iron chelators in retinal vascular diseases.

Iron is one of the necessary metal elements in the human body. There are numerous factors that control the balance of iron metabolism, and its storage and transportation mechanisms are intricate. As one of the most energy-intensive tissues in the body, the retina is susceptible to iron imbalance. The occurrence of iron overload in the retina leads to the generation of a significant quantity of reactive oxygen species. This will aggravate local oxidative stress and inflammatory reactions and even lead to ferroptosis, eventually resulting in retinal dysfunction. The blood-retina-retinal barrier is eventually harmed by oxidative stress and elevated inflammation, which are characteristics of retinal vascular disorders. The pathophysiology of retinal vascular disorders may be significantly influenced by iron. Recently, iron-chelating agents have been found to have antioxidative and anti-inflammatory actions in addition to iron chelating. Therefore, iron neutralization is considered to be a new and potentially useful therapeutic strategy. This article reviews the iron overload in retinal vascular diseases and discusses the therapeutic potential of iron-chelating agents.

Preventive Anti-inflammatory Effects of Apocynin on Acetic Acid-Induced Colitis in Rats.

Ulcerative colitis is an inflammatory bowel disease with a complex aetiology characterised by abnormal immune responses and oxidative stress-induced tissue injury. Inflammatory cells play an important role in the progression of this pathology through the overproduction of reactive oxygen species (ROS) from various sources including the NADPH oxidases (NOXs). The aim of this study was to investigate the preventive effect of apocynin, a natural antioxidant molecule and a selective inhibitor of NOXs, on acetic acid (AA)-induced ulcerative colitis in rats. Our results first confirmed that apocynin has a high free radical scavenging capacity as well as a potent iron chelating ability. Oral pretreatment of rats with apocynin (200mg/kg and 400mg/kg) for 7days prior to AA-induced colitis suppressed the increase in pro-oxidant markers in colonic homogenates and preserved colonic cytoarchitecture from acetic acid-induced damage. Oral administration of apocynin (200mg/kg and 400mg/kg) also reduced several systemic inflammatory markers such as alkaline phosphatase, iron, pro-inflammatory cytokines, C-reactive protein and myeloperoxidase. This study shows that apocynin protects rats from acetic acid-induced colonic inflammation and suggests that apocynin may have a promising beneficial effect in the prevention of ulcerative colitis.

Deferoxamine Promotes Peripheral Nerve Regeneration by Enhancing Schwann Cell Function and Promoting Axon Regeneration of Dorsal Root Ganglion

Deferoxamine (DFO) is a potent iron chelator for clinical treatment of various diseases. Recent studies have also shown its potential to promote vascular regeneration during peripheral nerve regeneration. However, the effect of DFO on the Schwann cell function and axon regeneration remains unclear. In this study, we investigated the effects of different concentrations of DFO on Schwann cell viability, proliferation, migration, expression of key functional genes, and axon regeneration of dorsal root ganglia (DRG) through a series of in vitro experiments. We found that DFO improves Schwann cell viability, proliferation, and migration in the early stages, with an optimal concentration of 25 μM. DFO also upregulates the expression of myelin-related genes and nerve growth-promoting factors in Schwann cells, while inhibiting the expression of Schwann cell dedifferentiation genes. Moreover, the appropriate concentration of DFO promotes axon regeneration in DRG. Our findings demonstrate that DFO, with suitable concentration and duration of action, can positively affect multiple stages of peripheral nerve regeneration, thereby improving the effectiveness of nerve injury repair. This study also enriches the theory of DFO promoting peripheral nerve regeneration and provides a basis for the design of sustained-release DFO nerve grafts.

In vitro controlled drug delivery of cationic substituted hydroxyapatite nanoparticles; enhanced anti-chelating and antibacterial response

Hydroxyapatite is naturally found in bones and it is used to deliver antibacterial agents such as chlorhexidine and gentamicin to bones. This study covered the development of hydroxyapatite and nickel (Nix ​= ​0.3,0.5) substituted hydroxyapatite nanoparticles by co-precipitation method. The characterization of nickel (Nix ​= ​0.3,0.5) substituted hydroxyapatite was done by X-ray diffraction, Infra-Red studies and Scanning Electron Microscopy. This study also includes in vitro controlled drug delivery of nickel (Nix ​= ​0.3,0.5) substituted hydroxyapatite nanoparticles which were loaded with widely consumed drug, ciprofloxacin. The antibacterial and antioxidant activity of nickel (Nix ​= ​0.3,0.5) substituted hydroxyapatite was also checked. Our results indicated that nickel substitution in hydroxyapatite increased the percentage of drug (ciprofloxacin) loading up to 96% and cumulative drug release up to 95% in a tunable controlled mode of action. Free radical scavenging or antioxidant comparative analysis of pure and cationic substituted hydroxyapatite further revealed significant enhancement in iron-chelating potential. Nonetheless, nickel (Nix ​= ​0.3,0.5) substituted hydroxyapatite nanoparticles loaded with ciprofloxacin showed strong antibacterial activity (22 ​mm and 24 ​mm zone of inhibition against E. coli (ATCC 35218) and P. aeruginosa (ATTC 27853) strains respectively). This development allows the researchers in the area to get a prompt comparison and sort out the best solutions for the cationic substitution of hydroxyapatite-based materials and enable the development of multi-functional biomedical drug delivery systems and designs for the most commonly used antibiotic molecules.

Allium paradoxum extract mediated green synthesis of SeNPs: Assessment of their anticancer, antioxidant, iron chelating activities, and antimicrobial activities against fungi, ATCC bacterial strains, Leishmania parasite, and catalytic reduction of methylene blue

Allium paradoxum extract was used to make selenium nanoparticles (A-SeNPs). The morphological features showed the semi-spherical A-SeNPs with an average diameter of 37.5 nm from the TEM image. The EDX and XRD data confirmed the synthesis of A-SeNPs and FT-IR spectrum observed the importance of bio-functional group existing in A-Extract in the fabrication of A-SeNPs. Also, TG/DTA diagram proved the presence of capping agent on the surface of nanoparticles and the stability of these NPs. Furthermore, the efficiency of Methylene blue (MB) dye degradation obtained 100% for 50, 60, and 70 μl of A-SeNPs (700 μg/ml). The antioxidant activity of A-SeNPs (2.73–87.7 μg/ml) was assessed via DPPH radical scavenging assay, demonstrating an IC50 value of 92.55 ± 1.35 μg/ml. In the Ferrozine assay, A-SeNPs (1.33–41.66 μg/ml) showed potent iron chelation activity with an IC50 value of 24.8 ± 0.73 μg/ml. In the antibacterial investigation, A-SeNPs (0.17–175 μg/ml) demonstrated the highest activity against P. aeruginosa and A. baumannii. Besides, our nanoparticles had high antifungal activity against several fungi strains and also presented IC50 value of 35.49 μg/ml against promastigotes. A-SeNPs exhibited anticancer activity on MCF-7 and AGS cells with IC50 values of 33.97 and 22.33 μg/ml, respectively. Therefore, synthesized SeNPs presented high potential in various applications.

Suppression of resistance to aminolevulinic acid-based photodynamic therapy in esophageal cell lines by administration of iron chelators in collagen type I matrices

Purpose Photodynamic therapy (PDT) utilizes visible light to activate the cytotoxic effects of photosensitizing drugs. PDT protocols require optimization to overcome treatment resistance and induce a beneficial anti-tumor immune response. The aim of this study was to examine the possibility to suppress the resistance of esophageal cell lines to aminolevulinic acid (ALA)-PDT by administration of iron chelators to induce sufficient cell cytotoxicity under pathophysiologically relevant conditions, mimicking the advanced stages of cancer. Materials and methods Effects of ALA-PDT in combination with iron chelators were compared in three esophageal cell lines in conventional monolayers and in 3 D cultures based on collagen type I. Modified colony assay and fluorescence-based live cell imaging, respectively were applied. The latter was used also to test the capability of pre-polarized macrophages to interact with cancer cells subjected to ALA-PDT with or without iron chelators. Results Iron chelators were effective in the enhancement of ALA-PDT in all cell lines under both culture conditions. Fluorescence evaluation of cell viability in 3 D cultures indicated the contribution of apoptotic cell death after ALA-PDT, both with and without iron chelators. Engulfment of remnants of dead cancer cells by macrophages in 2 D cultures was indicated, however, the interaction between macrophages and cancer cells in 3 D cultures subjected to ALA-PDT with or without iron chelators was not present. Conclusions The potential of iron chelators to enhance ALA-PDT was maintained in 3 D collagen matrices. Although PDT dose (ALA concentration, light exposure time) required modification in a cell line-dependent manner to achieve a comparable effect of PDT alone in conventional monolayers and in collagen matrices, the potential of iron chelators to suppress the resistance of esophageal cells to ALA-PDT was not influenced by a fibrillar collagen matrix.

A Review of Iron Overload in Beta-Thalassemia Major, and a Discussion on Alternative Potent Iron Chelation Targets

For years, arrhythmias have been well documented in the medical arena as a cardiovascular consequence of iron overload (IO). They are thought to be linked to the accumulation of iron in the myocardium. Iron is the earth's fourth most abundant element and the second most plentiful metal (after aluminium). When it comes to biology, iron fills two roles: it's necessary and it's poisonous. It is necessary as a trace iron element since it is found in hemoproteins such as haemo-globin, but it is poisonous in excess amounts of the ability to produce free radicals, which can harm the biological system. The high prevalence of cardiomyopathy in patients with hemosiderosis, particularly in cases of transfusional iron overload, strongly suggests that iron deposition in the heart plays a key role in the development of heart failure. Thalassemia major, which necessitates blood transfusion as a treatment, absorbs a large amount of iron in the patient's duodenum. Moreover, Iron Overload causes a threat to vital organs such as the liver and, initiates events of the pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. Furthermore, we discuss the iron overload issue as it relates to beta-thalassemia major patient blood transfusion treatment, as well as key individuals accountable for iron excess that ultimately leads to cardiomyopathy.

Prospective Phase I/II Study of Eltrombopag for the Treatment of Bone Marrow Failure in Fanconi Anemia

Fanconi anemia (FA) is an inherited disorder associated with loss of function mutations in gene members of the FA-BRCA pathway involved in interstrand cross-link DNA damage repair during cell division. Progressive bone marrow failure (BMF) is a primary cause of morbidity and mortality in patients with FA. Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation is the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Attempts at genetic correction of FA are underway but collection of sufficient numbers of autologous HSPCs is challenging in subjects with advanced BMF. Androgens have been successfully used but side effects often prevent prolonged therapy. The orally bioavailable small molecule mimetic of thrombopoietin, eltrombopag (EPAG), was recently shown to stimulate multipotent long-term repopulating HSPCs in patients with acquired BMF, resulting in persistent trilineage hematopoiesis. EPAG promotes DNA repair (Guenther, Exp Hematol 2019) and maintains HSPCs under inflammatory conditions (Alvarado, Blood 2019), indicating potential relevance in FA. In this study, we investigated whether EPAG may offer a novel therapeutic modality for FA-associated BMF.We have enrolled 10 patients (FANCA, n=9 and FANCC, n=1) to date in a prospective phase I/II study of EPAG in Fanconi anemia (NCT03204188). All subjects received EPAG at an oral daily dose adjusted for age and ethnicity. The primary efficacy endpoint was the proportion of subjects with at least 2-fold increase in marrow cellularity or CD34+ HSPC frequency (marrow response), or clinically significant improvement in peripheral blood (PB) counts at 6 months (blood response). The primary safety endpoint was the global toxicity profile assessed at 6 months using CTCAE criteria. Responders were invited to continue on the extension phase of the study for an additional 3 years.Four of 10 patients have reached the 6-month assessment endpoint, and a pre-specified 3-month interim analysis is available on two additional subjects. A marrow response was observed in all 4 subjects at 6 months. Mean marrow cellularity increased by a factor of 4 (Fig. A/B), and CD34+ HSPC frequency improved 2.5-fold at 6 months relative to pre-treatment values (Fig. C/D). Marrow response criteria were also met in the other two subjects at the 3-month interim assessment. Primary PB response was observed in 2 of 4 patients in one (hemoglobin) or two lineages (hemoglobin and platelets) at 6 months of treatment. Responders continue to receive EPAG at 10 or 25 months with sustained improvements in blood counts and transfusion independence. The subject treated for 25 months recently met response criteria in a third lineage (neutrophils) (Fig. E). Both patients who had a marrow but no PB response are clinically well; one subject (FANCA) underwent an unrelated allogeneic HSPC transplantation one year ago, and the other subject (FANCC) recently entered the extension phase of this study. Unilineage PB response criteria were also met in one of two subjects at the 3-month interim assessment.No drug-related serious adverse events have occurred during EPAG treatment. All patients tolerated the maximum dose of EPAG and no interruption or dose reduction was required for adverse events attributable to EPAG. Patients without transfusional iron overload at study entry developed progressive depletion of iron stores attributable to the known potent iron chelating and mobilizing properties of EPAG. At a median of 3 months after initiating EPAG (range, 1 to 6 months), affected patients initiated daily oral iron supplementation with gradual amelioration of iron store levels. To date, there has been no occurrence of marrow fibrosis, solid malignancies or clonal evolution, defined as abnormalities on standard metaphase analysis of bone marrow or overt clinical transformation to MDS/AML.In sum, treatment with EPAG was associated with increased marrow HSPCs in all subjects and PB responses in a subset of patients with Fanconi anemia. The overall safety profile was favorable. Further follow-up and expansion of the ongoing patient cohort will confirm EPAG's potential as a safe and efficient long-term therapeutic modality for FA-associated BMF. Alternatively, EPAG could also be used safely to boost marrow CD34+ cell numbers prior to autologous gene therapy applications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Iron status influences the response of cord blood megakaryocyte progenitors to eltrombopag in vitro

AbstractEltrombopag (ELT) is a thrombopoietic agent approved for immune thrombocytopenia and also a potent iron chelator. Here we found that ELT exhibited dose-dependent opposing effects on in vitro megakaryopoiesis: low concentrations (≤6 µM, ELT6) stimulated megakaryopoiesis, but high concentrations (30 µM, ELT30) suppressed megakaryocyte (MK) differentiation and proliferation. The suppressive effects of ELT30 were reproduced by other iron chelators, supporting iron chelation as a likely mechanism. During MK differentiation, committed MK progenitors (CD34+/CD41+ and CD34−/CD41+ cells) were significantly more sensitive than undifferentiated progenitors (CD34+/CD41− cells) to the suppressive effects of ELT30, which resulted from both decreased proliferation and increased apoptosis. The antiproliferative effects of ELT30 were reversed by increased iron in the culture, as were the proapoptotic effects when exposure to ELT30 was short. Because committed MK progenitors exhibited the highest proliferative rate and the highest sensitivity to iron chelation, we tested whether their iron status influenced their response to ELT during rapid cell expansion. In these studies, iron deficiency reduced the proliferation of CD41+ cells in response to all ELT concentrations. Severe iron deficiency also reduced the number of MKs generated in response to high thrombopoietin concentrations by ∼50%, compared with iron-replete cultures. Our findings support the hypothesis that although iron deficiency can stimulate certain cells and steps in megakaryopoiesis, it can also limit the proliferation of committed MK progenitors, with severity of iron deficiency and degree of thrombopoietic stimulation influencing the ultimate output. Further studies are needed to clarify how megakaryopoiesis, iron deficiency, and ELT stimulation are clinically interrelated.

Dehydroflavonolignans from Silymarin Potentiate Transition Metal Toxicity In Vitro but Are Protective for Isolated Erythrocytes Ex Vivo.

2,3-Dehydrosilybin (DHS) was previously shown to chelate and reduce both copper and iron ions. In this study, similar experiments with 2,3-dehydrosilychristin (DHSCH) showed that this congener of DHS also chelates and reduces both metals. Statistical analysis pointed to some differences between both compounds: in general, DHS appeared to be a more potent iron and copper chelator, and a copper reducing agent under acidic conditions, while DHSCH was a more potent copper reducing agent under neutral conditions. In the next step, both DHS and DHSCH were tested for metal-based Fenton chemistry in vitro using HPLC with coulometric detection. Neither of these compounds were able to block the iron-based Fenton reaction and, in addition, they mostly intensified hydroxyl radical production. In the copper-based Fenton reaction, the effect of DHSCH was again prooxidant or neutral, while the effect of DHS was profoundly condition-dependent. DHS was even able to attenuate the reaction under some conditions. Interestingly, both compounds were strongly protective against the copper-triggered lysis of red blood cells, with DHSCH being more potent. The results from this study indicated that, notwithstanding the prooxidative effects of both dehydroflavonolignans, their in vivo effect could be protective.

Elevated Iron Chelating Activity of Ilex paraguariensis Leaf Infusion: in vitro and in vivo Pilot Studies

HIGHLIGHTS Ilex paraguariensis infusion reaches elevated iron chelating potential. Storage for 24h decreases phenolic acids without affecting iron chelating activity. This infusion may be exploited as a natural iron chelating agent.

Microbial siderophores an envisaged tool for asbestos bioremediation – A microcosm approach

Abstract The stability of asbestos in natural environment with its biological aggressiveness and toxicity leading to carcinogenesis is related to its fibrous structure, dimensions and presence of iron in its chemical composition. In an effort to reduce its toxicity by limiting its biopersistence, physico-chemical methods have proved futile. A probable solution highlighted in the present investigation is bioremediation. Capitalizing the iron chelating ability of siderophores, as a tool for reducing asbestos toxicity is the main feature under study. A comparative assessment of the siderophore synthesizing ability and their iron chelation potential showed that the identified bacterial species namely Bacillus subtilis and Bacillus atrophaeus as well as the fungal species Aspergillus tubingenesis and Coemansia reversa harboured a similar effectivity towards reducing asbestos toxicity. A microcosm approach was thus envisaged as a probable tool for the same.

Quality Characteristics of Breast and Thigh Chicken Meat from Free- Range System: Comparative Antioxidant Profile of Indigenous and Improved Germplasm

Background: New chicken breeds are being evolved for backyard rural poultry production to overcome the slow growth, late sexual maturity and poor production of indigenous breeds. However, autochthonous poultry is epitomized for quality attributes of their products. With this in mind, the present study for the first time explored the antioxidant capacity of meat obtained from a unique Indian chicken, Kadaknath and a synthetic breed of poultry, Jabalpur colour (JBC). Methods: During the period 2018-2020, breast and thigh meat were collected from chickens (n=20/ group) at their commercial slaughter age (20 weeks). Meat extract was used for qualitative evaluation. Antioxidant activity was explored using five well established in vitro methods testing for different antioxidant mechanisms. Result: Both, Kadaknath and JBC meat was proteinaceous with higher protein concentration (g/100 g of wet weight) in the breast (Kadaknath, 25.21±0.31 and JBC, 25.65±0.39) than the thigh (Kadaknath, 19.98±0.29 and JBC, 19.04±0.23). Both the groups exhibited antioxidant capacity in all the assays. They showed good radical scavenging for ABTS and DPPH free radicals. Superiority of Kadaknath meat was ascertained unequivocally by the three assays viz. Ferric reducing antioxidant power (FRAP), lipid oxidation inhibition (TBARS) and metal chelating capacity. FRAP values (mM Fe2+/g of tissue) were 26.97±0.37 and 33.85±0.47 (Kadaknath) and 22.84±0.25 and 26.82±0.36 (JBC) for breast and thigh, respectively. Similarly, Kadaknath meat was more potent (% inhibition) iron chelator (breast, 62.71±0.99 and thigh, 75.07±0.98) in comparison to the JBC (breast, 46.30±2.36 and thigh, 63.12±1.87). Breast meat had better scavenging capacity than the thigh except in FRAP and metal chelating assays. Results provide insight into the antioxidant potential of backyard poultry germplasm thus, laying foundation for developing marketing strategies targeting consumers interested in nutritional quality, animal welfare and environmental sustainability. Furthermore, baseline data has been generated for studying medicinal properties attributed to the black chicken meat of Kadaknath.

Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1H)-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa.

2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS), a compound from P. aeruginosa, functions as both a quorum sensing (QS) regulator and a potent iron chelator to induce expression of pyoverdine and pyochelin which are involved in high-affinity iron transport systems. A potential dual-acting antibiofilm strategy requires molecules designed to interfere with iron uptake and the QS system of P. aeruginosa. A series of 2-substituted 3-hydroxy-1,6-dimethylpyridin-4-ones have been designed, synthesized, and tested as biofilm inhibitors of P. aeruginosa. One compound, N-((1,3,6-trimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)hexanamide (10d), exhibits 68.67% biofilm inhibitory activity at 20 μM. Further mechanistic studies have confirmed that this compound not only inhibits the QS systems of P. aeruginosa but also acts as an iron chelator to compete strongly with pyoverdine, causing iron deficiency in bacteria. The pyoverdine receptor FpvA was revealed as the target of 10d by the Pvds mutant strain, fpvA-overexpressed strain, and in silico studies.