0
selected
-
1.
The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
Habib, HM, Ibrahim, S, Zaim, A, Ibrahim, WH
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111228
Abstract
Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.
-
2.
Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content.
Kaur, S, Srivastava, G, Sharma, AN, Jolly, RS
British journal of pharmacology. 2015;(9):2286-99
-
-
Free full text
-
Abstract
BACKGROUND AND PURPOSE Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. EXPERIMENTAL APPROACH Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. KEY RESULTS CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation was reversible. CONCLUSIONS AND IMPLICATIONS CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron.
-
3.
Effect of supplementation with ferrous sulfate or iron bis-glycinate chelate on ferritin concentration in Mexican schoolchildren: a randomized controlled trial.
Duque, X, Martinez, H, Vilchis-Gil, J, Mendoza, E, Flores-Hernández, S, Morán, S, Navarro, F, Roque-Evangelista, V, Serrano, A, Mera, RM
Nutrition journal. 2014;:71
Abstract
BACKGROUND Iron deficiency is one of the most common nutritional deficiencies worldwide. It is more prevalent when iron requirements are increased during pregnancy and during growth spurts of infancy and adolescence. The last stage in the process of iron depletion is characterized by a decrease in hemoglobin concentration, resulting in iron deficiency anemia. Iron deficiency, even before it is clinically identified as anemia, compromises the immune response, physical capacity for work, and intellectual functions such as attention level. Therefore, interventions addressing iron deficiency should be based on prevention rather than on treatment of anemia. The aim of this study was to compare short- and medium-term effects on ferritin concentration of daily supplementation with ferrous sulfate or iron bis-glycinate chelate in schoolchildren with iron deficiency but without anemia. METHODS Two hundred schoolchildren from public boarding schools in Mexico City who had low iron stores as assessed by serum ferritin concentration but without anemia were randomly assigned to a daily supplement of 30 mg/day of elemental iron as ferrous sulfate or iron bis-glycinate chelate for 12 weeks. Iron status was evaluated at baseline, one week post-supplementation (short term), and 6 months (medium term) after supplementation. RESULTS Ferritin concentration increased significantly between baseline and post-supplementation as well as between baseline and 6 months after supplementation. One week post-supplementation no difference was found in ferritin concentration between iron compounds, but 6 months after supplementation ferritin concentration was higher in the group that received bis-glycinate chelate iron. However, there is no difference in the odds for low iron storage between 6 months after supplementation versus the odds after supplementation; nor were these odds different by type of supplement. Hemoglobin concentration did not change significantly in either group after supplementation. CONCLUSIONS Supplementing with 30 mg/d of elementary iron, either as ferrous sulfate or iron bis-glycinate chelate for 90 days, showed positive effects on increasing ferritin concentration in schoolchildren with low iron stores, and this effect persisted 6 months after supplementation.
-
4.
The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial.
van Eijk, LT, Heemskerk, S, van der Pluijm, RW, van Wijk, SM, Peters, WH, van der Hoeven, JG, Kox, M, Swinkels, DW, Pickkers, P
Haematologica. 2014;(3):579-87
Abstract
In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699).