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Fenton and Haber-Weiss reactions are a source of oxidative stress. The generation of oxygen free radicals occurs first with the reduction of ferric to ferrous iron and then by the Fenton reaction with ferrous iron catalyzing the breakdown of hydrogen peroxide to hydroxyl radical and hydroxyl. The net reaction is termed the Haber-Weiss reaction.
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Iron homeostasis is often disrupted in acute disease with an increase in catalytic free iron leading to the formation of reactive oxygen species and subsequent tissue-specific oxidative damage. This article highlights the potential therapeutic benefit of exogenous hepcidin to prevent and treat iron-induced injury, specifically in the management of...
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... iron (CFI) is undetectable and plasma iron is tightly bound to TF. CFI, which can be thought of as unbound iron, is a promiscuous molecule that functions as a "bad-actor." When CFI is in its ferrous state (Fe 21 ), CFI can initiate the Fenton reactions or when iron is unbound in its ferric state (Fe 31 ) CFI can initiate Haber-Weiss reactions (Fig. 2). These reactions generate oxygen free radicals, such as hydroxyl radical (OH À ), peroxynitrite (ONOO À ), superoxide free radical anion (O 2 À ), and hydrogen peroxide (H 2 O 2 ). 23,24 These oxygen free radicals are often referred to as reactive oxygen species (ROS) and can damage important macromolecules. ROS have been shown to ...
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Citations
... Iron chelators have been previously suggested as a potential adjunct therapy in murine models, preferably together with conventional antibiotics [100][101][102][103][104]. However, their toxicity and potential to deliver iron to the bacteria limit their use [105]. To overcome these limitations, exogenous administration of hepcidin has been suggested as an alternative to the body's natural hypoferremic pathways. ...
... This therapeutic modality is expected to be less toxic and more efficient. Alternately, endogenous hepcidin induction may be achieved by catecholamines (such as norepinephrine and dopamine) administration [105]. Hepcidin can be used in conjunction with standard therapy in patients with iron overload, suffering from deadly infections of siderophilic Gram-negative bacilli, such as Yersinia enterocolitica, Vibrio vulnificus, and Klebsiella pneumoniae. ...
The emergence of antibiotic-resistant bacteria is a pressing public health concern, highlighting the need for alternative approaches to control bacterial infections. Promising approaches include the development of therapeutic vaccines and the utilization of innate immune activation techniques, which may prove useful in conjunction with antibiotics, as well as other antibacterial modalities. However, innate activation should be fast and self- or actively- contained to prevent detrimental consequences. TLR ligand adjuvants are effective at rapidly activating, within minutes to hours, the innate immune system by inducing cytokine production and other signaling molecules that bolster the host's immune response. Neutrophils serve as the first line of defense against invading pathogens by capturing and destroying them through various mechanisms, such as phagocytosis, intracellular degradation, and the formation of NETs. Nutritional immunity is another host defense mechanism that limits the availability of essential metals, such as iron, from invading bacterial pathogens. Thus, iron starvation has been proposed as a potential antibacterial strategy. In this review, we focus on approaches that have the potential to enhance rapid and precise antibacterial responses, bridging the gap between the onset of infection and the elimination of bacteria, hence limiting the infection by antibiotic-resistant bacteria.
... Iron has been thought to contribute to both AKI and CKD [113][114][115][116][117][118]. Indeed, it has been observed that renal tubules are exposed to elevated levels of iron in patients with kidney disease, which is likely due to increased filtration of iron and iron-containing proteins through the glomerular apparatus [114,117,119]. ...
The kidney is a crucial organ that eliminates metabolic waste and reabsorbs nutritious elements. It also participates in the regulation of blood pressure, maintenance of electrolyte balance and blood pH homeostasis, as well as erythropoiesis and vitamin D maturation. Due to such a heavy workload, the kidney is an energy-demanding organ and is constantly exposed to endogenous and exogenous insults, leading to the development of either acute kidney injury (AKI) or chronic kidney disease (CKD). Nevertheless, there are no therapeutic managements to treat AKI or CKD effectively. Therefore, novel therapeutic approaches for fighting kidney injury are urgently needed. This review article discusses the role of α-lipoic acid (ALA) in preventing and treating kidney diseases. We focus on various animal models of kidney injury by which the underlying renoprotective mechanisms of ALA have been unraveled. The animal models covered include diabetic nephropathy, sepsis-induced kidney injury, renal ischemic injury, unilateral ureteral obstruction, and kidney injuries induced by folic acid and metals such as cisplatin, cadmium, and iron. We highlight the common mechanisms of ALA’s renal protective actions that include decreasing oxidative damage, increasing antioxidant capacities, counteracting inflammation, mitigating renal fibrosis, and attenuating nephron cell death. It is by these mechanisms that ALA achieves its biological function of alleviating kidney injury and improving kidney function. Nevertheless, we also point out that more comprehensive, preclinical, and clinical studies will be needed to make ALA a better therapeutic agent for targeting kidney disorders.
... Copper effectiveness is attributed to the ability of copper ions to easily interconvert between Cu(I)/Cu(II) by Fenton-like (2) and Haber-Weiss (3) reactions [73] and generate ROS molecules, leading to lipid peroxidation, protein oxidation, and DNA damage [71]. Cu NPs, when exposed to aqueous environments, are susceptible to oxidation and through dissolution Cu + ions release from metallic Cu NPs [74]. ...
The development of effective and ecofriendly agrochemicals, including bactericides, fungicides, insecticides, and nematicides, to control pests and prevent plant diseases remains a key challenge. Nanotechnology has provided opportunities for the use of nanomaterials as components in the development of anti-phytopathogenic agents. Indeed, inorganic-based nanoparticles (INPs) are among the promising ones. They may play an effective role in targeting and killing microbes via diverse mechanisms, such as deposition on the microbe surface, destabilization of cell walls and membranes by released metal ions, and the induction of a toxic mechanism mediated by the production of reactive oxygen species. Considering the lack of new agrochemicals with novel mechanisms of action, it is of particular interest to determine and precisely depict which types of INPs are able to induce antimicrobial activity with no phytotoxicity effects, and which microbe species are affected. Therefore, this review aims to provide an update on the latest advances in research focusing on the study of several types of engineered INPs, that are well characterized (size, shape, composition, and surface features) and show promising reactivity against assorted species (bacteria, fungus, virus). Since effective strategies for plant protection and plant disease management are urgently needed, INPs can be an excellent alternative to chemical agrochemical agents as indicated by the present studies.
... Several stimuli could associate with hepcidin. Such as in hepcidin production and severe ID with the inflammation [15,16]. ...
The hepcidin is antimicrobial peptide has antimicrobial effects discover before more than a thousand years; it has a great role in iron metabolism and innate immunity. Hepcidin is a regulator of iron homeostasis. Its production is increased by iron excess and inflammation and decreased by hypoxia and anemia. Iron-loading anemias are diseases in which hepcidin is controlled by ineffective erythropoiesis and concurrent iron overload impacts. Hepcidin reacts with ferroportin. The ferroportin is found in spleen, duodenum, placenta, if the ferroportin decrease, it results in the reduced iron intake and macrophage release of iron, and using the iron which stores in the liver. Gene of human hepcidin is carried out by chromosome 19q13.1. It consists of (2637) nucleated base. HAMP gene was founded in the liver cells, in brain, trachea, heart, tonsils, and lung. Changing in the HAMP gene will produce a change in hepcidin function. The hepcidin is made many stimulators are included opposing effects exerted by pathological and physiological conditions. Hepcidin is essential for iron metabolism, understanding stricter and genetic base of hepcidin is crucial step to know iron behavior and reactions to many health statuses.
... Human physiologic systems have evolved to orchestrate a careful balance of iron binding and release that enables us to avoid injury while effectively delivering this essential nutrient to tissues. In acute illnesses, however, iron homeostasis is often disrupted and ferrous iron is produced, which contributes to tissue injury, as well as to a higher risk of bacterial infection (44,45). Many investigations, based in clinical and laboratory settings, have shown that iron supplementation causes more severe infections of Mycobacterium tuberculosis (46) but lower virulence of the enteric pathogen Citrobacter (47). ...
... If true, this phenomenon may provide a reference for the development of strategies to reduce S. maltophilia infection or spread. Many c-di-GMP effectors, but few in comparison to c-di-GMP turnover enzymes, have been identified, which include transcription factors, HKs, RRs, riboswitches, and degenerated DGCs and PDEs (43,44). Among the reported c-di-GMP binding HKs and RRs, distinct domains are used to interact with c-di-GMP. ...
Stenotrophomonas maltophilia has become a great threat to human health because of the high mortality of infected patients. Swimming motility plays a crucial role in regulating bacterial virulence and adaptation.
... This is in line with experimental studies in murine models where the data show that hepcidin-induced hypoferremia can act as a defence mechanism against bacterial infection 22,[51][52][53][54] . Administration of exogenous hepcidin has been suggested to be of therapeutic value in selected cases of hyperferremia 55 . High iron concentrations have been reported to increase the lethal effects of siderophile bacteria in vivo and also in fungal infections and the reduction of available plasma iron is most likely beneficial for the host unless prolonged and leading to anaemia 51,55,56 . ...
... Administration of exogenous hepcidin has been suggested to be of therapeutic value in selected cases of hyperferremia 55 . High iron concentrations have been reported to increase the lethal effects of siderophile bacteria in vivo and also in fungal infections and the reduction of available plasma iron is most likely beneficial for the host unless prolonged and leading to anaemia 51,55,56 . ...
Initial differential diagnosis and prognosis for patients admitted to intensive care with suspected sepsis remain arduous. Hepcidin has emerged as a potential biomarker for sepsis. Here we report data on the relevance of levels of hepcidin versus other biomarkers as a diagnostic and prognostic tool for sepsis. 164 adult patients admitted to the intensive care unit (ICU) within 24 h upon arrival to the hospital were included. Blood samples collected daily for seven consecutive days and hepcidin levels, heparin binding protein (HBP) levels and standard biomarkers were determined. Blood cultures were initiated at inclusion. Clinical scores were evaluated daily and mortality after 28- and 180-days was recorded. One hundred of the patients were found to fulfil the criteria for sepsis whereas 64 did not. Hepcidin levels at admission were significantly higher in the septic than in the non-septic patients. In septic patients hepcidin levels declined significantly already at 24 h followed by a steady decline. A significant negative correlation was observed between hepcidin levels and SAPS 3 in patients with sepsis. Hepcidin levels at inclusion were significantly higher among septic patients that survived 180-days and predicted mortality. Our data show that hepcidin levels are indicative of sepsis in patients admitted to the ICU and has a prognostic value for mortality.
... Iron is an essential nutrient for both humans under physiological conditions and for pathogenic bacteria during infection [1][2][3]. Strict regulation of iron homeostasis in humans under both physiological and pathological conditions is essential [1,3,4]. Under normal physiological conditions, iron is mainly stored intracellularly in erythrocytes, or is bound in the plasma to transferrin, which has a high affinity for ferric iron (Fe 3+ ) [1,3]. ...
... Following an insult, such as an infection, iron homeostasis is disrupted, and nutritional immunity is enhanced [1,4]. Nutritional immunity is a vertebrate strategy to restrict the availability of essential nutrients, including iron, to invading pathogens [1,2,5,6]. ...
... During inflammation and infection, increased hepcidin levels, in response to increased levels of inflammatory molecules such as IL-6, can decrease serum iron levels to a degree that is consistent with iron deficiency or anemia [8]. Additionally, hepcidin can lead to a reduction in serum transferrin iron saturation [4]. Reduced iron availability at the infection site has the potential to decrease growth and virulence of pathogenic bacteria [1]. ...
Critically ill patients often present with low serum iron levels or anemia. We evaluated the impact of iron levels and iron homeostasis on the efficacy and safety of cefiderocol, an iron-chelator siderophore cephalosporin, in patients with nosocomial pneumonia in a post hoc analysis of the randomized, double-blind, Phase 3 APEKS-NP study (NCT03032380). Patients with Gram-negative nosocomial pneumonia received cefiderocol 2 g, 3-h infusion, q8h, or high-dose, extended-infusion meropenem 2 g, 3-h infusion, q8h, for 7–14 days. Efficacy and safety parameters, including specific iron homeostasis parameters (i.e., hepcidin, iron, total iron binding capacity, transferrin saturation), were analyzed according to baseline iron levels. In the cefiderocol and meropenem arms, 79.1% (117/148) and 83.3% (125/150) randomized patients, respectively, had low baseline serum iron levels. Rates of 14-day (12.3% [14/114] vs 11.6% [14/121]) and 28-day all-cause mortality (20.5% [23/112] vs 19.0% [23/121]), clinical cure (63.2% [72/114] vs 67.2% [82/122]), and microbiological eradication (43.6% [41/94] vs 48.1% [51/106]) at test of cure were similar in cefiderocol vs meropenem arms, respectively. In the overall safety population, rates of anemia-related adverse events were similar (cefiderocol arm 18.2% [27/148], meropenem arm 18.7% [28/150]). Changes from baseline to test of cure in hepcidin, iron, total iron binding capacity, and transferrin saturation were similar between treatment arms. Cefiderocol treatment did not affect iron homeostasis, and its efficacy and safety were not influenced by baseline serum iron levels. Clinicaltrials.gov registration: NCT03032380. Date of registration: 26 January 2017.
... In this way, the export of iron from reticuloendothelial macrophages, hepatocytes, and duodenal enterocytes is blocked (Casu et al., 2018). Hepcidin deficiency is a common feature of hereditary hemochromatosis (HH) and LJPC-401 has completed Phase 2 clinical trials for this therapeutic target, representing a "replacement therapy" to supplement inadequate hepcidin levels (Chawla et al., 2019). ...
Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.
... Ferritin comprises of multiple sub-unit protein shells surrounding an inorganic iron-core in the form of microcrystalline particles. When the demand for synthesis of Hb rises in the bone marrow, iron and amino acids of the liver are mobilized by the breakdown of ferritin and other storage proteins (Chawla, Beers-Mulroy, & Tidmarsh, 2019). Hemosiderin, another form of iron storage, is composed of variable granules with iron and organic constituents, as well as some ferritin protein. ...
Background
Anemia, a morbid condition, remains a global concern that affects people of all age groups. This scenario attracts the attention of several government organizations for implementing strict regulations to provide nutritional security. Iron fortification and supplementation has been in practice from the past decades. However, there is a need for determining an effective strategy to address this rising concern among the vulnerable population.
Scope and approach
Among the existing approaches, iron fortification of foods remains to be cheaper and effective in targeting large-scale population without the intervention of pharmaceutical drugs. The key challenge is the bioavailability of iron from fortified foods. Thus, this work presents a comprehensive review of morbidities of anemia, causes, the significance of haem and non-haem iron, absorption, and bioavailability, in context with different iron fortification approaches.
Key findings
Apart from the nutritional deficit, anemia is also associated with a sedentary lifestyle linked with obesity and diabetes. The complex interaction of elemental iron and its physiology have been highlighted in consideration with potential iron enhancers and inhibitors. It was found that the incorporation of haem iron would complement the effectiveness of non-haem iron through fortification. Several iron fortification techniques focused on combating iron deficiency have been described.
Conclusions
Food fortification remains to be a promising strategy for reducing the prevalence of anemia. Food vehicles must be designed in considering its synergistic effects with iron complexes for effective absorption and bioavailability. However, the scalability, cost economics, safety concerns and acceptability of the iron-fortified foods remain as constraints that have to be addressed. Further, the application of novel food processing techniques with food fortification can result in the emergence of novel approaches for addressing iron deficiency and anemia.
... It role in physiology and pathophysiology and the potential for its therapeutic effects are a crucial new development of great interest to ICU clinicians. 22 Finally, studies on the role of thyroid hormones 23 in the ICU, hormonal manipulation of organ donors, 24 and hormonal manipulation to prevent post-ICU accelerated osteoporosis 25 have markedly expanded our understanding of their pathophysiology and therapeutic potential. The implications of such new insights are reviewed in three key articles in this issue. ...
