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1.
Dual role of heme iron in cancer; promotor of carcinogenesis and an inducer of tumour suppression.
Gamage, SMK, Lee, KTW, Dissabandara, DLO, Lam, AK, Gopalan, V
Experimental and molecular pathology. 2021;:104642
Abstract
PURPOSE Heme is a crucial compound for cell survival but is also equipped with the potential to be toxic and carcinogenic to cells. However, with the recent advancement of knowledge regarding ferroptosis, the iron mediated cell death, heme can be postulated to induce tumour suppression through ferroptosis. This review summarizes the literature on the carcinogenic and anticarcinogenic properties of heme with specific emphasis on the alterations observed on heme synthesis, metabolism and transport in tumour cells. METHODS Literature search was performed in PubMed data base using the MeSH terms 'heme iron or heme', 'cancer or carcinogenesis' and 'tumour suppression' or 'anticarcinogenic properties. Out of 189 results, 166 were relevant to the current review. RESULTS Heme supports carcinogenesis via modulation of immune cell function, promoting inflammation and gut dysbiosis, impeding tumour suppressive potential of P53 gene, promoting cellular cytotoxicity and reactive oxygen species generation and modulating Nfr2 /HO-1 axis. The carcinogenic and anticarcinogenic properties of heme are both dose and oxygen concentration dependant. At low doses, heme is harmless and even helpful in maintaining the much-needed redox balance within the cell. However, when heme exceeds physiological concentrations, it could initiate and propagate carcinogenesis, due to its ability to produce reactive oxygen species (ROS). The same phenomenon of heme mediated ROS generation could be manipulated to initiate tumour suppression via ferroptosis, but the therapeutic doses are yet to be determined. CONCLUSION Heme iron possesses powerful carcinogenic and anticarcinogenic properties which are dosage and oxygen availability dependant.
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2.
Iron metabolism in infections: Focus on COVID-19.
Girelli, D, Marchi, G, Busti, F, Vianello, A
Seminars in hematology. 2021;(3):182-187
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Abstract
Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.
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Emerging role of ferrous iron in bacterial growth and host-pathogen interaction: New tools for chemical (micro)biology and antibacterial therapy.
Gonciarz, RL, Renslo, AR
Current opinion in chemical biology. 2021;:170-178
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Abstract
Chemical tools capable of detecting ferrous iron with oxidation-state specificity have only recently become available. Coincident with this development in chemical biology has been increased study and appreciation for the importance of ferrous iron during infection and more generally in host-pathogen interaction. Some of the recent findings are surprising and challenge long-standing assumptions about bacterial iron homeostasis and the innate immune response to infection. Here, we review these recent developments and their implications for antibacterial therapy.
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Immunogenicity of an oral rotavirus vaccine administered with prenatal nutritional support in Niger: A cluster randomized clinical trial.
Isanaka, S, Garba, S, Plikaytis, B, Malone McNeal, M, Guindo, O, Langendorf, C, Adehossi, E, Ciglenecki, I, Grais, RF
PLoS medicine. 2021;(8):e1003720
Abstract
BACKGROUND Nutritional status may play a role in infant immune development. To identify potential boosters of immunogenicity in low-income countries where oral vaccine efficacy is low, we tested the effect of prenatal nutritional supplementation on immune response to 3 doses of a live oral rotavirus vaccine. METHODS AND FINDINGS We nested a cluster randomized trial within a double-blind, placebo-controlled randomized efficacy trial to assess the effect of 3 prenatal nutritional supplements (lipid-based nutrient supplement [LNS], multiple micronutrient supplement [MMS], or iron-folic acid [IFA]) on infant immune response (n = 53 villages and 1,525 infants with valid serology results: 794 in the vaccine group and 731 in the placebo group). From September 2015 to February 2017, participating women received prenatal nutrient supplement during pregnancy. Eligible infants were then randomized to receive 3 doses of an oral rotavirus vaccine or placebo at 6-8 weeks of age (mean age: 6.3 weeks, 50% female). Infant sera (pre-Dose 1 and 28 days post-Dose 3) were analyzed for anti-rotavirus immunoglobulin A (IgA) using enzyme-linked immunosorbent assay (ELISA). The primary immunogenicity end point, seroconversion defined as ≥3-fold increase in IgA, was compared in vaccinated infants among the 3 supplement groups and between vaccine/placebo groups using mixed model analysis of variance procedures. Seroconversion did not differ by supplementation group (41.1% (94/229) with LNS vs. 39.1% (102/261) with multiple micronutrients (MMN) vs. 38.8% (118/304) with IFA, p = 0.91). Overall, 39.6% (n = 314/794) of infants who received vaccine seroconverted, compared to 29.0% (n = 212/731) of infants who received placebo (relative risk [RR]: 1.36; 95% confidence interval [CI]: 1.18, 1.57, p < 0.001). This study was conducted in a high rotavirus transmission setting. Study limitations include the absence of an immune correlate of protection for rotavirus vaccines, with the implications of using serum anti-rotavirus IgA for the assessment of immunogenicity and efficacy in low-income countries unclear. CONCLUSIONS This study showed no effect of the type of prenatal nutrient supplementation on immune response in this setting. Immune response varied depending on previous exposure to rotavirus, suggesting that alternative delivery modalities and schedules may be considered to improve vaccine performance in high transmission settings. TRIAL REGISTRATION ClinicalTrials.gov NCT02145000.
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GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism.
Rochette, L, Zeller, M, Cottin, Y, Vergely, C
Trends in endocrinology and metabolism: TEM. 2021;(11):875-889
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.
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Bacterial Responses to Iron Withholding by Calprotectin.
Obisesan, AO, Zygiel, EM, Nolan, EM
Biochemistry. 2021;(45):3337-3346
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Abstract
Iron (Fe) plays important roles in both essential cellular processes and virulence pathways for many bacteria. Consequently, Fe withholding by the human innate immune system is an effective form of defense against bacterial infection. In this Perspective, we review recent studies that have established a foundation for our understanding of the impact of the metal-sequestering host defense protein calprotectin (CP) on bacterial Fe homeostasis. We also discuss two recently uncovered strategies for bacterial adaptation to Fe withholding by CP. Together, these studies provide insight into how Fe sequestration by CP affects bacterial pathogens that include Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus. Overall, recent studies suggest that Fe withholding by CP may have implications for bacterial survival and virulence in the host, and further explorations that directly address this possibility present an important area for discovery.
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Iron Chelation in Local Infection.
Scott, C, Arora, G, Dickson, K, Lehmann, C
Molecules (Basel, Switzerland). 2021;(1)
Abstract
Iron is an essential element in multiple biochemical pathways in humans and pathogens. As part of the innate immune response in local infection, iron availability is restricted locally in order to reduce overproduction of reactive oxygen species by the host and to attenuate bacterial growth. This physiological regulation represents the rationale for the therapeutic use of iron chelators to support induced iron deprivation and to treat infections. In this review paper we discuss the importance of iron regulation through examples of local infection and the potential of iron chelation in treating infection.
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Iron in immune cell function and host defense.
Haschka, D, Hoffmann, A, Weiss, G
Seminars in cell & developmental biology. 2021;:27-36
Abstract
The control over iron availability is crucial under homeostatic conditions and even more in the case of an infection. This results from diverse properties of iron: first, iron is an important trace element for the host as well as for the pathogen for various cellular and metabolic processes, second, free iron catalyzes Fenton reaction and is therefore producing reactive oxygen species as a part of the host defense machinery, third, iron exhibits important effects on immune cell function and differentiation and fourth almost every immune activation in turn impacts on iron metabolism and spatio-temporal iron distribution. The central importance of iron in the host and microbe interplay and thus for the course of infections led to diverse strategies to restrict iron for invading pathogens. In this review, we focus on how iron restriction to the pathogen is a powerful innate immune defense mechanism of the host called "nutritional immunity". Important proteins in the iron-host-pathogen interplay will be discussed as well as the influence of iron on the efficacy of innate and adaptive immunity. Recently described processes like ferritinophagy and ferroptosis are further covered in respect to their impact on inflammation and infection control and how they impact on our understanding of the interaction of host and pathogen.
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Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?
Xu, X, Lin, D, Tu, S, Gao, S, Shao, A, Sheng, J
Frontiers in immunology. 2021;:598601
Abstract
Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.
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The first report of iron-rich population of adapted medicinal spinach (Blitum virgatum L.) compared with cultivated spinach (Spinacia oleracea L.).
Ammarellou, A, Mozaffarian, V
Scientific reports. 2021;(1):22169
Abstract
Folk medicine such as herbal and natural products have been used for centuries in every culture throughout the world. The Chenopodiaceae family with more than 1500 species is dispersed worldwide. The Iranian wild spinach (Blitum virgatum L.) is an important traditional medicinal plant used for antiviral diseases such as pneumonia and other respiratory track infections. This plant is a mountainous herb and is growing upper than 3000 m. We performed a mass selection plant breeding program on wild populations of this Iranian wild spinach during 2013-2020. Based on experimental and field characteristics this plant was identified as B. virgatum, |abbaricum|, and related characteristics were prepared with reference to the International Union for the Protection of New Varieties of Plants (UPOV). Mass selection program resulted from an adapted population named as medicinal spinach (MSP) population. To compare the mineral content of the mass-selected population with cultivated spinach (Spinacia oleracea L. |Varamin 88|), both plants were planted in pots and fields under similar conditions. In five leaves stage, plant samples were taken from both leaf and crown sections and used for experimental analysis. Atomic absorption spectroscopy was used to determine the mineral content including iron (Fe), zinc (Z), manganese (Mn), and copper (Cu). Our results showed the selected medicinal spinach population (MSP) with about 509 ppm iron was an important iron-rich population with about 3.5-4 times more than the amount of iron in cultivated spinach in the same conditions. Because iron is an important essential element for blood production, respiration process, energy metabolisms, synthesis of collagen, and some neurotransmitters are needed for proper immune function, so the supply of absorbable adequate iron is very important. The reasons such as the prevalence of the COVID-19 pandemic, which affects the amount of exchangeable oxygen in the lungs and historical local evidences of the use of this plant (MSP) for pneumonia, could open new horizons for focusing on studies related to the use of ancestral human experiences in addition to scientifically modern research.