-
1.
Overexpression of ZNT1 and NRAMP4 from the Ni Hyperaccumulator Noccaea caerulescens Population Monte Prinzera in Arabidopsis thaliana Perturbs Fe, Mn, and Ni Accumulation.
Fasani, E, DalCorso, G, Zorzi, G, Agrimonti, C, Fragni, R, Visioli, G, Furini, A
International journal of molecular sciences. 2021;(21)
Abstract
Metalliferous soils are characterized by a high content of metal compounds that can hamper plant growth. The pseudometallophyte Noccaea caerulescens is able to grow on metalliferous substrates by implementing both tolerance and accumulation of usually toxic metal ions. Expression of particular transmembrane transporter proteins (e.g., members of the ZIP and NRAMP families) leads to metal tolerance and accumulation, and its comparison between hyperaccumulator N. caerulescens with non-accumulator relatives Arabidopsis thaliana and Thlaspi arvense has deepened our knowledge on mechanisms adopted by plants to survive in metalliferous soils. In this work, two transporters, ZNT1 and NRAMP4, expressed in a serpentinic population of N. caerulescens identified on the Monte Prinzera (Italy) are considered, and their expression has been induced in yeast and in A. thaliana. In the latter, single transgenic lines were crossed to test the effect of the combined over-expression of the two transporters. An enhanced iron and manganese translocation towards the shoot was induced by overexpression of NcZNT1. The combined overexpression of NcZNT1 and NcNRAMP4 did perturb the metal accumulation in plants.
-
2.
Biomimetic poly(γ-glutamic acid) hydrogels based on iron (III) ligand coordination for cartilage tissue engineering.
Wang, P, Zhang, W, Yang, R, Liu, S, Ren, Y, Liu, X, Tan, X, Chi, B
International journal of biological macromolecules. 2021;:1508-1516
Abstract
For the problems in the research on differentiation of mesenchymal stem cells (BMSCs), such as poor differentiation tendency and low differentiation efficiency, a novel photo-crosslinked extracellular matrix (ECM) inspired double network hydrogel that composed of poly(γ-glutamic acid) (γ-PGA) hydrogel and Fe3+ ligand coordination was designed and manufactured. Compared with those traditional γ-PGA based hydrogels, the introduction of Fe3+ significantly enhanced the mechanical properties of the hydrogel and accelerated the chondrogenesis efficiency of BMSCs chondrogenesis. The experimental results confirmed that the mechanical properties of hydrogel enhanced by the introduction of metal ions Fe3+ could promote BMSCs proliferation, induce cartilage-specific gene expression, and increase secretion of hydroxyproline (HYP) and glycosaminoglycan (GAG). As a result, this method could promote chondrogenic differentiation of BMSCs, accelerate the regeneration of cartilage, and was prospective to be conducive to the research work of cartilage defect repair. Thus, the mechanically enhanced γ-PGA hydrogel scaffold by Fe3+ could mediate BMSCs differentiation and provide a scientific and theoretical basis for research and development of biomedical materials on cartilage tissue engineering field.
-
3.
Ferroptosis: mechanisms and links with diseases.
Yan, HF, Zou, T, Tuo, QZ, Xu, S, Li, H, Belaidi, AA, Lei, P
Signal transduction and targeted therapy. 2021;(1):49
Abstract
Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
-
4.
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.
-
5.
Broadening horizons: the role of ferroptosis in cancer.
Chen, X, Kang, R, Kroemer, G, Tang, D
Nature reviews. Clinical oncology. 2021;(5):280-296
Abstract
The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.
-
6.
Effects of dietary polyphenol supplementation on iron status and erythropoiesis: a systematic review and meta-analysis of randomized controlled trials.
Xu, T, Zhang, X, Liu, Y, Wang, H, Luo, J, Luo, Y, An, P
The American journal of clinical nutrition. 2021;(2):780-793
-
-
Free full text
-
Abstract
BACKGROUND The iron-chelating activities of polyphenols raise concern whether there is a risk of iron deficiency or anemia induced by polyphenol supplementation. Results from clinical trials regarding the effects of polyphenol supplementation on iron status and erythropoiesis are inconclusive. OBJECTIVE We performed a systematic review and meta-analysis of randomized controlled trials to determine the effects of polyphenol supplementation on iron status and erythropoiesis. METHODS Published articles were searched between May 1988 and 7 December, 2020. Finally, we identified 34 randomized controlled trials. Random-effects meta-analyses were performed to obtain the weighted mean difference of serum iron (SI), transferrin saturation (TS), ferritin, and hemoglobin concentration. Funnel plots and Egger's test were used to determine the risk of bias. The robustness of the effect sizes was examined by sensitivity analysis. RESULTS Polyphenol supplementation had an inhibitory effect on the SI concentration (-13.72 μg/dL; 95% CI: -20.74, -6.71) and TS (-3.10%; 95% CI: -4.93, -1.27), with no effect on ferritin (-9.34 ng/mL; 95% CI: -28.55, 9.87). Polyphenols increased the hemoglobin concentration (8.53 g/L; 95% CI: 3.33, 13.73). In healthy participants, polyphenol reduced the TS (-3.83%; 95% CI: -7.47, -0.19) and increased the hemoglobin concentration (12.87 g/L; 95% CI: 1.61, 24.14). Similarly, polyphenol reduced the SI concentration (-8.60 μg/dL; 95% CI: -16.10, -1.10) and increased the hemoglobin concentration (8.50 g/L; 95% CI: 0.86, 16.15) in patients with metabolic diseases. In patients with β-thalassemia, polyphenol decreased the SI concentration (-23.19 μg/dL; 95% CI: -35.84, -10.55), TS (-3.23%; 95% CI: -5.54, -0.91), and ferritin concentration (-223.62 ng/mL; 95% CI: -359.32, -87.91), but had no effect on the hemoglobin concentration. CONCLUSION Healthy individuals and patients with metabolic diseases may benefit from the positive impact of polyphenols on erythropoiesis. Patients with β-thalassemia may benefit from the effect of polyphenols on reducing SI. This trial was registered at PROSPERO (International prospective register of systematic reviews) as CRD42020161983.
-
7.
The role of iron in doxorubicin-induced cardiotoxicity: recent advances and implication for drug delivery.
Qin, Y, Guo, T, Wang, Z, Zhao, Y
Journal of materials chemistry. B. 2021;(24):4793-4803
Abstract
As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for treating various types of tumors. Unfortunately, the clinical application of this drug results in severe side effects, particularly dose-dependent cardiotoxicity. There are multiple mechanisms involved with the cardiotoxicity caused by DOX, among which intracellular iron homeostasis plays an essential role based on a recent discovery. In this mini-review, we summarize the clinical features and symptoms of DOX-dependent cardiotoxicity, discuss the correlation between iron and cardiotoxicity, and highlight the involvement of iron-dependent ferroptotic cell death therein. Recent advances in this topic will aid the development of novel DOX delivery systems with reduced adverse effects, and expand the clinical application of anthracycline.
-
8.
Iron at the Interface of Hepatocellular Carcinoma.
Paganoni, R, Lechel, A, Vujic Spasic, M
International journal of molecular sciences. 2021;(8)
Abstract
Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In this review, we focus on iron as a potential risk factor for liver carcinogenesis. Molecules involved in the regulation of iron metabolism are often upregulated in cancer cells, in order to provide a supply of this essential trace element for all stages of tumor development, survival, proliferation, and metastasis. Thus, cellular and systemic iron levels must be tightly regulated to prevent or delay liver cancer progression. Disorders associated with dysregulated iron metabolism are characterized with increased susceptibility to hepatocellular carcinoma. This review discusses the association of iron with metabolic disorders such as hereditary hemochromatosis, non-alcoholic fatty liver disease, obesity, and type 2 diabetes, in the background of hepatocellular carcinoma.
-
9.
Iron metabolism: an emerging therapeutic target underlying the anti-cancer effect of quercetin.
Yin, M, Liu, Y, Chen, Y
Free radical research. 2021;(3):296-303
Abstract
Iron, an essential micronutrient for all kinds of cells, is essential for the balance of body internal environment. Notably, cancer cells exhibit a strong dependence on iron and require a large amount of iron for proliferation. A growing number of studies suggested that iron metabolism imbalance and subsequent excess iron accumulation are closely related to the occurrence and progression of cancer. Precisely, excess iron promotes the development of cancer due to the pro-oxidative nature of iron and its damaging effects on DNA. Simultaneously, tumor cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide a new way for the treatment of cancer. Quercetin, a natural flavonoid, has long been regarded as potential drug for cancer treatments owing to its anti-inflammatory, antioxidant and anti-tumor effects. It is proven that quercetin possesses a high iron-chelating capacity, depriving cancer cells of iron or altering iron metabolism. Herein, we conduct a review on the mechanisms of iron imbalance in tumors and the role of quercetin in iron chelation, which will provide insight into the potential for quercetin as an anti-cancer drug.
-
10.
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.