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Wheat flour is widely used in Poland for the preparation of bread, pasta and other foods. Due to the increasing number of people diagnosed with diet-related diseases, consumer awareness of health-promoting issues and interest in gluten-free products (GFP). There is a dynamic development of the market for these foods with high quality and nutritional value and minerals that benefit human health and prevent deficiencies in patients on a gluten-free diet. The aim of this study was to determine the content of minerals: Ca, Fe, Mg and Zn in flours using the ICP-OES method. The mineral composition of selected GF flours available on the Polish market was analysed. It was tested how they supplement the mineral requirements compared to gluten-containing flours. It was found that these products can be a valuable source of essential minerals, which are often in short supply, especially in patients with gastrointestinal disorders. As our study has shown, flours from the GFP group are a good source of essential minerals, especially in the case of chia and flax flours, as well as buckwheat, amaranth, quinoa, lupin or almonds flours.

Salinization of cultivated land and the need to increase agricultural productivity make the development of salt-resistant crops imperative. Field trials show that a durum wheat containing a sodium transporter derived from an ancestral wheat relative produces substantially more grain than a commercial durum wheat lacking this transporter on saline soil. The ability of wheat to maintain a low sodium concentration ([Na + ]) in leaves correlates with improved growth under saline conditions 1 , 2 . This trait, termed Na + exclusion, contributes to the greater salt tolerance of bread wheat relative to durum wheat 3 , 4 . To improve the salt tolerance of durum wheat, we explored natural diversity in shoot Na + exclusion within ancestral wheat germplasm. Previously, we showed that crossing of Nax2 , a gene locus in the wheat relative Triticum monococcum into a commercial durum wheat ( Triticum turgidum ssp. durum var. Tamaroi) reduced its leaf [Na + ] (ref. 5 ). Here we show that a gene in the Nax2 locus, TmHKT1;5-A , encodes a Na + -selective transporter located on the plasma membrane of root cells surrounding xylem vessels, which is therefore ideally localized to withdraw Na + from the xylem and reduce transport of Na + to leaves. Field trials on saline soils demonstrate that the presence of TmHKT1;5-A significantly reduces leaf [Na + ] and increases durum wheat grain yield by 25% compared to near-isogenic lines without the Nax2 locus.

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD. Altered iron homeostasis resulting in excessive oxidative stress has been implicated in smoke-induced lung diseases. Here the authors show that ferroptosis of lung epithelial cells, potentially resulting from excessive ferritinophagy, is involved in the pathogenesis of COPD.

The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin 1 . Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias 2 . Here we determine cryogenic electron microscopy structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with hepcidin and the iron mimetic cobalt. These structures and accompanying molecular dynamics simulations identify two metal-binding sites within the N and C domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy terminus of hepcidin directly contacts the divalent metal in the ferroportin C domain. Hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, in which only ferroportin molecules loaded with iron are targeted for degradation. More broadly, our structural and functional insights may enable more targeted manipulation of the hepcidin–ferroportin axis in disorders of iron homeostasis. Structures of the iron transporter ferroportin and the peptide hormone hepcidin suggest how iron homeostasis is tightly regulated.

Glaucoma can result in retinal ganglion cell (RGC) death and permanently damaged vision. Pathologically high intraocular pressure (ph-IOP) is the leading cause of damaged vision during glaucoma; however, controlling ph-IOP alone does not entirely prevent the loss of glaucomatous RGCs, and the underlying mechanism remains elusive. In this study, we reported an increase in ferric iron in patients with acute primary angle-closure glaucoma (the most typical glaucoma with ph-IOP damage) compared with the average population by analyzing free iron levels in peripheral serum. Thus, iron metabolism might be involved in regulating the injury of RGCs under ph-IOP. In vitro and in vivo studies confirmed that ph-IOP led to abnormal accumulation of ferrous iron in cells and retinas at 1–8 h post-injury and elevation of ferric iron in serum at 8 h post-injury. Nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin heavy polypeptide 1(FTH1) is essential to disrupt iron metabolism in the retina after ph-IOP injury. Furthermore, knockdown of Ncoa4 in vivo inhibited FTH1 degradation and reduced the retinal ferrous iron level. Elevated ferrous iron induced by ph-IOP led to a marked accumulation of pro-ferroptotic factors (lipid peroxidation and acyl CoA synthetase long-chain family member 4) and a depletion of anti-ferroptotic factors (glutathione, glutathione peroxidase 4, and nicotinamide adenine dinucleotide phosphate). These biochemical changes resulted in RGC ferroptosis. Deferiprone can pass through the blood-retinal barrier after oral administration and chelated abnormally elevated ferrous iron in the retina after ph-IOP injury, thus inhibiting RGC ferroptosis and protecting visual function. In conclusion, this study revealed the role of NCOA4-FTH1-mediated disturbance of iron metabolism and ferroptosis in RGCs during glaucoma. We demonstrate the protective effect of Deferiprone on RGCs via inhibition of ferroptosis, providing a research direction to understand and treat glaucoma via the iron homeostasis and ferroptosis pathways.

Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, bla MBL and mcr , raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs. Multi-drug resistant pathogens remain a serious public health threat. Here, Sun and colleagues identify a role for auranofin, which is normally used as a drug for rheumatoid arthritis, for reversing antibiotic resistance to carbapenem and colistin.

Key Points Iron metabolism is a tightly regulated physiological process that has relatively low redundancy, and its deregulation often leads to iron deficiency or iron overload. Iron deficiency and iron overload are historically associated with erythroid disorders; however, deregulated iron metabolism is also implicated in numerous ageing-related, non-haematological disorders, including neurodegenerative disorders, atherosclerosis and cancer. Intracellular iron is directly involved in the formation of reactive oxygen species, which can cause cellular oxidative damage. Reactive oxygen species are also important for ferroptosis, a form of non-apoptotic cell death. The internalization of iron by macrophages can modulate macrophage activity towards a pro-inflammatory phenotype, which may also depend on the pathway of iron intake. Agents that interfere with key regulators of iron metabolism and cellular iron trafficking represent a promising new class of therapeutic agents for various diseases because these agents exploit pathological pathways that are complementary to those targeted by existing treatments. Targeting therapeutics to diseased tissues that express high levels of transferrin receptor is a strategy that is used by several agents currently in clinical development, and extending this strategy towards other iron metabolism-associated cellular transporters may be advantageous. Dysregulation of iron homeostasis occurs in haematological disorders and in other diseases such as cancer and neurodegeneration. Crielaard and colleagues discuss the progress made in interfering with iron metabolism as a therapeutic strategy, as well as in using iron metabolism to direct drugs to target tissues. Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents are likely to have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are currently available.

Pet owners often don’t acknowledge the need for home-prepared diet formulation by a trained professional and may use recipes from sources such as the internet. Macronutrient and mineral composition of home-prepared diets were analyzed and compared to NRC and FEDIAF recommendations, and heavy metal concentrations were analyzed and compared to FDA maximum tolerable levels (MTL) for dogs and cats. Recipes of home-prepared diets for adult dogs (n = 75) and cats (n = 25) were evaluated. Analyses of protein, fat, and fiber were performed according to AOAC, and mineral and heavy metal analyses were performed using inductively coupled plasma optical emission spectrometry (ICP-OES). None of the diets supplied recommended levels of all nutrients evaluated, and more than 84.0% of diets presented three or more nutrients below recommendations. Nutrients with most levels below recommendations were calcium and potassium in recipes for dogs and iron and zinc in recipes for cats. As for heavy metals, levels of lead, cobalt, mercury, uranium, and vanadium were above MTLs. Results suggest that home-prepared diets may be a health risk to dogs and cats if not properly formulated. Furthermore, the chronic heavy metal intake must be better elucidated in order to understand the full impact of results.

Through a quantitative proteomics analysis, a cohort of proteins is identified that associate with autophagosomes, among them a new cargo receptor called NCOA4 that, in response to iron deprivation, targets ferritin to autophagosomes and thereby releases iron. A novel autophagosomal cargo receptor In selective autophagy, specific molecules known as cargo receptors bind to cargo molecules and target them to autophagosomes — vesicles that subsequently fuse with the cellular organelles lysosomes for enzymatic degradation of their content. Only a handful of such cargo receptors have been well characterized. Through quantitative proteomics analysis, Alec Kimmelman and co-workers have identified a cohort of proteins that associate with autophagosomes, among them a new cargo receptor, nuclear receptor coactivator 4 (NCOA4). Intriguingly, when deprived of iron, NCOA4 targets ferritin to autophagosomes, thereby releasing iron from its ferritin stores. These findings not only represent a cell biology resource, but also have implications for understanding iron metabolism. Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration 1 , 2 . Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited 3 . Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo–receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species 4 but is degraded via autophagy to release iron 5 , 6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo–receptor connectivity.

[NiFe]-hydrogenases activate dihydrogen. Like all [NiFe]-hydrogenases, hydrogenase 2 of Escherichia coli has a bimetallic NiFe(CN) 2 CO cofactor in its catalytic subunit. Biosynthesis of the Fe(CN) 2 CO group of the [NiFe]-cofactor occurs on a distinct scaffold complex comprising the HybG and HypD accessory proteins. HybG is a member of the HypC-family of chaperones that confers specificity towards immature hydrogenase catalytic subunits during transfer of the Fe(CN) 2 CO group. Using native mass spectrometry of an anaerobically isolated HybG–HypD complex we show that HybG carries the Fe(CN) 2 CO group. Our results also reveal that only HybG, but not HypD, interacts with the apo-form of the catalytic subunit. Finally, HybG was shown to have two distinct, and apparently CO 2 -related, covalent modifications that depended on the presence of the N -terminal cysteine residue on the protein, possibly representing intermediates during Fe(CN) 2 CO group biosynthesis. Together, these findings suggest that the HybG chaperone is involved in both biosynthesis and delivery of the Fe(CN) 2 CO group to its target protein. HybG is thus suggested to shuttle between the assembly complex and the apo-catalytic subunit. This study provides new insights into our understanding of how organometallic cofactor components are assembled on a scaffold complex and transferred to their client proteins.