Genome-Wide Identification, Characterization and Expression Analysis of Soybean CHYR Gene Family

The CHYR (CHY ZINC-FINGER AND RING FINGER PROTEIN) proteins have been functionally characterized in iron regulation and stress response in Arabidopsis, rice and Populus. However, their roles in soybean have not yet been systematically investigated. Here, in this study, 16 GmCHYR genes with conserved Zinc_ribbon, CHY zinc finger and Ring finger domains were obtained and divided into three groups. Moreover, additional 2–3 hemerythrin domains could be found in the N terminus of Group III. Phylogenetic and homology analysis of CHYRs in green plants indicated that three groups might originate from different ancestors. Expectedly, GmCHYR genes shared similar conserved domains/motifs distribution within the same group. Gene expression analysis uncovered their special expression patterns in different soybean tissues/organs and under various abiotic stresses. Group I and II members were mainly involved in salt and alkaline stresses. The expression of Group III members was induced/repressed by dehydration, salt and alkaline stresses, indicating their diverse roles in response to abiotic stress. In conclusion, our work will benefit for further revealing the biological roles of GmCHYRs.

Serotonin regulates hepcidin expression via a gut-liver axis

Liver hepcidin, is well recognized as the central hormone of systemic iron regulation. Although serotonin is most recognized as a brain neurotransmitter, prodigious quantities are synthesized in gut enterochromaffin cells and several lines of evidence, also identified the gut as an essential sensor and regulator of iron homeostasis. Using a mouse model deficient for peripheral serotonin (Tph1 KO), we identified gut-derived serotonin as a key physiological factor in hepcidin regulation. Serotonin represses hepcidin's through a 5HT2B receptor-dependent pathway, independently of any other known hepcidin regulators, including bone marrow signals. This regulation is conserved in humans and shows physiological significance as a negative correlation between serotonin and hepcidin levels was observed in a cohort of healthy individuals. Moreover, in pathological situation such as acute heart failure, where iron deficiency has a negative prognostic impact, we provide evidence that an increase in serotonin level seems necessary to repress hepcidin level, to increase iron availability.

Differential Redox State and Iron Regulation in Chronic Obstructive Pulmonary Disease, Acute Respiratory Distress Syndrome and Coronavirus Disease 2019

In patients affected by Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD) and Coronavirus Disease 2019 (COVID-19), unclear mechanisms negatively interfere with the hematopoietic response to hypoxia. Although stimulated by physiological hypoxia, pulmonary hypoxic patients usually develop anemia, which may ultimately complicate the outcome. To characterize this non-adaptive response, we dissected the interplay among the redox state, iron regulation, and inflammation in patients challenged by either acute (ARDS and COVID-19) or chronic (COPD) hypoxia. To this purpose, we evaluated a panel of redox state biomarkers that may integrate the routine iron metabolism assays to monitor the patients’ inflammatory and oxidative state. We measured redox and hematopoietic regulators in 20 ARDS patients, 20 ambulatory COPD patients, 9 COVID-19 ARDS-like patients, and 10 age-matched non-hypoxic healthy volunteers (controls). All the examined pathological conditions induced hypoxia, with ARDS and COVID-19 depressing the hematopoietic response without remarkable effects on erythropoietin. Free iron was higher than the controls in all patients, with higher levels of hepcidin and soluble transferrin receptor in ARDS and COVID-19. All markers of the redox state and antioxidant barrier were overexpressed in ARDS and COVID-19. However, glutathionyl hemoglobin, a candidate marker for the redox imbalance, was especially low in ARDS, despite depressed levels of glutathione being present in all patients. Although iron regulation was dysfunctional in all groups, the depressed antioxidant barrier in ARDS, and to a lesser extent in COVID-19, might induce greater inflammatory responses with consequent anemia.

On Iron Metabolism and Its Regulation

Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.

Postnatal Iron Supplementation with Ferrous Sulfate vs. Ferrous Bis-Glycinate Chelate: Effects on Iron Metabolism, Growth, and Central Nervous System Development in Sprague Dawley Rat Pups

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.

Menstrual phase and ambient temperature do not influence iron regulation in the acute exercise period

The current study investigated whether ambient heat augments the inflammatory and post-exercise hepcidin response in women, and if menstrual phase and/or self-pacing modulate these physiological effects. Eight trained females (age: 37±7 y; VO2max: 46±7 mL∙kg-1∙min-1; peak power output: 4.5±0.8 W∙kg-1) underwent 20 min of fixed-intensity cycling (100 and 125 W) followed by a 30-min work trial (≈75% VO2max) in a moderate (MOD: 20±1 °C, 53±8% relative humidity) and warm-humid (WARM: 32±0 °C, 75±3% relative humidity) environment in both their early follicular (days 5±2) and mid-luteal (days 21±3) phases. Mean power output was 5±4 W higher in MOD than in WARM (p=0.02) such that the difference in core temperature rise was limited between environments (-0.29±0.18 °C in MOD, p<0.01). IL-6 and hepcidin both increased post-exercise (198% and 38%, respectively), however, neither were affected by ambient temperature or menstrual phase (all p>0.15). Multiple regression analysis demonstrated that the IL-6 response to exercise was explained by leukocyte and platelet count (r2=0.72, p<0.01) and the hepcidin response to exercise was explained by serum iron and ferritin (r2=0.62, p<0.01). During exercise participants almost matched their fluid loss (0.48±0.18 kg·h-1) with water intake (0.35±0.15 L·h-1) such that changes in body mass (-0.3±0.3%) and serum osmolality (0.5±2.0 mOsm·kg-1) were minimal or negligible, indicating a behavioral fluid-regulatory response. These results indicate that trained, iron sufficient women suffer no detriment to their iron regulation in response to exercise with acute ambient heat stress or between menstrual phases on account of a performance-physiological trade-off.

Using natural variation to understand plant responses to iron availability

Iron bioavailability varies dramatically between soils types across the globe. This has given rise to high levels of natural variation in plant iron responses, allowing members of even a single species to thrive across a wide range of soil types. In recent years we have seen the use of GWA analysis to identify natural variants underlying plant responses to changes in iron availability in both Arabidopsis and important crop species. These studies have provided insights into which genes have been important in shaping local adaptation to iron availability in different plant species and have allowed for the discovery of novel regulators and mechanisms, not previously identified using mutagenesis approaches. Furthermore, these studies have allowed for the identification of markers that can be used to accelerate breeding of future elite varieties with increased resilience to iron stress and improved nutritional quality. The studies highlighted here show that, in addition to studying plant responses to iron alone, it is important to consider these responses within the context of plant nutrition more broadly and to also consider iron regulation in relation to additional traits of agronomic importance such as yield and disease resistance.