Search

Animal flesh foods are rich in bioavailable iron but infrequently consumed by young children. We aimed to determine whether flesh food intake was associated with iron and anaemia status among 585 Malawian infants enroled in a 6-month egg-feeding trial. The percentage of days of small fish, large fish and meat consumption were assessed through weekly 7-day animal-source food screeners. Grams of intake were assessed through 24-h recalls conducted at 6-9, 9-12 and 12-15 months of age. Plasma ferritin, soluble transferrin receptor (sTfR) and haemoglobin concentrations were measured at 6-9 and 12-15 months of age. Iron biomarkers were adjusted for inflammation during analysis. At enrolment, each flesh food category was consumed by

BACKGROUND: Murine data suggest that the placenta downregulates ferroportin (FPN) when iron is limited to prioritize iron for its own needs. Human data on the impact of maternal and neonatal iron status on placental FPN expression are conflicting. OBJECTIVES: This study aimed to identify determinants of placental FPN protein abundance and to assess the utility of the placental iron deficiency index (PIDI) as a measure of maternal/fetal iron status in newborns at high risk for anemia. METHODS: Placental FPN protein abundance was measured by western blots in placentae collected from 133 neonates born to adolescents (17.4 ± 1.1 y) carrying singletons (delivery gestational age [GA]: 39.9 ± 1.3 wk) and from 130 neonates born to 65 females (30.4 ± 5.2 y) carrying multiples (delivery GA: 35.0 ± 2.8 wk). Placental FPN and the PIDI (FPN:transferrin receptor 1) were evaluated in relation to neonatal and maternal iron-related markers (hemoglobin [Hb], serum ferritin [SF], soluble transferrin receptor [sTfR], total body iron [TBI], hepcidin, erythropoietin [EPO], erythroferrone). RESULTS: FPN protein was detected in all placentae delivered between 25 and 42 wk GA. Placental FPN protein abundance was associated with neonatal iron and erythropoietic markers (EPO: β: 0.10; 95% confidence interval [CI]: 0.06, 0.35; sTfR: β: 0.20; 95% CI: 0.03, 0.18; hepcidin: β: -0.06; 95% CI: -0.13, -0.0003; all P < 0.05). Maternal sTfR was only indirectly associated with placental FPN, with neonatal sTfR as the mediator (β-indirect: 0.06; 95% CI; 0.03, 0.11; P = 0.003). The PIDI was associated with neonatal Hb (β: -0.02; 95% CI: -0.03, -0.003), EPO (β: 0.07; 95% CI: 0.01, 0.14), and sTfR (β: 0.13; 95% CI: 0.004, 0.3) and with maternal SF (β: 0.08, 95% CI: 0.02, 0.14), TBI (β: 0.02; 95% CI: 0.009, 0.04), EPO (β: -0.10; 95% CI: -0.19, -0.01), sTfR (β: -0.16: 95% CI: -0.27, -0.06), and hepcidin (β: 0.05; 95% CI: 0.002, 0.11) at delivery (all P < 0.05). CONCLUSIONS: Placental FPN abundance was positively associated with neonatal indicators of increased erythropoietic activity and poor iron status. The PIDI was associated with maternal and neonatal iron-related markers but in opposite directions. More data are needed from a lower-risk normative group of females to assess the generalizability of findings. These trials were registered at clinicaltrials.gov as NCT01019902 and NCT01582802.

Introduction: Iron is crucial for brain function, but excessive iron is neurotoxic. Abnormally high brain iron accumulation is one of the pathogenic factors in Alzheimer's disease (AD). Therefore, understanding the mechanistic basis of iron dyshomeostasis in AD is vital for disease mitigation. Calcium, another essential bioelement involved in cell signaling, also exhibits dysregulated homeostasis in AD. Calcium ion (Ca2+) signaling can influence iron homeostasis through multiple effectors. Our previous studies identified Ca2+/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) as a regulator of transferrin (TF)-bound iron trafficking through the TF receptor (TFRC). Given CAMKK2's high expression in brain cells, it was hypothesized that abnormal CAMKK2-TF/TFRC signaling may underlie excessive iron deposition in AD brains. This study aims to retrospectively investigate CAMKK2, TF, TFRC proteins, and iron content in temporal cortex tissues from AD patients and cognitively normal (CN) individuals, postmortem. Methods: Postmortem temporal cortex tissues from 74 AD patients, 27 Parkinson's disease (PD) patients, and 17 CN individuals were analyzed for CAMKK2, TF, and TFRC protein levels by Western blotting. Additionally, prefrontal/temporal cortex tissues from 30 CN individuals of various ages were examined for age-related effects. Iron content in cortical tissues was measured using a colorimetric assay. Results: CAMKK2, TF, and TFRC levels were significantly decreased in AD patients' temporal cortices compared to CN individuals, independent of age or postmortem interval-related changes. PD patients' also exhibited similar reductions in CAMKK2/TF/TFRC levels. The increased iron content in AD brains was significantly correlated with reduced TF/TFRC protein levels. Discussion: Building on the previous identification of CAMKK2 as a regulator of TF/TFRC trafficking and iron homeostasis, the findings from this study suggest that downregulation of CAMKK2 in AD cortices may disrupt TF/TFRC signaling and contribute to iron overloading and neurodegeneration through iron-induced toxicity. The decreased levels of TF/TFRC and increased iron in AD brains may result from enhanced clearance or post-trafficking degradation of TF/TFRC due to CAMKK2 downregulation. Restoring CAMKK2 levels in the AD brain could offer a novel therapeutic approach to reestablish iron homeostasis. Further studies are needed to explore the pathways linking CAMKK2 and iron dysregulation in AD and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective: As people get older, the innate and acquired immunity of the elderly are affected, resulting in immunosenescence. Prealbumin (PAB), transferrin (TRF), and albumin (ALB) are commonly used markers to monitor protein energy malnutrition (PEM). However, their relationship with the immune system has not been fully explored. Methods: In our study, a total of 93 subjects (≥65 years) were recruited from Tongji Hospital between January 2015 and February 2017. According to the serum levels of these proteins (PAB, TRF, and ALB), we divided the patients into the high serum protein group and the low serum protein group. Then, we compared the percent expression of lymphocyte subsets between two groups. Results: All the low serum protein groups (PAB, TRF, and ALB) had significant decreases in the percentage of CD4+ cells, CD3+CD28+ cells, CD4+CD28+ cells and significant increases in the percentage of CD8+ cells, CD8+CD28− cells. PAB, TRF, and ALB levels revealed positive correlations with CD4/CD8 ratio, proportions of CD4+ cells, CD3+CD28+ cells, CD4+CD28+ cells, and negative correlation with proportions of CD8+ cells, CD8+CD28− cells. Conclusions: This study suggested PAB, TRF, and ALB could be used as immunosenescence indicators. PEM might accelerate the process of immunosenescence in elderly males. [ABSTRACT FROM AUTHOR]

Glyceraldehyde‐3‐phosphate‐dehydrogenase (GAPDH; EC1.2.1.12) has several functions in Mycobacterium tuberculosis (Mtb) and the human host. Apart from its role in glycolysis, it serves both as a cell surface and a secreted receptor for plasmin(ogen) (Plg/Plm), transferrin (Tf), and lactoferrin (Lf). Plg sequestration by Mtb GAPDH facilitates bacterial adhesion and tissue invasion, while an equivalent interaction with host GAPDH regulates immune cell migration. In both, host and microbe, internalization of Tf/Lf‐GAPDH complexes serves as a route for iron acquisition. To date, the structure of Mtb GAPDH or the residues involved in these moonlighting interactions have not been identified. This study provides the first known X‐ray crystal structure of Mtb GAPDH. Through further mutagenesis and functional assays, we found that the C‐terminal lysines of Mtb and human GAPDH affect enzyme activity and ligand binding. We also establish the stoichiometry of Plg, Tf and Lf interactions with the GAPDH tetramer. Lastly, molecular simulation studies reveal the interactions of the C‐terminal lysine residues. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of cell death characterized by a pro‐oxidative cellular milieu and iron‐dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12‐ and 24‐month‐old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non‐haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor‐1. In female rats, the 24‐month‐old group had higher contents of thiobarbituric acid reactive substances compared with their 12‐month‐old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4‐hydroxnonenal‐modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis. What is the central question of this study?Do iron stores and ferroptosis mediators in the liver differ with age or sex?What is the main finding and its importance?We observed greater non‐haem iron, 4‐hydroxynonenal‐modified proteins and ACSL4 protein expression in female livers, suggesting greater susceptibility to ferroptosis. [ABSTRACT FROM AUTHOR]

Overcoming multiple barriers to deliver macromolecular drugs is an urgent challenge for glioma treatment. Herein, a strategy of protein corona-regulation synergizing with photoactivation based on T10 peptide-modified and indocyanine green (ICG)-loaded dendrigraft poly-L-lysines was proposed to augment prime editing therapy of glioma. First, the modified T10 peptide could escape the interference barrier of protein crown in blood via its specific binding with endogenous transferrin, thus crossing the blood-brain barrier (BBB) and achieving the targeting recognition of glioma cells. Next, the loaded ICG could weaken the tumor stromal barrier, decrease the cell membrane barrier and escape the lysosomal degradation/autophagy barrier via its photothermal and photodynamic effects. Subsequently, a therapeutic gene that could downregulate p-ERK1/2 for tumor growth inhibition and immunoregulation could be effectively delivered into the glioma cells. The glioma-targeted photo-gene combined immunotherapy effectively inhibit the glioma growth, especially co-dosing with the PD-1 antibody. [Display omitted] • A smart strategy employing photo- and protein corona-manipulation. • Delivery of therapeutic gene overcoming multiple physiological barriers. • Significant inhibition of glioma growth through inhibiting MEK1/2-ERK1/2 pathway. • Performance of glioma-targeted photo-gene combined immunotherapy. [ABSTRACT FROM AUTHOR]

The Hefang crucian carp (HFJ) derived from Carassius cuvieri (♀) × C. auratus red var. (♂) and the crucian carplike homodiploid fish (NCRC) derived from Cyprinus carpio (♀) × Megalobrama amblycephala (♂) are important germplasm resources of crucian carp. To investigate the population characteristics and reveal the current genetic situations of these hybrid varieties, we sequenced one nuclear molecular marker transferrin (Tf) among six Carassius populations, which included two hybrid varieties (HFJ and NCRC), one laboratory variety (red crucian carp, RCC) and three wild populations. A total of 166 distinct Tf alleles (A1~A166) were identified, with sequence lengths ranging from 1145 bp to 1244 bp. Unexpectedly, the nucleotide diversity of Tf alleles in cultured populations (HFJ, NCRC, and RCC) exceeded that of wild populations. The phylogenetic reconstruction analysis results showed that HFJ and C. cuvieri were closely related, but they could not be separated from C. auratus. Besides, while most Tf alleles of NCRC and other Carassius populations were intermixed in five clades, two Tf alleles, together with Cy. carpio, formed a distinct monophyletic clade. Moreover, network and genetic structure analyses failed to distinguish between wild and cultured populations. Although AMOVA analysis based on Tf alleles indicated genetic differentiation among all six populations, the majority of the genetic variation (92.00 %) was observed within populations. Furthermore, the population dynamics analysis suggested that these populations have maintained relative stability in recent history. Therefore, the elevated nucleotide diversity of Tf alleles in cultured populations, the ambiguous population structure, and the limited genetic divergence among the six Carassius populations highlighted the hybrid genetic characteristics of HFJ and NCRC. These findings, based on Tf alleles, differ from the results obtained using mitochondrial gene markers, providing an alternative perspective for germplasm evaluation of hybrid varieties and crucian carp breeding. [ABSTRACT FROM AUTHOR]

Malnutrition is a global phenomenon and may be contributing to the increasing size of the hemodialysis (HD) population in South Africa and is affecting morbidity and clinical outcomes. Our study assessed whether transferrin could be a possible marker for malnutrition in the HD population. Clinical parameters (including skinfold thickness and mid-upper arm circumference [MUAC]) and laboratory markers (including transferrin and hemoglobin) were measured during a six-month period in a sample of 59 HD patients. Linear regression analysis showed that MUAC (p = 0.027) as well as skinfold thickness (p = 0.021) had a significant association with transferrin levels within the HD participants. There was no significant association between transferrin levels or MUAC with hemoglobin levels (p = 0.075). Furthermore, the study found that decreased transferrin levels (< 2.15 g/dL to 3.80 g/dL) were closely related to malnutrition in the malnutrition distribution groups within the study, with 97.7% of HD participants being classified in one of the malnutrition groups. Thus, transferrin levels are a valuable marker for malnutrition within the HD patient population and can be included along with clinical assessment parameters such as MUAC and skinfold thickness as primary indicators for malnutrition. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Existing studies have shown that transferrin receptor (TfR) is highly expressed on the surface of lung cancer cells, and nanoparticles (NPs) have been widely used as delivery vehicles. The aim of this study was to investigate the effect of the targeted delivery of Fe3O4 NPs modified with transferrin (Tf) compared with photothermal treatment for lung cancer.The morphology and properties of Fe3O4 NPs modified with Tf were tested by internal morphological characterization experiments including transmission electron microscopy, particle size meter infrared spectrometer and other experiments. The delivery of materials was investigated by cell proliferation and apoptosis experiments, and western blot experiment was used to detect yes‐associated protein 1(YAP1) protein expression changes after delivering miR‐15a‐5p. In addition, animal models were constructed to further explore the targeting properties of the material.The results demonstrated that the nanomaterial has good stability and targeting properties. Meanwhile, we also discovered that the miR‐15a‐5p carried by NPs can inhibit cell growth after its entry to the lung cancer cells. The effect became more evident when the nanomaterials were assisted with laser therapy, as verified by in vivo and in vitro experiments. In terms of the related mechanism, miR‐15a‐5p inhibited YAP1 expression, which affected cell proliferation and apoptosis.In this study, Fe3O4 NPs modified with Tf delivered miR‐15a‐5p in combination with photothermal therapy for lung cancer. In future research, the targeted delivery of Tf and the photothermal synergy of nanomaterials will provide a theoretical basis for cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Physical training induces iron status impairment in athletic females in the short term and over prolonged periods. Nevertheless, the existing literature lacks a comprehensive evaluation of the differential impacts of aerobic vs. anaerobic training on hematological indices and iron status among adolescent female athletes. The aim of this study was to assess the hematological factors and iron status in aerobic vs. anaerobic training in athletic females. Methods: This observational, cross-sectional study recruited twenty-five adolescent athletic females; thirteen of them participated in an aerobic sport (long-distance running), while twelve of them participated in an anaerobic sport (broad jumping). Hematological factors were assessed by analyzing blood concentrations of hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC) count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin concentration (MCHC), while the iron status assessment was conducted through evaluating levels of serum transferrin and serum ferritin. Results: Athletic females who participated in the aerobic sport showed significantly lower Hb (MD −0.84; 95% CI −1.63: −0.04; p = 0.041), Hct (MD −5.49; 95% CI −7.86: −3.12; p = 0.0001), RBC count (MD −0.37; 95% CI −0.57: −0.17; p = 0.001), and MCV (MD −5.15; 95% CI −9.41: −0.89; p = 0.020), as well as significantly higher MCHC (MD 2.99; 95% CI 2.18: 3.79; p = 0.0001) and serum transferrin (MD 46.77; 95% CI 10.95: 82.59; p = 0.013) than athletic females who participated in the anaerobic sport. However, there was an insignificant difference in serum ferritin levels (MD −3.18; 95% CI −11.49: 5.13; p = 0.437) between both groups. Conclusion: Except for the ferritin level that exhibited an insignificant difference between aerobic and anaerobic training, aerobic training was associated with a worse impact on the hematological factors and iron status than anaerobic training in adolescent athletic females. [ABSTRACT FROM AUTHOR]

Host iron deficiency is protective against severe malaria as the human malaria parasite Plasmodium falciparum depends on bioavailable iron from its host to proliferate. The essential pathways of iron acquisition, storage, export, and detoxification in the parasite differ from those in humans, as orthologs of the mammalian transferrin receptor, ferritin, or ferroportin, and a functional heme oxygenase are absent in P. falciparum. Thus, the proteins involved in these processes may be excellent targets for therapeutic development, yet remain largely unknown. Here, we show that parasites cultured in erythrocytes from an iron-deficient donor displayed significantly reduced growth rates compared to those grown in red blood cells from healthy controls. Sequencing of parasite RNA revealed diminished expression of genes involved in overall metabolism, hemoglobin digestion, and metabolite transport under low-iron versus control conditions. Supplementation with hepcidin, a specific ferroportin inhibitor, resulted in increased labile iron levels in erythrocytes, enhanced parasite replication, and transcriptional upregulation of genes responsible for merozoite motility and host cell invasion. Through endogenous GFP tagging of differentially expressed putative transporter genes followed by confocal live-cell imaging, proliferation assays with knockout and knockdown lines, and protein structure predictions, we identified six proteins that are likely required for ferrous iron transport in P. falciparum. Of these, we localized Pf VIT and Pf ZIPCO to cytoplasmic vesicles, Pf MRS3 to the mitochondrion, and the novel putative iron transporter Pf E140 to the plasma membrane for the first time in P. falciparum. Pf NRAMP/ Pf DMT1 and Pf CRT were previously reported to efflux Fe2+ from the digestive vacuole. Our data support a new model for parasite iron homeostasis, in which Pf E140 is involved in iron uptake across the plasma membrane, Pf MRS3 ensures non-redundant Fe2+ supply to the mitochondrion as the main site of iron utilization, Pf VIT transports excess iron into cytoplasmic vesicles, and Pf ZIPCO exports Fe2+ from these organelles in case of iron scarcity. These results provide new insights into the parasite's response to differential iron availability in its environment and into the mechanisms of iron transport in P. falciparum as promising candidate targets for future antimalarial drugs. [ABSTRACT FROM AUTHOR]

Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4–5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time. The resistant cells showed altered molecular signatures, with differences in cell cycle regulation and the propensity of cell death. Dabrafenib-resistant cells maintained high proliferative activity, while AZ628-resistant cells, especially A375 cells, exhibited slow-cycling, and a senescent-like phenotype with high susceptibility to ferroptosis, a form of cell death driven by iron. Antiretroviral drugs doravirine and cabotegravir, known for their effects on human endogenous retroviruses, were tested for their impact on these resistant melanoma cells. Both drugs reduced cell viability and colony formation in resistant cell lines. Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16Ink4a and p27Kip1. These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance. [ABSTRACT FROM AUTHOR]

Ferroptosis and cuproptosis are emerging modes of programmed cell death and have been increasingly used to eliminate tumor cells. However, converting ferroptosis/cuproptosis into effective treatments is challenging because of the inherent antioxidant and plasma membrane repair systems and inefficient copper ion delivery. Herein, an engineered doping method is developed to encapsulate ZnO2 with Cu2+‐doped ZIF‐8 and modify the surface by transferrin (Tf). In the resulting ZnO2@Cu/ZIF‐8‐Tf nanosystem, Tf specifically binds to transferrin receptors for targeting and aggregation. In the tumor microenvironment, Cu2+/Fe3+ is released from the nanosystem and reacted with glutathione (GSH) to produce Cu+/Fe2+. Excessive accumulation of Cu+ interfered with the tricarboxylic acid cycle and induced coproptosis. Furthermore, the additional Fe2+ caused iron overload and enhanced ferroptosis. ZnO2 supplied hydrogen peroxide to mediate the overproduction of reactive oxygen species (ROS). Moreover, the depletion of GSH deactivated glutathione peroxidase 4 (GPX4) and inhibited the system Xc−‐GSH‐GPX4 pathway, and the amplified ROS triggered lipid peroxidation and reprogrammed lipid metabolism, causing malfunctioning of both antioxidant and membrane repair systems. In summary, the ferroptosis/cuproptosis pathways are activated at multiple levels in the ZnO2@Cu/ZIF‐8‐Tf nanosystem, which ensures its outstanding antitumor effect. [ABSTRACT FROM AUTHOR]

Simple Summary: Physiological equilibrium preservation is essential for an animal's survival, and any event that may disturb this equilibrium is defined as a stressor. Here, we aimed to evaluate the effect of scratch brushes and stages as an environmental enrichment to reduce stress in dairy goats. Twenty-four mixed-breed goats were divided into two groups according to common physiological conditions in breeding farms: milking and dry (milk-producing and non-milk-producing, respectively). Blood was sampled ten days post-exposure to enrichment treatment or not (control). Following the enrichment, we observed a reduction in dry goats' oxidative stress products and their binding protein, transferrin. In contrast, no change in these products, along with an increase in transferrin levels, was observed in milking goats. Moreover, the anti-stress hormones, oxytocin and serotonin, levels changed differentially between the dry- and milking-goat groups. Additionally, gene expression of immune-related and antioxidant molecules in white blood cells isolated from the goats' blood presented the same pattern: down-regulation in dry or up-regulation in milking goats. In conclusion, a reliable methodology was developed for measuring husbandry stress in goats. Current environmental enrichment produced different responsiveness in goats correlated to their physiological status: beneficial effect in dry goats, detrimental effect in milking goats. Homeostasis preservation is essential for animal survival, and any event that causes a disturbance in homeostasis is defined as a stressor. Here, we aimed to evaluate the effect of scratch brushes and stages as an environmental enrichment to alleviate stress in dairy goats. Twenty-four mixed-breed goats were divided into two groups according to common physiological conditions in breeding farms: milking and dry (milk-producing and non-milk-producing, respectively). Ten days after exposure to environmental enrichment treatment or not (control), blood was sampled. Following the enrichment, we observed a reduction in reactive oxidative stress metabolites, advanced glycation end products (AGEs), and their binding protein (transferrin) in the dry goats, as determined by an ELISA. In contrast, no change in AGEs, along with an increase in transferrin levels, was observed in the milking goats. Moreover, oxytocin levels decreased in the dry and increased in the milking goats, while serotonin levels increased in the dry and remained unchanged in the milking goats. Additionally, gene expression of the cytokines, IL-6 and IL-1ß, and anti-oxidative proteins, lysozyme and transferrin (in peripheral blood leukocytes), as determined by qPCR, presented the same pattern: down-regulation in the dry or up-regulation in the milking goats. In conclusion, a reliable methodology was developed for measuring husbandry stress in goats and to improve dairy goats' husbandry practice. Current environmental enrichment produced different responsiveness in goats correlated to their physiological status: beneficial effect in dry goats, detrimental effect in milking goats. [ABSTRACT FROM AUTHOR]

Rutin is a flavonoid compound with potential for treating Alzheimer's disease, preventing brain damage, mitigating cerebral ischemia–reperfusion injury, and exhibiting anti-glioblastoma activity. However, its efficacy is limited by its low solubility, poor bioavailability, and limited permeability across the blood–brain barrier (BBB). To enhance the bioavailability and brain-targeting ability of Rutin, transferrin-modified Rutin liposome (Tf-Rutin-Lip) was developed using liposomes as a delivery system. Rutin liposomes were prepared using the thin-film dispersion method, and the preparation conditions were optimized using the response surface methodology. Then, transferrin (Tf) was incorporated into the liposomes through covalent modification, yielding Tf-Rutin liposomes. The toxicity of these liposomes on bEnd.3 cells, as well as their impact on the tight junctions of these cells, was rigorously evaluated. Additionally, in vitro and in vivo experiments were conducted to validate the brain-targeting efficacy of the Tf-Rutin liposomes. A susceptible detection method was developed to characterize the pharmacokinetics of Tf-Rutin-Lip further. The optimized conditions for the preparation of Tf-Rutin-Lip were determined as follows: a lipid-to-cholesterol ratio of 4.63:1, a drug-to-lipid ratio of 1:45.84, a preparation temperature of 42.7 °C, a hydration volume of 20 mL, a sonication time of 10 min, a surfactant concentration of 80 mg/mL, a DSPE-MPEG-2000 concentration of 5%, and a DSPE-PEG2000-COOH to DSPE-MPEG-2000 molar ratio of 10%. The liposomes did not affect the cell activity of bEnd.3 cells at 24 h and did not disrupt the tight junction of the blood–brain barrier. Tf-modified liposomes were taken up by bEnd.3 cells, which, in turn, passed through the BBB, thus improving liposomal brain targeting. Furthermore, the results of pharmacokinetic experiments showed that the Cmax, AUC0-∞, AUC0-t, MRT0-∞, and t1/2 of Tf-Rutin-Lip increased 1.99-fold, 2.77-fold, 2.58-fold, 1.26-fold, and 1.19-fold compared to those of free Rutin solution, respectively. These findings suggest that Tf-Rutin-Lip is brain-targeted and may enhance the efficacy of Rutin in the treatment of brain disorders. [ABSTRACT FROM AUTHOR]

Aim: Out-of-hospital cardiac arrest (OHCA) is a major health concern in Western societies. Poor outcome after OHCA is determined by the extent of hypoxic-ischemic encephalopathy (HIE). Dysregulation of iron metabolism has prognostic relevance in patients with ischemic stroke and sepsis. The aim of this study was to determine whether serum iron parameters help to estimate outcomes after OHCA. Methods: In this prospective single-center study, 70 adult OHCA patients were analyzed. Serum ferritin, iron, transferrin (TRF), and TRF saturation (TRFS) were measured in blood samples drawn on day 0 (admission), day 2, day 4, and 6 months after the return of spontaneous circulation (ROSC). The association of 4 iron parameters with in-hospital mortality, neurological outcome (cerebral performance category [CPC]), and HIE was investigated by receiver operating characteristics and multivariate regression analyses. Results: OHCA subjects displayed significantly increased serum ferritin levels on day 0 and lowered iron, TRF, and TRFS on days 2 and 4 after ROSC, as compared to concentrations measured at a 6-month follow-up. Iron parameters were not associated with in-hospital mortality or neurological outcomes according to the CPC. Ferritin on admission was an independent predictor of features of HIE on cranial computed tomography and death due to HIE. Conclusion: OHCA is associated with alterations in iron metabolism that persist for several days after ROSC. Ferritin on admission can help to predict HIE. [ABSTRACT FROM AUTHOR]

[Display omitted] • HIF-1α eases OGD/R −induced ferroptosis. • HIF-1α enhances the transcriptional activity of transferrin FPN1. • FPN1 knockdown annuls HIF-1α-induced alleviation on OGD/R-induced ferroptosis. • HIF-1α boosts FPN1 to activate Nrf2/HO-1 and ease OGD/R-induced ferroptosis. • HIF-1α boosts FPN1 to activate Nrf2/HO-1 and ease cerebral I/R injury in rats. Cerebral ischemic/reperfusion (I/R) injury has high disability and morbidity. Hypoxia-inducible factor-1α (HIF-1α) may enhance the transcriptional activity of transferrin ferroportin 1 (FPN1) in regulating ferroptosis after cerebral ischemia injury (CII). In this study, cerebral I/R injury rat models were established and treated with pcDNA3.1-HIF-1α, pcDNA3.1-NC lentiviral plasmid, or ML385 (a specific Nrf2 inhibitor). Additionally, oxygen-glucose deprivation/reoxygenation (OGD/R) exposed PC12 cells were used as an in vitro model of cerebral ischemia and treated with pcDNA3.1-HIF-1α, si-FPN1, or ML385. The results elicited that cerebral I/R injury rats exhibited increased Longa scores, TUNEL and NeuN co-positive cells, Fe2+ concentration, ROS and HIF-1α levels, and MDA content, while reduced cell density and number, GSH content, and GPX4 protein level. Morphologically abnormal and disordered hippocampal neurons were also observed in CII rats. HIF-1α inhibited brain neuron ferroptosis and ameliorated I/R injury. HIF-1α alleviated OGD-induced PC12 cell ferroptosis. OGD/R decreased FPN1 protein level in PC12 cells, and HIF-1α enhanced FPN1 transcriptional activity. FPN1 knockdown reversed HIF-1α-mediated alleviation of OGD/R-induced ferroptosis. HIF-1α activated the Nrf2/HO-1 pathway by enhancing FPN1 expression and alleviating OGD/R-induced ferroptosis. Conjointly, HIF-1α enhanced the transcriptional activity of FPN1, activated the Nrf2/HO-1 pathway, and inhibited ferroptosis of brain neurons, thereby improving I/R injury in CII rats. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of traditional Chinese emotional nursing combined with lung rehabilitation training and oral nutrition preparation on improving the nutritional status and lung function of elderly patients with chronic obstructive pulmonary disease. The control group received conventional Western medicine and lung rehabilitation training, while the observation group received traditional Chinese emotional nursing combined with oral nutrition preparation. After nursing, the self-rating depression scale and self-rating anxiety scale scores in the observwere lower than those in the control group (P < 0.05), whereas forced vital capacity, forced expiratory volume in 1 s, and 6-min walk distance were higher (P < 0.05). Serum albumin, prealbumin, transferrin, immunoglobulin A, immunoglobulin G, and immunoglobulin M levels were higher than those in the control group (P < 0.05). After nursing, the scores for physical, material, social, and psychological functions in the observation group were higher than those in the control group (P < 0.05). In conclusion, traditional Chinese emotional nursing combined with lung rehabilitation training and oral nutrition preparation can relieve negative emotions, promote pulmonary function and nutritional status, and improve the quality of life of elderly patients with chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Concerns exist that intravenous (IV) iron might increase the risk of infections. The IRONMAN trial provided an opportunity to investigate whether giving IV ferric derisomaltose (FDI) to patients with heart failure and iron deficiency alters the rate of hospitalization or death due to infections.IRONMAN was a randomized trial of IV FDI versus usual care in patients with symptomatic heart failure, left ventricular ejection fraction (LVEF) ≤45%, and transferrin saturation (TSAT) <20% or ferritin <100 μg/L. Infection was a pre‐specified, blindly‐adjudicated, safety endpoint. The primary analysis of interest was infection as the main reason for hospitalization or death, using first and recurrent events analyses. The composite primary event of interest tended to be lower in those randomized to FDI when analysed as first (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.62–1.01, p = 0.055) or recurrent event (rate ratio 0.85, 95% CI 0.64–1.13, p = 0.089). The composite results were driven by fewer hospitalizations for infection (HR 0.76, 95% CI 0.49–0.98, p = 0.032), with 5% fewer patients (absolute reduction) experiencing such an event if assigned to FDI. Similar trends were observed for recurrent events (HR 0.82, 95% CI 0.62–1.10). Further analyses suggested that the reduction in hospitalizations due to infection with FDI was restricted to patients with TSAT <20%.In patients with heart failure and a reduced LVEF, correction of iron deficiency is not associated with an increased risk of hospitalization or death from infection, and may reduce such events, especially when TSAT is <20%.Clinical Trial Registration: ClinicalTrials.gov, NCT02642562. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD. Methods: A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age. Results: During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (P overall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD. Conclusion: This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) are potentially applicable in drug/nucleic acid delivery systems. Low toxicity, high stability, and bioavailability are crucial for the therapeutic use of AuNPs and they are mainly determined by their interactions with proteins and lipids on their route to the target cells. In this work, we investigated the interaction of two pegylated gold nanoparticles, AuNP14a and AuNP14b, with human serum proteins albumin (HSA) and transferrin (Tf) as well as dimyristoyl-phosphatidylcholine (DMPC) liposomes, which can be a representative of biomembranes. We showed that AuNP14a/b interacted with HSA and Tf changing their electrical, thermodynamic, and structural properties as evidenced by dynamic light scattering, zeta potential, transmission electron microscopy, circular dichroism, fluorescence quenching, and isothermal titration calorimetry. These nanoparticles penetrated the DMPC membrane suggesting their ability to reach a target inside the cell. In most of the effects, AuNP14b was more effective than AuNP14a, which might result from its more positive charge. Further studies are needed to evaluate whether the interaction of AuNP14a/b with HSA and Tf is safe for the cell/organism and whether they may safely penetrate natural membranes. [ABSTRACT FROM AUTHOR]

The human plasma proteome is rather well studied, but not that of other species, including horses. The aims of this study were to (1), explore differences in plasma proteomic profile of young elite harness trotters kept under standardised conditions and subjected to two different training programmes for 2 years and (2) explore changes in proteomic profile over time during the training period. From September at age 1.5 year to March at age 2 years, 16 Standardbred horses were exposed to the same training programme. In March, high-intensity training was introduced and the horses were divided into two training groups (High and Low). Blood samples were collected at rest in December as 1.5-year-olds, July as 2-year-olds, December as 2.5-year-olds and December as 3.5-year-olds. Untargeted proteomics was performed and a hypothesis-generating approach was used in statistical analysis (t-tests). At the age of 2.5 years, the level of serotransferrin was higher in the High group (P = 0.01) and at least at one sampling occasion, proteins associated with fat metabolism, oxidant/antioxidant processes, cardiovascular responses, bone formation and inflammation were lower in High group compared to Low (P < 0.05). Analyses of changes over time revealed that levels of proteins involved in energy metabolism, red cell metabolism, circulation, oxidant/antioxidant activity, bone formation, inflammation, immune modulation and cellular and vascular damage changed (P < 0.05). The results indicate that proteomics analysis of blood plasma could be a viable tool for evaluation of exercise adaptations, performance and for health monitoring, with several potential biomarkers identified in this study. [ABSTRACT FROM AUTHOR]

Background and Aim: In females of various species and experimental animals, iron (Fe) status in follicular fluid (FF) is associated with local physiological reproductive events related to follicle development, steroidogenesis, and oocyte maturation. However, these mechanisms remain unknown. This study aimed to determine and compare the intrafollicular and plasma concentrations of Fe, ferritin (Ferr), and transferrin (TRF) in cycling mares. Materials and Methods: Sixty ovaries were collected during the breeding season from 30 clinically normal mares raised for slaughterhouse meat production. Blood samples were collected before slaughter. Follicles were classified into three categories according to size: Small (20-30 mm; n = 20), medium (=31-40 mm; n = 20), and large (=41 mm; n = 20). The FF samples, after collection, were immediately taken to the laboratory for processing and were centrifuged, and the Fe and Ferr concentrations in the supernatant and plasma were determined by spectrophotometry. Results: Although intrafollicular Fe and Ferr were similar to plasma, TRF was significantly higher in FF than in systemic circulation (p < 0.05). Follicular development does not modify the status of Fe in the mare. Conclusions: Based on this evidence, it is possible that the acquisition of this molecule possibly originated from a local de novo source, whereas their diffusion through ultrafiltration does not play a relevant role. These results provide new scientific insights into the status of follicle Fe, suggesting its involvement in normal ovarian functions in mares. [ABSTRACT FROM AUTHOR]

Objective: Prostate tumors, if prostate cancer or adenoma, represent a major public health challenge. Progress in research on inflammation has revealed a connection between inflammation, immunity, and cancer. In this context, this study aimed to find IL-6 signaling systemic abnormalities in the inflammatory tumor microenvironment. Material and methods: This study was case–controlled, multicentered, and included 86 patients, 43 diagnosed with BPH and 43 diagnosed with PCa, between January 2019 and January 2020. The study group was homogenous and the studied parameters were IL-6 complex (IL-6, soluble receptor IL-6R, soluble glycoprotein gp130), acute phase proteins (C reactive protein—CRP, acid alpha1 glycoprotein—AGPA, ferritin, albumin, transferrin), and oxidative stress-associated variables (malondialdehyde—MDA, carbonylated protein—PCO, 8-hydroxy-deoxy guanosine-8-OHdG, total antioxidant status—bTAS). Results: The inflammatory microenvironment determined IL-6 signaling alterations (over-regulation of sIL-6R and suppression of sgp130 in PCa versus BPH), changes in acute phase reaction markers (increased serum levels of CRP, AGPA, ferritin, and decreased serum levels of albumin, transferrin) that were much more evident in PCa compared to BPH, an imbalance between macromolecular oxidative damage (MDA, PCO, 8-OHdG) and endogenous antioxidants (TAS) that was more accentuated in PCa compared with BPH, and a representative association between the sIL-6R/sgp130 ratio and inflammatory/oxidative stress-related factors only in PCa patients. Conclusions: Our study reconfirms the anterior concept that IL-6 promotes prostatic tumorigenesis. In this study, we first demonstrated that a high sIL-6R/sgp130 ratio facilitates prostate malignancy. [ABSTRACT FROM AUTHOR]

Objective: Hemoglobin A1c (HbA1c), a key indicator of glycemic status over the last 3 months, is increasingly favored by clinicians to diagnose diabetes. Iron deficiency anemia (IDA), the most prevalent anemia worldwide, may alter HbA1c levels. However, data from eastern India are scarce, and existing studies offer conflicting results. This study aimed to investigate the impact of IDA on HbA1c levels in nondiabetics and to explore the correlation of HbA1c with hemoglobin (Hb), parameters of the iron profile, and red blood cell (RBC) indices. Methods: This cross-sectional analytical study compared 60 euglycemic patients with IDA, aged 18 to 60, to 60 age- and sex-matched euglycemic individuals without anemia. Data analysis was performed using SPSS version 25, with significance set at P < .05. Spearman's rho correlation coefficients examined correlations between Hb, serum iron, serum ferritin, total iron binding capacity (TIBC), transferrin saturation, packed cell volume (PCV), reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) with HbA1c. Multinomial logistic regression analyzed the relationships of HbA1c (dependent variable) with RBC indices and iron profile parameters (independent variables). Results: The mean (SD) HbA1c value for IDA patients was 6.5 (0.5)% compared to 5.13 (0.80)% for controls (P < .001). HbA1c showed significant negative correlations with Hb, PCV, serum iron, serum ferritin, transferrin saturation, MCV, MCH, and MCHC, while TIBC was positively correlated with HbA1c. Each unit decrease in Hb increased the likelihood of HbA1c values in the prediabetic and diabetic range by 2.61 times (95% CI = 1.65-3.50) and 2.40 times (95% CI = 1.81-3.77), respectively (P < 0.001). Conclusion: The study highlights a significant increase in HbA1c levels with the worsening of IDA in non-diabetics, indicating that IDA should be addressed before interpreting HbA1c results accurately. [ABSTRACT FROM AUTHOR]

Background The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) in children with cancer is not well studied. The detection of ID and IDA using sensitive laboratory tools may facilitate early diagnosis and treatment in this cohort. In this regard, reticulocyte hemoglobin (Ret-He) content serves as a cost-effective measurement that remains unaffected by inflammation, unlike the ferritin test. Aim The objective of this study is to analyze the role of Ret-He as a diagnostic tool to identify functional and absolute ID and IDA in children with cancer. Methods We conducted a cross-sectional study in children aged 0 to 18 years. Blood samples were collected to compare Ret-He values with iron status, reflected by hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), serum iron (SI), total iron binding capacity (TIBC), and ferritin and transferrin saturation. The overall discriminative power of Ret-He in detecting ID and IDA was assessed using receiver operating characteristic analysis. Results Of the 135 children included in the study, 58 (43.0%) had anemia. Among them, 20 (14.8%) had IDA (8 [5.9%] absolute and 12 [8.9%] functional), while 25 (18.5%) had ID (16 [11.9%] absolute and 9 [6.7%] functional). The Ret-He value was significantly related to iron status (p = 0.002). Ret-He was also shown to have a significant correlation with the abovementioned hematological parameters (p=0.000), except TIBC. Multivariate analysis revealed a significant relationship between Hb (p=0.051), MCH (p=0.000), and MCHC (p=0.001) and Ret-He. Ret-He values of 33.7, 32.7, 32.4 and 28.6 pg were established as optimal cut-off values to identify functional ID, absolute ID, functional IDA, and absolute IDA, respectively. Conclusion Ret-He is a reliable diagnostic tool for absolute and functional IDA in children with cancer. [ABSTRACT FROM AUTHOR]

As an antioxidative isoquinoline quaternary alkaloid, berberine (BR) is derived from certain types of plants, such as Berberis aristate, and despite its ability to inhibit cell proliferation, its poor aqueous solubility has limited its effectiveness in treatments. This study attempted to extract cellulose nanocrystals (CNCs) from ginger sticks to perform BR delivery and proceeded by characterizing the prepared CNCs and CNCs-BR by the results of DLS, TEM, FESEM, XRD, and FTIR. Moreover, various biophysical methods were used to investigate the interaction of BR-loaded CNCs with human serum holo-transferrin (HTF). The obtained outcomes confirmed the effectiveness of our spherical CNCs in reducing the size of the drug from 403.06 to 203.42 nm in CNCs-BR and consequently improving the solubility of BR. The XRD analysis approved the successful elimination of amorphous regions in cellulose, while the diminution of crystallinity index after the loading of BR indicated the occurrence of their interaction. The induced alterations in the functional groups and hydrophilicity enhancement of CNCs and CNCs-BR were displayed by FTIR. The fluorescence studies indicated the capability of CNCs-BR in interacting with HTF and quenching its fluorescence emission intensity through a static quenching process, which was revealed by the inverse correlation between Ksv values and temperature. In conformity to the results of synchronous fluorescence spectroscopy, CNCs-BR caused more changes in the vicinity of Trp residue in contrast to Tyr, while the FRET analysis determined the energy transfer between HTF and CNCs-BR to be 0.18, and their distance to be 2.41 nm. The drawn conclusion from these observations confirmed the suitability of CNCs as a carrier for BR along with their improved bioavailability caused by the effective interaction between HTF and BR-loaded CNCs. The results also showed that loading BR on CNCs not only improved its water solubility but also led to a sustained release behavior in a simulated gastrointestinal condition of the body. [ABSTRACT FROM AUTHOR]

This study aimed to observe the effects of acupuncture on iron metabolism in the hippocampus of rats with cerebral ischemia-reperfusion injury (CIRI) and to explore the mechanism of acupuncture on neural repair in CIRI rats. After general feeding for 3 days, 16 of 48 healthy Sprague–Dawley rats were selected according to a random number table to form a sham-occlusion group, and the models were prepared in the remaining rats. After successful modeling, the rats were randomized into model and acupuncture groups, with 16 rats in each group. The CIRI models were prepared using the modified Zea Longa suture-occlusion method. In the acupuncture group, the rats were fixed and acupuncture was delivered at "Shuigou" (GV26), "Dazhui" (GV14), and "Baihui" (GV20), and the needles were manipulated once every 15 min. In the sham-occlusion and model groups, rats were fixed without acupuncture. The intervention was performed for 30 min in each group, once every 12 h, seven times. The degree of neurological impairment was assessed by using the modified Garcia score. Cerebral blood flow (CBF) was monitored using a laser speckle blood flow imaging system. The cerebral infarction area ratio was measured using triphenyltetrazolium chloride staining. Ferric ion aggregation in brain tissue was noted using Prussian blue staining. The ferric ion and glutathione (GSH) contents of the hippocampal tissue on the ischemic side were detected using ferric ion and GSH kits. The protein expression of transferrin receptor 1 (TFR1), iron regulatory protein 2 (IRP2), and ferroportin (FPN) was detected via western blotting. (1) Before intervention, compared with the sham-occlusion group, the Garcia neurological score was significantly reduced in the model and acupuncture groups (both P < 0.01). After the intervention, compared with the sham-occlusion group, the Garcia neurological score in the model group decreased significantly (P < 0.01), and the score in the acupuncture group was elevated compared with the model group (P < 0.05). Compared to before the intervention, the Garcia neurological score increased after the intervention in the acupuncture group (P < 0.05). (2) Compared with the sham-occlusion group, in the model group, CBF was reduced, the infarct area was significantly enlarged, ferric ion aggregation increased in the hippocampus, the content of ferric ion increased, and that of GSH decreased significantly (both P < 0.01), while the protein expression of TFR1 and IRP2 was upregulated and that of FPN was downregulated (both P < 0.05). When compared with the model group, in the acupuncture group, CBF was increased, the infarct area was reduced (P < 0.01), the ferric ion aggregation was reduced in the hippocampus, the content of ferric ion decreased, and that of GSH increased significantly (P < 0.05, P < 0.01); the protein expression of TFR1 and IRP2 was downregulated and that of FPN was upregulated (both P < 0.05). Acupuncture can alleviate CIRI, which may be related to the regulation of iron homeostasis-associated transferrin in the hippocampus, attenuation of ferric ion aggregation in hippocampal tissue, reduction of lipid peroxidation, and inhibition of ferroptosis. [ABSTRACT FROM AUTHOR]

Women diagnosed with late‐stage ovarian cancer suffer a very high rate of mortality. Accordingly, it is imperative to detect and diagnose the disease as early as possible in its development. Achievement of this aim implies relatively large‐scale screening of women at an age of clinical significance through assay of biomarkers for disease present in blood or serum. Biosensor detection offers an attractive technology for the automated detection of such species. Among several biomarkers that have been identified that are present in patients with ovarian cancer, the only one that is commonly tested for in clinical use is cancer antigen 125, which is considered to be a poor biomarker for the disease. Here, we describe several biosensors that developed in the past decade for the detection of ovarian cancer biomarkers such as CA125, human epididymis protein 4 (HE4) and apolipoprotein A1. The challenges presented by the fabrication of biosensor devices for detecting ovarian cancer and the limited number of biosensors developed for this purpose are discussed. [ABSTRACT FROM AUTHOR]

Rebecca Baqiyyah Conway,1 Katherine A Pratte,2 Russell Paul Bowler,3 Kendra A Young,1 Gregory l Kinney,1 Erin Austin,4 Yisha Li,1 Donald McClain,5 John Hokanson,1 James D Crapo6 1Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA; 2Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO, 80206, USA; 3Department of Genomic Sciences, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA; 4Department of Mathematical and Statistical Sciences, Denver, University of Colorado, Denver, CO, 80204, USA; 5Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, USA; 6Department of Medicine, National Jewish Health, Denver, CO, 80206, USACorrespondence: Rebecca Baqiyyah Conway, Department of Epidemiology, University of Colorado, Anschutz Medical Campus, 13001 East 17th Place, Mail Stop B119, Aurora, CO, 80045, USA, Email rebecca.conway@cuanschutz.eduBackground: Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers.Methods: NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes. The SomaScan was used to determine the relative amounts of natural log-transformed ferritin, transferrin, and hepcidin.Findings: During an average of 5.6 years of follow-up, diabetes incidence was 7.9%. Ferritin at follow-up was higher in NHB than NHW participants (p = < 0.0001). Ferritin at follow-up was associated with increased diabetes risk (OR = 1.36, 95% CI = 1.08– 1.70), while transferrin was associated with decreased risk (OR = 0.25, 95% CI = 0.08– 0.77) controlling for age, sex, BMI, smoking pack-years, hepcidin, CRP, and Il-6. Race-specifically, increased risk associated with higher ferritin levels among NHB (OR = 1.56, 95% CI = 1.13– 2.16) but not NHW (OR = 1.22, 95% CI = 0.89– 1.68) participants. Sex-specifically, ferritin’s relationship was similar among NHB men and women and NHW women (ORs ranging from 1.41– 1.59); but not NHW men (OR = 0.98, 95% CI = 0.64– 1.49). Similarly, transferrin ORs non-significantly ranged from 0.19– 0.30 for NHB men and women and NHW women, but was significant for NHW men (OR = 0.07, 95% CI = 0.01– 0.63).Interpretation: Higher body iron stores is associated with increased diabetes risk among both NHB and NHW people. Unsuspected elevated iron stores may increase diabetes risk in NHB patients and should be monitored.Keywords: diabetes, iron, ferritin, transferrin, African Americans

Background and Aim: In females of various species and experimental animals, iron (Fe) status in follicular fluid (FF) is associated with local physiological reproductive events related to follicle development, steroidogenesis, and oocyte maturation. However, these mechanisms remain unknown. This study aimed to determine and compare the intrafollicular and plasma concentrations of Fe, ferritin (Ferr), and transferrin (TRF) in cycling mares. Materials and Methods: Sixty ovaries were collected during the breeding season from 30 clinically normal mares raised for slaughterhouse meat production. Blood samples were collected before slaughter. Follicles were classified into three categories according to size: Small (20–30 mm; n = 20), medium (≥31–40 mm; n = 20), and large (≥41 mm; n = 20). The FF samples, after collection, were immediately taken to the laboratory for processing and were centrifuged, and the Fe and Ferr concentrations in the supernatant and plasma were determined by spectrophotometry. Results: Although intrafollicular Fe and Ferr were similar to plasma, TRF was significantly higher in FF than in systemic circulation (p < 0.05). Follicular development does not modify the status of Fe in the mare. Conclusion: Based on this evidence, it is possible that the acquisition of this molecule possibly originated from a local de novo source, whereas their diffusion through ultrafiltration does not play a relevant role. These results provide new scientific insights into the status of follicle Fe, suggesting its involvement in normal ovarian functions in mares.

Abstract Gold nanoparticles (AuNPs) are potentially applicable in drug/nucleic acid delivery systems. Low toxicity, high stability, and bioavailability are crucial for the therapeutic use of AuNPs and they are mainly determined by their interactions with proteins and lipids on their route to the target cells. In this work, we investigated the interaction of two pegylated gold nanoparticles, AuNP14a and AuNP14b, with human serum proteins albumin (HSA) and transferrin (Tf) as well as dimyristoyl-phosphatidylcholine (DMPC) liposomes, which can be a representative of biomembranes. We showed that AuNP14a/b interacted with HSA and Tf changing their electrical, thermodynamic, and structural properties as evidenced by dynamic light scattering, zeta potential, transmission electron microscopy, circular dichroism, fluorescence quenching, and isothermal titration calorimetry. These nanoparticles penetrated the DMPC membrane suggesting their ability to reach a target inside the cell. In most of the effects, AuNP14b was more effective than AuNP14a, which might result from its more positive charge. Further studies are needed to evaluate whether the interaction of AuNP14a/b with HSA and Tf is safe for the cell/organism and whether they may safely penetrate natural membranes.

Adaptive restructuring gets disrupted due to a reduction in the body’s reserve capacity at increased stress on the functional systems in response to the combined effects of adverse factors, including climatic. Determination of the state of blood transport systems and immune homeostasis broadens our understanding of how human body systems operate under adverse conditions of the North. The purpose of this article was to assess the state of the transport components of the blood system in relation to the immune status of the population of the European North of Russia. Materials and methods. A survey of 789 residents of the Arkhangelsk Region aged 21 to 55 years was conducted and their blood system parameters were analysed taking into account the levels of haptoglobin, transferrin, immunoglobulins and lipid transport complexes with their structural ligands. Results. Residents of the European North of Russia showed increased levels of transferrin in 31.8 %, IgM in 7.6 %, IgE in 7.8 % and low-density lipoproteins in 10.2 % of cases, as well as a deficit in IgA in 55.6 % and high-density lipoprotein apoA-I ligand in 56.2 % of cases. Elevated blood transferrin concentrations are associated with low CD71+ lymphocyte count, which reflects the inhibition of activation and proliferation processes when the signal from the CD3+ receptor is blocked. A decrease in the level of transferrin CD71+ receptors on lymphocytes is manifested in disturbed immunoglobulin class switching with the formation of IgA deficit, which is compensated by IgM and IgE. Increased immunoglobulin content ensures effective binding of metabolic products with autoantigen properties (low-density lipoproteins) when the functional properties of high-density lipoproteins are impaired due to the structural apoA-I deficit. Determination of the transport components of the blood system in relation to the state of the immune system is informative for assessing the risk of disruption of adaptive mechanisms.

Von Hippel-Lindau protein (VHL) is essential to hypoxic regulation of cellular processes. VHL promotes proteolytic clearance of hypoxia-inducible transcription factors (HIFs) that have been modified by oxygen-dependent HIF-prolyl hydroxylases. A homozygous loss-of-function VHLR200W mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia-sensing. Homozygous VHLR200W results in accumulation of HIFs that increase transcription of the erythropoietin gene and raise hematocrit. Phlebotomies reduce hematocrit and hyperviscosity symptoms. However, the major cause of morbidity and mortality in Chuvash erythrocytosis is thrombosis. Phlebotomies cause iron deficiency, which may further elevate HIF activity and transferrin, the HIF-regulated plasma iron transporter recently implicated in thrombogenesis. We hypothesized that transferrin is elevated in Chuvash erythrocytosis, and that iron deficiency contributes to its elevation and to thrombosis. We studied 155 patients and 154 matched controls at steady state and followed them for development of thrombosis. Baseline transferrin was elevated, and ferritin reduced in patients. VHLR200W homozygosity and lower ferritin correlated with higher erythropoietin and transferrin. During 11 years of follow-up, risk of thrombosis increased 8.9-fold in patients versus controls. Erythropoietin elevation, but not hematocrit or ferritin, correlated with thrombosis risk. Unexpectedly, transferrin elevation associated with reduced rather than increased thrombosis risk. The A allele of the promoter EPO single nucleotide polymorphisms (SNP), rs1617640, associated with elevated erythropoietin and increased thrombosis risk, whereas the A allele of the intronic TF SNP, rs3811647, associated with higher transferrin and protection from thrombosis in patients. Our findings suggest an unexpected causal relationship between increased transferrin and protection from thrombosis in Chuvash erythrocytosis.

BACKGROUND: It has been found that abnormal apoptosis of bone tissue cells induced by abnormal iron metabolism plays an important role in the progression of osteoporosis. OBJECTIVE: To investigate the effect of naringin on iron metabolism and cell apoptosis in bone tissue of rats with osteoporosis. METHODS: Fifty 2-month-old female Sprague-Dawley rats were randomly divided into five groups with 10 rats in each group: sham group, osteoporosis group, naringin low-dose group, naringin high-dose group, and naringin high-dose+DKK-1 group. Except for the sham group, rat models of osteoporosis were established by removing bilateral ovarian tissues in the other groups. At 8 weeks after modeling, rats in the naringin low- and high-dose groups were given 100 and 400 mg/kg/d naringenin by gavage, respectively, and rats in the naringenin high dose+DKK-1 group were given 400 mg/kg/d naringin by gavage and subcutaneous injection of 25 mg/kg/d DKK-1, an inhibitor of the Wnt1 signaling pathway, for 7 consecutive days. Relevant indexes were detected after administration. RESULTS AND CONCLUSION: Compared with the osteoporosis group, naringin could enhance the bone mineral density and serum calcium and superoxide dismutase levels in rats (P < 0.05), and reduce the serum levels of osteocalcin, malondialdehyde, and phosphorus (P < 0.05), while DKK-1 could partially inhibit the interventional effect of naringin (P < 0.05). Results from Micro-CT scanning, hematoxylin-eosin and TUNEL staining showed that compared with the osteoporosis group, naringin significantly improved bone microstructure and reduced the rate of cell apoptosis, while DKK-1 partially inhibited the interventional effect of naringin. Immunofluorescence staining results showed that compared with the osteoporosis group, naringin could reduce the oxygen content, anti-tartaric acid phosphatase expression, and elevate the expression of alkaline phosphatase in active tibia tissues (P < 0.05), while DKK-1 could partially inhibit the interventional effect of naringin (P < 0.05). Results from Prussian blue staining and immunohistochemical staining showed that compared with the osteoporosis group, naringin reduced iron deposition in bone and liver tissues as well as the expression of transferrin receptor 1 (P < 0.05), and elevated the protein expression of ferroportin 1 (P < 0.05) in bone tissue, and DKK-1 partially inhibited the intervention of naringin (P < 0.05). PCR and western blot assay of tibia specimens showed that compared with the osteoporosis group, naringin decreased the expression of anti-tartrate acid phosphatase, transferrin receptor 1 and Bax (P < 0.05), and elevated the expression of alkaline phosphatase, ferroportin 1, Bcl-2, Wnt1 and β-catenin (P < 0.05), while DKK- 1 partially inhibited the interfering effect of naringin (P < 0.05). To conclude, naringin inhibits the progression of osteoporosis by reducing iron deposition and apoptosis rate in bone tissue, which may be related to the activation of the Wnt1 signaling pathway. [ABSTRACT FROM AUTHOR]

Free iron in human serum or non-transferrin-bound iron (NTBI) can generate free radicals and lead to oxidative damage. Moreover, it is highly toxic to various tissues and a vital biomarker related to the iron-loading status of thalassemia and Alzheimer's patients. In NTBI in healthy individuals, NTBI levels are typically less than 1 µM; current NTBI analysis usually requires advanced instrumentation and many-step sample pretreatment. To address this issue, we employed our invented BODIPY derivative, BODIPY-PH, as a fluorescence probe and trapped it onto the microcentrifuge tube lid using tapioca starch. The fluorescence intensity of BODIPY-PH increased with increasing NTBI concentration (turn-on). The developed portable reaction chamber facilitates rapid analysis (∼5 min) using small sample volumes (10 μL sample in a total volume of 600 μL). Under optimum conditions, using the sample-developed portable fluorescence device and fluorescence spectrometer, we achieved impressive limits of detection (LOD) of 0.003 and 0.0015 μM, respectively. Furthermore, the developed sensors show relatively high selectivity toward Fe3+ over other metal ions and biomolecules (i.e., Fe2+, Cr3+, Cu2+, and glucose). The sensor performance in serum samples of thalassemia patients exhibited no significant difference compared to the labeled value (obtained from standard methods). Overall, the developed fluorescence sensor is suitable for determining NTBI and offers high sensitivity, high selectivity, and a short incubation time (5 min). Moreover, the method requires a limited number of reagents, is simple to use, and uses low-cost equipment to determine NTBI in human serum samples. [ABSTRACT FROM AUTHOR]

Background: According to reports, iron status has been associated with the risk of bone and joint-related diseases. However, the exact role of iron status in the development of these conditions remains uncertain. Method: We obtained genetic data on iron status, specifically serum iron, ferritin, transferrin saturation (TSAT), and transferrin, as well as data on five common bone and joint-related diseases (osteoarthritis, osteoporosis, rheumatoid arthritis [RA], ankylosing spondylitis [AS], and gout) from independent genome-wide association studies involving individuals of European ancestry. Our primary approach for causal estimation utilized the inverse variance weighted (IVW) method. To ensure the reliability of our findings, we applied complementary sensitivity analysis and conducted reverse causal analysis. Result: Using the IVW method, we revealed a positive causal relationship between ferritin levels and the risk of osteoarthritis (OR [95% CI], 1.0114 [1.0021-1.0207]). Besides, we identified a protective causal relationship between serum iron levels and TSAT levels in the risk of RA (OR [95% CI] values of serum iron and TSAT were 0.9987 [0.9973-0.9999] and 0.9977 [0.9966-0.9987], respectively). Furthermore, we found a positive causal relationship between serum iron levels and the risk of AS (OR [95% CI], 1.0015 [1.0005-1.0026]). Regarding gout, both serum iron and TSAT showed a positive causal relationship (OR [95% CI] values of 1.3357 [1.0915-1.6345] and 1.2316 [1.0666-1.4221] for serum iron and TSAT, respectively), while transferrin exhibited a protective causal relationship (OR [95% CI], 0.8563 [0.7802-0.9399]). Additionally, our reverse causal analysis revealed a negative correlation between RA and ferritin and TSAT levels (OR [95% CI] values of serum iron and TSAT were 0.0407 [0.0034-0.4814] and 0.0049 [0.0002-0.1454], respectively), along with a positive correlation with transferrin (OR [95% CI], 853.7592 [20.7108-35194.4325]). To ensure the validity of our findings, we replicated the results through sensitivity analysis during the validation process. Conclusion: Our study demonstrated a significant correlation between iron status and bone and joint-related diseases. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency (VDD) and anemia are both public health nutrition concerns. An association between VDD and anemia has been suggested in various healthy and diseased populations. The current study aimed to elucidate the effect of VDD on iron status in children with type I diabetes mellitus (T1DM). The study recruited two groups of children with T1DM: control group comprised of 38 T1DM children with sufficient vitamin D (> 30 ng/ml) and a case group, consisted of 52 T1DM children with VDD (< 20 ng/ml). Both groups had comparable gender, age, BMI, and disease duration. The laboratory measurements included analysis of blood indices, markers of iron metabolism, hepcidin and inflammatory markers included interleukin 6 (IL-6) and C-reactive protein (CRP). Compared to control group, T1DM children with VDD differs specifically in terms of some markers of blood indices, such as decreased hemoglobin and increased red blood cell distribution width. Moreover, decreased serum iron, ferritin, total iron-binding capacity and transferrin along with elevated inflammatory markers were observed in case group. Results of the study indicated that VDD had increased the risk of iron deficiency anemia in children with T1DM as well as inflammatory related anemia. Furthermore, in T1DM children, VDD had raised the incidence of both absolute and functional iron deficiency, with greater incidence of the former. This study may indicate that VDD may be a risk factor that may worsen iron deficiency anemia in T1DM. [ABSTRACT FROM AUTHOR]

A novel microfluidic paper-based analytical device with dual colorimetric and electrochemical detection (dual μPAD) was developed for the assessment of transferrin saturation (TSAT) in samples from ischemic stroke patients. TSAT was calculated from the ratio between transferrin-bound iron, which was colorimetrically measured, and the total iron-binding capacity, which was electrochemically measured. To this end, a μPAD was smartly designed, which integrated both colorimetric and electrochemical detection reservoirs, communicating via a microchannel acting as a chemical reactor, and with preloading/storing capabilities (reagent-free device). This approach allowed the dual and simultaneous determination of both parameters, providing an improvement in the reliability of the results due to an independent signal principle and processing. The μPADs were validated by analyzing a certified reference material, showing excellent accuracy (Er ≤ 5%) and precision (RSD ≤ 2%). Then they were applied to the analysis of diagnosed serum samples from ischemic stroke patients. The results were compared to those provided by a free-interference method (urea-PAGE). Impressively, both methods exhibited a good correlation (r = 0.96, p < 0.05) and no significant differences were found between them (slope 1.0 ± 0.1 and the intercept 1 ± 4, p < 0.05), demonstrating the excellent accuracy of our approach during the analysis of complex samples from ischemic stroke patients, using just 90 μL of clinical samples and taking less than 90 min in comparison with the 18 hours required by the urea-PAGE approach. The developed fully integrated colorimetric-electrochemical μPAD is a promising ready to use reagent-free device for the point-of-care testing of TSAT, which can be used to assist physicians in the fast diagnosis and prognosis of ischemic strokes, where the decision-time is crucial for the patient's survival. [ABSTRACT FROM AUTHOR]

Gallium-based therapy has been considered a potentially effective cancer therapy for decades and has recently re-emerged as a novel therapeutic strategy for the management of glioblastoma tumors. Gallium targets the iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation and gaining intracellular access through transferrin-receptor-mediated endocytosis. Mechanistically, it is believed that gallium inhibits critical iron-dependent enzymes like ribonucleotide reductase and NADH dehydrogenase (electron transport chain complex I) by replacing iron and removing the ability to transfer electrons through the protein secondary structure. However, information regarding the effects of gallium on cellular iron metabolism is limited. As mitochondrial iron metabolism serves as a central hub of the iron metabolic network, the goal of this study was to investigate the effects of gallium on mitochondrial iron metabolism in glioblastoma cells. Here, it has been discovered that gallium nitrate can induce mitochondrial iron depletion, which is associated with the induction of DNA damage. Moreover, the generation of gallium-resistant cell lines reveals a highly unstable phenotype characterized by impaired colony formation associated with a significant decrease in mitochondrial iron content and loss of the mitochondrial iron uptake transporter, mitoferrin-1. Moreover, gallium-resistant cell lines are significantly more sensitive to radiation and have an impaired ability to repair any sublethal damage and to survive potentially lethal radiation damage when left for 24 h following radiation. These results support the hypothesis that gallium can disrupt mitochondrial iron metabolism and serve as a potential radiosensitizer. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application. [ABSTRACT FROM AUTHOR]

Iron deficiency in pregnancy is related to many poor health outcomes, including anemia and low birth weight. A small number of previous studies have identified maternal body mass index (BMI) as a potential risk factor for poor iron status. Our objective was to examine the association between pre-pregnancy BMI, iron status, and anemia in a nationally representative sample of US adult women. We used data from the National Health and Nutrition Examination Survey (NHANES; 1999–2010) for pregnant women ages 18–49 years (n = 1156). BMI (kg/m2) was calculated using pre-pregnancy weight (self-reported) and height (measured at examination). Iron deficiency (ID) was defined as total body iron (calculated from serum ferritin and transferrin receptor using Cook's equation) < 0 mg/kg and anemia as hemoglobin < 11 g/dL. Associations were examined using weighted linear and Poisson regression models, adjusted for confounders (age, race/ethnicity, education, and trimester). Approximately 14% of pregnant women had ID and 8% had anemia in this sample. Ferritin and total body iron trended slightly lower (p = 0.12, p = 0.14) in women with pre-pregnancy BMI in the normal and overweight categories compared to the underweight and obese categories; hemoglobin concentrations were similar across BMI groups (p = 0.76). There were no differences in the prevalence of ID or anemia in women with pre-pregnancy overweight and obesity (ID: overweight, adjusted prevalence ratio (PR) = 1.27, 95%CI: 0.89–1.82; obesity, PR = 0.75, 95%CI: 0.39–1.45; anemia: overweight, PR = 1.08, 95%CI: 0.53–2.19; obesity, PR = 0.99, 95%CI: 0.49–2.01) compared to women with a normal BMI. Findings from these US nationally representative data indicate that total body iron, serum hemoglobin, ID, and anemia in pregnancy do not differ by pre-pregnancy BMI. Since ID and anemia during pregnancy remain significant public health concerns, NHANES should consider measuring current iron status in upcoming cycles. [ABSTRACT FROM AUTHOR]

Objective: The intricate connection between serum iron levels, adipose tissue, and metabolic parameters has been the subject of many clinical studies. In this direction, the aim of this study was to evaluate the relationship between the Dysfunctional Adiposity Index (DAI) and serum iron status. Methods: This single-center retrospective study included 32 women with iron deficiency (ID) as a patient group and 45 women without ID as a control group. The individuals' demographic data, laboratory tests, height, weight, and waist circumference (WC) measurements were obtained from our hospital's records. DAI was calculated by the following formula: [WC/[24.02 + [2.37 * Body Mass Index (BMI)]] * [triglyceride (mmol/L) / 1.32] * [1.43 / highdensity lipoprotein (mmol/L)]]. Results: We found statistically significant differences between the two groups in terms of hemoglobin values and iron parameters, such as ferritin, total iron-binding capacity, and transferrin saturation (p<0.001). While there was a statistically significant difference in waist circumference between the groups (p<0.001), the other DAI components did not differ. We also detected a negative correlation among DAI and serum iron, ferritin levels, and transferrin saturation (r=-0.321, p=0.004; r=-0.416, p<0.001; r=0.359, p=0.001, respectively). Conclusion: This study tries to add information to the current literature on the interaction between serum iron parameters and DAI as a metabolic risk marker. The results of our study emphasize the close relationship between iron deficiency and increased waist circumference, which are very common and constitute global health problems, and underline the importance of the interaction of these two entities in clinical evaluation. However, the contradictory results of the existing literature highlight the complexity of this relationship, pointing to the need for larger, well-designed prospective studies to provide a more detailed understanding of the role of serum iron parameters, especially among individuals with high waist circumference and DAI levels. [ABSTRACT FROM AUTHOR]

• Iron deficiency is a common comorbidity in cystic fibrosis, despite CFTR modulators. • Highly-effective modulator therapy is associated with improved iron deficiency labs. • CFTR modulator therapy is associated with improved hemoglobin. • Sex differences exist in iron deficiency in cystic fibrosis. Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. In a multicenter retrospective cohort study across 4 United States CF centers 2012–2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 μg/dL (<10.7 μmol/L). A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3–10.6 %; p < 0.0001) and +34.4 μg/dL serum iron (95 % CI, +26.7–42.1 μg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8–8.0 %; p = 0.0001) and +22.1 μg/dL serum iron (95 % CI, +13.5–30.8 μg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9–14.8 %; p < 0.0001) and +46.0 μg/dL serum iron (95 % CI, +33.3–58.8 μg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin). [ABSTRACT FROM AUTHOR]

Simple Summary: This study presents data on the immunohistochemical expression of key iron metabolism proteins in non-neoplastic and neoplastic canine testes. Iron is crucial for spermatogenesis, and its regulation in testicular cells is essential for normal function. This study confirms that Sertoli cells and Transferrin Receptor 1 (TfR1) play significant roles in iron uptake in dogs, aligning with findings in humans and mice. However, it highlights a unique expression of nuclear receptor coactivator 4 (NCOA4) in canine Sertoli cells, suggesting a specific role in iron recycling through ferritinophagy. Differences in iron metabolism were observed in various canine testicular tumors. Higher TfR1 and NCOA4 expressions were noted in Leydig cell tumors and diffuse seminomas, indicating a reliance on iron for tumor growth. The altered expression of iron-related proteins in tumors underscores their potential as therapeutic targets. Targeting TfR1 and utilizing iron-modulating therapies shows promise. Further research is needed to explore the therapeutic potential of modulating iron metabolism in canine testicular cancers. Iron is a key element in spermatogenesis; its metabolic pathway in the testis is strictly regulated. Alterations in iron metabolism are linked to various diseases, including cancer, and changes in iron metabolism-related proteins have been observed in multiple human, mouse and canine tumors. There is limited knowledge about iron metabolism in canine non-neoplastic and neoplastic testes. This study aimed to explore the immunohistochemical expression of molecules involved in iron uptake and storage [Transferrin Receptor 1 (TfR1), ferritin (FTH1), nuclear receptor coactivator 4 (NCOA4)] and PCNA in canine non-neoplastic and neoplastic testicular samples. Non-neoplastic testes showed moderate TfR1 expression in developing germ cells and Sertoli cells, high NCOA4 cytoplasmic immunostaining in the Sertoli cells and occasional cytoplasmic immunopositivity for FTH1 in the spermatogonia and Sertoli cells. In contrast, Leydig cell tumors (LCTs) and Diffuse Type Seminoma (DSEM) exhibited increased expression of TfR1, along with higher PCNA expression, suggesting a higher iron need for proliferation. Intratubular Type Seminoma (ITSEM) showed a higher FTH1 expression, indicating greater iron storage, while the increased NCOA4 expression in the LCTs and DSEM suggested ferritinophagy to release iron for proliferation. Sertoli cell tumors (SCTs) showed only NCOA4 expression. These preliminary findings highlight potential molecular targets for developing new anti-neoplastic treatments in canine testicular tumors. [ABSTRACT FROM AUTHOR]

Brain iron increases in several neurodegenerative diseases are associated with disease progression. However, the causes of increased brain iron remain unclear. This study investigates relationships between subcortical iron, systemic iron and inflammatory status. Brain magnetic resonance imaging (MRI) scans and blood plasma samples were collected from cognitively healthy females (n = 176, mean age = 61.4 ± 4.5 years, age range = 28–72 years) and males (n = 152, mean age = 62.0 ± 5.1 years, age range = 32–74 years). Regional brain iron was quantified using quantitative susceptibility mapping. To assess systemic iron, haematocrit, ferritin and soluble transferrin receptor were measured, and total body iron index was calculated. To assess systemic inflammation, C‐reactive protein (CRP), neutrophil:lymphocyte ratio (NLR), macrophage colony‐stimulating factor 1 (MCSF), interleukin 6 (IL6) and interleukin 1β (IL1β) were measured. We demonstrated that iron levels in the right hippocampus were higher in males compared with females, while iron in the right caudate was higher in females compared with males. There were no significant associations observed between subcortical iron levels and blood markers of iron and inflammatory status indicating that such blood measures are not markers of brain iron. These results suggest that brain iron may be regulated independently of blood iron and so directly targeting global iron change in the treatment of neurodegenerative disease may have differential impacts on blood and brain iron. [ABSTRACT FROM AUTHOR]

Background: Thalassemia is a hemoglobin synthesis disorder that causes patients to need lifelong blood transfusions, leading to iron overload and alter organ function, including the liver. Hepcidin, produced by the liver, plays a role in iron homeostasis and should be increased in excess iron stores. However, the level decreases in thalassemia due to some factors, such as ineffective erythropoiesis and liver damage. Recent publications revealed that hepcidin could be associated with iron overload and also a marker of liver diseases. Objective: To analyse the correlation between hepcidin level, markers of iron overload, and liver damage in β-thalassemia major. Methods: This cross-sectional study included all β-thalassemia major age 2-18 years admitted to Dr. Mohammad Hoesin Hospital, Palembang, South Sumatera, who underwent blood transfusions from March to August 2022. We measured the level of iron overload markers, hepcidin, liver function test (LFT), and performed liver ultrasonography (USG). Results: Of 97 subjects, median hepcidin level was 10.01 ng/mL and 68% of the subjects showed a decrease. The iron overload parameters were evaluated from serum iron levels (P=0.13), ferritin levels (P=0.90), and transferrin saturation (P=0.29) and 24.7% had abnormal liver USG findings. Spearman's correlation revealed that only direct bilirubin (DB) (r=0.35; P=0.001) and liver USG (r=0.20; P=0.05) had positive correlations with decreased levels of hepcidin. Also, it had 91.7% sensitivity in predicting liver damage from ultrasound. Conclusion: The hepcidin level was not significantly associated with iron overload markers. [ABSTRACT FROM AUTHOR]

Overdose of acetaminophen (APAP) produces fulminant hepatic necrosis. The underlying mechanism of APAP hepatotoxicity involves mitochondrial dysfunction, including mitochondrial oxidant stress and the onset of mitochondrial permeability transition (MPT). Reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity, and iron is a critical catalyst for ROS formation. This review summarizes the role of mitochondrial ROS formation in APAP hepatotoxicity and further focuses on the role of iron. Normally, hepatocytes take up Fe3+-transferrin bound to transferrin receptors via endocytosis. Concentrated into lysosomes, the controlled release of iron is required for the mitochondrial biosynthesis of heme and non-heme iron-sulfur clusters. After APAP overdose, the toxic metabolite, NAPQI, damages lysosomes, causing excess iron release and the mitochondrial uptake of Fe2+ by the mitochondrial calcium uniporter (MCU). NAPQI also inhibits mitochondrial respiration to promote ROS formation, including H2O2, with which Fe2+ reacts to form highly reactive •OH through the Fenton reaction. •OH, in turn, causes lipid peroxidation, the formation of toxic aldehydes, induction of the MPT, and ultimately, cell death. Fe2+ also facilitates protein nitration. Targeting pathways of mitochondrial iron movement and consequent iron-dependent mitochondrial ROS formation is a promising strategy to intervene against APAP hepatotoxicity in a clinical setting. [ABSTRACT FROM AUTHOR]

Prolonged exposure to hydroquinone (HQ), a metabolite of benzene, can cause severe haematologic disorders in humans. However, the mechanism is still unclear. In the present study, we investigated whether HQ can induce haematological diseases through ferroptosis, which is another form of cell death apart from apoptosis. The results showed that HQ inhibited the viability of Jurkat cells in a dose-dependent and time-dependent manner. The half inhibitory concentrations (IC50s) of HQ-treated Jurkat cells for 12 h, 24 h and 48 h were 107.16 μmol/L, 33.29 μmol/L, and 14.78 μmol/L. The exposure of Jurkat cells to HQ increased intracellular Fe 2 + , malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels and down-regulated glutathione (GSH) levels. We used erastin-treated cells as a positive control and cells treated with HQ combined with deferoxamine mesylate (DFO) and ferrostain-1 (Fer-1)-treated cells as the negative controls. DFO and Fer-1 partially restored the degradation of cell viability and GSH content and the accumulation of Fe 2 + , MDA and lipid ROS caused by HQ. In addition, we found that cellular mitochondria in the HQ-treated group showed a decrease in volume, an increase in the density of the bilayer membrane and a decrease or disappearance of mitochondrial cristae. Changes in the erastin-treated group were similar to those in the HQ-treated group. We inferred that HQ induces ferroptosis in Jurkat cells. Subsequently, we found that HQ up-regulated the levels of transferrin receptor 1 (TFRC) mRNA and protein expression and down-regulated FTH1, SLC7A11 and synthetic substrate of antioxidant enzyme 4 (GPX4) mRNA levels and protein expression levels. However, the exposure of Jurkat cells to HQ with DFO and Fer-1 alleviated these changes. Notably, the activation of TFRC and the inhibition of FTH1 and System X c − (cystine–glutamate reverse transporter protein) /GPX4 were associated with HQ-induced ferroptosis. These results provide novel insights into how HQ exacerbates haematopoietic cytotoxicity and provide potential targets for the prevention of HQ-induced diseases. [ABSTRACT FROM AUTHOR]