Iron-depleting nutritional immunity controls extracellular bacterial replication in Legionella pneumophila infections.

The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires' disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus-a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell-is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz's group unequivocally established that Legionella does not replicate extracellularly during infection-a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires' disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis.

Ferric citrate hydrate improves transferrin saturation in patients with low levels of transferrin saturation undergoing hemodialysis.

Although it has been established that patients with chronic kidney disease and iron deficiency, as indicated by a transferrin saturation of < 20%, are at increased risk of all-cause mortality and cardiovascular events, the optimal management of such patients has not yet been determined. In this post hoc subgroup analysis, we aimed to clarify the effect of ferric citrate hydrate on transferrin saturation in patients with chronic kidney disease and low transferrin saturation (< 20%) undergoing hemodialysis. To accomplish this, we extracted the relevant data on a subset of patients drawn from two previous studies: the ASTRIO study (A Study examining the contribution to Renal anemia treatment with ferric citrate hydrate, Iron-based Oral phosphate binder, UMIN000019176) and a post-marketing surveillance study. The subset of patients used for the present study were those with baseline transferrin saturation < 20%. We found that administration of ferric citrate hydrate increased transferrin saturation and maintained transferrin saturation at approximately 30%. However, because we did not have access to data on all-cause mortality or cardiovascular events, we could not ascertain whether the frequency of these outcomes was reduced in parallel with improvements in transferrin saturation. Further large studies are required.

Acute-phase proteins as indicators of disease severity and mortality in COVID-19 patients.

The aim of the study was to conduct of relationship of acute-phase proteins (APPs) with the severity of COVID-19 defined by National Institutes of Health and according to the criteria of MEWS scale, with the presence of a cytokine storm, oxygen therapy and patient survival. We enrolled 96 patients with COVID-19 and 30 healthy people. The samples were taken on the day of admission and after 9 days on average. Not only commonly used APPs such as CRP, procalcitonin and ferritin and also rarely assayed proteins such as transferrin, haptoglobin, α1-acid glycoprotein and α1-antitrypsin, were tested in the study. The levels of APPs depends on the severity of COVID-19 disease, on the presence of cytokine storm and used oxygen therapy. The greatest APPs changes occurred in the most advanced form of the disease, with the presence of a cytokine storm and the most intense oxygen therapy. The results obtained from MEWS scale were not consistent with National Institutes of Health scores. Studies in the second samples showed the quenching of the acute phase reactions and the effectiveness of oxygen therapy. Only two of the examined APPs i.e. procalcitonin and transferrin, differed between surviving and non-surviving patients, and these two predispose to the role of prognostic factors in Covid-19. In conclusion, the concentration of not all acute-phase proteins depends on the severity of COVID-19 disease, presence of cytokine storm, the used of oxygen therapy and only some of them (procalcitonin and transferrin) are related to the survival outcomes. Of the newly tested acute-phase proteins, only transferrin shows significance as a marker of disease severity and mortality in COVID-19 disease.

Preparation of transferrin-targeted temozolomide nano-micelles and their anti-glioma effect.

Objectives: This study aims to develop brain-targeted temozolomide (TMZ) nanograins using the biodegradable polymer material PEG-PLA as a carrier. The model drug TMZ was encapsulated within the polymer using targeted nanotechnology. Key characteristics such as appearance, particle size, size distribution, drug loading capacity, in vitro release rate, stability, and anti-tumor effects were systematically evaluated through in vitro experiments. Methods: Transmission electron microscopy (TEM) and Malvern size analyzer were employed to observe the morphological and particle size features of the TMZ nanospheres at various time points to assess stability. The effects of TMZ nanograins on glioma cell viability and apoptosis were evaluated using MTT assays and flow cytometry. Results: The targeted TMZ nano-micelles were successfully synthesized. After loading and targeted modifications, the particle size increased from 50.7 to 190 nm, indicating successful encapsulation of TMZ. The average particle size of the nano-micelles remained stable around 145 ± 10 nm at 1 day, 15 days, and 30 days post-preparation. The release rate of the nano-micelles was monitored at 2 h, 12 h, 24 h, and 48 h post-dialysis, ultimately reaching 95.8%. Compared to TMZ alone, the TMZ-loaded PEG-PLA nano-micelles exhibited enhanced cytotoxicity and apoptosis in glioma cells. This was accompanied by increased mitochondrial membrane potential and reactive oxygen species (ROS) levels following treatment with the TMZ nano-micelles. Conclusions: TMZ-loaded nano-micelles demonstrated a gradual release profile and significantly enhanced inhibitory effects on human glioma U251 cells compared to TMZ alone. The findings suggest that TMZ-loaded PEG-PLA nano-micelles may offer a more effective therapeutic approach for glioma treatment.

Association between serum transferrin saturation levels and heart failure in adults aged ≥40 years: a cross-sectional study based on NHANES (2017-2020.03).

Background: Limited data are available regarding the association between serum transferrin saturation (TSAT) levels and heart failure (HF). Methods: We utilized data from National Health and Nutrition Examination Survey (NHANES) 2017- 2020.03 for analysis. Data on TAST, HF and covariates were extracted and analyzed. Weighted logistic regression and subgroup analysis were used to explore the independent association between TSAT and HF. Furthermore, interaction tests were also carried out to evaluate the strata differences. We subsequently assessed whether there was a non-linear relationship between the 2 using Restricted cubic spline (RCS) and threshold effect models. Result: A total of 282 (3.87%) participants were identified to have HF. Among the total population, participants with HF had significantly lower TSAT levels compared to those without HF (24.63 vs. 27.95, P = 0.001). After fully adjusting for potential confounders, weighted multiple logistic regression models revealed a 2.6% reduced in the risk of HF when each unit of TSAT increased. There was also a negative association between elevated TSAT and developed risk of HF in the quartile groups (Q1 OR:1.00; Q2 OR: 0.924 [95%CI:0.593,1.440]; Q3 OR: 0.515 [95%CI:0.298,0.891]; Q4 OR:0.411 [95%CI:0.201,0.839]). The subgroup analysis results remained consistent across strata, with a strong negative correlation between TSAT and HF. Interaction tests showed no dependence on gender, age, Body Mass Index, race, diabetes, hypertension, hyperlipidemia, ratio of family income to poverty and education for this negative association between TSAT and HF (all p for interaction >0.05). The RCS and threshold effect models indicated a linear negative correlation between TSAT and HF, which was more pronounced when TSAT under 40%. Conclusion: Overall, these findings suggest a consistent and negative association between TSAT levels and the presence of HF among middle-aged and older adults in the United States.

Association between iron metabolism markers and triglyceride-glucose index: A cross-sectional study in China Health and Nutrition Survey.

Iron metabolism plays an important role in insulin resistance, and the triglyceride-glucose (TyG) index has been proposed in recent years as a more accessible and cost-effective marker for insulin resistance. This study aims to evaluate the association between iron metabolism markers, including ferritin (FER), transferrin (TRF), and transferrin receptor (TFR), and the TyG index. A total of 6524 Chinese individuals aged between 18 and 75 years were included in this study. Multivariable linear models were used to investigate the association between FER, TRF, and TFR levels, and the TyG index. Further subgroup analyses stratified by age and sex were also performed. There was a positive association between FER and TRF levels and the TyG index in all 3 multivariable linear regression models, regardless of stratification by sex and age. Additionally, TFR was positively associated with the TyG index among females and those aged ≥45 years, but not among males and those aged <45 years. Our findings reveal a positive association between FER and TRF levels and the TyG index in a Chinese population, while the association between TFR levels and the TyG index showed different patterns depending on age and gender.

[Hematological toxicity of disinfection by-product iodoacetic acid].

OBJECTIVE: To clarify the effect of iodoacetic acid(IAA) on the blood system and electrolyte balance, hence further study the intrinsic relation of blood routine parameters and electrolyte levels, major hematological toxicity effects and their pattern after IAA treatment. METHODS: Forty-eight 21-day-old male SPF grade Sprague-Dawley(SD) rats were gavaged with 0, 6.25, 12.5 and 25 mg/kg IAA for 31 days. After detections of blood routine and plasma inorganic ion levels, Spearman correlation coefficients were performed to evaluate their relationship. Changes in ferritin, transferrin, hepcidin, C-reactive protein and glyceraldehyde-3-phosphate dehydrogenase(GAPDH) were assessed by enzyme-linked immunosorbent assays. The EDock bioinformatics tool was applied to docking model of IAA and GAPDH. RESULTS: Compared to the control, high-dose IAA exposure had obvious inhibition effect on rat leukocytes with the total number declined by 51.12%, and neutrophils were particularly sensitive to IAA with the number reduced by 73.66%(P<0.01), and rat erythrocytes exhibited a small cell low pigment effect with hemoglobin and hematocrit decreased by 8.60% and 8.70%, respectively(P<0.05). But IAA had little effects on the platelet. Plasma iron, phosphorus, zinc and potassium levels were repressed significantly, while chlorine, sodium and magnesium levels were elevated obviously through IAA exposure. However, plasma calcium levels were hardly affected by IAA. In comparison with the control, iron levels declined by 67.09%, whereas magnesium levels increased by 131.82% in the high-dose group(P<0.01). Overall, correlation analyses uncovered that plasma iron metabolism was most strongly and positively correlated with levels of leukocyte, erythrocyte and platelet system parameters after IAA exposure, and the correlation coefficients of leukocyte number, mean hemoglobin content and mean erythrocyte volume were 0.637, 0.410 and 0.365, respectively(P<0.05). Compared to the control, in the high-dose IAA group, the plasma content of C-reactive protein was significantly upregulated by 13.30%(P<0.05), and plasma levels of transferrin and ferromodulin were also respectively elevated by 12.73% and 11.02%(P<0.05). But plasma levels of ferritin and GAPDH did not differ between groups. The docking model exhibited that IAA could bind to the 150 Cys active site of rat GAPDH did. CONCLUSION: IAA not only had toxic effects on rat leukocytes and the plasma electrolyte balance, but also generated inflammation and iron deficiency, leading to smaller erythrocytes and lower pigment.

Macrophage-derived extracellular vesicles represent a promising endogenous iron-chelating therapy for iron overload and cardiac injury in myocardial infarction.

BACKGROUND: Cardiac iron overload and ferroptosis greatly contribute to the poor prognosis of myocardial infarction (MI). Iron chelator is one of the most promising strategies for scavenging excessive iron and alleviating cardiac dysfunction post MI. However, various side effects of existing chemical iron chelators restrict their clinical application, which calls for a more viable and safer approach to protect against iron injury in ischemic hearts. RESULTS: In this study, we isolated macrophage-derived extracellular vesicles (EVs) and identified macrophage-derived EVs as a novel endogenous biological chelator for iron. The administration of macrophage-derived EVs effectively reduced iron overload in hypoxia-treated cardiomyocytes and hearts post MI. Moreover, the oxidative stress and ferroptosis induced by excessive iron were considerably suppressed by application of macrophage-derived EVs. Mechanistically, transferrin receptor (TfR), which was inherited from macrophage to the surface of EVs, endowed EVs with the ability to bind to transferrin and remove excess protein-bound iron. EVs with TfR deficiency exhibited a loss of function in preventing MI-induced iron overload and protecting the heart from MI injury. Furthermore, the iron-chelating EVs were ultimately captured and processed by macrophages in the liver. CONCLUSIONS: These results highlight the potential of macrophage-derived EVs as a powerful endogenous candidate for iron chelation therapy, offering a novel and promising therapeutic approach to protect against iron overload-induced injury in MI and other cardiovascular diseases.

A multi-component paclitaxel -loaded ß-elemene nanoemulsion by transferrin modification enhances anti-non-small-cell lung cancer treatment.

A multi-component paclitaxel (PTX) -loaded ß-elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (-10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and ß-elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer.

Graphene oxide nanoribbons conjugated with 1, 2-distearoyl-sn-glycero-3 phosphoethanolamine-poly (ethylene glycol)-transferrin enhanced targeted delivery and cytotoxicity of raloxifene against breast cancer.

The clinical utility of raloxifene (RLX), a selective estrogen receptor modulator (SERM), has been compromised by severe side effects and unfavorable drug properties. To address these, a transferrin (Tf) conjugated graphene oxide nanoribbon (GONR) platform was tried for RLX. The stability of GONRs in biological media was improved by surface modification with 1, 2-Distearoyl-sn-glycero-3 phosphoethanolamine-Poly (ethylene glycol) (DSPE-PEG). The Tf molecule was covalently attached to DSPE-PEG (DPT) using EDC-NHS chemistry. The surface of GONR was then modified with DSPE-PEG (DP) or DPT and loaded with RLX (GDP-RLX and GDPT-RLX). The final formulations were characterized for drug loading and stability. The anticancer activities of pure RLX, GDP-RLX, and GDPT-RLX were evaluated and compared in all the in vitro and in vivo studies. In vitro cell line studies showed that GDPT-RLX have significantly high cytotoxicity, cellular uptake, apoptosis induction, G2/M phase arrest, anti-migration properties, and apoptotic protein expression, followed by GDP-RLX and RLX. Pharmacokinetics and tumor biodistribution were also found to be excellent with GDPT-RLX. The in vivo tumor therapy and tumor evaluation outcomes were also consistent with the in vitro data. The Tf conjugated GDPT-RLX represents a promising approach for targeted and sustained delivery of RLX with enhanced therapeutic efficacy.

Nasal exudate for diagnosis of stroke: fundamental studies through iron fractionation, total iron, and targeted protein determinations.

During the last years, there has been an increasing research interest in the analysis of biological fluids requiring non-invasive sampling for biomedical and clinical applications. In this work, we have focused on the nasal exudate with the aim of investigating the potential use of this fluid to know the role of iron in stroke and also for diagnosis. Potential differences in the nasal exudate, collected in swabs, from diagnosed hemorrhagic stroke, ischemic stroke, and control groups were investigated with regard to total iron by inductively coupled plasma-mass spectrometry, iron fractionation studies by size exclusion chromatography together with post-column isotope dilution analysis, and four proteins containing iron (ferritin, transferrin, lactoferrin, and ferroportin) with ELISA kits. All these analyses represent an analytical challenge, considering the rather limited amount of sample (10-40 mg) available, being the nasal exudate extracted from the swab with 300 µL 10 mM Tris/HCl, pH = 7.4. Studies to obtain reliable analytical information, such as the blank contribution of the sampling step, evaluation of the extraction efficiency of the nasal exudate from the swab, and normalization strategies for data treatment, have been carried out. Results showed that despite the limited number of investigated samples, fractionation studies as well as the concentrations of ferritin and ferroportin obtained with ELISA kits showed a differential behavior between the different cohorts.

A dual colorimetric-electrochemical microfluidic paper-based analytical device for point-of-care testing of ischemic strokes.

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.

Transferrin-Conjugated Nanostructured Lipid Carriers for Targeting Artemisone to Melanoma Cells.

We report a successful formulation of Artemisone (ATM) in transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs), achieving nearly a five-times increase in cell toxicity. The escalating cost of new drug discoveries led to the repurposing of approved drugs for new indications. This study incorporated Artemisone, an antimalarial drug, into a nanostructured lipid carrier (NLC) and tested for possible anticancer effects. The aim was to develop NLCs, and transferrin-conjugated NLCs (NLC-Tf) encapsulating Artemisone to enhance its delivery and anticancer activity. NLC formulations were prepared using high-pressure homogenization followed by ultrasonication and were characterized by particle size, zeta potential, and PDI. The conjugation of (Tf) to (NLC) was confirmed using IR, and the anticancer activity was tested using MTS assay. All formulations were in the nanometer size range (140-167 nm) with different zeta potential values. IR spectroscopy confirmed the successful conjugation of transferrin to NLC. Upon testing the formulations on melanoma cell lines using MTS assay, there was a significant decrease in viability and an increase in the encapsulated ATM-Tf toxicity compared to positive control ATM. The NLCs presented a promising potential carrier for delivering ATM to melanoma cells, and further conjugation with Tf significantly improved the ATM cytotoxicity.

In silico analysis of aptamer-RNA conjugate interactions with human transferrin receptor.

The human transmembrane protein Transferrin Receptor-1 is regarded as a promising target for the systemic delivery of therapeutic agents, particularly of nucleic acid therapeutics, such as short double stranded RNAs. This ubiquitous receptor is involved in cellular iron uptake, keeping intracellular homeostasis. It is overexpressed in multiple cancer cell types and is internalized via clathrin-mediated endocytosis. In previous studies, a human transferrin receptor-1 RNA aptamer, identified as TR14 ST1-3, was shown to be capable of effectively internalizing into cells in culture and to deliver small, double stranded RNAs in vitro and in vivo, via systemic administration. To understand, at the molecular level, the aptamer binding to the receptor and the impact of conjugation with the therapeutic RNA, a multi-level in silico protocol was employed, including protein-aptamer docking, molecular dynamics simulations and free energy calculations. The competition for the binding pocket, between the aptamer and the natural ligand human Transferrin, was also evaluated. The results show that the aptamer binds to the same region as Transferrin, with residues from the helical domain showing a critical role. Moreover, the conjugation to the therapeutic RNA, was shown not to affect aptamer binding. Overall, this study provides an atomic-level understanding of aptamer association to human Transferrin Receptor-1 and of its conjugation with a short model-therapeutic RNA, providing also important clues for futures studies aiming to deliver other oligonucleotide-based therapeutics via Transferrin Receptor.

Targeting Glioblastoma: Efficacy of Ruthenium-Based Drugs.

Ruthenium compounds offer improved selectivity and fewer side effects compared to platinum-based drugs in glioblastoma treatment. Insights into their interactions with transferrin suggest targeted drug delivery, while photoactivated chemotherapy is a novel cytotoxic approach in tumor tissues.

Study on the molecular mechanism of gold nanorods interacting with fibrinogen and transferrin to form protein corona.

The molecular mechanism of the formation of protein corona by the interaction of gold nanorods (AuNRs) with fibrinogen and transferrin was studied by spectroscopic methods and molecular docking. Studies have shown that AuNRs can be used as quencher to quench the fluorescence of fibrinogen/transferrin. The quenching mechanism mainly comes from static quenching. Fibrinogen has two different binding sites on the longitudinal and the transverse plane of AuNRs respectively, while transferrin has only one binding site on the surface of AuNRs. The adsorption process conforms to Freundlich adsorption isotherm and the pseudo-second-order reaction. The chemisorption is the rate-limiting step. Fibrinogen/transferrin may be a component of the "hard corona" because they bind AuNRs with high binding affinity. The formation of protein corona leads to a decrease in the hydrophobicity of the microenvironment around transferrin tryptophan (Trp) residues and an increase in the hydrophobicity of the microenvironment around fibrinogen/transferrin tyrosine (Tyr) residues, affecting the tertiary and secondary structure of fibrinogen/transferrin. Molecular docking can clearly see the specific amino acid residues of fibrinogen and transferrin adsorbed on AuNRs, and verify the experimental results.

Driving under the influence of alcohol and alcohol use disorder: the relevance of early identification from an Italian retrospective outpatient study.

INTRODUCTION: Worldwide, almost 1.2 million people drive under the influence of alcohol. However, early identification of alcohol use disorder (AUD) in subjects driving under the influence (DUI) of alcohol is seldom achieved. AIM: The aim of our retrospective study is to investigate the presence of AUD in a population of DUI subjects who had their driving license suspended, and if they were following a specific rehabilitation program. METHODS AND RESULTS: 750 subjects were retrospectively enrolled from 2018 to 2021. DSM-V to assess AUD was used. Forty-eight (6.4%) subjects presented a diagnosis of AUD, after one month they showed a statistically significant reduction of carbohydrate-deficient transferrin (CDT) (p<0.0001); however, none were following a program for the treatment of AUD. CONCLUSIONS: This outpatient setting may be considered a place of primary and secondary prevention where DUI subjects with a diagnosis of AUD may be entrusted to a Centre in order to follow rehabilitation treatment.

Mendelian Randomization Analysis of Systemic Iron Status and Risk of Different Types of Kidney Disease.

With rapid increases in incidence, diverse subtypes, and complicated etiologies, kidney disease remains a global public health problem. Iron, as an essential trace element, has pleiotropic effects on renal function and the progression of kidney diseases. A two-sample Mendelian randomization (MR) analysis was implemented to determine the potential causal effects between systemic iron status on different kidney diseases. Systemic iron status was represented by four iron-related biomarkers: serum iron, ferritin, transferrin saturation (TfSat), and total iron binding capacity (TIBC). For systemic iron status, 163,511, 246,139, 131,471, and 135,430 individuals were included in the genome-wide association study (GWAS) of serum iron, ferritin, TfSat, and TIBC, respectively. For kidney diseases, 653,143 individuals (15,658 cases and 637,485 controls), 657,076 individuals (8160 cases and 648,916 controls), and 659,320 individuals (10,404 cases and 648,916 controls) were included for immunoglobulin A nephropathy (IgAN), acute kidney disease (AKD), and chronic kidney disease (CKD), respectively. Our MR results showed that increased serum iron [odds ratio (OR): 1.10; 95% confidence interval (95% CI): 1.04, 1.16; p < 0.0042], ferritin (OR: 1.30; 95% CI: 1.14, 1.48; p < 0.0042), and TfSat (OR: 1.07; 95% CI: 1.04, 1.11; p < 0.0042)] and decreased TIBC (OR: 0.92; 95% CI: 0.88, 0.97; p < 0.0042) were associated with elevated IgAN risk. However, no significant associations were found between systemic iron status and AKD or CKD. In our MR study, the genetic evidence supports elevated systemic iron status as a causal effect on IgAN, which suggests a potential protective effect of iron chelation on IgAN patients.

Meconium Proteins Involved in Iron Metabolism.

The lack of specific biological materials and biomarkers limits our knowledge of the mechanisms underlying intrauterine regulation of iron supply to the fetus. Determining the meconium content of proteins commonly used in the laboratory to assess the transport, storage, and distribution of iron in the body may elucidate their roles in fetal development. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and calprotectin were determined by ELISA in meconium samples obtained from 122 neonates. There were strong correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL (p < 0.05). Meconium concentrations of ferritin were several-fold higher than the concentrations of the other proteins, with the exception of calprotectin whose concentration was approximately three-fold higher than that of ferritin. Meconium ceruloplasmin concentration significantly correlated with the concentrations of MPO, NGAL, lactoferrin, and calprotectin. Correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL may reflect their collaborative involvement in the storage and transport of iron in the intrauterine environment in line with their recognized biological properties. High meconium concentrations of ferritin may provide information about the demand for iron and its utilization by the fetus. The associations between ceruloplasmin and neutrophil proteins may indicate the involvement of ceruloplasmin in the regulation of neutrophil activity in the intrauterine environment.