Regulation Of Iron Absorption Research Articles

Exploring the effects of pemetrexed on drug resistance mechanisms in human lung adenocarcinoma and its association with PGRMC1

According to the 2022 cancer statistics of the World Health Organization, lung cancer ranks among the top ten causes of death, with lung adenocarcinoma being the most prevalent type. Despite significant advancements in lung cancer therapeutics, many clinical limitations remain, primarily due to the development of drug resistance. The present study investigated the effects of pemetrexed on the drug resistance mechanisms in human lung adenocarcinoma and its association with progesterone receptor membrane component 1 (PGRMC1) expression. Given that KRAS-mutant lung adenocarcinoma cell lines (e.g., A549) exhibit a high folate synthesis activity, pemetrexed, which is structurally similar to folate, was selected as the therapeutic drug. The present study used a lung adenocarcinoma cell line (A549) and established a drug-resistant lung adenocarcinoma cell line (A549/PEM). The findings demonstrated that PGRMC1 expression was elevated in the A549/PEM cells. It has been hypothesized that PGRMC1 regulates iron absorption through heme binding, resulting in a preference for iron-related cell death pathways (ferroptosis). Our findings indicate that drug-resistant lung adenocarcinoma cells with high PGRMC1 levels exhibit elevated antioxidant activity on the cell membrane and increased reliance on iron-dependent cell death pathways. This suggests a correlation between PGRMC1 and pemetrexed-induced iron-dependent cell death. Our study contributes to the development of more effective therapeutic strategies to improve the prognosis of patients with lung adenocarcinoma, particularly those facing drug resistance challenges.

The Interplay of Iron and Lipid Homeostasis in Non-Alcoholic Fatty Liver Disease

The liver is essential for numerous metabolic functions and is the primary site of iron storage and regulation in addition to maintaining critical functions in lipid metabolism. Both iron deficiency and overload have been demonstrated as being involved with metabolic dysfunction; hence, tight regulation of iron absorption is essential to maintain health. Approximately one-third of individuals suffering from non-alcoholic fatty liver disease have elevated hepatic iron concentrations, with increased iron associated with increased disease severity, suggesting a convergence in dysregulation between lipid and iron metabolism. Increasingly, the literature is demonstrating, using a myriad of model organisms and iron-loading methods, that iron loading induces dysregulation in multiple aspects of hepatic lipid metabolism. However, the molecular mechanisms involved, and their subsequent effects on human diseases, are unclear. As iron is a fundamental component of many enzymes and proteins involved in lipid metabolism and is involved in the production of free radicals and oxidative stress, the mechanisms are numerous. In this review, we examine and summarise the dysregulation that iron loading elicits on hepatic lipid availability, de novo synthesis, catabolism, and export. We propose that understanding the interplay between iron and lipid metabolism holds the key to unlocking the complexities of disease development and progression, ultimately leading to improved therapeutic avenues.

Correlation of Hepcidin with Some Biochemical Parameters in Iraqi Children with Growth Hormone Deficiency

Hepcidin (Hep.) is a protein that maintains iron balance in the body. The Information about the role of Hep. in pathophysiology that is associated with growth hormone deficiency (GHD) is scarce. This study evaluates the correlation of Hep. with some biochemical parameters: Growth Hormone (GH), Insulin-Like Factor-1 (IGF-1), Iron, Vitamin D, Alkaline Phosphatase (ALP), Calcium, Phosphorous, and Ferritin in growth hormone deficient children. Children with GHD (60) and healthy volunteers (60) participated in this study, and their serum samples are collected from National Diabetes Center- Almustansirya University from the period January to April 2022. Enzyme Linked Immune Sorbent Assay (ELIZA) is used to measure Hep. while Chemiluminescence immunoassay is to measure GH and IGF-1.Results demonstrate significant decrease of p<0.01 in the Hep. level in the sera of GHD patients when compared to healthy individuals, and iron levels increase. This can be explain the inverse relationship between hepcidin and iron .It is an important regulator of iron absorption, this mechanism through Hep. preventive any impact against anemia by increasing the bioavailability of (Fe). Therefore, this study is carried out to give a better understanding about the parameters that affect the children with GHD and Hep. that can be a dependable parameter for better management of those children.

Pathophysiology of anemic syndrome in celiac disease and its therapeutic treatment

The review presents modern ideas about the pathophysiology of the anemia syndrome associated with celiac disease. Brief information is provided about the main proteins involved in iron metabolism and their role in maintaining homeostasis. Attention is paid to the multifactorial pathogenetic mechanisms of anemia in celiac disease, the state of the duodenal mucosa and ultrastructural changes in the villi of enterocytes with signs of atrophy, which play a key role in the regulation of iron absorption, and also provides information on the mechanisms of the development of functional iron deficiency and its role in the pathogenesis of anemia of chronic diseases.

To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism.

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

Iron Absorption and its Influencing Factors to Prevent Iron Deficiency

Iron is an important nutrient, required to support tissue oxygen delivery, cell growth and differentiation regulation, and energy metabolism. Body iron levels are mainly controlled by regulation of iron absorption in duodenum and proximal jejunum, allowing absorption to be accurately matched to unregulated losses. Since iron bioavailability often reduced, dietary iron absorption is controlled by cellular and systemic factors to ensure that overall body iron levels are maintained at adequate levels. A better understanding of the mechanism for iron absorption and factors influencing its absorption and bioavailability is important to avoid iron deficiency or iron overload. There are complex regulatory frameworks managing iron absorption, transportation, storage, and recycling. It is able to provide enough iron for critical body functions and react relatively quickly as iron demands increase, but mechanisms must also be in place to restrict iron absorption once the body is overwhelmed with iron. Several factors promote and impede iron absorption, such as phytate and ascorbic acid, respectively. The danger of iron deficiency for the world's population is of great significance, it is important to introduce effective strategies to tackle this issue through nutrition programs; food iron supplements; iron medication supplements; and probiotic, prebiotic, and symbiotic approaches.

Iron-peptide complexes from spent yeast: Evaluation of iron absorption using a Caco-2 monolayer

Anaemia is one of the most prevalent nutritional diseases worldwide with Fe deficiency being its major cause. In fact, the limited bioavailability of dietary iron and its interaction with food compounds contribute to its poor absorption in the human body and dietary Fe supplementation has been widely used to address this issue. By incorporating a circular economy framework, this study takes a novel approach of production of iron-peptide complexes from spent yeast peptide-rich extracts as a more effective substitute to conventional salt-based iron supplements, which are related with adverse consequences. Considering the regulation of iron absorption on duodenal enterocytes, iron-peptides complexes absorption was assessed using a Caco-2 monolayer, evaluating both iron uptake and the capacity to stimulate ferritin synthesis, after their in vitro simulated gastrointestinal digestion following INFOGEST protocol. An iron salt and a commercially available benchmark (iron bisglycinate) were also included in this study to compare the absorption performance. Results showed that iron-peptide complexes exhibited a similar behaviour (no statistically significant alterations (p > 0.05)) concerning the other tested samples, thus being a promising alternative for iron dietary supplementation. The remaining digested peptides from the complexes also showed potential antioxidant activity, suggesting protection of iron from oxidation within human body.

The effect of vitamin D on haemoglobin, patient assessed disease activity and endoscopic assessment in ulcerative colitis patients with anaemia

Background: Anemia has a dramatic impact on patient's quality of life, yet anemia in patients with UC is still underdiagnosed and undertreated. Hepcidin has been identified to be a central regulator of iron absorption from the intestines and of plasma iron levels. In this study we evaluated the effect of vitamin D supplementation on haemoglobin levels, patient assessed disease activity and endoscopic assessment in ulcerative colitis (UC). Methods: In this prospective, open-labeled, parallel-group, randomized, comparative clinical study, we assigned newly diagnosed cases of UC with haemoglobin levels between 8-11 gm/dL to receive either standard therapy for 12 weeks or to receive oral 4000IU vitamin D3 along with standard therapy for 12 weeks. Results: Data from 60 patients were analyzed after 12 weeks. Supplementation with vitamin D3 significantly raised haemoglobin level in treatment group from (9.09±0.20) (Mean ± SEM) at baseline to 9.62±0.22 (Mean ± SEM) at 12 weeks. On assessment of abdominal pain with NRS scale at the end of treatment at 12 weeks the reduction in NRS score was to 3.47±0.29 in group I and to 2.23±0.21 in group II (p=0.0012) which was highly significant. There was also a statistically significant reduction in the Likert scale at the end of 4, 8 and 12 weeks in both groups. At week 12, there was no statistical difference between the two groups in improving the endoscopy score. Conclusions: Daily high dose vitamin D supplementation is beneficial in ameliorating UC symptoms like abdominal pain and has a positive effect on haemoglobin levels.

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Anemic Syndrome and Molecular Mechanisms and Regulation of Iron Absorption in Gastroenterological Diseases

In this review, we tried to combine and systematize the accumulated information on the problem of anemic syndrome in the pathologies of the gastrointestinal tract. Anemic syndrome is the most frequent extraintestinal complication in patients with gastrointestinal tract pathology, which can significantly impair the quality of life. Depending on the combination of pathogenitic mechanisms, the iron deficiency, anemia of chronic diseases, B12-deficiency, and folate deficiency anemia are distinguished. Other types of anemia are less common. It is necessary to conduct a comprehensive laboratory examination to reveal the leading factor in the development of anemia and select adequate therapy. Anemia is one of the most common complications in patients with inflammatory bowel disease. In clinical practice, the intravenous iron is frequently administered. However, this therapy can lead to excess iron and cause exacerbation of the disease. Understanding the pathogenesis of anemia is important for the selection of therapy and minimizing the risk of complications. Parenteral forms of iron and vitamin preparations are more preferable for this category of patients due to their higher bioavailability, low safety profile, and minimal negative effect on the gastrointestinal tract. Erythropoietin preparations and inhibitors of proinflammatory cytokines are used mainly for the correction of anemia of chronic diseases. The latter showed themselves well in the treatment of patients with anemic syndrome on the background of severe inflammatory bowel diseases. Various clinical trials are being conducted to introduce new drugs to correct anemia. However, today, there is practically no experience of their application. Further study of patients with gastroenterological pathology complicated by anemia is required to form a final conclusion on the effectiveness and appropriateness of the intravenous iron administration in these categories of patients.

Duodenal macrophages control dietary iron absorption via local degradation of transferrin

AbstractIron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin (Tf), the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mechanistic target of rapamycin complex 1 (mTORC1), we found that these mice possessed various defects in iron metabolism, including defective steady-state erythropoiesis and a reduced saturation of Tf with iron. This iron deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of Tf, whereas the depletion of macrophages in mice increased Tf levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored Tf levels and Tf saturation in the Tsc2-deficient mice. Physiologically, Tf levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling Tf availability in the lamina propria villi.

Anemic Syndrome and Molecular Mechanisms and Regulation of Iron Absorption in Gastroenterological Diseases

Anemic syndrome is the most often extraintestinal complication in patients with diseases of the digestive tract (DT), which can significantly impair the quality of life. In the literature review, we tried to combine and systematize the accumulated information on the problem of anemic syndrome in DT diseases. Iron-deficiency anemia, chronic disease anemia, B12-deficiency and folio-deficiency anemia are determined depending on the combination of pathogenetic mechanisms. Other variants of anemia are rare. It is necessary to carry out a complex laboratory examination to establish the leading factor in the development of anemia and determine the adequate therapy. Anemia of inflammatory disease is one of the frequent complications in patients with DT diseases. For the correction of such anemia in clinical practice, iron preparations are used parenterally. However, such therapy can lead to an excess of iron and worsen the course of the underlying disease. The understanding the anemia pathogenesis is important for prescribing therapy and minimizing the risk of complications. Parenteral forms of iron and vitamin preparations should be prioritized for this category of patients due to their higher bioavailability, low safety profile and minimal negative impact on DT. Erythropoietin preparations and inhibitors of proinflammatory cytokines are mainly used to correct anemia of chronic inflammation. Pro-inflammatory cytokines are effective for patients with anemic syndrome and severe inflammatory bowel processes. According to the literature data, various clinical studies aimed at the introduction of new drugs that correct anemia are being conducted. The review presents modern methods of diagnosis and treatment of anemia in order to better understand this disease. A further study of patients with gastroenterological diseases, the course of which is complicated by anemia, is necessary to form a final conclusion about the disease, the effectiveness and feasibility of prescribing parenteral forms of iron preparations.

Regulation of iron absorption in infants

BackgroundIron programs in low- and middle-income countries often target infants and young children. Limited data from human infants and mouse models suggest that homeostatic control of iron absorption is incomplete in early infancy. Excess iron absorption during infancy may have detrimental effects. ObjectivesOur aims were to 1) investigate determinants of iron absorption in infants aged 3–15 mo and assess whether regulation of iron absorption is fully mature during this period and 2) define the threshold ferritin and hepcidin concentrations in infancy that trigger upregulation of iron absorption. MethodsWe performed a pooled analysis of standardized, stable iron isotope absorption studies performed by our laboratory in infants and toddlers. We used generalized additive mixed modeling (GAMM) to examine relationships between ferritin, hepcidin, and fractional iron absorption (FIA). ResultsKenyan and Thai infants aged 2.9–15.1 mo (n = 269) were included; 66.8% were iron deficient and 50.4% were anemic. In regression models, hepcidin, ferritin, and serum transferrin receptor were significant predictors of FIA, whereas C-reactive protein was not. In the model including hepcidin, hepcidin was the strongest predictor of FIA (β = -0.435). In all models, interaction terms, including age, were not significant predictors of FIA or hepcidin. The fitted GAMM trend of ferritin versus FIA showed a significant negative slope until ferritin of 46.3 μg/L (95% CI: 42.1, 50.5 μg/L), which corresponded to an FIA decrease from 26.5% to 8.3%; above this ferritin value, FIA remained stable. The fitted GAMM trend of hepcidin versus FIA showed a significant negative slope until hepcidin of 3.15 nmol/L (95% CI: 2.67, 3.63 nmol/L), above which FIA remained stable. ConclusionsOur findings suggest that the regulatory pathways of iron absorption are intact in infancy. In infants, iron absorption begins to increase at threshold ferritin and hepcidin values of ∼46 μg/L and ∼3 nmol/L, respectively, similar to adult values.

Consensus of Chinese experts on clinical application of lactoferrin

Lactoferrin is a natural protein with various physiological activities, which has the function of regulating immunity, anti-microbial, regulating iron absorption, promoting the proliferation of intestinal cells, and multiple pathophysiological processes. In recent years, lactoferrin has been widely used in infants, pregnant women, and the elderly. In order to more comprehensively understand the clinical application of lactoferrin and establish the method and index system of lactoferrin application in different populations, clinical nutritionists, together with experts from multiple disciplines, used the evidence grading method of GRADE Collaboration Network Ⅱ under the principle of evidence-based medicine to search for clinical evidence and repeatedly discuss. The experts group reached a consensus on the effect of lactoferrin reducing the risk of infection in premature infants, the incidence of respiratory and gastrointestinal diseases in infants, improving the anemia status of infants and pregnant women, improving the eradication rate of Helicobacter pylori in children and adults, and improving the immune function of the elderly, which could be used as a reference for medical professionals in clinical work.

Safety and efficacy of a novel iron chelator (HBED; (N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid)) in equine (Equus caballus) as a model for black rhinoceros (Diceros bicornis).

While iron overload disorder (IOD) and related disease states are not considered a common occurrence in domestic equids, these issues appear prevalent in black rhinoceroses under human care. In addressing IOD in black rhinos, altering dietary iron absorption and excretion may be the most globally practical approach. A main option for treatment used across other species such as humans, is chelation therapy using iron‐specific synthetic compounds. As horses may serve as an appropriate digestive model for the endangered rhinoceros, we evaluated the potential use of the oral iron chelator N,N‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N‐diacetic acid (HBED) in horses for safety and efficacy prior to testing in black rhinoceros. Health and iron digestibility and dynamics were assessed in horses (n = 6) before, and after treatment with HBED (50 mg/kg body weight) for 8 days using a crossover design with serum, faecal and urine collection. A preliminary pharmacokinetic trial was also performed but no trace of HBED was found in serially sampled plasma through 8 h post‐oral dosing. HBED increased urinary iron output in horses compared to control by 0.7% of total iron intake (p < 0.01), for an average of 27 mg urinary iron/day, similar to human chelation goals. Blood chemistry, blood cell counts and overall wellness were not affected by treatment. As healthy horses are able to regulate iron absorption, the lack of change in iron balance is unsurprising. Short‐term HBED administration appeared to be safely tolerated by horses, therefore it was anticipated it would also be safe to administer to black rhinos for the management of iron overload.

Auxin Functions Downstream of Ethylene to Regulate Iron Absorption Promoted by Phomopsis liquidambaris in Arachis hypogaea L.

Auxin Functions Downstream of Ethylene to Regulate Iron Absorption Promoted by Phomopsis liquidambaris in Arachis hypogaea L.

Dietary Approaches to Iron Deficiency Prevention in Childhood-A Critical Public Health Issue.

Iron is an essential nutrient, and individual iron status is determined by the regulation of iron absorption, which is driven by iron requirements. Iron deficiency (ID) disproportionately affects infants, children, and adolescents, particularly those who live in areas with unfavorable socioeconomic conditions. The main reason for this is that diet provides insufficient bioavailable iron to meet their needs. The consequences of ID include poor immune function and response to vaccination, and moderate ID anemia is associated with depressed neurodevelopment and impaired cognitive and academic performances. The persistently high prevalence of ID worldwide leads to the need for effective measures of ID prevention. The main strategies include the dietary diversification of foods with more bioavailable iron and/or the use of iron-fortified staple foods such as formula or cereals. However, this strategy may be limited due to its cost, especially in low-income countries where biofortification is a promising approach. Another option is iron supplementation. In terms of health policy, the choice between mass and targeted ID prevention depends on local conditions. In any case, this remains a critical public health issue in many countries that must be taken into consideration, especially in children under 5 years of age.

Effects of Excess Iron on the Retina: Insights From Clinical Cases and Animal Models of Iron Disorders.

Iron plays an important role in a wide range of metabolic pathways that are important for neuronal health. Excessive levels of iron, however, can promote toxicity and cell death. An example of an iron overload disorder is hemochromatosis (HH) which is a genetic disorder of iron metabolism in which the body’s ability to regulate iron absorption is altered, resulting in iron build-up and injury in several organs. The retina was traditionally assumed to be protected from high levels of systemic iron overload by the blood-retina barrier. However, recent data shows that expression of genes that are associated with HH can disrupt retinal iron metabolism. Thus, the effects of iron overload on the retina have become an area of research interest, as excessively high levels of iron are implicated in several retinal disorders, most notably age–related macular degeneration. This review is an effort to highlight risk factors for excessive levels of systemic iron build-up in the retina and its potential impact on the eye health. Information is integrated across clinical and preclinical animal studies to provide insights into the effects of systemic iron loading on the retina.

Gut HIF2α signaling is increased after VSG, and gut activation of HIF2α decreases weight, improves glucose, and increases GLP-1 secretion.

SUMMARYGastric bypass and vertical sleeve gastrectomy (VSG) remain the most potent and durable treatments for obesity and type 2 diabetes but are also associated with iron deficiency. The transcription factor HIF2α, which regulates iron absorption in the duodenum, increases following these surgeries. Increasing iron levels by means of dietary supplementation or hepatic hepcidin knockdown does not undermine the effects of VSG, indicating that metabolic improvements following VSG are not secondary to lower iron levels. Gut-specific deletion of Vhl results in increased constitutive duodenal HIF2α signaling and produces a profound lean, glucose-tolerant phenotype that mimics key effects of VSG. Interestingly, intestinal Vhl deletion also results in increased intestinal secretion of GLP-1, which is essential for these metabolic benefits. These data demonstrate a role for increased duodenal HIF2α signaling in regulating crosstalk between iron-regulatory systems and other aspects of systemic physiology important for metabolic regulation.

Iron Deficiency in Heart Failure: Characteristics and Treatment.

Purpose of the ReviewIron deficiency in heart failure has been associated with impaired functional capacity and quality of life. The purpose of this paper is to review mechanisms of iron homeostasis and current clinical data exploring mechanisms of iron repletion in heart failure.Recent FindingMultiple international societies now advise iron repletion for symptomatic heart failure patients with iron deficiency. Due to the chronic inflammation in heart failure, iron deficiency in heart failure is classically defined as ferritin < 100 µg/L or ferritin 100–300 µg/L and transferrin saturation < 20%. Multiple randomized clinical trials have demonstrated benefit from intravenous iron repletion, though studies have predominantly focused on functional capacity and quality of life. A recent study, AFFIRM-AHF, supports the treatment of iron deficiency identified during acute heart failure admissions, noting a reduction in future heart failure hospitalizations. Studies examining iron repletion in patients with heart failure with preserved ejection fraction are currently in process.SummaryIron homeostasis is maintained predominantly through the regulation of iron absorption, keeping iron levels tightly controlled in the normal state regardless of iron intake. In chronic heart failure however, iron homeostasis becomes dysregulated with resulting iron deficiency in many patients, with and without associated anemia. Iron is a critical element not only for erythropoiesis and oxygen carrying, but also for energy production at the level of the mitochondria and in other cell processes. We thus propose a standardized approach be utilized to screen and treat heart failure patients with iron deficiency.