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![Hepcidin causes a rapid, sustained fall in serum iron. Mice received a single 50-μg intraperitoneal injection of hHep (human hepcidin). Reproduced with permission from Rivera et al. [26].](publication/321983712/figure/fig4/AS:11431281079490898@1660733092505/Hepcidin-causes-a-rapid-sustained-fall-in-serum-iron-Mice-received-a-single-50-mg.JPG)
Hepcidin causes a rapid, sustained fall in serum iron. Mice received a single 50-μg intraperitoneal injection of hHep (human hepcidin). Reproduced with permission from Rivera et al. [26].
Source publication
The fact that humans must balance their need for iron against its potential for causing harm has been known for several centuries, but the molecular mechanisms by which we achieve this feat have only been revealed in the last 2 decades. Chief amongst these is the discovery of the master-regulatory liver-derived hormone hepcidin. By switching off fe...
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Anemia is considered by World Health Organization as a global health problem. It can be affected by the body mass index of an individual since increasing weight can result in low-grade systemic inflammation and elevation of hepcidin which results in sequestration of iron inside a variety of cells including macrophages, hepatocytes and enterocytes a...
Citations
... Hepcidin is found as Hamp1 and Hamp2 in mice, and human hepcidin is similar to mouse Hamp1 [37]. Hepcidin is an innate antimicrobial agent that is induced by most invasive bacteria and also by virus, then limits bacterial proliferation by reducing iron such as in plasma and extracellular fluids, and kills bacteria [38]. Hamp2 is more reactive as an antibacterial and antivirus activity than Hamp1 [39,40]. ...
Human old aged unmutated chronic lymphocytic leukemia U-CLL are the TCL1⁺ZAP70⁺CD5⁺ B cells. Since CD5 makes the BCR signaling tolerance, ZAP70 increased in U-CLL not only TCL1⁺ alone. In mice, TCL1 (TCL1A) is the negative from neonate to old aged, as TC–. VH8-12/Vk21-5 is the anti-thymocyte/Thy-1 autoreactive ATA B cell. When ATA μκTg generation in mice, ATA B cells are the neonate generated CD5⁺ B cells in B-1, and in the middle age, CD5⁺ can be down or continuously CD5⁺, then, old aged CLL/lymphoma generation with increased CD11b in TC–ZAP70–CD5– or TC–ZAP70⁺CD5⁺. In this old aged TC–ATA B microarray analysis showed most similar to human CLL and U-CLL, and TC–ZAP70⁺CD5⁺ showed certain higher present as U-CLL. Original neonate ATA B cells showed with several genes down or further increase in old aged tumor, and old aged T-bet⁺CD11c⁺, CTNNB1hi, HMGBhi, CXCR4hi, DPP4hi and decreased miR181b. These old aged increased genes and down miR181b are similar to human CLL. Also, in old age ATA B cell tumor, high CD38⁺⁺CD44⁺⁺, increased Ki67⁺ AID⁺, and decreased CD180– miR15Olow are similar to U-CLL. In this old aged ATA B, increased TLR7,9 and Wnt10b. TC⁺Tg generated with ATAμκTg mice occurred middle age tumor as TC⁺ZAP70–CD5⁺ or TC⁺ZAP70⁺CD5⁺, with high NF-kB1, TLR4,6 and Wnt5b,6 without increased CD11b. Since neonatal state to age with TC⁺Tg continuously, middle age CLL/lymphoma generation is not similar to old aged generated, however, some increased in TC⁺ZAP70⁺ are similar to the old age TC– ATA B tumor. Then, TC– ATA B old age tumor showed some difference to human CLL. ATA B cells showed CD11b⁺CD22⁺⁺, CD24 down, and hepcidin Hamp2⁺⁺ with iron down. This mouse V8-12 similar to human V2-5, and V2-5 showed several cancers with macrophages/neutrophils generated hepcidin⁺ ironlow or some showed hepcidin– iron⁺ with tumor, and mouse V8-12 with different Vk19-17 generate MZ B cells strongly increased macrophage⁺⁺ in old aged and generated intestine/colon tumor. Conclusion, neonate generated TC–ATA B1 cells in old aged tumor generation are CD11b⁺ in the leukemia CLL together with lymphoma cancer with hepcidin-related Hamp2⁺⁺ in B-1 cell generation to control iron.
... As discussed above, supplemental iron may increase the risk of malaria and other infections [176]. In a large intervention trial in Tanzania, there was a higher incidence of severe adverse events (hospitalizations from malaria and other infections and deaths) in children provided supplements with iron and folic acid compared with placebo [177]. ...
Anemia is a multifactorial condition; approaches to address it must recognize that the causal factors represent an ecology consisting of internal (biology, genetics, and health) and external (social/behavioral/demographic and physical) environments. In this paper, we present an approach for selecting interventions, followed by a description of key issues related to the multiple available interventions for prevention and reduction of anemia. We address interventions for anemia using the following 2 main categories: 1) those that address nutrients alone, and, 2) those that address nonnutritional causes of anemia. The emphasis will be on interventions of public health relevance, but we also consider the clinical context. We also focus on interventions at different stages of the life course, with a particular focus on women of reproductive age and preschool-age children, and present evidence on various factors to consider when selecting an intervention—inflammation, genetic mutations, nutrient delivery, bioavailability, and safety. Each section on an intervention domain concludes with a brief discussion of key research areas.
... 13,14 Inflammation, infection, and iron overload up-regulate hepcidin production and thereby explain the etiology of the anemia of chronic infection. 15,16 The mechanisms that underlie the regulation of circulating iron by hepcidin remain unclear. 17 There is still a knowledge gap on the utility of hepcidin as a biomarker among healthy women in the prenatal period. ...
Objective:
This study evaluated the correlation between maternal hepcidin and other biomarkers of iron status, markers of inflammation, and maternal body weight during pregnancy, as well as neurodevelopment in the offspring.
Data sources:
PubMed, Web of Science, Scopus, and Embase were searched from inception until March 2022.
Study eligibility criteria:
Studies conducted among pregnant women without apparent pregnancy complications were included. Eligible studies reported correlation coefficients between maternal hepcidin and any outcomes of maternal biomarkers of iron status or inflammatory load during pregnancy, prenatal maternal body weight, and offspring neurodevelopment. Studies without correlation data were eligible if they quantitatively reported volumes of both maternal hepcidin and any marker of iron status and/or inflammatory load during gestation.
Methods:
Pooled correlation coefficients between maternal hepcidin and outcomes of interest were calculated using the Fisher r-to-Z transformation. Both fixed-effects and DerSimonian and Laird random-effects models were used to calculate pooled correlation coefficient. When meta-analysis was not feasible, results were descriptively synthesized.
Results:
Forty-six studies with 6624 participants were eligible. Hepcidin was significantly correlated with hemoglobin in the third trimester (r=0.21; 95% confidence interval, 0.1-0.32); ferritin in the first (r=0.31; 95% confidence interval, 0.01-0.61) and third trimester (r=0.35; 95% confidence interval, 0.23-0.48); soluble transferrin receptor in the second trimester (r=-0.27; 95% confidence interval, -0.4 to -0.14); total iron-binding capacity in the second trimester (r=0.37; 95% confidence interval, 0.24-0.50); and serum iron in the third trimester (r=0.11; 95% confidence interval, 0.02-0.19). Hepcidin was significantly correlated with the inflammatory marker interleukin-6 in the third trimester (r=0.26; 95% confidence interval, 0.17-0.34) and C-reactive protein in the second (r=0.16; 95% confidence interval, 0.03-0.30) and third trimester (r=0.28; 95% confidence interval, 0.04-0.52). Four out of 5 studies reported weak-to-moderate positive correlation between hepcidin and body mass index. Hepcidin levels varied across body mass index categories. No single study reported the relationship between maternal hepcidin and neurodevelopment in offspring.
Conclusion:
Hepcidin weakly to moderately correlates with biomarkers of iron and inflammation in pregnancy.
... Subsequently, studies found that TFR2-mutant mice had decreased hepcidin expression and liver iron accumulation, and increased intestinal iron absorption [17,18]. Hepcidin is a circulatory peptide that is synthesized in the liver and acts as the key regulator of iron metabolism by modulating iron absorption through the duodenum and the release of iron from macrophages [19]. A previous study suggested that Tfr2, combined with hepcidin, led to excessive iron and affected the process of NAFLD [20]. ...
Background
Iron overload is frequently observed in non-alcoholic fatty liver disease (NAFLD). Transferrin receptor 2 (TFR2) is an important key factor in iron regulation. We aimed to investigate whether TFR2 single nucleotide polymorphisms (SNPs) contribute to susceptibility to NAFLD in a Chinese Han population.
Methods
Five tag SNPs (rs10247962, rs4434553, rs2075672, rs1052897, and rs3757859) in the TFR2 gene were selected and genotyped in a case–control study on participants who visited two affiliated hospitals of Fujian Medical University between June 2011 and August 2017. Propensity score matching and inverse probability of treatment weighting analyses were used to verify the risk associated with TFR2 SNPs.
Results
Logistic regression analyses suggested that subjects with the rs4434553 GA or GG genotype had a lower risk of NAFLD than those carrying the AA genotype (odds ratio = 0.630, 95% confidence interval = 0.504–0.788). Moreover, the rs4434553 GA or GG genotype was negatively correlated with body mass index, hepatic steatosis index, and serum ferritin (b = −0.363, P = 0.008; b = −1.040, P = 0.009; b = −35.258, P = 0.015, respectively), and positively associated with serum hepcidin level (b = 35.308, P < 0.001). Moreover, rs10247962 and rs1052897 had multiplicative interactions with age in relation to the risk of NAFLD (P for interactions, 0.041 and 0.034, respectively). The cumulative effects of the rs10247962, rs1052897, and rs4434553 SNPs were positively associated with the risk of NAFLD (adjusted Ptrend = 0.012).
Conclusions
In this Chinese Han population, the rs4434553 polymorphism in TFR2 may be an independent influencing factor associated with the susceptibility to NAFLD. The ageing effect on the development of NAFLD may be inhibited by SNPs rs10247962 and rs1052897.
... By targeting FPN1 which is the only-known exporter of iron at the surface of cells, hepcidin downregulated the expression of FPN1, reduced the export of iron from cells to circulation, and thereby regulates the concentration of iron in the circulation (Wunderer et al. 2020). Hepcidin is upregulated by iron overload and inflammation (Prentice 2017). In clinical studies, the increased hepcidin level was significantly associated with arterial stiffness and cardiovascular events (Afsar et al. 2021). ...
Vascular calcification (VC) has been associated with a risk of cardiovascular diseases. Iron may play a critical role in progressive VC. Therefore, we investigated the effects of iron overload on the aorta of rats. A rat model of iron overload was established by intraperitoneal injection of Iron-Dextran. The levels of iron, calcium, and ALP activity were detected. Von Kossa staining and Perl’s staining were conducted. The expression of iron metabolism-related and calcification related factors were examined in the aortic tissue of rats. The results showed serum and aortic tissue iron were increased induced by iron overload and excessive iron induced hepatic and renal damage. In iron overload rats, the expression of divalent metal transporter 1 (DMT1) and hepcidin were higher, but ferroportin1 (FPN1) was lower. Von Kossa staining demonstrated calcium deposition in the aorta of iron overload rats. The calcium content and ALP activity in serum and aortic tissue were increased and iron level in aortic tissue highly correlated with calcium content and ALP activity. The expressions of the osteogenic markers were increased while a decrease of Alpha-smooth muscle actin (α-SMA) in the aortic tissue of iron overload rats. IL-24 was increased during the calcification process induced by iron. Overall, we demonstrated excessive iron accumulation in the aortic tissue and induced organs damage. The iron metabolism-related factors were significantly changed during iron overload. Moreover, we found that iron overload leads to calcium deposition in aorta, playing a key role in the pathological process of VC by mediating osteoblast differentiation factors.
... Down regulation of ferroportin in macrophages exerts control of iron's distribution within tissues. This occurs as part innate immune response to infection as a critical mechanism in withholding iron from bacterial pathogens and maintaining relatively low iron conditions inhibiting microbial growth (Prentice, 2017). Excessive iron within cells is known to increase cellular damage through elevates ROS production catalysed by the Fenton reaction (Galaris et al., 2019). ...
Chemotherapy causes sensory disturbances in cancer patients that results in neuropathies and pain. As cancer survivorships has dramatically increased over the past 10 years, pain management of these patients is becoming clinically more important. Current analgesic strategies are mainly ineffective and long-term use is associated with severe side effects. The issue being that common analgesic strategies are based on ubiquitous pain mediator pathways, so when applied to clinically diverse neuropathic pain and neurological conditions, are unsuccessful. This is principally due to the lack of understanding of the driving forces that lead to chemotherapy induced neuropathies. It is well documented that chemotherapy causes sensory neurodegeneration through axonal atrophy and intraepidermal fibre degeneration causing alterations in pain perception. Despite the neuropathological alterations associated with chemotherapy-induced neuropathic pain being extensively researched, underlying causes remain elusive. Resent evidence from patient and rodent studies have indicated a prominent inflammatory cell component in the peripheral sensory nervous system in effected areas post chemotherapeutic treatment. This is accompanied by modulation of auxiliary cells of the dorsal root ganglia sensory neurons such as activation of satellite glia and capillary dysfunction. The presence of a neuroinflammatory component was supported by transcriptomic analysis of dorsal root ganglia taken from mice treated with common chemotherapy agents. With key inflammatory mediators identified, having potent immunoregulatory effects that directly influences nociception. We aim to evaluate the current understanding of these immune-neuronal interactions across different cancer therapy drug classes. In the belief this may lead to better pain management approaches for cancer survivors.
... The ability of inflammation and infections to provoke a hepcidin-induced restriction in iron recycling and a decrease in dietary iron absorption is a relatively recent observation [10,11]. Nevertheless, this inflammation/infection barrier would explain the difficulties observed in demonstrating the efficacy of iron-fortified foods that are consumed by women or children living in LMICs where infections and inflammation are widespread [12]. ...
... As human beings evolved, the physiological effort put into excluding dietary iron from the body was as high as the effort put into acquiring iron for normal body functions [10]. A major part of this effort was the development of an inflammation barrier as a defense mechanism to prevent circulating iron from exacerbating infections. ...
Iron fortification of foods has always been a challenge. This is because iron fortification compounds vary widely in relative absorption; because many foods undergo unacceptable changes in color or flavor from the addition of iron; and because many of the iron-fortified foods contain potent inhibitors of iron absorption. These technical barriers have largely been overcome, and efficacious iron-fortified foods, that maintain or improve the iron status of women or children in long-term feeding studies, can be designed. Commercially fortified infant foods are efficacious, and other commercial iron-fortified foods targeted at women and children will provide a useful amount of iron provided the fortification level is adjusted according to the relative absorption of the iron compound. Technologies for the large-scale fortification of wheat and maize flour are also well established, and iron fortification of rice, using the recently developed extruded premix technique, is showing great promise. However, some important knowledge gaps still remain, and further research and development is needed in relation to iron (and iodine)-fortified salt and iron-fortified liquid milk. The usefulness of less-soluble iron compounds, such as ferrous fumarate, to fortify foods for infants and young children in low- and middle-income countries (LMICs) also needs further investigation. A more formidable barrier to efficacious iron-fortified food has been reported in recent years. This is the infection-initiated inflammation barrier, which inhibits iron absorption in response to infection. This barrier is particularly important in LMICs where infections such as malaria and HIV are widespread, and gastrointestinal infections are common due to poor quality water supplies and sanitation. Another source of inflammation in such countries is the high prevalence of obesity in women. Most countries in sub-Saharan Africa have high inflammation which not only decreases the efficacy of iron-fortified and iron-biofortified foods but complicates the monitoring of large-scale iron fortification programs. This is because iron deficiency anemia cannot be differentiated from the more prominent anemia of inflammation and because inflammation confounds the measurement of iron status. There is an urgent need to better quantify the impact of inflammation on the efficacy of iron-fortified foods. However, at present, in LMICs with high inflammation exposure, infection control, cleaner water, improved sanitation, and a decrease in obesity prevalence will undoubtedly have a greater impact on iron status and anemia than the iron fortification of foods.
... In group I (healthy population), a nonsignificant positive correlation between serum hepcidin and serum ferritin may be indicative of the downregulation of serum hepcidin because of reduced iron stores [13]. A negative correlation between serum ferritin and hepcidin among CHC patients can be a clue that the HCV might be involved in the downregulation of hepcidin [14]. ...
Background
In addition to the known role of serum ferritin as an inflammatory mediator, its role in the induction of serum hepcidin is yet to be elucidated. This study aimed to identify a correlation between serum ferritin and hepcidin levels in chronic hepatitis C (CHC) patients and healthy individuals.
Methodology
A total of 44 male subjects, selected by convenient sampling technique, were included in this study. The study population was divided into group I including 22 healthy males and group II including age-matched 22 CHC patients. Serum hepcidin and serum ferritin levels of study participants in both groups were assessed. Serum parameters were compared between two groups using the Mann-Whitney U test. Spearman correlation test was applied between serum ferritin and serum hepcidin in each group. P-values of ≤0.05 were considered significant.
Results
The median values of serum ferritin in group I and group II were in the normal range, though serum ferritin of CHC patients was significantly higher than the healthy population (p = 0.03). The median values of serum hepcidin in both groups were below the normal range. In CHC patients, a negative nonsignificant correlation (rho = -0.34, p = 0.13) was observed between serum ferritin and serum hepcidin. A positive nonsignificant correlation (rho = 0.19, p = 0.4) was observed between serum ferritin and serum hepcidin in the healthy population.
Conclusions
Our study could not bring forth any conclusive remarks in favor of serum ferritin as an inflammatory mediator raising serum hepcidin levels among CHC patients. A negative nonsignificant correlation between studied parameters in CHC patients may indicate the involvement of some other factor such as hepatitis C virus in the reduction of serum hepcidin levels.
... Likewise, release of iron from the reservoirs in hepatic and splenic macrophages is also blocked. Several factors may affect synthesis of hepcidin, such as availability of iron, intensity of erythropoiesis, tissue hypoxia and presence of proinflammatory molecules [17,[19][20][21]. Processes of iron absorption in small intestine enterocytes and release from hepatic/spleen macrophages. ...
... Inflammation is an important factor in controlling iron metabolism via proinflammatory cytokines released by activated immune cells. Interleukin (IL)-1, IL-6, IL-22 and interferons (IFNs) induce secretion of hepcidin that blocks absorption of dietary iron and its release from reticuloendothelial deposits in liver and spleen [17,20,21]. Such a functional state of iron deficit (not true iron deficiency) protects against growth of pathogens and oxidative stress and is described as anemia of inflammation (AI) or anemia of chronic diseases (ACD). ...
Pregnancy is a physiological state that demands higher level of nutrients, including vitamins and minerals, for the growth and maintenance of the fetus. Iron deficiency is a part of most common diet deficiencies in pregnancy and has high clinical significance leading to the development of syderopenic anemia and its consequences for mother and child, such as higher risk of perinatal death, susceptibility to infection, intra-uteral growth inhibition, prematurity and low birth weight. Hence, iron supplementation is recommended for pregnant women; however dietary intake of iron from most commercially available formulas is often insufficient due to iron-poor bioavailability, or have undesired side-effects in the gastrointestinal tract, resulting in a discouraging and distrustful attitude to such treatment. The results of numerous studies indicate that diet supplementation with lactoferrin (LTF), an iron-binding protein, may be advantageous in prophylaxis and treatment of iron deficiency anemia. LTF, administered orally, normalizes iron homeostasis, not only by facilitating iron absorption, but also by inhibiting inflammatory processes responsible for anemia of chronic diseases, characterized by a functional iron deficit for physiological processes. LTF also protects against infections and inflammatory complications, caused by diagnostic surgical interventions in pregnant women. Beneficial, multidirectional actions of LTF during pregnancy encompass, in addition, inhibition of oxidative stress, normalization of intestine and genital tract microbiota and carbohydrate-lipid metabolism, protection of intestine barrier function, promotion of wound healing, as well as hypotensive, analgesic and antistress actions. Bovine lactoferrin (BLTF) is readily available on the nutritional market and generally recognized as safe (GRAS) for use in human diet.
... 37 Iron is essential for health but potentially harmfultight metabolic regulation limits the absorption of dietary iron to the amount required to maintain iron homeostasis. 38 Therefore iron absorption further varies with the iron status of an individual. 38 In remote Australia, socioeconomic and health indicators suggest that many children have poor iron status. ...
... 38 Therefore iron absorption further varies with the iron status of an individual. 38 In remote Australia, socioeconomic and health indicators suggest that many children have poor iron status. 39 Food insecurity, maternal anaemia in pregnancy, low birth weight, prematurity and early childhood anaemia are factors associated with poor iron status in early life that are prevalent in remote Australia. ...
Aims:
Early childhood anaemia due to iron deficiency is widespread in remote communities across northern Australia. Current recommendations for healthy food to complement breastfeeding at age 6 to 23 months include iron-rich and iron-enriched foods. An electronic nutrient analysis was undertaken to assess the iron content of hypothetical healthy diets for breastfed babies and young children aged 6 to 23 months in Australia, in comparison with their estimated requirements.
Methods:
Hypothetical diets for 1 day were developed that were consistent with the Foundation Diets for breastfed infants 6 to 12 months and for toddlers 13 to 23 months. Nutrient content was derived using the Australian Food Composition database in FoodWorks 10. The iron content of these two diets were compared with Estimated Average Requirements (EARs) and Recommended Dietary Intakes (RDIs) for iron for infants aged 7 to 12 months and children aged 1 to 3 years.
Results:
The iron content of the hypothetical diet for breastfed infants aged 6 to 12 months (5.8 mg) was less than the EAR (7 mg, 83%) and the RDI (11 mg, 53%). For young breastfed children aged 13 to 23 months, the iron content of the hypothetical diet was 4.4 mg; above the EAR (4 mg, 110%) but less than RDI (9 mg, 49%).
Conclusions:
Breastfeeding has health and neurodevelopmental benefits for infants and young children that are particularly important in remote Australia where food insecurity and poor nutrition compromise health and wellbeing. Adequate iron intake is also important for neurodevelopment in early life but healthy diets for breastfed babies and young children may have insufficient iron content to meet requirements. The upcoming revision of the Australian Dietary Guidelines provides an opportunity to consider this issue.
