Emu Oil Attenuates Disease Severity and Results in Fewer Large Colonic Tumors in a Mouse Model of Colitis-Associated Colorectal Cancer.

Ulcerative colitis patients have an increased risk of developing colorectal cancer (CRC). The aim of the current study was to determine whether Emu Oil (EO) could reduce the severity of colitis, thereby inhibiting colitis-associated CRC (CA-CRC) development. Female C57BL/6 mice (n = 8/group) were injected (i.p.) with saline or azoxymethane (AOM) (7.4 mg/kg). Mice underwent three dextran sulfate sodium (DSS)/water cycles. Mice were orally-administered either water (160 µL) or EO (80 µL or 160 µL) thrice weekly and euthanized after 12 weeks. AOM/DSS decreased bodyweight compared with normal controls (max. 20%; p < 0.05). In AOM/DSS mice, EO (160 µL) increased bodyweight compared with untreated and 80 µL EO-treated mice (max. 10%; p < 0.05). Both volumes of EO reduced disease activity index (DAI) scores on day 49, 56-63 (max. 40%; p < 0.05), compared with AOM/DSS controls. Histological damage was increased in the distal colon of AOM/DSS mice, and reduced by EO (160 µL; p < 0.05). Mucin-secreting goblet cells were increased by AOM/DSS compared to normal, with no effect observed following EO treatment (p > 0.05). Large tumor numbers were decreased in EO-treated mice (160 µL; 2 ± 0.6) compared with AOM/DSS controls (5 ± 0.7; p < 0.05). EO did not impact overall tumor number (p > 0.05). Other analyses remained unchanged across groups (p > 0.05). EO demonstrates promise as an adjunct to conventional treatment options for colitis management.

Emu oil and grape seed extract reduce tumour burden and disease parameters in murine colitis-associated colorectal cancer.

Ulcerative colitis is an incurable condition whereby patients are at an increased risk of developing colorectal cancer (CRC). We aimed to investigate the combination of Emu oil (EO) and grape seed extract (GSE) in an azoxymethane (AOM)/dextran sulphate sodium (DSS) model of colitis-associated CRC (CA-CRC). C57BL/6 mice (n = 10/group) were injected i.p. with saline or AOM (7.4 mg/kg) and underwent three DSS/water cycles. Mice were orally-gavaged thrice weekly with water (80 µl), EO (80 µl), GSE (80 µl; 400 mg/kg) or combined EO/GSE (160 µl). Mice were euthanized on day 63. AOM/DSS induced significant bodyweight loss (max -21%) and increased disease activity index (DAI) (max +83%) throughout the trial (P < 0.05). EO (max -53%), GSE (max -51%) and EO/GSE (max -71%) reduced DAI scores in AOM/DSS mice in all DSS cycles (P < 0.05). EO/GSE-treatment in AOM/DSS mice resulted in further DAI reduction compared with EO (max -62%) and GSE (max -71%) alone (P < 0.05). AOM/DSS mice presented with severe colonoscopically-assessed colitis at all time-points, which was reduced by EO, GSE and EO/GSE (P < 0.05). EO, GSE and EO/GSE reduced the number of colonic tumours compared with AOM/DSS controls (P < 0.05). Myeloperoxidase (acute inflammation) and fluorescein isothiocyanate-dextran levels (intestinal permeability) were increased in AOM/DSS controls (P < 0.05). EO (-58%) and EO/GSE (-77%) reduced fluorescein isothiocyanate-dextran compared with AOM/DSS controls (P < 0.05), with no effect on myeloperoxidase. Histologically-assessed severity scores were increased in the distal colon of AOM/DSS mice compared with saline (P < 0.05), with no effect observed following treatment. The combination of EO and GSE improved clinical indicators and reduced colonic tumours in AOM/DSS treated mice, suggesting potential in CA-CRC management.

Orally administered emu oil attenuates disease in a mouse model of Crohn's-like colitis.

Crohn's disease is a severe, incurable inflammatory bowel disease. Orally administered emu oil has demonstrated anti-inflammatory properties in previous models of gastrointestinal disease. We aimed to determine whether orally administered emu oil could attenuate disease in a mouse model of Crohn's-like colitis. Female ARC(s) mice (CD-1 equivalent, n = 10/group) were intra-rectally administered water (120 µL) or trinitrobenzene sulfonic acid (TNBS; 3 mg in 50% ethanol; 120 µL bolus) on day 0. Mice were orally administered water (80 µL) or emu oil (80 µL or 160 µL) daily for five days and euthanized on day six. Bodyweight and disease activity were recorded daily. Colonoscopy, burrowing activity, facial grimace, histological parameters (damage severity, small intestinal villus height/crypt depth and colonic crypt depth), myeloperoxidase activity and intestinal permeability were assessed. P < 0.05 was considered statistically significant. TNBS decreased bodyweight (days 1, 2, 4; P < 0.05) and increased disease activity (days 1-6; P < 0.01), compared to normal controls. Emu oil (80 µL) attenuated disease activity on days 5-6 (P < 0.05), although bodyweight loss was not significantly impacted (P > 0.05). Facial grimace and colonoscopy scores were significantly increased in TNBS-control mice; effects attenuated by both volumes of emu oil (P < 0.001). TNBS increased histological damage severity compared to normal controls (P < 0.05); an effect attenuated by 80 µL emu oil (proximal and distal colon; P < 0.05) and 160 µL emu oil (distal colon; P < 0.01). In the ileum, villus height and crypt depth were unaffected by TNBS or emu oil treatment compared to normal (P > 0.05). TNBS-induced distal colonic crypt lengthening was unaffected following emu oil administration (P > 0.05). Remaining parameters, including burrowing, myeloperoxidase activity and intestinal permeability, were unchanged across all treatment groups (P > 0.05). In normal mice, emu oil treatment did not significantly impact any parameter compared to normal controls. In conclusion, emu oil reduced overall disease severity and facial grimace scores in TNBS mice. These results suggest therapeutic potential for orally administered emu oil in the management of Crohn's disease.

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology.

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Decreased Physical Working Capacity in Adolescents With Nonalcoholic Fatty Liver Disease Associates With Reduced Iron Availability.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese individuals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness. METHODS: We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study-a longitudinal study of disease development in 2868 children in Western Australia. X2 and linear regression analyses were used to compare characteristics of study participants according to NAFLD status at age 17 years. RESULTS: Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants; MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH. CONCLUSIONS: In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.

The Impact of Morning versus Afternoon Exercise on Iron Absorption in Athletes.

PURPOSE: This study examined postexercise inflammatory, hepcidin, and iron absorption responses to endurance exercise performed in the morning versus the afternoon. METHODS: Sixteen endurance-trained runners (10 male, 6 female) with serum ferritin (sFer) < 50 µg·L completed a 90-min running protocol (65% vV˙O2max) in the morning (AM), or the afternoon (PM), in a crossover design. An iron-fortified fluid labeled with stable iron isotopes (Fe or Fe) was administered with a standardized meal 30 min following the exercise and control conditions during each trial, serving as a breakfast and dinner meal. Venous blood samples were collected before, immediately after, and 3 h after the exercise and control conditions to measure sFer, serum interleukin-6 (IL-6), and serum hepcidin-25. A final venous blood sample was collected 14 d after each trial to determine the erythrocyte iron incorporation, which was used to calculate iron absorption. Linear mixed-modeling was used to analyze the data. RESULTS: Overall, exercise significantly increased the concentrations of IL-6 (4.938 pg·mL; P = 0.006), and hepcidin-25 concentrations significantly increased 3 h after exercise by 0.380 nM (P < 0.001). During the PM trial, hepcidin concentrations exhibited diurnal tendency, increasing 0.55 nM at rest (P = 0.007), before further increasing 0.68 nM (P < 0.001) from prerun to 3 h postrun. Fractional iron absorption was significantly greater at breakfast after the AM run, compared with both the rested condition (0.778%; P = 0.020) and dinner in the AM run trial (0.672%; P = 0.011). CONCLUSIONS: Although exercise resulted in increased concentrations of IL-6 and hepcidin, iron was best absorbed in the morning after exercise, indicating there may be a transient mechanism during the acute postexercise window to promote iron absorption opposing the homeostatic regulation by serum hepcidin elevations.

Emu Oil reduces disease severity in a mouse model of chronic ulcerative colitis.

Objective: Ulcerative colitis (UC) is characterized by mucosal inflammation and ulceration of the large intestine. Emu Oil (EO) has been reported to protect the intestine against mucositis, NSAID-enteropathy, UC-associated colorectal cancer and acute UC. We aimed to determine whether EO could reduce the severity chronic UC in mice. Methods: Female C57BL/6 mice (n = 10/group) were orally administered (gavage) water (Groups 1-2) or EO (Groups 3: low dose-80 µl and 4: high dose-160 µl), thrice weekly. Group 1 mice consumed plain drinking water throughout the trial. Groups 2-4 mice underwent two cycles [each consisting of seven days dextran sulfate sodium (DSS; 2% w/v) and 14 days water], followed by a third DSS week. All mice were euthanized two days later (day 51). Bodyweight, disease activity index (DAI), burrowing activity, myeloperoxidase activity, crypt depth and histologically assessed damage severity were assessed. p < .05 was considered significant. Results: DSS decreased bodyweight and increased DAI compared to normal controls (p < .05), which was partially attenuated by both EO doses (p < .05). Burrowing activity was impaired in DSS-controls compared to normal controls (days 27 and 40); an effect prevented by both EO doses (p < .05). DSS increased colonic myeloperoxidase activity and crypt depth compared to controls (p < .05), with no significant EO effect. Moreover, DSS increased colonic damage severity compared to normal controls (p < .001). Importantly, both EO doses decreased distal colonic damage severity compared to DSS-controls (p < .001). Conclusions: Emu Oil attenuated clinically- and histologically-assessed disease severity in a mouse model of chronic UC. Emu Oil demonstrates promise as an adjunct to conventional treatment options for UC management.

Detection of HFE Haemochromatosis in the clinic and community using standard erythrocyte tests.

Detection of HFE Haemochromatosis (HH) is challenging in the absence of clinical features. HH subjects have elevated erythrocyte parameters compared to those without HH, but it remains unclear how this could be applied in clinical practice. Thus, we determined the sensitivity, specificity and clinical utility of erythrocyte parameters in 144 HH subjects with (n = 122) or without (n = 22) clinical and/or biochemical expression of iron overload, 1844 general population controls, and 700 chronic disease subjects. For both expressing and non-expressing HH subjects, the mean pre- and post-phlebotomy values of mean cell volume (MCV) and mean cell haemoglobin (MCH) were always significantly higher when compared to all other groups and demonstrated excellent diagnostic utility for detection of HH in men and women (AUROC 0.83-0.9; maximal sensitivity and specificity 82% and 78%) using cut-off values for MCV >91 fL or MCH >31 pg, respectively. Between 34 and 62% of all HH subjects would be detected, and <4% of all non-HH subjects would undergo unnecessary testing, if those with MCV or MCH values >94 fL or 32.2 pg, respectively, were evaluated.

A prospective cohort examination of haematological parameters in relation to cancer death and incidence: the Busselton Health Study.

BACKGROUND: Cancer risk is associated with serum iron levels. The aim of this study was to evaluate whether haematological parameters reflect serum iron levels and may also be associated with cancer risk. METHODS: We studied 1564 men and 1769 women who were enrolled in the Busselton Health Study, Western Australia. Haematological parameters evaluated included haemoglobin (Hb), mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC) and red cell distribution width (RCDW). Statistical analyses included t-tests for quantitative variables, chi-square tests for categorical variables and Cox proportional hazards regression modelling for cancer incidence and death. RESULTS: There was marginal evidence of an association between MCV (as a continuous variable) and non-skin cancer incidence in women (HR 1.15, 95% CI 1.013, 1.302; p = 0.030) but the hazard ratio was attenuated to non-significance after adjustment for serum ferritin (SF), iron and transferrin saturation (TS) (HR 1.11, 95% CI 0.972, 1.264; p = 0.126). There was strong evidence of an association between MCHC and prostate cancer incidence in men; the estimated hazard ratio for an increase of one SD (0.5) in MCHC was 1.27 (95% CI 1.064, 1.507; p = 0.008). These results remained significant after further adjustment for SF and iron; the estimated hazard ratio for an increase of one SD (0.5) in MCHC was 1.25 (p = 0.014, 95% CI 1.05 to 1.48). CONCLUSIONS: The MCHC and MCV were associated with cancer incidence in a Western Australian population, although only MCHC remained associated with prostate cancer after adjusting with serum iron and TS (circulating iron) and SF (storage iron). Haematological parameters are thus of limited utility in population profiling for future cancer risk.

Emu Oil Improves Clinical Indicators of Disease in a Mouse Model of Colitis-Associated Colorectal Cancer.

BACKGROUND/AIMS: Ulcerative colitis is a remitting and relapsing inflammatory bowel disorder. Current treatments are limited, and if poorly controlled, colitis may progress to colorectal cancer. Previously, Emu Oil protected the intestine in experimental models of gut damage. We aimed to determine whether Emu Oil could reduce the severity of chronic colitis and prevent the onset of neoplasia in a mouse model of colitis-associated colorectal cancer. METHODS: Female C57BL/6 mice were injected (day 0) with azoxymethane, followed by ad libitum access to three dextran sulfate sodium/water cycles (7 days of dextran sulfate sodium and 14 days of water). Mice (n = 9/group) were orally administered either water or Emu Oil (low dose 80 µL or high dose 160 µL), thrice weekly for 9 weeks. Bodyweight and disease activity index were measured daily. Colitis progression was monitored by colonoscopy on days 20, 41 and 62. At killing, tumor number and size were recorded. RESULTS: Azoxymethane/dextran sulfate sodium induced significant bodyweight loss (maximum 24%) which was attenuated by Emu Oil treatment (low dose days 9, 10, 14: maximum 7%; high dose days 7-15, 30-36: maximum 11%; p < 0.05). Emu Oil reduced disease activity index of azoxymethane/dextran sulfate sodium mice at most time points (maximum 20%; p < 0.05). Additionally, Emu Oil reduced colonoscopically assessed colitis severity (days 20 and 62) compared to disease controls (p < 0.05). Finally, in azoxymethane/dextran sulfate sodium mice, low-dose Emu Oil resulted in fewer small colonic tumors (p < 0.05) compared to controls. CONCLUSIONS: Emu Oil improved clinical indicators and reduced severity of colitis-associated colorectal cancer, suggesting therapeutic potential in colitis management.

Interleukin-6 and Hepcidin Levels during Hormone-Deplete and Hormone-Replete Phases of an Oral Contraceptive Cycle: A Pilot Study.

BACKGROUND: In the past, elevated estradiol levels were reported to downregulate the iron regulatory hormone hepcidin, thereby potentially improving iron metabolism. As estrogen plays a role in regulating the menstrual cycle and can influence the cytokine interleukin-6 (IL-6; a hepcidin up-regulator), this investigation examined the effects of estradiol supplementation achieved by the use of a monophasic oral contraceptive pill (OCP) on IL-6, hepcidin levels and iron status during the hormone-deplete versus hormone-replete phases within an oral contraceptive cycle (OCC). METHODS: Fifteen healthy female OCP users were recruited and provided a venous blood sample on 2 separate mornings during a 28-day period. These included (a) days 2-4 of the OCC, representing a hormone-free withdrawal period (WD); (b) days 12-14 of the OCC, representing the end of the first week of active hormone therapy (AHT). RESULTS: IL-6 and hepcidin levels were not significantly different at WD and AHT. Serum ferritin was significantly higher (p = 0.039) during AHT as compared to WD. CONCLUSIONS: Fluctuations in OCP hormones (estradiol and/or progestogen) had no effect on basal IL-6 and hepcidin levels in young women. Nevertheless, elevated ferritin levels recorded during AHT may indicate that OCP hormones can positively influence iron stores within an OCC despite unchanged hepcidin levels.

Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases.

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders.

Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes.

BACKGROUND: Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. OBJECTIVE: We investigated whether higher iron concentrations increased risk of cancer outcomes. DESIGN: A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations ≥20 µg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. RESULTS: After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76; P < 0.01); HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38; P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34; P < 0.05); HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56; P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48; 95% CI: 1.28, 4.82; P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65; 95% CI: 0.42, 0.99; P < 0.05) including colorectal cancer (HR: 0.34; 95% CI: 0.12, 0.95; P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. CONCLUSIONS: Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear.

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics.

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.

Oral contraception does not alter typical post-exercise interleukin-6 and hepcidin levels in females.

OBJECTIVES: The post-exercise interleukin-6 (IL-6) and hepcidin response was investigated during the hormone-deplete and hormone-replete phases of an estradiol and progestogen regulated oral contraceptive cycle (OCC). DESIGN: Counterbalanced, repeated measures cross-over study. METHODS: Ten active female monophasic oral contraceptive pill (OCP) users completed two 40 min treadmill running trials at 75% of their pre-determined peak oxygen uptake velocity (vVO2peak). These trials were randomly performed in two specific phases of the OCC: (a) Day 2-4, representing a hormone-free withdrawal period (D-0); (b) Day 12-14, representing the end of the first week of active hormone therapy (D+7). Venous blood samples were drawn pre-, post- and 3h post-exercise. RESULTS: In both trials, serum IL-6 was significantly elevated (p<0.05) immediately post-exercise, while serum hepcidin was significantly elevated (p<0.05) 3h post-exercise, with no significant differences recorded between trials. CONCLUSIONS: These findings suggest that exercise performed during the different phases (D-0 vs. D+7) of a monophasic OCP regulated cycle does not alter exercise induced IL-6 or hepcidin production. As such, future studies looking to investigate similar variables post-exercise, may not need to 'control' for different phases of the OCC, provided participants are current monophasic OCP users.

A seven day running training period increases basal urinary hepcidin levels as compared to cycling.

BACKGROUND: This investigation compared the effects of an extended period of weight-bearing (running) vs. non-weight-bearing (cycling) exercise on hepcidin production and its implications for iron status. METHODS: Ten active males performed two separate exercise training blocks with either running (RTB) or cycling (CTB) as the exercise mode. Each block consisted of five training sessions (Day 1, 2, 4, 5, 6) performed over a seven day period that were matched for exercise intensity. Basal venous blood samples were obtained on Day 1 (D1), and on Recovery Days 3 (R3) and 7 (R7) to assess iron status, while basal and 3 h post-exercise urinary hepcidin levels were measured on D1, D2, D6, as well as R3 and R7 (basal levels only) for each condition. RESULTS: Basal urinary hepcidin levels were significantly elevated (p ≤ 0.05) at D2, R3 and R7 as compared to D1 in RTB. Furthermore, 3 h post-exercise urinary hepcidin levels on D1 were also significantly higher in RTB compared to CTB (p ≤ 0.05). In CTB, urinary hepcidin levels were not statistically different on D1 as compared to R7. Iron parameters were not significantly different at D1 compared to R3 and R7 during both conditions. CONCLUSIONS: These results suggest that basal hepcidin levels may increase over the course of an extended training program, especially if a weight-bearing exercise modality is undertaken. However, despite any variations in hepcidin production, serum iron parameters in both RTB and CTB were unaffected, possibly due to the short duration of each training block. In comparing running to cycling, non-weight-bearing activity may require more training sessions, or sessions of extended duration, before any significant changes in basal hepcidin levels appear. Chronic elevations in hepcidin levels may help to explain the high incidence of iron deficiency in athletes.

Iron status and the acute post-exercise hepcidin response in athletes.

This study explored the relationship between serum ferritin and hepcidin in athletes. Baseline serum ferritin levels of 54 athletes from the control trial of five investigations conducted in our laboratory were considered; athletes were grouped according to values <30 µg/L (SF<30), 30-50 µg/L (SF30-50), 50-100 µg/L (SF50-100), or >100 µg/L (SF>100). Data pooling resulted in each athlete completing one of five running sessions: (1) 8 × 3 min at 85% vVO2peak; (2) 5 × 4 min at 90% vVO2peak; (3) 90 min continuous at 75% vVO2peak; (4) 40 min continuous at 75% vVO2peak; (5) 40 min continuous at 65% vVO2peak. Athletes from each running session were represented amongst all four groups; hence, the mean exercise duration and intensity were not different (p>0.05). Venous blood samples were collected pre-, post- and 3 h post-exercise, and were analysed for serum ferritin, iron, interleukin-6 (IL-6) and hepcidin-25. Baseline and post-exercise serum ferritin levels were different between groups (p<0.05). There were no group differences for pre- or post-exercise serum iron or IL-6 (p>0.05). Post-exercise IL-6 was significantly elevated compared to baseline within each group (p<0.05). Pre- and 3 h post-exercise hepcidin-25 was sequentially greater as the groups baseline serum ferritin levels increased (p<0.05). However, post-exercise hepcidin levels were only significantly elevated in three groups (SF30-50, SF50-100, and SF>100; p<0.05). An athlete's iron stores may dictate the baseline hepcidin levels and the magnitude of post-exercise hepcidin response. Low iron stores suppressed post-exercise hepcidin, seemingly overriding any inflammatory-driven increases.

Iron regulation in athletes: exploring the menstrual cycle and effects of different exercise modalities on hepcidin production.

The trace element iron plays a number of crucial physiological roles within the body. Despite its importance, iron deficiency remains a common problem among athletes. As an individual's iron stores become depleted, it can affect their well-being and athletic capacity. Recently, altered iron metabolism in athletes has been attributed to postexercise increases in the iron regulatory hormone hepcidin, which has been reported to be upregulated by exercise-induced increases in the inflammatory cytokine interleukin-6. As such, when hepcidin levels are elevated, iron absorption and recycling may be compromised. To date, however, most studies have explored the acute postexercise hepcidin response, with limited research seeking to minimize/attenuate these increases. This review summarizes the current knowledge regarding the postexercise hepcidin response under a variety of exercise scenarios and highlights potential areas for future research-such as: a) the use of hormones though the female oral contraceptive pill to manipulate the postexercise hepcidin response, b) comparing the use of different exercise modes (e.g., cycling vs. running) on hepcidin regulation.