Iron Overload Group Research Articles

A novel synthetic compound, deferiprone–resveratrol hybrid (DFP-RVT), promotes hepatoprotective effects and ameliorates iron-induced oxidative stress in iron-overloaded β-thalassemic mice

A high amount of iron in β-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded β-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor β1 (TGFβ1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFβ1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice.

Iron overload impact on peripheral blood cells, lymphocytes and karyotypes in newly diagnosed myelodysplastic syndromes (MDS) patients: a single-center retrospective analysis

We conducted a retrospective analysis of 68 newly diagnosed myelodysplastic syndrome (MDS) patients who were treated in the Department of Hematology at Yuncheng Central Hospital affiliated to Shanxi Medical University from October 2017 to March 2022. Based on the serum ferritin (SF) level, the newly diagnosed MDS patients were divided into two groups: iron overload (IOL) group (SF > 1000 ng/mL) and non-iron overload (NIOL) group(SF ≤ 1000 ng/mL). General clinical data, peripheral blood cells, lymphocyte subsets and marrow karyotypes were compared. We found that MDS patients with IOL had lower hemoglobin (Hb), lower reticulocyte (RET) counts, and lower absolute natural killer (NK) cell counts compared with NIOL group (p < 0.05). The correlation analysis also showed a negative correlation between the NK cell counts and SF level (r = −0.270, P = 0.026). Furthermore, we found IOL group had higher incidence of complex and poor karyotypes. In conclusion, we found that IOL is correlated with anemia in MDS patients, which may lead to a decrease in T lymphocyte cells, especially in NK cells, that play a role in the immune pathogenesis of MDS, thereby suppressing immune surveillance function. Additionally, IOL may contribute to the pathogenesis of MDS by affecting karyotypes.

Association of serum iron metabolism with muscle mass and frailty in older adults: A cross-sectional study of community-dwelling older adults.

This study aimed to explore the correlation between serum ferritin and additional biomarkers associated with iron metabolism, as well as their connection to muscle atrophy and frailty in the community-dwelling middle-aged and elderly population. The study included 110 middle-aged and elderly participants. Participants were categorized into an iron accumulation group (31 cases) and a normal iron group (79 cases) based on the standard ferritin values for men and women. Based on the criteria of the Asian Working Group on Muscular Dystrophy, participants were classified into a sarcopenia group (31 cases) and a non-sarcopenia group (79 cases). Using the Fried frailty syndrome criteria, participants were categorized into non-frailty (7 cases), pre-frailty (50 cases), and frailty (53 cases) groups. We employed multiple linear regression, binary logistic regression, partial correlation analysis, and ordinal logistic regression to assess the associations between iron metabolism indices and the presence of muscle atrophy and frailty. Compared with the normal iron group, the iron overload group had significantly higher ferritin, weight loss, fatigue, slow gait, and frailty scores (P < .05). Among the 3 models we set, ferritin was not significantly correlated with muscle mass in models 1 and 3 (P > .05), ferritin was positively correlated with muscle mass in model 2 (Pmodel2 = .048), but Transferrin saturation was positively correlated with muscle mass in all 3 models (Pmodel1 = .047, Pmodel2 = .026, Pmodel3 = .024). Ferritin, body mass index and iron overload were the influencing factors of sarcopenia (Pferritin = .027, PBMI < .001, Piron overload = .028). Ferritin was positively correlated with weight loss, fatigue, slow gait, frailty score, and frailty grade (P < .05). Age, gender and ferritin were the influencing factors of frailty classification (P < .05). Disrupted iron metabolism can lead to decreased muscle mass and function among the middle-aged and elderly, increasing frailty risk. It's crucial to prioritize community-based frailty screening and prevention, focusing on iron utilization as well as storage, since accelerating the body's iron metabolism cycle might influence muscle health more significantly than iron reserves.

Elevated Plasma C-reactive Protein Related to Iron Overload in Maintenance Hemodialysis Patients with Anemia: A Cross-Sectional Observational Study in Vietnam

Background: Iron overload in MHD patients is associated with many factors, including inflammation. Objectives: We conducted this study to determine the ratio of iron overload and its relationship with elevated plasma C-reactive protein (CRP) concentration in maintenance hemodialysis (MHD) patients with anemia. Methods: A cross-sectional observational study was conducted on 103 MHD patients with anemia. Plasma iron, ferritin, total iron-binding capacity (TIBC), and CRP concentrations were measured in all patients. Transferrin saturation (TSAT) was calculated based on plasma ferritin and TIBC concentrations. Patients with plasma ferritin &gt; 800 ng/mL and/or TSAT &gt; 50% were determined to have iron overload. Results: The proportion of iron overload was 51.5% (53/103 patients). The median CRP concentration in the iron overload group was 3.15 (1.66 - 6.67) mg/L, higher than that of the non-iron overload group [1.5 (0.78 - 3.24) mg/L], P &lt; 0.001. Plasma CRP was an independent factor associated with iron overload (P = 0.003). It was also a valuable predictor for iron overload in MHD patients with anemia (AUC = 0.703; P &lt; 0.001). Conclusions: Plasma CRP was a good predictor of iron overload in maintenance hemodialysis patients with anemia.

Investigation of the mutual crosstalk between ER stress and PI3K/AKT/mTOR signaling pathway in iron overload-induced liver injury in chicks.

Iron is an essential element for the normal functioning of living organisms, but excessive iron deposition can lead to organ damage. This study aims to investigate the interaction between the endoplasmic reticulum stress signaling pathway and the PI3K/AKT/mTOR signaling pathway in liver injury induced by iron overload in chicks. Rspectively, 150 one-day-old broilers were divided into three groups and supplemented with 50 (C), 500 (E1), and 1000 (E2) mg ferrous sulfate monohydrate/kg in the basal diet. Samples were taken after continuous feeding for 14days. The results showed that iron overload could upregulate the levels of ALT and AST. Histopathological examination revealed bleeding in the central vein of the liver accompanied by inflammatory cell infiltration. Hoechst staining showed that the iron overload group showed significant bright blue fluorescence, and ultrastructural observations showed chromatin condensation as well as mitochondrial swelling and cristae disorganization in the iron overload group. RT-qPCR and Western blot results showed that iron overload upregulated the expression of Bax, Caspase-3, Caspase-9, GRP78, GRP94, P-PERK, ATF4, eIF2α, IRE1, and ATF6, while downregulating the expression of Bcl-2 and the PI3K/AKT/mTOR pathway. XBP-1 splicing experiment showed significant splicing of XBP-1 gene after iron overload. PCA and correlation analysis suggested a potential association between endoplasmic reticulum stress, the PI3K/AKT/mTOR signaling pathway, and liver injury in chicks. In summary, iron overload can induce cell apoptosis and liver injury by affecting endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.

Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.

Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.

Chia seeds and coenzyme Q10 alleviate iron overload induced hepatorenal toxicity in mice via iron chelation and oxidative stress modulation

Iron overload (IOL) can cause hepatorenal damage due to iron-mediated oxidative and mitochondrial damage. Remarkably, combining a natural iron chelator with an antioxidant can exert greater efficacy than monotherapy. Thus, the present study aimed to evaluate the efficacy of Chia and CoQ10 to chelate excess iron and prevent hepatorenal oxidative damage in IOL mice. Male Swiss albino mice (n = 49) were randomly assigned to seven groups: control, dietary Chia, CoQ10, IOL, IOL + Chia, IOL + CoQ10, and IOL + Chia + CoQ10. Computational chemistry indicates that the phytic acid found in the Chia seeds is stable, reactive, and able to bind to up to three iron ions (both Fe2+ and Fe3+). IOL induced a significant (P < 0.05) increase in serum iron, ferritin, transferrin, TIBC, TSI, RBCs, Hb, MCV, MCH, WBCs, AST, ALT, creatinine, and MDA. IOL causes a significant (P < 0.05) decrease in UIBC, platelets, and antioxidant molecules (GSH, SOD, CAT, and GR). Also, IOL elicits mitochondrial membrane change depolarization, and DNA fragmentation and suppresses mitochondrial DNA copies. Furthermore, substantial changes in hepatic and renal tissue, including hepatocellular necrosis and apoptosis, glomerular degeneration, glomerular basement membrane thickening, and tubular degeneration, were observed in the IOL group. Dietary Chia and CoQ10 induced significant (P < 0.05) amelioration in all the mentioned parameters. They can mostly repair the abnormal architecture of hepatic and renal tissues induced by IOL, as signified by normal sinusoids, normal central veins, and neither glomerular damage nor degenerated tubules. In conclusion, the combined treatment with Chia + CoQ10 exerts more pronounced efficacy than monotherapy in hepatorenal protection via chelating excess iron and improved cellular antioxidant status and hepatorenal mitochondrial function in IOL mice.

Sonneratia apetala (Buch.-Ham.) Fruit Extracts Ameliorate Iron Overload and Iron-Induced Oxidative Stress in Mice.

Iron overload results in oxidative damage to various biomolecules including DNA, proteins and lipids which ultimately leads to cell death. The Sonneratia apetala fruit contains a high content of antioxidants and displays several bioactive properties. Therefore, the powder of the S. apetala fruit was successively fractionated into n-hexane (Hex), chloroform (Chl), and methanol (Met) fractions to evaluate their efficiency in ameliorating iron overload. In vitro, a colorimetric method was used to assess the Fe-chelating activity of the fractions using ferrozine. The fractions were also used in vivo to examine their efficacy in ameliorating iron overload and iron-induced oxidative stress in mice induced by intraperitoneal injection of ferric carboxymaltose at 100 mg/kg body weight (bw). Among the fractions, Met showed the highest Fe-chelation ability with an inhibitory concentration 50 of 165 μg/mL followed by Hex (270 μg/mL), and Chl (418 μg/mL). In vivo, the results showed a significantly (P<0.05) lower iron profile (iron and ferritin concentrations in serum and liver tissue and total iron-binding capacity of serum) in the Met and the Hex treated mice groups than in the iron-overloaded group. Met at 1,000 μg/kg bw completely ameliorated iron overload in the blood and the liver tissue of mice. At this concentration, Met also prevented iron-induced oxidative stress in the liver tissue of iron-overloaded mice by restoring reducing power, total antioxidant capacity, and total protein. Thus, the S. apetala fruit, especially its Met fraction can be used in treating iron overload and associated toxicity.

Iron overload induces colitis by modulating ferroptosis and interfering gut microbiota in mice

BackgroundIron plays a pivotal role in various physiological processes, including intestinal inflammation, ferroptosis, and the modulation of the gut microbiome. However, the way these factors interact with each other is unclear. MethodsMice models were fed with low, normal and high iron diets to assess their impacts on colitis, ferroptosis and gut microbiota. Untargeted fecal metabolomics analysis, 16S rRNA sequencing, histopathology analysis, real-time quantitative PCR and western blot were performed to analyze the differences in the intestinal inflammatory response and understanding its regulatory mechanisms between low, normal and high iron groups. ResultsThe iron overload changed the serum iron, colon iron and fecal iron. In addition, the iron overload induced the colitis, induced the ferroptosis and altered the microbiome composition in the fecal of mice. By using untargeted fecal metabolomics analysis to screen of metabolites in the fecal, we found that different metabolomics profiles in the fecal samples between iron deficiency, normal iron and iron overload groups. The correlation analysis showed that both of iron deficiency and overload were closely related to Dubosiella. The relationship between microbial communities (e.g., Akkermansia, Alistipes, and Dubosiella) and colitis-related parameters was highly significant. Additionally, Alistipes and Bacteroides microbial communities displayed a close association with ferroptosis-related parameters. Iron overload reduced the concentration of metabolites, which exert the anti-inflammatory effects (e.g., (+)-.alpha.-tocopherol) in mice. The nucleotide metabolism, enzyme metabolism and metabolic diseases were decreased and the lipid metabolism was increased in iron deficiency and iron overload groups compared with normal iron group. ConclusionIron overload exacerbated colitis in mice by modulating ferroptosis and perturbing the gut microbiota. Iron overload-induced ferroptosis was associated with NRF2/GPX-4 signaling pathway. Specific microbial taxa and their associated metabolites were closely intertwined with both colitis and ferroptosis markers.

Comparison between Gradient-Echo and Spin-Echo EPI MR Elastography at 3 T in quantifying liver stiffness of patients with and without iron overload; a prospective study

ObjectivesTo compare the maximum axial area of the confidence mask and the calculated liver stiffness (LS) on gradient-echo (GRE) and spin-echo echo planar imaging (SE-EPI) MR elastography (MRE) in patients with and without iron deposition. Methods104 patients underwent MRE by GRE and SE-EPI sequences at 3 T. R2* values >88 Hz in the liver were categorized in the iron overload group. The maximum axial area and the corresponding LS values were measured by manually contouring the whole area on one slice with the largest confidence mask at both GRE and SE-EPI sequences. ResultsIn patients with iron overload, SE-EPI provided larger maximum axial confidence area in unfailed images (57.6 ± 41.7 cm2) compared to GRE (45.7 ± 29.1 cm2) (p-value = 0.007). In five patients with iron overload, imaging failed at GRE sequence, whereas at the SE-EPI sequence the maximum area of the confidence mask had a mean value of 33.5 ± 54.9 cm2. In livers without iron overload (R2*: 50.7 ± 13.1 Hz), the maximum area on the confidence mask was larger at SE-EPI (118.3 ± 41.2 cm2) than on GRE (105.1 ± 31.7 cm2) (P-value = 0.003). There was no significant difference in mean LS between SE-EPI (2.0 ± 0.3 kPa) and GRE (2.1 ± 0.5 kPa) in livers with iron overload (P value = 0.24). Similarly, in the group without iron overload, mean LS was 2.3 ± 0.7 kPa at SE-EPI and 2.4 ± 0.8 kPa at GRE sequences (P-value = 0.11). ConclusionsSE-EPI MRE can successfully provide similar LS measurements as GRE MRE. Furthermore, it provides a larger measurable area on the confidence mask in both groups with and without iron overload.

Impact of Iron Overload and Iron Chelation with Deferasirox on Outcomes of Patients with Severe Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation

Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n=17) and the non-IO group (SF ≤1000 ng/mL; n=48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (ICsuccess) group (SF ≤1000 ng/mL; n=18) and the IC failure (ICfailure) group (SF >1000 ng/mL; n=28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P=.005) and 1-year TRM (52.9% versus 16.7%; P=.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P=.003) and 3-year OS (83.3% versus 42.9%; P=.007) were significantly better in the ICsuccess group, whereas 180-day TRM (11.1% versus 39.3%; P=.040) and 1-year TRM (11.1% versus 57.1%; P=.003) were significantly lower in the ICsuccess group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.

Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model.

Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.

Association of hepatic/pancreatic iron overload evaluated by quantitative T2* MRI with bone mineral density and trabecular bone score

BackgroundIron-overloaded patients are recognized as presenting an increased risk of osteoporosis. However, studies on the correlation between osteoporosis and organ iron overload are controversial or scarce. The aim of this study is to assess bone mineral density (BMD) and trabecular bone score (TBS) in correlation with hepatic and pancreatic iron overload.MethodsForty-one patients diagnosed with hemoglobinopathies, were studied. BMDs of the lumbar spine (LS), femoral neck (FN), and total hip (TH) were analyzed by Dual-energy X-ray absorptiometry (DXA) scan. LS bone quality was derived from each spine DXA examination using the TBS analysis. Hepatic and pancreatic iron overload were obtained with a multi-echo gradient echo T2* technique.ResultsAbnormal microarchitecture and abnormal bone mass were observed in 19/41 (46.3%) and 9/41 (22.0%) patients, respectively. For 26 males, BMD, T-score and Z-score of LS were significantly lower among subjects with moderate-severe hepatic iron-overload than their counterparts, as it is between no- and pancreatic iron-overload groups. For 15 females, patients with moderate-severe hepatic iron-overload had significantly lower BMD and T-score of FN and TH, and patients with pancreatic iron-overload had significantly lower BMD, T-score of FN, and lower BMD, T-score and Z-score of TH than their counterparts. Moreover, pancreatic T2*-value was positively correlated with BMD and T-score at all analyzed sites and Z-score at TH.ConclusionThese data showed lower bone mass in patients with organ iron overload, particularly for LS in males, FN and TH in females. TBS may well represent a complementary tool for the evaluation of bone quality and the risk of fracture in iron-overloaded patients.

The impact of liver iron overload determined by T2* MRI on liver fibrosis determined by FibroScan in patients with thalassemia major

Background:Thalassemia major (TM) is a form of hemolytic anemia requiring monthly blood transfusions from early childhood with each RBC introducing 200mg of iron to the patient system. The prognosis of liver iron overload is highly dependent on the one hand on both liver iron content (LIC) and the extent of liver fibrosis. In recent years, non-invasive methods were developed in order to replace liver biopsy. Magnetic resonance imaging (MRI) with T2*-weighted sequences has the potential to become a non-invasive standard technique in assessing tissue iron. Transient elastography TE (fibroScan) is a new non-invasive and reliable bedside method used to measure liver stiffness (LS) caused by fibrosis. Methods:This is a prospective study which was conducted on 40 patients diagnosed with a β-thalassemia major (22 males and 18 females) with age from 6 to 16 years old, regular blood transfusion and Iron chelation therapy for at least 18 months. All patients underwent evaluation of clinical manifestations, laboratory investigations and MR imaging techniques: liver to muscle signal intensity ratio and T2* and R2* Relaxometry. Results: R2* was significantly higher among sever iron overload stage than the other stages. T2* is reverse proportion with iron overload, but R2* is direct proportion with iron overload in liver. Age was significantly increased among severe iron overload group than mild and moderate groups. Also, there was significant relation between consanguinity and family history with iron overload stages among the studied patients. Virus C and splenectomy were significantly higher among severe iron overload stage than mild and moderate stages. Also, age at diagnosis was significantly higher among moderate iron overload stage than the other stages. There was highly significant relation between iron overload stages and fibrosis stage Also, Fibrosis reading was significantly higher among moderate iron overload stage than the other stages. Conclusions: MRI T2* is the best noninvasive method for assessment and evaluation of hepatic iron overload and determine its severity in β thalassemic major patients. There was significant relation between iron overload stages with MRI T2* and R2*

The use of carbon monoxide breath test to detect the effect of iron overload on erythrocyte lifespan in MDS.

To investigate the effect of iron overload (IO) on red blood cell (RBC) lifespan in MDS patients with the use of carbon monoxide breath test. The red blood cell lifespan of 93 patients with myelodysplastic syndrome (MDS) and 22 healthy volunteers in the control group were measured by alveolar gas carbon monoxide (CO) assay, with the detection of liver iron concentration, iron metabolism index, erythropoietin (EPO) concentration, peripheral blood inflammatory cytokines, etc. The MDS patients were divided into the severe IO group, mild IO group and non IO group according to liver iron concentration. The effect of IO on RBC lifespan was analyzed in MDS patients. The RBC lifespan of MDS patients in the severe IO group was significantly lower than that in the mild IO group (p<0.05), while the RBC life span in the mild IO group was significantly lower than that in the non IO group (p<0.05). The expression of inflammatory cytokines in the severe IO group was significantly higher than that of the mild and non IO groups. After receiving iron removal treatment(ICT), the expression of inflammatory cytokines was decreased significantly, and the RBC lifespan was significantly prolonged (p<0.05).Besides, liver iron concentration was significantly positively correlated with EPO concentration, while EPO concentration was significantly negatively correlated with RBC lifespan, especially in the MDS-RS subgroup. The RBC lifespan in the EPO>1000 group was significantly lower than that in the EPO<1000 group. IO can shorten RBC lifespan in MDS patients, which may be result from the increase of endogenous EPO and the over-expression of inflammatory cytokines. After ICT, the ineffective hematopoiesis caused by increased EPO may reduced and the decrease of inflammatory cytokine may significantly prolong the RBC lifespan in MDS patients.

Evaluating renal iron overload in diabetes mellitus by blood oxygen level-dependent magnetic resonance imaging: a longitudinal experimental study

BackgroundIron overload plays a critical role in the pathogenesis of diabetic nephropathy. Non-invasive evaluation of renal iron overload in diabetes in the management and intervention of diabetic nephropathy is of great significance. This study aimed to explore the feasibility of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in evaluating renal iron overload in diabetes using a rabbit model.MethodsThe rabbits were randomly divided into control, iron-overload (I), diabetes (D), and diabetes with iron-overload (DI) groups (each n = 19). The diabetes models were generated by injecting intravenous alloxan solution, and the iron-overload models were generated by injecting intramuscular iron-dextran. BOLD MRI was performed immediately (week 0) and at week 4, 8, and 12 following modeling. The differences in renal cortex (CR2*) and outer medulla R2* (MR2*) and the ratio of MR2*–CR2* (MCR) across the different time points were compared.ResultsIron was first deposited in glomeruli in the I group and in proximal tubular cells in renal cortex in the D group. In the DI group, there was iron deposition in both glomeruli and proximal tubular cells at week 4, and the accumulation increased subsequently. The degree of kidney injury and iron overload was more severe in the DI group than those in the I and D groups at week 12. At week 8 and 12, the CR2* and MR2* in the DI group were higher than those in the I and D groups (all P < 0.05). The MCR in the I, D, and DI groups decreased from week 0 to 4 (all P < 0.001), and that in the I group increased from week 8 to 12 (P = 0.034). CR2* and MR2* values displayed different trends from week 0–12. Dynamic MCR curves in the D and DI groups were different from that in the I group.ConclusionIt presents interactions between diabetes and iron overload in kidney injury, and BOLD MRI can be used to evaluate renal iron overload in diabetes.

Tip60/Kat5 may be a novel candidate histone acetyltransferase for the regulation of liver iron localization via acetylation.

Hepcidin (HAMP), an iron regulatory hormone synthesized by liver hepatocytes, works together with ferritin (FTH) and ferroportin (FPN) in regulating the storage, transport, and utilization of iron in the cell. Epigenetic mechanisms, especially acetylation, also play an important role in the regulation of iron metabolism. However, a target protein has not been mentioned yet. With this preliminary study, we investigated the effect of histone acetyltransferase TIP60 on the expression of HAMP, FTH, and FPN. In addition, how the depletion of Tip60, which regulates the circadian system, affects the daily expression of Hamp was examined at six Zeitgeber time (ZT) points. For this purpose, liver-specific Tip60 knockout mice (mutant) were produced with tamoxifen-inducible Cre/lox recombination and an iron overload model in mice was generated. While HAMP and FTH expressions decreased, FPN expression increased in the mutant group. Interestingly, there was no change in the iron content. A significant increase was observed in the expressions of HAMP, FTH, and FPN and total liver iron content in the liver tissue of the iron overload group. Since intracellular iron concentration is involved in regulating the circadian clock, temporal expression of Hamp was investigated in control and mutant groups at six ZT points. In the control group, Hamp accumulated in a circadian manner with maximal and minimal levels reaching around ZT16 and ZT8, respectively. In the mutant group, there was a significant reduction in Hamp expression in the light phase ZT0 and ZT4 and in the dark phase ZT16. These data are the first findings demonstrating a possible relationship between Tip60 and iron metabolism.

Association Between Serum Iron Status and Muscle Mass in Adults: Results From NHANES 2015-2018.

BackgroundIron deficiency or overload may contribute to complications associated with diseases, but the link between iron status and skeletal muscle disorder is poorly understood. This study aimed to investigate the relationship between serum iron status, reflected by serum ferritin concentration, and muscle mass in U.S. adults.MethodsWe utilized data from National Health and Nutrition Examination Survey (NHANES) 2015-2018 for analysis. Data on serum ferritin, appendicular skeletal muscle mass (ASM), body mass index (BMI) and confounding factors were extracted and analyzed. Multivariate linear regression analyses and smooth curve fittings were employed to investigate the association between serum ferritin and muscle mass. Subgroup analysis based on iron status, age, gender and race were performed.ResultsA total of 2,078 participants were included, and divided into iron deficiency (n = 225), normal iron status (n = 1,366), and iron overload (n = 487) groups. Participants with iron overload had significantly lower ASM and appendicular skeletal muscle index (ASMI) (ASM: 19.329 ± 4.879, ASMI: 0.709 ± 0.138) compared to those with iron deficiency (ASM: 22.660 ± 6.789, ASMI: 0.803 ± 0.206) and normal iron status (ASM: 22.235 ± 6.167, ASMI: 0.807 ± 0.201). The serum ferritin was negatively linked with muscle mass after adjusting for potential confounders (β = −0.0001, 95% CI: −0.0001, −0.0000). When stratified by iron status, the trend test between them remained significant (P for trend: 0.008). Furthermore, subgroup analysis identified a stronger association in men (β = −0.0001, 95% CI: −0.0002, −0.0001), age ≥ 40 years (β = −0.0001, 95% CI: −0.0002, −0.0000), non-Hispanic black (β = −0.0002, 95% CI: −0.0003, −0.0001) and other races (β = −0.0002, 95% CI: −0.0003, −0.0000).ConclusionsOur study revealed an inverse relationship between serum iron status and muscle mass in adults. This finding improves our understanding of the impact of serum iron status on muscle mass, and sheds new light on the prevention and treatment of muscle loss.

Acute iron overload aggravates blood-brainbarrier disruption and hemorrhagic transformation after transient focal ischemia in rats with hyperglycemia.

Hemorrhagic transformation (HT) has been reported to be associated with a poor prognosis after acute ischemic stroke. Blood-brain barrier (BBB) damage is considered as the major pathophysiologic mechanism of HT. Our aim was to investigate the role of acute iron overload in BBB damage and HT after transient focal ischemia in rats with hyperglycemia. Transient middle cerebral artery occlusion (MCAO) was induced in rats with hyperglycemia. Animals were assigned to four groups: Sham, Vehicle, Iron overload and Iron chelator treatment groups. Brain samples were collected at 24 h after surgery to quantify the amount of hemorrhage, determine extravasation of Evans blue and detect the levels of following proteins: ferritin, matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), Occludin and Claudin-5 by western blot analysis and immunohistochemistry. Compared to the Vehicle group, the Iron overload group had a significantly higher amount of hemorrhage and more extravasation of Evans blue. The Iron overload group had lower levels of ZO-1, Occludin and Claudin-5 and higher levels of ferritin and MMP-9 than the Vehicle group. Administering iron chelator reduced the extension of hemorrhage and extravasation of Evans blue, reversed the MCAO-induced reduction of ZO-1, Occludin and Claudin-5 and decreased the levels of ferritin and MMP-9. Our results suggest that acute iron overload aggravates BBB damage and HT after transient ischemia in rats with hyperglycemia, which provides basic evidence for iron overload as a potential factor associated with BBB damage and HT in ischemic stroke patients when accompanied with hyperglycemia.

Influencing factors of iron metabolism assessment in patients with myelodysplastic syndrome: A retrospective study

目的分析骨髓增生异常综合征（MDS）患者铁代谢评估的影响因素。方法181例MDS患者接受磁共振成像（MRI）和（或）能谱CT（DECT）对肝脏和心脏铁浓度的检测，其中41例患者在2次检查期间接受了规律铁螯合治疗（ICT）。同步检测调整铁蛋白（ASF）、红细胞生成素（EPO）、心功能、肝转氨酶、肝炎抗体、外周血T细胞极化等指标，并收集患者是否合并骨髓纤维化、脾大、环孢素A使用等信息进行比较分析。结果MRI组、DECT组肝铁浓度均与ASF呈正相关（r分别为0.512、0.606，P值均<0.001），MRI组心铁浓度与ASF仅呈弱相关（r＝0.303，P<0.001），而DECT组心铁浓度与ASF无明显相关性（r＝0.231，P＝0.053）。输血依赖显著影响患者肝和心铁浓度［MRI组：LIC：（28.370±10.706）mg/g对（7.593±3.508）mg/g，t＝24.30，P<0.001；MIC：1.81对0.95，z＝2.625，P<0.05，DECT组：肝VIC：（4.269±1.258）g/L对（1.078±0.383）g/L，t＝23.14，P<0.001：心VIC：1.69对0.68，z＝3.142，P<0.05］。重度以上铁过载组患者EPO浓度明显高于轻中度铁过载组及正常组（P值均<0.001）；MDS伴环状铁粒幼红细胞（MDS-RS）患者与和其他MDS低危组患者相比，肝铁浓度明显增高［DECT组：3.80（1.97,5.51）g/L对1.66（0.67,2.94）g/L，P＝0.004；MRI组：13.7（8.1,29.1）mg/g对11.6（7.1,21.1）mg/g，P＝0.032］。而年龄、骨髓纤维化、脾大、T细胞极化、环孢素A的使用、肝转氨酶、肝炎抗体阳性等因素对铁代谢无明显影响。结论MDS患者肝铁浓度与ASF呈正相关，心铁浓度与ASF无明显相关性。输血依赖、EPO浓度、合并RS是铁代谢的影响因素。