Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obes...Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obesity.Here,it is demonstrated that the specific accumulation of oleic acid-modified polyoxovanadates(OPOVs)in adipose tissue leads to the reduction of iron concentrations in adipocytes in mice fed with a high-fat diet(HFD).Conjugation of oleic acids to polyoxovanadates enables tissue-specific depletion of iron from white adipose tissue(WAT)by OPOVs,protecting mice from HFD-induced obesity and obesity-associated metabolic deteriorations.Glucose tolerance and insulin sensitivity are improved in OPOV-treated mice,which demonstrates that the OPOV-induced iron depletion can reverse the metabolic degeneration caused by HFD-induced obesity.Furthermore,a decrease in expression of the marker genes of iron overload suggests the participation of OPOVs in maintaining iron homeostasis and a potential medical application of vanadium clusters in targeting the iron overload caused by obesity.These findings underscore the potential of vanadate-based clusters tailored to address the complex interplay between iron metabolism and metabolic health.展开更多
BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulatio...BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulation in many organs,especially when iron enters the cells via specific calcium channels.AIM To validate our hypothesis that adding amlodipine to the iron chelation regimen is more efficient in alleviating myocardial iron overload.METHODS Five databases,including PubMed,Cochrane Library,Embase,ScienceDirect,and ClinicalTrials.gov,were systematically searched,and three randomized controlled trials involving 144 pediatric patients with transfusion-dependent thalassemia were included in our meta-analysis based on the predefined eligibility criteria.The quality of the included studies was assessed based on the Cochrane collab-oration tool for bias assessment.The primary outcome assessed was myocardial-T2 and myocardial iron concentration,while the secondary results showed serum ferritin level,liver iron concentration,and treatment adverse outcomes.Weighted mean difference and odds ratio were calculated to measure the changes in the estimated treatment effects.RESULTS During the follow-up period,Amlodipine treatment significantly improved cardiac T2 by 2.79 ms compared to the control group[95%confidence interval(CI):0.34-5.24,P=0.03,I2=0%].Additionally,a significant reduction of 0.31 in myocardial iron concentration was observed with amlodipine treatment compared to the control group[95%CI:-0.38-(-0.25),P<0.00001,I2=0%].Liver iron concentration was slightly lower in the amlodipine group by-0.04 mg/g,but this difference was not statistically significant(95%CI:-0.33-0.24,P=0.77,I2=0%).Amlodipine also showed a non-significant trend toward a reduction in serum ferritin levels(-328.86 ng/mL,95%CI:-1212.34-554.62,P=0.47,I2=90%).Regarding safety,there were no significant differences between the groups in the incidence of gastrointestinal upset,hypotension,or lower limb edema.CONCLUSION Amlodipine with iron chelation therapy significantly improved cardiac parameters,including cardiac-T2 and myocardial iron,in patients with transfusion-dependent thalassemia without causing significant adverse events but enhancing the efficacy of iron chelation therapy.展开更多
Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induce...Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.展开更多
Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients...Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.展开更多
Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer＇s disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in ...Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer＇s disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer＇s disease mice,although the underlying mechanism remains unclear.In the present study,APPswe/PS1ΔE9 transgenic mice were administered icariin,astragalus,and puerarin（120,80,and 80 mg/kg,respectively,once a day,for 3 months）.Iron levels were detected by flame atomic absorption spectroscopy.Interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay.Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry.Our results demonstrate that after treatment,iron levels and malondialdehyde content are decreased,while glutathione peroxidase and superoxide dismutase activities are increased.Further,interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were reduced.These results confirm that compounds of icariin,astragalus,and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response.展开更多
BACKGROUND: The liver, as the main iron storage compart-ment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Exces-sive accumulation of iron is an import...BACKGROUND: The liver, as the main iron storage compart-ment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Exces-sive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES: PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease pro-gression. We have also included literature on adjuvant thera-peutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identiifcation of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause signiifcant improvement of liver functions in patients with iron overload. Phlebotomy can have beneifcial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and avail-able data suggest that it can be considered as target for adju-vant therapy in this condition.展开更多
AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been tho...AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.展开更多
In the present study,we investigated the mechanisms underlying the mediation of iron transport by Ltype Ca^2+ channels(LTCCs)in primary cultured ventral mesencephalon(VM)neurons from rats.We found that cotreatment wit...In the present study,we investigated the mechanisms underlying the mediation of iron transport by Ltype Ca^2+ channels(LTCCs)in primary cultured ventral mesencephalon(VM)neurons from rats.We found that cotreatment with 100 lmol/L FeSO4 and MPP^+(1-methyl-4-phenylpyridinium)significantly increased the production of intracellular reactive oxygen species,decreased the mitochondrial transmembrane potential and increased the caspase-3 activation compared to MPP^+ treatment alone.Co-treatment with 500 lmol/L CaCl2 further aggravated the FeSO4-induced neurotoxicity in MPP^+-treated VM neurons.Co-treatment with 10 lmol/L isradipine,an LTCC blocker,alleviated the neurotoxicity induced by co-application of FeSO4 and FeSO4/CaCl2.Further studies indicated that MPP^+treatment accelerated the iron influx into VM neurons.In addition,FeSO4 treatment significantly increased the intracellular Ca^2+ concentration.These effects were blocked by isradipine.These results suggest that elevated extracellular Ca^2+ aggravates ironinduced neurotoxicity.LTCCs mediate iron transport in dopaminergic neurons and this,in turn,results in elevated intracellular Ca^2+ and further aggravates iron-induced neurotoxicity.展开更多
Iron deficiency anemia and iron overload conditions affect more than one billion people worldwide.Iron homeostasis involves the regulation of cells that export iron into the plasma and cells that utilize or store iron...Iron deficiency anemia and iron overload conditions affect more than one billion people worldwide.Iron homeostasis involves the regulation of cells that export iron into the plasma and cells that utilize or store iron.The cellular iron balance in humans is primarily mediated by the hepcidin-ferroportin axis.Ferroportin is the sole cellular iron export protein,and its expression is regulated transcriptionally,post-transcriptionally and posttranslationally.Hepcidin,a hormone produced by liver cells,post-translationally regulates ferroportin expression on iron exporting cells by binding with ferroportin and promoting its internalization by endocytosis and subsequent degradation by lysosomes.Dysregulation of iron homeostasis leading to iron deposition in vital organs is the main cause of death in betathalassemia patients.Beta-thalassemia patients show marked hepcidin suppression,ineffective eiythropoiesis,anemia and iron overload.Beta-thalassemia is common in the Mediterranean region,Southeast Asia and the Indian subcontinent,and the focus of this review is to provide an update on the factors mediating hepcidin related iron dysregulation in beta-thalassemia disease.Understanding this process may pave the way for new treatments to ameliorate iron overloading and improve the long term prognosis of these patients.展开更多
Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine.Its primary therapies include clearing heat and detoxification,activating blood circulation,and re...Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine.Its primary therapies include clearing heat and detoxification,activating blood circulation,and removing blood stasis.Lonicera japonica flos(LJF)has long been known as an excellent antipyretic and antidote.Luteoloside(Lut)is one of the main components of LJF and exhibits antioxidant,anti-inflammatory,and cytoprotective properties.However,the protection of Lut against iron overload injury and its underlying mechanisms remain unclear.Therefore,HUVECs were exposed to 50μmol·L^(−1)iron dextran for 48 h to establish an iron overload damage model and the effects of Lut were assessed.Our results showed that 20μmol·L^(−1)Lut not only increased cell viability and weakened LDH activity,but also significantly up-regulated DDAHⅡexpression and activity,increased p-eNOS/eNOS ratio and NO content,and reduced ADMA content in HUVECs exposed to iron overload.Furthermore,Lut significantly attenuated intracellular/mitochondrial ROS generation,improved SOD,CAT,and GSH-Px activities,reduced MDA content,maintained MMP,inhibited mPTP opening,prevented cyt c from mitochondria released into cytoplasm,reduced cleaved-caspase3 expression,and ultimately decreased cell apoptosis induced by iron overload.The effects of Lut were similar to those of L-arginine(an ADMA competitive substrate),cyclosporin A(a mPTP blocker agent),and edaravone(a free radical scavenger)as positive controls.However,addition of pAD/DDAHⅡ-shRNA adenovirus reversed the above beneficial effects of Lut.In conclusion,Lut can protect HUVECs against iron overload injury via the ROS/ADMA/DDAHⅡ/eNOS/NO pathway.The mitochondria are the target organelles of Lut’s protective effects.展开更多
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form ...It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver.In this review,we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin,transferrin,and ferritin in iron homeostasis.The regulation of ferroptosis by endogenous and exogenous modulators will be examined.Furthermore,the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease,chronic hepatitis B and C,liver fibrosis,and hepatocellular carcinoma(HCC)will be analyzed.Finally,experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented.Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC,where induction of ferroptosis is the desired effect.Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.展开更多
Elevated iron stores as indicated by hyperferritinemiawith normal or mildly elevated transferrin saturation a n d m o s t l y m i l d h e p a t i c i r o n d e p o s i t i o n a r e a characteristic finding in subject...Elevated iron stores as indicated by hyperferritinemiawith normal or mildly elevated transferrin saturation a n d m o s t l y m i l d h e p a t i c i r o n d e p o s i t i o n a r e a characteristic finding in subjects with non-alcoholic fatty liver disease(NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.展开更多
Objective: To investigate the electrophysiology effects and mechanism of iron overload on the slow response autorhythmic cells in the left ventricular outflow tract of guinea pigs.Methods: Standard microelectrode cell...Objective: To investigate the electrophysiology effects and mechanism of iron overload on the slow response autorhythmic cells in the left ventricular outflow tract of guinea pigs.Methods: Standard microelectrode cell recording techniques were adopted to observe the electrophysiological effects of different concentrations of Fe^(2+)(100 μmol/L, 200 μmol/L) on the left ventricular outflow tract autorhythmic cells.Heart tissues were perfused with FeSO_4(200 μmol/L) combing with CaCl_2(4.2 mmol/L), Verapamil,(1 μmol/L), and nickel chloride(200μmol/L) respectively to observe the influences of these contents on electrophysiology of FeSO_4(200μmol/L) on the left ventricular outflow tract autorhythmic cells.Results: Fe^(2+)at both 100 μmol/L and 200 μmol/L could change the electrophysiological parameters of the slow response autorhythmic cells of the left ventricular outflow tract in a concentrationdependent manner resulting into decrease in Vmax, APA and MDP, slower RPF and VDD, and prolonged APD_(50) and APD_(90)(P all <0.05).Besides, perfusion of increased Ca^(2+) concentration could partially offset the electrophysiological effects of Fe^(2+)(200 μmol/L).The L-type calcium channel(LTCC) blocker Verapamil(1 μmol/L) could block the electrophysiological effects of Fe^(2+)(200 μmol/L).But the T-type calcium channel(TTCC) blocker nickel chloride(NiCl_2, 200 μmol/L) could not block the electrophysiological effects of Fe^(2+)(200 μmol/L).Conclusions: Fe^(2+) can directly change the electrophysiological characteristics of the slow response autorhythmic cells of the left ventricular outflow tract probably through the L-type calcium channel.展开更多
BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver ...BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.展开更多
Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrha...Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.展开更多
Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chron...Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver d isease and severeiron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis.Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis.An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.展开更多
The anemia of chronic kidney disease and hemodialysisis characterized by chronic inflammation and releaseof cytokines, resulting in the upregulation of the ironhormone hepcidin, also increased by iron therapy andreduc...The anemia of chronic kidney disease and hemodialysisis characterized by chronic inflammation and releaseof cytokines, resulting in the upregulation of the ironhormone hepcidin, also increased by iron therapy andreduced glomerular filtration, with consequent reduc-tion in iron absorption, recycling, and availability to theerythron. This response proves advantageous in theshort-term to restrain iron availability to pathogens, buultimately leads to severe anemia, and impairs the re-sponse to erythropoietin （Epo） and iron. Homozygosityfor the common C282Y and H63D HFE polymorphismsinfluence iron metabolism by hampering hepcidin re-lease by hepatocytes in response to increased ironstores, thereby resulting in inadequate inhibition othe activity of Ferroportin-1, inappropriately high ironabsorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive beneft by decreasing hepcidin release in response to iron infusion and infammation, thereby improving iron availability to erythropoiesis,anemia control, the response to Epo, and possibly sur-vival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization indepen-dently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a benefcial anti-infammatory and anti-micro-bic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic stud-ies may offer a valuable tool to test these hypotheses and guide the research of new therapies.展开更多
BACKGROUND:Increased liver iron stores may contribute to the progression of liver injury and fibrosis,and are associated with a higher risk of hepatocellular carcinoma development.Pre-transplant symptoms of iron overl...BACKGROUND:Increased liver iron stores may contribute to the progression of liver injury and fibrosis,and are associated with a higher risk of hepatocellular carcinoma development.Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients.HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins.This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis.METHODS:Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases.Liver function tests and serum iron markers were assessed in both groups.All patients were screened for HFE mutations (C282Y,H63D,S65C).Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes.RESULTS:The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis.There were no differences in the prevalence of all HFE mutations in both groups.In patients with a diagnosis of hepatocellular carcinoma,no significant associations with iron disorders and HFE gene mutations were found.CONCLUSIONS:Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations.Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis.As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease,there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.展开更多
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of exc...Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe （HFE） gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non- alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.展开更多
Iron is one of the necessary metal elements in the human body.There are numerous factors that control the balance of iron metabolism,and its storage and transportation mechanisms are intricate.As one of the most energ...Iron is one of the necessary metal elements in the human body.There are numerous factors that control the balance of iron metabolism,and its storage and transportation mechanisms are intricate.As one of the most energyintensive tissues in the body,the retina is susceptible to iron imbalance.The occurrence of iron overload in the retina leads to the generation of a significant quantity of reactive oxygen species.This will aggravate local oxidative stress and inflammatory reactions and even lead to ferroptosis,eventually resulting in retinal dysfunction.The blood-retinaretinal barrier is eventually harmed by oxidative stress and elevated inflammation,which are characteristics of retinal vascular disorders.The pathophysiology of retinal vascular disorders may be significantly influenced by iron.Recently,iron-chelating agents have been found to have antioxidative and anti-inflammatory actions in addition to iron chelating.Therefore,iron neutralization is considered to be a new and potentially useful therapeutic strategy.This article reviews the iron overload in retinal vascular diseases and discusses the therapeutic potential of iron-chelating agents.展开更多
基金supported by the National Natural Science Foundation of China(No.22101086)Guangzhou Basic and Applied Basic Research Project(No.202201010052)Guangdong Basic and Applied Basic Research Foundation(No.2023A1515140030).
文摘Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obesity.Here,it is demonstrated that the specific accumulation of oleic acid-modified polyoxovanadates(OPOVs)in adipose tissue leads to the reduction of iron concentrations in adipocytes in mice fed with a high-fat diet(HFD).Conjugation of oleic acids to polyoxovanadates enables tissue-specific depletion of iron from white adipose tissue(WAT)by OPOVs,protecting mice from HFD-induced obesity and obesity-associated metabolic deteriorations.Glucose tolerance and insulin sensitivity are improved in OPOV-treated mice,which demonstrates that the OPOV-induced iron depletion can reverse the metabolic degeneration caused by HFD-induced obesity.Furthermore,a decrease in expression of the marker genes of iron overload suggests the participation of OPOVs in maintaining iron homeostasis and a potential medical application of vanadium clusters in targeting the iron overload caused by obesity.These findings underscore the potential of vanadate-based clusters tailored to address the complex interplay between iron metabolism and metabolic health.
文摘BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulation in many organs,especially when iron enters the cells via specific calcium channels.AIM To validate our hypothesis that adding amlodipine to the iron chelation regimen is more efficient in alleviating myocardial iron overload.METHODS Five databases,including PubMed,Cochrane Library,Embase,ScienceDirect,and ClinicalTrials.gov,were systematically searched,and three randomized controlled trials involving 144 pediatric patients with transfusion-dependent thalassemia were included in our meta-analysis based on the predefined eligibility criteria.The quality of the included studies was assessed based on the Cochrane collab-oration tool for bias assessment.The primary outcome assessed was myocardial-T2 and myocardial iron concentration,while the secondary results showed serum ferritin level,liver iron concentration,and treatment adverse outcomes.Weighted mean difference and odds ratio were calculated to measure the changes in the estimated treatment effects.RESULTS During the follow-up period,Amlodipine treatment significantly improved cardiac T2 by 2.79 ms compared to the control group[95%confidence interval(CI):0.34-5.24,P=0.03,I2=0%].Additionally,a significant reduction of 0.31 in myocardial iron concentration was observed with amlodipine treatment compared to the control group[95%CI:-0.38-(-0.25),P<0.00001,I2=0%].Liver iron concentration was slightly lower in the amlodipine group by-0.04 mg/g,but this difference was not statistically significant(95%CI:-0.33-0.24,P=0.77,I2=0%).Amlodipine also showed a non-significant trend toward a reduction in serum ferritin levels(-328.86 ng/mL,95%CI:-1212.34-554.62,P=0.47,I2=90%).Regarding safety,there were no significant differences between the groups in the incidence of gastrointestinal upset,hypotension,or lower limb edema.CONCLUSION Amlodipine with iron chelation therapy significantly improved cardiac parameters,including cardiac-T2 and myocardial iron,in patients with transfusion-dependent thalassemia without causing significant adverse events but enhancing the efficacy of iron chelation therapy.
基金supported by the National Natural Science Foundation of China(No.82273628).
文摘Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.
文摘Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.
基金supported by the National Natural Science Foundation of China,No.81273983
文摘Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer＇s disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer＇s disease mice,although the underlying mechanism remains unclear.In the present study,APPswe/PS1ΔE9 transgenic mice were administered icariin,astragalus,and puerarin（120,80,and 80 mg/kg,respectively,once a day,for 3 months）.Iron levels were detected by flame atomic absorption spectroscopy.Interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay.Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry.Our results demonstrate that after treatment,iron levels and malondialdehyde content are decreased,while glutathione peroxidase and superoxide dismutase activities are increased.Further,interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were reduced.These results confirm that compounds of icariin,astragalus,and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response.
基金supported by a grant from Polish National Science Centre(2011/01/B/NZ6/00320)
文摘BACKGROUND: The liver, as the main iron storage compart-ment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Exces-sive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES: PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease pro-gression. We have also included literature on adjuvant thera-peutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identiifcation of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause signiifcant improvement of liver functions in patients with iron overload. Phlebotomy can have beneifcial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and avail-able data suggest that it can be considered as target for adju-vant therapy in this condition.
文摘AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.
基金supported by grants from the National Natural Science Foundation of China(81671249)the Natural Science Foundation of Shandong Province,China(ZR2016CM04).
文摘In the present study,we investigated the mechanisms underlying the mediation of iron transport by Ltype Ca^2+ channels(LTCCs)in primary cultured ventral mesencephalon(VM)neurons from rats.We found that cotreatment with 100 lmol/L FeSO4 and MPP^+(1-methyl-4-phenylpyridinium)significantly increased the production of intracellular reactive oxygen species,decreased the mitochondrial transmembrane potential and increased the caspase-3 activation compared to MPP^+ treatment alone.Co-treatment with 500 lmol/L CaCl2 further aggravated the FeSO4-induced neurotoxicity in MPP^+-treated VM neurons.Co-treatment with 10 lmol/L isradipine,an LTCC blocker,alleviated the neurotoxicity induced by co-application of FeSO4 and FeSO4/CaCl2.Further studies indicated that MPP^+treatment accelerated the iron influx into VM neurons.In addition,FeSO4 treatment significantly increased the intracellular Ca^2+ concentration.These effects were blocked by isradipine.These results suggest that elevated extracellular Ca^2+ aggravates ironinduced neurotoxicity.LTCCs mediate iron transport in dopaminergic neurons and this,in turn,results in elevated intracellular Ca^2+ and further aggravates iron-induced neurotoxicity.
基金supported by the Thailand Research Fund(BRG5780004, IRG5780009 and IRN58W0002)by a Research Chair Grant from the National Science and Technology Development Agency(NSTDA)supported by a Thai Royal Golden Jubilee Ph.D.Research Scholarship(PHD/0101/2553)
文摘Iron deficiency anemia and iron overload conditions affect more than one billion people worldwide.Iron homeostasis involves the regulation of cells that export iron into the plasma and cells that utilize or store iron.The cellular iron balance in humans is primarily mediated by the hepcidin-ferroportin axis.Ferroportin is the sole cellular iron export protein,and its expression is regulated transcriptionally,post-transcriptionally and posttranslationally.Hepcidin,a hormone produced by liver cells,post-translationally regulates ferroportin expression on iron exporting cells by binding with ferroportin and promoting its internalization by endocytosis and subsequent degradation by lysosomes.Dysregulation of iron homeostasis leading to iron deposition in vital organs is the main cause of death in betathalassemia patients.Beta-thalassemia patients show marked hepcidin suppression,ineffective eiythropoiesis,anemia and iron overload.Beta-thalassemia is common in the Mediterranean region,Southeast Asia and the Indian subcontinent,and the focus of this review is to provide an update on the factors mediating hepcidin related iron dysregulation in beta-thalassemia disease.Understanding this process may pave the way for new treatments to ameliorate iron overloading and improve the long term prognosis of these patients.
基金the National Natural Science Foundation of China(Nos.21467017,81660583,81673431,and 81803534)Jiangxi Applied Research and Cultivation Program(No.20181BBG78059).
文摘Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine.Its primary therapies include clearing heat and detoxification,activating blood circulation,and removing blood stasis.Lonicera japonica flos(LJF)has long been known as an excellent antipyretic and antidote.Luteoloside(Lut)is one of the main components of LJF and exhibits antioxidant,anti-inflammatory,and cytoprotective properties.However,the protection of Lut against iron overload injury and its underlying mechanisms remain unclear.Therefore,HUVECs were exposed to 50μmol·L^(−1)iron dextran for 48 h to establish an iron overload damage model and the effects of Lut were assessed.Our results showed that 20μmol·L^(−1)Lut not only increased cell viability and weakened LDH activity,but also significantly up-regulated DDAHⅡexpression and activity,increased p-eNOS/eNOS ratio and NO content,and reduced ADMA content in HUVECs exposed to iron overload.Furthermore,Lut significantly attenuated intracellular/mitochondrial ROS generation,improved SOD,CAT,and GSH-Px activities,reduced MDA content,maintained MMP,inhibited mPTP opening,prevented cyt c from mitochondria released into cytoplasm,reduced cleaved-caspase3 expression,and ultimately decreased cell apoptosis induced by iron overload.The effects of Lut were similar to those of L-arginine(an ADMA competitive substrate),cyclosporin A(a mPTP blocker agent),and edaravone(a free radical scavenger)as positive controls.However,addition of pAD/DDAHⅡ-shRNA adenovirus reversed the above beneficial effects of Lut.In conclusion,Lut can protect HUVECs against iron overload injury via the ROS/ADMA/DDAHⅡ/eNOS/NO pathway.The mitochondria are the target organelles of Lut’s protective effects.
文摘It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver.In this review,we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin,transferrin,and ferritin in iron homeostasis.The regulation of ferroptosis by endogenous and exogenous modulators will be examined.Furthermore,the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease,chronic hepatitis B and C,liver fibrosis,and hepatocellular carcinoma(HCC)will be analyzed.Finally,experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented.Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC,where induction of ferroptosis is the desired effect.Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
基金Supported by PMU-Forschungsforderungsfonds,No.E-13/17/086-AIGthe Austrian Research Funds,FWF to Weiss G,Project TRP-188SPAR Austria to Christian Datz is gratefully acknowledged
文摘Elevated iron stores as indicated by hyperferritinemiawith normal or mildly elevated transferrin saturation a n d m o s t l y m i l d h e p a t i c i r o n d e p o s i t i o n a r e a characteristic finding in subjects with non-alcoholic fatty liver disease(NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.
基金supported by Zhangjiakou Project of Science and Technology Studies and Development Planning(Grand No.1321078D)
文摘Objective: To investigate the electrophysiology effects and mechanism of iron overload on the slow response autorhythmic cells in the left ventricular outflow tract of guinea pigs.Methods: Standard microelectrode cell recording techniques were adopted to observe the electrophysiological effects of different concentrations of Fe^(2+)(100 μmol/L, 200 μmol/L) on the left ventricular outflow tract autorhythmic cells.Heart tissues were perfused with FeSO_4(200 μmol/L) combing with CaCl_2(4.2 mmol/L), Verapamil,(1 μmol/L), and nickel chloride(200μmol/L) respectively to observe the influences of these contents on electrophysiology of FeSO_4(200μmol/L) on the left ventricular outflow tract autorhythmic cells.Results: Fe^(2+)at both 100 μmol/L and 200 μmol/L could change the electrophysiological parameters of the slow response autorhythmic cells of the left ventricular outflow tract in a concentrationdependent manner resulting into decrease in Vmax, APA and MDP, slower RPF and VDD, and prolonged APD_(50) and APD_(90)(P all <0.05).Besides, perfusion of increased Ca^(2+) concentration could partially offset the electrophysiological effects of Fe^(2+)(200 μmol/L).The L-type calcium channel(LTCC) blocker Verapamil(1 μmol/L) could block the electrophysiological effects of Fe^(2+)(200 μmol/L).But the T-type calcium channel(TTCC) blocker nickel chloride(NiCl_2, 200 μmol/L) could not block the electrophysiological effects of Fe^(2+)(200 μmol/L).Conclusions: Fe^(2+) can directly change the electrophysiological characteristics of the slow response autorhythmic cells of the left ventricular outflow tract probably through the L-type calcium channel.
基金supported by agrant from Medical University of Gdansk(W-175)
文摘BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.
基金supported by the National Natural Science Foundation of China,Nos.U2004106 (to WY),81971061 (to JC)the Key Scientific Research Project of Colleges and Universities in Henan Province,No.21A320039 (to WY)。
文摘Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.
文摘Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver d isease and severeiron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis.Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis.An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.
文摘The anemia of chronic kidney disease and hemodialysisis characterized by chronic inflammation and releaseof cytokines, resulting in the upregulation of the ironhormone hepcidin, also increased by iron therapy andreduced glomerular filtration, with consequent reduc-tion in iron absorption, recycling, and availability to theerythron. This response proves advantageous in theshort-term to restrain iron availability to pathogens, buultimately leads to severe anemia, and impairs the re-sponse to erythropoietin （Epo） and iron. Homozygosityfor the common C282Y and H63D HFE polymorphismsinfluence iron metabolism by hampering hepcidin re-lease by hepatocytes in response to increased ironstores, thereby resulting in inadequate inhibition othe activity of Ferroportin-1, inappropriately high ironabsorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive beneft by decreasing hepcidin release in response to iron infusion and infammation, thereby improving iron availability to erythropoiesis,anemia control, the response to Epo, and possibly sur-vival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization indepen-dently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a benefcial anti-infammatory and anti-micro-bic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic stud-ies may offer a valuable tool to test these hypotheses and guide the research of new therapies.
基金supported by a grant from the Medical University of Gdansk (W-175)
文摘BACKGROUND:Increased liver iron stores may contribute to the progression of liver injury and fibrosis,and are associated with a higher risk of hepatocellular carcinoma development.Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients.HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins.This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis.METHODS:Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases.Liver function tests and serum iron markers were assessed in both groups.All patients were screened for HFE mutations (C282Y,H63D,S65C).Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes.RESULTS:The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis.There were no differences in the prevalence of all HFE mutations in both groups.In patients with a diagnosis of hepatocellular carcinoma,no significant associations with iron disorders and HFE gene mutations were found.CONCLUSIONS:Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations.Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis.As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease,there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.
文摘Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe （HFE） gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non- alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
基金Supported by Luzhou Municipal People’s Government and Southwest Medical University(No.2021LZXNYD-J03)Science and Technology Department of Sichuan Province Project(No.2022YFS0611).
文摘Iron is one of the necessary metal elements in the human body.There are numerous factors that control the balance of iron metabolism,and its storage and transportation mechanisms are intricate.As one of the most energyintensive tissues in the body,the retina is susceptible to iron imbalance.The occurrence of iron overload in the retina leads to the generation of a significant quantity of reactive oxygen species.This will aggravate local oxidative stress and inflammatory reactions and even lead to ferroptosis,eventually resulting in retinal dysfunction.The blood-retinaretinal barrier is eventually harmed by oxidative stress and elevated inflammation,which are characteristics of retinal vascular disorders.The pathophysiology of retinal vascular disorders may be significantly influenced by iron.Recently,iron-chelating agents have been found to have antioxidative and anti-inflammatory actions in addition to iron chelating.Therefore,iron neutralization is considered to be a new and potentially useful therapeutic strategy.This article reviews the iron overload in retinal vascular diseases and discusses the therapeutic potential of iron-chelating agents.
