Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.

• Klíčová slova
• erythroferrone, exosomes, hepcidin, transferrin receptor,
• MeSH
• cytokiny genetika   metabolismus   MeSH
• erythropoetin farmakologie   MeSH
• erytroblasty účinky léků   metabolismus   MeSH
• exozómy metabolismus   MeSH
• hepcidiny genetika   metabolismus   MeSH
• játra metabolismus   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• receptory transferinu genetika   metabolismus   MeSH
• slezina metabolismus   MeSH
• svalové proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• Erfe protein, mouse MeSH Prohlížeč
• erythropoetin MeSH
• hepcidiny MeSH
• receptory transferinu MeSH
• svalové proteiny MeSH
• TFR2 protein, mouse MeSH Prohlížeč

Patients with porphyria cutanea tarda (PCT) reveal a susceptibility to reversible inactivation of hepatic uroporphyrinogen decarboxylase, which might be triggered by alcohol, hepatitis C virus infection, and iron overload. Inherited factors that may predispose to clinically overt PCT also include sequence deviations in the HFE gene that is mutated in classical hemochromatosis. Here, we studied the prevalence of both common and rare hemochromatosis gene variations in 51 PCT patients and 54 healthy controls of German origin. The frequency of the common HFE gene mutation C282Y was 15.7 % in PCT patients and 2.8 % in healthy control individuals (P < 0.001). By contrast, the frequencies of the common H63D mutation did not differ, and the allele frequencies of the less frequently observed sequence deviations as substitution S65C in the HFE gene and mutation Y250X in the TFR2 gene underlying hemochromatosis type 3 (HFE3) were < 0.02 both in PCT patients and controls. Our results comprise the first molecular studies of both common and rare hemochromatosis gene variants in German PCT patients, indicating a significant role of the C282Y mutation in the pathogenesis of PCT.

• MeSH
• frekvence genu MeSH
• genotyp MeSH
• histokompatibilita - antigeny třídy I genetika   MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• porphyria cutanea tarda genetika   patologie   MeSH
• protein hemochromatózy MeSH
• receptory transferinu genetika   MeSH
• teplota MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Německo epidemiologie   MeSH
• Názvy látek
• HFE protein, human MeSH Prohlížeč
• histokompatibilita - antigeny třídy I MeSH
• membránové proteiny MeSH
• protein hemochromatózy MeSH
• receptory transferinu MeSH
• TFR2 protein, human MeSH Prohlížeč

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content of hemojuvelin protein. Vice versa, the absence of hemojuvelin results in decreased liver content of matriptase-2, indicating that the two proteins interact. To further characterize the role of matriptase-2, we investigated iron metabolism in mask mice fed experimental diets. Administration of iron-enriched diet increased liver iron stores as well as hepcidin expression. Treatment of iron-overloaded mask mice with erythropoietin increased hemoglobin and hematocrit, indicating that the response to erythropoietin is intact in mask mice. Feeding of an iron-deficient diet to mask mice significantly increased spleen weight as well as the splenic content of erythroferrone and transferrin receptor proteins, indicating stress erythropoiesis. Liver hepcidin expression was decreased; expression of Id1 was not changed. Overall, the results suggest a complex interaction between matriptase-2 and hemojuvelin, and demonstrate that hepcidin can to some extent be regulated even in the absence of matriptase-2 proteolytic activity.

• Klíčová slova
• Hjv, Tfr2, Tfrc, Tmprss6, hepcidin, neogenin, transferrin receptor,
• MeSH
• deficit železa MeSH
• dietní železo farmakologie   MeSH
• erythropoetin farmakologie   MeSH
• GPI-vázané proteiny biosyntéza   nedostatek   genetika   fyziologie   MeSH
• hepcidiny biosyntéza   genetika   MeSH
• inhibitor diferenciace 1 biosyntéza   genetika   MeSH
• játra metabolismus   MeSH
• kostní morfogenetický protein 6 biosyntéza   genetika   MeSH
• membránové proteiny nedostatek   genetika   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• orgánová specificita MeSH
• přetížení železem metabolismus   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein hemochromatózy biosyntéza   nedostatek   genetika   fyziologie   MeSH
• proteinové domény MeSH
• regulace genové exprese účinky léků   MeSH
• rekombinantní proteiny metabolismus   MeSH
• serinové endopeptidasy nedostatek   genetika   fyziologie   MeSH
• slezina metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Bmp6 protein, mouse MeSH Prohlížeč
• dietní železo MeSH
• erythropoetin MeSH
• GPI-vázané proteiny MeSH
• Hamp protein, mouse MeSH Prohlížeč
• hepcidiny MeSH
• HJV protein, mouse MeSH Prohlížeč
• Idb1 protein, mouse MeSH Prohlížeč
• inhibitor diferenciace 1 MeSH
• kostní morfogenetický protein 6 MeSH
• matriptase 2 MeSH Prohlížeč
• membránové proteiny MeSH
• protein hemochromatózy MeSH
• rekombinantní proteiny MeSH
• serinové endopeptidasy MeSH

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

• Klíčová slova
• epidemiology, genetic susceptibility, hepcidin, iron metabolism pathway, pancreatic cancer,
• MeSH
• adenokarcinom metabolismus   MeSH
• genotyp MeSH
• hepcidiny genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory slinivky břišní metabolismus   MeSH
• regulace genové exprese u nádorů fyziologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• železo metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• hepcidiny MeSH
• železo MeSH

BACKGROUND: Iron overload and hepatitis C virus (HCV) infection are independent factors which are thought to play a role in the pathogenesis of porphyria cutanea tarda (PCT). OBJECTIVES: To determine the prevalence of the HFE gene mutations p.Cys282Tyr (C282Y), p.His63Asp (H63D) and p.Ser65Cys (S65C), the p.Tyr250X (Y250X) mutation of the TFR2 gene, and HCV infection in patients with PCT in the Czech population, and to make comparison of the iron status among the respective genotypes. METHODS: Iron metabolism indices, results of mutational analysis and serological markers of HCV infection were examined in 63 patients with PCT. RESULTS: The HFE gene mutations were detected in 70% of patients with PCT compared with 35% in the control group (P < 0.001). Mean serum ferritin levels were increased in all genotypes, the highest being in homozygotes for the p.Cys282Tyr mutation. HCV infection was detected in only 8% of patients with PCT. CONCLUSIONS: There was a very high prevalence of the p.Cys282Tyr and p.His63Asp mutations observed in patients with PCT accompanied by mild degrees of iron overload, which was genotype dependent.

• MeSH
• biologické markery krev   MeSH
• chronická hepatitida C komplikace   MeSH
• dospělí MeSH
• ferritin analýza   MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• Hepacivirus MeSH
• histokompatibilita - antigeny třídy I genetika   MeSH
• homozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• porphyria cutanea tarda genetika   virologie   MeSH
• přetížení železem komplikace   genetika   MeSH
• prevalence MeSH
• protein hemochromatózy MeSH
• rozdělení chí kvadrát MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• biologické markery MeSH
• ferritin MeSH
• HFE protein, human MeSH Prohlížeč
• histokompatibilita - antigeny třídy I MeSH
• membránové proteiny MeSH
• protein hemochromatózy MeSH

Matriptase-2, a membrane protein encoded by the Tmprss6 gene, is a negative regulator of hepcidin expression. Although matriptase-2 has been proposed to cleave membrane hemojuvelin, we have recently found decreased hemojuvelin protein levels in Tmprss6 -/- mice. The purpose of this study was to confirm this observation by determining hemojuvelin protein levels in another strain of mice with disrupted Tmprss6 gene, and to determine the effect of matriptase-2 deficiency on the expression of other membrane proteins participating in the bone morphogenetic protein signal transduction. Mask mice, which lack the proteolytic domain of matriptase-2, displayed decreased liver hemojuvelin protein content, while Id1 mRNA level, an indicator of hemojuvelin-dependent signal transduction, was increased. Protein levels of bone morphogenetic protein receptors Alk3 and Acvr2a were unchanged, and transferrin receptor 2 and neogenin protein levels were slightly decreased. The results confirm that the loss of matriptase-2 increases bone morphogenetic protein-dependent signaling, while paradoxically decreasing liver hemojuvelin protein content. The regulation of transferrin receptor 2 protein levels by transferrin saturation was not affected in mask mice. How the loss of matriptase-2 proteolytic activity leads to decreased hemojuvelin protein levels is at present unclear.

• MeSH
• aktivinové receptory typu II metabolismus   MeSH
• deficit železa MeSH
• down regulace MeSH
• GPI-vázané proteiny MeSH
• inhibitor diferenciace 1 genetika   metabolismus   MeSH
• injekce intraperitoneální MeSH
• játra účinky léků   metabolismus   MeSH
• membránové proteiny nedostatek   genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• protein hemochromatózy MeSH
• receptory morfogenetických kostních proteinů typu I metabolismus   MeSH
• receptory transferinu metabolismus   MeSH
• serinové endopeptidasy nedostatek   genetika   MeSH
• železo-dextranový komplex aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• activin receptor type II-A MeSH Prohlížeč
• aktivinové receptory typu II MeSH
• Bmpr1a protein, mouse MeSH Prohlížeč
• GPI-vázané proteiny MeSH
• HJV protein, mouse MeSH Prohlížeč
• Idb1 protein, mouse MeSH Prohlížeč
• inhibitor diferenciace 1 MeSH
• matriptase 2 MeSH Prohlížeč
• membránové proteiny MeSH
• messenger RNA MeSH
• neogenin MeSH Prohlížeč
• protein hemochromatózy MeSH
• receptory morfogenetických kostních proteinů typu I MeSH
• receptory transferinu MeSH
• serinové endopeptidasy MeSH
• TFR2 protein, mouse MeSH Prohlížeč
• železo-dextranový komplex MeSH

PURPOSE: Pheochromocytomas and paragangliomas (PCPG) are usually benign neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB-mutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species, suggesting that targeting the redox balance pathway could be a potential therapeutic approach. EXPERIMENTAL DESIGN: We studied the genetic alterations of cluster I PCPGs compared with cluster II PCPGs, which usually present as benign tumors. By targeting the signature molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using in vitro and in vivo models. RESULTS: By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PCPG cells with low SDHB levels. Moreover, through a preclinical animal model with PCPG allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. CONCLUSIONS: The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PCPGs.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• feochromocytom farmakoterapie   genetika   patologie   MeSH
• genový knockdown MeSH
• kyselina askorbová farmakologie   terapeutické užití   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši MeSH
• nádorové buněčné linie transplantace   MeSH
• oxidační stres účinky léků   MeSH
• paragangliom MeSH
• poškození DNA účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• sukcinátdehydrogenasa nedostatek   genetika   MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• kyselina askorbová MeSH
• reaktivní formy kyslíku MeSH
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH
• železo MeSH

Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.

• MeSH
• cytokiny genetika   metabolismus   MeSH
• erythropoetin genetika   farmakologie   MeSH
• GPI-vázané proteiny MeSH
• hepcidiny genetika   metabolismus   MeSH
• játra metabolismus   patologie   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mutantní kmeny myší MeSH
• myši MeSH
• protein hemochromatózy MeSH
• proteiny vázající RNA genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   genetika   MeSH
• serinové endopeptidasy genetika   metabolismus   MeSH
• slezina metabolismus   patologie   MeSH
• svalové proteiny genetika   metabolismus   MeSH
• velikost orgánu účinky léků   genetika   MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Ankrd17 protein, mouse MeSH Prohlížeč
• cytokiny MeSH
• Erfe protein, mouse MeSH Prohlížeč
• erythropoetin MeSH
• GPI-vázané proteiny MeSH
• Hamp protein, mouse MeSH Prohlížeč
• hepcidiny MeSH
• HJV protein, mouse MeSH Prohlížeč
• matriptase 2 MeSH Prohlížeč
• membránové proteiny MeSH
• protein hemochromatózy MeSH
• proteiny vázající RNA MeSH
• serinové endopeptidasy MeSH
• svalové proteiny MeSH
• železo MeSH