Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 16.970
Filtrar
1.
Sci Rep ; 11(1): 19618, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608227

RESUMO

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.


Assuntos
COVID-19/patologia , Ferro/sangue , Adulto , Idoso , COVID-19/mortalidade , COVID-19/virologia , Estudos Transversais , Feminino , Ferritinas/sangue , Ferritinas/metabolismo , Hepcidinas/sangue , Hepcidinas/metabolismo , Mortalidade Hospitalar , Humanos , Ferro/química , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Respiração Artificial , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Transferrina/química , Transferrina/metabolismo
2.
Clin Lab ; 67(9)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34542961

RESUMO

BACKGROUND: We aimed to evaluate the use of population-based-reference-intervals by calculating the individuality index and reference change value of iron, transferrin, ferritin, folate, vitamin B12, and 25-OH vitamin D parameters. METHODS: A total of 5 venous blood samples were taken from 11 female and 10 male individuals on days 0, 7, 14, 21, and 28. All tests were performed on an autoanalyzer and CVI, CVG, II, and RCV values were calculated for both genders and the whole groups. RESULTS: CVA (%)/CVI (%)/CVG (%) for iron, 0.67/27.3/32.3 transferrin, 0.62/3.60/10.27 ferritin, 2.27/6.21/105.6 folate 4.71/10.3/28.56 vitamin B12, 6.1/5.77/34.6, 25-OH Vitamin D 3.4/8.2/54.9 respectively. RCV calculated as a 2-tailed value at level of probability of significant change set at 0.95 - 0.99; 74.9/98.7 - 10.1/13.3 - 18.3/24.1 - 31.4/41.3 - 23.4/30.8 - 24.7/32.5 and II were 0.8-0.4-0.-0.4-0.17-0.1 respectively. CONCLUSIONS: CVI and CVG values for iron, transferrin, folate, vitamin B12, and 25-OH vitamin D are in accordance with the literature. Ferritin was calculated differently from the values in the database. This difference might be due to the characteristics of selected individuals for study. Evaluating the suitability and utility of the use of RR with values found for II. For iron, the use of RR was considered appropriate when taken as II < 0.6 and II > 1.4. However, the use of RCV is more appropriate for Transferrin, Folate, Vitamin B12, and 25-OH Vitamin D.


Assuntos
Ferritinas , Vitamina B 12 , Feminino , Ácido Fólico , Humanos , Ferro , Masculino , Transferrina , Vitamina D
3.
Am Fam Physician ; 104(3): 263-270, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34523883

RESUMO

Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload. It is the most common inherited disorder among people of northern European ancestry. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. Women are often diagnosed later than men, likely because of menstrual blood loss. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation. Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis. Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications. Liver transplantation may be considered in select patients. Individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition.


Assuntos
Hemocromatose/diagnóstico , Hemocromatose/epidemiologia , Hemocromatose/fisiopatologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Programas de Rastreamento/métodos , Transferrina/análise
5.
Nutrients ; 13(7)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34371810

RESUMO

Ferrous sulphate (FS) is a cost effective, readily available iron supplement for iron deficiency (ID). The pro-oxidant effect of oral ferrous iron is known to induce inflammation, causing gastric side-effects and resulting in poor compliance. Curcumin is a potent antioxidant and has also been shown to exhibit iron chelation in-vitro, although it is not established whether these effects are retained in-vivo. The aim of this study was therefore to assess the influence of a formulated bioavailable form of curcumin (HydroCurcTM; 500 mg) on acute iron absorption and status in a double blind, placebo-controlled randomized trial recruiting 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54). Participants were randomly allocated to five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Participants were provided with the supplements according to their relevant treatment groups at baseline (0 min), and blood collection was carried out at 0 min and at 180 min following supplementation. In the treatment groups, significant difference was observed in mean serum iron between baseline (0 min) and at end-point (180 min) (F (1, 144) = 331.9, p < 0.0001) with statistically significant intra-group increases after 180 min (p < 0.0001) in the FS18_Plac (8.79 µmol/L), FS18_Curc (11.41 µmol/L), FS65_Plac (19.09 µmol/L), and FS65_Curc (16.39 µmol/L) groups. A significant difference was also observed between the two time points in serum TIBC levels and in whole blood haemoglobin (HGB) in the treatment groups, with a significant increase (1.55%/2.04 g/L) in HGB levels from baseline to end-point observed in the FS65_Curc group (p < 0.05). All groups receiving iron demonstrated an increase in transferrin saturation (TS%) in a dose-related manner, demonstrating that increases in serum iron are translated into increases in physiological iron transportation. This study demonstrates, for the first time, that regardless of ferrous dose, formulated curcumin in the form of HydroCurc™ does not negatively influence acute iron absorption in healthy humans.


Assuntos
Absorção Fisiológica/efeitos dos fármacos , Curcumina/administração & dosagem , Suplementos Nutricionais , Compostos Ferrosos/administração & dosagem , Ferro/sangue , Administração Oral , Adulto , Disponibilidade Biológica , Método Duplo-Cego , Feminino , Ferritinas/sangue , Voluntários Saudáveis , Hemoglobinas/análise , Humanos , Proteínas de Ligação ao Ferro/sangue , Masculino , Transferrina/análise
6.
J Insect Sci ; 21(4)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34401920

RESUMO

Glycosylation is one of the most common post-translational modifications to occur during protein biosynthesis, but remains poorly understood in insects. In this study, we collected serum proteins from two silkworm developmental stages, namely day 7 of the fifth instar larval stage and day 2 of the pupal stage. Results of SDS-PAGE and periodic acid-Schiff staining revealed that most serum proteins with high abundance were putative glycoproteins. LC-MS/MS identified 149 larval and 303 pupal serum proteins in the Con A lectin-enriched fractions. GO analysis revealed that many serum proteins were involved in the proteolysis and carbohydrate metabolic process. 82 N-linked glycoproteins with at least one glycosylation site were identified. N-Linked glycosylation occurred at the sequon, Asn-X-Ser/Thr, and the proportions of Ser and Thr glycosylation at the hydroxy position were found 39.6% and 60.3%, respectively. The N-glycan structures found in serum glycoproteins were mainly Man2FucGlcNAc2 (67.9%). Since storage protein 1 and transferrin had a relatively high abundance in the serum and could be significantly enriched by Con A lectin, their glycosylation was analyzed in detail. Glycoside hydrases, serine proteases and serpins were found to form three interacting glycoprotein networks using the website STRING. This study provides important clues for the understanding of the function of N-linked glycosylation in metabolism, immunity, and metamorphosis.


Assuntos
Bombyx/metabolismo , Glicoproteínas/metabolismo , Receptores de Concanavalina A/metabolismo , Animais , Cromatografia de Afinidade , Glicosilação , Proteínas de Insetos/metabolismo , Espectrometria de Massas , Proteômica , Transferrina/metabolismo
7.
Blood Adv ; 5(16): 3102-3112, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34402883

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer, but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in patients with AML at diagnosis and explored the mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile, not associated with inflammation or transfusion, characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.


Assuntos
Anemia , Leucemia Mieloide Aguda , Animais , Eritroblastos , Humanos , Ferro , Camundongos , Transferrina
8.
Fish Shellfish Immunol ; 117: 169-178, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34389379

RESUMO

It is known that iron transporter proteins and their regulation can modulate the fish's immune system, suggesting these proteins as a potential candidate for fish vaccines. Previous studies have evidenced the effects of Atlantic salmon immunized with the chimeric iron-related protein named IPath® against bacterial and ectoparasitic infections. The present study aimed to explore the transcriptome modulation and the morphology of the sea louse Caligus rogercresseyi in response to Atlantic salmon injected with IPath®. Herein, Atlantic salmon were injected with IPath® and challenged to sea lice in controlled laboratory conditions. Then, female adults were collected after 25 days post-infection for molecular and morphological evaluation. Transcriptome analysis conducted in lice collected from immunized fish revealed high modulation of transcripts compared with the control groups. Notably, the low number of up/downregulated transcripts was mainly found in lice exposed to the IPath® fish group. Among the top-25 differentially expressed genes, Vitellogenin, Cytochrome oxidases, and proteases genes were strongly downregulated, suggesting that IPath® can alter lipid transport, hydrogen ion transmembrane transport, and proteolysis. The morphological analysis in lice collected from IPath® fish revealed abnormal embryogenesis and inflammatory processes of the genital segment. Furthermore, head kidney, spleen, and skin were also analyzed in immunized fish to evaluate the transcription expression of immune and iron homeostasis-related genes. The results showed downregulation of TLR22, MCHII, IL-1ß, ALAs, HO, BLVr, GSHPx, and Ferritin genes in head kidney and skin tissues; meanwhile, those genes did not show significant differences in spleen tissue. Overall, our findings suggest that IPath® can be used to enhance the fish immune response, showing a promissory commercial application against lice infections.


Assuntos
Copépodes/genética , Ectoparasitoses/prevenção & controle , Doenças dos Peixes/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Salmo salar/parasitologia , Transcriptoma , Vacinas/administração & dosagem , Animais , Ectoparasitoses/veterinária , Feminino , Ferritinas/genética , Salmo salar/imunologia , Transferrina/genética , Vacinação
9.
Int J Pharm ; 608: 121038, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34438008

RESUMO

New drug discovery and development processes encounter significant challenges including requirement of huge investments and lengthy time frames especially in cancer research field. Repurposing of old drugs against cancer provides a possible alternative while associated scale-up complexities with production of nanoparticles at industrial scale could be overcome by using a scalable nanoparticle technique. We previously described use of polymeric nanoparticles for inhaled delivery of amodiaquine (AQ) for non-small cell lung cancer (NSCLC) treatment. In this study, targeting potential of transferrin ligand conjugated inhalable AQ-loaded nanoparticles (Tf-AMQ NPs) was investigated against NSCLC. Tf-AMQ NP (liquid formulation) demonstrated an aerodynamic diameter of 4.4 ± 0.1 µm and fine particle fraction of 83.2 ± 3.0%, representing AQ deposition in the respirable region of airways. Cytotoxicity studies in NSCLC cell line with overexpressed transferrin receptors shown significant reduction in IC50 values with Tf-decorated AQ-loaded nanoparticles compared to AQ or non-targeted NPs, along with significant apoptosis induction (caspase assay) and reduced % colony growth in A549 and H1299 cells with Tf-AMQ NP. Furthermore, 3D spheroid studies (~7-fold reduction in spheroid volume compared to AMQ NPs) explained efficiency of conjugated nanoparticles in penetrating tumor core, and growth inhibition. AQ's autophagy inhibition ability significantly increased with nanoparticle encapsulation and transferrin conjugation. In conclusion, amodiaquine can be an assuring candidate for repurposing to consider for NSCLC treatment while delivering inhalable transferrin conjugated nanoparticles developed using a scalable HPH process to the target site, thus reducing the dose, side effects.


Assuntos
Amodiaquina , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Células A549 , Amodiaquina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Transferrina
10.
Int J Pharm ; 607: 121034, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34425193

RESUMO

Our previous studies have proven that carnosic acid (CA) induces apoptosis of liver cancer cells. However, the poor chemical properties of CA limit its in vivo anti-cancer effects. In this study, CA was loaded into liposomes (LP-CA), and LP-CA was further conjugated with transferrin (Tf-LP-CA) to overcome the shortcomings of poor solubility and absorption at the lesion site. In HepG2 and SMMC-7721 cells, compared with CA and LP-CA, more Tf-LP-CA was absorbed by liver cancer cells, which induced higher levels of apoptosis and reduced the mitochondrial membrane potential more effectively. In HepG2- and SMMC-7721-xenotransplanted mice, Tf-LP-CA inhibited tumor growth with no cytotoxicity to the liver, spleen, or kidney. Furthermore, compared with CA and LP-CA, Tf-LP-CA targeted the tumor site more effectively, enhanced the expressions of cleaved poly(ADP-ribose) polymerase, and Caspase-3 and -9, and regulated the expression levels of B-cell lymphoma 2 (Bcl2) family members in the tumor tissues. Tf-LP-CA was taken up by tumor cells and targeted at tumor tissues, ensuring the precise delivery of CA, which further promoted mitochondria-mediated intrinsic apoptosis in the liver cancer cells. These results provide evidence for the clinical application of the Tf-LP-based CA drug delivery system for liver cancer.


Assuntos
Lipossomos , Neoplasias Hepáticas , Abietanos , Animais , Apoptose , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Mitocôndrias , Transferrina
11.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299237

RESUMO

Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.


Assuntos
Biomarcadores , Lúpus Eritematoso Sistêmico/patologia , Adolescente , Idade de Início , Autoanticorpos/imunologia , Biomarcadores/sangue , Biomarcadores/urina , Ceruloplasmina , Quimiocina CCL2 , Criança , Pré-Escolar , Feminino , Humanos , Oxirredutases Intramoleculares , Rim/patologia , Lipocalina-2 , Lipocalinas , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Orosomucoide , Fenótipo , Índice de Gravidade de Doença , Transferrina
12.
Int J Biol Macromol ; 185: 434-440, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197848

RESUMO

This study investigated the interacting mechanism of CdTe quantum dots (QDs) with typical plasma protein transferrin (TF) as well as the impact of the formation of QDs-TF complex on the structure of TF and the cytotoxicity of mouse primary kidney cells. Dialysis experiments and cell viability assays revealed that the formation of QDs-TF complex reduced the contents of Cd released from CdTe QDs and thus counteracted the cytotoxicity of CdTe QDs. The assay of isothermal titration calorimetry found that CdTe QDs complexed with TF majorly through hydrophobic interaction. Multi-spectroscopic measurements showed that CdTe QDs caused the loosening of polypeptide chain, the changes of secondary and tertiary structures as well as the attenuated aggregation of TF molecule. Moreover, these structural and conformational changes were attributed to the nano-effects of CdTe QDs rather than the released Cd. This study is of great significance for fully evaluating the biocompatibility of Cd-QDs and comprehensively understanding the mechanism of Cd-QDs toxicity at the molecular and cellular level.


Assuntos
Compostos de Cádmio/toxicidade , Rim/citologia , Telúrio/toxicidade , Transferrina/química , Transferrina/metabolismo , Animais , Compostos de Cádmio/química , Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Rim/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Cultura Primária de Células , Estrutura Secundária de Proteína , Pontos Quânticos/química , Telúrio/química
13.
Anal Chim Acta ; 1175: 338753, 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34330448

RESUMO

Undoubtedly, light-emitting diodes (LEDs) and photodiodes (PDs) are indispensable optoelectronic devices in modern analytical chemistry. LEDs can serve as either light emitters or detectors, thus being an alternative to the most popular detection systems consisted of PD. In this contribution, a comparison between LED-LED and LED-PD detectors, operating in turbidimetric and nephelometric modes, has been carried out for immunoprecipitation detection of transferrin and ferritin. The greatest emphasis was placed on the study of detectors responses under different measurement conditions including current powering an emitter, amplification gain in the case of PD as detector or the construction of detection cells designed for the Multicommutated Flow Analysis (MCFA). The assumption was to obtain the fully-mechanized system with simple but efficient detection system to enable the determination of iron-binding proteins occurring at different concentration ranges in human body. As a result, the optimized arrangements of LED-LED and LED-PD setups were characterized by similar analytical characteristics, enabling the determination of transferrin with the detection limit (LOD) of 0.2 mg/L and RSDs of 2.8-4.8% for LED-LED, and LOD of 0.1 mg/L and RSDs of 0.9-3.6% for LED-PD. In the case of ferritin detection, only the response of the LED-PD detector was statistically distinguishable in the range of 130-198 µg/L of protein with recorded analytical signal change of 20 mV value. The addition of polymer for signal enhancement provided the increase of response range to 107-253 µg/L, enabling the developed system for detection of pathological serum ferritin levels.


Assuntos
Análise de Injeção de Fluxo , Transferrina , Ferritinas , Humanos , Imunoprecipitação , Nefelometria e Turbidimetria
14.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210014

RESUMO

Human serum transferrin (HST) is a glycoprotein involved in iron transport that may be a candidate for functionalized nanoparticles to bind and target cancer cells. In this study, the effects of the simple and doped with cobalt (Co) and copper (Cu) ferrihydrite nanoparticles (Fh-NPs, Cu-Fh-NPs, and Co-Fh-NPs) were studied by spectroscopic and molecular approaches. Fluorescence spectroscopy revealed a static quenching mechanism for all three types of Fh-NPs. All Fh-NPs interacted with HST with low affinity, and the binding was driven by hydrogen bonding and van der Waals forces for simple Fh-NPs and by hydrophobic interactions for Cu-Fh-NPs and Co-Fh-NPs binding, respectively. Of all samples, simple Fh-NPs bound the most to the HST binding site. Fluorescence resonance energy transfer (FRET) allowed the efficient determination of the energy transfer between HST and NPs and the distance at which the transfer takes place and confirmed the mechanism of quenching. The denaturation of the HST is an endothermic process, both in the case of apo HST and HST in the presence of the three types of Fh-NPs. Molecular docking studies revealed that Fh binds with a low affinity to HST (Ka = 9.17 × 103 M-1) in accord with the fluorescence results, where the interaction between simple Fh-NPs and HST was described by a binding constant of 9.54 × 103 M-1.


Assuntos
Cobalto/química , Compostos Férricos/síntese química , Transferrina/química , Transferrina/metabolismo , Cobre/química , Compostos Férricos/química , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Acoplamento Molecular , Nanopartículas , Ligação Proteica , Conformação Proteica , Espectrometria de Fluorescência , Termodinâmica
15.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199599

RESUMO

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2'-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.


Assuntos
Hepatopatias Alcoólicas/genética , Fígado/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Receptores de Estrogênio/genética , Receptores da Transferrina/genética , Álcoois/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerídeos/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Camundongos , Regiões Promotoras Genéticas , Receptor CB1 de Canabinoide/agonistas , Deleção de Sequência/genética , Transferrina/genética , Transferrina/metabolismo
16.
Sci Rep ; 11(1): 13431, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183735

RESUMO

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.


Assuntos
COVID-19/patologia , Ferro/sangue , Adulto , Idoso , COVID-19/complicações , COVID-19/virologia , Feminino , Ferritinas/sangue , Hospitalização , Humanos , Ferro/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/etiologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Transferrina/análise
17.
Biomolecules ; 11(5)2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063276

RESUMO

Diversion colitis is a non-specific inflammation of a defunctionalised segment of the colon after a temporary stoma has been performed. This inflammation is associated with an alteration of certain inflammatory serum markers. The aims of this study were, firstly, to evaluate the modification of inflammatory biomarkers after stimulation with probiotics prior to closure of the protective ileostomy. Secondly, to identify if a relationship could be established between the severity of diversion colitis and the alteration of inflammatory biomarkers in the blood. A prospective, randomized, double-blind, controlled study was conducted. Patients who underwent surgery for colorectal carcinoma with protective ileostomy between January 2017 and December 2018 were included, pending reconstructive surgery and with diversion colitis as diagnosis. The sample was randomly divided into a group stimulated with probiotics (SG) (n = 34) and a control group (CG) (n = 35). Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery, including the correlation with pro-inflammatory biomarkers in blood. As main findings, a significant decrease in C-reactive protein (CRP), Neutrophil/lymphocyte ratio (NLR ratio), and monocyte/lymphocyte ratio (LMR ratio) was observed in the SG versus the CG with a p < 0.001. A significant increase in transferrin values and in the platelet/lymphocyte ratio (PLR) was observed in the SG versus CG after stimulation with probiotics with a p < 0.001. A normalisation of CRP and transferrin levels was observed in the third month of follow-up after closure ileostomy, and NLR, LMR and PLR ratios were equal in both groups. Decreased modified Glasgow prognostic score was found in SG compared to CG after probiotic stimulation (p < 0.001). The endoscopic and histological severity of diversion colitis is associated with a greater alteration of blood inflammatory biomarkers. The stimulation with probiotics prior to reconstructive surgery promotes an early normalization of these parameters.


Assuntos
Biomarcadores/sangue , Neoplasias Colorretais/cirurgia , Ileostomia/efeitos adversos , Probióticos/administração & dosagem , Proctocolite/dietoterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neutrófilos/metabolismo , Contagem de Plaquetas , Probióticos/farmacologia , Proctocolite/sangue , Proctocolite/etiologia , Prognóstico , Estudos Prospectivos , Transferrina/metabolismo
18.
Am J Cardiol ; 152: 138-145, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34162484

RESUMO

Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Dissacarídeos/uso terapêutico , Óxido de Ferro Sacarado/uso terapêutico , Insuficiência Cardíaca/sangue , Hematínicos/uso terapêutico , Insuficiência Renal Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Anemia Ferropriva/sangue , Anemia Ferropriva/complicações , Estudos de Casos e Controles , Feminino , Compostos Férricos/uso terapêutico , Ferritinas/sangue , Insuficiência Cardíaca/complicações , Hemoglobinas/metabolismo , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/complicações , Índice de Gravidade de Doença , Transferrina/metabolismo , Resultado do Tratamento
19.
Exp Hematol ; 99: 12-20.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077792

RESUMO

Red blood cell production, or erythropoiesis, is a proliferative process that requires tight regulation. Erythropoietin (Epo) is a glycoprotein cytokine that plays a major role in erythropoiesis by triggering erythroid progenitors/precursors of varying sensitivity. The concentration of Epo in bone marrow is hypothesized to be suboptimal, and the survival of erythroid cells has been suggested to depend on Epo sensitivity. However, the key factors that control Epo sensitivity remain unknown. Two types of transferrin receptors (TfRs), TfR1 and TfR2, are known to play a role in iron uptake in erythroid cells. Here, we hypothesized that TfRs may additionally modulate Epo sensitivity during erythropoiesis by modulating Epo receptor (EpoR) signaling. Using an Epo-sensitive UT-7 (UT7/Epo) erythroid cell and human erythroid progenitor cell models, we report that iron-loaded transferrin, that is, holo-transferrin (holo-Tf), synergizes with suboptimal Epo levels to improve erythroid cell survival, proliferation, and differentiation. This is accomplished via the major signaling pathways of erythropoiesis, which include signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide-3-kinase (PI3K)/AKT. Furthermore, we found that this cooperation is improved by, but does not require, the internalization of TfR1. Interestingly, we observed that loss of TfR2 stabilizes EpoR levels and abolishes the beneficial effects of holo-Tf. Overall, these data reveal novel signaling properties of TfRs, which involve the regulation of erythropoiesis through EpoR signaling.


Assuntos
Antígenos CD/metabolismo , Proliferação de Células/efeitos dos fármacos , Eritroblastos/metabolismo , Eritropoetina/farmacologia , Ferro/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores da Transferrina/metabolismo , Transferrina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eritropoetina/metabolismo , Humanos , Ferro/metabolismo , Transferrina/metabolismo
20.
ACS Appl Mater Interfaces ; 13(23): 27533-27547, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34082528

RESUMO

Exposure of nanomaterials (NMs) to biological medium results in their direct interaction with biomolecules and the formation of a dynamic biomolecular layer known as the biomolecular corona. Despite numerous published data on nano-biointeractions, the role of protein glycosylation in the formation, characteristics, and fate of such nano-biocomplexes has been almost completely neglected, although most serum proteins are glycosylated. This study aimed to systematically investigate the differences in interaction of metallic NPs with glycosylated vs nonglycosylated transferrin. To reach this aim, we compared interaction mechanisms between differently sized, shaped, and surface-functionalized silver NMs and gold NMs to commercially available human transferrin (TRF), a glycosylated protein, and to its nonglycosylated recombinant form (ngTRF). Bovine serum albumin (BSA) was also included in the study for comparative purposes. Characterization of NMs was performed using transmission electron microscopy and dynamic and electrophoretic light scattering techniques. Fluorescence quenching and circular dichroism methods were used to evaluate protein binding constants on the nanosurface and conformational changes after the protein-NM interactions, respectively. Competitive binding of TRF, ngTRF, and BSA to the surface of different NMs was evaluated by separating them after extraction from protein corona by gel electrophoresis following quantification with a commercial protein assay. The results showed that the binding strength between NMs and transferrin and the changes in the secondary protein structure largely depend not only on NM physicochemical properties but also on the protein glycosylation status. Data gained by this study highlight the relevance of protein glycosylation for all future design, development, and efficacy and safety assessment of NMs.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Prata/química , Transferrina/metabolismo , Glicosilação , Humanos , Nanoestruturas , Ligação Proteica , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Transferrina/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...