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1.
Sci Rep ; 12(1): 18572, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329148

RESUMO

Trypanosoma brucei causes human African trypanosomiasis (HAT) and nagana in cattle. During infection of a vertebrate, endocytosis of host transferrin (Tf) is important for viability of the parasite. The majority of proteins involved in trypanosome endocytosis of Tf are unknown. Here we identify pseudokinase NRP1 (Tb427tmp.160.4770) as a regulator of Tf endocytosis. Genetic knockdown of NRP1 inhibited endocytosis of Tf without blocking uptake of bovine serum albumin. Binding of Tf to the flagellar pocket was not affected by knockdown of NRP1. However the quantity of Tf per endosome dropped significantly, consistent with NRP1 promoting robust capture and/or retention of Tf in vesicles. NRP1 is involved in motility of Tf-laden vesicles since distances between endosomes and the kinetoplast were reduced after knockdown of the gene. In search of possible mediators of NRP1 modulation of Tf endocytosis, the gene was knocked down and the phosphoproteome analyzed. Phosphorylation of protein kinases forkhead, NEK6, and MAPK10 was altered, in addition to EpsinR, synaptobrevin and other vesicle-associated proteins predicted to be involved in endocytosis. These candidate proteins may link NRP1 functionally either to protein kinases or to vesicle-associated proteins.


Assuntos
Trypanosoma brucei brucei , Trypanosoma , Tripanossomíase Africana , Animais , Bovinos , Humanos , Endocitose/genética , Endossomos/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Proteínas Quinases/metabolismo , Receptores da Transferrina/metabolismo , Transferrina/genética , Transferrina/metabolismo , Trypanosoma/metabolismo , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/parasitologia , Neuropilina-1/metabolismo
2.
Biomed Res Int ; 2022: 2413176, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36420092

RESUMO

Background: Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety. Methods: PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when p value <0.05. Results: A total of 842 articles were retrieved, and 16 trials in the 15 articles were finally included. Roxadustat treatment significantly increased Hb levels. Iron (SMD 1.43, 95% CI 0.31 to 2.55), total iron-binding capacity (SMD 2.06, 95% CI 0.91 to 3.22), ferritin (WMD 21.33, 95% CI 3.04 to 39.62), transferrin saturation (SMD 4.17, 95% CI 3.90 to 4.45), and LDL-cholesterol (SMD -0.64, 95% CI -0.73 to -0.55) showed statistical significance in dialysis-dependent (DD) study. And hepcidin (SMD -1.56, 95% CI -2.63 to -0.50), transferrin (SMD 1.80, 95% CI 1.53 to 2.06), total iron-binding capacity (SMD 1.62, 95% CI 1.39 to 1.86), total cholesterol (SMD -0.88, 95% CI -1.68 to -0.09), ferritin (WMD -52.68, 95% CI -62.68 to -42.67), transferrin saturation (SMD -5.57, 95% CI -7.47 to -3.68), and LDL-cholesterol (SMD -0.85, 95% CI -1.37 to -0.34) showed statistical significance in not dialysis-dependent (NDD) study. In terms of safety, roxadustat treatment did not increase risk of total adverse events either in dialysis-dependent or not dialysis-dependent patients. Conclusion: Roxadustat can effectively improve anemia in patients with chronic kidney disease. There was no significant difference in total adverse events compared with the control group.


Assuntos
Anemia , Insuficiência Renal Crônica , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/etiologia , Transferrina , Ferro , Ferritinas , Colesterol
3.
Blood ; 140(19): 2006-2008, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36355465
4.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36361528

RESUMO

Aberrations in blood cells are common among heavy alcohol drinkers. In order to shed further light on such responses, we compared blood cell status with markers of hemolysis, mediators of inflammation and immune responses to ethanol metabolites in alcohol-dependent patients at the time of admission for detoxification and after abstinence. Blood cell counts, indices of hemolysis (LDH, haptoglobin, bilirubin), calprotectin (a marker of neutrophil activation), suPAR, CD163, pro- and anti-inflammatory cytokines and autoantibodies against protein adducts with acetaldehyde, the first metabolite of ethanol, were measured from alcohol-dependent patients (73 men, 26 women, mean age 43.8 ± 10.4 years) at baseline and after 8 ± 1 days of abstinence. The assessments also included information on the quantities of alcohol drinking and assays for biomarkers of alcohol consumption (CDT), liver function (AST, ALT, ALP, GGT) and acute phase reactants of inflammation. At baseline, the patients showed elevated values of CDT and biomarkers of liver status, which decreased significantly during abstinence. A significant decrease also occurred in LDH, bilirubin, CD163 and IgA and IgM antibodies against acetaldehyde adducts, whereas a significant increase was noted in blood leukocytes, platelets, MCV and suPAR levels. The changes in blood leukocytes correlated with those in serum calprotectin (p < 0.001), haptoglobin (p < 0.001), IL-6 (p < 0.02) and suPAR (p < 0.02). The changes in MCV correlated with those in LDH (p < 0.02), MCH (p < 0.01), bilirubin (p < 0.001) and anti-adduct IgG (p < 0.01). The data indicates that ethanol-induced changes in blood leukocytes are related with acute phase reactants of inflammation and release of neutrophil calprotectin. The studies also highlight the role of hemolysis and immune responses to ethanol metabolites underlying erythrocyte abnormalities in alcohol abusers.


Assuntos
Alcoolismo , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Hemólise , Proteínas de Fase Aguda/metabolismo , Haptoglobinas/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Consumo de Bebidas Alcoólicas , Acetaldeído , Etanol/metabolismo , Índices de Eritrócitos , Biomarcadores , Células Sanguíneas/metabolismo , Inflamação , Imunidade , Complexo Antígeno L1 Leucocitário , Bilirrubina/metabolismo , Transferrina/metabolismo
5.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36361544

RESUMO

Iron is essential for retinal metabolism, but an excess of ferrous iron causes oxidative stress. In glaucomatous eyes, retinal ganglion cell (RGC) death has been associated with dysregulation of iron homeostasis. Transferrin (TF) is an endogenous iron transporter that controls ocular iron levels. Intraocular administration of TF is neuroprotective in various models of retinal degeneration, preventing iron overload and reducing iron-induced oxidative stress. Herein, we assessed the protective effects of TF on RGC survival, using ex vivo rat retinal explants exposed to iron, NMDA-induced excitotoxicity, or CoCl2-induced hypoxia, and an in vivo rat model of ocular hypertension (OHT). TF significantly preserved RGCs against FeSO4-induced toxicity, NMDA-induced excitotoxicity, and CoCl2-induced hypoxia. TF protected RGCs from apoptosis, ferroptosis, and necrosis. In OHT rats, TF reduced RGC loss by about 70% compared to vehicle-treated animals and preserved about 47% of the axons. Finally, increased iron staining was shown in the retina of a glaucoma patient's eye as compared to non-glaucomatous eyes. These results indicate that TF can interfere with different cell-death mechanisms involved in glaucoma pathogenesis and demonstrate the ability of TF to protect RGCs exposed to elevated IOP. Altogether, these results suggest that TF is a promising treatment against glaucoma neuropathy.


Assuntos
Glaucoma , Fármacos Neuroprotetores , Hipertensão Ocular , Animais , Ratos , Modelos Animais de Doenças , Glaucoma/metabolismo , Hipóxia , Pressão Intraocular , Ferro/metabolismo , N-Metilaspartato , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/metabolismo , Transferrina/farmacologia
6.
Infect Immun ; 90(11): e0041422, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-36321833

RESUMO

TonB-dependent transporters (TDTs) are essential proteins for metal acquisition, an important step in the growth and pathogenesis of many pathogens, including Neisseria gonorrhoeae, the causative agent of gonorrhea. There is currently no available vaccine for gonorrhea; TDTs are being investigated as vaccine candidates because they are highly conserved and expressed in vivo. Transferrin binding protein A (TbpA) is an essential virulence factor in the initiation of experimental infection in human males and functions by acquiring iron upon binding to host transferrin (human transferrin [hTf]). The loop 3 helix (L3H) is a helix finger that inserts into the hTf C-lobe and is required for hTf binding and subsequent iron acquisition. This study identified and characterized the first TbpA single-point substitutions resulting in significantly decreased hTf binding and iron acquisition, suggesting that the helix structure is more important than charge for hTf binding and utilization. The tbpA D355P ΔtbpB and tbpA A356P ΔtbpB mutants demonstrated significantly reduced hTf binding and impaired iron uptake from Fe-loaded hTf; however, only the tbpA A356P ΔtbpB mutant was able to grow when hTf was the sole source of iron. The expression of tbpB was able to restore function in all tbpA mutants. These results implicate both D355 and A356 in the key binding, extraction, and uptake functions of gonococcal TbpA.


Assuntos
Gonorreia , Neisseria meningitidis , Proteína A de Ligação a Transferrina , Masculino , Humanos , Proteína A de Ligação a Transferrina/genética , Proteína A de Ligação a Transferrina/química , Proteína A de Ligação a Transferrina/metabolismo , Neisseria gonorrhoeae/metabolismo , Transferrina/genética , Transferrina/metabolismo , Mutação Puntual , Receptores da Transferrina/genética , Ferro/metabolismo , Neisseria meningitidis/metabolismo
7.
Int J Mol Sci ; 23(22)2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36430428

RESUMO

Cyanobacteria are characterized by high iron content. In this research, we collected ten commercial samples of Arthrospira spp. sold as food supplement to determine iron content and assess whether iron speciation showed variability among samples and changed respect to A. platensis grown in controlled conditions. Particular attention was also paid to phycocyanin, as an iron-binding protein. In six of the ten samples, 14 essential and non-essential trace elements were analysed using ICP-MS. Iron content measured in samples using atomic absorption spectrometry (AAS) varied from 353 (sample S5) to 1459 (sample S7) µg g-1 dry weight and was in the range of those reported by other authors in commercial supplements. Iron speciation was studied using size exclusion chromatography followed by the analysis of the collected fraction for the determination of iron by AAS and for protein separation using SDS-PAGE. Overlapping chromatographic profiles were obtained for total proteins, phycocyanin and iron, although quantitative differences were evidenced among the samples analysed. In most samples, iron was mainly bound to ligands with high molecular mass; however, in four samples iron was also bound to ligands with low molecular mass. In fractions containing the most relevant iron burden, the principal protein was phycocyanin, confirming its role as an iron-binding protein in commercial samples.


Assuntos
Ficocianina , Spirulina , Ficocianina/metabolismo , Spirulina/metabolismo , Ferro/metabolismo , Espectrofotometria Atômica , Transferrina/metabolismo
8.
Molecules ; 27(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36235117

RESUMO

The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam "staples", but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein-protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression.


Assuntos
Hemocromatose , Hepcidinas , Hemocromatose/genética , Hemocromatose/metabolismo , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismo , Hepcidinas/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ferro/metabolismo , Lactamas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
9.
Clin Lab ; 68(10)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36250841

RESUMO

BACKGROUND: Inflammatory processes activated by rapid viral replication of SARS-CoV-2 can play a key role in the pathogenesis of multiple organ damage and be responsible for the COVID-19 patients' dramatic outcomes and common abnormal laboratory findings. The aim of this study was to assess the correlation between various laboratory biomarkers, ferritin/transferrin ratio (FTR) and receiver operating characteristic (ROC) analysis in monitoring COVID-19 patients. METHODS: This observational study was conducted in three groups: healthy participants, non COVID-19 patients with COVID-19-like clinical signs, and COVID-19 patients (severe and non-severe). Biochemical (CRP, ferritin, transferrin and albumin) and hematological (WBC, lymphocytes) parameters were assessed by automated methods. Moreover, FTR and NLR markers were calculated in the three groups mentioned. Statistical analyses were done using R (version 4.1.0). ROC curve was used to validate the predictive value of parameters. RESULTS: The COVID-19 positive group had significantly higher NEU, CRP, ferritin, FTR values, while it's WBC, absolute counts of lymphocytes and albumin were significantly lower compared to the non-COVID-19 patients (p < 0.001). Serum ferritin and FTR level of the severe group was significantly higher than that of the non-severe group (p = 0.006 and (p = 0.011, respectively). The strongest correlation in all subjects showed between lymphocytopenia and increased NEU (r = -0.99, p < 0.001). The AUC values of WBC (0.95), lymphocytes (0.89), NEU (0.88), and NLR (0.88) were higher than CRP (0.64) or Ferritin (0.81). CONCLUSIONS: We recommend using FTR, WBC, and NLR changes as simple, useful, and inexpensive indicators in early detection of COVID-19 patients.


Assuntos
COVID-19 , Albuminas , Biomarcadores , COVID-19/diagnóstico , Ferritinas , Humanos , Neutrófilos , Prognóstico , Curva ROC , Estudos Retrospectivos , SARS-CoV-2 , Transferrina
10.
Int J Mol Sci ; 23(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36293552

RESUMO

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.


Assuntos
Ferroptose , NF-kappa B , Ratos , Animais , Feminino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Ferritinas/metabolismo , Regulação para Cima , Nitritos/metabolismo , Transferrina/metabolismo , Estradiol/metabolismo , Nitratos/metabolismo , Ovário/metabolismo , Apoferritinas/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Envelhecimento , Estresse Oxidativo , Ferro/metabolismo , Receptores da Transferrina/metabolismo
11.
Org Biomol Chem ; 20(44): 8766-8774, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36314473

RESUMO

Human serum transferrin binds ferric ions with high affinity and delivers them into cells via receptor-mediated endocytosis upon a decrease in pH in the endosome. Protonation events and conformational changes are known to play an important role in iron-release though the release is not yet fully understood. Human serum transferrin consists of two similar lobes which release iron at different rates. In this study, we investigate the iron binding sites of N- and C-lobes using quantum mechanical tools, particularly, the quantum chemical cluster approach. This study supports the inevitable role of axial tyrosine for the release of iron in quantum chemical models and provides valuable information about the proton transfer pathways for the protonation of Tyr188 and Tyr517 in N- and C-lobes, respectively. The calculations show that the release process is similar in both lobes; however, the energetic differences of the release process in N- and C-lobes, demonstrated for the first time, indicated that the release of iron in the N-lobe is thermodynamically favorable, in contrast to the one in the C-lobe.


Assuntos
Ferro , Transferrina , Humanos , Ferro/química , Transferrina/química , Transferrina/metabolismo , Sítios de Ligação , Endossomos/metabolismo , Endocitose , Concentração de Íons de Hidrogênio
12.
Fluids Barriers CNS ; 19(1): 79, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192747

RESUMO

BACKGROUND: The blood brain barrier (BBB) limits the therapeutic perspective for central nervous system (CNS) disorders. Previously we found an anti-mouse transferrin receptor (TfR) VHH (Nb62) that was able to deliver a biologically active neuropeptide into the CNS in mice. Here, we aimed to test its potential to shuttle a therapeutic relevant cargo. Since this VHH could not recognize the human TfR and hence its translational potential is limited, we also aimed to find and validate an anti-human transferrin VHH to deliver a therapeutic cargo into the CNS. METHODS: Alpaca immunizations with human TfR, and subsequent phage selection and screening for human TfR binding VHHs was performed to find a human TfR specific VHH (Nb188). Its ability to cross the BBB was determined by fusing it to neurotensin, a neuropeptide that reduces body temperature when present in the CNS but is not able to cross the BBB on its own. Next, the anti-ß-secretase 1 (BACE1) 1A11 Fab and Nb62 or Nb188 were fused to an Fc domain to generate heterodimeric antibodies (1A11AM-Nb62 and 1A11AM-Nb188). These were then administered intravenously in wild-type mice and in mice in which the murine apical domain of the TfR was replaced by the human apical domain (hAPI KI). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed to assess the concentration of the heterodimeric antibodies in the brain over time and the ability to inhibit brain-specific BACE1 by analysing the brain levels of Aß1-40. RESULTS: Selections and screening of a phage library resulted in the discovery of an anti-human TfR VHH (Nb188). Fusion of Nb188 to neurotensin induced hypothermia after intravenous injections in hAPI KI mice. In addition, systemic administration 1A11AM-Nb62 and 1A11AM-Nb188 fusions were able to reduce Aß1-40 levels in the brain whereas 1A11AM fused to an irrelevant VHH did not. A PK/PD experiment showed that this effect could last for 3 days. CONCLUSION: We have discovered an anti-human TfR specific VHH that is able to reach the CNS when administered systemically. In addition, both the currently discovered anti-human TfR VHH and the previously identified mouse-specific anti-TfR VHH, are both able to shuttle a therapeutically relevant cargo into the CNS. We suggest the mouse-specific VHH as a valuable research tool in mice and the human-specific VHH as a moiety to enhance the delivery efficiency of therapeutics into the CNS in human patients.


Assuntos
Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Animais , Anticorpos/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/metabolismo , Humanos , Camundongos , Neurotensina , Receptores da Transferrina , Transferrina/metabolismo
13.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232527

RESUMO

Egg-derived peptides play important roles in insulin secretion and sensitivity, oxidative stress, and inflammation, suggesting their possible involvement in obesity management. Hence, the aim of this study is to explore the alleviating effects of IRW (lle-Arg-Trp) and IQW (lle-Gln-Trp) on obesity via the mouse model induced by a high-fat diet. The entire experimental period lasted eight weeks. The results demonstrated that IQW prevented weight gain (6.52%), decreased the glucose, low-density lipoprotein (LDL), malonaldehyde, triglycerides, total cholesterol (TC), and leptin levels, and increased the concentration of adiponectin (p < 0.05, n = 8). Although IRW failed to prevent weight gain, it reduced the concentration of glucose, high-density lipoprotein (HDL), LDL, and leptin, and increased the concentration of adiponectin (p < 0.05, n = 8). Moreover, IRW and IQW increased glucose tolerance and insulin resistance based on the results of the intraperitoneal glucose test and insulin tolerance test (p < 0.05, n = 8). The quantitative polymerase chain reaction results revealed that IRW and IQW downregulated the mRNA expression of DGAT1 (Diacylglycerol O-Acyltransferase 1), DGAT2 (Diacylglycerol O-Acyltransferase 2), TNF-α, IL-6, and IL-1ß of liver tissue (p < 0.05, n = 8). The results of the 16S ribosomal RNA amplicon sequencing showed that IQW and IRW tended to reduce the relative abundance of Firmicutes and Parabacteroides, and that IRW enhanced the abundance of Bacteroides (p < 0.05, n = 8). Collectively, IRW and IQW supplementation could alleviate the progression of obesity due to the fact that the supplementation reduced lipid deposition, maintained energy balance, and reprogrammed gut microbiota.


Assuntos
Microbioma Gastrointestinal , Insulinas , Adiponectina/metabolismo , Animais , Colesterol/farmacologia , Diacilglicerol O-Aciltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas do Ovo/metabolismo , Glucose/farmacologia , Insulinas/metabolismo , Interleucina-6/metabolismo , Leptina/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Malondialdeído , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Peptídeos/farmacologia , RNA Mensageiro , RNA Ribossômico 16S/metabolismo , Transferrina/farmacologia , Triglicerídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Aumento de Peso
14.
PLoS One ; 17(10): e0275098, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36240192

RESUMO

BACKGROUND: Iron deficiency is the commonest cause of anaemia worldwide. Serum ferritin is the most sensitive non-invasive indicator of iron stores but its utility is compromised in inflammatory states as it is an acute phase reactant. This study sought to estimate the burden of iron deficiency in a healthy adult population residing in Kenya and to determine the association between various ferritin cut-offs and anaemia in a population known to have chronic low-grade inflammation. METHODS: Healthy adults aged 18-65 years were recruited from urban towns in 4 counties in Kenya at average altitudes of 1683-2099m above sea level as part of a global study conducted by the International Federation of Clinical Chemistry (IFCC) to determine reference intervals (RIs) for common laboratory tests. We analyzed complete blood count (CBC), C-reactive protein, iron, transferrin, transferrin saturation and ferritin data. RESULTS: We obtained data from 528 participants. There were 254 (48.1%) males and 274 females (51.9%). Based on a ferritin cut-off of 15 µg/L and Hb cut-offs of 14.5 g/dL and 12 g/dL, the prevalence of iron deficiency anaemia was 0.8% and 7.3% in males and females respectively. The odds of having anaemia was highest if one had a ferritin value less than 15 µg/L with a sensitivity of 28.6% and specificity of 98.4% in males, and sensitivity of 83.3% and specificity of 78.0% in females. CONCLUSION: Only the ferritin cut-off of 15 ug/L had an association with anaemia where it can be used for ruling out iron deficiency as the cause. Sex specific ferritin cut-offs for diagnosing iron deficiency in adults in sub-Saharan Africa need to be derived by comparing ferritin levels to stainable iron in bone marrow aspirates and trephines in order to ensure that we are using appropriate clinical decision limits.


Assuntos
Anemia Ferropriva , Anemia , Deficiências de Ferro , Adulto , Anemia/diagnóstico , Anemia/epidemiologia , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/epidemiologia , Proteína C-Reativa/metabolismo , Feminino , Ferritinas , Hemoglobinas/metabolismo , Humanos , Inflamação/complicações , Ferro/metabolismo , Quênia/epidemiologia , Masculino , Transferrina
15.
Sci Rep ; 12(1): 17490, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36261681

RESUMO

Disorders of iron metabolism has been implicated in cardiovascular disease. However, the association of serum iron stores and coronary artery disease (CAD) remains inconsistent. Here, we investigated the associations of serum iron metabolism with the incidence of CAD, the severity of coronary artery stenosis, metabolic biomarkers, and the risk of major adverse cardiovascular event (MACE). A total of 643 CAD patients and 643 healthy controls were enrolled to assess the associations of serum iron status with the presence of CAD, the severity of CAD, and the risk of MACE. Serum iron metabolism and other metabolic markers were measured in all subjects. All statistical analyses were analyzed using SPSS22.0 software and STATA statistical package. Serum level of iron metabolism markers, including serum iron, unsaturated transferrin iron binding capacity (UIBC), Total iron binding capacity (TIBC) levels, in CAD groups was significantly lower than the control group (P < 0.001). UIBC and TIBC were negatively correlated with ferritin in both sexes. Each unit increase of serum iron and TIBC were found to have a protective role for CAD in women (iron: OR 0.794, 95% CI (0.647-0.973), TIBC: OR 0.891, 95% CI (0.795-0.999), P < 0.05). However, high ferritin level was significant associated the CAD incident in both sexes (OR 1.029, 95% CI (1.002-1.058) in men, OR 1.013, 95% CI (1.0-1.025) in women, P < 0.05). Serum iron metabolism markers exhibited no significant association with the severity of CAD. Increased serum level of iron and TIBC levels were found to have a protective role for CAD in women, but not in men. Elevated serum ferritin is independently and positively associated with CAD in men and women.


Assuntos
Doença da Artéria Coronariana , Estenose Coronária , Masculino , Humanos , Feminino , Doença da Artéria Coronariana/epidemiologia , Estudos de Coortes , Ferro , Transferrina , Ferritinas , Projetos de Pesquisa
16.
Bioconjug Chem ; 33(10): 1803-1810, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36194889

RESUMO

The systemic delivery of exogenous proteins to cells within the brain and central nervous system (CNS) is challenging due to the selective impermeability of the blood-brain barrier (BBB). Herein, we hypothesized that protein delivery to the brain could be improved via functionalization with DNA aptamers designed to bind transferrin (TfR) receptors present on the endothelial cells that line the BBB. Using ß-galactosidase (ß-Gal) as a model protein, we synthesized protein spherical nucleic acids (ProSNAs) comprised of ß-Gal decorated with TfR aptamers (Transferrin-ProSNAs). The TfR aptamer motif significantly increases the accumulation of ß-Gal in brain tissue in vivo following intravenous injection over both the native protein and ProSNAs containing nontargeting DNA sequences. Furthermore, the widespread distribution of ß-Gal throughout the brain is only observed for Transferrin-ProSNAs. Together, this work shows that the SNA architecture can be used to selectively deliver protein cargo to the brain and CNS if the appropriate aptamer sequence is employed as the DNA shell. Moreover, this highlights the importance of DNA sequence design and provides a potential new avenue for designing highly targeted protein delivery systems by combining the power of DNA aptamers together with the SNA platform.


Assuntos
Aptâmeros de Nucleotídeos , Ácidos Nucleicos , Barreira Hematoencefálica/metabolismo , Transferrina/metabolismo , Receptores da Transferrina/metabolismo , Aptâmeros de Nucleotídeos/metabolismo , Ácidos Nucleicos/metabolismo , Células Endoteliais/metabolismo , beta-Galactosidase/metabolismo
18.
Int J Pharm ; 626: 122167, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36075524

RESUMO

Despite the efforts of the pharmaceutical and research sectors, Alzheimer's disease (AD) remains incurable, imposing the demand for new effective strategies. Vitamin B12 (VB12) has aroused interest due to its in vitro anti-amyloidogenic properties. However, the high molecular weight and hydrophilicity of VB12 are the main obstacles to its clinical application by hindering its passage through the blood-brain barrier (BBB). In recent years, drug delivery systems (DDSs) capable of transporting molecules across the BBB have gained attention for their effective brain delivery. In this work, VB12-loaded liposomes functionalized with transferrin (Tf) were produced, envisaging the dual-targeting of VB12 to the BBB and neuronal cells, due to the overexpression of Tf receptors in these cells. The produced liposomes presented sizes smaller than 200 nm, with low polydispersity and neutral zeta potential, being suitable for brain delivery. The nanoparticles exhibited an adequate encapsulation efficiency, a sustained release of VB12 for 9 days, and physical stability at storage conditions for up to 2 months. The developed nanosystem was capable of delaying the formation of Aß fibrils and disrupting mature fibrils, highlighting its great potential for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer , Nanopartículas , Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Preparações de Ação Retardada/farmacologia , Humanos , Lipossomos/farmacologia , Transferrina/metabolismo , Vitamina B 12 , Vitaminas
19.
Front Public Health ; 10: 922863, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091521

RESUMO

Background: This study aimed to explore the relationship between iron markers and metabolic obesity phenotypes and the role of age. Methods: Data were from the China Health and Nutrition Survey 2009. Metabolic obesity phenotypes included metabolically healthy with normal weight (MHNW), metabolically unhealthy with normal weight (MUNW), metabolically healthy with overweight/obesity (MHO), and metabolically unhealthy with overweight/obesity (MUO). Iron markers including ferritin, transferrin, and soluble transferrin receptor were calculated as Log and quartered. The linear regression and multinomial logistic regression were used to explore the association of iron markers with age and metabolic obesity phenotypes, respectively. Results: Ferritin was linearly related with age, with ß (95% confidence interval, CI) of 0.029 (0.027 to 0.032) and -0.005 (-0.007 to -0.002) for women and men. Transferrin was negatively associated with age in both men and women (ß < -0.011). Furthermore, compared with participants in the quartile 1 ferritin group, those in the quartile 4 had increased odds of MUNW, MHO, and MUO, with odds ratio and 95% confidence interval (OR, 95% CI) of 3.06 (2.20 to 4.25), 1.66 (1.35 to 2.05), and 5.27 (4.17 to 6.66). Transferrin showed similar relationships with MUNW, MUO, and MHO; whereas transferrin receptor showed no significance. We also found joint associations of ferritin and transferrin with MUNW, MUO, and MHO. The interactive effect of ferritin and transferrin on MUO was significant (P = 0.015). Conclusion: Increased ferritin and transferrin were associated with MUNW, MHO, and MUO. Age should be considered when investigating iron.


Assuntos
Ferritinas , Obesidade , Receptores da Transferrina , Transferrina , Fatores Etários , China/epidemiologia , Feminino , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Inquéritos Nutricionais/estatística & dados numéricos , Obesidade/classificação , Obesidade/epidemiologia , Obesidade/metabolismo , Obesidade Metabolicamente Benigna/epidemiologia , Obesidade Metabolicamente Benigna/metabolismo , Sobrepeso/epidemiologia , Sobrepeso/metabolismo , Fenótipo , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
20.
ScientificWorldJournal ; 2022: 9217268, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081606

RESUMO

Alpha-mangostin, a natural xanthone mainly extracted from the pericarp of Garcinia mangostana, has been shown to have promising anticancer properties in many types of cancer. However, the therapeutic potential of α-mangostin has been limited so far due to its poor aqueous solubility and low oral bioavailability, which limited its biopharmaceutical applications. Furthermore, α-mangostin failed to specifically reach tumors at a therapeutic concentration due and rapid elimination in vivo. We hypothesized that this drawback could be overcome by loading the drug within a delivery system conjugated to transferrin (Tf), whose receptors are overexpressed on many cancer cells and would enhance the specific delivery of α-mangostin to cancer cells, thereby enhancing its therapeutic efficacy. The objectives of this study were therefore to prepare and characterize transferrin-conjugated lipid-polymer hybrid nanoparticles (LPHN) entrapping α-mangostin, as well as to evaluate their therapeutic efficacy in vitro. We successfully prepared α-mangostin loaded LPHN using a one-step nanoprecipitation method with high drug entrapment efficiency. The conjugation of Tf to the LPHN was achieved by using the thiol-maleimide "click" reaction, leading to an increase in the particle hydrodynamic size of Tf-LPHN compared to that of unconjugated (control) LPHN (Ctrl-LPHN). Both Tf-LPHN and Ctrl-LPHN were bearing negative surface charges. Tf-LPHN and Ctrl-LPHN exhibited a sustained release of α-mangostin at pH 7.4, following an initial burst release, unlike rapid release of drug solution. The entrapment of α-mangostin in the LPHN led to an increase in α-mangostin uptake by cancer cells, and thus improved its antiproliferative activity compared to that observed with the drug solution. In conclusion, α-mangostin entrapped in the Tf-LPHN is therefore a highly promising therapeutic system that should be further optimized as therapeutic tools for cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias , Xantonas , Humanos , Lipídeos , Neoplasias/tratamento farmacológico , Polímeros , Transferrina , Xantonas/química
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