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PubMed1987

Complete structure of the human transferrin gene. Comparison with analogous chicken gene and human pseudogene.

The complete structure of the human transferrin gene is presented. This gene has a total size of about 33.5 kb and is organized in 17 exons separated by 16 introns. The chicken ovotransferrin gene has a size of 10.5 kb and is also organized in 17 exons and 16 introns. The analysis of the structure of the two genes confirm, at the gene level, that transferrins originated by a gene duplication phenomenon. Finally, the existence of a new member of the transferrin family, a human transferrin non-processed pseudogene is demonstrated.

Amino Acid Sequence↗
PubMed1989

Gastric luminal digestion of lactoferrin and transferrin by preterm infants.

Lactoferrin, a milk iron-binding protein, may play antimicrobial, iron-absorptive and growth-promoting roles in the developing gastrointestinal tract. To perform such functions, lactoferrin must survive digestive processes in the gut lumen in an active form. We investigated the gastric digestion of lactoferrin in addition to that of the other milk proteins, transferrin and casein, in preterm infants by measuring their degradation during incubation in vitro at 37 degrees C with gastric fluid at pH 1.8, 3.2 and 5.8. Fluid was obtained 1 h after a milk feeding, a time of maximum peptic activity, from 12 infants with a mean gestational age of 29.7 +/- 0.8 weeks at birth and a postnatal age of 24.7 +/- 3.2 days at sampling. Hydrolysis of all three proteins as indicated by generation of trichloroacetic acid soluble material from iodinated substrate was maximal at acid pH and declined by greater than 75% at pH 5.8, lactoferrin was less rapidly degraded than casein at low pH and transferrin breakdown was intermediate. Analysis of reaction mixtures by SDS-polyacrylamide gel electrophoresis showed degradation of lactoferrin and transferrin to low molecular weight products at pH 3.2 but minimal breakdown at pH 5.8. Several discrete fragments were generated at low pH, including species with molecular weights of 41,000-42,000 which may represent half-molecules. We conclude that dietary lactoferrin and transferrin may be degraded by preterm infant gastric fluid to discrete species, but that hydrolysis may be minimal at the prevailing postprandial pH. Consequently they may be rendered available for possible subsequent biological action within the infant.

Caseins↗
PubMed1988

Gallium-transferrin as a macromolecular tracer of vascular permeability.

Labeling of plasma transferrin with gallium was investigated to determine whether the gallium-transferrin complex could be effectively used as a macromolecular tracer in studies of capillary permeability using Positron Emission Tomography (PET). Three gallium-plasma preparations were tested and 2 h biodistribution studies were performed in rats. The three preparations gave similar blood clearance and tissue distribution data, but the methods used for evaluating gallium-transferrin binding were found to be suboptimal. Gallium clearance from blood was biexpoential with both components faster than that of 125I-albumin. Gallium distribution spaces in all tissues including intracerebral Walker-256 tumors were larger than those of albumin. These results indicate a relative instability of the gallium-transferrin complex in vivo, which appears to preclude its use as an acceptable radiolabeled protein for vascular permeability studies using PET.

Animals↗
PubMedDate not supplied

Testicular toxicity of the transferrin binding radionuclide 114mIn in adult and neonatal rats.

Adult (70 d) and neonatal (7 d) male rats were dosed (i.p.) with 37 MBq/kg (1 mCi/kg; approximately 1 microgram elemental indium/kg) 114mIn, a transferrin-binding radionuclide. In adults, approximately 0.25% of the injected activity localised within the testis by 48 h postinjection and remained constant for up to 63 d. In neonates, 0.06% of the activity was in the testis by 48 h, and this declined such that by 63 d only 0.03% remained. At 63 d, treated rats had reduced sperm head counts and abnormal testicular histology that was more marked in animals dosed as adults than as neonates. In vitro, uptake of 114mIn into seminiferous tubules isolated from 7-, 20-, or 70-d-old rats was compared with that of 125I. Both radionuclides were readily accumulated by the tubules. Whilst 114In uptake into 20- and 70-d tubules was inhibited by excess transferrin, uptake into 7-d tubules was unchanged. 125I uptake was not affected by excess transferrin. These data support the contention that some radionuclides may cross the blood-testis barrier by utilisation of the physiologic iron-transferrin pathway, which may lead to greater testicular damage in adult compared to neonatal animals.

Animals↗
PubMed1996

Protection against oxidative injury and permeability alteration in cultured alveolar epithelium by transferrin-catalase conjugate.

The successful prevention of hydrogen peroxide-induced alveolar permeability alterations and cell injury by transferrin-catalase conjugate is described in this study. Permeability alterations and cell injury were induced in cultured alveolar epithelial monolayers by hydrogen peroxide. Transepithelial transport of a permeability marker, [14C] mannitol, and cellular nuclear fluorescence of a membrane integrity indicator, propidium iodide, were used to quantitate epithelial permeability and damage respectively. Hydrogen peroxide (0.1 - 10 mM) induced a dose-dependent increase in both alveolar permeability and cellular damage; however, the oxidant effect on monolayer permeability did not require prior cell damage. Electron spin resonance measurements using the spin trap 5,5-dimethyl-l-pyrroline-N-oxide indicated the formation of hydroxyl radicals in hydrogen peroxide-treated cells. Chelation of the cellular pool of iron by deferoxamine inhibited radical formation and helped protect the cells from oxidative changes. Prior treatment of the cells with catalase (0.1 U-10 U/ml) had minimal protective effects on cell injury and permeability alterations. In contrast, transferrin-catalase conjugate, at the same concentration range, exhibited much improved protective effects on the cells in response to oxidant stress. This enhanced protection was found to correlate well with an increase in cellular uptake of the enzyme conjugate via the transferrin receptor endocytosis pathway. Effective protection by the enzyme conjugate was shown to require both the antioxidant enzyme moiety and the cognate moiety for the cell surface receptor. These findings indicate the potential therapeutic merit of transferrin-catalase conjugate for the treatment of pathological processes in the lung, whenever oxidative stress is involved.

Animals↗
PubMed1995

Rapid and efficient isolation of transferrin and ferritin from Manduca sexta.

We report methods for the rapid purification of two iron-binding proteins from larval hemolymph of Manduca sexta. Ferritin was purified in two steps by density gradient ultracentrifugation. To accomplish this, we utilized the relatively high level of ferritin present in the hemolymph of this animal and augmented the density of the protein in vivo by injection of iron sulfate. Nitrocellulose blots analyzed by laser densitometry showed hemolymph from iron-injected insects contained about 0.4 mg of ferritin per ml (approximately 0.7% of total hemolymph protein); of this, 62% was found as pure ferritin in the pellet formed during ultracentrifugation. Following the density ultracentrifugation, we purified transferrin from the hemolymph subphase by immobilized metal ion affinity chromatography using a new gel, Novarose-SE1000/40 coupled to dipicolylamine (DPA) chelated with nickel. Higher capacity Ni2+DPA-gel permitted good resolution of transferrin in the first chromatography; a lower capacity of the same gel allowed purification of transferrin in a second step. Overall transferrin recovery was 52%. Larval hemolymph contained 0.770 mg transferrin/ml, representing about 1.3% of the total protein.

Animals↗
PubMed2005

Evolution of duplications in the transferrin family of proteins.

The transferrin family is a group of proteins, defined by conserved amino acid motifs and putative function, found in both vertebrates and invertebrates. Included in this group are molecules known to bind iron, including serum transferrin, ovotransferrin, lactotransferrin, and melanotransferrin (MTF). Additional members of this family include inhibitor of carbonic anhydrase (ICA; mammals), major yolk protein (sea urchins), saxiphilin (frog), pacifastin (crayfish), and TTF-1 (algae). Most family members contain two lobes (N and C) of around 340 amino acids, the result of an ancient duplication event. In this article, we review the known functions of these proteins and speculate as to when the different homologs arose. From multiple-sequence alignments and neighbor-joining trees using 71 transferrin family sequences from 51 different species, including several novel sequences found in the Takifugu and Ciona genome databases, we conclude that melanotransferrins are much older (>670 MY) and more pervasive than previously thought, and the serum transferrin/melanotransferrin split may have occurred not long after lobe duplication. All subsequent duplication events diverged from the serum transferrin gene. The creation of such a large multiple-sequence alignment provides important information and could, in the future, highlight the role of specific residues in protein function.

Amino Acid Sequence↗
PubMed2004

Recombinant transferrin induces nitric oxide response in goldfish and murine macrophages.

We have previously demonstrated that the serum protein transferrin plays a key role in the activation of primary goldfish macrophages. The ability of this protein to activate goldfish macrophages was also shown to be dependent on enzymatic cleavage of the native (i.e. full-length) protein into immunostimulatory fragments. In this study, we report that immunostimulatory fragments of recombinant goldfish transferrin (rGTf), induced a potent nitric oxide (NO) response in goldfish as well as in murine macrophages. Specifically, recombinant goldfish transferrin N- and C-lobe fragments expressed in Escherichia coli induced the NO response in goldfish and murine macrophages. As little as 75-150 ng of the recombinant proteins (N- or C-lobe) had biological activity, even in the presence of 10 microg/ml of the LPS inhibitor polymixin B sulphate (PMB). These findings indicate that transferrin is a key conserved component required for induction of macrophage antimicrobial responses of fish and provide evidence that a similar induction pathway exists in mammals, which has not been reported previously.

Adjuvants, Immunologic↗
PubMed2005

Solenopsis invicta transferrin: cDNA cloning, gene architecture, and up-regulation in response to Beauveria bassiana infection.

Transferrin genes from several insects have been shown to be induced in response to bacterial or fungal infection. We were interested to know whether transferrin genes in the red imported fire ant, Solenopsis invicta, are similarly induced by microbial challenge. Hence, the cDNA and structure of a gene exhibiting significant homology to insect transferrins were elucidated for S. invicta. The cDNA was comprised of 2417 nucleotides, excluding the poly(A) tail, with a large open reading frame of 2106 nucleotides. The predicted translation product of the S. invicta tranferrin (SiTf) gene was a 702 amino acid polypeptide with an estimated molecular mass of 77.3 kDa and a pI value of 5.66, characteristics consistent with transferrin proteins. Comparative analysis of genomic and cDNA sequences revealed that the SiTf gene was comprised of 8 exons. Quantitative real-time PCR was used to examine the expression of SiTf. Expression of SiTf was induced in worker ants exposed to Beauveria bassiana conidia. Autoclave-killed conidia did not elicit a SiTf induction response from worker ants. Genes, like SiTf, responding to microbe attack or infection may provide a unique approach to assist in the discovery of microbial control organisms for the target insect pest.

Animals↗
PubMed2006

Transferrin and iron induce insulin resistance of glucose transport in adipocytes.

Normal serum can increase the rate of lipolysis in isolated adipocytes. Recently, we reported that the lipolytic effect of serum could be partly explained by effects of iron and transferrin. To further investigate these effects on fat cell metabolism, we have investigated effects of serum, iron, and transferrin on glucose transport in isolated rat adipocytes. Adipocytes were isolated by collagenase digestion of rat epididymal fat pads, and glucose transport was measured as uptake of [3H]2-deoxyglucose, measured in the presence of 0 to 25 ng/mL insulin. Insulin stimulated glucose transport approximately 8- to 10-fold, with a half-maximally effective concentration (EC50) of approximately 0.15 ng/mL. This was not affected by 45-minute treatment with normal human serum. However, when adipocytes were incubated with serum for 4 hours, cells became markedly insulin resistant. This was manifested as decrease in maximally stimulated glucose transport and a rightward shift in the dose-response curve. Both FeS04 (3 microg/mL) and transferrin (100 microg/mL) had similar, although less pronounced effects on insulin-stimulated glucose transport. Treatment of adipocytes with palmitic acid (120 micromol/L), representing the concentration of fatty acids released into the media after 4 hours of serum treatment, did not alter the effect of insulin on glucose transport. We conclude that transferrin and iron induce insulin resistance of glucose transport in adipocytes through a mechanism independent of fatty acids. These findings may further explain the association between body iron stores and risk of type 2 diabetes mellitus.

Adipocytes↗
PubMed2003

Proteomic and postproteomic characterization of keratan sulfate-glycanated isoforms of thyroglobulin and transferrin uniquely elaborated by papillary thyroid carcinomas.

Previous studies have suggested that surface components of papillary thyroid carcinoma (PTC) cells may be aberrantly glycanated, but the precise nature of these molecules has not been unveiled nor documented to be of clinical relevance. A monoclonal antibody was raised against a unique keratan sulfate (KS) determinant and used to differentially screen benign and malignant thyroid tissue for the expression of components carrying these moieties. In a total of 349 cases of benign and malignant thyroid lesions, 100% of the 115 PTC cases examined (including various histological subtypes) were found to contain KS-bearing molecules, whereas these were virtually absent from benign tissues and other thyroid tumors, with the exception of 21% of the follicular carcinoma cases analyzed. A composite immunoaffinity chromatography, immunochemistry, and mass spectrometric approach revealed that the PTC-specific KS-bearing macromolecules were unique glycoforms of thyroglobulin and transferrin. Combined, reciprocal immunoprecipitation and Western blotting further indicated that the former glycoform predominated and that most of the transferrin produced by PTC was glycanated with KS moieties. Fluorescent keratanase II-based fingerprinting of the KS moieties bound to these isoforms further demonstrated several PTC-specific peculiarities: 1) that a considerable portion of the moieties was covalently attached via a novel core protein linkage structure; 2) they had an unusual extended average length; 3) an unusual relative ratio of highly sulfated disaccharides terminating with alpha (2-3)-linked N-acetylneuraminic acid capping residues; and 4) a novel unidentified oligosaccharide moiety at the nonreducing terminus. Comparative analysis of the relative distribution of transferrin in benign versus PTC tissues highlighted a marked malignancy-associated abundance of the molecule, with a >75% frequency in expression in PTC. These findings demonstrate that PTC cells synthesize unique post-translationally modified thyroglobulin and transferrin variants in situ that may be directly exploitable for diagnosis, through histological and noninvasive cytological procedures; for devising novel strategies for antibody-guided imaging of this tumor in vivo; and for postsurgery follow-up of PTC patients.

Amino Acid Sequence↗
PubMed2000

Efficient gene transfer by transferrin lipoplexes in the presence of serum.

Cationic lipids are being used increasingly as reagents for gene delivery both in vitro and in vivo. One of the limitations to the application of cationic lipid-DNA complexes (lipoplexes) in vivo is the inhibition of gene delivery by serum. In this study, we have shown that transferrin (Tf)-lipoplexes, which had transferrin adsorbed at their surface via electrostatic interactions, are much more effective than plain lipoplexes in transfecting cells in the presence of relatively high concentrations (up to 60%) of fetal bovine serum (FBS). Serum even enhanced transfection by Tf-lipoplexes composed of 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/dioleoylphosphatidylethanolamine (DOPE)/pCMVLacZ at high lipid/DNA (+/-) charge ratios, and inhibited lipofection for those with low charge ratios when they were added to the cells immediately after the preparation of complexes. The effect of serum on lipofection was dose-dependent. Preincubation of the complexes at 20 degrees C for 6 h led to serum resistance, even for the negatively charged transferrin-lipoplexes. A similar tendency was observed for DOTAP/cholesterol and DOTAP/DOPE/cholesterol liposomes. The percentage of cells transfected, measured by beta-galactosidase expression, also increased with the serum concentration. Cell viability was not affected significantly when the cells were incubated with the complexes for 4 h at 37 degrees C, followed by a 48-h incubation. Our findings extend the scope of previous studies where transferrin-lipoplexes were used to introduce DNA into cells, rendering these complexes and their future derivatives potential alternatives to viral vectors for gene delivery in vivo.

Animals↗
PubMed2002

Leishmania chagasi: uptake of iron bound to lactoferrin or transferrin requires an iron reductase.

Leishmania chagasi can utilize iron bound to transferrin, lactoferrin, or other chelates. We investigated the mechanism of iron uptake. Promastigotes preferentially took up iron in a reduced rather than an oxidized form, suggesting that extracellular iron must be reduced prior to internalization. Similar to literature reports, a 70-kDa protein in promastigote membrane-containing microsomes bound to [125I]-labeled transferrin. However, [125I]lactoferrin and [125I]albumin also bound a similar 70-kDa protein, suggesting that binding might not be specific. Both total and fractionated promastigotes exhibited an NADPH-dependent iron reductase activity. In contrast to trypanosomes, which take up transferrin through a specific receptor, these data support a model in which a parasite-associated or secreted reductase reduces ferric to ferrous iron, decreasing its affinity for the extracellular chelate and allowing it to be readily internalized by the parasite. This could account for the ability of the parasite to utilize iron from multiple sources in diverse host environments. Index Descriptors and Abbreviations. Index descriptors: Cryptococcus neoformans, Histoplasma capsulatum, iron, iron reductase, lactoferrin, L. chagasi, leishmaniasis, nutrient acquisition, protozoan, Saccharomyces cerevisiae, Trypanosoma brucei, Trypanosoma cruzi, transferrin; Abbreviations used: DNA, deoxyribonucleic acid; DTT, dithiothreitol; HBSS, Hanks' balanced salt solution; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NEM, N-ethylmaleimide; RNA, ribonucleic acid.

Animals↗
PubMed2000

Inhibition of endosome fusion in primary hepatocytes prevents asialoglycoprotein degradation but not uptake of transferrin iron demonstrating that intracellular iron release occurs from early endosomes.

A comparison of the effects of inhibitors of membrane fusion on the uptake of asialoglycoprotein and transferrin by primary rat hepatocytes was made. This showed that while high potassium medium inhibited the degradation but not the uptake of asialoorosomucoid, both transferrin endocytosis and iron delivery to the cells were unaffected. This difference between the two pathways was also observed with an inhibitor of phospholipase A2, bromophenacyl bromide. With the latter, it was found that the asialoglycoproteins failed to traverse from a low-density to a high-density intracellular compartment, implying a role for phospholipase A2 in the trafficking of asialoglycoprotein receptor but not that for transferrin or iron. This demonstrates that, after its release from transferrin, iron is transported to the cytoplasm directly from the early endosome without the need for fusion of the iron-containing vesicle with a lysosome.

Acetophenones↗
PubMed1989

Separation of the human transferrin isoforms by carrier-free high-performance zone electrophoresis and isoelectric focusing.

Human transferrin isoforms, i.e., molecules with different carbohydrate contents which differ from each other by only one negative charge, were resolved by high-performance zone electrophoresis in free solution. The di-, tri-, tetra-, penta-, hexa- and heptasialo transferrins could be assigned in the electrophoretic pattern. The pattern changed when iron-free transferrin was treated with neuraminidase, which splits off the sialic acid from the carbohydrate chains. The final digest contained transferrin molecules without sialic acids, as was confirmed by isoelectric focusing.

Electrophoresis↗
PubMed1983

Separation of transferrin types in human plasma by anion-exchange high-performance liquid chromatography.

An anion-exchange high-performance liquid chromatographic procedure was developed for the separation of transferrin in human plasma. The procedure allowed the four molecular forms of transferrin, which differ with respect to bound iron, to be separated from each other and from other plasma proteins. Transferrin variants, including B and D types, could also be identified using anion-exchange high-performance liquid chromatography. The approach followed for optimizing the separation of transferrin included identification of the peaks in the chromatogram by two-dimensional polyacrylamide gel electrophoresis. This approach could be extended to other proteins in plasma or biological fluids in order to optimize their separation.

Blood Proteins↗
PubMed1987

Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.

We measured cord transferrin and ferritin levels in 50 newborn infants with fetal conditions associated with either uteroplacental vascular insufficiency or chronic hypoxia. Sixteen small for gestational age infants, 21 infants of mothers with preeclampsia, and 13 symptomatic infants of diabetic mothers had significantly higher transferrin levels and lower ferritin levels and calculated iron stores than did asymptomatic gestational age-matched control infants without these conditions. Cord ferritin levels and calculated iron stores were significantly lower in the infants of diabetic mothers than in any other group of infants. Cord transferrin levels were inversely correlated with ferritin levels (r = -0.59, P less than 0.001) and were unrelated to transthyretin levels and birth weight in the high-risk infants, but were positively correlated with ferritin levels (r = 0.50, P less than 0.001), transthyretin levels (r = 0.65, P less than 0.001), and birth weight (r = 0.75, P less than 0.001) in the control infants. We conclude that cord transferrin levels do not reflect protein-energy status in newborn infants with prenatal histories suggesting uteroplacental insufficiency or chronic hypoxia, and that when associated with decreased cord ferritin levels, indicate possible impaired iron stores in these infants.

Chronic Disease↗
PubMed1986

The binding of plutonium to transferrin in the presence of tri-n-butyl phosphate or nitrate and its release by diethylenetriaminepenta-acetate and the tetrameric catechoylamide ligand LICAMC(C).

The binding of plutonium to human apo-transferrin and to rat serum was investigated following delivery of the metal to the protein either as the plutonium-tri-n-butyl phosphate (Pu-TBP) complex in n-dodecane or as plutonium nitrate. Chromatographic behaviour, the failure to bind to iron-saturated transferrin and the release of plutonium by the chelating agents CaNa3DTPA and 3,4,3-LICAM(C) suggest that the transferrin complexes formed from the two plutonium compounds are similar. The tetracatechoylamide ligand LICAM(C) was found to be about 500 times more effective than DTPA, on a molar basis, for the release of plutonium from transferrin in rat serum.

Animals↗