Heparin-interacting sites of bovine lactoferrin are involved in anti-adenovirus activity

Lactoferrin, a member of the transferrin family of approximately 80 kDa, consists of a single polypeptide chain folded in two symmetric, globular lobes (N- and C-lobes), each able to bind one ferric ion. This glycoprotein, found in physiological fluids of mammals, plays an important role in immune regulation and in defense mechanisms against bacteria, fungi, parasites, and viruses. Although the antiviral activity of lactoferrin is one of the major biological functions of such protein, the mechanism of action is still under debate. We have investigated both the role of tryptic fragments of bovine lactoferrin and the mechanism of lactoferrin antiviral effect toward adenovirus infection in HEp-2 cells. The results obtained demonstrated that the anti-adenovirus activity of lactoferrin is mediated by the N-terminal half of the protein as the N-lobe was able to inhibit adenovirus infection, even if at lower extent than undigested lactoferrin, whereas C-lobe was ineffective. The results also showed that the anti-adenovirus action of lactoferrin and of its N-terminal peptide lactoferricin took place on virus attachment to cell membrane, mainly through competition for common glycosaminoglycan receptors. The data provide evidence that the anti-adenovirus activity of lactoferrin is mediated mainly by the cluster of positive charges at the N-terminus of whole molecule and that the N-terminal peptide lactoferricin alone is sufficient to prevent infection.     

Protective effect of propionyl carnitine against peroxidative damage to arterial endothelium membranes

Endothelial cells may be damaged by oxygen reactive species produced by granulocytes, by transition metal ions or by xanthine oxidase, an enzyme present in great quantity in these cells. Since it has been observed that propionyl carnitine protects the heart from peroxidation, we have investigated the effect of this compound on the formation of thiobarbituric acid reactive oxidation products (TBAR) in endothelial membranes. The peroxidation systems used were a mixture of Fe3+ and Fe2+, hydrogen peroxide and Fe2+, or xanthine oxidase-- xanthine. Propionyl carnitine at millimolar concentrations decreases TBAR formation. The protection is concentration-dependent and is almost absent in the presence of propionate and carnitine. From these results it appears that propionyl carnitine may protect not only myocardium but also vessels from peroxidative damage that occurs during ischaemia and reperfusion.     

Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

This study represents the first longitudinal, within‐subject ¹H MRS investigation of the developing rat brain spanning infancy, adolescence and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for the cortex, thalamus and hypothalamus, on postnatal days 7, 35 and 60. Water‐scaled metabolite signals were corrected for T₁ effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age‐related concentration changes in N‐acetylaspartate + N‐acetylaspartylglutamate, myo‐inositol, glutamate + glutamine, taurine, creatine + phosphocreatine and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment changes across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in the concentrations of N‐acetylaspartate + N‐acetylaspartylglutamate, glutamate + glutamine and glycerophosphocholine + phosphocholine. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence and adulthood. Copyright © 2013 John Wiley & Sons, Ltd.     

Long pentraxin‐3 as an epithelial–stromal fibroblast growth factor‐targeting inhibitor in prostate cancer

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up‐regulates FGF2 and FGF8b production in murine TRAMP‐C2 prostate cancer cells, activating a FGF‐dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin‐3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N‐terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3‐derived pentapeptide Ac‐ARPCA‐NH₂ abolish the mitogenic response of murine TRAMP‐C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT‐activated TRAMP‐C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP‐C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP‐C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP‐C2 cells overexpress only the FGF‐binding N‐terminal PTX3 domain. In keeping with the anti‐tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high‐grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti‐angiogenic and anti‐neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Assessment of advanced age candidates for liver transplantation warrants more caution

For patients with fulminant liver failure and end-stage liver disease, liver transplantation remains the only effective treatment. Over the years, as a result of the ageing population, the average age of liver transplant donors and recipients has increased and currently about one quarter of patients receiving transplantation in the United States are above the age of 65. Recently, a study reported that patients aged 65 years or older had lower one-year survival compared to a younger cohort. Herein, we express our opinion about this interesting publication.     

Delivering cytokines at tumor site: The immunocytokine-conjugated anti-EDB-fibronectin antibody case

Although considerable efforts have been made in the discovery of new agents for cancer treatment, several promising therapeutics cannot be applied systemically because of their severe side effects. This is the case for various recombinant pro-inflammatory cytokines that, despite their potent anti-cancer activity, can not find their way to clinical exploitation due to their devastating toxicity shown during dose escalation to therapeutically active concentrations. To circumvent these problems, an elegant and efficient way to accumulate therapeutic agents at the tumor site, thus reducing systemic side effects, is their conjugation to tumor-specific antibodies. Here, we review preclinical data about immunocytokines conjugated to a promising single-chain human antibody that selectively targets tumor-associated stroma and blood vessels by binding with high affinity and specificity to the extra domain-B (EDB) of fibronectin.     

Perinatal stimulation and adaptation of the neonate

The present report describes psychobiological studies of behavior around the time of birth. An adaptive, ecological perspective is presented in which stimulation of the fetus and newborn is purported to instigate adaptive postpartum behavior. Studies describing the perinatal sensory environment are reviewed, with a consideration of emergent sensory function of the fetus. It is asserted that afferent input associated with parturition perturbs the fetus and neonate, producing a general arousal state that facilitates breathing, suckling, and early learning. The view developed herein is that perinatal sensory input induces and canalizes the newborn's behavior, thereby regulating adaptive postpartum function. Deviations in afferent input may alter ontogenetic trajectories and compromise developmental outcome by reducing availability of conditions necessary for adequate postpartum adaptation.