The use of the saber in the army of Napoleon

Though Napoleonic warfare is usually associated with guns and cannons, edged weapons still played an important role on the battlefield. Swords and sabers could dominate battles and this was certainly the case in the hands of experienced cavalrymen. In contrast to gunshot wounds, wounds caused by the saber could be treated quite easily and caused fewer casualties. In 18th and 19th century France, not only manuals about the use of foil and epee were published, but also some important works on the military saber: de Saint Martin, Alexandre Muller… The saber was not only used in individual fights against the enemy, but also as a duelling weapon in the French army

Cell-penetrating peptides selectively cross the blood-brain barrier in vivo

Cell-penetrating peptides (CPPs) are a group of peptides, which have the ability to cross cell membrane bilayers. CPPs themselves can exert biological activity and can be formed endogenously. Fragmentary studies demonstrate their ability to enhance transport of differ- ent cargoes across the blood-brain barrier (BBB). However, comparative, quantitative data on the BBB permeability of different CPPs are currently lacking. Therefore, the in vivo BBB transport characteristics of five chemically diverse CPPs, i.e. pVEC, SynB3, Tat 47–57, transportan 10 (TP10) and TP10-2, were determined. The results of the multiple time regression (MTR) analysis revealed that CPPs show divergent BBB influx properties: Tat 47–57, SynB3, and especially pVEC showed very high unidirectional influx rates of 4.73 μl/ (g × min), 5.63 μl/(g × min) and 6.02 μl/(g × min), respectively, while the transportan analogs showed a negligible to low brain influx. Using capillary depletion, it was found that 80% of the influxed peptides effectively reached the brain parenchyma. Except for pVEC, all pep- tides showed a significant efflux out of the brain. Co-injection of pVEC with radioiodinated bovine serum albumin (BSA) did not enhance the brain influx of radiodionated BSA, indicat- ing that pVEC does not itself significantly alter the BBB properties. A saturable mechanism could not be demonstrated by co-injecting an excess dose of non-radiolabeled CPP. No sig- nificant regional differences in brain influx were observed, with the exception for pVEC, for which the regional variations were only marginal. The observed BBB influx transport proper- ties cannot be correlated with their cell-penetrating ability, and therefore, good CPP proper- ties do not imply efficient brain influx

Receptor and blood-brain barrier characterization of opioid peptides in drug research and early development

The penetration of the blood–brain barrier (BBB) combined with the receptor-subtype selectivity determines the medical activity of opioid peptides within the central nervous system (CNS). The opioid receptor-subtype selectivity can be assessed not only by the classic radio-ligand binding methods, but also by novel techniques such as SAW (surface acoustic wave) measuring binding kinetics. Pharmacokinetics include metabolic stability, brain influx and efflux characteristics, as well as brain capillary retention. Metabolic stability is evaluated by in vitro kinetic studies using different target tissues. When applying the in vivo mouse model, the influx transfer constant from serum into mouse brain is determined by multiple time regression, while the efflux kinetics are investigated with the intra-cerebroventricular injection technique. Furthermore, brain parenchyma-capillary cell distribution is evaluated by capillary depletion. Finally, the in vivo antinociceptive activity can be quantified in a mouse model. Since the evaluation of opioid peptides as potential therapeutic or diagnostic CNS agents requires the consideration of these opposing criteria, the CNS-functional drugability of opioid peptides is evaluated using a desirability criterion combining these different requirements. Information about the BBB behaviour of peptides, including the opioid peptides, are found in the database Brainpeps, which can also be used for QSPR

Fish hydrolysates : a regulatory perspective of bioactive peptides

For the first time introduced on the Japanese market, bioactive fish hydrolysates are now available all over the world as food supplements, functional food ingredients or nutricosmeceuticals. They are generally produced from low value fish waste, an almost inexhaustible source of raw material, and are sold as high value products, making them economically interesting from a manufacturer's view point. Most of these products have health or structure/function claims on their packages with different actions like antihypertensive, blood-glucose lowering, anxiolytic, and skin anti-aging activities. Although the different regional legislations all aim to assure consumer safety and prevent misleading of the consumer, the number of legally approved fish hydrolysate containing products drastically differs among different regions. This is because products that have been positively evaluated based on safety and efficacy in one region were found to have not enough evidence for efficacy in another region. These findings call for further international harmonization of the regulation and classification of these products. Moreover, interaction studies of these bioactive products with the normal diet or medicines are generally not performed, keeping the consumer uninformed of the possible risks of combining these products with medicinal products or other food ingredients

Quorum sensing peptides selectively penetrate the blood-brain barrier

Bacteria communicate with each other by the use of signaling molecules, a process called 'quorum sensing'. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 μl/(g×min)) and very low (Kin = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis

In vitro functional quality characterization of NOTA-modified somatropins

Chemical modifications on protein biopharmaceuticals introduce extra variability in addition to their inherent complexity, hence require more comprehensive analytical and functional characterization during their discovery, development, and manufacturing. Somatropin (i.e., recombinant human growth hormone, rhGH) modified with the chelating agent S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) allows the incorporation of radiometals for research and possible theranostic purposes. We previously demonstrated that this conjugation leads to multiple substitution degrees and positional isomers within the product. In vitro techniques at the molecular and cellular levels were now applied to assess their functional quality: (i) size exclusion chromatography (SEC) demonstrated functional complexation with human growth hormone binding protein (hGHBp) to the different NOTA-modified somatropins as well as to gallium chelated NOTA-functionalities (Ga-10:1 NOTA-somatropin); (ii) native mass spectrometry (MS) offered in-depth information, a substitution degree up to four NOTAs was still functional; (iii) circular dichroism (CD) analysis confirmed the complexation of unmodified and NOTA-modified somatropin to hGHBp; and (iv) a hGHR bioassay demonstrated initiation of the signal transduction cascade, after binding of all investigated products to the receptor presented on cells with a similar potency (pEC50 values between 9.53 and 9.78) and efficacy (Emax values between 130 and 160%). We conclude that the NOTA-modified somatropins do not possess a significantly different in vitro functionality profile compared to unmodified somatropin. Techniques such as SEC, MS, and CD, traditionally used in the physicochemical characterization of proteins have a demonstrated potential use in the functionality evaluation not only in drug discovery and development but also in quality control settings.Grants from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) to B.G. (Grant 121512) and F.V. (Grant 131356), and the PhD research grants from China Scholarship Council (CSC) to H.Y. and X.X.http://pubs.acs.org/loi/ancham2018-03-07hj2017Nuclear Medicin