The Neuroprotective Action of Amidated-Kyotorphin on Amyloid β Peptide-Induced Alzheimer’s Disease Pathophysiology

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer’s disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid β peptide (Aβ). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aβ administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aβ-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aβ-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aβ oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aβ caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aβ-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.publishersversionpublishe

Re-evaluating the role of strongly charged sequences in amphipathic cell-penetrating peptides: A fluorescence study using Pep-1

Cell-penetrating peptides (CPPs) are able to translocate across biological membranes and deliver bioactive proteins. Cellular uptake and intracellular distribution of CPPs is commonly evaluated with fluorescent labels, which can alter peptide properties. The effect of carboxyfluorescein label in the Lys-rich domain of the amphipathic CPP pep-1, was evaluated and compared with non-labelled pep-1 in vitro and in vivo. A reduced membrane affinity and an endosomal-dependent translocation mechanism, at variance with non-labelled pep-1, were detected. Therefore, the charged domain is not a mere enabler of peptide adsorption but has a crucial role in the translocation pathway of non-labelled pep-1. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Estimating peptide half‐life in serum from tunable, sequence‐related physicochemical properties

Data de publicació electrònica: 28-02-2021Proteolytic instability is a critical limitation for peptide-based products. Although significant efforts are devoted to stabilize sequences against proteases/peptidases in plasma/serum, such approaches tend to be rather empirical, unspecific, time-consuming, and frequently not cost-effective. A more rational and potentially rewarding alternative is to identify the chemical grounds of susceptibility to enzymatic degradation of peptides so that proteolytic resistance can be tuned by manipulation of key chemical properties. In this regard, we conducted a meta-analysis of literature published over the last decade reporting experimental data on the lifetimes of peptides exposed to proteolytic conditions. Our initial database contained 579 entries and was curated with regard to amino acid sequence, chemical modification, terminal half-life (t1/2 ) or other stability readouts, type of stability assay, and biological application of the study. Although the majority of entries in the database corresponded to (slightly or substantially) modified peptides, we chose to focus on unmodified ones, as we aimed to decipher intrinsic characteristics of peptide proteolytic susceptibility. Specifically, we developed a multivariable regression model to unravel those peptide properties with most impact on proteolytic stability and thus potential t1/2 predicting ability. Model validation was done by two different approaches. First, a library of peptides spanning a large interval of properties that modulate stability was synthesized and their t1/2 in human serum were experimentally determined. Second, the t1/2 of 21 selected peptides approved for clinical use or in clinical trials were recorded and matched with the model-estimated values. With both approaches, good correlation between experimental and predicted t1/2 data was observed.This research was supported by the Portuguese Fundação para a Ciência e a Tecnologia (FCT; grants PD/BD/128281/2017, PTDC/BBB‐NAN/1578/2014, PTDC/BIA‐VIR/29495/2017, UID/Multi/04349/2019, and PTDC/QUI‐NUC/30147/2017), the Spanish Ministry of Economy and Innovation (MINECO, grants AGL2014‐52395‐C2‐2‐R and AGL2017‐84097‐C2‐2‐R, and Maria de Maeztu Program for Centers of Excellence); the European Union H2020‐MSCA‐RISE‐2014 program (grant no. 828774), and the “La Caixa” Banking Foundation (grant HR17‐00409)

The man in the white suit: Alexander Mackendrick (1951)

Original article can be found at: http://www.bergpublishers.com/BergJournals/DesignandCulture/tabid/3594/Default.aspx Copyright Design Studies ForumThe Man in the White Suit (TMITWS) is rarely mentioned in relation to design practice, beyond its relevance to “smart fabrics,” but every design professional should see this cautionary tale of an individual battling an industry. [1] The film’s obsessive protagonist, Sidney Stratton (Alec Guinness) works as a cleaner at Corland textile mill while secretly pursuing chemical experiments. Upon discovery, he is sacked and moves to Birnley mill where his technical expertise gains him access to the research lab. Birnley’s daughter (Joan Crawford) persuades her father to give Stratton a contract and facilities. He no longer needs to improvise his experiments on borrowed bench space and is granted exclusive use of lab facilities, to avoid industrial espionage. The dangerous nature of his experiments (and his disregard for personal safety) ensures that the physical destruction of his workshop serves as a visual manifestation of the fate of his invention. His fabric, which never gets dirty or tears, can mimic a range of existing applications. Its durability threatens the entire textile industry and it is opposed by trade unions and mill owners alike. The title suggests both savior (as Stratton’s champion/love-interest Crawford sees it) and madman (The Man in the White Straightjacket?): ultimately, Stratton’s determination to realize his invention remains undefeated.Peer reviewe