Glycodendrimers as Potential Multitalented Therapeutics in Alzheimer’s Disease

Finding successful therapies for the treatment of Alzheimer’s disease (AD) is one of the most challenging tasks existing for human health. Several drugs have been found and validated in preclinical studies with some success, but not with the desired breakthroughs in the following clinical development phases. AD causes multiple brain dysfunctions that can be described as a brain organ failure, resulting in significant cognitive decline. Aggregation of amyloid proteins and neuronal loss are the hallmarks of AD. Thus, one of the strategies to treat AD is to find a multifunctional drug that may combine both anti-aggregation and neuroprotective properties. Such a candidate could be chemically modified dendrimers. Dendrimers are branched, nonlinear molecules with multiple reactive groups located on their surface. Chemical modification of reactive surface groups defines the property of the dendrimers. In this chapter, I will discuss poly(propylene imine) dendrimers with the surface functionalized with histidine and maltose as an example of a multifunctional therapeutic drug candidate able to protect the memory of AD transgenic model mice

Mathematical layout model of coupling with tangentially located ropes

The article deals with the results of mathematical modeling of layout coupling with tangentially located ropes. Arrangement considered limiting geometric nature that must be considered when designing joints. These conditions take into account the possibility of tightening fasteners, bushings opportunity neighborhood inner coupling halves, the possibility of relative rotation of the coupling halves, the lack of interference of the outer and inner sleeves of the coupling halves, the absence of interference of adjacent ropes and sleeves inner halfcoupling. As a result of research obtained mathematical expressions to be used in the calculation of engineering couplings checking the basic conditions of their geometric existence. These have been tested according to the design of the coupling, and the calculation results are checked by comparing them with the results of construction and found a match. The results can be used in the design of the coupling with the end of direct installation of ropes tangential location

Poly(propylene imine) dendrimers with histidine-maltose shell as novel type of nanoparticles for synapse and memory protection

Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood-brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood-brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood-brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection. © 2019 The Author

Effect of Poly(propylene imine) Glycodendrimers on beta-Amyloid Aggregation in Vitro and in APP/PS1 Transgenic Mice, as a Model of Brain Amyloid Deposition and Alzheimer's Disease

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Poly(propylene imine) dendrimers with histidine-maltose shell as novel type of nanoparticles for synapse and memory protection

Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical andbiomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core andmaltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood-brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment.Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood-brain barrier in vivo.Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood-brain barrier ofdendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer diseasetransgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection

In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer’s disease transgenic mice using synchrotron-based infrared imaging

Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer's disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques

Transcriptomic changes triggered by ouabain in rat cerebellum granule cells: Role of α3- and α1-Na+,K+-ATPase-mediated signaling

It was shown previously that inhibition of the ubiquitous α1 isoform of Na+,K+-ATPase by ouabain sharply affects gene expression profile via elevation of intracellular [Na+]i/[K+]i ratio. Unlike other cells, neurons are abundant in the α3 isoform of Na+,K+-ATPase, whose affinity in rodents to ouabain is 104-fold higher compared to the α1 isoform. With these sharp differences in mind, we compared transcriptomic changes in rat cerebellum granule cells triggered by inhibition of α1- and α3-Na+,K+-ATPase isoforms. Inhibition of α1- and α3-Na+,K+-ATPase isoforms by 1 mM ouabain resulted in dissipation of transmembrane Na+ and K+ gradients and differential expression of 994 transcripts, whereas selective inhibition of α3-Na+,K+-ATPase isoform by 100 nM ouabain affected expression of 144 transcripts without any impact on the [Na+]i/[K+]i ratio. The list of genes whose expression was affected by 1 mM ouabain by more than 2-fold was abundant in intermediates of intracellular signaling and transcription regulators, including augmented content of Npas4, Fos, Junb, Atf3, and Klf4 mRNAs, whose upregulated expression was demonstrated in neurons subjected to electrical and glutamatergic stimulation. The role [Na+]i/[K+]i-mediated signaling in transcriptomic changes involved in memory formation and storage should be examined further

Risk Assessment and Management for Maritime SAR and Oil Spill Response

This report summarizes selected publications that deal with maritime Search and Rescue (SAR) operations, winter navigation as well as oil spill response. In the first part of this report, the SAR capabilities, response times and effects of weather on Finnish Search and Rescue Units (SRUs) are evaluated. Besides this, the risk of oil spill and effects of winter conditions were evaluated. Two of the most relevant accident types – collisions consequences on oil tanker and RoPAx vessels – were evaluated. Both tankers as well as RoPax vessels are very common vessels in the Gulf of Finland, carrying thousands passengers or tonnes of oil. However, during the project it was found that there are currently no particularly reliable methods for assessing which sea areas are most prone to accidents. This highlights the need for future research in the methodology. Furthermore, a model is presented that describes the interaction between ships and the ice when navigating in an ice channel. This model helps to understand better the increased side forces and yaw that occurs in ice channel when compared to sailing in open waters. This can be used to train bridge personnel to better understand their ship's behavior under challenging ice channel conditions, thus decreasing risk.  A final model describes how fast an oil slick will spread in an ice channel as a function of factors such as the ice concentration and ice floe size, allowing for better estimation of how far oil will spread until effective clean-up measures can be taken

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD

Impaired glucose metabolism and other metabolic disorders in patients with primary hyperparathyroidism

The clinical picture of primary hyperparathyroidism (PHPT) which caused by parathyroid neoplasms often includes metabolic syndrome leading to the development of cardiovascular diseases. According to clinical studies, an increased incidence of diabetes mellitus, insulin resistance, obesity, dyslipidemia, hyperuricemia and other disorders that signifi tly affect the life span and quality are observed in patients with PHPT regardless of the form and the severity of the underlying disease. Basic research shows the potential nonclassical effects of high levels of parathyroid hormone and calcium on adipose tissue, pancreas, gastrointestinal tract and kidneys. However, the pathogenetic mechanisms of impaired carbohydrate and other types of metabolism in patients with parathyroid hyperfunction remain unclear because of the lack of relevant experimental models and the heterogeneity of patient groups. Besides, the effect of surgery on metabolic abnormalities is also controversial. Nowadays a deeper understanding of this issue is required, which can subsequently help in the creation of optimal approach to diagnosis and treatment of patients. This review covers different aspects of metabolic disorders in patients with PHPT, as well as potential key factors of their development