Search Results (5)

In this study, we hypothesized that biotinylated and/or glycidol-flanked fourth-generation polyamidoamine (PAMAM G4) dendrimers could be a tool for efficient drug transport into glioma and liver cancer cells. For this purpose, native PAMAM (G4) dendrimers, biotinylated (G4B), glycidylated (G4gl), and biotinylated and glycidylated (G4Bgl), were synthesized, and their cytotoxicity, uptake, and accumulation in vitro and in vivo were studied in relation to the transport mediated by the sodium-dependent multivitamin transporter (SMVT). The studies showed that the human temozolomide-resistant glioma cell line (U-118 MG) and hepatocellular carcinoma cell line (HepG2) indicated a higher amount of SMVT than human HaCaT keratinocytes (HaCaTs) used as a model of normal cells. The G4gl and G4Bgl dendrimers were highly biocompatible in vitro (they did not affect proliferation and mitochondrial activity) against HaCaT and U-118 MG glioma cells and in vivo (against Caenorhabditis elegans and Wistar rats). The studied compounds penetrated efficiently into all studied cell lines, but inconsistently with the uptake pattern observed for biotin and disproportionately for the level of SMVT. G4Bgl was taken up and accumulated after 48 h to the highest degree in glioma U-118 MG cells, where it was distributed in the whole cell area, including the nuclei. It did not induce resistance symptoms in glioma cells, unlike HepG2 cells. Based on studies on Wistar rats, there are indications that it can also penetrate the blood–brain barrier and act in the central nervous system area. Therefore, it might be a promising candidate for a carrier of therapeutic agents in glioma therapy. In turn, visualization with a confocal microscope showed that biotinylated G4B penetrated efficiently into the body of C. elegans, and it may be a useful vehicle for drugs used in anthelmintic therapy. Full article

Clusters of sea stacks, called rauks, are unique rocky landforms characteristic of Baltic Sea coasts. These limestone stacks raise interest due to their spectacular morphology and yet unexplained origin. This study presents the results of seasonal observations (2019–2020) of rauk coast changes carried out in one of the key rauk fields on Fårö Island, Sweden. The landforms developing within three test sites were examined. At Langhammars ‘classic’ field of rauks built from homogeneous limestone (1) and a shore platform devoid of rauks, underlain clearly separate limestone slabs were explored (2); and at Gamla Hamn, the analysis covered a non-typical rauk field built of densely laminated limestone (3). We applied terrestrial laser scanning (TLS) to obtain data needed in morphometric analyses and rauk surface change monitoring. We identified and determined contemporary erosional rates and dominant processes responsible for eroding and downwearing of rauk coasts. The observed changes were strongly associated with differences in local lithological and structural conditions—from a nearly complete absence within massive limestone rauks notches, to clear signs of erosion within limestone slabs eroded by waves, almost 1 m² in size. Full article

In the current literature, many non-covalent interaction (NCI) donors have been proposed that can potentially catalyze Diels-Alder (DA) reactions. In this study, a detailed analysis of the governing factors in Lewis acid and non-covalent catalysis of three types of DA reactions was carried out, for which we selected a set of hydrogen-, halogen-, chalcogen-, and pnictogen-bond donors. We found that the more stable the NCI donor–dienophile complex, the larger the reduction in DA activation energy. We also showed that for active catalysts, a significant part of the stabilization was caused by orbital interactions, though electrostatic interactions dominated. Traditionally, DA catalysis was attributed to improved orbital interactions between the diene and dienophile. Recently, Vermeeren and co-workers applied the activation strain model (ASM) of reactivity, combined with the Ziegler-Rauk-type energy decomposition analysis (EDA), to catalyzed DA reactions in which energy contributions for the uncatalyzed and catalyzed reaction were compared at a consistent geometry. They concluded that reduced Pauli repulsion energy, and not enhanced orbital interaction energy, was responsible for the catalysis. However, when the degree of asynchronicity of the reaction is altered to a large extent, as is the case for our studied hetero-DA reactions, the ASM should be employed with caution. We therefore proposed an alternative and complementary approach, in which EDA values for the catalyzed transition-state geometry, with the catalyst present or deleted, can be compared one to one, directly measuring the effect of the catalyst on the physical factors governing the DA catalysis. We discovered that enhanced orbital interactions are often the main driver for catalysis and that Pauli repulsion plays a varying role. Full article

Neurodegeneration in Alzheimer’s disease (AD) is defined by pathology featuring amyloid-β (Aβ) deposition in the brain. Aβ monomers themselves are generally considered to be nontoxic, but misfold into β-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to Aβ and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against Aβ(1–42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind Aβ in anti-parallel orientation, demonstrated neuroprotection against Aβ(1–42). A third inhibitor, predicted to bind parallel to Aβ, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against Aβ toxicity. Full article

A causative factor for neurotoxicity associated with Alzheimer’s disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ_13–23 (the core recognition site of Aβ) and full-length Aβ_1–42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ_13–23. The highest ∆G_binding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ_1–42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ_1–42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer’s disease. Full article