Mechanical properties of plasma membrane vesicles correlate with lipid order, viscosity and cell density

Regulation of plasma membrane curvature and composition governs essential cellular processes. The material property of bending rigidity describes the energetic cost of membrane deformations and depends on the plasma membrane molecular composition. Because of compositional fluctuations and active processes, it is challenging to measure it in intact cells. Here, we study the plasma membrane using giant plasma membrane vesicles (GPMVs), which largely preserve the plasma membrane lipidome and proteome. We show that the bending rigidity of plasma membranes under varied conditions is correlated to readout from environment-sensitive dyes, which are indicative of membrane order and microviscosity. This correlation holds across different cell lines, upon cholesterol depletion or enrichment of the plasma membrane, and variations in cell density. Thus, polarity- and viscosity-sensitive probes represent a promising indicator of membrane mechanical properties. Additionally, our results allow for identifying synthetic membranes with a few well defined lipids as optimal plasma membrane mimetics

Benzodeazaoxaflavins as Sirtuin Inhibitors with Antiproliferative Properties in Cancer Stem Cells

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Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

Borbély AN, Figueras Agustí E, Martins A, et al. Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery. ChemistryOpen. 2019;8(6):737-742.RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin alphavbeta3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin alphavbeta3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin alphavbeta3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective alphavbeta3 integrin-mediated drug delivery

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time-and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy

Expanding Thurston Maps

We study the dynamics of Thurston maps under iteration. These are branched covering maps $f$ of 2-spheres $S^2$ with a finite set $\mathop{post}(f)$ of postcritical points. We also assume that the maps are expanding in a suitable sense. Every expanding Thurston map $f\: S^2 \to S^2$ gives rise to a type of fractal geometry on the underlying sphere $S^2$. This geometry is represented by a class of \emph{visual metrics} $\varrho$ that are associated with the map. Many dynamical properties of the map are encoded in the geometry of the corresponding {\em visual sphere}, meaning $S^2$ equipped with a visual metric $\varrho$. For example, we will see that an expanding Thurston map is topologically conjugate to a rational map if and only if $(S^2, \varrho)$ is quasisymmetrically equivalent to the Riemann sphere $\widehat{\mathbf{C}}$. We also obtain existence and uniqueness results for $f$-invariant Jordan curves $\mathcal{C}\subset S^2$ containing the set $\mathop{post}(f)$. Furthermore, we obtain several characterizations of Latt\`{e}s maps

Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery

Borbély AN, Figueras Agustí E, Martins A, et al. Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery. Pharmaceutics. 2019;11(4): 151.Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin αvβ3, across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)–cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin αvβ3 expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscop

Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition

Growing epidemiological data demonstrate that acute kidney injury (AKI) is associated with long-term cardiovascular morbidity and mortality. Here, the authors present a 1-year study of cardiorenal outcomes following bilateral ischemia-reperfusion injury in male mice. These data suggest that AKI causes long-term dysfunction in the cardiac metabolome, which is associated with diastolic dysfunction and hypertension. Mice treated with the histone deacetylase inhibitor, ITF2357, had preservation of cardiac function and remained normotensive throughout the study. ITF2357 did not protect against the development of kidney fibrosis after AKI

Heterogene Studierendenschaft - Zur Sozialstruktur und Studiensituation der Studierenden in Deutschland

An den Hochschulen finden sich Studierende in unterschiedlichen Lebenssituationen und mit differierenden Bildungsbiografien. Der Beitrag beschreibt die Heterogenität der Studierenden mit Blick auf vier Kategorien: soziodemografische Merkmale, Bildungsherkunft, Wege zur Hochschule und Zeitbudget für das Studium. Nur eine Minderheit der Studierenden entspricht heute noch dem traditionellen "Normaltyp", ist also direkt nach dem Erwerb der Hochschulzugangsberechtigung, ohne berufliche Qualifizierung an die Hochschule gekommen, nicht älter als 30 Jahre und nicht durch Kinderbetreuung, Pflegeaufgaben oder eine mehr als 19 Wochenstunden umfassende Erwerbstätigkeit gebunden. Für eine auf Lübben et al. (2015) zurückgehende Studierendentypologie, die auf den Dimensionen Bildungsbiografie und Zeitbudget beruht, wird die Verteilung abschließend auf der institutionellen Ebene dargestellt.Students in German higher education are characterized by differences in their life situations and educational biographies. The article describes the heterogeneity of students with regard to four categories: socio-demographic characteristics, educational background, routes to higher education and time budget for studies. Only a minority of the students still corresponds to the traditional "normal type", i.e., they came to the university directly after acquiring their higher education entrance qualification, without vocational training, are not older than 30 years, have no tasks in childcare or caregiving, and are not employed more than 19 hours per week. For a student typology borrowed from Lübben et al. (2015), based on the dimensions of educational biography and time budget, the distribution is finally presented at the institutional level