Biology subjects

Jeltsch, M.

Publications and source records attributed to Jeltsch, M..

4 recordsLinked to original sources

bioRxiv2026

Composition and activity of the proteasome in human iPSC-derived neuronal model of early-stage sporadic Alzheimer's disease

IntroductionThe proteasome is a critical cellular degradative machinery impaired in late-stage Alzheimers disease (AD). However, the status and activity of the proteasome in early-stage sporadic AD (sAD) is unknown. MethodsA cellular model of human early-stage sAD was generated from sAD patient iPSC-derived cortical neurons by dual-SMAD inhibition. The iPSCs, neuroprogenitors, and cortical neurons were validated by the expressions of key markers. The level of total intraneuronal A{beta} was measured by ELISA. Composition and native proteolytic activities of the proteasome in control and sAD cortical neurons were measured using complementary fluorogenic probes. ResultsControl and sAD patients iPSCs expressed pluripotent markers OCT4, NANOG, and SSEA4 which induced into neuroprogenitors expressing NESTIN and PAX6. The neuroprogenitors terminally differentiated into cortical neurons expressing neuronal markers MAP2 and TUJ1, and cortical layer marker TBR1. The level of intraneuronal A{beta} in the sAD cortical neurons was significantly higher compared to control. Control and sAD cortical neurons expressed native 30S, 26S, and 20S proteasome assemblies with the sAD cortical neurons displaying higher 20S assemblies. Increased active 20S assemblies was associated with higher {beta}1, {beta}2, and {beta}5 proteolytic sites activities. DiscussionThe significant elevation in the proteolytic activities of the {beta}1, {beta}2, and {beta}5 subunits of 20S proteasome in sAD cortical neurons suggests that this may be a possible compensatory response to elevated intraneuronal A{beta}. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/734021v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d8c382org.highwire.dtl.DTLVardef@b92e8org.highwire.dtl.DTLVardef@1d9c699org.highwire.dtl.DTLVardef@7d826d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Biomass-derived Lignin Nanoparticles for the Sustained Delivery of Vascular Endothelial Growth Factor-C

Vascular Endothelial Growth Factor C (VEGFC) is a promising biological drug, as preclinical studies have shown its potential in treating a variety of conditions, including myocardial infarction and neurodegenerative diseases. For lymphedema, a disease that currently can only be treated symptomatically, adenoviral VEGFC gene therapy has been evaluated up to phase II studies. However, the AdVEGFC is rapidly inactivated by the immune system, and alternative delivery methods might yield better results. Thus, we wanted to investigate the synthesis, characterization, and stability of lignin nanoparticles (LNPs) as carriers for VEGFC. As biomass-derived lignin nanoparticles provide a sustainable, cost-effective, and tunable platform for drug delivery, with the potential to enhance drug stability and release, lignin was extracted from wood biomass derived from grape shoots using the organosolv method and subsequently synthesized into nanoparticles. The resulting lignin nanoparticles (LNPs), with an average size of 142{+/-}62 nm and a zeta potential of -40{+/-}8 mV, were characterized through comprehensive techniques, including spectroscopy and microscopy, to gain insights into their structural and morphological properties. Furthermore, the loading and release efficiency of VEGFC onto LNPs were evaluated, demonstrating effective loading and controlled release. Stability tests in plasma and cell proliferation/viability assessments using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay were conducted to assess biocompatibility and therapeutic potential. Our data shows that VEGFC is a relatively stable protein and that the primary advantage of nanoparticle-based delivery would be to delay release as opposed to protect VEGFC from degradation/inactivation. Graphical AbstractFlow chart of the generation and analysis of biomass-derived VEGFC-loaded lignin nanoparticles. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/649697v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1476841org.highwire.dtl.DTLVardef@10d861corg.highwire.dtl.DTLVardef@dfa209org.highwire.dtl.DTLVardef@72c81_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Gliflozins, sucrose and flavonoids are allosteric activators of lecithin:cholesterol acyltransferase

Lecithin:cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

biochemistry↗

bioRxiv2022

Expansion and collapse of VEGF diversity in major clades of the animal kingdom

The vascular endothelial growth factor (VEGF) family comprises in vertebrates five or six members: VEGF(-A), PlGF, VEGF-B, VEGF-C, VEGF-D, and - in venomous reptiles - VEGF-F. They fulfill mainly functions for the blood and lymphatic vascular systems. Together with the platelet-derived growth factors (PDGF-A to -D), they form the PDGF/VEGF subgroup among cystine-knot growth factors. Despite an absent vascular system in most invertebrates, PDGF/VEGF-like molecules have been found in, e.g., Drosophila melanogaster and Caenorhabditis elegans. The evolutionary relationship between PDGF and VEGF growth factors has only been addressed by older analyses, which were limited by the sparse sequencing data at the time. Here we perform a comprehensive analysis of the occurrence of PDGF/VEGF-like growth factors (PVFs) throughout all animal phyla and propose a likely phylogenetic tree. The three major vertebrate whole genome duplications play a role in the expansion of PDGF/VEGF diversity, but several limited duplications are necessary to account for the temporal pattern of emergence. The phylogenetically oldest PVFs likely featured a C-terminus with a BR3P signature, a hallmark of the modern-day lymphangiogenic growth factors VEGF-C and VEGF-D. Some of the younger VEGF genes appeared completely absent in some clades, e.g., functional VEGFB genes in the clade Archosauria, which includes crocodiles, birds, and other dinosaurs, and pgf in amphibians. The lack of precise counterparts for human genes poses limitations but also offers opportunities for research using organisms that diverge considerably from humans if the goal is to understand human physiology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/507521v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@16b1abforg.highwire.dtl.DTLVardef@a91012org.highwire.dtl.DTLVardef@15e4994org.highwire.dtl.DTLVardef@1309753_HPS_FORMAT_FIGEXP M_FIG Sources for the graphical abstract: 326 MYA and older [1] 272-240 MYA [2] 235-65 MYA [3] C_FIG

evolutionary biology↗