Biology subjects

Bordag, N.

Publications and source records attributed to Bordag, N..

6 recordsLinked to original sources

bioRxiv2026

A metabolic perspective on eIF1A and eIF3B inhibition as a potential therapeutic strategy in psoriasis

Psoriasis is a chronic inflammatory skin disease marked by epidermal hyperplasia and distinct metabolic alterations. Here, we investigated the metabolic impact of targeting translation initiation factors by performing 1H NMR-based metabolomic profiling on polar skin extracts from imiquimod-induced (IMQ) and K5.TGF{beta}1 transgenic (TGF{beta}) mouse models treated with eIF1A or eIF3B siRNA. IMQ-treated skin demonstrated significant, human-like metabolic shifts, including depleted energy substrates (glucose, glycogen, 3-hydroxybutyrate) and elevated phospholipid/nucleotide markers, which correlated strongly with epidermal thickness. In contrast, TGF{beta} skin exhibited no broad baseline polar metabolome changes. eIF1A/eIF3B inhibition selectively attenuated IMQ-associated energy and phospholipid alterations without causing widespread metabolic disruption in TGF{beta} skin. Overall, eIF1A/eIF3B inhibition ameliorated psoriasis-like pathology and mitigated disease-associated metabolic demands in a context-dependent manner.

molecular biology↗

bioRxiv2024

Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMC) and adventitial fibroblasts (PAAF). Mechanisms driving the transition to a diseased phenotype remain elusive. Utilizing a combination of transcriptomic and proteomic profiling, along with phenotyping of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH), our investigation uncovered that while PASMC and PAAF retained their original cellular identities, they acquired distinct disease-associated states. Though both cell types exhibited reduced mitochondrial content and hyperpolarization, IPAH-PASMC displayed heightened glycosaminoglycan production and downregulation of contractile machinery, contrasting a hyperproliferative phenotype of IPAH-PAAF. We investigated the involvement of cellular crosstalk in regulating cell state dynamics and identified pentraxin-3 and hepatocyte growth factor as potential modulators of PASMC phenotypic transition orchestrated by PAAF. Our findings contribute to a deeper understanding of pulmonary vascular mesenchyme dynamics in disease pathogenesis.

cell biology↗

bioRxiv2024

Inhibition of eukaryotic translation initiation factor 1A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples

BackgroundPsoriasis is a systemic inflammatory disease for which new topical treatments are required. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which critically regulate gene expression in many important cellular processes, including proliferation, apoptosis, and differentiation. However, the exact link between overexpression of eIF and psoriasis is unknown. Here, we investigated the role of eIFs, particularly eIF1A and eIF3B, and the impact of their inhibition on the pathophysiology of psoriasis. MethodsWe used two mouse models reflecting the pathophysiology of psoriasis: (i) BALB/c mice topically treated with the immune activator imiquimod (IMQ) and (ii) K5.TGF{beta} transgenic mice. eIF1A and eIF3B were inhibited by either topical or systemic application of specific small interfering RNA (siRNA). In addition, we employed commercial human 3D psoriatic skin model samples. Importantly, in situ mRNA detection-based padlock probes against transcript variants of eIF1A und eIF3B was performed. ResultsTopical and systemic inhibition of eIF1A and eIF3B inhibited inflammation in both imiquimod and TGF{beta} mouse models as well as in a human 3D psoriasis model. Downregulation of eIF1A and eIF3B was associated with normalization of cell proliferation, restoration of the inflammatory milieu and epidermal hyperplasia of psoriasis, and normalization of levels of proinflammatory cytokines (e.g., TNF, IL-1b, IL-17, and IL-22) and keratinocyte differentiation markers (e.g., KRT16 and FLG). ConclusionThese results reveal an imbalance in translation and emphasize the crucial role of eIF1A and eIF3B in the pathophysiology of psoriasis. Targeting eIFs opens new avenues for the development of novel therapeutic treatment strategies against psoriasis.

molecular biology↗

bioRxiv2020

Plasma glutathione status as indicator of pre-analytical centrifugation delay

Prolonged incubation of blood prior to plasma preparation can significantly influence the quality of the resulting data. Different markers for this pre-clinical variability have been proposed over the years but with limited success. In this study we explored the usefulness of glutathione (GSH) status, namely ratio of reduced to oxidized glutathione (GSH/GSSG), as potential marker of plasma preparation delay. For that purpose, blood from 20 healthy volunteers was collected into tubes with a cysteine quencher (N-ethylmaleimide; NEM) for GSH stabilization. Plasma preparation was delayed at room temperature for up to 3 hours and every hour, a plasma sample was prepared and the GSH/GSSG ratio measured. We report that over the course of the investigation, plasma concentrations of both GSH and GSSG increased linearly (R2 = 0.99 and 0.98, respectively). Since GSH increased at a much faster rate compared to GSSG, the GSH/GSSG ratio also increased linearly in a time dependent manner (R2 = 0.99). As GSH is an intracellular antioxidant, we speculated that this might stem from ongoing blood hemolysis, which was confirmed by the time dependent rise in lactate dehydrogenase (LDH) activity in the plasma samples. Moreover, we demonstrate that the addition of the thiol alkylating reagent NEM directly to the blood tubes does not seem to influence downstream analysis of clinical parameters. In conclusion we propose that the glutathione status could be used as an indicator of the centrifugation delay prior to plasma preparation.

pathology↗

bioRxiv2020

Machine learning analysis of the bleomycin-mouse model reveals the spatial and temporal pulmonary inflammatory fingerprint

The bleomycin mouse-model is the extensively used model to study pulmonary fibrosis, however, the inflammatory cell kinetics and their compartmentalisation is still incompletely understood. Here we assembled historical flow cytometry data, totalling 303 samples and 16 inflammatory-cell populations, and applied advanced data modelling and machine learning methods to conclusively detail these kinetics. Three days post-bleomycin, the inflammatory profile was typified by acute innate inflammation, pronounced neutrophilia, especially of SiglecF+ neutrophils, and alveolar macrophage loss. Between 14 and 21 days, rapid-responders were increasingly replaced by T and B cells, and monocyte-derived alveolar macrophages. Multi-colour imaging revealed the spatial-temporal cell distribution and the close association of T cells with deposited collagen. Unbiased immunophenotyping and data modelling exposed the dynamic shifts in immune-cell composition over the course of bleomycin-triggered lung injury. These results and workflow provides a reference point for future investigations, and can easily be applied in the analysis of other datasets.

immunology↗

bioRxiv2018

Structural determinants of the interactions between Influenza A Virus Matrix protein M1 and lipid membranes

Influenza A virus is a pathogen responsible for severe seasonal epidemics threatening human and animal populations every year. One of the ten proteins encoded by the viral genome, the matrix protein M1, is abundantly produced in infected cells and plays a structural role in determining the morphology of the virus. During assembly of new viral particles, M1 is recruited to the host cell membrane where it associates with lipids and other viral proteins. The structure of M1 is only partially known. In particular, structural details of M1 interactions with the cellular plasma membrane as well as M1-protein interactions and multimerization have not been clarified, yet.\n\nIn this work, we employed a set of complementary experimental and theoretical tools to tackle these issues. Using raster image correlation, surface plasmon resonance and circular dichroism spectroscopies, we quantified membrane association and oligomerization of full-length M1 and of different genetically engineered M1 constructs (i.e., N- and C-terminally truncated constructs and a mutant of the polybasic region, residues 95-105). Furthermore, we report novel information on structural changes in M1 occurring upon binding to membranes. Our experimental results are corroborated by an all-atom model of the full-length M1 protein bound to a negatively charged lipid bilayer.

biophysics↗