Biology subjects

Schorpp, K.

Publications and source records attributed to Schorpp, K..

4 recordsLinked to original sources

bioRxiv2023

CellDeathPred: A Deep Learning framework for Ferroptosis and Apoptosis prediction based on cell painting

Cell death, such as apoptosis and ferroptosis, play essential roles in the process of development, homeostasis, and pathogenesis of acute and chronic diseases. The increasing number of studies investigating cell death types in various diseases, particularly cancer and degenerative diseases, has raised hopes for their modulation in disease therapies. However, identifying the presence of a particular cell death type is not an obvious task, as it requires computationally intensive work and costly experimental assays. To address this challenge, we present CellDeathPred, a novel deep learning framework that uses high-content-imaging based on cell painting to distinguish cells undergoing ferroptosis or apoptosis from healthy cells. In particular, we incorporate a deep neural network that effectively embeds microscopic images into a representative and discriminative latent space, classifies the learned embedding into cell death modalities and optimizes the whole learning using the supervised contrastive loss function. We assessed the efficacy of the proposed framework using cell painting microscopy datasets from human HT-1080 cells, where multiple inducers of ferroptosis and apoptosis were used to trigger cell death. Our model confidently separates ferroptotic and apoptotic cells from healthy controls, with an averaged accuracy of 95% on non-confocal datasets, supporting the capacity of the CellDeathPred framework for cell death discovery.

cell biology↗

bioRxiv2022

Farnesoid X Receptor suppresses lipid peroxidation and ferroptosis

ObjectiveFerroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. The recent decade of research has uncovered many regulators driving ferroptosis as well as cellular gatekeepers preventing ferroptosis. Yet, many processes and networks remain to be elucidated. Methods and resultsIn this study, we performed a chemical screen using small molecules with known mode of action and identified two agonists (Turofexorate and Fexaramine) of the nuclear receptor Farnesoid X Receptor (FXR), also known as NR1H4, to suppress ferroptosis, but not apoptosis or necroptosis. Further, we demonstrate that in liver cells with high FXR protein levels, inhibition of FXR sensitizes cells to undergo ferroptotic cell death, while activation of FXR inhibits ferroptosis. Importantly, FXR also inhibits ferroptosis in ex vivo primary mouse hepatocytes. Activation of FXR by Turofexorate and Fexaramine significantly reduces lipid peroxidation. Mechanistically, overexpression of FXR or activation of FXR by bile acids upregulates the ferroptosis-inhibitory regulators FSP1, PPAR, GPX4, SCD1, and ACSL3 to reduce peroxidized lipids and to counteract ferroptosis. ConclusionIn this study, we demonstrate that activation of FXR inhibits ferroptotic cell death via upregulation of a number of ferroptosis-inhibitory proteins (FSP1, PPAR, GPX4, SCD1, and ACSL3) to reduce lipid peroxidation. Hence, modulating FXR activity may be beneficial to overcome ferroptosis-mediated degenerative diseases.

cell biology↗

bioRxiv2021

Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses

SO_SCPLOWUMMARYC_SCPLOWThe COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

microbiology↗

bioRxiv2020

Identification and characterization of distinct murine brown adipocyte lineages

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. While increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Using single cell RNA sequencing of the stromal vascular fraction of murine BAT and analysis of 67 brown preadipocyte and adipocyte clones we unravel heterogeneity within brown preadipocytes. Statistical analysis of gene expression profiles from these clones identifies markers distinguishing brown adipocyte lineages. We confirm the presence of distinct brown adipocyte populations in vivo using three identified markers; Eif5, Tcf25, and Bin1. Functionally, we demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that Bin1 marks a dormant brown adipocyte type. The existence of multiple brown adipocyte lineages suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct function in thermogenesis and the regulation of whole body energy homeostasis.

cell biology↗