TY  - JOUR
AB  - Natural compounds are a valuable source of highly active biomolecules for the discovery of innovative drug targets as well as drug leads. The natural compound neocarzilin A (NCA) exhibits pronounced antiproliferative and antimigratory activity, which we previously ascribed to the target proteins vesicle amine transporter protein 1 (VAT-1) and bone marrow stromal antigen 2 (BST-2). We here additionally demonstrate the perturbation of mitochondrial functions (fragmentation of mitochondrial networks, ultrastructural changes, increased Opa1 splicing, loss of mitochondrial membrane potential, and excessive ROS generation) upon treatment with NCA. We observe impairment of the electron transfer chain and diminished ATP synthesis. Furthermore, NCA triggers apoptosis via activation of caspase-8, enhanced Bid processing, and cytochrome c release from mitochondria into the cytosol, leading to the activation of caspase-3 and -9 and, finally, PARP cleavage and DNA fragmentation. Endoplasmic reticulum (ER) stress is induced by treatment with NCA, and subsequently, the unfolded protein response (UPR) via the protein kinase r-like ER kinase (PERK) branch is prompted. Proteomic ABPP data indicate reticulon 4 (Rtn4, Nogo), an ER-located protein mainly involved in shaping ER tubules and maintaining proper ER function, as a promising hit to explain those effects. This novel molecular target was verified by co-staining of the target probe NC-4 and Rtn4, as well as RNA interference experiments, which resulted in reduced responsiveness of HeLa cells to NCA treatment. We propose NCA as a powerful tool to study the biology of Rtn4, and to develop more specific modulators of reticulons in the future. Furthermore, we introduce-to our knowledge-the first small molecular modulator of reticulon proteins.
AU  - Jauch, A.T.*
AU  - Sailer, J.*
AU  - Braun, J.*
AU  - Czeslik, E.*
AU  - Geyer, J.*
AU  - Eberhagen, C.
AU  - Vollmar, A.M.*
AU  - Zischka, H.
AU  - Sieber, S.A.*
AU  - Zahler, S.*
C1  - 74983
C2  - 57766
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Neocarzilin A induces apoptosis and mitochondrial disturbance by targeting reticulon 4-mediated endoplasmic reticulum stress.
JO  - Cell Death Discov.
VL  - 11
IS  - 1
PB  - Springernature
PY  - 2025
SN  - 2058-7716
ER  - 

TY  - JOUR
AB  - Oxygen toxicity constitutes a key contributor to bronchopulmonary dysplasia (BPD). Critical step in the pathogenesis of BPD is the inflammatory response in the immature lung with the release of pro-inflammatory cytokines and the influx of innate immune cells. Identification of efficient therapies to alleviate the inflammatory response remains an unmet research priority. First, we studied macrophage and neutrophil profiles in tracheal aspirates of n = 103 preterm infants <29 weeks´ gestation requiring mechanical ventilation. While no differences were present at birth, a higher fraction of macrophages, the predominance of the CD14+CD16+ subtype on day 5 of life was associated with moderate/severe BPD. Newborn CCL-2-/- mice insufficient in pulmonary macrophage recruitment had a reduced influx of neutrophils, lower apoptosis induction in the pulmonary tissue and better-preserved lung morphometry with higher counts of type II cells, mesenchymal stem cells and vascular endothelial cells when exposed to hyperoxia for 7 days. To study the benefit of a targeted approach to prevent the pulmonary influx of macrophages, wildtype mice were repeatedly treated with CCL-2 blocking antibodies while exposed to hyperoxia for 7 days. Congruent with the results in CCL-2-/- animals, the therapeutic intervention reduced the pulmonary inflammatory response, attenuated cell death in the lung tissue and better-preserved lung morphometry. Overall, our preclinical and clinical datasets document the predominant role of macrophage recruitment to the pathogenesis of BPD and establish the abrogation of CCL-2 function as novel approach to protect the immature lung from hyperoxic injury.
AU  - Shahzad, T.*
AU  - Dong, Y.*
AU  - Behnke, N.K.*
AU  - Brandner, J.*
AU  - Hilgendorff, A.
AU  - Chao, C.M.*
AU  - Behnke, J.*
AU  - Bellusci, S.*
AU  - Ehrhardt, H.*
C1  - 71049
C2  - 55992
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Anti-CCL2 therapy reduces oxygen toxicity to the immature lung.
JO  - Cell Death Discov.
VL  - 10
IS  - 1
PB  - Springernature
PY  - 2024
SN  - 2058-7716
ER  - 

TY  - JOUR
AB  - 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 data sets 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 average accuracy of 95% on non-confocal data sets, supporting the capacity of the CellDeathPred framework for cell death discovery.
AU  - Schorpp, K.
AU  - Bessadok, A.
AU  - Biibosunov, A.
AU  - Rothenaigner, I.
AU  - Strasser, S.
AU  - Peng, T.
AU  - Hadian, K.
C1  - 68044
C2  - 54522
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - CellDeathPred: A deep learning framework for ferroptosis and apoptosis prediction based on cell painting.
JO  - Cell Death Discov.
VL  - 9
IS  - 1
PB  - Springernature
PY  - 2023
SN  - 2058-7716
ER  - 

TY  - JOUR
AB  - Retinitis pigmentosa is a group of progressive inherited retinal dystrophies that may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. In an Indian family suffering from retinitis pigmentosa, we identified a missense variation in CNGA1 affecting the cyclic nucleotide binding domain (CNBD) and characterized a mouse model developed with mutated CNBD. A gene panel analysis comprising 105 known RP genes was used to analyze a family with autosomal-recessive retinitis pigmentosa (arRP) and revealed that CNGA1 was affected. From sperm samples of ENU mutagenesis derived F1 mice, we re-derived a mutant with a Cnga1 mutation. Homozygous mutant mice, developing retinal degeneration, were examined for morphological and functional consequences of the mutation. In the family, we identified a rare CNGA1 variant (NM_001379270.1) c.1525 G > A; (p.Gly509Arg), which co-segregated among the affected family members. Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on. This study supports a role for CNGA1 as a disease gene for arRP and provides new insights on the pathobiology of cGMP-binding domain mutations in CNGA1-RP.
AU  - Kandaswamy, S.
AU  - Zobel, L.*
AU  - John, B.*
AU  - Santhiya, S.T.*
AU  - Bogedein, J.*
AU  - Przemeck, G.K.H.
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Biel, M.*
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
AU  - Michalakis, S.*
AU  - Amarie, O.V.
C1  - 66255
C2  - 52790
TI  - Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.
JO  - Cell Death Discov.
VL  - 8
IS  - 1
PY  - 2022
SN  - 2058-7716
ER  -