المؤلفون: Zubeldia‐Varela, Elisa, Blanco‐Pérez, Frank, Barker‐Tejeda, Tomás Clive, Rojo, David, Villaseñor, Alma, Islam, Jahidul, Gonzalez‐Menendez, Irene, Laiño, Jonathan, Krause, Maren, Steigerwald, Hanna, Martella, Manuela, Quintanilla‐Martinez, Leticia, Yu, Philipp, Barbas, Coral, Vieths, Stefan, Nochi, Tomonori, Barber, Domingo, Toda, Masako, Pérez‐Gordo, Marina

المساهمون: Instituto de Salud Carlos III, European Regional Development Fund

المصدر: Allergy ; ISSN 0105-4538 1398-9995

الوصف: Background The pathological mechanism of the gastrointestinal forms of food allergies is less understood in comparison to other clinical phenotypes, such as asthma and anaphylaxis Importantly, high‐IgE levels are a poor prognostic factor in gastrointestinal allergies. Methods This study investigated how high‐IgE levels influence the development of intestinal inflammation and the metabolome in allergic enteritis (AE), using IgE knock‐in (IgEki) mice expressing high levels of IgE. In addition, correlation of the altered metabolome with gut microbiome was analysed. Results Ovalbumin‐sensitized and egg‐white diet‐fed (OVA/EW) BALB/c WT mice developed moderate AE, whereas OVA/EW IgEki mice induced more aggravated intestinal inflammation with enhanced eosinophil accumulation. Untargeted metabolomics detected the increased levels of N‐tau‐methylhistamine and 2,3‐butanediol, and reduced levels of butyric acid in faeces and/or sera of OVA/EW IgEki mice, which was accompanied with reduced Clostridium and increased Lactobacillus at the genus level. Non‐sensitized and egg‐white diet‐fed (NC/EW) WT mice did not exhibit any signs of AE, whereas NC/EW IgEki mice developed marginal degrees of AE. Compared to NC/EW WT mice, enhanced levels of lysophospholipids, sphinganine and sphingosine were detected in serum and faecal samples of NC/EW IgEki mice. In addition, several associations of altered metabolome with gut microbiome—for example Akkermansia with lysophosphatidylserine—were detected. Conclusions Our results suggest that high‐IgE levels alter intestinal and systemic levels of endogenous and microbiota‐associated metabolites in experimental AE. This study contributes to deepening the knowledge of molecular mechanisms for the development of AE and provides clues to advance diagnostic and therapeutic strategies of allergic diseases.

الإتاحة: https://doi.org/10.1111/all.16202Test

المؤلفون: Steigerwald, Hanna, Blanco-Pérez, Frank, Macías-Camero, Andrea, Albrecht, Melanie, Huch, Melanie, Bender, Caroline, Schülke, Stefan, Keller, Judith, Krause, Maren, Barbas, Coral, Gonzalez-Menendez, Irene, Quintanilla-Martinez, Leticia, Toda, Masako, Barber, Domingo, Kulling, Sabine, Bunzel, Mirko, Vieths, Stefan, Villaseñor, Alma, Stoll, Dominic, Scheurer, Stephan

المصدر: Carbohydrate Polymers, 334, Art.-Nr.: 122007 ; ISSN: 0144-8617, 1879-1344

مصطلحات موضوعية: ddc:570, Life sciences, biology, info:eu-repo/classification/ddc/570

الوصف: Pectins are dietary fibers that are attributed with several beneficial immunomodulatory effects. Depending on the degree of esterification (DE), pectins can be classified as high methoxyl pectin (HMP) or low methoxyl pectin (LMP). The aim of this study was to investigate the effects of pectin methyl-esterification on intestinal microbiota and its immunomodulatory properties in naive mice. Supplementation of the diet with LMP or HMP induced changes in the composition of the intestinal microbiota in mice toward Bacteroides, which was mainly promoted by HMP. Metabolome analysis of stool samples from pectin-fed mice showed a different effect of the two types of pectin on the levels of short-chain fatty acids and bile acids, which was consistent with highly efficient in vivo fermentation of LMP. Analysis of serum antibody levels showed a significant increase in IgG and IgA levels by both pectins, while FACS analysis revealed a decrease of infiltrating inflammatory cells in the intestinal lamina propria by HMP. Our study revealed that the structural properties of the investigated pectins determine fermentability, effects on microbial composition, metabolite production, and modulation of immune responses. Consumption of HMP preferentially altered the gut microbiota and suppressed pro-inflammatory immune responses, suggesting a beneficial role in inflammatory diseases.

وصف الملف: application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/issn/0144-8617; info:eu-repo/semantics/altIdentifier/issn/1879-1344; https://publikationen.bibliothek.kit.edu/1000170012Test; https://publikationen.bibliothek.kit.edu/1000170012/152675694Test; https://doi.org/10.5445/IR/1000170012Test

الإتاحة: https://doi.org/10.5445/IR/1000170012Test
https://doi.org/10.1016/j.carbpol.2024.122007Test
https://publikationen.bibliothek.kit.edu/1000170012Test
https://publikationen.bibliothek.kit.edu/1000170012/152675694Test

المؤلفون: Knopf, Philipp, Stowbur, Dimitri, Hoffmann, Sabrina H. L., Hermann, Natalie, Maurer, Andreas, Bucher, Valentina, Poxleitner, Marilena, Tako, Bredi, Sonanini, Dominik, Krishnamachary, Balaji, Sinharay, Sanhita, Fehrenbacher, Birgit, Gonzalez-Menendez, Irene, Reckmann, Felix, Bomze, David, Flatz, Lukas, Kramer, Daniela, Schaller, Martin, Forchhammer, Stephan, Bhujwalla, Zaver M., Quintanilla-Martinez, Leticia, Schulze-Osthoff, Klaus, Pagel, Mark D., Fransen, Marieke F., Röcken, Martin, Martins, André F., Pichler, Bernd J., Ghoreschi, Kamran, Kneilling, Manfred

المصدر: Knopf , P , Stowbur , D , Hoffmann , S H L , Hermann , N , Maurer , A , Bucher , V , Poxleitner , M , Tako , B , Sonanini , D , Krishnamachary , B , Sinharay , S , Fehrenbacher , B , Gonzalez-Menendez , I , Reckmann , F , Bomze , D , Flatz , L , Kramer , D , Schaller , M , Forchhammer , S , Bhujwalla , Z M , Quintanilla-Martinez , L , Schulze-Osthoff , K , Pagel , M D , Fransen , M ....

الوصف: Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ−/− mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.

العلاقة: https://research.vumc.nl/en/publications/feb921f5-4968-4186-bc8d-462fd52c73f2Test

الإتاحة: https://doi.org/10.1186/s12943-023-01900-0Test
https://research.vumc.nl/en/publications/feb921f5-4968-4186-bc8d-462fd52c73f2Test
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85179703345&origin=inwardTest
https://www.ncbi.nlm.nih.gov/pubmed/38102680Test

المؤلفون: Fischer, Anja, Lersch, Robert, de Andrade Krätzig, Niklas, Strong, Alexander, Friedrich, Mathias J., Weber, Julia, Engleitner, Thomas, Öllinger, Rupert, Yen, Hsi Yu, Kohlhofer, Ursula, Gonzalez-Menendez, Irene, Sailer, David, Kogan, Liz, Lahnalampi, Mari, Laukkanen, Saara, Kaltenbacher, Thorsten, Klement, Christine, Rezaei, Majdaddin, Ammon, Tim, Montero, Juan J., Schneider, Günter, Mayerle, Julia, Heikenwälder, Mathias, Schmidt-Supprian, Marc, Quintanilla-Martinez, Leticia, Steiger, Katja, Liu, Pentao, Cadiñanos, Juan, Vassiliou, George S., Saur, Dieter, Lohi, Olli, Heinäniemi, Merja, Conte, Nathalie, Bradley, Allan, Rad, Lena, Rad, Roland

المساهمون: Tampere University, Clinical Medicine, TAYS Cancer Centre, BioMediTech

مصطلحات موضوعية: 3111 Biomedicine, 3122 Cancers

الوصف: In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct cell-of-origin associations in T-ALL subtypes. We compile catalogs of non-coding regions linked to quasi-insufficiency, show their enrichment with human cancer risk variants, and provide functional insights by engineering regulatory alterations in mice. As such, kilo-/megabase deletions in a Bcl11b-linked non-coding region triggered aggressive malignancies, with allele-specific tumor spectra reflecting gradual gene dysregulations through modular and cell-type-specific enhancer activities. Our study constitutes a first survey toward a systems-level understanding of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations. ; Peer reviewed

وصف الملف: fulltext

العلاقة: 100276; https://trepo.tuni.fi/handle/10024/146801Test; URN:NBN:fi:tuni-202303293268

الإتاحة: https://doi.org/10.1016/j.xgen.2023.100276Test
https://trepo.tuni.fi/handle/10024/146801Test

المؤلفون: El‐Ayoubi, Ali, Arakelyan, Arsen, Klawitter, Moritz, Merk, Luisa, Hakobyan, Siras, Gonzalez‐Menendez, Irene, Quintanilla Fend, Leticia, Holm, Per Sonne, Mikulits, Wolfgang, Schwab, Matthias, Danielyan, Lusine, Naumann, Ulrike

المساهمون: Deutsche Krebshilfe

المصدر: Molecular Oncology ; volume 18, issue 3, page 528-546 ; ISSN 1574-7891 1878-0261

الوصف: Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti‐cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX‐2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non‐tumorigenic after INA. Our data show that LX‐2 cells can longer withstand the OAV XVir‐N‐31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX‐2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV‐TK) integration into LX‐2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno‐compromised mice 3 months after INA of LX‐2 cells. Our data suggest that LX‐2 is a novel, robust, and safe cell line for delivering anti‐cancer and other therapeutic agents to the brain.

الإتاحة: https://doi.org/10.1002/1878-0261.13569Test

المؤلفون: Stransky, Nicolai, Ganser, Katrin, Quintanilla-Martinez, Leticia, Gonzalez-Menendez, Irene, Naumann, Ulrike, Eckert, Franziska, Koch, Pierre, Huber, Stephan M., Ruth, Peter

المساهمون: Deutsche Krebshilfe, Gesellschaft für Kinderkrebsforschung, Deutsche Forschungsgemeinschaft, Universitätsklinikum Tübingen

المصدر: Scientific Reports ; volume 13, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: The intermediate-conductance calcium-activated potassium channel K Ca 3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and K Ca 3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560’s intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-β1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3 + , CD8 + or FoxP3 + T cells was not impacted by either irradiation or K Ca 3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.

الإتاحة: https://doi.org/10.1038/s41598-023-47552-4Test
https://www.nature.com/articles/s41598-023-47552-4.pdfTest
https://www.nature.com/articles/s41598-023-47552-4Test

المؤلفون: Patzwaldt, Kristin, Berezhnoy, Georgy, Ionescu, Tudor, Schramm, Linda, Wang, Yi, Owczorz, Miriam, Calderón, Eduardo, Poli, Sven, Serna Higuita, Lina M, Gonzalez-Menendez, Irene, Quintanilla-Martinez, Leticia, Herfert, Kristina, Pichler, Bernd, Trautwein, Christoph, Castaneda-Vega, Salvador

المساهمون: Clinician-Scientist Programme of the Faculty of Medicine, University of Tuebingen, Werner Siemens Stiftung, Bruker Biospin

المصدر: Brain Communications ; volume 5, issue 2 ; ISSN 2632-1297

مصطلحات موضوعية: Neurology, Cellular and Molecular Neuroscience, Biological Psychiatry, Psychiatry and Mental health

الوصف: Ambroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson’s and Gaucher’s disease. A specific focus has been placed on ambroxol’s glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson’s disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.

الإتاحة: https://doi.org/10.1093/braincomms/fcad099Test
https://academic.oup.com/braincomms/article-pdf/5/2/fcad099/49855493/fcad099.pdfTest

المؤلفون: Schwenck, Johannes, Sonanini, Dominik, Seyfried, Dominik, Ehrlichmann, Walter, Kienzle, Gabriele, Reischl, Gerald, Krezer, Pascal, Wilson, Ian, Korn, Ron, Gonzalez-Menendez, Irene, Quintanilla-Martinez, Leticia, Seith, Ferdinand, Forschner, Andrea, Eigentler, Thomas, Zender, Lars, Röcken, Martin, Pichler, Bernd J, Flatz, Lukas, Kneilling, Manfred, Fougere, Christian la

المصدر: Theranostics ; volume 13, issue 8, page 2408-2423 ; ISSN 1838-7640

مصطلحات موضوعية: Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Medicine (miscellaneous)

الإتاحة: https://doi.org/10.7150/thno.79976Test
https://www.thno.org/v13p2408.htmTest

المؤلفون: Ganser, Katrin, Stransky, Nicolai, Abed, Tayeb, Quintanilla-Martinez, Leticia, Gonzalez-Menendez, Irene, Naumann, Ulrike, Koch, Pierre, Krueger, Marcel, Ruth, Peter, Huber, Stephan M, Eckert, Franziska

المصدر: Int J Cancer ; ISSN:1097-0215

مصطلحات موضوعية: DNA damage response, glioma, ionizing radiation, orthotopic xenograft mouse model, potassium channels

الوصف: Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

العلاقة: https://doi.org/10.1002/ijc.35064Test; https://pubmed.ncbi.nlm.nih.gov/38938062Test

الإتاحة: https://doi.org/10.1002/ijc.35064Test
https://pubmed.ncbi.nlm.nih.gov/38938062Test

المؤلفون: Zelaya, Hortensia, Grunz, Kristin, Nguyen, Thanh Son, Habibi, Anxhela, Witzler, Claudius Leon, Reyda, Sabine, Gonzalez-Menendez, Irene, Quintanilla-Martinez, Leticia, Bosmann, Markus, Weiler, Hartmut, Ruf, Wolfram

المصدر: Zelaya , H , Grunz , K , Nguyen , T S , Habibi , A , Witzler , C L , Reyda , S , Gonzalez-Menendez , I , Quintanilla-Martinez , L , Bosmann , M , Weiler , H & Ruf , W 2024 , ' Nucleic acid sensing promotes inflammatory monocyte migration through biased coagulation factor VIIa signaling ' , Blood , vol. 143 , no. 10 , pp. 845-857 . https://doi.org/10.1182/blood.2023021149Test

الوصف: Protease activated receptors (PARs) are cleaved by coagulation proteases and thereby connect hemostasis with innate immune responses. Signaling of the tissue factor (TF) complex with factor VIIa (FVIIa) via PAR2 stimulates extracellular signal-regulated kinase (ERK) activation and cancer cell migration, but functions of cell autonomous TF-FVIIa signaling in immune cells are unknown. Here, we show that myeloid cell expression of FVII but not of FX is crucial for inflammatory cell recruitment to the alveolar space after challenge with the double-stranded viral RNA mimic polyinosinic:polycytidylic acid [Poly(I:C)]. In line with these data, genetically modified mice completely resistant to PAR2 cleavage but not FXa-resistant PAR2–mutant mice are protected from lung inflammation. Poly(I:C)-stimulated migration of monocytes/macrophages is dependent on ERK activation and mitochondrial antiviral signaling (MAVS) but independent of toll-like receptor 3 (TLR3). Monocyte/macrophage-synthesized FVIIa cleaving PAR2 is required for integrin α M β 2 -dependent migration on fibrinogen but not for integrin β 1 -dependent migration on fibronectin. To further dissect the downstream signaling pathway, we generated PAR2 S365/T368A -mutant mice deficient in β-arrestin recruitment and ERK scaffolding. This mutation reduces cytosolic, but not nuclear ERK phosphorylation by Poly(I:C) stimulation, and prevents macrophage migration on fibrinogen but not fibronectin after stimulation with Poly(I:C) or CpG-B, a single-stranded DNA TLR9 agonist. In addition, PAR2 S365/T368A -mutant mice display markedly reduced immune cell recruitment to the alveolar space after Poly(I:C) challenge. These results identify TF-FVIIa-PAR2-β-arrestin–biased signaling as a driver for lung infiltration in response to viral nucleic acids and suggest potential therapeutic interventions specifically targeting TF-VIIa signaling in thrombo-inflammation.

العلاقة: https://cris.maastrichtuniversity.nl/en/publications/9770b1fb-a1c5-4f61-9c22-bf17a252ceb6Test

الإتاحة: https://doi.org/10.1182/blood.2023021149Test
https://cris.maastrichtuniversity.nl/en/publications/9770b1fb-a1c5-4f61-9c22-bf17a252ceb6Test