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  1. Article ; Online: Delivery of the VIVIT Peptide to Human Glioma Cells to Interfere with Calcineurin-NFAT Signaling.

    Ellert-Miklaszewska, Aleksandra / Szymczyk, Agata / Poleszak, Katarzyna / Kaminska, Bozena

    Molecules (Basel, Switzerland)

    2021  Volume 26, Issue 16

    Abstract: The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many ... ...

    Abstract The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary brain tumor, gliomas. In the present study, we demonstrate the expression of NFATs and NFAT-driven transcription in several human glioma cells. We used a VIVIT peptide for interference in calcineurin binding to NFAT via a conserved PxIxIT motif. VIVIT was expressed as a fusion protein with a green fluorescent protein (VIVIT-GFP) or conjugated to cell-penetrating peptides (CPP), Sim-2 or 11R. We analyzed the NFAT expression, phosphorylation, subcellular localization and their transcriptional activity in cells treated with peptides. Overexpression of VIVIT-GFP decreased the NFAT-driven activity and inhibited the transcription of endogenous NFAT-target genes. These effects were not reproduced with synthetic peptides: Sim2-VIVIT did not show any activity, and 11R-VIVIT did not inhibit NFAT signaling in glioma cells. The presence of two calcineurin docking sites in NFATc3 might require dual-specificity blocking peptides. The cell-penetrating peptides Sim-2 or 11R linked to VIVIT did not improve its action making it unsuitable for evaluating NFAT dependent events in glioma cells with high expression of NFATc3.
    MeSH term(s) Amino Acid Sequence ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Calcineurin/metabolism ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Cell-Penetrating Peptides/pharmacology ; Glioma/genetics ; Glioma/pathology ; Green Fluorescent Proteins/metabolism ; Humans ; NFATC Transcription Factors/chemistry ; NFATC Transcription Factors/metabolism ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Peptides/pharmacology ; Protein Transport/drug effects ; Signal Transduction ; Transcription, Genetic/drug effects
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Cell-Penetrating Peptides ; NFATC Transcription Factors ; Oligopeptides ; Peptides ; SIM2 protein, human ; VIVIT peptide ; transcription factor NF-AT c3 ; Green Fluorescent Proteins (147336-22-9) ; polyarginine (25212-18-4) ; Calcineurin (EC 3.1.3.16)
    Language English
    Publishing date 2021-08-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules26164785
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  2. Article ; Online: The atypical β-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

    Yuan, Luping / Springer, Jochen / Palus, Sandra / Busquets, Silvia / Jové, Queralt / Alves de Lima Junior, Edson / Anker, Markus S / von Haehling, Stephan / Álvarez Ladrón, Natalia / Millman, Oliver / Oosterlee, Annemijn / Szymczyk, Agata / López-Soriano, Francisco Javier / Anker, Stefan D / Coats, Andrew J S / Argiles, Josep M

    Journal of cachexia, sarcopenia and muscle

    2022  Volume 14, Issue 1, Page(s) 653–660

    Abstract: Background: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two ... ...

    Abstract Background: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model.
    Methods and results: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK.
    Conclusions: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.
    MeSH term(s) Mice ; Rats ; Humans ; Animals ; Cachexia/drug therapy ; Cachexia/etiology ; Cachexia/metabolism ; Oxprenolol/therapeutic use ; Rats, Wistar ; Quality of Life ; Rats, Inbred Lew ; Adrenergic beta-Antagonists/therapeutic use ; Liver Neoplasms ; Pindolol
    Chemical Substances Oxprenolol (519MXN9YZR) ; ACM-001 COVID-19 vaccine ; Adrenergic beta-Antagonists ; Pindolol (BJ4HF6IU1D)
    Language English
    Publishing date 2022-11-08
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2586864-0
    ISSN 2190-6009 ; 2190-5991
    ISSN (online) 2190-6009
    ISSN 2190-5991
    DOI 10.1002/jcsm.13116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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