Biology subjects

Cuendet, M.

Publications and source records attributed to Cuendet, M..

3 recordsLinked to original sources

bioRxiv2025

Reversing Nicotine Toxicity: how Platelet-Rich Plasma Enhances Cell Recovery through Autophagy Modulation

BackgroundChronic exposure to nicotine significantly exacerbates periodontitis, a prevalent inflammatory disease, by inducing cellular processes such as autophagy and inflammation in gingival fibroblasts. Current therapies often fail to fully address these cellular alterations in smokers, highlighting a need for innovative therapeutic and generative approaches. ObjectiveThis study explores the therapeutic potential of Platelet-Rich Plasma (PRP), a blood-derived product, to modulate nicotine-induced biological activities in primary gingival fibroblasts. It aims at understanding the underlying cellular mechanisms and assessing the efficacy of PRP as an adjunct treatment for periodontitis in smokers. MethodsGingival fibroblasts were treated with increasing concentrations of nicotine, which led to senescence and autophagy. Subsequent treatment with autologous PRP was evaluated for its effect on the reversion of these processes, by measuring cell migration and proliferation, metabolic activity, as well as by looking at senescence and autophagic markers. A Caenorhabditis elegans model of autophagy was used to assess nicotine and PRP biological activities in an in vivo environment. ResultsNicotine at high concentrations triggered cellular vacuolization, a decrease in metabolism, viability and proliferation that was partially (with 500 ng/ml nicotine) or completely (with 250 ng/ml nicotine) reversed by a concomitant treatment with 10% PRP. Nicotine alone (250 ng/ml) slightly enhanced migration, while concomitant treatment between nicotine and PRP significantly increased their migration potential. In Caenorhabditis elegans, PRP reduced the nicotine-induced autophagic activity, as evidenced by decreased numbers of autophagosome and a higher number of viable worms during adulthood in comparison to nicotine control conditions. A screening of gingival fibroblast secretome revealed a modulation of autophagy-related cytokines in response to nicotine and/or PRP. ConclusionThe findings demonstrate that PRP could effectively inhibit nicotine-induced autophagy gingival fibroblasts, offering insights into its possible use as a therapeutic tool for managing periodontitis in smokers. The study underscores the potential of PRP in altering disease progression by modulating key cellular processes affected by smoking.

cell biology↗

bioRxiv2024

Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell proliferation

Multiple myeloma is a plasma cell malignancy with poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma patients and may be involved in the acquisition of resistance to conventional anti-proteasome treatments. Beyond displaying a deacetylase catalytic activity, HDAC6 can recognize ubiquitinated motifs from misfolded proteins through its C-terminal ZnF-UBP binding domain and send the defective proteins to the aggresome for degradation. Here, we explore the role of the ZnF-UBP binding domain of HDAC6 in the function of multiple myeloma cells. A non-functional ZnF-UBP domain containing a 2-residue mutation in the binding site was designed and the absence of ubiquitin binding was confirmed in a cell-free assay. Molecular docking simulations and electrostatic calculations revealed a significant decrease in the electrostatic potential of the mutated peptide, which is crucial for the stability of the complex with ubiquitin. A multiple myeloma cell line containing the non-functional ZnF-UBP domain was then engineered. Although the deacetylase activity of HDAC6 was maintained in these cells, they showed reduced cell growth, impaired aggresome formation and a dysregulated gene expression profile that was more pronounced than cells entirely deficient in HDAC6. These results indicate that a non-functional ZnF-UBP binding domain impacts the function of multiple myeloma cells. Based on these findings, a series of quinazolinylpropanoic acid derivatives was synthesized to explore the inhibitory activity of small molecules to this domain. We propose that ZnF-UBP binding domain inhibitors should be further evaluated as potential therapeutic agents in multiple myeloma.

cancer biology↗

bioRxiv2021

Truly Privacy-Preserving Federated Analytics for Precision Medicine with Multiparty Homomorphic Encryption

Using real-world evidence in biomedical research, an indispensable complement to clinical trials, requires access to large quantities of patient data that are typically held separately by multiple healthcare institutions. Centralizing those data for a study is often infeasible due to privacy and security concerns. Federated analytics is rapidly emerging as a solution for enabling joint analyses of distributed medical data across a group of institutions, without sharing patient-level data. However, existing approaches either provide only limited protection of patients privacy by requiring the institutions to share intermediate results, which can in turn leak sensitive patient-level information, or they sacrifice the accuracy of results by adding noise to the data to mitigate potential leakage. We propose FAMHE, a novel federated analytics system that, based on multiparty homomorphic encryption (MHE), enables privacy-preserving analyses of distributed datasets by yielding highly accurate results without revealing any intermediate data. We demonstrate the applicability of FAMHE to essential biomedical analysis tasks, including Kaplan-Meier survival analysis in oncology and genome-wide association studies in medical genetics. Using our system, we accurately and efficiently reproduce two published centralized studies in a federated setting, enabling biomedical insights that are not possible from individual institutions alone. Our work represents a necessary key step towards overcoming the privacy hurdle in enabling multi-centric scientific collaborations.

bioinformatics↗