Biology subjects

Junglas, E.

Publications and source records attributed to Junglas, E..

3 recordsLinked to original sources

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2023

An ex vivo human model for safety assessment of immunotoxicity of engineered nanomaterials

The unique physicochemical properties of nanomaterials (NM) and engineered nanomaterials (ENM) have pushed their use in many applications ranging from medicine to the food industry, textiles, and many more fields. Thus, human exposure to NM and ENM is growing by the day. However, the current toxicity tests do not reflect the special characteristics of ENM and are not developed for ENM risk assessment. Here we propose a high-throughput cell-based assay using human peripheral blood mononuclear cells (PBMCs) that can monitor the effects of NM and ENM on cytotoxicity and innate immunity. The proposed assay is fully automated and miniaturized, with excellent assay performance parameters (Z-score >0.5), amenable for large screening campaigns in industrial setting. Immunotoxicity data for ENM safety assessment are collected in dose-response format. At different states, multiparametric readouts for cytotoxicity, and innate immunity are conducted in a combinatorial method, avoiding ENM-induced bias by endotoxin contamination. Integrating this high-dimensional data, allows (i) holistic safety assessment of immunotoxicity effects caused by ENM, classifying safe and toxic ENM phenotypes, and (ii) to deconvolve mode of action of the ENM effect on the PBMCs. As added value the data obtained can be used to troubleshoot ENM or for a safe-by-design approach in product development.

immunology↗

bioRxiv2023

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1{beta} release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1{beta} release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimers disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimers disease, providing new mechanistic insight into the biology of neuroinflammation.

neuroscience↗