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Publikation Methotrexate-induced liver injury is associated with oxidative stress, impaired mitochondrial respiration, and endoplasmic reticulum stress in vitro(MDPI, 01.12.2022) Schmidt, Saskia; Messner, Catherine; Gaiser, Carine; Hämmerli, Carina; Suter-Dick, LauraLow-dose methotrexate (MTX) is a standard therapy for rheumatoid arthritis due to its low cost and efficacy. Despite these benefits, MTX has been reported to cause chronic drug-induced liver injury, namely liver fibrosis. The hallmark of liver fibrosis is excessive scarring of liver tissue, triggered by hepatocellular injury and subsequent activation of hepatic stellate cells (HSCs). However, little is known about the precise mechanisms through which MTX causes hepatocellular damage and activates HSCs. Here, we investigated the mechanisms leading to hepatocyte injury in HepaRG and used immortalized stellate cells (hTERT-HSC) to elucidate the mechanisms leading to HSC activation by exposing mono- and co-cultures of HepaRG and hTERT-HSC to MTX. The results showed that at least two mechanisms are involved in MTX-induced toxicity in HepaRG: (i) oxidative stress through depletion of glutathione (GSH) and (ii) impairment of cellular respiration in a GSH-independent manner. Furthermore, we measured increased levels of endoplasmic reticulum (ER) stress in activated HSC following MTX treatment. In conclusion, we established a human-relevant in vitro model to gain mechanistical insights into MTX-induced hepatotoxicity, linked oxidative stress in HepaRG to a GSH-dependent and -independent pathway, and hypothesize that not only oxidative stress in hepatocytes but also ER stress in HSCs contribute to MTX-induced activation of HSCs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation How to Foster ‘New Approach Methodology’ Toxicologists(SAGE, 18.02.2022) Doktorova, Tatyana Y.; Azzi, Pamela; Hofer, Joelle; Werner, Sophie; Singh, Pranika; Hardy, Barry; Chesne, Christophe; Messner, Catherine; Gaiser, Carine; Suter-Dick, LauraThe need to reduce, refine and replace animal experimentation has led to a boom in the establishment of new approach methodologies (NAMs). This promising trend brings the hope that the replacement of animals by using NAMs will become increasingly accepted by regulators, included in legislation, and consequently more-often implemented by industry. The majority of NAMs, however, are still not very well understood, either due to the complexity of the applied approach or the data analysis workflow. A potential solution to this problem is the provision of better educational resources to scientists new to the area — showcasing the added value of NAMs and outlining various ways of overcoming issues associated with knowledge gaps. In this paper, the educational exchange between four institutions — namely, two universities and two SMEs — via a series of video training sessions, is described. The goal of this exchange was to showcase an exemplary event to help introduce scientists to non-animal approaches, and to actively support the development of resources enabling the use of alternatives to laboratory animals.01A - Beitrag in wissenschaftlicher Zeitschrift