Bridging dimensions: a comparative analysis of 2D and 3D in vitro models for hepatocellular carcinoma research.

The tumor microenvironment (TME) influences hepatocellular carcinoma (HCC) behavior and disease progression. Cell-cell dynamics of non-parenchymal components, such as hepatic stellate cells (HSC), are key factors in understanding HCC onset and progression. This study established mono- and co-culture in vitro HCC models in both 2D and 3D configurations to investigate HCC cell behavior at both functional and transcriptional levels.

Unravelling drug-induced hepatic steatosis: Clinical sub-phenotypes, outcome prediction, and identification of high-concern drugs and hazardous chemical attributes.

Background: Drug-induced liver injury (DILI) is a rare but serious adverse drug reaction with a wide range of clinical presentations. While three major DILI phenotypes-hepatocellular, cholestatic, and mixed-are well established, other injury patterns such as steatosis-associated DILI (DIS) are harder to identify and remain underexplored. Existing limited evidence suggests that steatosis is frequent among DILI patients, yet this subtype and its causative drugs have not been systematically characterized in large patient cohorts.

A mechanistically-anchored and human stem cell-based in vitro test battery for assessing liver steatogenic potential of chemicals.

Fatty liver disease, which can result from various factors including chemical exposure, is an increasing clinical concern. A key event in its development is steatosis, referring to the accumulation of lipids within hepatocytes. To enable early detection of chemical-induced liver steatosis, we developed a mechanistically-anchored, human-relevant new approach methodology (NAM).

Silybin, silychristin and silydianin are potential novel plant-based Pannexin1 channel inhibitors.

Pannexin1 (Panx1) channels are crucial for cellular communication, and their abnormal opening is linked to inflammation and cell death. Developing novel inhibitors for these channels represents a promising therapeutic approach. Silymarin, the biologically active mixture derived from Silybum marianum L.

Nanobody-based Pannexin1 channel inhibitors increase survival after cardiac ischemia/reperfusion.

Reperfusion following myocardial infarction salvages the ischemic heart but paradoxically exacerbates injury. Yet, efficient treatment for cardiac ischemia/reperfusion injury is still missing in clinics. ATP release through Pannexin1 (PANX1) channels facilitates recruitment of leukocytes to the injured myocardium.

Unlocking liver physiology: comprehensive pathway maps for mechanistic understanding.

Aims: methods provide a resourceful toolbox for new approach methodologies (NAMs). They can revolutionize chemical safety assessment by offering more efficient and human-relevant alternatives to traditional animal testing. In this study, we introduce two Liver Physiological Maps (PMs); comprehensive and machine-readable graphical representations of the intricate mechanisms governing two major liver functions.

In vitro test battery for testing molecular initiating events in chemical-induced cholestasis.

Cholestatic liver injury is a complex adversity leading to the toxic accumulation of.noxious bile salts in the liver and systemic circulation. Cholestasis can be instigated by a plethora of chemicals originating from several applicability domains.

Taking the 3Rs to a higher level: replacement and reduction of animal testing in life sciences in space research.

Human settlements on the Moon, crewed missions to Mars and space tourism will become a reality in the next few decades. Human presence in space, especially for extended periods of time, will therefore steeply increase. However, despite more than 60 years of spaceflight, the mechanisms underlying the effects of the space environment on human physiology are still not fully understood.

Optimization of the drug-induced cholestasis index based on advanced modeling for predicting liver toxicity.

Cholestatic drug-induced liver injury (cDILI) is a frequent reason for drug failure and withdrawal during premarketing and postmarketing stages of drug development. Strategies for reliable detection of cDILI in early drug development are therefore urgently needed. The drug-induced cholestasis index (DICI) concept was previously introduced as a tool for assessing the cholestatic potential of drug candidates.

Pharmacological countermeasures for long-duration space missions: addressing cardiovascular challenges and advancing space-adapted healthcare.

Future long-duration crewed space missions beyond Low Earth Orbit (LEO) will bring new healthcare challenges for astronauts for which pharmacological countermeasures (pharmacological countermeasures) are crucial. This paper highlights current pharmacological countermeasures challenges described in the ESA SciSpacE Roadmap, with a focus on the cardiovascular system as a model to demonstrate the potential implication of the challenges and recommendations. New pharmacological approaches and procedures need to be adapted to spaceflight (spaceflight) conditions, including ethical and reglementary considerations.

Mapping physiology: A systems biology approach for the development of alternative methods in toxicology.

Chemical safety assessment still heavily relies on animal testing, which is associated with ethical dilemmas and has limited human predictive value. New approach methodologies (NAMs), including in vitro and in silico techniques, offer alternative solutions. In silico toxicology has made progress in predicting chemical effects but frequently lacks biological mechanistic founda­tions.

Design and synthesis of cyclic lipidated peptides derived from the C-terminus of Cx43 for hemichannel inhibition and cardiac endothelium targeting.

A peptide segment that is 10 residues long at the C-terminal (CT) region of Cx43 is known to be involved in interactions, both with the Cx43 protein itself and with other proteins, that result in hemichannel (HC) activity regulation. Previously reported mimetic peptides based on this region (, , ) have been revealed to be promising therapeutic agents in the context of cardiovascular diseases. In this work, novel approaches, such as C- and N-terminal modification and cyclization, to improve the proteolytic stability and bioavailability of the peptide are presented.

Report of the First ONTOX Hackathon: Hack to Save Lives and Avoid Animal Suffering. The Use of Artificial Intelligence in Toxicology - A Potential Driver for Reducing/Replacing Laboratory Animals in the Future.

The first ONTOX Hackathon of the EU Horizon 2020-funded ONTOX project was held on 21-23 April 2024 in Utrecht, The Netherlands (https://ontox-project.eu/hackathon/). This participatory event aimed to collectively advance innovation for human safety through the use of Artificial Intelligence (AI), and hence significantly reduce reliance on animal-based testing.