Investigation of parenteral nutrition-induced hepatotoxicity using human liver spheroid co-cultures.

Parenteral nutrition (PN) is typically administered to individuals with gastrointestinal dysfunction, a contraindication for enteral feeding, and a need for nutritional therapy. When PN is the only energy source in patients, it is defined as total parenteral nutrition (TPN). TPN is a life-saving approach for different patient populations, both in infants and adults. However, despite numerous benefits, TPN can cause adverse effects, including metabolic disorders and liver injury. TPN-associated liver injury, known as intestinal failure-associated liver disease (IFALD), represents a significant problem affecting up to 90% of individuals receiving TPN. IFALD pathogenesis is complex, depending on the TPN components as well as on the patient's medical conditions. Despite numerous animal studies and clinical observations, the molecular mechanisms driving IFALD remain largely unknown. The present study was set up to elucidate the mechanisms underlying IFALD. For this purpose, human liver spheroid co-cultures were treated with a TPN mixture, followed by RNA sequencing analysis. Subsequently, following exposure to TPN and its single nutritional components, several key events of liver injury, including mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis, and lipid accumulation (steatosis), were studied using various techniques. It was found that prolonged exposure to TPN substantially changes the transcriptome profile of liver spheroids and affects multiple metabolic and signaling pathways contributing to liver injury. Moreover, TPN and its main components, especially lipid emulsion, induce changes in all key events measured and trigger steatosis.

Optimization of an adverse outcome pathway network on chemical-induced cholestasis using an artificial intelligence-assisted data collection and confidence level quantification approach.

BACKGROUND: Adverse outcome pathway (AOP) networks are versatile tools in toxicology and risk assessment that capture and visualize mechanisms driving toxicity originating from various data sources. They share a common structure consisting of a set of molecular initiating events and key events, connected by key event relationships, leading to the actual adverse outcome. AOP networks are to be considered living documents that should be frequently updated by feeding in new data. Such iterative optimization exercises are typically done manually, which not only is a time-consuming effort, but also bears the risk of overlooking critical data. The present study introduces a novel approach for AOP network optimization of a previously published AOP network on chemical-induced cholestasis using artificial intelligence to facilitate automated data collection followed by subsequent quantitative confidence assessment of molecular initiating events, key events, and key event relationships. METHODS: Artificial intelligence-assisted data collection was performed by means of the free web platform Sysrev. Confidence levels of the tailored Bradford-Hill criteria were quantified for the purpose of weight-of-evidence assessment of the optimized AOP network. Scores were calculated for biological plausibility, empirical evidence, and essentiality, and were integrated into a total key event relationship confidence value. The optimized AOP network was visualized using Cytoscape with the node size representing the incidence of the key event and the edge size indicating the total confidence in the key event relationship. RESULTS: This resulted in the identification of 38 and 135 unique key events and key event relationships, respectively. Transporter changes was the key event with the highest incidence, and formed the most confident key event relationship with the adverse outcome, cholestasis. Other important key events present in the AOP network include: nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation and apoptosis. CONCLUSIONS: This process led to the creation of an extensively informative AOP network focused on chemical-induced cholestasis. This optimized AOP network may serve as a mechanistic compass for the development of a battery of in vitro assays to reliably predict chemical-induced cholestatic injury.

Pannexin1 channels in the liver: an open enemy.

Pannexin1 proteins form communication channels at the cell plasma membrane surface, which allow the transfer of small molecules and ions between the intracellular compartment and extracellular environment. In this way, pannexin1 channels play an important role in various cellular processes and diseases. Indeed, a plethora of human pathologies is associated with the activation of pannexin1 channels. The present paper reviews and summarizes the structure, life cycle, regulation and (patho)physiological roles of pannexin1 channels, with a particular focus on the relevance of pannexin1 channels in liver diseases.