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To explore the hepatotoxicity of copper sulfide nanoparticles (CuSNPs) toward hepatocyte spheroids. Other than the traditional agarose method to generate hepatocyte spheroids, we developed a multi-concave agarose chip (MCAC) method to investigate changes in hepatocyte viability, morphology, mitochondrial membrane potential, reactive oxygen species and hepatobiliary transporter by CuSNPs. The MCAC method allowed a large number of spheroids to be obtained per sample. CuSNPs showed hepatotoxicity through a decrease in spheroid viability, albumin/urea production and glycogen deposition. CuSNPs also introduced hepatocyte spheroid injury through alteration of mitochondrial membrane potential and reactive oxygen species, that could be reversed by N-acetyl-l-cysteine. CuSNPs significantly decreased the activity of BSEP transporter by downregulating its mRNA and protein levels. Activity of the MRP2 transporter remained unchanged. We observed the hepatotoxicity of CuSNPs with associated mechanisms in an advanced 3D culture system.
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http://dx.doi.org/10.2217/nnm-2021-0011 | DOI Listing |
Environ Int
September 2025
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address:
Background: Although per- and polyfluoroalkyl substances (PFAS) have been linked to chronic liver diseases, the specific cellular and molecular mechanisms by which different PFAS contribute to human liver dysfunction remain unclear. This study aims to elucidate those mechanisms.
Methods: We exposed a multi-donor human liver spheroid model composed of multiple cell types to 20 µM of PFHxS, PFOA, PFOS, or PFNA for seven days, followed by single-cell RNA sequencing and lipid staining.
Biochem Biophys Rep
September 2025
U.S. Food and Drug Administration, National Center for Toxicological Research (NCTR), Jefferson, AR, USA.
The tire rubber antioxidant -(1,3-dimethylbutyl)--phenyl--phenylenediamine (6PPD) and its oxidation product 6PPD-quinone (6PPD-Q) were recently found in human bodies. Though 6PPD/6PPD-Q showed species-dependent toxicity in animals, human relevant data are scarce. Here, primary human hepatocytes (PHHs), the gold standard in vitro model for hepatotoxicity, were used for acute and subacute toxicity assessments, with test concentrations normalized to average human serum concentrations (C).
View Article and Find Full Text PDFRegen Ther
December 2025
Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Azabu University, Sagamihara City, Kanagawa, Japan.
Introduction: Developing canine hepatocyte culture systems is critical for liver transplantation, toxicity evaluation, and drug metabolism studies. However, maintaining viable and functional hepatocytes in long-term cultures remains challenging. Our prior research demonstrated differentiation of cryopreserved canine hepatocytes into hepatic progenitor cells (cHPCs) using three small-molecule compounds: Y-27632 (ROCK inhibitor), A-83-01 (TGFβ inhibitor), and CHIR99021 (GSK3 inhibitor).
View Article and Find Full Text PDFCholestasis, or disruption in bile flow, is a common yet poorly understood feature of many liver diseases and injuries. Despite this, many engineered human tissue models of liver disease fail to recapitulate physiological bile flow. Here, we present a 3D multicellular spheroid-based model of the human hepatobiliary junction, the interface between hepatocytes and cholangiocytes often disrupted in liver disease that is required for directing bile excreted by hepatocytes into the biliary ductal system.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
September 2025
Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, Brno, CZ-62500, Czechia.
The rational design and selective self-assembly of flexible and unsymmetric ligands into large coordination complexes is an eminent challenge in supramolecular coordination chemistry. Here, we present the coordination-driven self-assembly of natural ursodeoxycholic-bile-acid-derived unsymmetric tris-pyridyl ligand (L) resulting in the selective and switchable formation of chiral stellated PdL and PdL cages. The selectivity of the cage originates in the adaptivity and flexibility of the arms of the ligand bearing pyridyl moieties.
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