There is evidence that chemical exposure during development can cause irreversible impairments of the human developing nervous system. Therefore, testing compounds for their developmentally neurotoxic potential has high priority for different stakeholders: academia, industry, and regulatory bodies. Due to the resource-intensity of current developmental neurotoxicity (DNT) in vivo guidelines, alternative methods that are scientifically valid and have a high predictivity for humans are especially desired by regulators. Here, we review availability of stem-/progenitor cell-based in vitro methods for DNT evaluation that is based on the concept of neurodevelopmental process assessment. These test methods are assembled into a DNT in vitro testing battery. Gaps in this testing battery addressing research needs are also pointed out.
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http://dx.doi.org/10.1093/toxsci/kfy178 | DOI Listing |
J Zhejiang Univ Sci B
September 2024
Center for Rehabilitation Medicine, Department of Neurosurgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, China.
Oligodendrocytes are the myelinating cells of the central nervous system. Brain injury and neurodegenerative disease often lead to oligodendrocyte death and subsequent demyelination-related pathological changes, resulting in neurological defects and cognitive impairment (Spaas et al., 2021; Zhang J et al.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address:
PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Introduction: Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation.
View Article and Find Full Text PDFSci Rep
December 2024
Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
Breast cancer (BRCA) is one of the pivotal causes of female death worldwide. And the morbidity and mortality of breast cancer have increased rapidly. Immune checkpoints are important to maintain immune tolerance and are regarded as important therapeutic targets.
View Article and Find Full Text PDFStem Cell Reports
December 2024
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Shandong 266071, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong 510080, China; Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangdong 510080, China. Electronic address:
Definitive endoderm (DE) derived from human pluripotent stem cells (hPSCs) holds great promise for cell-based therapies and drug discovery. However, current DE differentiation methods required undefined components and/or expensive recombinant proteins, limiting their scalable manufacture and clinical use. Homogeneous DE differentiation in defined and recombinant protein-free conditions remains a major challenge.
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