AI Article Synopsis
- Many peptide drugs rely on peptide transporter 1 for absorption, making it crucial to assess this transport in early drug development.
- Current methods using inhibitors to test drug candidates' interaction with peptide transporter 1 are not specific enough.
- This study created a more accurate model by generating peptide transporter 1-knockout iPSCs, which were differentiated into intestinal cells, confirming that the absence of this transporter reduces the absorption of specific drugs.
Article Abstract
Because many peptide and peptide-mimetic drugs are substrates of peptide transporter 1, it is important to evaluate the peptide transporter 1-mediated intestinal absorption of drug candidates in the early phase of drug development. Although intestinal cell lines treated with inhibitors of peptide transporter 1 are widely used to examine whether drug candidates are substrates for peptide transporter 1, these inhibitors are not sufficiently specific for peptide transporter 1. In this study, to generate a more precise evaluation model, we established peptide transporter 1-knockout induced pluripotent stem cells (iPSCs) by using a CRISPR-Cas9 system and differentiated the cells into intestinal epithelial-like cells. The permeability value and uptake capacity of glycylsarcosine (substrate of peptide transporter 1) in peptide transporter 1-knockout intestinal epithelial-like cells were significantly lower than those in wild-type intestinal epithelial-like cells, suggesting that peptide transporter 1 was successfully depleted in the epithelial cells. Taken together, our model can be useful in the development of peptide and peptide-mimetic drugs.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926248 | PMC |
| http://dx.doi.org/10.1016/j.omtm.2019.11.008 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inactivation of CaV1 and CaV2 channels.
J Gen Physiol
March 2025
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Voltage-gated Ca2+ channels (VGCCs) are highly expressed throughout numerous biological systems and play critical roles in synaptic transmission, cardiac excitation, and muscle contraction. To perform these various functions, VGCCs are highly regulated. Inactivation comprises a critical mechanism controlling the entry of Ca2+ through these channels and constitutes an important means to regulate cellular excitability, shape action potentials, control intracellular Ca2+ levels, and contribute to long-term potentiation and depression.
View Article and Find Full Text PDFBackground: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been added to the mainstay of treatment for chronic heart failure. Recent studies suggest that empagliflozin may also reverse cardiac remodeling in heart failure by reducing N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. In our study, we wanted to show the decrease in NT-proBNP levels, which is an indicator of poor prognosis in heart failure, and to see if there was a decrease in the rate of renal progression in patients with HF after empagliflozin use.
View Article and Find Full Text PDFUncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library.
Front Mol Neurosci
January 2025
Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
Introduction: The neuron-specific K-Cl cotransporter KCC2 maintains low intracellular chloride levels, which are crucial for fast GABAergic and glycinergic neurotransmission. KCC2 also plays a pivotal role in the development of excitatory glutamatergic neurotransmission by promoting dendritic spine maturation. The cytoplasmic C-terminal domain (KCC2-CTD) plays a critical regulatory role in the molecular mechanisms controlling the cotransporter activity through dimerization, phosphorylation, and protein interaction.
View Article and Find Full Text PDFDefective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
Mol Med
January 2025
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Background: Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities.
View Article and Find Full Text PDFRecent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.
Mol Biol Rep
January 2025
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli Transit Campus, Bijnour-Sisendi Road, Sarojini Nagar, Lucknow, Uttar Pradesh, 226002, India.
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!