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A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment.
J Pharmacokinet Pharmacodyn
January 2025
Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu, 610064, China.
Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose.
View Article and Find Full Text PDFRANK/RANKL Signaling Pathway in Breast Development and Cancer.
Adv Exp Med Biol
January 2025
Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
RANK pathway has attracted increasing interest as a promising target in breast cancer, given the availability of denosumab, an anti-RANKL drug. RANK signaling mediates progesterone-driven regulation of mammary gland development and favors breast cancer initiation by controlling mammary cell proliferation and stem cell fate. RANK activation promotes luminal mammary epithelial cell senescence, acting as an initial barrier to tumorigenesis but ultimately facilitating tumor progression and metastasis.
View Article and Find Full Text PDFMolecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD.
Cell Mol Biol Lett
January 2025
PhD Program in Medical Neuroscience, Taipei Medical University, Taipei, Taiwan (R.O.C.).
Background: Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive.
View Article and Find Full Text PDFU2AF1 mutation causes an oxidative stress and DNA repair defect in hematopoietic and leukemic cells.
Free Radic Biol Med
January 2025
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College,Tianjin, 300030, China; Tianjin Institutes of Health Science, Tianjin 301617, China. Electronic address:
U2AF1 is a core component of spliceosome and controls cell-fate specific alternative splicing. U2AF1 mutations have been frequently identified in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients, and mutations in U2AF1 are associated with poor prognosis in hematopoietic malignant diseases. Here, by forced expression of mutant U2AF1 (U2AF1 S34F) in hematopoietic and leukemic cell lines, we find that U2AF1 S34F causes increased reactive oxygen species (ROS) production.
View Article and Find Full Text PDFA patient with TPCN2-related hypopigmentation and ocular phenotype.
Eur J Hum Genet
January 2025
Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Pigmentation is orchestrated by hundreds of genes involved in cellular functions going from early developmental fate of pigment cells to melanin synthesis. The Two Pore Channel 2 (TPC2) a Ca2+ and Na+ channel acidifies melanosomal pH and thus inhibits pigmentation. A young patient was recently reported with generalized hypopigmentation but uneventful ocular examination, caused by the de novo heterozygous TPCN2 variant c.
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