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Structure-activity relationship studies and design of a PTPN22 inhibitor with enhanced isozyme selectivity and cellular efficacy.
Eur J Med Chem
February 2025
Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address:
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) lies downstream of the T cell receptor (TCR) and attenuates T cell signaling by dephosphorylating key effector proteins such as LCK, Zap70, and the intracellular region of the TCR. Recent evidence implicates PTPN22 as an exciting target for enabling immunotherapeutic efficacy against cancer. We carried out structural optimization of a benzofuran salicylic acid-based orthosteric PTPN22 inhibitor 8b, using a combination of crystal structure analysis, synthesis, matched molecular pairs analysis, and biochemical and cell-based assays.
View Article and Find Full Text PDFImpact of therapeutic doses of prednisolone and other glucocorticoids on insulin secretion from human islets.
Ann Endocrinol (Paris)
December 2024
University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France. Electronic address:
Introduction: Glucocorticoid-induced diabetes (GCID) is a prevalent health issue, generally attributed to insulin resistance. High doses of dexamethasone (DEX) are known to inhibit glucose-stimulated insulin secretion (GSIS), but the effects of lower doses, commonly used in chronic therapy, and equipotent doses of other glucocorticoids (GCs) such as hydrocortisone (HC) and prednisone (PRED) remain underexplored. This study aimed to investigate these effects in vitro, and explore variations between patients.
View Article and Find Full Text PDFCarmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship and Efficacy.
ACS Infect Dis
December 2024
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screened, the causative agent of human and animal African trypanosomiasis, with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit the20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells.
View Article and Find Full Text PDFLow-Dose Prophylactic Oral Iron Supplementation (Ferrous Fumarate, Ferrous Bisglycinate, and Ferrous Sulphate) in Pregnancy Is Not Associated With Clinically Significant Gastrointestinal Complaints: Results From Two Randomized Studies.
J Pregnancy
November 2024
Department of Obstetrics and Gynecology, Herlev and Gentofte University Hospital DK-2730, Herlev, Denmark.
Article Synopsis
- Many pregnant women hesitate to take oral iron supplements due to fears of gastrointestinal (GI) side effects, leading to a study comparing the effects of three different iron formulas on GI complaints in healthy pregnant women.* -
- Two double-blind studies were conducted, involving a total of 482 women, to assess side effects like nausea, constipation, and black stools from different iron dosages and formulas during pregnancy.* -
- Among the iron supplements tested, ferrous bisglycinate at 25 mg showed the least GI side effects, while higher doses of ferrous fumarate resulted in more constipation and black stools, indicating it might be the least preferable option for pregnant women.*
The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study.
Clin Pharmacol Ther
February 2025
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC).
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