Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and β-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters β-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of β-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts.
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http://dx.doi.org/10.1021/acschembio.5b00993 | DOI Listing |
Cancer Lett
February 2025
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:
Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest.
View Article and Find Full Text PDFNature
November 2024
Institute of Organic Chemistry, RWTH-Aachen University, Landoltweg 1, Aachen, Germany.
Thiazoles and isothiazoles are privileged motifs in drug and agrochemical discovery. The synthesis of these derivatives is generally approached, designed and developed on a case-by-case basis. Sometimes, the lack of robust synthetic methods to a given target can pose significant difficulties or even thwart the preparation of specific derivatives for further study.
View Article and Find Full Text PDFBehav Brain Res
February 2025
Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico. Electronic address:
Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one.
View Article and Find Full Text PDFSci Adv
November 2024
Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells.
View Article and Find Full Text PDFClin Cancer Res
January 2025
Harvard Medical School, Boston, Massachusetts.
Purpose: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ataxia-telangiectasia-mutated (ATM), genes conferring replication stress (RS), or SDH.
Patients And Methods: Patients were recruited to four cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient gastrointestinal stromal tumors (GIST).
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