Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763401 | PMC |
| http://dx.doi.org/10.7554/eLife.68832 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of Non-Peptide GLP-1 Positive Allosteric Modulators from Natural Products: Virtual Screening, Molecular Dynamics, ADMET Profiling, Repurposing, and Chemical Scaffolds Identification.
Pharmaceutics
December 2024
Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation.
View Article and Find Full Text PDFAntiproliferative and Morphological Analysis Triggered by Drugs Contained in the Medicines for Malaria Venture COVID-Box Against Tachyzoites.
Microorganisms
December 2024
Laboratório de Quimioterapia de Protozoários Egler Chiari, Departamento de Parasitologia-ICB, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
is a protozoan, and the etiologic agent of toxoplasmosis, a disease that causes high mortality in immunocompromised individuals and newborns. Despite the medical importance of toxoplasmosis, few drugs, which are associated with side effects and parasite resistance, are available for its treatment. Here, we show a screening of molecules present in COVID-Box to discover new hits with anti- activity.
View Article and Find Full Text PDFIntegrated Network-Based Analysis of Diseases Associated with Amyloid Deposition Through a Disease-Protein-Drug Network.
Pharmaceuticals (Basel)
December 2024
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens, Greece.
At present, the complexity that governs the associations between different biological entities is understood better than ever before, owing to high-throughput techniques and systems biology. Networks of interactions are necessary not only for the visualization of these complex relationships but also because their analysis tends to be valuable for the extraction of novel biological knowledge. For this reason, we constructed a disease-protein-drug network, focusing on a category of rare protein-misfolding diseases, known as amyloidoses, and on other pathological conditions also associated with amyloid deposition.
View Article and Find Full Text PDFRepurposing Dapagliflozin for Mitigation of the Kidney Injury Triggered by Cadmium in Rats: Role of Autophagy, Apoptosis, and the SIRT1/Nrf2/HO-1 Pathway.
Pharmaceuticals (Basel)
December 2024
Department of Pharmacology, Egyptian Drug Authority (EDA)-Formerly NODCAR, Giza 12654, Egypt.
The antioxidant/antiapoptotic features of dapagliflozin (DPG) have mediated its beneficial actions against several experimental models. However, no studies have been conducted to determine whether DPG mitigates the renal injury triggered by cadmium (Cd). Herein, DPG was studied for its potential to attenuate kidney damage in Cd-intoxicated rats, as well as to unravel the mechanisms involving oxidative events, autophagy, and apoptosis.
View Article and Find Full Text PDFRepurposing Osimertinib and Gedatolisib for Glioblastoma Treatment: Evidence of Synergistic Effects in an In Vitro Phenotypic Study.
Pharmaceuticals (Basel)
December 2024
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
Glioblastoma is a malignant tumor with a poor prognosis for the patient due to its high lethality and limited chemotherapy available. Therefore, from the point of view of chemotherapy treatment, glioblastoma can be considered an unmet medical need. This has led to the investigation of new drugs for monotherapy or associations, acting by synergistic pharmacological mechanisms.
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!