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Drug Development.
Alzheimers Dement
December 2024
The University of Texas Health Science Center at Houston, Houston, TX, USA.
Background: Developing drugs for treating Alzheimer's disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies.
Method: To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates RESULT: Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase 2/3 clinical trials.
Background: Lecanemab is an approved anti-amyloid monoclonal antibody that binds with highest affinity to soluble Aβ protofibrils, which are more toxic than monomers or insoluble fibrils/plaque. In clinical studies, biweekly lecanemab treatment demonstrated a slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease (AD). Herein, we describe the impact of lecanemab treatment on tau PET.
View Article and Find Full Text PDFDrug Development.
Alzheimers Dement
December 2024
Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Background: Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disease that still has no cure. Different pathological processes contribute to the disease's development, such as the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFTs), glutamatergic excitotoxicity, oxidative stress, and neuroinflammation. Chalcones are polyphenolic compounds of natural origin with a wide range of biological activities, and emerging studies have reported neurotrophic activity, anti-inflammatory and antioxidant effects, and the inhibition of Aβ aggregation.
View Article and Find Full Text PDFGamma-secretases play a pivotal role in the generation of Aβ peptides. Mutations in these enzymes that cause early-onset, autosomal dominant AD shift Aβ production towards generation of longer peptides. We have recently shown that the mutation-induced shifts in the ratio of short-to-long Aβ peptides not only inform about mutation pathogenicity but also allow experimental prediction of the age at dementia onset.
View Article and Find Full Text PDFUtilizing Plant Phytoconstituents in Metal Oxide Nanoparticle Synthesis for Cancer Therapies.
Curr Pharm Des
January 2025
Department of Pharmacy, Delhi Pharmaceutical Sciences and Research University, New Delhi, India.
Background: The metal oxide nanoparticles possess unique properties such as biological compatibility, superior reactivity, and capacity to develop reactive oxygen species, due to this they have drawn significant interest in cancer treatment. The various MONPs such as cerium oxide, Copper oxide, Iron oxide, Titanium dioxide, and Zinc oxide have been investigated for several types of cancers including brain, breast, cervical, colon, leukemia, liver, lung, melanoma, ovarian, and prostate cancers. However, traditional physiochemical synthetic methods for MONPs commonly include toxic materials, a major concern that raises questions regarding their biocompatibility and safety.
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